PT J
AU Zhang, HN
   Qiao, AN
   Yang, DH
   Yang, LL
   Dai, AT
   De Graaf, C
   Reedtz-Runge, S
   Dharmarajan, V
   Zhang, H
   Han, GW
   Grant, TD
   Sierra, RG
   Weierstall, U
   Nelson, G
   Liu, W
   Wu, YH
   Ma, LM
   Cai, XQ
   Lin, GY
   Wu, XA
   Geng, Z
   Dong, YH
   Song, GJ
   Griffin, PR
   Lau, J
   Chrezov, V
   Yang, HY
   Hanson, MA
   Stevens, RC
   Zhao, Q
   Jiang, HL
   Wang, MW
   Wu, BL
AF Zhang, Haonan
   Qiao, Anna
   Yang, Dehua
   Yang, Linlin
   Dai, Antao
   De Graaf, Chris
   Reedtz-Runge, Steffen
   Dharmarajan, Venkatasubramanian
   Zhang, Hui
   Han, Gye Won
   Grant, Thomas D.
   Sierra, Raymond G.
   Weierstall, Uwe
   Nelson, Garrett
   Liu, Wei
   Wu, Yanhong
   Ma, Limin
   Cai, Xiaoqing
   Lin, Guangyao
   Wu, Xiaoai
   Geng, Zhi
   Dong, Yuhui
   Song, Gaojie
   Griffin, Patrick R.
   Lau, Jesper
   Chrezov, Vadim
   Yang, Huaiyu
   Hanson, Michael A.
   Stevens, Raymond C.
   Zhao, Qiang
   Jiang, Hualiang
   Wang, Ming-Wei
   Wu, Beili
TI Structure of the full-length glucagon class B G-protein-coupled receptor
SO NATURE
LA English
DT Article
ID serial femtosecond crystallography; corticotropin-releasing-factor; lipidic cubic phase; extracellular domains; drug discovery; binding-site; ligand; refinement; validation; software
AB The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 angstrom crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a beta-strand conformation, instead of forming an alpha-helix as observed in the previously solved structure of the GCGR transmembrane domain. The first extracellular loop exhibits a beta-hairpin conformation and interacts with the stalk to form a compact beta-sheet structure. Hydrogen-deuterium exchange, disulfide crosslinking and molecular dynamics studies suggest that the stalk and the first extracellular loop have critical roles in modulating peptide ligand binding and receptor activation. These insights into the full-length GCGR structure deepen our understanding of the signalling mechanisms of class B G-protein-coupled receptors.
C1 [Zhang, Haonan; Qiao, Anna; Yang, Dehua; Dai, Antao; Zhang, Hui; Wu, Yanhong; Ma, Limin; Cai, Xiaoqing; Lin, Guangyao; Zhao, Qiang; Jiang, Hualiang; Wang, Ming-Wei; Wu, Beili] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China.
   [Zhang, Haonan; Qiao, Anna; Zhang, Hui; Wu, Yanhong; Lin, Guangyao; Zhao, Qiang; Wu, Beili] Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China.
   [Yang, Dehua; Dai, Antao; Cai, Xiaoqing; Lin, Guangyao; Wang, Ming-Wei] Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China.
   [Yang, Linlin] Zhengzhou Univ, Sch Basic Med Sci, Dept Pharmacol, 100 Sci Ave, Zhengzhou 450001, Peoples R China.
   [De Graaf, Chris] Vrije Univ Amsterdam, AIMMS, Fac Sci, Div Med Chem, De Boelelaan 1108, NL-1081 HZ Amsterdam, Netherlands.
   [Dharmarajan, Venkatasubramanian; Lau, Jesper] Novo Nordisk AS, Novo Nordisk Pk, DK-2760 Malov, Denmark.
   [Dharmarajan, Venkatasubramanian; Griffin, Patrick R.] Scripps Res Inst, Dept Mol Med, 130 Scripps Way, Jupiter, FL 33458 USA.
   [Han, Gye Won; Chrezov, Vadim] Univ Southern Calif, Dept Chem, Bridge Inst, 3430 S Vermont Ave, Los Angeles, CA 90089 USA.
   [Grant, Thomas D.] SUNY Buffalo, Hauptman Woodward Inst, 700 Ellicott St, Buffalo, NY 14203 USA.
   [Sierra, Raymond G.] SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA.
   [Weierstall, Uwe; Nelson, Garrett] Arizona State Univ, Dept Phys, Tempe, AZ 85287 USA.
   [Liu, Wei] Arizona State Univ, Biodesign Inst, Sch Mol Sci, Biodesign Ctr Appl Struct Discovery, Tempe, AZ 85287 USA.
   [Wu, Yanhong; Lin, Guangyao; Stevens, Raymond C.; Wang, Ming-Wei; Wu, Beili] ShanghaiTech Univ, Sch Life Sci & Technol, 393 Hua Xia Zhong Rd, Shanghai 201210, Peoples R China.
   [Wu, Xiaoai] Novo Nordisk Res Ctr China, 20 Life Sci Pk Rd, Beijing 102206, Peoples R China.
   [Geng, Zhi; Dong, Yuhui] Chinese Acad Sci, Beijing Synchrotron Radiat Facil, Inst High Energy Phys, Beijing 100049, Peoples R China.
   [Song, Gaojie; Stevens, Raymond C.] ShanghaiTech Univ, iHuman Inst, 393 Hua Xia Zhong Rd, Shanghai 201210, Peoples R China.
   [Yang, Huaiyu; Jiang, Hualiang] Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China.
   [Hanson, Michael A.] GPCR Consortium, San Marcos, CA 92078 USA.
   [Zhao, Qiang; Jiang, Hualiang] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China.
   [Zhao, Qiang; Wu, Beili] Chinese Acad Sci, CAS Ctr Excellence Biomacromol, Beijing 100101, Peoples R China.
   [Wang, Ming-Wei] Fudan Univ, Sch Pharm, 826 Zhangheng Rd, Shanghai 201203, Peoples R China.
C3 Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Zhengzhou University; Vrije Universiteit Amsterdam; Novo Nordisk; State University System of Florida; University of Florida; Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology; University of Southern California; State University of New York (SUNY) System; University at Buffalo, SUNY; Hauptman Woodward Medical Research Institute; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; Arizona State University; Arizona State University-Tempe; Arizona State University; Arizona State University-Tempe; ShanghaiTech University; Chinese Academy of Sciences; Institute of High Energy Physics, CAS; ShanghaiTech University; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Chinese Academy of Sciences; Fudan University
RP Jiang, HL; Wang, MW; Wu, BL (corresponding author), Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China.; Wu, BL (corresponding author), Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China.; Wang, MW (corresponding author), Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China.; Wang, MW; Wu, BL (corresponding author), ShanghaiTech Univ, Sch Life Sci & Technol, 393 Hua Xia Zhong Rd, Shanghai 201210, Peoples R China.; Jiang, HL (corresponding author), Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China.; Jiang, HL (corresponding author), Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China.; Wu, BL (corresponding author), Chinese Acad Sci, CAS Ctr Excellence Biomacromol, Beijing 100101, Peoples R China.; Wang, MW (corresponding author), Fudan Univ, Sch Pharm, 826 Zhangheng Rd, Shanghai 201203, Peoples R China.
EM hljiang@simm.ac.cn; mwwang@simm.ac.cn; beiliwu@simm.ac.cn
FU National Basic Research Program of China [2014CB910400, 2015CB910304]; CAS Strategic Priority Research Program [XDB08020000]; CAS [QYZDB-SSW-SMC024]; National Science Foundation of China [31422017, 81525024, 81230076, 81573479]; National Health and Family Planning Commission [2012ZX09304-011, 2013ZX09401003-005, 2013ZX09507001, 2013ZX09507-002]; Shanghai Science and Technology Development Fund [15DZ2291600]; National Institutes of Health [R01 GM108635, R21 DA042298, P41GM103393]; National Science Foundation STC award [1231306]; GPCR Consortium; Shanghai local government; Netherlands eScience Center (NLeSC)/NWO (Enabling Technologies project: 3D-e-Chem) [027.014.201]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
NR 44
TC 180
Z9 199
U1 4
U2 229
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 8
PY 2017
VL 546
IS 7657
BP 259
EP +
DI 10.1038/nature22363
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW9FY
UT WOS:000402823400031
PM 28514451
DA 2026-03-09
ER

PT J
AU Jónsson, H
   Sulem, P
   Kehr, B
   Kristmundsdottir, S
   Zink, F
   Hjartarson, E
   Hardarson, MT
   Hjorleifsson, KE
   Eggertsson, HP
   Gudjonsson, SA
   Ward, LD
   Arnadottir, GA
   Helgason, EA
   Helgason, H
   Gylfason, A
   Jonasdottir, A
   Jonasdottir, A
   Rafnar, T
   Frigge, M
   Stacey, SN
   Magnusson, OT
   Thorsteinsdottir, U
   Masson, G
   Kong, A
   Halldorsson, BV
   Helgason, A
   Gudbjartsson, DF
   Stefansson, K
AF Jonsson, Hakon
   Sulem, Patrick
   Kehr, Birte
   Kristmundsdottir, Snaedis
   Zink, Florian
   Hjartarson, Eirikur
   Hardarson, Marteinn T.
   Hjorleifsson, Kristjan E. .
   Eggertsson, Hannes P.
   Gudjonsson, Sigurjon Axel
   Ward, Lucas D.
   Arnadottir, Gudny A.
   Helgason, Einar A.
   Helgason, Hannes
   Gylfason, Arnaldur
   Jonasdottir, Adalbjorg
   Jonasdottir, Aslaug
   Rafnar, Thorunn
   Frigge, Mike
   Stacey, Simon N.
   Magnusson, Olafur Th.
   Thorsteinsdottir, Unnur
   Masson, Gisli
   Kong, Augustine
   Halldorsson, Bjarni V.
   Helgason, Agnar
   Gudbjartsson, Daniel F.
   Stefansson, Kari
TI Parental influence on human germline de novo mutations in 1,548 trios from Iceland
SO NATURE
LA English
DT Article
ID molecular clock; sequence; origin; signatures; alignment; sex
AB The characterization of mutational processes that generate sequence diversity in the human genome is of paramount importance both to medical genetics(1,2) and to evolutionary studies(3). To understand how the age and sex of transmitting parents affect de novo mutations, here we sequence 1,548 Icelanders, their parents, and, for a subset of 225, at least one child, to 35x genome-wide coverage. We find 108,778 de novo mutations, both single nucleotide polymorphisms and indels, and determine the parent of origin of 42,961. The number of de novo mutations from mothers increases by 0.37 per year of age (95% CI 0.32-0.43), a quarter of the 1.51 per year from fathers (95% CI 1.45-1.57). The number of clustered mutations increases faster with the mother's age than with the father's, and the genomic span of maternal de novo mutation clusters is greater than that of paternal ones. The types of de novo mutation from mothers change substantially with age, with a 0.26% (95% CI 0.19-0.33%) decrease in cytosine-phosphate-guanine to thymine-phosphate-guanine (CpG > TpG) de novo mutations and a 0.33% (95% CI 0.28-0.38%) increase in C > G de novo mutations per year, respectively. Remarkably, these age-related changes are not distributed uniformly across the genome. A striking example is a 20 megabase region on chromosome 8p, with a maternal C > G mutation rate that is up to 50-fold greater than the rest of the genome. The age-related accumulation of maternal non-crossover gene conversions also mostly occurs within these regions. Increased sequence diversity and linkage disequilibrium of C > G variants within regions affected by excess maternal mutations indicate that the underlying mutational process has persisted in humans for thousands of years. Moreover, the regional excess of C > G variation in humans is largely shared by chimpanzees, less by gorillas, and is almost absent from orangutans. This demonstrates that sequence diversity in humans results from evolving interactions between age, sex, mutation type, and genomic location.
C1 [Jonsson, Hakon; Sulem, Patrick; Kehr, Birte; Kristmundsdottir, Snaedis; Zink, Florian; Hjartarson, Eirikur; Hardarson, Marteinn T.; Hjorleifsson, Kristjan E. .; Eggertsson, Hannes P.; Gudjonsson, Sigurjon Axel; Ward, Lucas D.; Arnadottir, Gudny A.; Helgason, Einar A.; Helgason, Hannes; Gylfason, Arnaldur; Jonasdottir, Adalbjorg; Jonasdottir, Aslaug; Rafnar, Thorunn; Frigge, Mike; Stacey, Simon N.; Magnusson, Olafur Th.; Thorsteinsdottir, Unnur; Masson, Gisli; Kong, Augustine; Halldorsson, Bjarni V.; Helgason, Agnar; Gudbjartsson, Daniel F.; Stefansson, Kari] deCODE Genet Amgen Inc, IS-101 Reykjavik, Iceland.
   [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Sch Hlth Sci, Fac Med, IS-101 Reykjavik, Iceland.
   [Kong, Augustine; Gudbjartsson, Daniel F.] Univ Iceland, Sch Engn & Nat Sci, IS-101 Reykjavik, Iceland.
   [Halldorsson, Bjarni V.] Reykjavik Univ, Sch Sci & Engn, IS-101 Reykjavik, Iceland.
   [Helgason, Agnar] Univ Iceland, Dept Anthropol, IS-101 Reykjavik, Iceland.
C3 Decode Genetics; University of Iceland; University of Iceland; Reykjavik University; University of Iceland
RP Gudbjartsson, DF; Stefansson, K (corresponding author), deCODE Genet Amgen Inc, IS-101 Reykjavik, Iceland.
EM daniel.gudbjartsson@decode.is; kari.stefansson@decode.is
NR 33
TC 368
Z9 429
U1 6
U2 73
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 28
PY 2017
VL 549
IS 7673
BP 519
EP +
DI 10.1038/nature24018
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI4GT
UT WOS:000411930000050
PM 28959963
DA 2026-03-09
ER

PT J
AU Aktas, T
   Ilik, IA
   Maticzka, D
   Bhardwaj, V
   Rodrigues, CP
   Mittler, G
   Manke, T
   Backofen, R
   Akhtar, A
AF Aktas, Tugce
   Ilik, Ibrahim Avsar
   Maticzka, Daniel
   Bhardwaj, Vivek
   Rodrigues, Cecilia Pessoa
   Mittler, Gerhard
   Manke, Thomas
   Backofen, Rolf
   Akhtar, Asifa
TI DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome
SO NATURE
LA English
DT Article
ID in-vivo; dosage compensation; repetitive elements; sequencing data; cross-linking; circular rnas; web server; complex; cells; identification
AB Transposable elements are viewed as 'selfish genetic elements', yet they contribute to gene regulation and genome evolution in diverse ways(1). More than half of the human genome consists of transposable elements(2). Alu elements belong to the short interspersed nuclear element (SINE) family of repetitive elements, and with over 1 million insertions they make up more than 10% of the human genome(2). Despite their abundance and the potential evolutionary advantages they confer, Alu elements can be mutagenic to the host as they can act as splice acceptors, inhibit translation of mRNAs and cause genomic instability(3). Alu elements are the main targets of the RNA-editing enzyme ADAR(4) and the formation of Alu exons is suppressed by the nuclear ribonucleoprotein HNRNPC5, but the broad effect of massive secondary structures formed by inverted-repeat Alu elements on RNA processing in the nucleus remains unknown. Here we show that DHX9, an abundant(6) nuclear RNA helicase(7), binds specifically to inverted-repeat Alu elements that are transcribed as parts of genes. Loss of DHX9 leads to an increase in the number of circular-RNA-producing genes and amount of circular RNAs, translational repression of reporters containing inverted-repeat Alu elements, and transcriptional rewiring (the creation of mostly nonsensical novel connections between exons) of susceptible loci. Biochemical purifications of DHX9 identify the interferon-inducible isoform of ADAR (p150), but not the constitutively expressed ADAR isoform (p110), as an RNA-independent interaction partner. Co-depletion of ADAR and DHX9 augments the double-stranded RNA accumulation defects, leading to increased circular RNA production, revealing a functional link between these two enzymes. Our work uncovers an evolutionarily conserved function of DHX9. We propose that it acts as a nuclear RNA resolvase that neutralizes the immediate threat posed by transposon insertions and allows these elements to evolve as tools for the post-transcriptional regulation of gene expression.
C1 [Aktas, Tugce; Ilik, Ibrahim Avsar; Bhardwaj, Vivek; Rodrigues, Cecilia Pessoa; Mittler, Gerhard; Manke, Thomas; Akhtar, Asifa] Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany.
   [Maticzka, Daniel; Backofen, Rolf] Albert Ludwigs Univ, Inst Informat, Freiburg, Germany.
   [Bhardwaj, Vivek; Rodrigues, Cecilia Pessoa] Univ Freiburg, Fac Biol, D-79104 Freiburg, Germany.
C3 Max Planck Society; University of Freiburg; University of Freiburg
RP Akhtar, A (corresponding author), Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany.
EM akhtar@ie-freiburg.mpg.de
FU [CRC 992/2 2016];  [CRC 746];  [CRC 1140];  [BA2168/11-1];  [SPP 1738];  [CRC TRR 167]
NR 51
TC 452
Z9 509
U1 3
U2 115
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 6
PY 2017
VL 544
IS 7648
BP 115
EP +
DI 10.1038/nature21715
PG 27
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EQ8GQ
UT WOS:000398323300044
PM 28355180
DA 2026-03-09
ER

PT J
AU Kempenaers, B
   Valcu, M
AF Kempenaers, Bart
   Valcu, Mihai
TI Breeding site sampling across the Arctic by individual males of a polygynous shorebird
SO NATURE
LA English
DT Article
ID buff-breasted sandpiper; sexual selection; pectoral sandpiper; sage-grouse; snow melt; lekking; success; markers
AB Males of many polygynous species compete for access to fertile females without providing them with resources other than sperm and without investing in care for the offspring (male dominance polygyny)(1-4). In such systems, local competition for access to females is intense and typically only a few males obtain matings, leading to strong sexual selection(2,4,5). Sampling multiple breeding areas could then provide a mechanism for males to increase their chances to reproduce. However, little is known about such sampling behaviour and about the spatial scale at which males compete(6-8). Here we show that most males of a migratory, polygynous shorebird, the pectoral sandpiper (Calidris melanotos)(9,10), that arrived at a known breeding location in northern Alaska(9) subsequently moved through a considerable part of the entire species' breeding range (up to 13,045 km in a four-week period), sampling as many as 23 additional potential breeding sites. Our data suggest that males do not have a final breeding destination after migration from their wintering quarters, but make nomadic movements that are probably not a consequence of breeding failure. Tenure, the duration of stay at a site, correlated strongly with the number of breeding females at the site, suggesting that decisions to leave are dependent on local mating opportunities. Nomadic movements may allow males to display and sire offspring at multiple sites within a single breeding season. Sexual selection may then favour high-performance males that are able to reduce sleep to compete locally(9) and to fly long distances between breeding sites, leading to a population with unrestricted interbreeding and without local adaptation and speciation.
C1 [Kempenaers, Bart; Valcu, Mihai] Max Planck Inst Ornithol, Dept Behav Ecol & Evolutionary Genet, Eberhard Gwinner Str, D-82319 Seewiesen, Germany.
C3 Max Planck Society
RP Kempenaers, B (corresponding author), Max Planck Inst Ornithol, Dept Behav Ecol & Evolutionary Genet, Eberhard Gwinner Str, D-82319 Seewiesen, Germany.
EM b.kempenaers@orn.mpg.de
FU Max Planck Society
NR 43
TC 53
Z9 62
U1 2
U2 34
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 26
PY 2017
VL 541
IS 7638
BP 528
EP 531
DI 10.1038/nature20813
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6LX
UT WOS:000396116600050
PM 28068667
DA 2026-03-09
ER

PT J
AU Xiao, YB
   Ng, S
   Nam, KH
   Ke, AL
AF Xiao, Yibei
   Ng, Sherwin
   Nam, Ki Hyun
   Ke, Ailong
TI How type II CRISPR-Cas establish immunity through Cas1-Cas2-mediated spacer integration
SO NATURE
LA English
DT Article
ID crystal-structure; host factor; dna; acquisition; repeats; adaptation; sequences; elements; complex; targets
AB CRISPR (clustered regularly interspaced short palindromic repeats) and the nearby Cas (CRISPR-associated) operon establish an RNA-based adaptive immunity system in prokaryotes(1-5). Molecular memory is created when a short foreign DNA-derived prespacer is integrated into the CRISPR array as a new spacer(6-9). Whereas the RNA-guided CRISPR interference mechanism varies widely among CRISPR-Cas systems, the spacer integration mechanism is essentially identical(7-9). The conserved Cas1 and Cas2 proteins form an integrase complex consisting of two distal Cas1 dimers bridged by a Cas2 dimer(6,10). The prespacer is bound by Cas1-Cas2 as a dual-forked DNA, and the terminal 3'-OH of each 3' overhang serves as an attacking nucleophile during integration(11-14). The prespacer is preferentially integrated into the leader-proximal region of the CRISPR array(1,7,10,15,) guided by the leader sequence and a pair of inverted repeats inside the CRISPR repeat(7,15-20). Spacer integration in the well-studied Escherichia coli type I-E CRISPR system also relies on the bacterial integration host factor(21,22). In type II-A CRISPR, however, Cas1-Cas2 alone integrates spacers efficiently in vitro(18); other Cas proteins (such as Cas9 and Csn2) have accessory roles in the biogenesis phase of prespacers(17,23). Here we present four structural snapshots from the type II-A system(24) of Enterococcus faecalis Cas1 and Cas2 during spacer integration. Enterococcus faecalis Cas1-Cas2 selectively binds to a splayed 30-base-pair prespacer bearing 4-nucleotide 3' overhangs. Three molecular events take place upon encountering a target: first, the Cas1-Cas2-prespacer complex searches for half-sites stochastically, then it preferentially interacts with the leader-side CRISPR repeat, and finally, it catalyses a nucleophilic attack that connects one strand of the leader-proximal repeat to the prespacer 3' overhang. Recognition of the spacer half-site requires DNA bending and leads to full integration. We derive a mechanistic framework to explain the stepwise spacer integration process and the leader-proximal preference.
C1 [Xiao, Yibei; Ng, Sherwin; Ke, Ailong] Cornell Univ, Dept Mol Biol & Genet, 253 Biotechnol Bldg, Ithaca, NY 14353 USA.
   [Nam, Ki Hyun] Pohang Univ Sci & Technol, Pohang Accelerator Lab, Pohang, South Korea.
C3 Cornell University; Pohang University of Science & Technology (POSTECH)
RP Ke, AL (corresponding author), Cornell Univ, Dept Mol Biol & Genet, 253 Biotechnol Bldg, Ithaca, NY 14353 USA.
EM ak425@cornell.edu
FU NIH/NIGMS [GM118174, GM102543, P41-GM103403, S10-RR029205, GM-103485]; CHESS and MACCHESS; NSF [DMR-1332208]; US Department of Energy [DE-AC02-06CH11357]; National Institute of General Medical Sciences [R35GM118174] Funding Source: NIH RePORTER
NR 39
TC 104
Z9 120
U1 5
U2 92
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 5
PY 2017
VL 550
IS 7674
BP 137
EP +
DI 10.1038/nature24020
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI7XU
UT WOS:000412214100061
PM 28869593
DA 2026-03-09
ER

PT J
AU Latrubesse, EM
   Arima, EY
   Dunne, T
   Park, E
   Baker, VR
   d'Horta, FM
   Wight, C
   Wittmann, F
   Zuanon, J
   Baker, PA
   Ribas, CC
   Norgaard, RB
   Filizola, N
   Ansar, A
   Flyvbjerg, B
   Stevaux, JC
AF Latrubesse, Edgardo M.
   Arima, Eugenio Y.
   Dunne, Thomas
   Park, Edward
   Baker, Victor R.
   d'Horta, Fernando M.
   Wight, Charles
   Wittmann, Florian
   Zuanon, Jansen
   Baker, Paul A.
   Ribas, Camila C.
   Norgaard, Richard B.
   Filizola, Naziano
   Ansar, Atif
   Flyvbjerg, Bent
   Stevaux, Jose C.
TI Damming the rivers of the Amazon basin
SO NATURE
LA English
DT Article
ID sediment distribution patterns; suspended sediment; hydropower; infrastructure; impact; andes
AB More than a hundred hydropower dams have already been built in the Amazon basin and numerous proposals for further dam constructions are under consideration. The accumulated negative environmental effects of existing dams and proposed dams, if constructed, will trigger massive hydrophysical and biotic disturbances that will affect the Amazon basin's floodplains, estuary and sediment plume. We introduce a Dam Environmental Vulnerability Index to quantify the current and potential impacts of dams in the basin. The scale of foreseeable environmental degradation indicates the need for collective action among nations and states to avoid cumulative, far-reaching impacts. We suggest institutional innovations to assess and avoid the likely impoverishment of Amazon rivers.
C1 [Latrubesse, Edgardo M.; Arima, Eugenio Y.; Park, Edward; Wight, Charles] Univ Texas Austin, Dept Geog & Environm, Austin, TX 78712 USA.
   [Latrubesse, Edgardo M.] Nanyang Technol Univ, Earth Observ Singapore, Singapore, Singapore.
   [Latrubesse, Edgardo M.] Nanyang Technol Univ, Asian Sch Environm, Singapore, Singapore.
   [Dunne, Thomas] Univ Calif Santa Barbara, Bren Sch Environm Sci & Management, Santa Barbara, CA 93106 USA.
   [Baker, Victor R.] Univ Arizona, Dept Hydrol & Atmospher Sci, Tucson, AZ USA.
   [d'Horta, Fernando M.; Zuanon, Jansen] Natl Inst Amazonian Res INPA, Manaus, Amazonas, Brazil.
   [Wittmann, Florian] Karlsruhe Inst Technol, Inst Floodplain Ecol, Rastatt, Germany.
   [Baker, Paul A.] Duke Univ, Nicholas Sch Environm, Durham, NC 27708 USA.
   [Baker, Paul A.] Yachay Tech, Geol Sci, Urcuqui, Ecuador.
   [Norgaard, Richard B.] Univ Calif Berkeley, Energy & Resources Grp, Berkeley, CA 94720 USA.
   [Norgaard, Richard B.; Filizola, Naziano] Univ Fed Amazonas, Dept Geog, Manaus, Amazonas, Brazil.
   [Ansar, Atif; Flyvbjerg, Bent] Univ Oxford, Said Business Sch, Oxford, England.
   [Stevaux, Jose C.] State Univ Sao Paulo UNESP Rio Claro, Dept Appl Geol, Rio Claro, Brazil.
C3 University of Texas System; University of Texas Austin; Nanyang Technological University; Nanyang Technological University; University of California System; University of California Santa Barbara; University of Arizona; Institute Nacional de Pesquisas da Amazonia; Helmholtz Association; Karlsruhe Institute of Technology; Duke University; Universidad Yachay Tech; University of California System; University of California Berkeley; Universidade Federal de Amazonas; University of Oxford
RP Latrubesse, EM (corresponding author), Univ Texas Austin, Dept Geog & Environm, Austin, TX 78712 USA.; Latrubesse, EM (corresponding author), Nanyang Technol Univ, Earth Observ Singapore, Singapore, Singapore.; Latrubesse, EM (corresponding author), Nanyang Technol Univ, Asian Sch Environm, Singapore, Singapore.
EM latrubesse@austin.utexas.edu
FU NSF [FESD-1338694, EAR-1147954, DDRI-1558446]; NASA [NAG5-6120]; National Geographic Society-Research and Exploration Grant [8855-10]; LLILAS-Mellon; Brazilian Council for Scientific and Technological Development-CNPq; CAPES Foundation; Direct For Social, Behav & Economic Scie; Division Of Behavioral and Cognitive Sci [1558446] Funding Source: National Science Foundation
NR 61
TC 570
Z9 634
U1 22
U2 552
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 15
PY 2017
VL 546
IS 7658
BP 363
EP 369
DI 10.1038/nature22333
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EX5BK
UT WOS:000403250900026
PM 28617466
DA 2026-03-09
ER

PT J
AU Weyrich, LS
   Duchene, S
   Soubrier, J
   Arriola, L
   Llamas, B
   Breen, J
   Morris, AG
   Alt, KW
   Caramelli, D
   Dresely, V
   Farrell, M
   Farrer, AG
   Francken, M
   Gully, N
   Haak, W
   Hardy, K
   Harvati, K
   Held, P
   Holmes, EC
   Kaidonis, J
   Lalueza-Fox, C
   De la Rasilla, M
   Rosas, A
   Semal, P
   Soltysiak, A
   Townsend, G
   Usai, D
   Wahl, J
   Huson, DH
   Dobney, K
   Cooper, A
AF Weyrich, Laura S.
   Duchene, Sebastian
   Soubrier, Julien
   Arriola, Luis
   Llamas, Bastien
   Breen, James
   Morris, Alan G.
   Alt, Kurt W.
   Caramelli, David
   Dresely, Veit
   Farrell, Milly
   Farrer, Andrew G.
   Francken, Michael
   Gully, Neville
   Haak, Wolfgang
   Hardy, Karen
   Harvati, Katerina
   Held, Petra
   Holmes, Edward C.
   Kaidonis, John
   Lalueza-Fox, Carles
   De la Rasilla, Marco
   Rosas, Antonio
   Semal, Patrick
   Soltysiak, Arkadiusz
   Townsend, Grant
   Usai, Donatella
   Wahl, Joachim
   Huson, Daniel H.
   Dobney, Keith
   Cooper, Alan
TI Neanderthal behaviour, diet, and disease inferred from ancient DNA in dental calculus
SO NATURE
LA English
DT Article
ID isotopic evidence; rast server; el-sidron; microbiome; health; plaque
AB Recent genomic data have revealed multiple interactions between Neanderthals and modern humans(1), but there is currently little genetic evidence regarding Neanderthal behaviour, diet, or disease. Here we describe the shotgun-sequencing of ancient DNA from five specimens of Neanderthal calcified dental plaque (calculus) and the characterization of regional differences in Neanderthal ecology. At Spy cave, Belgium, Neanderthal diet was heavily meat based and included woolly rhinoceros and wild sheep (mouflon), characteristic of a steppe environment. In contrast, no meat was detected in the diet of Neanderthals from El Sidron cave, Spain, and dietary components of mushrooms, pine nuts, and moss reflected forest gathering(2,3). Differences in diet were also linked to an overall shift in the oral bacterial community (microbiota) and suggested that meat consumption contributed to substantial variation within Neanderthal microbiota. Evidence for self-medication was detected in an El Sidron Neanderthal with a dental abscess(4) and a chronic gastrointestinal pathogen (Enterocytozoon bieneusi). Metagenomic data from this individual also contained a nearly complete genome of the archaeal commensal Methanobrevibacter oralis (10.2x depth of coverage)-the oldest draft microbial genome generated to date, at around 48,000 years old. DNA preserved within dental calculus represents a notable source of information about the behaviour and health of ancient hominin specimens, as well as a unique system that is useful for the study of long-term microbial evolution.
C1 [Weyrich, Laura S.; Soubrier, Julien; Arriola, Luis; Llamas, Bastien; Breen, James; Farrer, Andrew G.; Haak, Wolfgang; Cooper, Alan] Univ Adelaide, Australian Ctr Ancient DNA, Sch Biol Sci, Adelaide, SA, Australia.
   [Weyrich, Laura S.; Duchene, Sebastian; Soubrier, Julien; Arriola, Luis; Llamas, Bastien; Breen, James; Farrer, Andrew G.; Haak, Wolfgang; Holmes, Edward C.; Cooper, Alan] Univ Adelaide, Inst Environm, Adelaide, SA, Australia.
   [Duchene, Sebastian; Holmes, Edward C.] Univ Sydney, Sch Life & Environm Sci, Charles Perkins Ctr, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW, Australia.
   [Duchene, Sebastian; Alt, Kurt W.; Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW, Australia.
   [Morris, Alan G.] Univ Cape Town, Dept Human Biol, Cape Town, South Africa.
   [Alt, Kurt W.] Danube Private Univ, Krems, Austria.
   [Alt, Kurt W.; Dresely, Veit] State Off Heritage Management & Archaeol, Saxony Anhalt, Germany.
   [Alt, Kurt W.; Dresely, Veit] Heritage Museum, Halle, Germany.
   [Alt, Kurt W.] Basel Univ, Inst Prehist & Archaeol Sci, Basel, Switzerland.
   [Caramelli, David] Univ Florence, Dept Biol, Florence, Italy.
   [Farrell, Milly] Oxford Brookes Univ, Human Origins & Palaeo Environm Grp, Oxford, England.
   [Francken, Michael; Harvati, Katerina] Eberhard Karls Univ Tubingen, Senckenberg Ctr Human Evolut & Paleoenvironm, Paleoanthropol, Tubingen, Germany.
   [Gully, Neville; Kaidonis, John; Townsend, Grant] Univ Adelaide, Sch Dent, Adelaide, SA, Australia.
   [Hardy, Karen] Catalan Inst Res & Adv Studies ICREA, Pg Lluis Co 23, Barcelona 08010, Catalonia, Spain.
   [Hardy, Karen] Univ Autonoma Barcelona, Fac Filosofia & Lletres, Dept Prehist, Barcelona, Catalonia, Spain.
   [Held, Petra] Johannes Gutenberg Univ Mainz, Inst Anthropol, Mainz, Germany.
   [Lalueza-Fox, Carles] Univ Pompeu Fabra, CSIC, Inst Evolutionary Biol, Barcelona, Spain.
   [De la Rasilla, Marco] Univ Oviedo, Dept Hist, Area Prehist, Oviedo, Spain.
   [Rosas, Antonio] CSIC, Museo Nacl Ciencias Nat, Dept Paleobiol, Paleoanthropol Grp, Madrid, Spain.
   [Semal, Patrick] Royal Belgian Inst Nat Sci, Sci Serv Heritage, Brussels, Belgium.
   [Soltysiak, Arkadiusz] Univ Warsaw, Inst Archaeol, Dept Bioarchaeol, Warsaw, Poland.
   [Usai, Donatella] Ist Italiano Africa & Oriente IsIAO, Rome, Italy.
   [Wahl, Joachim] State Off Cultural Heritage Management Baden Wurt, Esslingen, Germany.
   [Huson, Daniel H.] Univ Tubingen, Dept Algorithms Bioinformat, Tubingen, Germany.
   [Dobney, Keith] Univ Liverpool, Sch Hist Languages & Cultures, Dept Archaeol Class & Egyptol, Liverpool, Merseyside, England.
   [Dobney, Keith] Univ Aberdeen, Dept Archaeol, Aberdeen, Scotland.
   [Dobney, Keith] Simon Fraser Univ, Dept Archaeol, Burnaby, BC, Canada.
C3 Adelaide University; University of Adelaide; Adelaide University; University of Adelaide; University of Sydney; University of Sydney; University of Cape Town; University of Florence; Oxford Brookes University; Eberhard Karls University of Tubingen; Leibniz Association; Senckenberg Gesellschaft fur Naturforschung (SGN); Adelaide University; University of Adelaide; ICREA; Autonomous University of Barcelona; Johannes Gutenberg University of Mainz; Pompeu Fabra University; Consejo Superior de Investigaciones Cientificas (CSIC); University of Oviedo; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Museo Nacional de Ciencias Naturales (MNCN); Royal Belgian Institute of Natural Sciences; University of Warsaw; Eberhard Karls University of Tubingen; University of Liverpool; University of Aberdeen; Simon Fraser University
RP Weyrich, LS; Cooper, A (corresponding author), Univ Adelaide, Australian Ctr Ancient DNA, Sch Biol Sci, Adelaide, SA, Australia.; Weyrich, LS; Cooper, A (corresponding author), Univ Adelaide, Inst Environm, Adelaide, SA, Australia.
EM laura.weyrich@adelaide.edu.au; alan.cooper@adelaide.edu.au
FU Australian Research Council; ICREA Funding Source: Custom
NR 46
TC 351
Z9 395
U1 6
U2 282
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 20
PY 2017
VL 544
IS 7650
BP 357
EP +
DI 10.1038/nature21674
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ES4SG
UT WOS:000399524400038
PM 28273061
DA 2026-03-09
ER

PT J
AU Wang, HZ
   Nicolay, BN
   Chick, JM
   Gao, XL
   Geng, Y
   Ren, H
   Gao, H
   Yang, GZ
   Williams, JA
   Suski, JM
   Keibler, MA
   Sicinska, E
   Gerdemann, U
   Haining, WN
   Roberts, TM
   Polyak, K
   Gygi, SP
   Dyson, NJ
   Sicinski, P
AF Wang, Haizhen
   Nicolay, Brandon N.
   Chick, Joel M.
   Gao, Xueliang
   Geng, Yan
   Ren, Hong
   Gao, Hui
   Yang, Guizhi
   Williams, Juliet A.
   Suski, Jan M.
   Keibler, Mark A.
   Sicinska, Ewa
   Gerdemann, Ulrike
   Haining, W. Nicholas
   Roberts, Thomas M.
   Polyak, Kornelia
   Gygi, Steven P.
   Dyson, Nicholas J.
   Sicinski, Piotr
TI The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival
SO NATURE
LA English
DT Article
ID pyruvate-kinase; protein-phosphorylation; cdk4/6 inhibition; flux analysis; m2; site; phosphofructokinases; catabolism; confidence; glutamine
AB D-type cyclins (D1, D2 and D3) and their associated cyclin-dependent kinases (CDK4 and CDK6) are components of the core cell cycle machinery that drives cell proliferation(1,2). Inhibitors of CDK4 and CDK6 are currently being tested in clinical trials for patients with several cancer types, with promising results(2). Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. This re-directs the glycolytic intermediates into the pentose phosphate (PPP) and serine pathways. Inhibition of cyclin D3-CDK6 in tumour cells reduces flow through the PPP and serine pathways, thereby depleting the antioxidants NADPH and glutathione. This, in turn, increases the levels of reactive oxygen species and causes apoptosis of tumour cells. The pro-survival function of cyclin D-associated kinase operates in tumours expressing high levels of cyclin D3-CDK6 complexes. We propose that measuring the levels of cyclin D3-CDK6 in human cancers might help to identify tumour subsets that undergo cell death and tumour regression upon inhibition of CDK4 and CDK6. Cyclin D3-CDK6, through its ability to link cell cycle and cell metabolism, represents a particularly powerful oncoprotein that affects cancer cells at several levels, and this property can be exploited for anti-cancer therapy.
C1 [Wang, Haizhen; Gao, Xueliang; Geng, Yan; Ren, Hong; Suski, Jan M.; Roberts, Thomas M.; Sicinski, Piotr] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.
   [Wang, Haizhen; Geng, Yan; Ren, Hong; Suski, Jan M.; Sicinski, Piotr] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.
   [Nicolay, Brandon N.; Dyson, Nicholas J.] Massachusetts Gen Hosp, Canc Ctr, Boston, MA 02129 USA.
   [Chick, Joel M.; Gygi, Steven P.] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
   [Gao, Xueliang; Roberts, Thomas M.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.
   [Gao, Hui; Yang, Guizhi; Williams, Juliet A.] Novartis Inst Biomed Res, Cambridge, MA 02139 USA.
   [Keibler, Mark A.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA.
   [Sicinska, Ewa] Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA 02215 USA.
   [Gerdemann, Ulrike] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.
   [Haining, W. Nicholas] Childrens Hosp, Div Pediat Hematol & Oncol, Boston, MA 02115 USA.
   [Haining, W. Nicholas] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Polyak, Kornelia] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.
C3 Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Novartis; Novartis USA; Massachusetts Institute of Technology (MIT); Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute
RP Sicinski, P (corresponding author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.; Sicinski, P (corresponding author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.
EM peter_sicinski@dfci.harvard.edu
FU NIH [T32CA009361, P50 CA090381-14]; Mobilnosc Plus fellowship;  [R01 CA083688];  [R01 CA202634];  [P01 CA080111];  [R01 CA163698];  [F32 CA165856]; National Institute of General Medical Sciences [R01GM067945] Funding Source: NIH RePORTER
NR 36
TC 136
Z9 168
U1 2
U2 75
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 15
PY 2017
VL 546
IS 7658
BP 426
EP +
DI 10.1038/nature22797
PG 27
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EX5BK
UT WOS:000403250900039
PM 28607489
DA 2026-03-09
ER

PT J
AU Jin, P
   Bulkley, D
   Guo, YM
   Zhang, W
   Guo, ZH
   Huynh, W
   Wu, SP
   Meltzer, S
   Cheng, T
   Jan, LY
   Jan, YN
   Cheng, YF
AF Jin, Peng
   Bulkley, David
   Guo, Yanmeng
   Zhang, Wei
   Guo, Zhenhao
   Huynh, Walter
   Wu, Shenping
   Meltzer, Shan
   Cheng, Tong
   Jan, Lily Yeh
   Jan, Yuh-Nung
   Cheng, Yifan
TI Electron cryo-microscopy structure of the mechanotransduction channel NOMPC
SO NATURE
LA English
DT Article
ID trp channel; ion-channel; crystal-structure; ankyrin repeats; activation; validation; microscopy; dynactin; force; helix
AB Mechanosensory transduction for senses such as proprioception, touch, balance, acceleration, hearing and pain relies on mechanotransduction channels, which convert mechanical stimuli into electrical signals in specialized sensory cells(1). How force gates mechanotransduction channels is a central question in the field, for which there are two major models. One is the membrane-tension model: force applied to the membrane generates a change in membrane tension that is sufficient to gate the channel, as in the bacterial MscL channel and certain eukaryotic potassium channels(2-5). The other is the tether model: force is transmitted via a tether to gate the channel. The transient receptor potential (TRP) channel NOMPC is important for mechanosensation-related behaviours such as locomotion, touch and sound sensation across different species including Caenorhabditis elegans(6), Drosophila(7-9) and zebrafish(10). NOMPC is the founding member of the TRPN subfamily(11), and is thought to be gated by tethering of its ankyrin repeat domain to microtubules of the cytoskeleton(12-15). Thus, a goal of studying NOMPC is to reveal the underlying mechanism of force-induced gating, which could serve as a paradigm of the tether model. NOMPC fulfils all the criteria that apply to mechanotransduction channels(1,7) and has 29 ankyrin repeats, the largest number among TRP channels. A key question is how the long ankyrin repeat domain is organized as a tether that can trigger channel gating. Here we present a de novo atomic structure of Drosophila NOMPC determined by single-particle electron cryo-microscopy. Structural analysis suggests that the ankyrin repeat domain of NOMPC resembles a helical spring, suggesting its role of linking mechanical displacement of the cytoskeleton to the opening of the channel. The NOMPC architecture underscores the basis of translating mechanical force into an electrical signal within a cell.
C1 [Jin, Peng; Guo, Yanmeng; Zhang, Wei; Guo, Zhenhao; Meltzer, Shan; Cheng, Tong; Jan, Lily Yeh; Jan, Yuh-Nung] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA.
   [Bulkley, David; Jan, Lily Yeh; Jan, Yuh-Nung; Cheng, Yifan] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA.
   [Zhang, Wei; Wu, Shenping; Cheng, Tong; Jan, Lily Yeh; Jan, Yuh-Nung; Cheng, Yifan] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA.
   [Huynh, Walter] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA.
C3 University of California System; University of California San Francisco; University of California System; University of California San Francisco; Howard Hughes Medical Institute; University of California System; University of California San Francisco; University of California System; University of California San Francisco
RP Jan, YN (corresponding author), Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA.; Jan, YN; Cheng, YF (corresponding author), Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA.; Jan, YN; Cheng, YF (corresponding author), Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA.
EM yuhnung.jan@ucsf.edu; ycheng@ucsf.edu
FU NIH [R01NS069229, 5R37NS040929, 1R35NS097227, R01GM098672, S10OD020054]; UCSF Program for Breakthrough Biomedical Research; National Institute of Neurological Disorders and Stroke [R35NS097227] Funding Source: NIH RePORTER
NR 49
TC 176
Z9 202
U1 5
U2 110
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 6
PY 2017
VL 547
IS 7661
BP 118
EP +
DI 10.1038/nature22981
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EZ6PM
UT WOS:000404839900042
PM 28658211
DA 2026-03-09
ER

PT J
AU Vu, TM
   Ishizu, AN
   Foo, JC
   Toh, XR
   Zhang, FY
   Whee, DM
   Torta, F
   Cazenave-Gassiot, A
   Matsumura, T
   Kim, S
   Toh, SAES
   Suda, T
   Silver, DL
   Wenk, MR
   Nguyen, LN
AF Vu, Thiet M.
   Ishizu, Ayako-Nakamura
   Foo, Juat Chin
   Xiu Ru Toh
   Zhang, Fangyu
   Whee, Ding Ming
   Torta, Federico
   Cazenave-Gassiot, Amaury
   Matsumura, Takayoshi
   Kim, Sangho
   Toh, Sue-Anne E. S.
   Suda, Toshio
   Silver, David L.
   Wenk, Markus R.
   Nguyen, Long N.
TI Mfsd2b is essential for the sphingosine-1-phosphate export in erythrocytes and platelets
SO NATURE
LA English
DT Article
ID sphingosine 1-phosphate; lymphocyte egress; endothelial-cells; mice; transporter; release; plasma; disease; fty720; blood
AB Sphingosine-1-phosphate (S1P), a potent signalling lipid secreted by red blood cells and platelets(1,2), plays numerous biologically significant roles(3-6). However, the identity of its long-sought exporter is enigmatic. Here we show that the major facilitator superfamily transporter 2b (Mfsd2b), an orphan transporter, is essential for S1P export from red blood cells and platelets. Comprehensive lipidomic analysis indicates a dramatic and specific accumulation of S1P species in Mfsd2b knockout red blood cells and platelets compared with that of wild-type controls. Consistently, biochemical assays from knockout red blood cells, platelets, and cell lines overexpressing human and mouse Mfsd2b proteins demonstrate that Mfsd2b actively exports S1P. Plasma S1P level in knockout mice is significantly reduced by 42-54% of that of wild-type level, indicating that Mfsd2b pathway contributes approximately half of the plasma S1P pool. The reduction of plasma S1P in knockout mice is insufficient to cause blood vessel leakiness, but it does render the mice more sensitive to anaphylactic shock. Stress-induced erythropoiesis significantly increased plasma S1P levels and knockout mice were sensitive to these treatments. Surprisingly, knockout mice exhibited haemolysis associated with red blood cell stomatocytes, and the haemolytic phenotype was severely increased with signs of membrane fragility under stress erythropoiesis. We show that S1P secretion by Mfsd2b is critical for red blood cell morphology. Our data reveal an unexpected physiological role of red blood cells in sphingolipid metabolism in circulation. These findings open new avenues for investigating the signalling roles of S1P derived from red blood cells and platelets.
C1 [Vu, Thiet M.; Xiu Ru Toh; Zhang, Fangyu; Whee, Ding Ming; Torta, Federico; Cazenave-Gassiot, Amaury; Wenk, Markus R.; Nguyen, Long N.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, 5 Med Dr, Singapore 117545, Singapore.
   [Ishizu, Ayako-Nakamura; Matsumura, Takayoshi; Suda, Toshio] Natl Univ Singapore, Yong Loo Lin Sch Med, Canc Sci Inst, 14 Med Dr, Singapore 117599, Singapore.
   [Foo, Juat Chin; Torta, Federico; Cazenave-Gassiot, Amaury; Wenk, Markus R.] Natl Univ Singapore, Life Sci Inst, Singapore Lipid Incubator SLING, 28 Med Dr, Singapore 117456, Singapore.
   [Kim, Sangho] Natl Univ Singapore, Dept Biomed Engn, 4 Engn Dr 3, Singapore 1175835, Singapore.
   [Kim, Sangho] Natl Univ Singapore, Biomed Inst Global Hlth Res & Technol, 14 Med Dr, Singapore 117599, Singapore.
   [Kim, Sangho] Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, 28 Med Dr, Singapore 117456, Singapore.
   [Toh, Sue-Anne E. S.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 117599, Singapore.
   [Silver, David L.] Duke NUS Med Sch, Signature Res Program Cardiovasc & Metab Dis, 8 Coll Rd, Singapore 169857, Singapore.
C3 National University of Singapore; National University of Singapore; National University of Singapore; National University of Singapore; National University of Singapore; National University of Singapore; National University of Singapore; National University of Singapore
RP Nguyen, LN (corresponding author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, 5 Med Dr, Singapore 117545, Singapore.
EM bchnnl@nus.edu.sg
FU Singapore Ministry of Health's National Medical Research Council [NMRC/BNIG/2023/2014]; National University of Singapore (NUS); NUS Young Investigator Award [NRF2016NRF-NRFI001-15, NRFI2015-05]; Biomedical Research Council; Science and Engineering Research Council [BMRC-SERC 112 148 0006, NMRC/ CIRG/1377/2013]; Grants-in-Aid for Scientific Research [26221309] Funding Source: KAKEN
NR 39
TC 196
Z9 226
U1 1
U2 39
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 26
PY 2017
VL 550
IS 7677
BP 524
EP +
DI 10.1038/nature24053
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK7OW
UT WOS:000413697800044
PM 29045386
DA 2026-03-09
ER

PT J
AU Wu, D
   Bacaj, T
   Morishita, W
   Goswami, D
   Arendt, KL
   Xu, W
   Chen, L
   Malenka, RC
   Südhof, TC
AF Wu, Dick
   Bacaj, Taulant
   Morishita, Wade
   Goswami, Debanjan
   Arendt, Kristin L.
   Xu, Wei
   Chen, Lu
   Malenka, Robert C.
   Sudhof, Thomas C.
TI Postsynaptic synaptotagmins mediate AMPA receptor exocytosis during LTP
SO NATURE
LA English
DT Article
ID long-term potentiation; synaptic vesicle exocytosis; calmodulin kinase-ii; neurotransmitter release; hippocampal-neurons; transmitter release; complexin controls; genetic-analysis; nmda receptors; ca2+ sensor
AB Strengthening of synaptic connections by NMDA (N-methyl-d-aspartate) receptor-dependent long-term potentiation (LTP) shapes neural circuits and mediates learning and memory. During the induction of NMDA-receptor-dependent LTP, Ca2+ influx stimulates recruitment of synaptic AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, thereby strengthening synapses. How Ca2+ induces the recruitment of AMPA receptors remains unclear. Here we show that, in the pyramidal neurons of the hippocampal CA1 region in mice, blocking postsynaptic expression of both synaptotagmin-1 (Syt1) and synaptotagmin-7 (Syt7), but not of either alone, abolished LTP. LTP was restored by expression of wild-type Syt7 but not of a Ca2+-binding-deficient mutant Syt7. Blocking postsynaptic expression of Syt1 and Syt7 did not impair basal synaptic transmission, reduce levels of synaptic or extrasynaptic AMPA receptors, or alter other AMPA receptor trafficking events. Moreover, expression of dominant-negative mutant Syt1 which inhibits Ca2+-dependent presynaptic vesicle exocytosis, also blocked Ca2+-dependent postsynaptic AMPA receptor exocytosis, thereby abolishing LTP. Our results suggest that postsynaptic Syt1 and Syt7 act as redundant Ca2+-sensors for Ca2+-dependent exocytosis of AMPA receptors during LTP, and thereby delineate a simple mechanism for the recruitment of AMPA receptors that mediates LTP.
C1 [Wu, Dick; Bacaj, Taulant; Xu, Wei; Sudhof, Thomas C.] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
   [Wu, Dick; Bacaj, Taulant; Xu, Wei; Sudhof, Thomas C.] Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Wu, Dick; Morishita, Wade; Goswami, Debanjan; Malenka, Robert C.] Stanford Univ, Sch Med, Nancy Pritzker Lab, Stanford, CA 94305 USA.
   [Wu, Dick; Morishita, Wade; Goswami, Debanjan; Malenka, Robert C.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA.
   [Arendt, Kristin L.; Chen, Lu] Stanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USA.
   [Xu, Wei] UT Southwestern Med Ctr, Dept Neurosci, Dallas, TX 75235 USA.
C3 Stanford University; Howard Hughes Medical Institute; Stanford University; Stanford University; Stanford University; Stanford University; University of Texas System; University of Texas Southwestern Medical Center
RP Südhof, TC (corresponding author), Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.; Südhof, TC (corresponding author), Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA.; Malenka, RC (corresponding author), Stanford Univ, Sch Med, Nancy Pritzker Lab, Stanford, CA 94305 USA.; Malenka, RC (corresponding author), Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA.
EM malenka@stanford.edu; tcs1@stanford.edu
FU NIH [P50 MH086403, F32 MH100752, K99 MH107618]
NR 46
TC 147
Z9 175
U1 1
U2 53
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 20
PY 2017
VL 544
IS 7650
BP 316
EP +
DI 10.1038/nature21720
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ES4SG
UT WOS:000399524400030
PM 28355182
DA 2026-03-09
ER

PT J
AU Chan, LN
   Chen, ZS
   Braas, D
   Lee, JW
   Xiao, G
   Geng, HM
   Cosgun, KN
   Hurtz, C
   Shojaee, S
   Cazzaniga, V
   Schjerven, H
   Ernst, T
   Hochhaus, A
   Kornblau, SM
   Konopleva, M
   Pufall, MA
   Cazzaniga, G
   Liu, GJ
   Milne, TA
   Koeffler, HP
   Ross, TS
   Sánchez-García, I
   Borkhardt, A
   Yamamoto, KR
   Dickins, RA
   Graeber, TG
   Müschen, M
AF Chan, Lai N.
   Chen, Zhengshan
   Braas, Daniel
   Lee, Jae-Woong
   Xiao, Gang
   Geng, Huimin
   Cosgun, Kadriye Nehir
   Hurtz, Christian
   Shojaee, Seyedmehdi
   Cazzaniga, Valeria
   Schjerven, Hilde
   Ernst, Thomas
   Hochhaus, Andreas
   Kornblau, Steven M.
   Konopleva, Marina
   Pufall, Miles A. .
   Cazzaniga, Giovanni
   Liu, Grace J.
   Milne, Thomas A.
   Koeffler, H. Phillip
   Ross, Theodora S.
   Sanchez-Garcia, Isidro
   Borkhardt, Arndt
   Yamamoto, Keith R.
   Dickins, Ross A.
   Graeber, Thomas G.
   Mueschen, Markus
TI Metabolic gatekeeper function of B-lymphoid transcription factors
SO NATURE
LA English
DT Article
ID acute lymphoblastic-leukemia; minimal residual disease; hematopoietic stem-cells; regulatory network; energy stress; gene; activation; expression; differentiation; macrophages
AB B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development(1,2), yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL)(3,4). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK(5-7). Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor)(8), TXNIP (encoding a glucose-feedback sensor)(9) and CNR2 (encoding a cannabinoid receptor)(10) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation.
C1 [Chan, Lai N.; Chen, Zhengshan; Lee, Jae-Woong; Xiao, Gang; Cosgun, Kadriye Nehir; Mueschen, Markus] Beckman Res Inst, Dept Syst Biol, Pasadena, CA 91016 USA.
   [Chan, Lai N.; Chen, Zhengshan; Lee, Jae-Woong; Xiao, Gang; Cosgun, Kadriye Nehir; Mueschen, Markus] City Hope Natl Med Ctr, Pasadena, CA 91016 USA.
   [Chan, Lai N.; Chen, Zhengshan; Lee, Jae-Woong; Xiao, Gang; Cosgun, Kadriye Nehir; Mueschen, Markus] City Hope Comprehens Canc Ctr, Duarte, CA 91010 USA.
   [Braas, Daniel; Graeber, Thomas G.] Univ Calif Los Angeles, Metabol Ctr, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA.
   [Braas, Daniel; Graeber, Thomas G.] Univ Calif Los Angeles, Crump Inst Mol Imaging, Los Angeles, CA 90095 USA.
   [Geng, Huimin; Hurtz, Christian; Shojaee, Seyedmehdi; Cazzaniga, Valeria; Schjerven, Hilde; Yamamoto, Keith R.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA.
   [Geng, Huimin; Hurtz, Christian; Shojaee, Seyedmehdi; Cazzaniga, Valeria; Schjerven, Hilde; Yamamoto, Keith R.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA.
   [Ernst, Thomas; Hochhaus, Andreas] Univ Klinikum Jena, Klin Innere Med 2, Hamatol Onkol, D-07743 Jena, Germany.
   [Kornblau, Steven M.; Konopleva, Marina] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA.
   [Pufall, Miles A. .] Univ Iowa, Dept Biochem, Iowa City, IA 52242 USA.
   [Cazzaniga, Giovanni] Univ Milano Bicocca, Ctr Ric Tettamanti Clin Pediat, Osped S Gerardo, I-20052 Monza, MB, Italy.
   [Liu, Grace J.; Dickins, Ross A.] Monash Univ, Australian Ctr Blood Dis, Melbourne, Vic 3004, Australia.
   [Milne, Thomas A.] Univ Oxford, Weatherall Inst Mol Med, MRC Mol Haematol Unit, Oxford OX3 9DS, England.
   [Koeffler, H. Phillip] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117599, Singapore.
   [Koeffler, H. Phillip] Univ Calif Los Angeles, Cedars Sinai Med Ctr, Sch Med, Div Hematol Oncol, Los Angeles, CA 90095 USA.
   [Ross, Theodora S.] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med & Canc Genet, Dallas, TX 75390 USA.
   [Sanchez-Garcia, Isidro] Univ Salamanca, CSIC, Inst Biol Mol Celular & Cancer, Expt Therapeut & Translat Oncol Program, Salamanca 37007, Spain.
   [Sanchez-Garcia, Isidro] Inst Biomed Res Salamanca IBSAL, Salamanca 37007, Spain.
   [Borkhardt, Arndt] Heinrich Heine Univ, Fac Med, Pediat Oncol Hematol & Clin Immunol, D-40225 Dusseldorf, Germany.
C3 City of Hope; City of Hope; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Friedrich Schiller University of Jena; University of Texas System; UTMD Anderson Cancer Center; University of Iowa; San Gerardo Hospital; University of Milano-Bicocca; Monash University; University of Oxford; National University of Singapore; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; Cedars Sinai Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Consejo Superior de Investigaciones Cientificas (CSIC); University of Salamanca; University of Salamanca; Heinrich Heine University Dusseldorf
RP Müschen, M (corresponding author), Beckman Res Inst, Dept Syst Biol, Pasadena, CA 91016 USA.; Müschen, M (corresponding author), City Hope Natl Med Ctr, Pasadena, CA 91016 USA.; Müschen, M (corresponding author), City Hope Comprehens Canc Ctr, Duarte, CA 91010 USA.
EM mmuschen@coh.org
FU NIH/NCI [R35CA197628, R01CA137060, R01CA157644, R01CA172558]; Wellcome Trust; Leukemia and Lymphoma Scholar award; Howard Hughes Medical Institute [HHMI-55108547]; Alex's Lemonade Stand Foundation for Childhood Cancer; William Lawrence & Blanche Hughes Foundation for childhood cancer; Norman and Sadie Lee Foundation; Falk Trust through a Falk Medical Research Trust; Cancer Research Institute (CRI) through a Clinic and Laboratory Integration Program (CLIP) grant; Melanoma Research Alliance; German Bundesministerium fur Bildung und Forschung, BMBF; German Carreras Foundation [DJCLS R13/26]; MRC [MC_UU_00016/6, MC_UU_12009/6] Funding Source: UKRI; Medical Research Council [MC_UU_00016/6, MC_UU_12009/6] Funding Source: researchfish; National Cancer Institute [R01CA213138, P30CA086862, R35CA197628, R01CA157644] Funding Source: NIH RePORTER
NR 38
TC 199
Z9 222
U1 2
U2 61
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 23
PY 2017
VL 542
IS 7642
BP 479
EP +
DI 10.1038/nature21076
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1RG
UT WOS:000395094100037
PM 28192788
DA 2026-03-09
ER

PT J
AU Camell, CD
   Sander, J
   Spadaro, O
   Lee, A
   Nguyen, KY
   Wing, A
   Goldberg, EL
   Youm, YH
   Brown, CW
   Elsworth, J
   Rodeheffer, MS
   Schultze, JL
   Dixit, VD
AF Camell, Christina D.
   Sander, Jil
   Spadaro, Olga
   Lee, Aileen
   Nguyen, Kim Y.
   Wing, Allison
   Goldberg, Emily L.
   Youm, Yun-Hee
   Brown, Chester W.
   Elsworth, John
   Rodeheffer, Matthew S.
   Schultze, Joachim L.
   Dixit, Vishwa Deep
TI Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing
SO NATURE
LA English
DT Article
ID adipose-tissue; monoamine-oxidase; obesity; cells; age; identification; accumulation; deficiency; activation; protects
AB Catecholamine-induced lipolysis, the first step in the generation of energy substrates by the hydrolysis of triglycerides(1), declines with age(2,3). The defect in the mobilization of free fatty acids in the elderly is accompanied by increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. Although catecholamine signalling in adipocytes is normal in the elderly, how lipolysis is impaired in ageing remains unknown(2,4). Here we show that adipose tissue macrophages regulate the age-related reduction in adipocyte lipolysis in mice by lowering the bioavailability of noradrenaline. Unexpectedly, unbiased whole-transcriptome analyses of adipose macrophages revealed that ageing upregulates genes that control catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in ageing restored catecholamine-induced lipolysis by downregulating growth differentiation factor-3 (GDF3) and monoamine oxidase A (MAOA) that is known to degrade noradrenaline. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing levels of MAOA and caspase-1. Furthermore, inhibition of MAOA reversed the age-related reduction in noradrenaline concentration in adipose tissue, and restored lipolysis with increased levels of the key lipolytic enzymes adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-immunometabolic signalling between the sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.
C1 [Camell, Christina D.; Spadaro, Olga; Lee, Aileen; Nguyen, Kim Y.; Goldberg, Emily L.; Youm, Yun-Hee; Rodeheffer, Matthew S.; Dixit, Vishwa Deep] Yale Sch Med, Dept Comparat Med, New Haven, CT 06520 USA.
   [Camell, Christina D.; Spadaro, Olga; Lee, Aileen; Nguyen, Kim Y.; Goldberg, Emily L.; Youm, Yun-Hee; Dixit, Vishwa Deep] Yale Sch Med, Dept Immunobiol, New Haven, CT 06520 USA.
   [Sander, Jil; Schultze, Joachim L.] Univ Bonn, LIMES Inst, Genom & Immunoregulat, D-53115 Bonn, Germany.
   [Wing, Allison] Yale Sch Med, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA.
   [Brown, Chester W.] Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Div Genet, Memphis, TN 38163 USA.
   [Elsworth, John] Yale Sch Med, Dept Psychiat, New Haven, CT 06520 USA.
   [Schultze, Joachim L.] Univ Bonn, Single Cell Genom & Epigen Unit, Bonn, Germany.
   [Schultze, Joachim L.] German Ctr Neurodegenerat Dis, Bonn, Germany.
   [Dixit, Vishwa Deep] Yale Sch Med, Yale Ctr Res Aging, New Haven, CT USA.
C3 Yale University; Yale University; University of Bonn; Yale University; University of Tennessee System; University of Tennessee Health Science Center; Yale University; University of Bonn; Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE); Yale University
RP Dixit, VD (corresponding author), Yale Sch Med, Dept Comparat Med, New Haven, CT 06520 USA.; Dixit, VD (corresponding author), Yale Sch Med, Dept Immunobiol, New Haven, CT 06520 USA.
EM vishwa.dixit@yale.edu
FU German Research Foundation [SFB704, SFB645]; ImmunoSensation Cluster of Excellence Bonn; NIA postdoctoral training fellowship [AG043608]; AFAR (American Federation of Aging Research); NIH [P01AG051459, AI105097, AG051459, AR070811]; Glenn Foundation on Aging Research; Cure Alzheimer's Fund; National Institute of Allergy and Infectious Diseases [T32AI007019] Funding Source: NIH RePORTER; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR070811] Funding Source: NIH RePORTER; National Institute on Aging [P01AG051459] Funding Source: NIH RePORTER
CR Amano SU, 2014, CELL METAB, V19, P162, DOI 10.1016/j.cmet.2013.11.017
   Andersson O, 2008, P NATL ACAD SCI USA, V105, P7252, DOI 10.1073/pnas.0800272105
   Unknown -, 2015, NUCLEIC ACIDS RES, V43, P0
   Ashburner M, 2000, NAT GENET, V25, P25, DOI 10.1038/75556
   BALTER NJ, 1977, J PHARMACOL EXP THER, V201, P636
   BENJAMINI Y, 1995, J ROY STAT SOC B, V57, P289, DOI 10.1111/j.2517-6161.1995.tb02031.x
   Berry R, 2014, METHOD ENZYMOL, V537, P47, DOI 10.1016/B978-0-12-411619-1.00004-5
   Berry R, 2013, NAT CELL BIOL, V15, P302, DOI 10.1038/ncb2696
   BERTRAND HA, 1987, J GERONTOL, V42, P666, DOI 10.1093/geronj/42.6.666
   Campisi J, 2007, NAT REV MOL CELL BIO, V8, P729, DOI 10.1038/nrm2233
   Chen HY, 2014, CELL, V159, P829, DOI 10.1016/j.cell.2014.10.028
   Czimmerer Z, 2012, IMMUNOBIOLOGY, V217, P1301, DOI 10.1016/j.imbio.2012.08.270
   ELSWORTH JD, 1989, NEUROSCIENCE, V33, P323, DOI 10.1016/0306-4522(89)90212-1
   FEINGOLD KR, 1992, ENDOCRINOLOGY, V130, P10, DOI 10.1210/en.130.1.10
   Ferrante AW, 2013, DIABETES OBES METAB, V15, P34, DOI 10.1111/dom.12154
   Gerber JG, 1999, J GERONTOL A-BIOL, V54, PB71, DOI 10.1093/gerona/54.2.B71
   Guo TQ, 2014, ELIFE, V3, P0, DOI 10.7554/eLife.03245
   Hotamisligil GS, 2006, NATURE, V444, P860, DOI 10.1038/nature05485
   JAMES RC, 1971, J LAB CLIN MED, V77, P254
   Kim D, 2013, GENOME BIOL, V14, P0, DOI 10.1186/gb-2013-14-4-r36
   Lavin Y, 2014, CELL, V159, P1312, DOI 10.1016/j.cell.2014.11.018
   LONNQVIST F, 1990, J CLIN INVEST, V85, P1614, DOI 10.1172/JCI114612
   Love MI, 2014, GENOME BIOL, V15, P0, DOI 10.1186/s13059-014-0550-8
   Lumeng CN, 2011, J CLIN INVEST, V121, P2111, DOI 10.1172/JCI57132
   Mariathasan S, 2006, NATURE, V440, P228, DOI 10.1038/nature04515
   Mowers J, 2013, ELIFE, V2, P0, DOI 10.7554/eLife.01119
   Newman AM, 2015, NAT METHODS, V12, P453, DOI 10.1038/nmeth.3337
   Nolan T, 2006, NAT PROTOC, V1, P1559, DOI 10.1038/nprot.2006.236
   Rodeheffer MS, 2008, CELL, V135, P240, DOI 10.1016/j.cell.2008.09.036
   Rogers NH, 2012, AGING CELL, V11, P1074, DOI 10.1111/acel.12010
   Schweiger M, 2006, J BIOL CHEM, V281, P40236, DOI 10.1074/jbc.M608048200
   Shannon P, 2003, GENOME RES, V13, P2498, DOI 10.1101/gr.1239303
   Shen JJ, 2009, MOL ENDOCRINOL, V23, P113, DOI 10.1210/me.2007-0322
   Shih JC, 1999, ANNU REV NEUROSCI, V22, P197, DOI 10.1146/annurev.neuro.22.1.197
   Shoelson SE, 2006, J CLIN INVEST, V116, P1793, DOI 10.1172/JCI29069
   Spadaro O, 2016, CELL REP, V14, P1571, DOI 10.1016/j.celrep.2016.01.044
   Tacutu R, 2013, NUCLEIC ACIDS RES, V41, PD1027, DOI 10.1093/nar/gks1155
   Theocharidis A, 2009, NAT PROTOC, V4, P1535, DOI 10.1038/nprot.2009.177
   Vega A, 2004, J LEUKOCYTE BIOL, V75, P1093, DOI 10.1189/jlb.1003459
   Xu XY, 2013, CELL METAB, V18, P816, DOI 10.1016/j.cmet.2013.11.001
   Xue J, 2014, IMMUNITY, V40, P274, DOI 10.1016/j.immuni.2014.01.006
   Yogosawa S, 2013, DIABETES, V62, P115, DOI 10.2337/db12-0295
   Youdim MBH, 2006, NAT REV NEUROSCI, V7, P295, DOI 10.1038/nrn1883
   Youm YH, 2013, CELL METAB, V18, P519, DOI 10.1016/j.cmet.2013.09.010
   Young SG, 2013, GENE DEV, V27, P459, DOI 10.1101/gad.209296.112
NR 45
TC 381
Z9 427
U1 1
U2 73
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 5
PY 2017
VL 550
IS 7674
BP 119
EP +
DI 10.1038/nature24022
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI7XU
UT WOS:000412214100057
PM 28953873
DA 2026-03-09
ER

PT J
AU Esteva, A
   Kuprel, B
   Novoa, RA
   Ko, J
   Swetter, SM
   Blau, HM
   Thrun, S
AF Esteva, Andre
   Kuprel, Brett
   Novoa, Roberto A.
   Ko, Justin
   Swetter, Susan M.
   Blau, Helen M.
   Thrun, Sebastian
TI Dermatologist-level classification of skin cancer with deep neural networks
SO NATURE
LA English
DT Article
ID melanoma; diagnosis; accuracy; lesions
AB Skin cancer, the most common human malignancy(1-3), is primarily diagnosed visually, beginning with an initial clinical screening and followed potentially by dermoscopic analysis, a biopsy and histopathological examination. Automated classification of skin lesions using images is a challenging task owing to the fine-grained variability in the appearance of skin lesions. Deep convolutional neural networks (CNNs)(4,5) show potential for general and highly variable tasks across many fine-grained object categories(6-11). Here we demonstrate classification of skin lesions using a single CNN, trained end-to-end from images directly, using only pixels and disease labels as inputs. We train a CNN using a dataset of 129,450 clinical images-two orders of magnitude larger than previous datasets(12)-consisting of 2,032 different diseases. We test its performance against 21 board-certified dermatologists on biopsy-proven clinical images with two critical binary classification use cases: keratinocyte carcinomas versus benign seborrheic keratoses; and malignant melanomas versus benign nevi. The first case represents the identification of the most common cancers, the second represents the identification of the deadliest skin cancer. The CNN achieves performance on par with all tested experts across both tasks, demonstrating an artificial intelligence capable of classifying skin cancer with a level of competence comparable to dermatologists. Outfitted with deep neural networks, mobile devices can potentially extend the reach of dermatologists outside of the clinic. It is projected that 6.3 billion smartphone subscriptions will exist by the year 2021 (ref. 13) and can therefore potentially provide low-cost universal access to vital diagnostic care.
C1 [Esteva, Andre; Kuprel, Brett] Stanford Univ, Dept Elect Engn, Stanford, CA 94305 USA.
   [Novoa, Roberto A.; Ko, Justin; Swetter, Susan M.] Stanford Univ, Dept Dermatol, Stanford, CA 94305 USA.
   [Novoa, Roberto A.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA.
   [Swetter, Susan M.] Vet Affairs Palo Alto Hlth Care Syst, Dept Serv, Palo Alto, CA USA.
   [Blau, Helen M.] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA.
   [Thrun, Sebastian] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; Stanford University; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Palo Alto Health Care System; Stanford University; Stanford University
RP Esteva, A; Kuprel, B (corresponding author), Stanford Univ, Dept Elect Engn, Stanford, CA 94305 USA.; Novoa, RA (corresponding author), Stanford Univ, Dept Dermatol, Stanford, CA 94305 USA.; Novoa, RA (corresponding author), Stanford Univ, Dept Pathol, Stanford, CA 94305 USA.; Thrun, S (corresponding author), Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA.
EM esteva@cs.stanford.edu; kuprel@stanford.edu; rnovoa@stanford.edu; thrun@stanford.edu
FU Baxter Foundation; California Institute for Regenerative Medicine (CIRM) [TT3-05501, RB5-07469]; US National Institutes of Health (NIH) [AG044815, AG009521, NS089533, AR063963, AG020961]
NR 30
TC 8270
Z9 10275
U1 93
U2 2986
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 2
PY 2017
VL 542
IS 7639
BP 115
EP +
DI 10.1038/nature21056
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6MY
UT WOS:000396119300042
PM 28117445
DA 2026-03-09
ER

PT J
AU Pritchard, HD
AF Pritchard, Hamish D.
TI RETRACTED: Asia's glaciers are a regionally important buffer against drought (Publication with Expression of Concern. See vol. 550, 2017) (Retracted article. See vol. 555, 2018)
SO NATURE
LA English
DT Article; Retracted Publication
ID precipitation data; mass-loss; climate; river; himalaya; yield; basin; melt; dam
AB The high mountains of Asia-encompassing the Himalayas, the Hindu Kush, Karakoram, Pamir Alai, Kunlun Shan, and Tian Shan mountains-have the highest concentration of glaciers globally, and 800 million people depend in part on meltwater from them. Water stress makes this region vulnerable economically and socially to drought, but glaciers are a uniquely drought-resilient source of water. Here I show that these glaciers provide summer meltwater to rivers and aquifers that is sufficient for the basic needs of 136 million people, or most of the annual municipal and industrial needs of Pakistan, Tajikistan, Turkmenistan, Uzbekistan and Kyrgyzstan. During drought summers, meltwater dominates water inputs to the upper Indus and Aral river basins. Uncertainties in mountain precipitation are poorly known, but, given the magnitude of this water supply, predicted glacier loss would add considerably to drought-related water stress. Such additional water stress increases the risk of social instability, conflict and sudden, uncontrolled population migrations triggered by water scarcity, which is already associated with the large and rapidly growing populations and hydroeconomies of these basins.
C1 [Pritchard, Hamish D.] British Antarctic Survey, Madingley Rd, Cambridge CB3 0ET, England.
C3 UK Research & Innovation (UKRI); Natural Environment Research Council (NERC); NERC British Antarctic Survey
RP Pritchard, HD (corresponding author), British Antarctic Survey, Madingley Rd, Cambridge CB3 0ET, England.
EM hprit@bas.ac.uk
FU NERC [bas0100034, NE/R000107/1] Funding Source: UKRI; Natural Environment Research Council [NE/R000107/1, bas0100034] Funding Source: researchfish
NR 44
TC 164
Z9 192
U1 4
U2 146
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 11
PY 2017
VL 545
IS 7653
BP 169
EP +
DI 10.1038/nature22062
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EU3XG
UT WOS:000400963800024
PM 28492255
DA 2026-03-09
ER

PT J
AU Troja, E
   Lipunov, VM
   Mundell, CG
   Butler, NR
   Watson, AM
   Kobayashi, S
   Cenko, SB
   Marshall, FE
   Ricci, R
   Fruchter, A
   Wieringa, MH
   Gorbovskoy, ES
   Kornilov, V
   Kutyrev, A
   Lee, WH
   Toy, V
   Tyurina, NV
   Budnev, NM
   Buckley, DAH
   González, J
   Gress, O
   Horesh, A
   Panasyuk, MI
   Prochaska, JX
   Ramirez-Ruiz, E
   Lopez, RR
   Richer, MG
   Román-Zúñiga, C
   Serra-Ricart, M
   Yurkov, V
   Gehrels, N
AF Troja, E.
   Lipunov, V. M.
   Mundell, C. G.
   Butler, N. R.
   Watson, A. M.
   Kobayashi, S.
   Cenko, S. B.
   Marshall, F. E.
   Ricci, R.
   Fruchter, A.
   Wieringa, M. H.
   Gorbovskoy, E. S.
   Kornilov, V.
   Kutyrev, A.
   Lee, W. H.
   Toy, V.
   Tyurina, N. V.
   Budnev, N. M.
   Buckley, D. A. H.
   Gonzalez, J.
   Gress, O.
   Horesh, A.
   Panasyuk, M. I.
   Prochaska, J. X.
   Ramirez-Ruiz, E.
   Rebolo Lopez, R.
   Richer, M. G.
   Roman-Zuniga, C.
   Serra-Ricart, M.
   Yurkov, V.
   Gehrels, N.
TI Significant and variable linear polarization during the prompt optical flash of GRB 160625B
SO NATURE
LA English
DT Article
ID gamma-ray burst; induced magnetic reconnection; internal shocks; reverse shock; light curves; emission; afterglows; 041219a; jets; simulations
AB Newly formed black holes of stellar mass launch collimated outflows (jets) of ionized matter that approach the speed of light. These outflows power prompt, brief and intense flashes of gamma-rays known as gamma-ray bursts (GRBs), followed by longer-lived afterglow radiation that is detected across the electromagnetic spectrum. Measuring the polarization of the observed GRB radiation provides a direct probe of the magnetic fields in the collimated jets. Rapid-response polarimetric observations of newly discovered bursts have probed the initial afterglow phase(1-3), and show that, minutes after the prompt emission has ended, the degree of linear polarization can be as high as 30 per cent-consistent with the idea that a stable, globally ordered magnetic field permeates the jet at large distances from the central source(3). By contrast, optical(4-6) and gamma-ray(7-9) observations during the prompt phase have led to discordant and often controversial(10-12) results, and no definitive conclusions have been reached regarding the origin of the prompt radiation or the configuration of the magnetic field. Here we report the detection of substantial (8.3 +/- 0.8 per cent from our most conservative simulation), variable linear polarization of a prompt optical flash that accompanied the extremely energetic and long-lived prompt gamma-ray emission from GRB 160625B. Our measurements probe the structure of the magnetic field at an early stage of the jet, closer to its central black hole, and show that the prompt phase is produced via fast-cooling synchrotron radiation in a large-scale magnetic field that is advected from the black hole and distorted by dissipation processes within the jet.
C1 [Troja, E.; Cenko, S. B.; Kutyrev, A.; Toy, V.] Univ Maryland, Dept Astron, College Pk, MD 20742 USA.
   [Troja, E.; Cenko, S. B.; Marshall, F. E.; Kutyrev, A.; Gehrels, N.] NASA, Goddard Space Flight Ctr, 8800 Greenbelt Rd, Greenbelt, MD 20771 USA.
   [Lipunov, V. M.; Gorbovskoy, E. S.; Kornilov, V.; Tyurina, N. V.] Moscow MV Lomonosov State Univ, Dept Phys, GSP-1, Moscow 119991, Russia.
   [Lipunov, V. M.; Gorbovskoy, E. S.; Kornilov, V.; Tyurina, N. V.] Moscow MV Lomonosov State Univ, Sternberg Astron Inst, Univ Prospekt 13, Moscow 119234, Russia.
   [Mundell, C. G.] Univ Bath, Dept Phys, Bath BA2 7AY, Avon, England.
   [Butler, N. R.] Arizona State Univ, Sch Earth & Space Explorat, Tempe, AZ 85287 USA.
   [Watson, A. M.; Lee, W. H.; Gonzalez, J.] Univ Nacl Autonoma Mexico, Inst Astron, Apartado Postal 70-264, Mexico City 04510, DF, Mexico.
   [Kobayashi, S.] Liverpool John Moores Univ, Astrophys Res Inst, IC2 Bldg,Liverpool Sci Pk,146 Brownlow Hill, Liverpool L3 5RF, Merseyside, England.
   [Ricci, R.] INAF Ist Radioastron, Via Gobetti 101, I-40129 Bologna, Italy.
   [Fruchter, A.] Space Telescope Sci Inst, 3700 San Martin Dr, Baltimore, MD 21218 USA.
   [Wieringa, M. H.] CSIRO Astron & Space Sci, POB 76, Epping, NSW 1710, Australia.
   [Budnev, N. M.; Gress, O.] Irkutsk State Univ, Inst Appl Phys, 20 Gagarin Blvd, Irkutsk 664003, Russia.
   [Buckley, D. A. H.] South African Astron Observ, POB 9, ZA-7935 Cape Town, South Africa.
   [Horesh, A.] Hebrew Univ Jerusalem, Racah Inst Phys, IL-91904 Jerusalem, Israel.
   [Panasyuk, M. I.] Moscow MV Lomonosov State Univ, Skobeltsyn Inst Nucl Phys Lomonosov, Moscow 119991, Russia.
   [Prochaska, J. X.; Ramirez-Ruiz, E.] Univ Calif Observ, 1156 High St, Santa Cruz, CA 95064 USA.
   [Rebolo Lopez, R.; Serra-Ricart, M.] Inst Astrofis Canarias, Via Lactea S-N, E-38205 Tenerife, Spain.
   [Richer, M. G.; Roman-Zuniga, C.] Univ Nacl Autonoma Mexico, Inst Astron, Apartado Postal 106, Ensenada 22800, Baja California, Mexico.
   [Yurkov, V.] Blagoveshchensk State Pedag Univ, Lenin St 104, Blagoveshchensk 675000, Amur Region, Russia.
C3 University System of Maryland; University of Maryland College Park; National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center; Lomonosov Moscow State University; Lomonosov Moscow State University; University of Bath; Arizona State University; Arizona State University-Tempe; Universidad Nacional Autonoma de Mexico; Liverpool John Moores University; Istituto Nazionale Astrofisica (INAF); Space Telescope Science Institute; Commonwealth Scientific & Industrial Research Organisation (CSIRO); CSIRO Astronomy & Space; Irkutsk State University; Institute of Applied Physics of the Russian Academy of Sciences; National Research Foundation - South Africa; South African Astronomical Observatory; Hebrew University of Jerusalem; Lomonosov Moscow State University; University of California System; University of California Santa Cruz; Instituto de Astrofisica de Canarias; Universidad Nacional Autonoma de Mexico
RP Troja, E (corresponding author), Univ Maryland, Dept Astron, College Pk, MD 20742 USA.; Troja, E (corresponding author), NASA, Goddard Space Flight Ctr, 8800 Greenbelt Rd, Greenbelt, MD 20771 USA.
EM eleonora.troja@nasa.gov
FU NASA [NNX09AH71G, NNX09AT02G, NNX10AI27G, NNX12AE66G]; CONACyT [INFR-2009-01-122785, CB-2008-101958]; UNAM PAPIIT [IN113810]; UC MEXUS-CONACyT grant [CN 09-283]; Development Program of Lomonosov Moscow State University; Moscow Union OPTICA; Russian Science Foundation [16-12-00085]; NASA Fermi grants [NNH14ZDA001N, NNH15ZDA001N]; UK Space Agency; Russian Science Foundation [16-12-00085] Funding Source: Russian Science Foundation
NR 53
TC 111
Z9 116
U1 0
U2 23
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 27
PY 2017
VL 547
IS 7664
BP 425
EP +
DI 10.1038/nature23289
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB7ZK
UT WOS:000406358300029
PM 28748924
DA 2026-03-09
ER

PT J
AU Jarvis, DE
   Ho, YS
   Lightfoot, DJ
   Schmöckel, SM
   Li, B
   Borm, TJA
   Ohyanagi, H
   Mineta, K
   Michell, CT
   Saber, N
   Kharbatia, NM
   Rupper, RR
   Sharp, AR
   Dally, N
   Boughton, BA
   Woo, YH
   Gao, G
   Schijlen, EGWM
   Guo, XJ
   Momin, AA
   Negrao, S
   Al-Babili, S
   Gehring, C
   Roessner, U
   Jung, C
   Murphy, K
   Arold, ST
   Gojobori, T
   van der Linden, CG
   van Loo, EN
   Jellen, EN
   Maughan, PJ
   Tester, M
AF Jarvis, David E.
   Ho, Yung Shwen
   Lightfoot, Damien J.
   Schmockel, Sandra M.
   Li, Bo
   Borm, Theo J. A.
   Ohyanagi, Hajime
   Mineta, Katsuhiko
   Michell, Craig T.
   Saber, Noha
   Kharbatia, Najeh M.
   Rupper, Ryan R.
   Sharp, Aaron R.
   Dally, Nadine
   Boughton, Berin A.
   Woo, Yong H.
   Gao, Ge
   Schijlen, Elio G. W. M.
   Guo, Xiujie
   Momin, Afaque A.
   Negrao, Sonia
   Al-Babili, Salim
   Gehring, Christoph
   Roessner, Ute
   Jung, Christian
   Murphy, Kevin
   Arold, Stefan T.
   Gojobori, Takashi
   van der Linden, C. Gerard
   van Loo, Eibertus N.
   Jellen, Eric N.
   Maughan, Peter J.
   Tester, Mark
TI The genome of Chenopodium quinoa
SO NATURE
LA English
DT Article
ID flowering-locus-t; evolutionary analysis; read alignment; ft homologs; sequence; willd.; annotation; rna; quantification; identification
AB Chenopodium quinoa (quinoa) is a highly nutritious grain identified as an important crop to improve world food security. Unfortunately, few resources are available to facilitate its genetic improvement. Here we report the assembly of a high-quality, chromosome-scale reference genome sequence for quinoa, which was produced using single-molecule real-time sequencing in combination with optical, chromosome-contact and genetic maps. We also report the sequencing of two diploids from the ancestral gene pools of quinoa, which enables the identification of sub-genomes in quinoa, and reduced-coverage genome sequences for 22 other samples of the allotetraploid goosefoot complex. The genome sequence facilitated the identification of the transcription factor likely to control the production of anti-nutritional triterpenoid saponins found in quinoa seeds, including a mutation that appears to cause alternative splicing and a premature stop codon in sweet quinoa strains. These genomic resources are an important first step towards the genetic improvement of quinoa.
C1 [Jarvis, David E.; Ho, Yung Shwen; Lightfoot, Damien J.; Schmockel, Sandra M.; Li, Bo; Saber, Noha; Woo, Yong H.; Gao, Ge; Guo, Xiujie; Negrao, Sonia; Gehring, Christoph; Tester, Mark] KAUST, Biol & Environm Sci & Engn Div BESE, Thuwal 239556900, Saudi Arabia.
   [Borm, Theo J. A.; van der Linden, C. Gerard; van Loo, Eibertus N.] Wageningen Univ & Res, Wageningen UR Plant Breeding, Wageningen, Netherlands.
   [Ohyanagi, Hajime; Momin, Afaque A.; Arold, Stefan T.; Gojobori, Takashi] KAUST, CBRC, Biol & Environm Sci & Engn Div BESE, Thuwal 239556900, Saudi Arabia.
   [Mineta, Katsuhiko] KAUST, CBRC, Comp Elect & Math Sci & Engn Div CEMSE, Thuwal 239556900, Saudi Arabia.
   [Michell, Craig T.] KAUST, RSRC, Biol & Environm Sci & Engn Div BESE, Thuwal 239556900, Saudi Arabia.
   [Kharbatia, Najeh M.] KAUST, Analyt Core Lab, Thuwal 239556900, Saudi Arabia.
   [Rupper, Ryan R.; Sharp, Aaron R.; Jellen, Eric N.; Maughan, Peter J.] Brigham Young Univ, Dept Plant & Wildlife Sci, Coll Life Sci, Provo, UT 84602 USA.
   [Dally, Nadine; Jung, Christian] Christian Albrechts Univ Kiel, Plant Breeding Inst, Olshausenstr 40, D-24118 Kiel, Germany.
   [Boughton, Berin A.; Roessner, Ute] Univ Melbourne, Metabol Australia, Sch Biosci, Parkville, Vic 3010, Australia.
   [Schijlen, Elio G. W. M.] Wageningen UR, Plant Res Int, PRI Biosci, Wageningen, Netherlands.
   [Murphy, Kevin] Washington State Univ, Dept Crop & Soil Sci, Coll Agr Human & Nat Resource Sci, Pullman, WA 99164 USA.
C3 King Abdullah University of Science & Technology; Wageningen University & Research; King Abdullah University of Science & Technology; King Abdullah University of Science & Technology; King Abdullah University of Science & Technology; King Abdullah University of Science & Technology; Brigham Young University; University of Kiel; University of Melbourne; Wageningen University & Research; Washington State University
RP Tester, M (corresponding author), KAUST, Biol & Environm Sci & Engn Div BESE, Thuwal 239556900, Saudi Arabia.
EM mark.tester@kaust.edu.sa
FU King Abdullah University of Science and Technology (KAUST); USDA/NIFA-REEIS [2012-51300-20100]; NSF [1339412]; German Research Foundation, DFG [JU205/24-1]; NIFA [2012-51300-20100, 578144] Funding Source: Federal RePORTER; Direct For Biological Sciences; Division Of Integrative Organismal Systems [1339412] Funding Source: National Science Foundation
NR 79
TC 536
Z9 649
U1 13
U2 227
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 16
PY 2017
VL 542
IS 7641
BP 307
EP +
DI 10.1038/nature21370
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2LQ
UT WOS:000394451600028
PM 28178233
DA 2026-03-09
ER

PT J
AU Li, MH
   Zhou, XY
   Wang, S
   Michailidis, I
   Gong, Y
   Su, DY
   Li, H
   Li, XM
   Yang, J
AF Li, Minghui
   Zhou, Xiaoyuan
   Wang, Shu
   Michailidis, Ioannis
   Gong, Ye
   Su, Deyuan
   Li, Huan
   Li, Xueming
   Yang, Jian
TI Structure of a eukaryotic cyclic-nucleotide-gated channel
SO NATURE
LA English
DT Article
ID crystal-structure; c-linker; functional expression; ligand-binding; ion permeation; ca2+ blockage; hcn channels; k+ channel; pore; selectivity
AB Cyclic-nucleotide-gated channels are essential for vision and olfaction. They belong to the voltage-gated ion channel superfamily but their activities are controlled by intracellular cyclic nucleotides instead of transmembrane voltage. Here we report a 3.5-angstrom-resolution single-particle electron cryo-microscopy structure of a cyclic-nucleotide-gated channel from Caenorhabditis elegans in the cyclic guanosine monophosphate (cGMP)-bound open state. The channel has an unusual voltage-sensor-like domain, accounting for its deficient voltage dependence. A carboxy-terminal linker connecting S6 and the cyclic-nucleotide-binding domain interacts directly with both the voltage-sensor-like domain and the pore domain, forming a gating ring that couples conformational changes triggered by cyclic nucleotide binding to the gate. The selectivity filter is lined by the carboxylate side chains of a functionally important glutamate and three rings of backbone carbonyls. This structure provides a new framework for understanding mechanisms of ion permeation, gating and channelopathy of cyclic-nucleotide-gated channels and cyclic nucleotide modulation of related channels.
C1 [Li, Minghui; Michailidis, Ioannis; Yang, Jian] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA.
   [Zhou, Xiaoyuan; Li, Xueming] Tsinghua Univ, Tsinghua Peking Joint Ctr Life Sci, Sch Life Sci, Beijing Adv Innovat Ctr Struct Biol, Beijing 100084, Peoples R China.
   [Wang, Shu; Gong, Ye; Su, Deyuan; Li, Huan; Yang, Jian] Chinese Acad Sci, Key Lab Anim Models & Human Dis Mech, Kunming 650223, Peoples R China.
   [Wang, Shu; Gong, Ye; Su, Deyuan; Li, Huan; Yang, Jian] Chinese Acad Sci, Key Lab Bioact Peptides Yunnan Prov, Kunming 650223, Peoples R China.
   [Wang, Shu; Gong, Ye; Su, Deyuan; Li, Huan; Yang, Jian] Chinese Acad Sci, Kunming Inst Zool, Ion Channel Res & Drug Dev Ctr, Kunming 650223, Peoples R China.
   [Wang, Shu; Su, Deyuan; Li, Huan] Univ Chinese Acad Sci, Kunming Coll Life Sci, Kunming 650204, Peoples R China.
C3 Columbia University; Tsinghua University; Chinese Academy of Sciences; Chinese Academy of Sciences; Chinese Academy of Sciences; Kunming Institute of Zoology, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS
RP Yang, J (corresponding author), Columbia Univ, Dept Biol Sci, New York, NY 10027 USA.; Li, XM (corresponding author), Tsinghua Univ, Tsinghua Peking Joint Ctr Life Sci, Sch Life Sci, Beijing Adv Innovat Ctr Struct Biol, Beijing 100084, Peoples R China.; Yang, J (corresponding author), Chinese Acad Sci, Key Lab Anim Models & Human Dis Mech, Kunming 650223, Peoples R China.; Yang, J (corresponding author), Chinese Acad Sci, Key Lab Bioact Peptides Yunnan Prov, Kunming 650223, Peoples R China.; Yang, J (corresponding author), Chinese Acad Sci, Kunming Inst Zool, Ion Channel Res & Drug Dev Ctr, Kunming 650223, Peoples R China.
EM lixueming@mail.tsinghua.edu.cn; jy160@columbia.edu
FU National Key Basic Research Program of China [2014CB910301]; National Institutes of Health [R01GM085234, RO1NS053494]; National Natural Science Foundation of China [31370821, 31570730, 81302865]; Top Talents Program of Yunnan Province [2011HA012]; High-level Overseas Talents of Yunnan Province; China Youth 1000-Talent Program of the State Council of China; Beijing Advanced Innovation Center for Structural Biology; Tsinghua-Peking Joint Center for Life Sciences; Key Research Program of the Chinese Academy of Sciences [KJZD-EW-L03]; West Light Foundation of the Chinese Academy of Sciences; Yunnan Applied Basic Research Projects [2013FB074]; Youth Innovation Promotion Association of the Chinese Academy of Sciences; National Institute of General Medical Sciences [R01GM085234] Funding Source: NIH RePORTER
NR 57
TC 125
Z9 144
U1 2
U2 47
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 2
PY 2017
VL 542
IS 7639
BP 60
EP 65
DI 10.1038/nature20819
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EZ5FE
UT WOS:000404737700001
PM 28099415
DA 2026-03-09
ER

PT J
AU Wahl, S
   Drong, A
   Lehne, B
   Loh, M
   Scott, WR
   Kunze, S
   Tsai, PC
   Ried, JS
   Zhang, WH
   Yang, YW
   Tan, SL
   Fiorito, G
   Franke, L
   Guarrera, S
   Kasela, S
   Kriebel, J
   Richmond, RC
   Adamo, M
   Afzal, U
   Ala-Korpela, M
   Albetti, B
   Ammerpohl, O
   Apperley, JF
   Beekman, M
   Bertazzi, PA
   Black, SL
   Blancher, C
   Bonder, MJ
   Brosch, M
   Carstensen-Kirberg, M
   de Craen, AJM
   de Lusignan, S
   Dehghan, A
   Elkalaawy, M
   Fischer, K
   Franco, OH
   Gaunt, TR
   Hampe, J
   Hashemi, M
   Isaacs, A
   Jenkinson, A
   Jha, S
   Kato, N
   Krogh, V
   Laffan, M
   Meisinger, C
   Meitinger, T
   Mok, ZY
   Motta, V
   Ng, HK
   Nikolakopoulou, Z
   Nteliopoulos, G
   Panico, S
   Pervjakova, N
   Prokisch, H
   Rathmann, W
   Roden, M
   Rota, F
   Rozario, MA
   Sandling, JK
   Schafmayer, C
   Schramm, K
   Siebert, R
   Slagboom, PE
   Soininen, P
   Stolk, L
   Strauch, K
   Tai, ES
   Tarantini, L
   Thorand, B
   Tigchelaar, EF
   Tumino, R
   Uitterlinden, AG
   van Duijn, C
   van Meurs, JBJ
   Vineis, P
   Wickremasinghe, AR
   Wijmenga, C
   Yang, TP
   Yuan, W
   Zhernakova, A
   Batterham, RL
   Smith, GD
   Deloukas, P
   Heijmans, BT
   Herder, C
   Hofman, A
   Lindgren, CM
   Milani, L
   van der Harst, P
   Peters, A
   Illig, T
   Relton, CL
   Waldenberger, M
   Järvelin, MR
   Bollati, V
   Soong, R
   Spector, TD
   Scott, J
   McCarthy, MI
   Elliott, P
   Bell, JT
   Matullo, G
   Gieger, C
   Kooner, JS
   Grallert, H
   Chambers, JC
AF Wahl, Simone
   Drong, Alexander
   Lehne, Benjamin
   Loh, Marie
   Scott, William R.
   Kunze, Sonja
   Tsai, Pei-Chien
   Ried, Janina S.
   Zhang, Weihua
   Yang, Youwen
   Tan, Sili
   Fiorito, Giovanni
   Franke, Lude
   Guarrera, Simonetta
   Kasela, Silva
   Kriebel, Jennifer
   Richmond, Rebecca C.
   Adamo, Marco
   Afzal, Uzma
   Ala-Korpela, Mika
   Albetti, Benedetta
   Ammerpohl, Ole
   Apperley, Jane F.
   Beekman, Marian
   Bertazzi, Pier Alberto
   Black, S. Lucas
   Blancher, Christine
   Bonder, Marc-Jan
   Brosch, Mario
   Carstensen-Kirberg, Maren
   de Craen, Anton J. M.
   de Lusignan, Simon
   Dehghan, Abbas
   Elkalaawy, Mohamed
   Fischer, Krista
   Franco, Oscar H.
   Gaunt, Tom R.
   Hampe, Jochen
   Hashemi, Majid
   Isaacs, Aaron
   Jenkinson, Andrew
   Jha, Sujeet
   Kato, Norihiro
   Krogh, Vittorio
   Laffan, Michael
   Meisinger, Christa
   Meitinger, Thomas
   Mok, Zuan Yu
   Motta, Valeria
   Ng, Hong Kiat
   Nikolakopoulou, Zacharoula
   Nteliopoulos, Georgios
   Panico, Salvatore
   Pervjakova, Natalia
   Prokisch, Holger
   Rathmann, Wolfgang
   Roden, Michael
   Rota, Federica
   Rozario, Michelle Ann
   Sandling, Johanna K.
   Schafmayer, Clemens
   Schramm, Katharina
   Siebert, Reiner
   Slagboom, P. Eline
   Soininen, Pasi
   Stolk, Lisette
   Strauch, Konstantin
   Tai, E-Shyong
   Tarantini, Letizia
   Thorand, Barbara
   Tigchelaar, Ettje F.
   Tumino, Rosario
   Uitterlinden, Andre G.
   van Duijn, Cornelia
   van Meurs, Joyce B. J.
   Vineis, Paolo
   Wickremasinghe, Ananda Rajitha
   Wijmenga, Cisca
   Yang, Tsun-Po
   Yuan, Wei
   Zhernakova, Alexandra
   Batterham, Rachel L.
   Smith, George Davey
   Deloukas, Panos
   Heijmans, Bastiaan T.
   Herder, Christian
   Hofman, Albert
   Lindgren, Cecilia M.
   Milani, Lili
   van der Harst, Pim
   Peters, Annette
   Illig, Thomas
   Relton, Caroline L.
   Waldenberger, Melanie
   Jaervelin, Marjo-Riitta
   Bollati, Valentina
   Soong, Richie
   Spector, Tim D.
   Scott, James
   McCarthy, Mark I.
   Elliott, Paul
   Bell, Jordana T.
   Matullo, Giuseppe
   Gieger, Christian
   Kooner, Jaspal S.
   Grallert, Harald
   Chambers, John C.
TI Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity
SO NATURE
LA English
DT Article
ID dna methylation; mendelian randomization; obesity; disease; glucose; health; trends; tissue; blood
AB Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type (2) diabetes, cardiovascular disease and related metabolic and inflammatory disturbances(1,2). Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation(3-6), a key regulator of gene expression and molecular phenotype(7). Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 x 10(-7), range P = 9.2 x 10(-8) to 6.0 x 10(-46); n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 x 10(-6), range P = 5.5 x 10(-6) to 6.1 x 10(-35), n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 x 10(-54)). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.
C1 [Wahl, Simone; Kunze, Sonja; Kriebel, Jennifer; Illig, Thomas; Waldenberger, Melanie; Gieger, Christian; Grallert, Harald] Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.
   [Wahl, Simone; Kunze, Sonja; Kriebel, Jennifer; Meisinger, Christa; Thorand, Barbara; Waldenberger, Melanie; Gieger, Christian; Grallert, Harald] Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany.
   [Wahl, Simone; Kriebel, Jennifer; Roden, Michael; Thorand, Barbara; Herder, Christian; Peters, Annette; Grallert, Harald] German Ctr Diabet Res DZD, Neuherberg, Germany.
   [Drong, Alexander] Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England.
   [Lehne, Benjamin; Loh, Marie; Scott, William R.; Zhang, Weihua; Yang, Youwen; Afzal, Uzma; Elliott, Paul; Kooner, Jaspal S.; Chambers, John C.] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.
   [Loh, Marie] Inst Hlth Sci, POB 5000, FI-90014 Oulu, Finland.
   [Loh, Marie] Translat Lab Genet Med TLGM, Agcy Sci, Technol & Res ASTAR, 8A Biomed Grove, Singapore 138648, Singapore.
   [Scott, William R.; Zhang, Weihua; Afzal, Uzma; Scott, James; Kooner, Jaspal S.; Grallert, Harald; Chambers, John C.] Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England.
   [Tsai, Pei-Chien; Yuan, Wei; Spector, Tim D.; Bell, Jordana T.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England.
   [Ried, Janina S.; Strauch, Konstantin] German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.
   [Zhang, Weihua; Afzal, Uzma; Kooner, Jaspal S.; Chambers, John C.] Ealing Hosp NHS Trust, Middlesex UB1 3HW, England.
   [Mok, Zuan Yu; Ng, Hong Kiat; Soong, Richie] Natl Univ Singapore, Cancer Sci Inst Singapore, Singapore, Singapore.
   [Fiorito, Giovanni; Guarrera, Simonetta; Matullo, Giuseppe] Human Genet Fdn Torino, Turin, Italy.
   [Fiorito, Giovanni; Guarrera, Simonetta; Matullo, Giuseppe] Univ Torino, Dept Med Sci, Turin, Italy.
   [Franke, Lude; Bonder, Marc-Jan; Tigchelaar, Ettje F.; Wijmenga, Cisca; Zhernakova, Alexandra] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.
   [Kasela, Silva; Fischer, Krista; Pervjakova, Natalia; Milani, Lili] Univ Tartu, Estonian Genome Ctr, Riia 23b, EE-51010 Tartu, Estonia.
   [Kasela, Silva; Pervjakova, Natalia] Univ Tartu, Inst Mol & Cell Biol, Dept Biotechnol, Riia 23, EE-51010 Tartu, Estonia.
   [Richmond, Rebecca C.; Gaunt, Tom R.; Smith, George Davey; Relton, Caroline L.] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England.
   [Adamo, Marco; Elkalaawy, Mohamed; Hashemi, Majid; Jenkinson, Andrew; Batterham, Rachel L.] Univ Coll London Hosp, UCLH Bariatr Ctr Weight Loss, Weight Management & Metab & Endocrine Surg, Ground Floor West Wing,250 Euston Rd, London NW1 2PG, England.
   [Ala-Korpela, Mika; Soininen, Pasi] Univ Oulu & Bioctr Oulu, Computat Med, Fac Med, Oulu, Finland.
   [Ala-Korpela, Mika; Soininen, Pasi] Univ Eastern Finland, Sch Pharm, NMR Metabol Lab, Kuopio, Finland.
   [Ala-Korpela, Mika] Univ Bristol & Med Res Council Integrat Epidemiol, Univ Bristol, Sch Social & Community Med, Computat Med, Bristol, Avon, England.
   [Albetti, Benedetta; Bertazzi, Pier Alberto; Motta, Valeria; Rota, Federica; Tarantini, Letizia; Bollati, Valentina] Univ Studi Milano & Fondazione IRCCS CaGranda Osp, Dept Clin Sci & Community Hlth, EPIGET Lab, Milan, Italy.
   [Ammerpohl, Ole; Siebert, Reiner] Univ Hosp Schleswig Holstein, Inst Human Genet, Kiel Campus, Kiel, Germany.
   [Apperley, Jane F.; Laffan, Michael; Nteliopoulos, Georgios] Imperial Coll London, Dept Med, Ctr Haematol, Fac Med, Hammersmith Campus, London W12 0NN, England.
   [Beekman, Marian; Slagboom, P. Eline] Leiden Univ Med Ctr, Mol Epidemiol, NL-2333 ZC Leiden, Netherlands.
   [Black, S. Lucas] Imperial Coll London, Dept Med, Sect Infect Dis & Immun, London W12 0NN, England.
   [Brosch, Mario; Hampe, Jochen] Univ Oxford, High Throughput Genom Oxford Genom Ctr, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.
   [Brosch, Mario] Tech Univ Dresden, Univ Hosp, Med Dept 1, Dresden, Germany.
   [Carstensen-Kirberg, Maren; Roden, Michael; Herder, Christian] Heinrich Heine Univ Dusseldorf, German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Clin Diabetol, Dusseldorf, Germany.
   [de Craen, Anton J. M.] Leiden Univ Med Ctr, Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands.
   [de Lusignan, Simon] Univ Surrey, Dept Clin & Expt Med, Guildford GU2 7PX, Surrey, England.
   [Dehghan, Abbas; Franco, Oscar H.; Isaacs, Aaron; van Duijn, Cornelia; Hofman, Albert] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
   [Wahl, Simone; Elkalaawy, Mohamed] Univ Alexandria, Med Res Inst, Clin & Expt Surg Dept, Hadara, Alexandria 21561, Egypt.
   [Jha, Sujeet] Dept Endocrinol, Diabet & Obes, Max Healthcare, New Delhi 110017, India.
   [Kato, Norihiro] Res Inst, Natl Ctr Global Hlth & Med, Dept Gene Diagnost & Therapeut, Tokyo 1628655, Japan.
   [Krogh, Vittorio] Epidemiol & Prevent Unit, Fondazione IRCSS Ist Nazl Tumori, Milan, Italy.
   [Meitinger, Thomas] German Res Ctr Environm Hlth, Int Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany.
   [Meitinger, Thomas; Prokisch, Holger; Schramm, Katharina] Tech Univ Munich, Inst Human Genet, Munich, Germany.
   [Meitinger, Thomas; Motta, Valeria; Peters, Annette] Partner site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany.
   [Nikolakopoulou, Zacharoula] Natl Heart & Lung Inst, London SW3 6LY, England.
   [Panico, Salvatore] Dipartmento Med Clin Chirurgia Federio II Univ, Naples, Italy.
   [Rathmann, Wolfgang] Heinrich Heine Univ Dusseldorf, German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Biometr & Epidemiol, Dusseldorf, Germany.
   [Roden, Michael] Heinrich Heine Univ Hosp Dusseldorf, Fac Med, Dept Endocrinol & Diabetol, Dusseldorf, Germany.
   [Sandling, Johanna K.] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England.
   [Sandling, Johanna K.] Uppsala Univ, Mol Med & Sci Life Lab, Dept Med Sci, S-75144 Uppsala, Sweden.
   [Schafmayer, Clemens] Univ Hosp Schleswig Holstein, Dept Visceral & Thorac Surg, Kiel Campus, Kiel, Germany.
   [Siebert, Reiner] Univ Hosp Ulm, Inst Human Genet, Albert Einstein Allee 11, D-89081 Ulm, Germany.
   [Stolk, Lisette; van Meurs, Joyce B. J.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands.
   [Strauch, Konstantin] Ludwig Maximilians Univ Munchen, Inst Med Informat, Biometry & Epidemiol, Chair Genet Epidemiol, Munich, Germany.
   [Tai, E-Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 119228, Singapore.
   [Tai, E-Shyong] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore.
   [Tai, E-Shyong] Duke Natl Univ, Singapore Grad Med Sch, Singapore 169857, Singapore.
   [Tumino, Rosario] Cancer Registry & Histopathol Unit, Civile MP Arezzo Hosp, ASP 7, Ragusa, Italy.
   [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med & Epidemiol, Rotterdam, Netherlands.
   [Vineis, Paolo] Imperial Coll London, Epidemiol & Publ Hlth, London, England.
   [Wickremasinghe, Ananda Rajitha] Univ Kelaniya, Dept Publ Hlth, Fac Med, Box 6,Thalagolla Rd, Ragama 11010, Sri Lanka.
   [Yuan, Wei] Inst Canc Res, Surrey SM2 5NG, England.
   [Batterham, Rachel L.] UCL, Rayne Inst, Dept Med, Ctr Obes Res, London WC1E 6JJ, England.
   [Deloukas, Panos] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London EC1M 6BQ, England.
   [Deloukas, Panos] King Abdulaziz Univ, Princess Jawhara Brahim Ctr Excellence Res Heredi, Jeddah 21589, Saudi Arabia.
   [Lindgren, Cecilia M.] Broad Inst, Massachusetts Inst Technol & Harvard Univ, Cambridge, MA 02142 USA.
   [van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands.
   [van der Harst, Pim] ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, NL-3511 GC Utrecht, Netherlands.
   [Illig, Thomas] Hannover Med Sch, Hannover Unified Biobank, Feodor Lynen St 15, Hannover, Germany.
   [Illig, Thomas] Hannover Med Sch, Inst Human Genet, Carl Neuberg St 1, Hannover, Germany.
   [Jaervelin, Marjo-Riitta] Imperial Coll London, Sch Publ Hlth, MRC Hlth Protect Agcy HPE Ctr Environm & Hlth, Dept Epidemiol & Biostatist, London, England.
   [Jaervelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, POB 5000, Oulu, Finland.
   [Jaervelin, Marjo-Riitta] Univ Oulu, Ctr Life Course Epidemiol, Fac Med, POB 5000, Oulu 90014, Finland.
   [Jaervelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, Kajaanintie 50,Box 20, Oulu, Finland.
   [Soong, Richie] Natl Univ Singapore Hosp, Dept Pathol, Singapore, Singapore.
   [McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.
   [McCarthy, Mark I.] Oxford NIHR Biomed Res Ctr, Churchill Hosp, Oxford OX3 7LJ, England.
   [Kooner, Jaspal S.; Chambers, John C.] Imperial Coll Healthcare NHS Trust, London W12 0HS, England.
   [Chambers, John C.] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore.
C3 Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; German Center for Diabetes Research (DZD); University of Oxford; Wellcome Centre for Human Genetics; Imperial College London; Agency for Science Technology & Research (A*STAR); Imperial College London; University of London; King's College London; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; National University of Singapore; University of Turin; University of Groningen; University of Tartu; University of Tartu; University of Bristol; University of London; University College London; University College London Hospitals NHS Foundation Trust; University of Eastern Finland; University of Bristol; University of Kiel; Schleswig Holstein University Hospital; Imperial College London; Leiden University; Leiden University Medical Center (LUMC); Imperial College London; University of Oxford; Wellcome Centre for Human Genetics; Technische Universitat Dresden; Carl Gustav Carus University Hospital; Heinrich Heine University Dusseldorf; Leibniz Association; Deutsches Diabetes-Zentrum (DDZ); Leiden University; Leiden University Medical Center (LUMC); University of Surrey; Erasmus University Rotterdam; Erasmus MC; Egyptian Knowledge Bank (EKB); Alexandria University; Japan Institute for Health Security (JIHS); National Center for Global Health & Medicine - Japan; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Technical University of Munich; German Centre for Cardiovascular Research; Munich Heart Alliance; Imperial College London; Heinrich Heine University Dusseldorf; Leibniz Association; Deutsches Diabetes-Zentrum (DDZ); Heinrich Heine University Dusseldorf; Heinrich Heine University Dusseldorf Hospital; Wellcome Trust Sanger Institute; Uppsala University; University of Kiel; Schleswig Holstein University Hospital; Ulm University; Erasmus University Rotterdam; Erasmus MC; University of Munich; National University of Singapore; National University of Singapore; Civile M.P. Arezzo Hospital; Erasmus University Rotterdam; Erasmus MC; Imperial College London; University Kelaniya; University of London; Institute of Cancer Research - UK; University of London; King's College London; University College London; University of London; Queen Mary University London; King Abdulaziz University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Groningen; Hannover Medical School; Hannover Medical School; Imperial College London; University of Oulu; University of Oulu; University of Oulu; National University of Singapore; University of Oxford; University of Oxford; Imperial College London; Nanyang Technological University
RP Grallert, H (corresponding author), Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany.; Kooner, JS; Chambers, JC (corresponding author), Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.; Kooner, JS (corresponding author), Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England.
EM j.kooner@ic.ac.uk; harald.grallert@helmholtz-muenchen.de; john.chambers@ic.ac.uk
FU BBSRC [BB/I025263/1] Funding Source: UKRI; MRC [MC_UU_12013/1, MR/K002414/1, G0700931, MC_G0802523, MC_UU_12013/2, MR/N015355/1, MC_UU_12013/8, G0601966, MR/L01341X/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/I025263/1] Funding Source: researchfish; British Heart Foundation [RG/14/5/30893, PG/14/56/30976] Funding Source: researchfish; Medical Research Council [G0700931, MC_G0802523, MR/N015355/1, MC_UU_12013/8, G0601966, MR/K002414/1, MR/L01341X/1, MC_UU_12013/2, MC_UU_12013/1, G9815508, MC_PC_15018] Funding Source: researchfish; National Institute for Health Research [RP-2015-06-005, NF-SI-0611-10136, ACF-2009-18-005, NF-SI-0611-10275, NF-SI-0514-10027, NF-SI-0611-10099] Funding Source: researchfish; British Heart Foundation [RG/14/5/30893, PG/14/56/30976] Funding Source: Medline; Medical Research Council [MR/K002414/1, G0700931, MC_G0802523, MC_UU_12013/1, G0601966, MC_PC_15018, MC_UU_12013/8, MR/N015355/1, MC_UU_12013/2, G9815508] Funding Source: Medline; Wellcome Trust [084723] Funding Source: Medline; Department of Health [RP-PG-0407-10371, RP-2015-06-005] Funding Source: Medline
NR 30
TC 686
Z9 763
U1 4
U2 223
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 5
PY 2017
VL 541
IS 7635
BP 81
EP +
DI 10.1038/nature20784
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6NA
UT WOS:000396119500033
PM 28002404
DA 2026-03-09
ER

PT J
AU Pulido, A
   Chen, LJ
   Kaczorowski, T
   Holden, D
   Little, MA
   Chong, SY
   Slater, BJ
   McMahon, DP
   Bonillo, B
   Stackhouse, CJ
   Stephenson, A
   Kane, CM
   Clowes, R
   Hasell, T
   Cooper, AI
   Day, GM
AF Pulido, Angeles
   Chen, Linjiang
   Kaczorowski, Tomasz
   Holden, Daniel
   Little, Marc A.
   Chong, Samantha Y.
   Slater, Benjamin J.
   McMahon, David P.
   Bonillo, Baltasar
   Stackhouse, Chloe J.
   Stephenson, Andrew
   Kane, Christopher M.
   Clowes, Rob
   Hasell, Tom
   Cooper, Andrew I.
   Day, Graeme M.
TI Functional materials discovery using energy-structure-function maps
SO NATURE
LA English
DT Article
ID crystal-structure prediction; metal-organic frameworks; improved force-fields; methane storage; design; identification
AB Molecular crystals cannot be designed in the same manner as macroscopic objects, because they do not assemble according to simple, intuitive rules. Their structures result from the balance of many weak interactions, rather than from the strong and predictable bonding patterns found in metal-organic frameworks and covalent organic frameworks. Hence, design strategies that assume a topology or other structural blueprint will often fail. Here we combine computational crystal structure prediction and property prediction to build energy-structure-function maps that describe the possible structures and properties that are available to a candidate molecule. Using these maps, we identify a highly porous solid, which has the lowest density reported for a molecular crystal so far. Both the structure of the crystal and its physical properties, such as methane storage capacity and guest-molecule selectivity, are predicted using the molecular structure as the only input. More generally, energy-structure-function maps could be used to guide the experimental discovery of materials with any target function that can be calculated from predicted crystal structures, such as electronic structure or mechanical properties.
C1 [Pulido, Angeles; McMahon, David P.; Day, Graeme M.] Univ Southampton, Sch Chem, Computat Syst Chem, Southampton, Hants, England.
   [Chen, Linjiang; Kaczorowski, Tomasz; Holden, Daniel; Little, Marc A.; Chong, Samantha Y.; Slater, Benjamin J.; Bonillo, Baltasar; Stackhouse, Chloe J.; Stephenson, Andrew; Kane, Christopher M.; Clowes, Rob; Hasell, Tom; Cooper, Andrew I.] Univ Liverpool, Dept Chem, Liverpool, Merseyside, England.
C3 University of Southampton; University of Liverpool
RP Day, GM (corresponding author), Univ Southampton, Sch Chem, Computat Syst Chem, Southampton, Hants, England.
EM G.M.Day@soton.ac.uk
FU European Research Council under the European Union/ERC [321156, 307358]; EPSRC [EP/N004884/1, EP/K018396/1, EP/K018132/1, EP/K000225/1, EP/L000202, EP/N004884]; N8 consortium; Royal Society; US Department of Energy [DE-AC02-05CH11231]; Engineering and Physical Sciences Research Council [EP/K000225/1, EP/K018132/1, EP/N004884/1, EP/L000202/1, EP/K018396/1] Funding Source: researchfish; EPSRC [EP/K018396/1, EP/K018132/1, EP/K000225/1, EP/N004884/1, EP/L000202/1] Funding Source: UKRI
NR 48
TC 410
Z9 456
U1 13
U2 559
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 30
PY 2017
VL 543
IS 7647
BP 657
EP +
DI 10.1038/nature21419
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EP8IS
UT WOS:000397619700044
PM 28329756
DA 2026-03-09
ER

PT J
AU Gong, C
   Li, L
   Li, ZL
   Ji, HW
   Stern, A
   Xia, Y
   Cao, T
   Bao, W
   Wang, CZ
   Wang, YA
   Qiu, ZQ
   Cava, RJ
   Louie, SG
   Xia, J
   Zhang, X
AF Gong, Cheng
   Li, Lin
   Li, Zhenglu
   Ji, Huiwen
   Stern, Alex
   Xia, Yang
   Cao, Ting
   Bao, Wei
   Wang, Chenzhe
   Wang, Yuan
   Qiu, Z. Q.
   Cava, R. J.
   Louie, Steven G.
   Xia, Jing
   Zhang, Xiang
TI Discovery of intrinsic ferromagnetism in two-dimensional van der Waals crystals
SO NATURE
LA English
DT Article
ID ultrathin magnetic-films; point-defects; graphene
AB The realization of long-range ferromagnetic order in two-dimensional van der Waals crystals, combined with their rich electronic and optical properties, could lead to new magnetic, magnetoelectric and magneto-optic applications(1-4). In two-dimensional systems, the long-range magnetic order is strongly suppressed by thermal fluctuations, according to the Mermin-Wagner theorem(5); however, these thermal fluctuations can be counteracted by magnetic anisotropy. Previous efforts, based on defect and composition engineering(6-10), or the proximity effect, introduced magnetic responses only locally or extrinsically. Here we report intrinsic long-range ferromagnetic order in pristine Cr2Ge2Te6 atomic layers, as revealed by scanning magneto-optic Kerr microscopy. In this magnetically soft, two-dimensional van der Waals ferromagnet, we achieve unprecedented control of the transition temperature (between ferromagnetic and paramagnetic states) using very small fields (smaller than 0.3 tesla). This result is in contrast to the insensitivity of the transition temperature to magnetic fields in the three-dimensional regime. We found that the small applied field leads to an effective anisotropy that is much greater than the near-zero magnetocrystalline anisotropy, opening up a large spin-wave excitation gap. We explain the observed phenomenon using renormalized spin-wave theory and conclude that the unusual field dependence of the transition temperature is a hallmark of soft, two-dimensional ferromagnetic van der Waals crystals. Cr2Ge2Te6 is a nearly ideal two-dimensional Heisenberg ferromagnet and so will be useful for studying fundamental spin behaviours, opening the door to exploring new applications such as ultra-compact spintronics.
C1 [Gong, Cheng; Xia, Yang; Bao, Wei; Wang, Chenzhe; Wang, Yuan; Zhang, Xiang] Univ Calif Berkeley, NSEC, 3112 Etcheverry Hall, Berkeley, CA 94720 USA.
   [Li, Lin; Stern, Alex; Xia, Jing] Univ Calif Irvine, Dept Phys & Astron, Irvine, CA 92697 USA.
   [Li, Zhenglu; Cao, Ting; Qiu, Z. Q.; Louie, Steven G.] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Li, Zhenglu; Cao, Ting; Wang, Yuan; Louie, Steven G.; Zhang, Xiang] Lawrence Berkeley Natl Lab, Mat Sci Div, 1 Cyclotron Rd, Berkeley, CA 94720 USA.
   [Ji, Huiwen; Cava, R. J.] Princeton Univ, Dept Chem, Princeton, NJ 08540 USA.
C3 University of California System; University of California Berkeley; University of California System; University of California Irvine; University of California System; University of California Berkeley; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; Princeton University
RP Zhang, X (corresponding author), Univ Calif Berkeley, NSEC, 3112 Etcheverry Hall, Berkeley, CA 94720 USA.; Xia, J (corresponding author), Univ Calif Irvine, Dept Phys & Astron, Irvine, CA 92697 USA.; Louie, SG (corresponding author), Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.; Louie, SG; Zhang, X (corresponding author), Lawrence Berkeley Natl Lab, Mat Sci Div, 1 Cyclotron Rd, Berkeley, CA 94720 USA.
EM sglouie@berkeley.edu; xia.jing@uci.edu; xiang@berkeley.edu
FU US Department of Energy, Office of Science, Office of Basic Energy Sciences, Materials Sciences and Engineering Division [DE-AC02-05-CH11231]; US DOE; NSF MRSEC programme [NSF DMR-1420541]; NSF [DMR-1350122]; Direct For Mathematical & Physical Scien; Division Of Materials Research [1350122] Funding Source: National Science Foundation; Directorate For Engineering [1542741] Funding Source: National Science Foundation; Emerging Frontiers & Multidisciplinary Activities [1542741] Funding Source: National Science Foundation
NR 37
TC 4402
Z9 4859
U1 75
U2 2747
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 8
PY 2017
VL 546
IS 7657
BP 265
EP +
DI 10.1038/nature22060
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW9FY
UT WOS:000402823400032
PM 28445468
DA 2026-03-09
ER

PT J
AU Hazlett, HC
   Gu, HB
   Munsell, BC
   Kim, SH
   Styner, M
   Wolff, JJ
   Elison, JT
   Swanson, MR
   Zhu, HT
   Otteron, KNB
   Collins, DL
   Constantino, JN
   Dager, SR
   Estes, AM
   Evans, AC
   Fonov, VS
   Gerig, G
   Kostopoulos, P
   McKinstry, RC
   Pandey, J
   Paterson, S
   Pruett, JR
   Schultz, RT
   Shaw, DW
   Zwaigenbaum, L
   Piven, J
AF Hazlett, Heather Cody
   Gu, Hongbin
   Munsell, Brent C.
   Kim, Sun Hyung
   Styner, Martin
   Wolff, Jason J.
   Elison, Jed T.
   Swanson, Meghan R.
   Zhu, Hongtu
   Otteron, Kelly N. B.
   Collins, D. Louis
   Constantino, John N.
   Dager, Stephen R.
   Estes, Annette M.
   Evans, Alan C.
   Fonov, Vladimir S.
   Gerig, Guido
   Kostopoulos, Penelope
   McKinstry, Robert C.
   Pandey, Juhi
   Paterson, Sarah
   Pruett, John R., Jr.
   Schultz, Robert T.
   Shaw, Dennis W.
   Zwaigenbaum, Lonnie
   Piven, Joseph
TI Early brain development in infants at high risk for autism spectrum disorder
SO NATURE
LA English
DT Article
ID cortical surface-area; 16p11.2 deletion; cerebral-cortex; gray-matter; size; expansion; children; birth; abnormality; segmentation
AB Brain enlargement has been observed in children with autism spectrum disorder (ASD), but the timing of this phenomenon, and the relationship between ASD and the appearance of behavioural symptoms, are unknown. Retrospective head circumference and longitudinal brain volume studies of two-year olds followed up at four years of age have provided evidence that increased brain volume may emerge early in development(1,2). Studies of infants at high familial risk of autism can provide insight into the early development of autism and have shown that characteristic social deficits in ASD emerge during the latter part of the first and in the second year of life(3,4). These observations suggest that prospective brain-imaging studies of infants at high familial risk of ASD might identify early postnatal changes in brain volume that occur before an ASD diagnosis. In this prospective neuroimaging study of 106 infants at high familial risk of ASD and 42 low-risk infants, we show that hyperexpansion of the cortical surface area between 6 and 12 months of age precedes brain volume overgrowth observed between 12 and 24 months in 15 high-risk infants who were diagnosed with autism at 24 months. Brain volume overgrowth was linked to the emergence and severity of autistic social deficits. A deep-learning algorithm that primarily uses surface area information from magnetic resonance imaging of the brain of 6-12-month-old individuals predicted the diagnosis of autism in individual high-risk children at 24 months (with a positive predictive value of 81% and a sensitivity of 88%). These findings demonstrate that early brain changes occur during the period in which autistic behaviours are first emerging.
C1 [Hazlett, Heather Cody; Gu, Hongbin; Kim, Sun Hyung; Styner, Martin; Piven, Joseph] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA.
   [Hazlett, Heather Cody; Swanson, Meghan R.; Piven, Joseph] Carolina Inst Dev Disabil, Chapel Hill, NC 27599 USA.
   [Munsell, Brent C.] Coll Charleston, Charleston, SC 29424 USA.
   [Wolff, Jason J.] Univ Minnesota, Dept Educ Psychol, Minneapolis, MN 55455 USA.
   [Elison, Jed T.] Univ Minnesota, Inst Child Dev, Minneapolis, MN 55455 USA.
   [Zhu, Hongtu] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA.
   [Otteron, Kelly N. B.; Constantino, John N.; Pruett, John R., Jr.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA.
   [Dager, Stephen R.; Shaw, Dennis W.] Univ Washington, Dept Radiol, Seattle, WA 98105 USA.
   [Dager, Stephen R.; Estes, Annette M.; Shaw, Dennis W.] Univ Washington, Ctr Human Dev & Disabil, Seattle, WA 98105 USA.
   [Estes, Annette M.] Univ Washington, Dept Speech & Hearing Sci, Seattle, WA 98105 USA.
   [Collins, D. Louis; Evans, Alan C.; Fonov, Vladimir S.; Kostopoulos, Penelope] McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 0G4, Canada.
   [Gerig, Guido] NYU, Tandon Sch Engn, New York, NY 10003 USA.
   [McKinstry, Robert C.] Washington Univ, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA.
   [Pandey, Juhi; Schultz, Robert T.] Childrens Hosp Philadelphia, Ctr Autism Res, Philadelphia, PA 19104 USA.
   [Pandey, Juhi; Schultz, Robert T.] Univ Penn, Philadelphia, PA 19104 USA.
   [Paterson, Sarah] Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA.
   [Zwaigenbaum, Lonnie] Univ Alberta, Dept Pediat, Edmonton, AB T6G 2R3, Canada.
C3 University of North Carolina; University of North Carolina Chapel Hill; College of Charleston; University of Minnesota System; University of Minnesota Twin Cities; University of Minnesota System; University of Minnesota Twin Cities; University of North Carolina; University of North Carolina Chapel Hill; Washington University (WUSTL); University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; McGill University; New York University; New York University Tandon School of Engineering; Washington University (WUSTL); University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Commonwealth System of Higher Education (PCSHE); Temple University; University of Alberta
RP Hazlett, HC (corresponding author), Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA.; Hazlett, HC (corresponding author), Carolina Inst Dev Disabil, Chapel Hill, NC 27599 USA.
EM hcody@med.unc.edu
FU NIH [HD055741, 054 EB005149]; NIH Autism Center of Excellence grant (NIMH and NICHD) [HD055741]; Autism Speaks [6020]; Simons Foundation [140209]; National Alliance for Medical Image Computing (NA-MIC); IDDRC Imaging and Participant Registry cores (NICHD) [HD003110];  [R01 MH093510]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Deafness and Other Communication Disorders [R01HD055741] Funding Source: NIH RePORTER; National Institute of Environmental Health Sciences [P30ES010126] Funding Source: NIH RePORTER
NR 51
TC 772
Z9 956
U1 6
U2 432
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 16
PY 2017
VL 542
IS 7641
BP 348
EP +
DI 10.1038/nature21369
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2LQ
UT WOS:000394451600037
PM 28202961
DA 2026-03-09
ER

PT J
AU Ju, YS
   Martincorena, I
   Gerstung, M
   Petljak, M
   Alexandrov, LB
   Rahbari, R
   Wedge, DC
   Davies, HR
   Ramakrishna, M
   Fullam, A
   Martin, S
   Alder, C
   Patel, N
   Gamble, S
   O'Meara, S
   Giri, DD
   Sauer, T
   Pinder, SE
   Purdie, CA
   Borg, Å
   Stunnenberg, H
   van de Vijver, M
   Tan, BKT
   Caldas, C
   Tutt, A
   Ueno, NT
   van't Veer, LJ
   Martens, JWM
   Sotiriou, C
   Knappskog, S
   Span, PN
   Lakhani, SR
   Eyfjörd, JE
   Borresen-Dale, AL
   Richardson, A
   Thompson, AM
   Viari, A
   Hurles, ME
   Nik-Zainal, S
   Campbell, PJ
   Stratton, MR
AF Ju, Young Seok
   Martincorena, Inigo
   Gerstung, Moritz
   Petljak, Mia
   Alexandrov, Ludmil B.
   Rahbari, Raheleh
   Wedge, David C.
   Davies, Helen R.
   Ramakrishna, Manasa
   Fullam, Anthony
   Martin, Sancha
   Alder, Christopher
   Patel, Nikita
   Gamble, Steve
   O'Meara, Sarah
   Giri, Dilip D.
   Sauer, Torril
   Pinder, Sarah E.
   Purdie, Colin A.
   Borg, Ake
   Stunnenberg, Henk
   van de Vijver, Marc
   Tan, Benita K. T.
   Caldas, Carlos
   Tutt, Andrew
   Ueno, Naoto T.
   van't Veer, Laura J.
   Martens, John W. M.
   Sotiriou, Christos
   Knappskog, Stian
   Span, Paul N.
   Lakhani, Sunil R.
   Eyfjord, Jorunn Erla
   Borresen-Dale, Anne-Lise
   Richardson, Andrea
   Thompson, Alastair M.
   Viari, Alain
   Hurles, Matthew E.
   Nik-Zainal, Serena
   Campbell, Peter J.
   Stratton, Michael R.
TI Somatic mutations reveal asymmetric cellular dynamics in the early human embryo
SO NATURE
LA English
DT Article
ID whole-genome sequences; early mammalian embryo; clonal hematopoiesis; breast-cancer; normal-cells; number; age; blastocyst; mosaicism; landscape
AB Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects(1). Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes(2) and predispose carriers to cancer(3,4). They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues(5). Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos(6), our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures(7). We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2: 1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.
C1 [Ju, Young Seok; Martincorena, Inigo; Gerstung, Moritz; Petljak, Mia; Alexandrov, Ludmil B.; Wedge, David C.; Davies, Helen R.; Ramakrishna, Manasa; Fullam, Anthony; Martin, Sancha; Alder, Christopher; Patel, Nikita; Gamble, Steve; O'Meara, Sarah; Nik-Zainal, Serena; Campbell, Peter J.; Stratton, Michael R.] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England.
   [Ju, Young Seok] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon, South Korea.
   [Gerstung, Moritz] European Mol Biol Lab, European Bioinformat Inst, Hinxton CB10 1SD, England.
   [Alexandrov, Ludmil B.] Los Alamos Natl Lab, Theoret Biol & Biophys T6, Los Alamos, NM 87545 USA.
   [Rahbari, Raheleh; Hurles, Matthew E.] Wellcome Trust Sanger Inst, Genom Mutat & Genet Dis, Hinxton, England.
   [Wedge, David C.] Oxford Big Data Inst, Oxford, England.
   [Wedge, David C.] Wellcome Trust Ctr Human Genet, Oxford Ctr Canc Gene Res, Oxford, England.
   [Giri, Dilip D.] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA.
   [Sauer, Torril] Univ Oslo, Inst Clin Med, Campus Akershus Univ Hosp, Lorenskog, Norway.
   [Pinder, Sarah E.] Kings Coll London, Kings Hlth Partners Canc Biobank, Guys Hosp, Sch Med, London, England.
   [Purdie, Colin A.] Ninewells Hosp & Med Sch, Dept Pathol, Dundee, Scotland.
   [Borg, Ake] BioCare, Strateg Canc Res Program, Lund, Sweden.
   [Borg, Ake] CREATE Hlth, Strateg Ctr Translat Canc Res, Lund, Sweden.
   [Borg, Ake] Lund Univ, Ctr Canc, Dept Pathol & Oncol, Lund, Sweden.
   [Stunnenberg, Henk] Radboud Univ Nijmegen, Med Ctr, Nijmegen, Netherlands.
   [van de Vijver, Marc] Acad Med Ctr, Dept Pathol, Amsterdam, Netherlands.
   [Tan, Benita K. T.] Singapore Gen Hosp, SingHlth Duke NUS Breast Ctr, Div Surg Oncol, Natl Canc Ctr Singapore,Dept Gen Surg, Singapore, Singapore.
   [Caldas, Carlos] Univ Cambridge, Canc Res UK CRUK Cambridge Inst, Cambridge, England.
   [Tutt, Andrew] Kings Coll London, Breast Canc Now Res Unit, London SE1 9RT, England.
   [Tutt, Andrew] Inst Canc Res, Breast Canc Now Toby Robins Res Ctr, London SW3 6JB, England.
   [Ueno, Naoto T.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA.
   [van't Veer, Laura J.] Univ Calif San Francisco, Dept Lab Med, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA.
   [Martens, John W. M.] Erasmus Univ, Med Ctr, Erasmus MC Canc Inst, Dept Med Oncol, Rotterdam, Netherlands.
   [Sotiriou, Christos] Inst Jules Bordet, Brussels, Belgium.
   [Knappskog, Stian] Univ Bergen, Dept Clin Sci, Sect Oncol, Bergen, Norway.
   [Knappskog, Stian] Haukeland Hosp, Dept Oncol, Bergen, Norway.
   [Span, Paul N.] Radboud Univ Nijmegen, Med Ctr, Dept Radiat Oncol, Nijmegen, Netherlands.
   [Span, Paul N.] Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, Nijmegen, Netherlands.
   [Lakhani, Sunil R.] Univ Queensland, Sch Med, Brisbane, Qld, Australia.
   [Lakhani, Sunil R.] Royal Brisbane & Womens Hosp, Pathol Queensland, Brisbane, Qld, Australia.
   [Lakhani, Sunil R.] Univ Queensland, UQ Ctr Clin Res, Brisbane, Qld, Australia.
   [Eyfjord, Jorunn Erla] Univ Iceland, Canc Res Lab, Reykjavik, Iceland.
   [Borresen-Dale, Anne-Lise] Norwegian Radium Hosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway.
   [Borresen-Dale, Anne-Lise] Univ Oslo, Inst Clin Med, Fac Med, KG Jebsen Ctr Breast Canc Res, Oslo, Norway.
   [Richardson, Andrea] Johns Hopkins Med, Sibley Pathol Dept, Washington, DC 20016 USA.
   [Thompson, Alastair M.] Univ Texas MD Anderson Canc Ctr, Dept Breast Surg Oncol, Houston, TX 77030 USA.
   [Viari, Alain] Ctr Leon Berard, Plateforme Gilles Thomas, Synergie Lyon Canc, Lyon 08, France.
C3 Wellcome Trust Sanger Institute; Korea Advanced Institute of Science & Technology (KAIST); European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute; United States Department of Energy (DOE); Los Alamos National Laboratory; Wellcome Trust Sanger Institute; University of Oxford; Wellcome Centre for Human Genetics; Memorial Sloan Kettering Cancer Center; University of Oslo; Guy's & St Thomas' NHS Foundation Trust; University of London; King's College London; University of Dundee; Lund University; Radboud University Nijmegen; University of Amsterdam; Academic Medical Center Amsterdam; National Cancer Centre Singapore (NCCS); Singapore General Hospital; University of Cambridge; Cancer Research UK; CRUK Cambridge Institute; University of London; King's College London; University of London; Institute of Cancer Research - UK; Royal Marsden NHS Foundation Trust; University of Texas System; UTMD Anderson Cancer Center; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; Erasmus University Rotterdam; Erasmus MC; Erasmus MC Cancer Institute; Institut Jules Bordet; University of Bergen; University of Bergen; Haukeland University Hospital; Radboud University Nijmegen; Radboud University Nijmegen; University of Queensland; Royal Brisbane & Women's Hospital; University of Queensland; University of Iceland; University of Oslo; University of Oslo; Johns Hopkins University; Johns Hopkins Medicine; University of Texas System; UTMD Anderson Cancer Center; UNICANCER; Centre Leon Berard
RP Stratton, MR (corresponding author), Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England.
EM mrs@sanger.ac.uk
FU Wellcome Trust [077012/Z/05/Z]; EMBO long-term fellowship [LTF 1203_2012]; KAIST [G04150052]; Korea Health Technology R&D project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HI16C2387]; European Union (BASIS); Wellcome Trust; Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6]; Scottish Funding Council [HR03006]; Cancer Research UK [16942] Funding Source: researchfish; Cancer Research UK; Versus Arthritis [21777] Funding Source: researchfish; National Institute for Health Research [NF-SI-0611-10154, NF-SI-0515-10090] Funding Source: researchfish
NR 38
TC 211
Z9 236
U1 0
U2 46
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 30
PY 2017
VL 543
IS 7647
BP 714
EP +
DI 10.1038/nature21703
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EP8IS
UT WOS:000397619700055
PM 28329761
DA 2026-03-09
ER

PT J
AU Kilpinen, H
   Goncalves, A
   Leha, A
   Afzal, V
   Alasoo, K
   Ashford, S
   Bala, S
   Bensaddek, D
   Casale, FP
   Ulley, OJC
   Danecek, P
   Faulconbridge, A
   Harrison, PW
   Kathuria, A
   McCarthy, D
   McCarthy, SA
   Meleckyte, R
   Memari, Y
   Moens, N
   Soares, F
   Mann, A
   Streeter, I
   Agu, CA
   Alderton, A
   Nelson, R
   Harper, S
   Patel, M
   White, A
   Patel, SR
   Clarke, L
   Halai, R
   Kirton, CM
   Kolb-Kokocinski, A
   Beales, P
   Birney, E
   Danovi, D
   Lamond, AI
   Ouwehand, WH
   Vallier, L
   Watt, FM
   Durbin, R
   Stegle, O
   Gaffney, DJ
AF Kilpinen, Helena
   Goncalves, Angela
   Leha, Andreas
   Afzal, Vackar
   Alasoo, Kaur
   Ashford, Sofie
   Bala, Sendu
   Bensaddek, Dalila
   Casale, Francesco Paolo
   Ulley, Oliver J. C.
   Danecek, Petr
   Faulconbridge, Adam
   Harrison, Peter W.
   Kathuria, Annie
   McCarthy, Davis
   McCarthy, Shane A.
   Meleckyte, Ruta
   Memari, Yasin
   Moens, Nathalie
   Soares, Filipa
   Mann, Alice
   Streeter, Ian
   Agu, Chukwuma A.
   Alderton, Alex
   Nelson, Rachel
   Harper, Sarah
   Patel, Minal
   White, Alistair
   Patel, Sharad R.
   Clarke, Laura
   Halai, Reena
   Kirton, Christopher M.
   Kolb-Kokocinski, Anja
   Beales, Philip
   Birney, Ewan
   Danovi, Davide
   Lamond, Angus I.
   Ouwehand, Willem H.
   Vallier, Ludovic
   Watt, Fiona M.
   Durbin, Richard
   Stegle, Oliver
   Gaffney, Daniel J.
TI Common genetic variation drives molecular heterogeneity in human iPSCs
SO NATURE
LA English
DT Article
ID genome-wide association; pluripotent stem-cells; susceptibility loci; copy number; breast-cancer; dna methylation; multiple common; risk loci; identification; expression
AB Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.
C1 [Kilpinen, Helena; Casale, Francesco Paolo; Faulconbridge, Adam; Harrison, Peter W.; McCarthy, Davis; Streeter, Ian; Clarke, Laura; Birney, Ewan; Stegle, Oliver] European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England.
   [Goncalves, Angela; Leha, Andreas; Alasoo, Kaur; Bala, Sendu; Danecek, Petr; McCarthy, Shane A.; Memari, Yasin; Mann, Alice; Agu, Chukwuma A.; Alderton, Alex; Nelson, Rachel; Harper, Sarah; Patel, Minal; White, Alistair; Patel, Sharad R.; Halai, Reena; Kirton, Christopher M.; Kolb-Kokocinski, Anja; Ouwehand, Willem H.; Vallier, Ludovic; Durbin, Richard; Gaffney, Daniel J.] Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England.
   [Afzal, Vackar; Bensaddek, Dalila] Univ Dundee, Sch Life Sci, Ctr Gene Regulat & Express, Dundee, Scotland.
   [Ashford, Sofie; Ouwehand, Willem H.] Univ Cambridge, Dept Haematol, Cambridge Biomed Campus, Cambridge CB2 0XY, England.
   [Kathuria, Annie; Meleckyte, Ruta; Moens, Nathalie; Danovi, Davide; Watt, Fiona M.] Kings Coll London, Guys Hosp, Ctr Stem Cells & Regenerat Med, Tower Wing, London SE1 9RT, England.
   [McCarthy, Davis] St Vincents Inst Med Res, 41 Victoria Parade, Fitzroy, Vic 3065, Australia.
   [Soares, Filipa; Vallier, Ludovic] Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0SZ, England.
   [Soares, Filipa; Vallier, Ludovic] Univ Cambridge, Biomed Res Ctr, Anne McLaren Lab, Dept Surg, Cambridge CB2 0SZ, England.
   [Kilpinen, Helena; Beales, Philip] UCL, Inst Child Hlth, UCL Great Ormond St, London WC1N 1EH, England.
   [Ouwehand, Willem H.] NHS Blood & Transplant, Cambridge Biomed Campus, Cambridge CB2 0PT, England.
   [Leha, Andreas] Univ Med Ctr Groningen, Dept Med Stat, Humboldtallee 32, D-37073 Gottingen, Germany.
C3 European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute; Wellcome Trust Sanger Institute; University of Dundee; University of Cambridge; Guy's & St Thomas' NHS Foundation Trust; University of London; King's College London; St. Vincent's Institute of Medical Research; University of Cambridge; University of Cambridge; University of London; University College London; University of Gottingen; University of Gottingen Hospital
RP Stegle, O (corresponding author), European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England.; Durbin, R; Gaffney, DJ (corresponding author), Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England.; Watt, FM (corresponding author), Kings Coll London, Guys Hosp, Ctr Stem Cells & Regenerat Med, Tower Wing, London SE1 9RT, England.
EM fiona.watt@kcl.ac.uk; rd@sanger.ac.uk; stegle@ebi.ac.uk; dg13@sanger.ac.uk
FU Wellcome Trust [WT090851]; UK Medical Research Council [WT098503]; MRC eMedLab Medical Bioinformatics career development award from the UK Medical Research Council [MR/L016311/1]; Department of Health via the NIHR Biomedical Research Centre; Biotechnology and Biological Sciences Research Council [BB/M020991/1] Funding Source: researchfish; Engineering and Physical Sciences Research Council [TS/H001220/1] Funding Source: researchfish; Fight for Sight [1848/49] Funding Source: researchfish; Great Ormond Street Hospital Childrens Charity [V1296] Funding Source: researchfish; Medical Research Council [1365667, G0801843, MR/L016311/1, MC_PC_12026, MC_PC_12009] Funding Source: researchfish; National Institute for Health Research [NF-SI-0513-10008, NF-SI-0513-10151] Funding Source: researchfish; Wellcome Trust [105024/Z/14/Z] Funding Source: researchfish; BBSRC [BB/M020991/1] Funding Source: UKRI; EPSRC [TS/H001220/1] Funding Source: UKRI; MRC [MR/L016311/1, G0801843, MC_PC_12026] Funding Source: UKRI
NR 93
TC 411
Z9 489
U1 4
U2 122
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 15
PY 2017
VL 546
IS 7658
BP 370
EP +
DI 10.1038/nature22403
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EX5BK
UT WOS:000403250900027
PM 28489815
DA 2026-03-09
ER

PT J
AU Keckesova, Z
   Donaher, JL
   De Cock, J
   Freinkman, E
   Lingrell, S
   Bachovchin, DA
   Bierie, B
   Tischler, V
   Noske, A
   Okondo, MC
   Reinhardt, F
   Thiru, P
   Golub, TR
   Vance, JE
   Weinberg, RA
AF Keckesova, Zuzana
   Donaher, Joana Liu
   De Cock, Jasmine
   Freinkman, Elizaveta
   Lingrell, Susanne
   Bachovchin, Daniel A.
   Bierie, Brian
   Tischler, Verena
   Noske, Aurelia
   Okondo, Marian C.
   Reinhardt, Ferenc
   Thiru, Prathapan
   Golub, Todd R.
   Vance, Jean E.
   Weinberg, Robert A.
TI LACTB is a tumour suppressor that modulates lipid metabolism and cell state
SO NATURE
LA English
DT Article
ID hamster ovary cells; mutant mouse model; myogenic differentiation; phospholipase-d; lysophosphatidylethanolamine acyltransferase; phosphatidylserine biosynthesis; saccharomyces-cerevisiae; cancer-cells; protein; phosphatidylethanolamine
AB Post-mitotic, differentiated cells exhibit a variety of characteristics that contrast with those of actively growing neoplastic cells, such as the expression of cell-cycle inhibitors and differentiation factors. We hypothesized that the gene expression profiles of these differentiated cells could reveal the identities of genes that may function as tumour suppressors. Here we show, using in vitro and in vivo studies in mice and humans, that the mitochondrial protein LACTB potently inhibits the proliferation of breast cancer cells. Its mechanism of action involves alteration of mitochondrial lipid metabolism and differentiation of breast cancer cells. This is achieved, at least in part, through reduction of the levels of mitochondrial phosphatidylserine decarboxylase, which is involved in the synthesis of mitochondrial phosphatidylethanolamine. These observations uncover a novel mitochondrial tumour suppressor and demonstrate a connection between mitochondrial lipid metabolism and the differentiation program of breast cancer cells, thereby revealing a previously undescribed mechanism of tumour suppression.
C1 [Keckesova, Zuzana; Donaher, Joana Liu; De Cock, Jasmine; Freinkman, Elizaveta; Bierie, Brian; Reinhardt, Ferenc; Thiru, Prathapan; Weinberg, Robert A.] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA.
   [Lingrell, Susanne; Vance, Jean E.] Univ Alberta, Dept Med, Edmonton, AB T6G 2S2, Canada.
   [Lingrell, Susanne; Vance, Jean E.] Univ Alberta, Grp Mol & Cell Biol Lipids, Edmonton, AB T6G 2S2, Canada.
   [Bachovchin, Daniel A.; Golub, Todd R.] MIT, Broad Inst, Cambridge, MA 02142 USA.
   [Bachovchin, Daniel A.; Okondo, Marian C.] Mem Sloan Kettering Canc Ctr, Chem Biol Program, New York, NY 10065 USA.
   [Tischler, Verena; Noske, Aurelia] Univ Zurich Hosp, Inst Surg Pathol, Zurich, Switzerland.
   [Weinberg, Robert A.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Weinberg, Robert A.] MIT, Ludwig Ctr Mol Oncol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Freinkman, Elizaveta] Metabolon Inc, POB 110407, Res Triangle Pk, NC 27709 USA.
C3 Massachusetts Institute of Technology (MIT); Whitehead Institute; University of Alberta; University of Alberta; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Memorial Sloan Kettering Cancer Center; University of Zurich; University Zurich Hospital; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Metabolon
RP Keckesova, Z; Weinberg, RA (corresponding author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA.; Weinberg, RA (corresponding author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Weinberg, RA (corresponding author), MIT, Ludwig Ctr Mol Oncol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
EM keckesov@wi.mit.edu; weinberg@wi.mit.edu
FU NIH [R01 CA078461]; Samuel Waxman Cancer Research Foundation; Josie Robertson Foundation; MSKCC Core Grant [P30 CA008748]; National Cancer Institute [P30CA008748] Funding Source: NIH RePORTER
NR 42
TC 147
Z9 166
U1 4
U2 93
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 30
PY 2017
VL 543
IS 7647
BP 681
EP +
DI 10.1038/nature21408
PG 26
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EP8IS
UT WOS:000397619700048
PM 28329758
DA 2026-03-09
ER

PT J
AU Agostini, M
   Allardt, M
   Bakalyarov, AM
   Balata, M
   Barabanov, I
   Baudis, L
   Bauer, C
   Bellotti, E
   Belogurov, S
   Belyaev, ST
   Benato, G
   Bettini, A
   Bezrukov, L
   Bode, T
   Borowicz, D
   Brudanin, V
   Brugnera, R
   Caldwell, A
   Cattadori, C
   Chernogorov, A
   D'Andrea, V
   Demidova, EV
   Di Marco, N
   di Vacri, A
   Domula, A
   Doroshkevich, E
   Egorov, V
   Falkenstein, R
   Fedorova, O
   Freund, K
   Frodyma, N
   Gangapshev, A
   Garfagnini, A
   Gooch, C
   Grabmayr, P
   Gurentsov, V
   Gusev, K
   Hakenmüller, J
   Hegai, A
   Heisel, M
   Hemmer, S
   Hofmann, W
   Hult, M
   Inzhechik, LV
   Csathy, JJ
   Jochum, J
   Junker, M
   Kazalov, V
   Kihm, T
   Kirpichnikov, IV
   Kirsch, A
   Kish, A
   Klimenko, A
   Kneissl, R
   Knöpfle, KT
   Kochetov, O
   Kornoukhov, VN
   Kuzminov, VV
   Laubenstein, M
   Lazzaro, A
   Lebedev, VI
   Lehnert, B
   Liao, HY
   Lindner, M
   Lippi, I
   Lubashevskiy, A
   Lubsandorzhiev, B
   Lutter, G
   Macolino, C
   Majorovits, B
   Maneschg, W
   Medinaceli, E
   Miloradovic, M
   Mingazheva, R
   Misiaszek, M
   Moseev, P
   Nemchenok, I
   Palioselitis, D
   Panas, K
   Pandola, L
   Pelczar, K
   Pullia, A
   Riboldi, S
   Rumyantseva, N
   Sada, C
   Salamida, F
   Salathe, M
   Schmitt, C
   Schneider, B
   Schönert, S
   Schreiner, J
   Schulz, O
   Schütz, AK
   Schwingenheuer, B
   Selivanenko, O
   Shevchik, E
   Shirchenko, M
   Simgen, H
   Smolnikov, A
   Stanco, L
   Vanhoefer, L
   Vasenko, AA
   Veresnikova, A
   von Sturm, K
   Wagner, V
   Walter, M
   Wegmann, A
   Wester, T
   Wiesinger, C
   Wojcik, M
   Yanovich, E
   Zhitnikov, I
   Zhukov, SV
   Zinatulina, D
   Zuber, K
   Zuzel, G
AF Agostini, M.
   Allardt, M.
   Bakalyarov, A. M.
   Balata, M.
   Barabanov, I.
   Baudis, L.
   Bauer, C.
   Bellotti, E.
   Belogurov, S.
   Belyaev, S. T.
   Benato, G.
   Bettini, A.
   Bezrukov, L.
   Bode, T.
   Borowicz, D.
   Brudanin, V.
   Brugnera, R.
   Caldwell, A.
   Cattadori, C.
   Chernogorov, A.
   D'Andrea, V.
   Demidova, E. V.
   Di Marco, N.
   di Vacri, A.
   Domula, A.
   Doroshkevich, E.
   Egorov, V.
   Falkenstein, R.
   Fedorova, O.
   Freund, K.
   Frodyma, N.
   Gangapshev, A.
   Garfagnini, A.
   Gooch, C.
   Grabmayr, P.
   Gurentsov, V.
   Gusev, K.
   Hakenmueller, J.
   Hegai, A.
   Heisel, M.
   Hemmer, S.
   Hofmann, W.
   Hult, M.
   Inzhechik, L. V.
   Csathy, J. Janicsko
   Jochum, J.
   Junker, M.
   Kazalov, V.
   Kihm, T.
   Kirpichnikov, I. V.
   Kirsch, A.
   Kish, A.
   Klimenko, A.
   Kneissl, R.
   Knoepfle, K. T.
   Kochetov, O.
   Kornoukhov, V. N.
   Kuzminov, V. V.
   Laubenstein, M.
   Lazzaro, A.
   Lebedev, V. I.
   Lehnert, B.
   Liao, H. Y.
   Lindner, M.
   Lippi, I.
   Lubashevskiy, A.
   Lubsandorzhiev, B.
   Lutter, G.
   Macolino, C.
   Majorovits, B.
   Maneschg, W.
   Medinaceli, E.
   Miloradovic, M.
   Mingazheva, R.
   Misiaszek, M.
   Moseev, P.
   Nemchenok, I.
   Palioselitis, D.
   Panas, K.
   Pandola, L.
   Pelczar, K.
   Pullia, A.
   Riboldi, S.
   Rumyantseva, N.
   Sada, C.
   Salamida, F.
   Salathe, M.
   Schmitt, C.
   Schneider, B.
   Schoenert, S.
   Schreiner, J.
   Schulz, O.
   Schuetz, A. -K.
   Schwingenheuer, B.
   Selivanenko, O.
   Shevchik, E.
   Shirchenko, M.
   Simgen, H.
   Smolnikov, A.
   Stanco, L.
   Vanhoefer, L.
   Vasenko, A. A.
   Veresnikova, A.
   von Sturm, K.
   Wagner, V.
   Walter, M.
   Wegmann, A.
   Wester, T.
   Wiesinger, C.
   Wojcik, M.
   Yanovich, E.
   Zhitnikov, I.
   Zhukov, S. V.
   Zinatulina, D.
   Zuber, K.
   Zuzel, G.
TI Background-free search for neutrinoless double-β decay of 76Ge with GERDA
SO NATURE
LA English
DT Article
ID phase-i; shape; detectors
AB Many extensions of the Standard Model of particle physics explain the dominance of matter over antimatter in our Universe by neutrinos being their own antiparticles. This would imply the existence of neutrinoless double-beta decay, which is an extremely rare lepton-number-violating radioactive decay process whose detection requires the utmost background suppression. Among the programmes that aim to detect this decay, the GERDA Collaboration is searching for neutrinoless double-beta decay of Ge-76 by operating bare detectors, made of germanium with an enriched Ge-76 fraction, in liquid argon. After having completed Phase I of data taking, we have recently launched Phase II. Here we report that in GERDA Phase II we have achieved a background level of approximately 10(-3) counts keV(-1) kg(-1) yr(-1). This implies that the experiment is background-free, even when increasing the exposure up to design level. This is achieved by use of an active veto system, superior germanium detector energy resolution and improved background recognition of our new detectors. No signal of neutrinoless double-beta decay was found when Phase I and Phase II data were combined, and we deduce a lower-limit half-life of 5.3 x 10(25) years at the 90 per cent confidence level. Our half-life sensitivity of 4.0 x 10(25) years is competitive with the best experiments that use a substantially larger isotope mass. The potential of an essentially background-free search for neutrinoless double-beta decay will facilitate a larger germanium experiment with sensitivity levels that will bring us closer to clarifying whether neutrinos are their own antiparticles.
C1 [Agostini, M.; Bakalyarov, A. M.; di Vacri, A.; Macolino, C.] Ist Nazl Fis Nucl, Lab Nazl Gran Sasso & Gran Sass Sci Inst, Assergi, Italy.
   [Allardt, M.; Domula, A.; Lehnert, B.; Schneider, B.; Wester, T.; Zuber, K.] Tech Univ Dresden, Inst Kern & Teilchenphys, Dresden, Germany.
   [Bakalyarov, A. M.; Belyaev, S. T.; Gusev, K.; Lebedev, V. I.; Zhukov, S. V.] Kurchatov Inst, Natl Res Ctr, Moscow, Russia.
   [Barabanov, I.; Belogurov, S.; Bettini, A.; Bezrukov, L.; Doroshkevich, E.; Fedorova, O.; Gangapshev, A.; Gurentsov, V.; Inzhechik, L. V.; Kazalov, V.; Kornoukhov, V. N.; Kuzminov, V. V.; Lubsandorzhiev, B.; Moseev, P.; Selivanenko, O.; Veresnikova, A.; Yanovich, E.] Russian Acad Sci, Inst Nucl Res, Moscow, Russia.
   [Baudis, L.; Benato, G.; Kish, A.; Miloradovic, M.; Mingazheva, R.; Walter, M.] Univ Zurich, Inst Phys, Zurich, Switzerland.
   [Bauer, C.; Gangapshev, A.; Hakenmueller, J.; Heisel, M.; Hofmann, W.; Kihm, T.; Kirsch, A.; Klimenko, A.; Knoepfle, K. T.; Lindner, M.; Lubashevskiy, A.; Maneschg, W.; Salathe, M.; Schreiner, J.; Schwingenheuer, B.; Simgen, H.; Smolnikov, A.; Wagner, V.; Wegmann, A.] Max Planck Inst Kernphys, Heidelberg, Germany.
   [Bellotti, E.] Univ Milano Bicocca, Dipartimento Fis, Milan, Italy.
   [Bellotti, E.; Cattadori, C.; Salamida, F.] INFN Milano Bicocca, Milan, Italy.
   [Belogurov, S.; Chernogorov, A.; Demidova, E. V.; Kirpichnikov, I. V.; Kornoukhov, V. N.; Vasenko, A. A.] Inst Theoret & Expt Phys, Moscow, Russia.
   [Bettini, A.; Brugnera, R.; Garfagnini, A.; Hemmer, S.; Medinaceli, E.; Sada, C.; von Sturm, K.] Univ Padua, Dipartimento Fis & Astron, Padua, Italy.
   [Bettini, A.; Brugnera, R.; Garfagnini, A.; Hemmer, S.; Lippi, I.; Medinaceli, E.; Sada, C.; Stanco, L.; von Sturm, K.] INFN Padova, Padua, Italy.
   [Bode, T.; Gusev, K.; Csathy, J. Janicsko; Lazzaro, A.; Schoenert, S.; Wiesinger, C.] Tech Univ Munich, Phys Dept & Excellence Cluster Universe, Munich, Germany.
   [Borowicz, D.; Frodyma, N.; Misiaszek, M.; Panas, K.; Pelczar, K.; Wojcik, M.; Zuzel, G.] Jagiellonian Univ, Inst Phys, Krakow, Poland.
   [Borowicz, D.; Brudanin, V.; Egorov, V.; Gusev, K.; Klimenko, A.; Kochetov, O.; Lubashevskiy, A.; Nemchenok, I.; Rumyantseva, N.; Shevchik, E.; Shirchenko, M.; Smolnikov, A.; Zhitnikov, I.; Zinatulina, D.] Joint Inst Nucl Res, Dubna, Russia.
   [Brugnera, R.; Caldwell, A.; Gooch, C.; Kneissl, R.; Liao, H. Y.; Majorovits, B.; Palioselitis, D.; Schulz, O.; Vanhoefer, L.] Max Planck Inst Phys & Astrophys, Munich, Germany.
   [Falkenstein, R.; Freund, K.; Grabmayr, P.; Hegai, A.; Jochum, J.; Schmitt, C.; Schuetz, A. -K.] Eberhard Karls Univ Tubingen, Phy Inst, Tubingen, Germany.
   [Hult, M.; Lutter, G.] European Commiss, JRC Geel, Geel, Belgium.
   [Pandola, L.] Ist Nazl Fis Nucl, Lab Nazl Sud, Catania, Italy.
   [Pullia, A.; Riboldi, S.] Univ Milan, Dipartimento Fis, Milan, Italy.
   [Pullia, A.; Riboldi, S.] INFN Milano, Milan, Italy.
C3 Istituto Nazionale di Fisica Nucleare (INFN); Technische Universitat Dresden; National Research Centre - Kurchatov Institute; Russian Academy of Sciences; Institute for Nuclear Research of the Russian Academy of Sciences; University of Zurich; Max Planck Society; University of Milano-Bicocca; Istituto Nazionale di Fisica Nucleare (INFN); National Research Centre - Kurchatov Institute; Alikhanov Institute for Theoretical & Experimental Physics; University of Padua; Istituto Nazionale di Fisica Nucleare (INFN); Technical University of Munich; Jagiellonian University; Joint Institute for Nuclear Research - Russia; Max Planck Society; Eberhard Karls University of Tubingen; Istituto Nazionale di Fisica Nucleare (INFN); University of Milan; Istituto Nazionale di Fisica Nucleare (INFN)
RP Agostini, M (corresponding author), Ist Nazl Fis Nucl, Lab Nazl Gran Sasso & Gran Sass Sci Inst, Assergi, Italy.
FU German Federal Ministry for Education and Research (BMBF); German Research Foundation (DFG) via the Excellence Cluster Universe; Italian Istituto Nazionale di Fisica Nucleare (INFN); Max Planck Society (MPG); Polish National Science Centre (NCN); Russian Foundation for Basic Research (RFBR); Swiss National Science Foundation (SNF)
NR 47
TC 186
Z9 209
U1 0
U2 75
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 6
PY 2017
VL 544
IS 7648
BP 47
EP +
DI 10.1038/nature21717
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EQ8GQ
UT WOS:000398323300030
PM 28382980
DA 2026-03-09
ER

PT J
AU Anderson, MW
   Gebbie-Rayet, JT
   Hill, AR
   Farida, N
   Attfield, MP
   Cubillas, P
   Blatov, VA
   Proserpio, DM
   Akporiaye, D
   Arstad, B
   Gale, JD
AF Anderson, Michael W.
   Gebbie-Rayet, James T.
   Hill, Adam R.
   Farida, Nani
   Attfield, Martin P.
   Cubillas, Pablo
   Blatov, Vladislav A.
   Proserpio, Davide M.
   Akporiaye, Duncan
   Arstad, Bjornar
   Gale, Julian D.
TI Predicting crystal growth via a unified kinetic three-dimensional partition model
SO NATURE
LA English
DT Article
ID aqueous silicate solutions; l-cystine; si-29 nmr; crystallization; relaxation; microscopy; design
AB Understanding and predicting crystal growth is fundamental to the control of functionality in modern materials. Despite investigations for more than one hundred years(1-5), it is only recently that the molecular intricacies of these processes have been revealed by scanning probe microscopy(6-8). To organize and understand this large amount of new information, new rules for crystal growth need to be developed and tested. However, because of the complexity and variety of different crystal systems, attempts to understand crystal growth in detail have so far relied on developing models that are usually applicable to only one system(9-11). Such models cannot be used to achieve the wide scope of understanding that is required to create a unified model across crystal types and crystal structures. Here we describe a general approach to understanding and, in theory, predicting the growth of a wide range of crystal types, including the incorporation of defect structures, by simultaneous molecular-scale simulation of crystal habit and surface topology using a unified kinetic three-dimensional partition model. This entails dividing the structure into natural tiles' or Voronoi polyhedra that are metastable and, consequently, temporally persistent. As such, these units are then suitable for re-construction of the crystal via a Monte Carlo algorithm. We demonstrate our approach by predicting the crystal growth of a diverse set of crystal types, including zeolites, metal-organic frameworks, calcite, urea and l-cystine.
C1 [Anderson, Michael W.; Gebbie-Rayet, James T.; Hill, Adam R.; Farida, Nani; Attfield, Martin P.; Cubillas, Pablo] Univ Manchester, Sch Chem, Ctr Nanoporous Mat, Oxford Rd, Manchester M13 9PL, Lancs, England.
   [Blatov, Vladislav A.; Proserpio, Davide M.] Samara Univ, SCTMS, Academician Pavlov St 1, Samara 443011, Russia.
   [Blatov, Vladislav A.] Northwestern Polytech Univ, Sch Mat Sci & Engn, Xian 710072, Shaanxi, Peoples R China.
   [Proserpio, Davide M.] Univ Milan, Dipartimento Chim, Via Camillo Golgi 19, I-20133 Milan, Italy.
   [Akporiaye, Duncan; Arstad, Bjornar] SINTEF Mat & Chem, POB 124, N-0314 Oslo, Norway.
   [Gale, Julian D.] Curtin Univ, Curtin Inst Computat, Dept Chem, GPO Box U1987, Perth, WA 6845, Australia.
   [Gebbie-Rayet, James T.] STFC Daresbury Lab, Sci Comp Dept, Warrington WA4 4AD, Cheshire, England.
   [Cubillas, Pablo] Univ Durham, Earth Sci Dept, South Rd, Durham DH1 3LE, England.
C3 University of Manchester; Samara National Research University; Northwestern Polytechnical University; University of Milan; SINTEF; Curtin University; STFC Daresbury Laboratory; Durham University
RP Anderson, MW (corresponding author), Univ Manchester, Sch Chem, Ctr Nanoporous Mat, Oxford Rd, Manchester M13 9PL, Lancs, England.
EM m.anderson@manchester.ac.uk; adam.hill@manchester.ac.uk
FU Russian Science Foundation [16-13-10158]; Research Council of Norway through project Catlife 'Catalyst transformation and lifetimes by in-situ techniques and modelling' [233848]; EPSRC through CASE awards; Australian Research Council; Leverhulme Trust; Royal Society; Russian Science Foundation [16-13-10158] Funding Source: Russian Science Foundation; Engineering and Physical Sciences Research Council [1500862] Funding Source: researchfish
NR 33
TC 109
Z9 128
U1 5
U2 312
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 27
PY 2017
VL 544
IS 7651
BP 456
EP +
DI 10.1038/nature21684
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET1TN
UT WOS:000400051900038
PM 28371799
DA 2026-03-09
ER

PT J
AU Maring, N
   Farrera, P
   Kutluer, K
   Mazzera, M
   Heinze, G
   de Riedmatten, H
AF Maring, Nicolas
   Farrera, Pau
   Kutluer, Kutlu
   Mazzera, Margherita
   Heinze, Georg
   de Riedmatten, Hugues
TI Photonic quantum state transfer between a cold atomic gas and a crystal
SO NATURE
LA English
DT Article
ID light-matter interface; single photons; linear optics; entanglement; ensembles; information; distance; qubits; logic; bits
AB Interfacing fundamentally different quantum systems is key to building future hybrid quantum networks(1). Such heterogeneous networks offer capabilities superior to those of their homogeneous counterparts, as they merge the individual advantages of disparate quantum nodes in a single network architecture(2). However, few investigations of optical hybrid interconnections have been carried out, owing to fundamental and technological challenges such as wavelength and bandwidth matching of the interfacing photons. Here we report optical quantum interconnection of two disparate matter quantum systems with photon storage capabilities. We show that a quantum state can be transferred faithfully between a cold atomic ensemble(3,4) and a rare-earth-doped crystal(5-8) by means of a single photon at 1,552 nanometre telecommunication wavelength, using cascaded quantum frequency conversion. We demonstrate that quantum correlations between a photon and a single collective spin excitation in the cold atomic ensemble can be transferred to the solid-state system. We also show that single-photon time-bin qubits generated in the cold atomic ensemble can be converted, stored and retrieved from the crystal with a conditional qubit fidelity of more than 85 per cent. Our results open up the prospect of optically connecting quantum nodes with different capabilities and represent an important step towards the realization of large-scale hybrid quantum networks.
C1 [Maring, Nicolas; Farrera, Pau; Kutluer, Kutlu; Mazzera, Margherita; Heinze, Georg; de Riedmatten, Hugues] Barcelona Inst Sci & Technol, ICFO Inst Ciencies Foton, Castelldefels 08860, Barcelona, Spain.
   [de Riedmatten, Hugues] ICREA, Barcelona 08015, Spain.
C3 Barcelona Institute of Science & Technology; Universitat Politecnica de Catalunya; Institut de Ciencies Fotoniques (ICFO); ICREA
RP Heinze, G; de Riedmatten, H (corresponding author), Barcelona Inst Sci & Technol, ICFO Inst Ciencies Foton, Castelldefels 08860, Barcelona, Spain.; de Riedmatten, H (corresponding author), ICREA, Barcelona 08015, Spain.
EM georg.heinze@icfo.eu; hugues.deriedmatten@icfo.eu
FU ERC starting grant QuLIMA; Spanish Ministry of Economy and Competitiveness (MINECO); Fondo Europeo de Desarrollo Regional (FEDER) [FIS2015-69535-R]; MINECO [SEV-2015-0522]; AGAUR [SGR 1554]; Fundacio Privada Cellex; CERCA programme of the Generalitat de Catalunya; ICFOnest international postdoctoral fellowship program
NR 40
TC 125
Z9 147
U1 2
U2 51
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 23
PY 2017
VL 551
IS 7681
BP 485
EP +
DI 10.1038/nature24468
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FN5JO
UT WOS:000416043700041
PM 29168806
DA 2026-03-09
ER

PT J
AU Mews, P
   Donahue, G
   Drake, AM
   Luczak, V
   Abel, T
   Berger, SL
AF Mews, Philipp
   Donahue, Greg
   Drake, Adam M.
   Luczak, Vincent
   Abel, Ted
   Berger, Shelley L.
TI Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory
SO NATURE
LA English
DT Article
ID gene-expression; synaptic plasticity; metabolism; chromatin; coenzyme; brain; consolidation; acetate; epigenetics; activation
AB Metabolic production of acetyl coenzyme A (acetyl-CoA) is linked to histone acetylation and gene regulation, but the precise mechanisms of this process are largely unknown. Here we show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) directly regulates histone acetylation in neurons and spatial memory in mammals. In a neuronal cell culture model, ACSS2 increases in the nuclei of differentiating neurons and localizes to upregulated neuronal genes near sites of elevated histone acetylation. A decrease in ACSS2 lowers nuclear acetyl-CoA levels, histone acetylation, and responsive expression of the cohort of neuronal genes. In adult mice, attenuation of hippocampal ACSS2 expression impairs long-term spatial memory, a cognitive process that relies on histone acetylation. A decrease in ACSS2 in the hippocampus also leads to defective upregulation of memory-related neuronal genes that are pre-bound by ACSS2. These results reveal a connection between cellular metabolism, gene regulation, and neural plasticity and establish a link between acetyl-CoA generation 'on-site' at chromatin for histone acetylation and the transcription of key neuronal genes.
C1 [Mews, Philipp; Donahue, Greg; Drake, Adam M.; Luczak, Vincent; Abel, Ted; Berger, Shelley L.] Univ Penn, Epigenet Inst, Dept Cell & Dev Biol, Perelman Sch Med, Philadelphia, PA 19104 USA.
   [Mews, Philipp; Donahue, Greg; Drake, Adam M.; Luczak, Vincent; Abel, Ted; Berger, Shelley L.] Univ Penn, Dept Biol, Perelman Sch Med, Philadelphia, PA 19104 USA.
   [Mews, Philipp; Donahue, Greg; Drake, Adam M.; Luczak, Vincent; Abel, Ted; Berger, Shelley L.] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA.
   [Abel, Ted] Univ Iowa, Carver Coll Med, Iowa Neurosci Inst, Iowa City, IA 52242 USA.
C3 University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Iowa
RP Berger, SL (corresponding author), Univ Penn, Epigenet Inst, Dept Cell & Dev Biol, Perelman Sch Med, Philadelphia, PA 19104 USA.; Berger, SL (corresponding author), Univ Penn, Dept Biol, Perelman Sch Med, Philadelphia, PA 19104 USA.; Berger, SL (corresponding author), Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA.
EM bergers@upenn.edu
FU NIH [P01AG031862];  [RO1 MH 087463]; National Institute of Mental Health [R01MH087463] Funding Source: NIH RePORTER; National Institute on Aging [P01AG031862] Funding Source: NIH RePORTER
NR 34
TC 373
Z9 460
U1 8
U2 160
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 15
PY 2017
VL 546
IS 7658
BP 381
EP +
DI 10.1038/nature22405
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EX5BK
UT WOS:000403250900030
PM 28562591
DA 2026-03-09
ER

PT J
AU Golden, RJ
   Chen, B
   Li, T
   Braun, J
   Manjunath, H
   Chen, X
   Wu, J
   Schmid, V
   Chang, TC
   Kopp, F
   Ramirez-Martinez, A
   Tagliabracci, VS
   Chen, ZJ
   Xie, Y
   Mendell, JT
AF Golden, Ryan J.
   Chen, Beibei
   Li, Tuo
   Braun, Juliane
   Manjunath, Hema
   Chen, Xiang
   Wu, Jiaxi
   Schmid, Vanessa
   Chang, Tsung-Cheng
   Kopp, Florian
   Ramirez-Martinez, Andres
   Tagliabracci, Vincent S.
   Chen, Zhijian J.
   Xie, Yang
   Mendell, Joshua T.
TI An Argonaute phosphorylation cycle promotes microRNA-mediated silencing
SO NATURE
LA English
DT Article
ID rnai screen; human-cells; c-myc; target; identification; genes; let-7; mirna; expression; pathways
AB MicroRNAs (miRNAs) perform critical functions in normal physiology and disease by associating with Argonaute proteins and downregulating partially complementary messenger RNAs (mRNAs). Here we use clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) genome-wide loss-of-function screening coupled with a fluorescent reporter of miRNA activity in human cells to identify new regulators of the miRNA pathway. By using iterative rounds of screening, we reveal a novel mechanism whereby target engagement by Argonaute 2 (AGO2) triggers its hierarchical, multi-site phosphorylation by CSNK1A1 on a set of highly conserved residues (S824-S834), followed by rapid dephosphorylation by the ANKRD52-PPP6C phosphatase complex. Although genetic and biochemical studies demonstrate that AGO2 phosphorylation on these residues inhibits target mRNA binding, inactivation of this phosphorylation cycle globally impairs miRNA-mediated silencing. Analysis of the transcriptome-wide binding profile of non-phosphorylatable AGO2 reveals a pronounced expansion of the target repertoire bound at steady-state, effectively reducing the active pool of AGO2 on a per-target basis. These findings support a model in which an AGO2 phosphorylation cycle stimulated by target engagement regulates miRNA:target interactions to maintain the global efficiency of miRNA-mediated silencing.
C1 [Golden, Ryan J.; Li, Tuo; Braun, Juliane; Manjunath, Hema; Chen, Xiang; Chang, Tsung-Cheng; Kopp, Florian; Ramirez-Martinez, Andres; Tagliabracci, Vincent S.; Chen, Zhijian J.; Mendell, Joshua T.] Univ Texas Southwestern Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA.
   [Golden, Ryan J.] Univ Texas Southwestern Med Ctr Dallas, Med Scientist Training Program, Dallas, TX 75390 USA.
   [Chen, Beibei; Xie, Yang] Univ Texas Southwestern Med Ctr Dallas, Quantitat Biomed Res Ctr, Dallas, TX 75390 USA.
   [Chen, Beibei; Xie, Yang] Univ Texas Southwestern Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA.
   [Wu, Jiaxi] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA.
   [Schmid, Vanessa] Univ Texas Southwestern Med Ctr Dallas, Eugene McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA.
   [Chen, Zhijian J.; Mendell, Joshua T.] Univ Texas Southwestern Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA.
   [Xie, Yang; Mendell, Joshua T.] Univ Texas Southwestern Med Ctr Dallas, Harold C Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA.
   [Mendell, Joshua T.] Univ Texas Southwestern Med Ctr Dallas, Hamon Ctr Regenerat Sci & Med, Dallas, TX 75390 USA.
C3 University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of California System; University of California San Francisco; University of Texas System; University of Texas Southwestern Medical Center; Howard Hughes Medical Institute; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center
RP Mendell, JT (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA.; Mendell, JT (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA.; Mendell, JT (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Harold C Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA.; Mendell, JT (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Hamon Ctr Regenerat Sci & Med, Dallas, TX 75390 USA.
EM Joshua.Mendell@UTSouthwestern.edu
FU Cancer Prevention and Research Institute of Texas (CPRIT) [R1008, RP160249, RP101251, RP120718, RR150033]; National Institutes of Health [R01CA120185, R35CA197311, R01CA152301, R00DK099254]; Cancer Research Institute; Leopoldina Fellowship Program from the German National Academy of Sciences Leopoldina [LPDS 2014-12]; National Cancer Institute [R35CA197311, P30CA142543] Funding Source: NIH RePORTER
NR 38
TC 212
Z9 241
U1 2
U2 123
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 9
PY 2017
VL 542
IS 7640
BP 197
EP 202
DI 10.1038/nature21025
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK2DJ
UT WOS:000393737500033
PM 28114302
DA 2026-03-09
ER

PT J
AU Fan, FJ
   Voznyy, O
   Sabatini, RP
   Bicanic, KT
   Adachi, MM
   McBride, JR
   Reid, KR
   Park, YS
   Li, XY
   Jain, A
   Quintero-Bermudez, R
   Saravanapavanantham, M
   Liu, M
   Korkusinski, M
   Hawrylak, P
   Klimov, VI
   Rosenthal, SJ
   Hoogland, S
   Sargent, EH
AF Fan, Fengjia
   Voznyy, Oleksandr
   Sabatini, Randy P.
   Bicanic, Kristopher T.
   Adachi, Michael M.
   McBride, James R.
   Reid, Kemar R.
   Park, Young-Shin
   Li, Xiyan
   Jain, Ankit
   Quintero-Bermudez, Rafael
   Saravanapavanantham, Mayuran
   Liu, Min
   Korkusinski, Marek
   Hawrylak, Pawel
   Klimov, Victor I.
   Rosenthal, Sandra J.
   Hoogland, Sjoerd
   Sargent, Edward H.
TI Continuous-wave lasing in colloidal quantum dot solids enabled by facet-selective epitaxy
SO NATURE
LA English
DT Article
ID auger recombination; stimulated-emission; shell nanocrystals; optical gain; cdse; threshold; exciton; semiconductors; surface; photoluminescence
AB Colloidal quantum dots (CQDs) feature a low degeneracy of electronic states at the band edges compared with the corresponding bulk material(1), as well as a narrow emission linewidth(2,3). Unfortunately for potential laser applications, this degeneracy is incompletely lifted in the valence band, spreading the hole population among several states at room temperature(4-6). This leads to increased optical gain thresholds, demanding high photoexcitation levels to achieve population inversion (more electrons in excited states than in ground states-the condition for optical gain). This, in turn, increases Auger recombination losses(7), limiting the gain lifetime to sub-nanoseconds and preventing steady laser action(8,9). State degeneracy also broadens the photoluminescence linewidth at the single-particle level(10). Here we demonstrate a way to decrease the band-edge degeneracy and single-dot photoluminescence linewidth in CQDs by means of uniform biaxial strain. We have developed a synthetic strategy that we term facet-selective epitaxy: we first switch off, and then switch on, shell growth on the (0001) facet of wurtzite CdSe cores, producing asymmetric compressive shells that create built-in biaxial strain, while still maintaining excellent surface passivation (preventing defect formation, which otherwise would cause non-radiative recombination losses). Our synthesis spreads the excitonic fine structure uniformly and sufficiently broadly that it prevents valence-band-edge states from being thermally depopulated. We thereby reduce the optical gain threshold and demonstrate continuous-wave lasing from CQD solids, expanding the library of solution-processed materials(11,12) that may be capable of continuous-wave lasing. The individual CQDs exhibit an ultranarrow single-dot linewidth, and we successfully propagate this into the ensemble of CQDs.
C1 [Fan, Fengjia; Voznyy, Oleksandr; Sabatini, Randy P.; Bicanic, Kristopher T.; Adachi, Michael M.; Li, Xiyan; Jain, Ankit; Quintero-Bermudez, Rafael; Saravanapavanantham, Mayuran; Liu, Min; Hoogland, Sjoerd; Sargent, Edward H.] Univ Toronto, Dept Elect & Comp Engn, 10 Kings Coll Rd, Toronto, ON M5S 3G4, Canada.
   [McBride, James R.; Reid, Kemar R.; Rosenthal, Sandra J.] Vanderbilt Univ, Vanderbilt Inst Nanoscale Sci & Engn, 221 Kirkland Hall, Nashville, TN 37235 USA.
   [Park, Young-Shin; Klimov, Victor I.] Los Alamos Natl Lab, Div Chem, Los Alamos, NM 87545 USA.
   [Park, Young-Shin] Univ New Mexico, Ctr High Technol Mat, Albuquerque, NM 87131 USA.
   [Korkusinski, Marek] CNR, Emerging Technol Div, Secur & Disrupt Technol, Ottawa, ON K1A 0R6, Canada.
   [Hawrylak, Pawel] Univ Ottawa, Dept Phys, Ottawa, ON K1A 0R6, Canada.
   [Adachi, Michael M.] Simon Fraser Univ, Sch Engn Sci, 8888 Univ Dr Burnaby, Burnaby, BC V5A IS6, Canada.
C3 University of Toronto; Vanderbilt University; United States Department of Energy (DOE); Los Alamos National Laboratory; University of New Mexico; National Research Council Canada; University of Ottawa; Simon Fraser University
RP Sargent, EH (corresponding author), Univ Toronto, Dept Elect & Comp Engn, 10 Kings Coll Rd, Toronto, ON M5S 3G4, Canada.
EM ted.sargent@utoronto.ca
FU Ontario Research Fund-Research Excellence Program; Natural Sciences and Engineering Research Council (NSERC) of Canada; Canada Foundation for Innovation under the Compute Canada; Government of Ontario; Ontario Research Fund-Research Excellence; University of Toronto; Chemical Sciences, Biosciences and Geosciences Division, Office of Basic Energy Sciences, Office of Science, US Department of Energy; National Science Foundation [CHE-1506587, EPS 1004083]; IBM Canada Research and Development Center through the Southern Ontario Smart Computing Innovation Platform (SOSCIP) postdoctoral fellowship; Ontario Government; Federal Economic Development Agency for Southern Ontario; University of Ottawa Research Chair in Quantum Theory of Materials, Nanostructures and Devices; Direct For Mathematical & Physical Scien; Division Of Chemistry [1506587] Funding Source: National Science Foundation
NR 49
TC 394
Z9 437
U1 9
U2 542
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 6
PY 2017
VL 544
IS 7648
BP 75
EP +
DI 10.1038/nature21424
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EQ8GQ
UT WOS:000398323300035
PM 28321128
DA 2026-03-09
ER

PT J
AU Hensgens, T
   Fujita, T
   Janssen, L
   Li, X
   Van Diepen, CJ
   Reichl, C
   Wegscheider, W
   Das Sarma, S
   Vandersypen, LMK
AF Hensgens, T.
   Fujita, T.
   Janssen, L.
   Li, Xiao
   Van Diepen, C. J.
   Reichl, C.
   Wegscheider, W.
   Das Sarma, S.
   Vandersypen, L. M. K.
TI Quantum simulation of a Fermi-Hubbard model using a semiconductor quantum dot array
SO NATURE
LA English
DT Article
ID coulomb-blockade; spin; insulator; spectroscopy; lattice; system; states; atoms; qubit
AB Interacting fermions on a lattice can develop strong quantum correlations, which are the cause of the classical intractability of many exotic phases of matter(1-3). Current efforts are directed towards the control of artificial quantum systems that can be made to emulate the underlying Fermi-Hubbard models(4-6). Electrostatically confined conduction-band electrons define interacting quantum coherent spin and charge degrees of freedom that allow all-electrical initialization of low-entropy states and readily adhere to the Fermi-Hubbard Hamiltonian(7-17). Until now, however, the substantial electrostatic disorder of the solid state has meant that only a few attempts at emulating Fermi-Hubbard physics on solid-state platforms have been made(18,19). Here we show that for gate-defined quantum dots this disorder can be suppressed in a controlled manner. Using a semi-automated and scalable set of experimental tools, we homogeneously and independently set up the electron filling and nearest-neighbour tunnel coupling in a semiconductor quantum dot array so as to simulate a Fermi-Hubbard system. With this set-up, we realize a detailed characterization of the collective Coulomb blockade transition(20), which is the finite-size analogue of the interaction-driven Mott metal-to-insulator transition(1). As automation and device fabrication of semiconductor quantum dots continue to improve, the ideas presented here will enable the investigation of the physics of ever more complex many-body states using quantum dots.
C1 [Hensgens, T.; Fujita, T.; Janssen, L.; Vandersypen, L. M. K.] Delft Univ Technol, QuTech, NL-2600 GA Delft, Netherlands.
   [Hensgens, T.; Fujita, T.; Janssen, L.; Vandersypen, L. M. K.] Delft Univ Technol, Kavli Inst Nanosci, NL-2600 GA Delft, Netherlands.
   [Li, Xiao; Das Sarma, S.] Univ Maryland, Condensed Matter Theory Ctr, College Pk, MD 20742 USA.
   [Li, Xiao; Das Sarma, S.] Univ Maryland, Joint Quantum Inst, College Pk, MD 20742 USA.
   [Van Diepen, C. J.] QuTech, NL-2600 AD Delft, Netherlands.
   [Van Diepen, C. J.] Netherlands Org Appl Sci Res TNO, NL-2600 AD Delft, Netherlands.
   [Reichl, C.; Wegscheider, W.] Swiss Fed Inst Technol, Solid State Phys Lab, CH-8093 Zurich, Switzerland.
C3 Delft University of Technology; Delft University of Technology; University System of Maryland; University of Maryland College Park; University System of Maryland; University of Maryland College Park; Delft University of Technology; Netherlands Organization Applied Science Research; Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Vandersypen, LMK (corresponding author), Delft Univ Technol, QuTech, NL-2600 GA Delft, Netherlands.; Vandersypen, LMK (corresponding author), Delft Univ Technol, Kavli Inst Nanosci, NL-2600 GA Delft, Netherlands.
EM l.m.k.vandersypen@tudelft.nl
FU Netherlands Organization of Scientific Research (NWO) VICI programme; European Commission via the integrated project SIQS; Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellowship for Research Abroad; LPS-MPO-CMTC; Swiss National Science Foundation
NR 37
TC 289
Z9 325
U1 4
U2 103
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 3
PY 2017
VL 548
IS 7665
BP 70
EP +
DI 10.1038/nature23022
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FC4SU
UT WOS:000406831700038
PM 28770852
DA 2026-03-09
ER

PT J
AU Ricci, C
   Trakhtenbrot, B
   Koss, MJ
   Ueda, Y
   Chawinski, KS
   Oh, K
   Lamperti, I
   Mushotzky, R
   Treister, E
   Ho, LC
   Weigel, A
   Bauer, FE
   Paltani, S
   Fabian, AC
   Xie, YX
   Gehrels, N
AF Ricci, Claudio
   Trakhtenbrot, Benny
   Koss, Michael J.
   Ueda, Yoshihiro
   Chawinski, Kevin S.
   Oh, Kyuseok
   Lamperti, Isabella
   Mushotzky, Richard
   Treister, Ezequiel
   Ho, Luis C.
   Weigel, Anna
   Bauer, Franz E.
   Paltani, Stephane
   Fabian, Andrew C.
   Xie, Yanxia
   Gehrels, Neil
TI The close environments of accreting massive black holes are shaped by radiative feedback
SO NATURE
LA English
DT Article
ID active galactic nuclei; agn spectroscopic survey; ray luminosity function; dust covering factor; swift bat survey; seyfert-galaxy; infrared luminosity; alpha emission; absorbed agns; merger rate
AB The majority of the accreting supermassive black holes in the Universe are obscured by large columns of gas and dust(1-3). The location and evolution of this obscuring material have been the subject of intense research in the past decades(4,5), and are still debated. A decrease in the covering factor of the circumnuclear material with increasing accretion rates has been found by studies across the electromagnetic spectrum(1,6-8). The origin of this trend may be driven by the increase in the inner radius of the obscuring material with incident luminosity, which arises from the sublimation of dust(9); by the gravitational potential of the black hole(10); by radiative feedback(11-14); or by the interplay between outflows and inflows(15). However, the lack of a large, unbiased and complete sample of accreting black holes, with reliable information on gas column density, luminosity and mass, has left the main physical mechanism that regulates obscuration unclear. Here we report a systematic multi-wavelength survey of hard-X-rayselected black holes that reveals that radiative feedback on dusty gas is the main physical mechanism that regulates the distribution of the circumnuclear material. Our results imply that the bulk of the obscuring dust and gas is located within a few to tens of parsecs of the accreting supermassive black hole (within the sphere of influence of the black hole), and that it can be swept away even at low radiative output rates. The main physical driver of the differences between obscured and unobscured accreting black holes is therefore their mass-normalized accretion rate.
C1 [Ricci, Claudio; Treister, Ezequiel; Bauer, Franz E.] Pontificia Univ Catolica Chile, Fac Fis, Inst Astrofis, Casilla 306, Santiago 22, Chile.
   [Ricci, Claudio] Chinese Acad Sci South Amer Ctr Astron & China Ch, Camino El Observ 1515, Santiago, Chile.
   [Ricci, Claudio; Ho, Luis C.; Xie, Yanxia] Peking Univ, Kavli Inst Astron & Astrophys, Beijing 100871, Peoples R China.
   [Trakhtenbrot, Benny; Koss, Michael J.; Chawinski, Kevin S.; Oh, Kyuseok; Lamperti, Isabella; Weigel, Anna] Swiss Fed Inst Technol, Dept Phys, Inst Astron, Wolfgang Pauli Str 27, CH-8093 Zurich, Switzerland.
   [Koss, Michael J.] Eureka Sci Inc, 2452 Delmer St Suite 100, Oakland, CA 94602 USA.
   [Ueda, Yoshihiro] Kyoto Univ, Dept Astron, Kyoto 6068502, Japan.
   [Mushotzky, Richard] Univ Maryland, Dept Astron, College Pk, MD 20742 USA.
   [Mushotzky, Richard] Univ Maryland, Joint Space Sci Inst, College Pk, MD 20742 USA.
   [Ho, Luis C.; Xie, Yanxia] Peking Univ, Sch Phys, Dept Astron, Beijing 100871, Peoples R China.
   [Bauer, Franz E.] Space Sci Inst, 4750 Walnut St,Suite 205, Boulder, CO 80301 USA.
   [Bauer, Franz E.] Millenium Inst Astrophys, Santiago, Chile.
   [Paltani, Stephane] Univ Geneva, Dept Astron, Chemin Ecogia 16, CH-1290 Versoix, Switzerland.
   [Fabian, Andrew C.] Inst Astron, Madingley Rd, Cambridge CB3 0HA, England.
   [Gehrels, Neil] NASA Goddard Space Flight Ctr, Greenbelt, MD 20771 USA.
C3 Pontificia Universidad Catolica de Chile; Peking University; Swiss Federal Institutes of Technology Domain; ETH Zurich; Eureka Scientific; Kyoto University; University System of Maryland; University of Maryland College Park; University System of Maryland; University of Maryland College Park; Peking University; University of Geneva; University of Cambridge; National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center
RP Ricci, C (corresponding author), Pontificia Univ Catolica Chile, Fac Fis, Inst Astrofis, Casilla 306, Santiago 22, Chile.
EM cricci@astro.puc.cl
FU Chinese Academy of Sciences (CAS); FONDECYT [1141218, 1160999]; Basal-CATA [PFB-06/2007]; China-CONICYT fund; Swiss National Science Foundation [PP00P2 138979, PP00P2 166159]; Swiss National Science Foundation (SNSF) through the Ambizione fellowship [PZ00P2 154799/1]; NASA ADAP award [NNH16CT03C]; Chinese Academy of Science [XDB09030102]; National Natural Science Foundation of China [11473002]; Ministry of Science and Technology of China [2016YFA0400702]; ERC [340442]; Ministry of Economy, Development, and Tourism's Millennium Science Initiative [IC120009]; Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) [17K05384]; Grants-in-Aid for Scientific Research [17K05384] Funding Source: KAKEN; Science and Technology Facilities Council [ST/N000927/1] Funding Source: researchfish
NR 118
TC 249
Z9 274
U1 0
U2 12
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 28
PY 2017
VL 549
IS 7673
BP 488
EP +
DI 10.1038/nature23906
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI4GT
UT WOS:000411930000043
PM 28959966
DA 2026-03-09
ER

PT J
AU Zhang, CS
   Hawley, SA
   Zong, Y
   Li, MQ
   Wang, ZC
   Gray, A
   Ma, T
   Cui, JW
   Feng, JW
   Zhu, MJ
   Wu, YQ
   Li, TY
   Ye, ZY
   Lin, SY
   Yin, HY
   Piao, HL
   Hardie, DGR
   Lin, SC
AF Zhang, Chen-Song
   Hawley, Simon A.
   Zong, Yue
   Li, Mengqi
   Wang, Zhichao
   Gray, Alexander
   Ma, Teng
   Cui, Jiwen
   Feng, Jin-Wei
   Zhu, Mingjiang
   Wu, Yu-Qing
   Li, Terytty Yang
   Ye, Zhiyun
   Lin, Shu-Yong
   Yin, Huiyong
   Piao, Hai-Long
   Hardie, D. G. Rahame
   Lin, Sheng-Cai
TI Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK
SO NATURE
LA English
DT Article
ID vacuolar h+-atpase; activated protein-kinase; phosphorylation; disease; cells; metabolism; mechanism; autophagy; reveals; complex
AB The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK)(1), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK(2-5). Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation(6,7). Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.
C1 [Zhang, Chen-Song; Zong, Yue; Li, Mengqi; Ma, Teng; Cui, Jiwen; Feng, Jin-Wei; Wu, Yu-Qing; Li, Terytty Yang; Ye, Zhiyun; Lin, Shu-Yong; Lin, Sheng-Cai] Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Signaling Network, State Key Lab Cellular Stress Biol, Xiamen 361102, Fujian, Peoples R China.
   [Hawley, Simon A.; Gray, Alexander; Hardie, D. G. Rahame] Univ Dundee, Div Cell Signalling & Immunol, Coll Life Sci, Dundee DD1 5EH, Scotland.
   [Wang, Zhichao; Piao, Hai-Long] Chinese Acad Sci, Dalian Inst Chem Phys, Sci Res Ctr Translat Med, Dalian 116023, Liaoning, Peoples R China.
   [Wang, Zhichao] Chinese Acad Sci, Dalian Inst Chem Phys, Key Lab Separat Sci Analyt Chem, Dalian 116023, Liaoning, Peoples R China.
   [Wang, Zhichao] Univ Chinese Acad Sci, Beijing 100049, Peoples R China.
   [Zhu, Mingjiang; Yin, Huiyong] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Key Lab Food Safety Res, Shanghai 200031, Peoples R China.
C3 Xiamen University; University of Dundee; Chinese Academy of Sciences; Dalian Institute of Chemical Physics, CAS; Chinese Academy of Sciences; Dalian Institute of Chemical Physics, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences
RP Lin, SC (corresponding author), Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Signaling Network, State Key Lab Cellular Stress Biol, Xiamen 361102, Fujian, Peoples R China.; Hardie, DGR (corresponding author), Univ Dundee, Div Cell Signalling & Immunol, Coll Life Sci, Dundee DD1 5EH, Scotland.
EM d.g.hardie@dundee.ac.uk; linsc@xmu.edu.cn
FU Wellcome Trust [097726]; Cancer Research UK [C37030/ A15101]; National Key Research and Development Project of China [2016YFA0502001]; National Natural Science Foundation of China [31430094, 31690101, 31571214, 31601152, J1310027]; Cancer Research UK [15101] Funding Source: researchfish; Wellcome Trust [204766/Z/16/Z] Funding Source: researchfish
NR 35
TC 570
Z9 654
U1 15
U2 518
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 3
PY 2017
VL 548
IS 7665
BP 112
EP +
DI 10.1038/nature23275
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FC4SU
UT WOS:000406831700047
PM 28723898
DA 2026-03-09
ER

PT J
AU Tao, Z
   Shen, LS
   Gu, XF
   Wang, YZ
   Yu, H
   He, YH
AF Tao, Zeng
   Shen, Lisha
   Gu, Xiaofeng
   Wang, Yizhong
   Yu, Hao
   He, Yuehui
TI Embryonic epigenetic reprogramming by a pioneer transcription factor in plants
SO NATURE
LA English
DT Article
ID arabidopsis leafy cotyledon1; locus-c expression; floral transition; domain protein; vernalization; winter; gene; inheritance; vectors; complex
AB Epigenetic modifications, including chromatin modifications and DNA methylation, have a central role in the regulation of gene expression in plants and animals. The transmission of epigenetic marks is crucial for certain genes to retain cell lineage-specific expression patterns and maintain cell fate(1,2). However, the marks that have accumulated at regulatory loci during growth and development or in response to environmental stimuli need to be deleted in gametes or embryos, particularly in organisms such as plants that do not set aside a germ line, to ensure the proper development of offspring(1,2). In Arabidopsis thaliana, prolonged exposure to cold temperatures (winter cold), in a process known as vernalization, triggers the mitotically stable epigenetic silencing of the potent floral repressor FLOWERING LOCUS C (FLC), and renders plants competent to flower in the spring; however, this silencing is reset during each generation(3-5). Here we show that the seed-specific transcription factor LEAFY COTYLEDON1 (LEC1) promotes the initial establishment of an active chromatin state at FLC and activates its expression de novo in the pro-embryo, thus reversing the silenced state inherited from gametes. This active chromatin state is passed on from the pro-embryo to postembryonic life, and leads to transmission of the embryonic memory of FLC activation to post-embryonic stages. Our findings reveal a mechanism for the reprogramming of embryonic chromatin states in plants, and provide insights into the epigenetic memory of embryonic active gene expression in post-embryonic phases, through which an embryonic factor acts to 'control' post-embryonic development processes that are distinct from embryogenesis in plants.
C1 [Tao, Zeng; Wang, Yizhong; He, Yuehui] Chinese Acad Sci, Shanghai Inst Biol Sci, CAS Ctr Excellence Mol Plant Sci, Shanghai Ctr Plant Stress Biol, Shanghai 201602, Peoples R China.
   [Tao, Zeng; Shen, Lisha; Gu, Xiaofeng; Yu, Hao; He, Yuehui] Natl Univ Singapore, Dept Biol Sci, Singapore 117604, Singapore.
   [Tao, Zeng; Shen, Lisha; Gu, Xiaofeng; Yu, Hao; He, Yuehui] Natl Univ Singapore, Temasek Life Sci Lab, Singapore 117604, Singapore.
   [Gu, Xiaofeng] Chinese Acad Agr Sci, Biotechnol Res Inst, Beijing 100081, Peoples R China.
   [Wang, Yizhong] Huazhong Normal Univ, Sch Life Sci, 152 Luoyu Rd, Wuhan, Hubei, Peoples R China.
C3 Chinese Academy of Sciences; Center for Excellence in Molecular Plant Sciences, CAS; National University of Singapore; National University of Singapore; Chinese Academy of Agricultural Sciences; Biotechnology Research Institute, CAAS; Central China Normal University
RP He, YH (corresponding author), Chinese Acad Sci, Shanghai Inst Biol Sci, CAS Ctr Excellence Mol Plant Sci, Shanghai Ctr Plant Stress Biol, Shanghai 201602, Peoples R China.; He, YH (corresponding author), Natl Univ Singapore, Dept Biol Sci, Singapore 117604, Singapore.; He, YH (corresponding author), Natl Univ Singapore, Temasek Life Sci Lab, Singapore 117604, Singapore.
EM yhhe@sibs.ac.cn
FU National Key Research and Development Program of China [2017YFA0503803]; Chinese Academy of Sciences [XDPB0404]; Temasek Life Sciences Laboratory (Singapore)
NR 40
TC 151
Z9 178
U1 4
U2 232
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 2
PY 2017
VL 551
IS 7678
BP 124
EP +
DI 10.1038/nature24300
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FL4SY
UT WOS:000414222900058
PM 29072296
DA 2026-03-09
ER

PT J
AU Norris, CA
   Wood, BJ
AF Norris, C. Ashley
   Wood, Bernard J.
TI Earth's volatile contents established by melting and vaporization
SO NATURE
LA English
DT Article
ID oxidation-state; core formation; isotopic evidence; giant impact; origin; mantle; moon; differentiation; accretion; geochemistry
AB The silicate Earth is strongly depleted in moderately volatile elements (such as lead, zinc, indium and alkali elements) relative to CI chondrites, the meteorites that compositionally most closely resemble the Sun(1). This depletion may be explained qualitatively by accretion of 10 to 20 per cent of a volatile-rich body to a reduced volatile-free proto-Earth(2,3), followed by partial extraction of some elements to the core(1). However, there are several unanswered questions regarding the sources of Earth's volatiles(4,5), notably the overabundance of indium in the silicate Earth. Here we examine the melting processes that occurred during accretion on Earth and precursor bodies and report vaporization experiments under conditions of fixed temperature and oxygen fugacity. We find that the pattern of volatile element depletion in the silicate Earth is consistent with partial melting and vaporization rather than with simple accretion of a volatile-rich chondrite-like body. We argue that melting and vaporization on precursor bodies and possibly during the giant Moon-forming impact(6-8) were responsible for establishing the observed abundances of moderately volatile elements in Earth.
C1 [Norris, C. Ashley; Wood, Bernard J.] Univ Oxford, Dept Earth Sci, South Parks Rd, Oxford OX1 3AN, England.
C3 University of Oxford
RP Wood, BJ (corresponding author), Univ Oxford, Dept Earth Sci, South Parks Rd, Oxford OX1 3AN, England.
EM bernie.wood@earth.ox.ac.uk
FU European Research Council [267764]; Science and Technology Facilities Council (UK); STFC; NERC [NE/M000370/1] Funding Source: UKRI; Natural Environment Research Council [NE/M000370/1] Funding Source: researchfish
NR 34
TC 133
Z9 143
U1 0
U2 65
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 28
PY 2017
VL 549
IS 7673
BP 507
EP +
DI 10.1038/nature23645
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI4GT
UT WOS:000411930000047
PM 28959970
DA 2026-03-09
ER

PT J
AU Yang, HJ
   Jiang, XL
   Li, BR
   Yang, HJ
   Miller, M
   Yang, A
   Dhar, A
   Pavletich, NP
AF Yang, Haijuan
   Jiang, Xiaolu
   Li, Buren
   Yang, Hyo J.
   Miller, Meredith
   Yang, Angela
   Dhar, Ankita
   Pavletich, Nikola P.
TI Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40
SO NATURE
LA English
DT Article
ID cryo-em structure; p70 s6 kinase; mammalian target; cell-growth; complex; raptor; substrate; tor; mutations; phosphorylation
AB The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the RAPTOR subunit that binds to the Tor signalling sequence (TOS) motif of substrates and regulators. mTORC1 is activated by the small GTPase RHEB (Ras homologue enriched in brain) and inhibited by PRAS40. Here we present the 3.0 angstrom cryo-electron microscopy structure of mTORC1 and the 3.4 angstrom structure of activated RHEB-mTORC1. RHEB binds to mTOR distally from the kinase active site, yet causes a global conformational change that allosterically realigns active-site residues, accelerating catalysis. Cancer-associated hyperactivating mutations map to structural elements that maintain the inactive state, and we provide biochemical evidence that they mimic RHEB relieving auto-inhibition. We also present crystal structures of RAPTOR-TOS motif complexes that define the determinants of TOS recognition, of an mTOR FKBP12-rapamycin-binding (FRB) domain-substrate complex that establishes a second substrate-recruitment mechanism, and of a truncated mTOR-PRAS40 complex that reveals PRAS40 inhibits both substrate-recruitment sites. These findings help explain how mTORC1 selects its substrates, how its kinase activity is controlled, and how it is activated by cancer-associated mutations.
C1 [Yang, Haijuan; Jiang, Xiaolu; Li, Buren; Yang, Hyo J.; Miller, Meredith; Yang, Angela; Dhar, Ankita; Pavletich, Nikola P.] Mem Sloan Kettering Canc Ctr, Struct Biol Program, New York, NY 10065 USA.
   [Jiang, Xiaolu; Yang, Hyo J.; Miller, Meredith; Yang, Angela; Pavletich, Nikola P.] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA.
C3 Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Howard Hughes Medical Institute
RP Pavletich, NP (corresponding author), Mem Sloan Kettering Canc Ctr, Struct Biol Program, New York, NY 10065 USA.; Pavletich, NP (corresponding author), Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA.
EM pavletin@mskcc.org
FU Howard Hughes Medical Institute; National Institutes of Health [CA008748]; National Cancer Institute [P30CA008748] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [P41GM103310] Funding Source: NIH RePORTER
NR 54
TC 406
Z9 484
U1 5
U2 103
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 21
PY 2017
VL 552
IS 7685
BP 368
EP +
DI 10.1038/nature25023
PG 28
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ7RI
UT WOS:000418559800051
PM 29236692
DA 2026-03-09
ER

PT J
AU Guo, JT
   She, J
   Zeng, WZ
   Chen, QF
   Bai, XC
   Jiang, YX
AF Guo, Jiangtao
   She, Ji
   Zeng, Weizhong
   Chen, Qingfeng
   Bai, Xiao-chen
   Jiang, Youxing
TI Structures of the calcium-activated, non-selective cation channel TRPM4
SO NATURE
LA English
DT Article
ID kinase; nucleotides; sensitivity; validation; nanodiscs; protein; sodium; domain
AB TRPM4 is a calcium-activated, phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P-2)-modulated, non-selective cation channel that belongs to the family of melastatin-related transient receptor potential (TRPM) channels. Here we present the electron cryo-microscopy structures of the mouse TRPM4 channel with and without ATP. TRPM4 consists of multiple transmembrane and cytosolic domains, which assemble into a three-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the channel; ATP binds at the nucleotide-binding domain and inhibits channel activity. TRPM4 has an exceptionally wide filter but is only permeable to monovalent cations; filter residue Gln973 is essential in defining monovalent selectivity. The S1-S4 domain and the post-S6 TRP domain form the central gating apparatus that probably houses the Ca2+- and PtdIns(4,5)P-2-binding sites. These structures provide an essential starting point for elucidating the complex gating mechanisms of TRPM4 and reveal the molecular architecture of the TRPM family.
C1 [Guo, Jiangtao; She, Ji; Zeng, Weizhong; Chen, Qingfeng; Jiang, Youxing] Univ Texas Southwestern Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA.
   [Guo, Jiangtao; She, Ji; Zeng, Weizhong; Chen, Qingfeng; Bai, Xiao-chen; Jiang, Youxing] Univ Texas Southwestern Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA.
   [Zeng, Weizhong; Chen, Qingfeng; Jiang, Youxing] Univ Texas Southwestern Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA.
   [Bai, Xiao-chen] Univ Texas Southwestern Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA.
C3 University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Howard Hughes Medical Institute; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center
RP Jiang, YX (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA.; Bai, XC; Jiang, YX (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA.; Jiang, YX (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA.; Bai, XC (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA.
EM xiaochen.bai@utsouthwestern.edu; youxing.jiang@utsouthwestern.edu
FU Howard Hughes Medical Institute; National Institutes of Health [GM079179]; Welch Foundation [I-1578]; Cancer Prevention and Research Initiative of Texas; Virginia Murchison Linthicum Scholar in Medical Research fund
NR 59
TC 154
Z9 173
U1 4
U2 79
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 14
PY 2017
VL 552
IS 7684
BP 205
EP +
DI 10.1038/nature24997
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ0FK
UT WOS:000418029500037
PM 29211714
DA 2026-03-09
ER

PT J
AU Rodríguez-Colman, MJ
   Schewe, M
   Meerlo, M
   Stigter, E
   Gerrits, J
   Pras-Raves, M
   Sacchetti, A
   Hornsveld, M
   Oost, KC
   Snippert, HJ
   Verhoeven-Duif, N
   Fodde, R
   Burgering, BMT
AF Rodriguez-Colman, Maria J.
   Schewe, Matthias
   Meerlo, Maaike
   Stigter, Edwin
   Gerrits, Johan
   Pras-Raves, Mia
   Sacchetti, Andrea
   Hornsveld, Marten
   Oost, Koen C.
   Snippert, Hugo J.
   Verhoeven-Duif, Nanda
   Fodde, Riccardo
   Burgering, Boudewijn M. T.
TI Interplay between metabolic identities in the intestinal crypt supports stem cell function
SO NATURE
LA English
DT Article
ID cancer-cells; nuclear-dna; p38 mapk; colon; progenitors; dichloroacetate; differentiation; identification
AB The small intestinal epithelium self-renews every four or five days. Intestinal stem cells (Lgr5(+) crypt base columnar cells (CBCs)) sustain this renewal and reside between terminally differentiated Paneth cells at the bottom of the intestinal crypt(1). Whereas the signalling requirements for maintaining stem cell function and crypt homeostasis have been well studied, little is known about how metabolism contributes to epithelial homeostasis. Here we show that freshly isolated Lgr5(+) CBCs and Paneth cells from the mouse small intestine display different metabolic programs. Compared to Paneth cells, Lgr5(+) CBCs display high mitochondrial activity. Inhibition of mitochondrial activity in Lgr5(+) CBCs or inhibition of glycolysis in Paneth cells strongly affects stem cell function, as indicated by impaired organoid formation. In addition, Paneth cells support stem cell function by providing lactate to sustain the enhanced mitochondrial oxidative phosphorylation in the Lgr5(+) CBCs. Mechanistically, we show that oxidative phosphorylation stimulates p38 MAPK activation by mitochondrial reactive oxygen species signalling, thereby establishing the mature crypt phenotype. Together, our results reveal a critical role for the metabolic identity of Lgr5(+) CBCs and Paneth cells in supporting optimal stem cell function, and we identify mitochondria and reactive oxygen species signalling as a driving force of cellular differentiation.
C1 [Rodriguez-Colman, Maria J.; Meerlo, Maaike; Stigter, Edwin; Hornsveld, Marten; Oost, Koen C.; Snippert, Hugo J.; Burgering, Boudewijn M. T.] Univ Med Ctr Utrecht, Ctr Mol Med, Mol Canc Res, Heidelberglaan 100, NL-3584 CG Utrecht, Netherlands.
   [Schewe, Matthias; Sacchetti, Andrea; Fodde, Riccardo] Erasmus Univ, Med Ctr, Erasmus MC Canc Inst, Dept Pathol, Rotterdam, Netherlands.
   [Gerrits, Johan; Pras-Raves, Mia; Verhoeven-Duif, Nanda] Dept Genet, Lundlaan 6, NL-3584 EA Utrecht, Netherlands.
   [Gerrits, Johan; Pras-Raves, Mia; Verhoeven-Duif, Nanda] Ctr Mol Med, Lundlaan 6, NL-3584 EA Utrecht, Netherlands.
C3 Utrecht University; Utrecht University Medical Center; Erasmus University Rotterdam; Erasmus MC; Erasmus MC Cancer Institute
RP Burgering, BMT (corresponding author), Univ Med Ctr Utrecht, Ctr Mol Med, Mol Canc Res, Heidelberglaan 100, NL-3584 CG Utrecht, Netherlands.
EM b.m.t.burgering@umcutrecht.nl
FU CGC.nl; Utrecht Life Sciences; Dutch Cancer Society [EMCR 2012-5473, UU 2013-6070]; Netherlands Institute of Regenerative Medicine
NR 36
TC 397
Z9 477
U1 2
U2 146
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 16
PY 2017
VL 543
IS 7645
BP 424
EP +
DI 10.1038/nature21673
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN9RN
UT WOS:000396337400051
PM 28273069
DA 2026-03-09
ER

PT J
AU Yamaji, N
   Takemoto, Y
   Miyaji, T
   Mitani-Ueno, N
   Oshida, KTY
   Ma, JF
AF Yamaji, Naoki
   Takemoto, Yuma
   Miyaji, Takaaki
   Mitani-Ueno, Namiki
   Oshida, Kaoru T. Y.
   Ma, Jian Feng
TI Reducing phosphorus accumulation in rice grains with an impaired transporter in the node
SO NATURE
LA English
DT Article
ID efficiency; silicon; phytate; cereal; crops
AB Phosphorus is an important nutrient for crop productivity. More than 60% of the total phosphorus in cereal crops is finally allocated into the grains and is therefore removed at harvest. This removal accounts for 85% of the phosphorus fertilizers applied to the field each year(1,2). However, because humans and non-ruminants such as poultry, swine and fish cannot digest phytate, the major form of phosphorus in the grains, the excreted phosphorus causes eutrophication of waterways. A reduction in phosphorus accumulation in the grain would contribute to sustainable and environmentally friendly agriculture. Here we describe a rice transporter, SULTR-like phosphorus distribution transporter (SPDT), that controls the allocation of phosphorus to the grain. SPDT is expressed in the xylem region of both enlarged-and diffuse-vascular bundles of the nodes, and encodes a plasma-membrane-localized transporter for phosphorus. Knockout of this gene in rice (Oryza sativa) altered the distribution of phosphorus, with decreased phosphorus in the grains but increased levels in the leaves. Total phosphorus and phytate in the brown de-husked rice were 20-30% lower in the knockout lines, whereas yield, seed germination and seedling vigour were not affected. These results indicate that SPDT functions in the rice node as a switch to allocate phosphorus preferentially to the grains. This finding provides a potential strategy to reduce the removal of phosphorus from the field and lower the risk of eutrophication of waterways.
C1 [Yamaji, Naoki; Takemoto, Yuma; Mitani-Ueno, Namiki; Ma, Jian Feng] Okayama Univ, Inst Plant Sci & Resources, Chuo 2-20-1, Kurashiki, Okayama 7100046, Japan.
   [Miyaji, Takaaki] Okayama Univ, Adv Sci Res Ctr, Okayama 7008530, Japan.
   [Oshida, Kaoru T. Y.] Univ Tokyo, Grad Sch Agr & Life Sci, Bunkyo Ku, Tokyo 1138657, Japan.
C3 Okayama University; Okayama University; University of Tokyo
RP Ma, JF (corresponding author), Okayama Univ, Inst Plant Sci & Resources, Chuo 2-20-1, Kurashiki, Okayama 7100046, Japan.
EM maj@rib.okayama-u.ac.jp
FU JSPS [15H04469, 16H06296]; Grants-in-Aid for Scientific Research [16H06296, 16H04856, 15H04469] Funding Source: KAKEN
NR 26
TC 244
Z9 272
U1 13
U2 525
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 5
PY 2017
VL 541
IS 7635
BP 92
EP +
DI 10.1038/nature20610
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6NA
UT WOS:000396119500035
PM 28002408
DA 2026-03-09
ER

PT J
AU Ohashi, M
   Liu, F
   Hai, Y
   Chen, MB
   Tang, MC
   Yang, ZY
   Sato, M
   Watanabe, K
   Houk, KN
   Tang, Y
AF Ohashi, Masao
   Liu, Fang
   Hai, Yang
   Chen, Mengbin
   Tang, Man-cheng
   Yang, Zhongyue
   Sato, Michio
   Watanabe, Kenji
   Houk, K. N.
   Tang, Yi
TI SAM-dependent enzyme-catalysed pericyclic reactions in natural product biosynthesis
SO NATURE
LA English
DT Article
ID adenosyl-l-methionine; diels-alder reactions; methyltransferase; rearrangement; bifurcations; spinosyn; analogs; cascade; bond
AB Pericyclic reactions-which proceed in a concerted fashion through a cyclic transition state-are among the most powerful synthetic transformations used to make multiple regioselective and stereoselective carbon-carbon bonds(1). They have been widely applied to the synthesis of biologically active complex natural products containing contiguous stereogenic carbon centres(2-6). Despite the prominence of pericyclic reactions in total synthesis, only three naturally existing enzymatic examples (the intramolecular Diels-Alder reaction(7), and the Cope(8) and the Claisen rearrangements(9)) have been characterized. Here we report a versatile S-adenosyl-l-methionine (SAM)-dependent enzyme, LepI, that can catalyse stereoselective dehydration followed by three pericyclic transformations: intramolecular Diels-Alder and hetero-Diels-Alder reactions via a single ambimodal transition state, and a retro-Claisen rearrangement. Together, these transformations lead to the formation of the dihydropyran core of the fungal natural product, leporin(10). Combined in vitro enzymatic characterization and computational studies provide insight into how LepI regulates these bifurcating biosynthetic reaction pathways by using SAM as the cofactor. These pathways converge to the desired biosynthetic end product via the (SAM-dependent) retro-Claisen rearrangement catalysed by LepI. We expect that more pericyclic biosynthetic enzymatic transformations remain to be discovered in naturally occurring enzyme 'toolboxes'(11). The new role of the versatile cofactor SAM is likely to be found in other examples of enzyme catalysis.
C1 [Ohashi, Masao; Hai, Yang; Chen, Mengbin; Tang, Man-cheng; Sato, Michio; Houk, K. N.; Tang, Yi] Univ Calif Los Angeles, Dept Chem & Biomol Engn, Los Angeles, CA 90095 USA.
   [Ohashi, Masao; Sato, Michio; Watanabe, Kenji] Univ Shizuoka, Dept Pharmaceut Sci, Shizuoka 4228526, Japan.
   [Liu, Fang; Yang, Zhongyue; Houk, K. N.; Tang, Yi] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA.
C3 University of California System; University of California Los Angeles; University of Shizuoka; University of California System; University of California Los Angeles
RP Houk, KN; Tang, Y (corresponding author), Univ Calif Los Angeles, Dept Chem & Biomol Engn, Los Angeles, CA 90095 USA.; Watanabe, K (corresponding author), Univ Shizuoka, Dept Pharmaceut Sci, Shizuoka 4228526, Japan.; Houk, KN; Tang, Y (corresponding author), Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA.
EM kenji55@u-shizuoka-ken.ac.jp; houk@chem.ucla.edu; yitang@ucla.edu
FU NIH [1DP1GM106413, 1R35GM118056]; NSF [CHE-1361104]; JSPS Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers [G2604]; Direct For Mathematical & Physical Scien [1361104] Funding Source: National Science Foundation; Division Of Chemistry [1361104] Funding Source: National Science Foundation; National Institute of General Medical Sciences [R35GM118056] Funding Source: NIH RePORTER; Grants-in-Aid for Scientific Research [16H06449] Funding Source: KAKEN
NR 32
TC 163
Z9 185
U1 2
U2 282
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 28
PY 2017
VL 549
IS 7673
BP 502
EP +
DI 10.1038/nature23882
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI4GT
UT WOS:000411930000046
PM 28902839
DA 2026-03-09
ER

PT J
AU Yang, YS
   Chen, CC
   Scott, MC
   Ophus, C
   Xu, R
   Pryor, A
   Wu, L
   Sun, F
   Theis, W
   Zhou, JH
   Eisenbach, M
   Kent, PRC
   Sabirianov, RF
   Zeng, H
   Ercius, P
   Miao, JW
AF Yang, Yongsoo
   Chen, Chien-Chun
   Scott, M. C.
   Ophus, Colin
   Xu, Rui
   Pryor, Alan, Jr.
   Wu, Li
   Sun, Fan
   Theis, Wolfgang
   Zhou, Jihan
   Eisenbach, Markus
   Kent, Paul R. C.
   Sabirianov, Renat F.
   Zeng, Hao
   Ercius, Peter
   Miao, Jianwei
TI Deciphering chemical order/disorder and material properties at the single-atom level
SO NATURE
LA English
DT Article
ID fept nanoparticles; electron tomography; state; crystallography; reconstruction; segregation; scale
AB Perfect crystals are rare in nature. Real materials often contain crystal defects and chemical order/disorder such as grain boundaries, dislocations, interfaces, surface reconstructions and point defects(1-3). Such disruption in periodicity strongly affects material properties and functionality(1-3). Despite rapid development of quantitative material characterization methods(1,4-18), correlating three-dimensional (3D) atomic arrangements of chemical order/disorder and crystal defects with material properties remains a challenge. On a parallel front, quantum mechanics calculations such as density functional theory (DFT) have progressed from the modelling of ideal bulk systems to modelling 'real' materials with dopants, dislocations, grain boundaries and interfaces(19,20); but these calculations rely heavily on average atomic models extracted from crystallography. To improve the predictive power of first-principles calculations, there is a pressing need to use atomic coordinates of real systems beyond average crystallographic measurements. Here we determine the 3D coordinates of 6,569 iron and 16,627 platinum atoms in an iron-platinum nanoparticle, and correlate chemical order/disorder and crystal defects with material properties at the single-atom level. We identify rich structural variety with unprecedented 3D detail including atomic composition, grain boundaries, anti-phase boundaries, anti-site point defects and swap defects. We show that the experimentally measured coordinates and chemical species with 22 picometre precision can be used as direct input for DFT calculations of material properties such as atomic spin and orbital magnetic moments and local magnetocrystalline anisotropy. This work combines 3D atomic structure determination of crystal defects with DFT calculations, which is expected to advance our understanding of structure-property relationships at the fundamental level.
C1 [Yang, Yongsoo; Chen, Chien-Chun; Scott, M. C.; Xu, Rui; Pryor, Alan, Jr.; Wu, Li; Zhou, Jihan; Miao, Jianwei] Univ Calif Los Angeles, Dept Phys & Astron, Los Angeles, CA 90095 USA.
   [Yang, Yongsoo; Chen, Chien-Chun; Scott, M. C.; Xu, Rui; Pryor, Alan, Jr.; Wu, Li; Zhou, Jihan; Miao, Jianwei] Univ Calif Los Angeles, Calif NanoSyst Inst, Los Angeles, CA 90095 USA.
   [Chen, Chien-Chun] Natl Sun Yat Sen Univ, Dept Phys, Kaohsiung 80424, Taiwan.
   [Scott, M. C.; Ophus, Colin; Ercius, Peter] Lawrence Berkeley Natl Lab, Natl Ctr Electro Microscopy, Mol Foundry, Berkeley, CA 94720 USA.
   [Sun, Fan; Zeng, Hao] SUNY Buffalo, Univ Buffalo, Dept Phys, Buffalo, NY 14260 USA.
   [Theis, Wolfgang] Univ Birmingham, Sch Phys & Astron, Nanoscale Phys Res Lab, Birmingham B15 2TT, W Midlands, England.
   [Eisenbach, Markus] Oak Ridge Natl Lab, Natl Ctr Computat Sci, Oak Ridge, TN 37831 USA.
   [Kent, Paul R. C.] Oak Ridge Natl Lab, Comp Sci & Math Div, Oak Ridge, TN 37831 USA.
   [Kent, Paul R. C.] Oak Ridge Natl Lab, Ctr Nanophase Mat Sci, Oak Ridge, TN 37831 USA.
   [Sabirianov, Renat F.] Univ Nebraska, Dept Phys, Omaha, NE 68182 USA.
C3 University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; National Sun Yat Sen University; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; State University of New York (SUNY) System; University at Buffalo, SUNY; University of Birmingham; United States Department of Energy (DOE); Oak Ridge National Laboratory; United States Department of Energy (DOE); Oak Ridge National Laboratory; United States Department of Energy (DOE); Oak Ridge National Laboratory; Center for Nanophase Materials Sciences; University of Nebraska System
RP Miao, JW (corresponding author), Univ Calif Los Angeles, Dept Phys & Astron, Los Angeles, CA 90095 USA.; Miao, JW (corresponding author), Univ Calif Los Angeles, Calif NanoSyst Inst, Los Angeles, CA 90095 USA.
EM miao@physics.ucla.edu
FU Office of Basic Energy Sciences of the US DOE [DE-SC0010378]; Division of Materials Research of the US NSF [DMR-1548924, DMR-1437263]; DARPA [DARPA-BAA-12-63]; U.S. Department of Energy (DOE) [DE-SC0010378] Funding Source: U.S. Department of Energy (DOE); Division Of Materials Research; Direct For Mathematical & Physical Scien [1623947] Funding Source: National Science Foundation
NR 56
TC 260
Z9 344
U1 15
U2 656
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 2
PY 2017
VL 542
IS 7639
BP 75
EP +
DI 10.1038/nature21042
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6MY
UT WOS:000396119300034
PM 28150758
DA 2026-03-09
ER

PT J
AU Bayeh, L
   Le, PQ
   Tambar, UK
AF Bayeh, Liela
   Le, Phong Q.
   Tambar, Uttam K.
TI Catalytic allylic oxidation of internal alkenes to a multifunctional chiral building block
SO NATURE
LA English
DT Article
ID acid catalysis; ene reactions; olefins; amination; functionalization; acetylenes; reagents; strategy; bonds
AB The stereoselective oxidation of hydrocarbons is one of the most notable advances in synthetic chemistry over the past fifty years(1-3). Inspired by nature, enantioselective dihydroxylations, epoxidations and other oxidations of unsaturated hydrocarbons have been developed. More recently, the catalytic enantioselective allylic carbon-hydrogen oxidation of alkenes has streamlined the production of pharmaceuticals, natural products, fine chemicals and other functional materials(4-7). Allylic functionalization provides a direct path to chiral building blocks with a newly formed stereocentre from petrochemical feedstocks while preserving the olefin functionality as a handle for further chemical elaboration. Various metal-based catalysts have been discovered for the enantioselective allylic carbon-hydrogen oxidation of simple alkenes with cyclic or terminal double bonds(8-16). However, a general and selective allylic oxidation using the more common internal alkenes remains elusive. Here we report the enantioselective, regioselective and E/Z-selective allylic oxidation of unactivated internal alkenes via a catalytic hetero-ene reaction with a chalcogen-based oxidant. Our method enables non-symmetric internal alkenes to be selectively converted into allylic functionalized products with high stereoselectivity and regioselectivity. Stereospecific transformations of the resulting multifunctional chiral building blocks highlight the potential for rapidly converting internal alkenes into a broad range of enantioenriched structures that can be used in the synthesis of complex target molecules.
C1 [Bayeh, Liela; Le, Phong Q.; Tambar, Uttam K.] Univ Texas Southwestern Med Ctr Dallas, Dept Biochem, 5323 Harry Hines Blvd, Dallas, TX 75390 USA.
C3 University of Texas System; University of Texas Southwestern Medical Center
RP Tambar, UK (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Biochem, 5323 Harry Hines Blvd, Dallas, TX 75390 USA.
EM Uttam.Tambar@utsouthwestern.edu
FU W. W. Caruth Jr Endowed Scholarship; Robert A. Welch Foundation [I-1748]; National Institutes of Health [R01GM102604]; National Science Foundation CAREER Award [1150875]; Sloan Research Fellowship; National Institute of General Medical Sciences [R01GM102604] Funding Source: NIH RePORTER; Division Of Chemistry; Direct For Mathematical & Physical Scien [1150875] Funding Source: National Science Foundation
NR 32
TC 101
Z9 117
U1 8
U2 147
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 13
PY 2017
VL 547
IS 7662
BP 196
EP +
DI 10.1038/nature22805
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FA3AX
UT WOS:000405314500034
PM 28636605
DA 2026-03-09
ER

PT J
AU LePage, DP
   Metcalf, JA
   Bordenstein, SR
   On, JM
   Perlmutter, JI
   Shropshire, JD
   Layton, EM
   Funkhouser-Jones, LJ
   Beckmann, JF
   Bordenstein, SR
AF LePage, Daniel P.
   Metcalf, Jason A.
   Bordenstein, Sarah R.
   On, Jungmin
   Perlmutter, Jessamyn I.
   Shropshire, J. Dylan
   Layton, Emily M.
   Funkhouser-Jones, Lisa J.
   Beckmann, John F.
   Bordenstein, Seth R.
TI Prophage WO genes recapitulate and enhance Wolbachia-induced cytoplasmic incompatibility
SO NATURE
LA English
DT Article
ID drosophila-melanogaster; phage wo; protein; expression; database; model
AB The genus Wolbachia is an archetype of maternally inherited intracellular bacteria that infect the germline of numerous invertebrate species worldwide. They can selfishly alter arthropod sex ratios and reproductive strategies to increase the proportion of the infected matriline in the population. The most common reproductive manipulation is cytoplasmic incompatibility, which results in embryonic lethality in crosses between infected males and uninfected females. Females infected with the same Wolbachia strain rescue this lethality. Despite more than 40 years of research(1) and relevance to symbiont-induced speciation(2,3), as well as control of arbovirus vectors(4-6) and agricultural pests(7), the bacterial genes underlying cytoplasmic incompatibility remain unknown. Here we use comparative and transgenic approaches to demonstrate that two differentially transcribed, co-diverging genes in the eukaryotic association module of prophage WO8 from Wolbachia strain wMel recapitulate and enhance cytoplasmic incompatibility. Dual expression in transgenic, uninfected males of Drosophila melanogaster crossed to uninfected females causes embryonic lethality. Each gene additively augments embryonic lethality in crosses between infected males and uninfected females. Lethality associates with embryonic defects that parallel those of wild-type cytoplasmic incompatibility and is notably rescued by wMel-infected embryos in all cases. The discovery of cytoplasmic incompatibility factor genes cifA and cifB pioneers genetic studies of prophage WO-induced reproductive manipulations and informs the continuing use of Wolbachia to control dengue and Zika virus transmission to humans.
C1 [LePage, Daniel P.; Metcalf, Jason A.; Bordenstein, Sarah R.; On, Jungmin; Perlmutter, Jessamyn I.; Shropshire, J. Dylan; Layton, Emily M.; Funkhouser-Jones, Lisa J.; Bordenstein, Seth R.] Vanderbilt Univ, Dept Biol Sci, 221 Kirkland Hall, Nashville, TN 37235 USA.
   [Beckmann, John F.] Yale Univ, Dept Mol Biophys & Biochem, POB 6666, New Haven, CT 06520 USA.
   [Bordenstein, Seth R.] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, 221 Kirkland Hall, Nashville, TN 37235 USA.
C3 Vanderbilt University; Yale University; Vanderbilt University
RP Bordenstein, SR (corresponding author), Vanderbilt Univ, Dept Biol Sci, 221 Kirkland Hall, Nashville, TN 37235 USA.
EM s.bordenstein@vanderbilt.edu
FU National Institutes of Health (NIH) [R21 HD086833]; National Science Foundation [IOS 1456778, DEB-1501398]; NIH [5T32GM008554, T32GM07347, AI081322, CA68485, DK20593, DK58404, DK59637, EY08126]; Division Of Environmental Biology; Direct For Biological Sciences [1501398] Funding Source: National Science Foundation; Division Of Integrative Organismal Systems; Direct For Biological Sciences [1456778] Funding Source: National Science Foundation; National Cancer Institute [P30CA068485] Funding Source: NIH RePORTER; National Eye Institute [P30EY008126] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [U2CDK059637, P30DK020593, P30DK058404] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007347] Funding Source: NIH RePORTER
NR 55
TC 365
Z9 421
U1 0
U2 207
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 9
PY 2017
VL 543
IS 7644
BP 243
EP +
DI 10.1038/nature21391
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0GQ
UT WOS:000395688700039
PM 28241146
DA 2026-03-09
ER

PT J
AU Capelli, P
   Pivetta, C
   Esposito, MS
   Arber, S
AF Capelli, Paolo
   Pivetta, Chiara
   Esposito, Maria Soledad
   Arber, Silvia
TI Locomotor speed control circuits in the caudal brainstem
SO NATURE
LA English
DT Article
ID medullary reticular-formation; intact unanesthetized cat; spinal-cord; functional-organization; gabaergic neurons; activation; stimulation; generation; forelimb; variant
AB Locomotion is a universal behaviour that provides animals with the ability to move between places. Classical experiments have used electrical microstimulation to identify brain regions that promote locomotion1-5, but the identity of neurons that act as key intermediaries between higher motor planning centres and executive circuits in the spinal cord has remained controversial6-14. Here we show that the mouse caudal brainstem encompasses functionally heterogeneous neuronal subpopulations that have differential effects on locomotion. These subpopulations are distinguishable by location, neurotransmitter identity and connectivity. Notably, glutamatergic neurons within the lateral paragigantocellular nucleus (LPGi), a small subregion in the caudal brainstem, are essential to support high-speed locomotion, and can positively tune locomotor speed through inputs from glutamatergic neurons of the upstream midbrain locomotor region. By contrast, glycinergic inhibitory neurons can induce different forms of behavioural arrest mapping onto distinct caudal brainstem regions. Anatomically, descending pathways of glutamatergic and glycinergic LPGi subpopulations communicate with distinct effector circuits in the spinal cord. Our results reveal that behaviourally opposing locomotor functions in the caudal brainstem were historically masked by the unexposed diversity of intermingled neuronal subpopulations. We demonstrate how specific brainstem neuron populations represent essential substrates to implement key parameters in the execution of motor programs.
C1 [Capelli, Paolo; Pivetta, Chiara; Esposito, Maria Soledad; Arber, Silvia] Univ Basel, Biozentrum, Dept Cell Biol, CH-4056 Basel, Switzerland.
   [Capelli, Paolo; Pivetta, Chiara; Esposito, Maria Soledad; Arber, Silvia] Friedrich Miescher Inst Biomed Res, CH-4058 Basel, Switzerland.
C3 University of Basel; Friedrich Miescher Institute for Biomedical Research
RP Arber, S (corresponding author), Univ Basel, Biozentrum, Dept Cell Biol, CH-4056 Basel, Switzerland.; Arber, S (corresponding author), Friedrich Miescher Inst Biomed Res, CH-4058 Basel, Switzerland.
EM silvia.arber@unibas.ch
FU ERC; Swiss National Science Foundation, Kanton Basel-Stadt; Novartis Research Foundation; Louis Jeantet Prize for Medicine; HFSP; Synapsis Foundation; NARSAD by the Brain and Behavior Foundation
NR 45
TC 209
Z9 253
U1 1
U2 34
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 16
PY 2017
VL 551
IS 7680
BP 373
EP +
DI 10.1038/nature24064
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM8UK
UT WOS:000415365500041
PM 29059682
DA 2026-03-09
ER

PT J
AU Liu, KH
   Niu, YJ
   Konishi, M
   Wu, Y
   Du, H
   Chung, HS
   Li, L
   Boudsocq, M
   McCormack, M
   Maekawa, S
   Ishida, T
   Zhang, C
   Shokat, K
   Yanagisawa, S
   Sheen, J
AF Liu, Kun-hsiang
   Niu, Yajie
   Konishi, Mineko
   Wu, Yue
   Du, Hao
   Chung, Hoo Sun
   Li, Lei
   Boudsocq, Marie
   McCormack, Matthew
   Maekawa, Shugo
   Ishida, Tetsuya
   Zhang, Chao
   Shokat, Kevan
   Yanagisawa, Shuichi
   Sheen, Jen
TI Discovery of nitrate-CPK-NLP signalling in central nutrient-growth networks
SO NATURE
LA English
DT Article
ID transient gene-expression; transcription factors; arabidopsis roots; protein-kinases; calcium; glucose; stress; translation; protoplasts; metabolism
AB Nutrient signalling integrates and coordinates gene expression, metabolism and growth. However, its primary molecular mechanisms remain incompletely understood in plants and animals. Here we report unique Ca2+ signalling triggered by nitrate with live imaging of an ultrasensitive biosensor in Arabidopsis leaves and roots. A nitrate-sensitized and targeted functional genomic screen identifies subgroup III Ca2+-sensor protein kinases (CPKs) as master regulators that orchestrate primary nitrate responses. A chemical switch with the engineered mutant CPK10(M141G) circumvents embryo lethality and enables conditional analyses of cpk10 cpk30 cpk32 triple mutants to define comprehensive nitrate-associated regulatory and developmental programs. Nitrate-coupled CPK signalling phosphorylates conserved NIN-LIKE PROTEIN (NLP) transcription factors to specify the reprogramming of gene sets for downstream transcription factors, transporters, nitrogen assimilation, carbon/nitrogen metabolism, redox, signalling, hormones and proliferation. Conditional cpk10 cpk30 cpk32 and nlp7 mutants similarly impair nitrate-stimulated system-wide shoot growth and root establishment. The nutrient-coupled Ca2+ signalling network integrates transcriptome and cellular metabolism with shoot-root coordination and developmental plasticity in shaping organ biomass and architecture.
C1 [Liu, Kun-hsiang; Niu, Yajie; Wu, Yue; Du, Hao; Chung, Hoo Sun; Li, Lei; Boudsocq, Marie; McCormack, Matthew; Sheen, Jen] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.
   [Liu, Kun-hsiang; Niu, Yajie; Wu, Yue; Du, Hao; Chung, Hoo Sun; Li, Lei; Boudsocq, Marie; McCormack, Matthew; Sheen, Jen] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA.
   [Liu, Kun-hsiang; Niu, Yajie; Wu, Yue; Du, Hao; Chung, Hoo Sun; Li, Lei; Boudsocq, Marie; McCormack, Matthew; Sheen, Jen] Harvard Med Sch, Dept Genet, Boston, MA 02114 USA.
   [Liu, Kun-hsiang] Fujian Agr & Forestry Univ, Basic Forestry & Prote Res Ctr, Fuzhou 350002, Fujian, Peoples R China.
   [Konishi, Mineko; Maekawa, Shugo; Ishida, Tetsuya; Yanagisawa, Shuichi] Univ Tokyo, Biotechnol Res Ctr, Bunkyo Ku, Yayoi 1-1-1, Tokyo 1138657, Japan.
   [Boudsocq, Marie] Univ Paris Saclay, Univ Paris Sud, Univ Evry Val Essonne,Sorbonne Paris Cite, Inst Plant Sci Paris Saclay IPS2,CNRS,INRA,Univ P, Batiment 630, F-91405 Orsay, France.
   [Zhang, Chao; Shokat, Kevan] UCSF, Howard Hughes Med Inst, 600 16th St, San Francisco, CA 94143 USA.
   [Zhang, Chao; Shokat, Kevan] UCSF, Dept Cellular & Mol Pharmacol, 600 16th St, San Francisco, CA 94143 USA.
C3 Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Fujian Agriculture & Forestry University; University of Tokyo; Universite Paris Saclay; Universite Paris Cite; Centre National de la Recherche Scientifique (CNRS); INRAE; Howard Hughes Medical Institute; University of California System; University of California San Francisco; University of California System; University of California San Francisco
RP Liu, KH; Sheen, J (corresponding author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Liu, KH; Sheen, J (corresponding author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA.; Liu, KH; Sheen, J (corresponding author), Harvard Med Sch, Dept Genet, Boston, MA 02114 USA.; Liu, KH (corresponding author), Fujian Agr & Forestry Univ, Basic Forestry & Prote Res Ctr, Fuzhou 350002, Fujian, Peoples R China.; Yanagisawa, S (corresponding author), Univ Tokyo, Biotechnol Res Ctr, Bunkyo Ku, Yayoi 1-1-1, Tokyo 1138657, Japan.
EM khliu@molbio.mgh.harvard.edu; asyanagi@mail.ecc.u-tokyo.ac.jp; sheen@molbio.mgh.harvard.edu
FU NIH; NSF; WJC Special Project RDA-Korea [PJ009106]; JST [CREST-JPMJCR15O5]; JSPS-KAKENHI [25252014/26221103, 15H05616]; NSFC [31670246]; Grants-in-Aid for Scientific Research [15H05616, 26221103, 25252014, 15J08368] Funding Source: KAKEN
NR 67
TC 498
Z9 558
U1 22
U2 581
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 18
PY 2017
VL 545
IS 7654
BP 311
EP +
DI 10.1038/nature22077
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV0WF
UT WOS:000401466500055
PM 28489820
DA 2026-03-09
ER

PT J
AU Ruan, LH
   Zhou, CK
   Jin, EL
   Kucharavy, A
   Zhang, Y
   Wen, ZH
   Florens, L
   Li, R
AF Ruan, Linhao
   Zhou, Chuankai
   Jin, Erli
   Kucharavy, Andrei
   Zhang, Ying
   Wen, Zhihui
   Florens, Laurence
   Li, Rong
TI Cytosolic proteostasis through importing of misfolded proteins into mitochondria
SO NATURE
LA English
DT Article
ID green fluorescent protein; saccharomyces-cerevisiae; budding yeast; identification technology; membrane; stress; cells; neurodegeneration; translocation; aggregation
AB Loss of proteostasis underlies ageing and neurodegeneration characterized by the accumulation of protein aggregates and mitochondrial dysfunction(1-5). Although many neurodegenerative-disease-associated proteins can be found in mitochondria(4,6), it remains unclear how mitochondrial dysfunction and protein aggregation could be related. In dividing yeast cells, protein aggregates that form under stress or during ageing are preferentially retained by the mother cell, in part through tethering to mitochondria, while the disaggregase Hsp104 helps to dissociate aggregates and thereby enables refolding or degradation of misfolded proteins(7-10). Here we show that, in yeast, cytosolic proteins prone to aggregation are imported into mitochondria for degradation. Protein aggregates that form under heat shock contain both cytosolic and mitochondrial proteins and interact with the mitochondrial import complex. Many aggregation-prone proteins enter the mitochondrial intermembrane space and matrix after heat shock, and some do so even without stress. Timely dissolution of cytosolic aggregates requires the mitochondrial import machinery and proteases. Blocking mitochondrial import but not proteasome activity causes a marked delay in the degradation of aggregated proteins. Defects in cytosolic Hsp70s leads to enhanced entry of misfolded proteins into mitochondria and elevated mitochondrial stress. We term this mitochondria-mediated proteostasis mechanism MAGIC (mitochondria as guardian in cytosol) and provide evidence that it may exist in human cells.
C1 [Ruan, Linhao; Kucharavy, Andrei; Li, Rong] Johns Hopkins Univ, Sch Med, Dept Cell Biol, Ctr Cell Dynam, 855 North Wolfe St, Baltimore, MD 21205 USA.
   [Ruan, Linhao; Jin, Erli; Kucharavy, Andrei; Li, Rong] Johns Hopkins Univ, Whiting Sch Engn, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA.
   [Zhou, Chuankai; Zhang, Ying; Wen, Zhihui; Florens, Laurence] Stowers Inst Med Res, 1000 East 50th St, Kansas City, MO 64110 USA.
C3 Johns Hopkins University; Johns Hopkins University; Stowers Institute for Medical Research
RP Li, R (corresponding author), Johns Hopkins Univ, Sch Med, Dept Cell Biol, Ctr Cell Dynam, 855 North Wolfe St, Baltimore, MD 21205 USA.; Li, R (corresponding author), Johns Hopkins Univ, Whiting Sch Engn, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA.
EM rong@jhu.edu
FU National Institute of Health [R35 GM118172]; American Heart Association
NR 47
TC 362
Z9 417
U1 2
U2 170
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 16
PY 2017
VL 543
IS 7645
BP 443
EP +
DI 10.1038/nature21695
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN9RN
UT WOS:000396337400055
PM 28241148
DA 2026-03-09
ER

PT J
AU Ren, JG
   Xu, P
   Yong, HL
   Zhang, L
   Liao, SK
   Yin, J
   Liu, WY
   Cai, WQ
   Yang, M
   Li, L
   Yang, KX
   Han, X
   Yao, YQ
   Li, J
   Wu, HY
   Wan, S
   Liu, L
   Liu, DQ
   Kuang, YW
   He, ZP
   Shang, P
   Guo, C
   Zheng, RH
   Tian, K
   Zhu, ZC
   Liu, NL
   Lu, CY
   Shu, R
   Chen, YA
   Peng, CZ
   Wang, JY
   Pan, JW
AF Ren, Ji-Gang
   Xu, Ping
   Yong, Hai-Lin
   Zhang, Liang
   Liao, Sheng-Kai
   Yin, Juan
   Liu, Wei-Yue
   Cai, Wen-Qi
   Yang, Meng
   Li, Li
   Yang, Kui-Xing
   Han, Xuan
   Yao, Yong-Qiang
   Li, Ji
   Wu, Hai-Yan
   Wan, Song
   Liu, Lei
   Liu, Ding-Quan
   Kuang, Yao-Wu
   He, Zhi-Ping
   Shang, Peng
   Guo, Cheng
   Zheng, Ru-Hua
   Tian, Kai
   Zhu, Zhen-Cai
   Liu, Nai-Le
   Lu, Chao-Yang
   Shu, Rong
   Chen, Yu-Ao
   Peng, Cheng-Zhi
   Wang, Jian-Yu
   Pan, Jian-Wei
TI Ground-to-satellite quantum teleportation
SO NATURE
LA English
DT Article
ID entanglement distribution; state; light; spins
AB An arbitrary unknown quantum state cannot be measured precisely or replicated perfectly(1). However, quantum teleportation enables unknown quantum states to be transferred reliably from one object to another over long distances(2), without physical travelling of the object itself. Long-distance teleportation is a fundamental element of protocols such as large-scale quantum networks(3,4) and distributed quantum computation(5,6). But the distances over which transmission was achieved in previous teleportation experiments, which used optical fibres and terrestrial free-space channels(7-12), were limited to about 100 kilometres, owing to the photon loss of these channels. To realize a global-scale 'quantum internet'(13) the range of quantum teleportation needs to be greatly extended. A promising way of doing so involves using satellite platforms and space-based links, which can connect two remote points on Earth with greatly reduced channel loss because most of the propagation path of the photons is in empty space. Here we report quantum teleportation of independent single-photon qubits from a ground observatory to a low-Earth-orbit satellite, through an uplink channel, over distances of up to 1,400 kilometres. To optimize the efficiency of the link and to counter the atmospheric turbulence in the uplink, we use a compact ultra-bright source of entangled photons, a narrow beam divergence and high-bandwidth and high-accuracy acquiring, pointing and tracking. We demonstrate successful quantum teleportation of six input states in mutually unbiased bases with an average fidelity of 0.80 +/- 0.01, well above the optimal state-estimation fidelity on a single copy of a qubit (the classical limit)(14). Our demonstration of a ground-to-satellite uplink for reliable and ultra-long-distance quantum teleportation is an essential step towards a global-scale quantum internet.
C1 [Ren, Ji-Gang; Xu, Ping; Yong, Hai-Lin; Liao, Sheng-Kai; Yin, Juan; Liu, Wei-Yue; Cai, Wen-Qi; Yang, Meng; Li, Li; Yang, Kui-Xing; Han, Xuan; Shang, Peng; Guo, Cheng; Liu, Nai-Le; Lu, Chao-Yang; Chen, Yu-Ao; Peng, Cheng-Zhi; Pan, Jian-Wei] Univ Sci & Technol China, Dept Modern Phys, Hefei 230026, Peoples R China.
   [Ren, Ji-Gang; Xu, Ping; Yong, Hai-Lin; Liao, Sheng-Kai; Yin, Juan; Liu, Wei-Yue; Cai, Wen-Qi; Yang, Meng; Li, Li; Yang, Kui-Xing; Han, Xuan; Shang, Peng; Guo, Cheng; Liu, Nai-Le; Lu, Chao-Yang; Chen, Yu-Ao; Peng, Cheng-Zhi; Pan, Jian-Wei] Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Peoples R China.
   [Ren, Ji-Gang; Xu, Ping; Yong, Hai-Lin; Zhang, Liang; Liao, Sheng-Kai; Yin, Juan; Liu, Wei-Yue; Cai, Wen-Qi; Yang, Meng; Li, Li; Yang, Kui-Xing; Han, Xuan; Shang, Peng; Guo, Cheng; Liu, Nai-Le; Lu, Chao-Yang; Shu, Rong; Chen, Yu-Ao; Peng, Cheng-Zhi; Wang, Jian-Yu; Pan, Jian-Wei] Univ Sci & Technol China, CAS, Ctr Excellence & Synerget Innovat Ctr Quantum Inf, Shanghai 201315, Peoples R China.
   [Zhang, Liang; Liu, Ding-Quan; Kuang, Yao-Wu; He, Zhi-Ping; Shu, Rong; Wang, Jian-Yu] Chinese Acad Sci, Shanghai Inst Tech Phys, Key Lab Space Act Optoelect Technol, Shanghai 200083, Peoples R China.
   [Yao, Yong-Qiang] Chinese Acad Sci, Natl Astron Observ, Beijing 100012, Peoples R China.
   [Li, Ji; Wu, Hai-Yan] Chinese Acad Sci, Nanjing Astron Instruments Co Ltd, Nanjing 210042, Jiangsu, Peoples R China.
   [Wan, Song; Liu, Lei; Zhu, Zhen-Cai] Shanghai Engn Ctr Microsatellites, Shanghai 201203, Peoples R China.
   [Zheng, Ru-Hua] Beijing Inst Tracking & Telecommun Technol, Beijing 100094, Peoples R China.
   [Tian, Kai] Xian Satellite Control Ctr, State Key Lab Astronaut Dynam, Xian 710061, Shaanxi, Peoples R China.
C3 Chinese Academy of Sciences; University of Science & Technology of China, CAS; Chinese Academy of Sciences; University of Science & Technology of China, CAS; Chinese Academy of Sciences; University of Science & Technology of China, CAS; Chinese Academy of Sciences; Shanghai Institute of Technical Physics, CAS; Chinese Academy of Sciences; National Astronomical Observatory, CAS; Chinese Academy of Sciences
RP Peng, CZ; Pan, JW (corresponding author), Univ Sci & Technol China, Dept Modern Phys, Hefei 230026, Peoples R China.; Peng, CZ; Pan, JW (corresponding author), Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Peoples R China.; Peng, CZ; Wang, JY; Pan, JW (corresponding author), Univ Sci & Technol China, CAS, Ctr Excellence & Synerget Innovat Ctr Quantum Inf, Shanghai 201315, Peoples R China.; Wang, JY (corresponding author), Chinese Acad Sci, Shanghai Inst Tech Phys, Key Lab Space Act Optoelect Technol, Shanghai 200083, Peoples R China.
EM pcz@ustc.edu.cn; jywang@mail.sitp.ac.cn; pan@ustc.edu.cn
FU Strategic Priority Research Program on Space Science; Chinese Academy of Sciences; National Natural Science Foundation of China
NR 30
TC 673
Z9 797
U1 9
U2 322
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 7
PY 2017
VL 549
IS 7670
BP 70
EP +
DI 10.1038/nature23675
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG0DH
UT WOS:000409388700034
PM 28825708
DA 2026-03-09
ER

PT J
AU Beier, KT
   Kim, CK
   Hoerbelt, P
   Hung, LW
   Heifets, BD
   DeLoach, KE
   Mosca, TJ
   Neuner, S
   Deisseroth, K
   Luo, LQ
   Malenka, RC
AF Beier, Kevin T.
   Kim, Christina K.
   Hoerbelt, Paul
   Hung, Lin Wai
   Heifets, Boris D.
   DeLoach, Katherine E.
   Mosca, Timothy J.
   Neuner, Sophie
   Deisseroth, Karl
   Luo, Liqun
   Malenka, Robert C.
TI Rabies screen reveals GPe control of cocaine-triggered plasticity
SO NATURE
LA English
DT Article
ID basal ganglia; gabaergic neurons; dopamine neurons; globus-pallidus; transgenic mice; circuits; output; input; organization; behavior
AB Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labelling. Inhibition of GPe activity revealed that it contributes to two forms of cocaine-triggered behavioural plasticity, at least in part by disinhibiting dopamine neurons in the ventral tegmental area. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioural adaptations.
C1 [Beier, Kevin T.; Hoerbelt, Paul; Hung, Lin Wai; Heifets, Boris D.; Neuner, Sophie; Malenka, Robert C.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Nancy Pritzker Lab, Stanford, CA 94305 USA.
   [Beier, Kevin T.; DeLoach, Katherine E.; Mosca, Timothy J.; Luo, Liqun] Stanford Univ, Dept Biol, Stanford, CA 94305 USA.
   [Kim, Christina K.] Stanford Univ, Neurosci Program, Stanford, CA 94305 USA.
   [Heifets, Boris D.] Stanford Univ, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Stanford, CA 94305 USA.
   [Deisseroth, Karl] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.
   [Deisseroth, Karl] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA.
   [DeLoach, Katherine E.; Deisseroth, Karl; Luo, Liqun] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Mosca, Timothy J.] Thomas Jefferson Univ, Dept Neurosci, Philadelphia, PA 19107 USA.
C3 Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Howard Hughes Medical Institute; Thomas Jefferson University
RP Malenka, RC (corresponding author), Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Nancy Pritzker Lab, Stanford, CA 94305 USA.; Luo, LQ (corresponding author), Stanford Univ, Dept Biol, Stanford, CA 94305 USA.; Luo, LQ (corresponding author), Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.
EM lluo@stanford.edu; malenka@stanford.edu
FU Howard Hughes Medical Institute; National Institutes of Health [R01-NS50835, PO1 DA008227, TR01-MH099647, F32-DA038913, K99-DC013059, K99-DA041445]; Stanford Neurosciences Institute; National Institute of Neurological Disorders and Stroke [R01NS050835] Funding Source: NIH RePORTER
NR 45
TC 85
Z9 104
U1 0
U2 26
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 21
PY 2017
VL 549
IS 7672
BP 345
EP +
DI 10.1038/nature23888
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FH7PB
UT WOS:000411381300027
PM 28902833
DA 2026-03-09
ER

PT J
AU Amy, C
   Budenstein, D
   Bagepalli, M
   England, D
   DeAngelis, F
   Wilk, G
   Jarrett, C
   Kelsall, C
   Hirschey, J
   Wen, H
   Havan, C
   Gilleland, B
   Yuan, C
   Chueh, WC
   Sandhage, KH
   Kawajiri, Y
   Henry, A
AF Amy, C.
   Budenstein, D.
   Bagepalli, M.
   England, D.
   DeAngelis, F.
   Wilk, G.
   Jarrett, C.
   Kelsall, C.
   Hirschey, J.
   Wen, H.
   Chavan, A.
   Gilleland, B.
   Yuan, C.
   Chueh, W. C.
   Sandhage, K. H.
   Kawajiri, Y.
   Henry, A.
TI Pumping liquid metal at high temperatures up to 1,673 kelvin
SO NATURE
LA English
DT Article
ID concentrated solar power; heat-transfer fluids; central receiver systems; thermal-energy storage; design; aluminum; alloys; tin; technology; efficiency
AB Heat is fundamental to power generation and many industrial processes, and is most useful at high temperatures because it can be converted more efficiently to other types of energy. However, efficient transportation, storage and conversion of heat at extreme temperatures (more than about 1,300 kelvin) is impractical for many applications. Liquid metals can be very effective media for transferring heat at high temperatures, but liquid-metal pumping has been limited by the corrosion of metal infrastructures. Here we demonstrate a ceramic, mechanical pump that can be used to continuously circulate liquid tin at temperatures of around 1,473-1,673 kelvin. Our approach to liquid-metal pumping is enabled by the use of ceramics for the mechanical and sealing components, but owing to the brittle nature of ceramics their use requires careful engineering. Our set-up enables effective heat transfer using a liquid at previously unattainable temperatures, and could be used for thermal storage and transport, electric power production, and chemical or materials processing.
C1 [Amy, C.; Budenstein, D.; Bagepalli, M.; England, D.; DeAngelis, F.; Wilk, G.; Jarrett, C.; Kelsall, C.; Hirschey, J.; Wen, H.; Chavan, A.; Gilleland, B.; Yuan, C.; Henry, A.] Georgia Inst Technol, George W Woodruff Sch Mech Engn, Atlanta, GA 30332 USA.
   [Chueh, W. C.] Stanford Univ, Dept Mat Sci & Engn, Stanford, CA 94305 USA.
   [Sandhage, K. H.; Henry, A.] Georgia Inst Technol, Sch Mat Sci & Engn, Atlanta, GA 30332 USA.
   [Sandhage, K. H.] Purdue Univ, Sch Mat Engn, W Lafayette, IN 47907 USA.
   [Kawajiri, Y.] Georgia Inst Technol, Sch Chem & Biomol Engn, Atlanta, GA 30332 USA.
   [Henry, A.] Georgia Inst Technol, Heat Lab, Atlanta, GA 30332 USA.
C3 University System of Georgia; Georgia Institute of Technology; Stanford University; University System of Georgia; Georgia Institute of Technology; Purdue University System; Purdue University; University System of Georgia; Georgia Institute of Technology; University System of Georgia; Georgia Institute of Technology
RP Henry, A (corresponding author), Georgia Inst Technol, George W Woodruff Sch Mech Engn, Atlanta, GA 30332 USA.; Henry, A (corresponding author), Georgia Inst Technol, Sch Mat Sci & Engn, Atlanta, GA 30332 USA.; Henry, A (corresponding author), Georgia Inst Technol, Heat Lab, Atlanta, GA 30332 USA.
EM ase@gatech.edu
FU Advanced Research Projects Agency - Energy (ARPA-E) [DE-AR0000339]
NR 60
TC 70
Z9 87
U1 8
U2 129
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 12
PY 2017
VL 550
IS 7675
BP 199
EP +
DI 10.1038/nature24054
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FJ5YG
UT WOS:000412829500038
PM 29022590
DA 2026-03-09
ER

PT J
AU Birey, F
   Andersen, J
   Makinson, CD
   Islam, S
   Wei, W
   Huber, N
   Fan, HC
   Metzler, KRC
   Panagiotakos, G
   Thom, N
   O'Rourke, NA
   Steinmetz, LM
   Bernstein, JA
   Hallmayer, J
   Huguenard, JR
   Pasca, SP
AF Birey, Fikri
   Andersen, Jimena
   Makinson, Christopher D.
   Islam, Saiful
   Wei, Wu
   Huber, Nina
   Fan, H. Christina
   Metzler, Kimberly R. Cordes
   Panagiotakos, Georgia
   Thom, Nicholas
   O'Rourke, Nancy A.
   Steinmetz, Lars M.
   Bernstein, Jonathan A.
   Hallmayer, Joachim
   Huguenard, John R.
   Pasca, Sergiu P.
TI Assembly of functionally integrated human forebrain spheroids
SO NATURE
LA English
DT Article
ID pluripotent stem-cells; interneuron migration; gene-expression; in-vitro; neurons; dysfunction; progenitor; inhibition; astrocytes; maturation
AB The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (gamma-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome-a neurodevelopmental disorder that is caused by mutations in the Ca(V)1.2 calcium channel-interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.
C1 [Birey, Fikri; Andersen, Jimena; Huber, Nina; Thom, Nicholas; O'Rourke, Nancy A.; Hallmayer, Joachim; Pasca, Sergiu P.] Stanford Univ, Sch Med, Ctr Sleep Sci & Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA.
   [Makinson, Christopher D.; Huguenard, John R.] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA.
   [Islam, Saiful; Wei, Wu; Steinmetz, Lars M.] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA.
   [Wei, Wu; Steinmetz, Lars M.] Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA.
   [Fan, H. Christina; Metzler, Kimberly R. Cordes] BD Genom, Menlo Pk, CA 94025 USA.
   [Panagiotakos, Georgia] Univ Calif San Francisco, Dept Biochem & Biophys, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA.
   [Steinmetz, Lars M.] EMBL, Genome Biol Unit, D-69117 Heidelberg, Germany.
   [Bernstein, Jonathan A.] Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; Stanford University; Stanford University; University of California System; University of California San Francisco; European Molecular Biology Laboratory (EMBL); Stanford University
RP Pasca, SP (corresponding author), Stanford Univ, Sch Med, Ctr Sleep Sci & Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA.
EM spasca@stanford.edu
FU NIH/National Institute of Mental Health (NIMH) [R01MH100900, R01MH100900-02S1]; NIMH BRAINS Award [R01MH107800]; California Institute of Regenerative Medicine (CIRM); MQ Fellow Award; Donald E. and Delia B. Baxter Foundation; Kwan Research Fund; Stanford Start-up Funds; Child Research Health Institute (CHRI); Walter V. and Idun Berry Postdoctoral Fellowship; Stanford Medicine Dean's Fellowship; American Epilepsy Society; Wishes for Elliott Foundation; NIH [5P01HG00020526]; UCSF Program for Breakthrough Biomedical Research; Sandler Foundation; National Institute of Mental Health [R01MH107800] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [R01NS034774] Funding Source: NIH RePORTER
NR 56
TC 966
Z9 1164
U1 9
U2 255
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 4
PY 2017
VL 545
IS 7652
BP 54
EP +
DI 10.1038/nature22330
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET7MK
UT WOS:000400480400029
PM 28445465
DA 2026-03-09
ER

PT J
AU Vatankhah-Varnosfaderani, M
   Daniel, WFM
   Everhart, MH
   Pandya, AA
   Liang, HY
   Matyjaszewski, K
   Dobrynin, AV
   Sheiko, SS
AF Vatankhah-Varnosfaderani, Mohammad
   Daniel, William F. M.
   Everhart, Matthew H.
   Pandya, Ashish A.
   Liang, Heyi
   Matyjaszewski, Krzysztof
   Dobrynin, Andrey V.
   Sheiko, Sergei S.
TI Mimicking biological stress-strain behaviour with synthetic elastomers
SO NATURE
LA English
DT Article
ID mechanical-property; networks; biomaterials; electronics; elasticity; copolymers; supersoft; polymers; rheology; design
AB Despite the versatility of synthetic chemistry, certain combinations of mechanical softness, strength, and toughness can be difficult to achieve in a single material. These combinations are, however, commonplace in biological tissues, and are therefore needed for applications such as medical implants, tissue engineering, soft robotics, and wearable electronics(1-9). Present materials synthesis strategies are predominantly Edisonian, involving the empirical mixing of assorted monomers, crosslinking schemes, and occluded swelling agents, but this approach yields limited property control(2,10-16). Here we present a general strategy for mimicking the mechanical behaviour of biological materials by precisely encoding their stress-strain curves in solventfree brush-and comb-like polymer networks (elastomers). The code consists of three independent architectural parameters-network strand length, side-chain length and grafting density. Using prototypical poly(dimethylsiloxane) elastomers, we illustrate how this parametric triplet enables the replication of the strain-stiffening characteristics of jellyfish, lung, and arterial tissues.
C1 [Vatankhah-Varnosfaderani, Mohammad; Daniel, William F. M.; Everhart, Matthew H.; Pandya, Ashish A.; Sheiko, Sergei S.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA.
   [Liang, Heyi; Dobrynin, Andrey V.] Univ Akron, Dept Polymer Sci, Akron, OH 44325 USA.
   [Matyjaszewski, Krzysztof] Carnegie Mellon Univ, Dept Chem, 4400 Fifth Ave, Pittsburgh, PA 15213 USA.
C3 University of North Carolina; University of North Carolina Chapel Hill; University System of Ohio; University of Akron; Carnegie Mellon University
RP Sheiko, SS (corresponding author), Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA.; Dobrynin, AV (corresponding author), Univ Akron, Dept Polymer Sci, Akron, OH 44325 USA.
EM adobrynin@uakron.edu; sergei@email.unc.edu
FU National Science Foundation [DMR 1436201, DMR 1407645, DMR 1624569]; Division Of Materials Research; Direct For Mathematical & Physical Scien [1624569, 1407645] Funding Source: National Science Foundation
NR 30
TC 355
Z9 409
U1 13
U2 474
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 28
PY 2017
VL 549
IS 7673
BP 497
EP 501
DI 10.1038/nature23673
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI4GT
UT WOS:000411930000045
PM 28869962
DA 2026-03-09
ER

PT J
AU Sulzer, D
   Alcalay, RN
   Garretti, F
   Cote, L
   Kanter, E
   Agin-Liebes, J
   Liong, C
   McMurtrey, C
   Hildebrand, WH
   Mao, XB
   Dawson, VL
   Dawson, TM
   Oseroff, C
   Pham, J
   Sidney, J
   Dillon, MB
   Carpenter, C
   Weiskopf, D
   Phillips, E
   Mallal, S
   Peters, B
   Frazier, A
   Arlehamn, CSL
   Sette, A
AF Sulzer, David
   Alcalay, Roy N.
   Garretti, Francesca
   Cote, Lucien
   Kanter, Ellen
   Agin-Liebes, Julian
   Liong, Christopher
   McMurtrey, Curtis
   Hildebrand, William H.
   Mao, Xiaobo
   Dawson, Valina L.
   Dawson, Ted M.
   Oseroff, Carla
   Pham, John
   Sidney, John
   Dillon, Myles B.
   Carpenter, Chelsea
   Weiskopf, Daniela
   Phillips, Elizabeth
   Mallal, Simon
   Peters, Bjoern
   Frazier, April
   Arlehamn, Cecilia S. Lindestam
   Sette, Alessandro
TI T cells from patients with Parkinson's disease recognize α-synuclein peptides
SO NATURE
LA English
DT Article
ID binding repertoires; mouse model; activation; cleavage; neurodegeneration; aggregation; association; contributes; expression; truncation
AB Genetic studies have shown the association of Parkinson's disease with alleles of the major histocompatibility complex(1-3). Here we show that a defined set of peptides that are derived from a-synuclein, a protein aggregated in Parkinson's disease(4), act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in patients with Parkinson's disease. These responses may explain the association of Parkinson's disease with specific major histocompatibility complex alleles.
C1 [Sulzer, David; Garretti, Francesca; Kanter, Ellen; Agin-Liebes, Julian] Columbia Univ, Dept Psychiat, Div Molcular Therapeut, New York State Psychiat Inst, New York, NY 10032 USA.
   [Sulzer, David; Alcalay, Roy N.; Cote, Lucien; Liong, Christopher] Columbia Univ, Dept Neurol, New York, NY 10032 USA.
   [Sulzer, David] Columbia Univ, Dept Pharmacol, New York, NY 10032 USA.
   [McMurtrey, Curtis; Hildebrand, William H.] Univ Oklahoma, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA.
   [Mao, Xiaobo; Dawson, Valina L.; Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Neuroregenerat & Stem Cell Program, Inst Cell Engn, Baltimore, MD 21205 USA.
   [Mao, Xiaobo; Dawson, Valina L.; Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA.
   [Mao, Xiaobo; Dawson, Valina L.; Dawson, Ted M.] Adrienne Helis Malvin Med Res Fdn, New Orleans, LA 70130 USA.
   [Dawson, Valina L.] Johns Hopkins Univ, Dept Physiol, Sch Med, Baltimore, MD 21205 USA.
   [Dawson, Valina L.; Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA.
   [Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA.
   [Oseroff, Carla; Pham, John; Sidney, John; Dillon, Myles B.; Carpenter, Chelsea; Weiskopf, Daniela; Peters, Bjoern; Frazier, April; Arlehamn, Cecilia S. Lindestam; Sette, Alessandro] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA 92037 USA.
   [Phillips, Elizabeth; Mallal, Simon] Murdoch Univ, Inst Immunol & Infect Dis, Perth, WA 6150, Australia.
   [Phillips, Elizabeth; Mallal, Simon] Vanderbilt Univ, Sch Med, Nashville, TN 37235 USA.
C3 Columbia University; New York State Psychiatry Institute; Columbia University; Columbia University; University of Oklahoma System; University of Oklahoma Health Sciences Center; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; La Jolla Institute for Immunology; Murdoch University; Vanderbilt University
RP Sulzer, D (corresponding author), Columbia Univ, Dept Psychiat, Div Molcular Therapeut, New York State Psychiat Inst, New York, NY 10032 USA.; Sulzer, D (corresponding author), Columbia Univ, Dept Neurol, New York, NY 10032 USA.; Sulzer, D (corresponding author), Columbia Univ, Dept Pharmacol, New York, NY 10032 USA.; Sette, A (corresponding author), La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA 92037 USA.
EM ds43@cumc.columbia.edu; alex@lji.org
FU JPB's Foundation; William F. Richter's Foundation; Michael J. Fox's Foundation; Parkinson's Foundation; NIH/NINDS [P50 NS38377]; NIA [ADRC P50AG005146]; AHMMRF Parkinson's disease program [M-2014]; JHH Parkinson's disease program [M-2014]; JHUSOM Parkinson's disease program [M-2014]; National Institute of Neurological Disorders and Stroke [R37NS067525] Funding Source: NIH RePORTER
NR 44
TC 664
Z9 754
U1 4
U2 170
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 29
PY 2017
VL 546
IS 7660
BP 656
EP +
DI 10.1038/nature22815
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY9QB
UT WOS:000404332000048
PM 28636593
DA 2026-03-09
ER

PT J
AU Harding, SM
   Benci, JL
   Irianto, J
   Discher, DE
   Minn, AJ
   Reenberg, RAG
AF Harding, Shane M.
   Benci, Joseph L.
   Irianto, Jerome
   Discher, Dennis E.
   Minn, Andy J.
   Reenberg, Roger A. G.
TI Mitotic progression following DNA damage enables pattern recognition within micronuclei
SO NATURE
LA English
DT Article
ID interferon regulatory factor-3; target genes; radiation; radiotherapy; sensor; cells; mechanisms; resistance
AB Inflammatory gene expression following genotoxic cancer therapy is well documented, yet the events underlying its induction remain poorly understood. Inflammatory cytokines modify the tumour microenvironment by recruiting immune cells and are critical for both local and systemic (abscopal) tumour responses to radiotherapy(1). A poorly understood feature of these responses is the delayed onset (days), in contrast to the acute DNA-damage responses that occur in minutes to hours. Such dichotomous kinetics implicate additional rate-limiting steps that are essential for DNA-damage-induced inflammation. Here we show that cell cycle progression through mitosis following double-stranded DNA breaks leads to the formation of micronuclei, which precede activation of inflammatory signalling and are a repository for the pattern-recognition receptor cyclic GMP-AMP synthase (cGAS). Inhibiting progression through mitosis or loss of pattern recognition by stimulator of interferon genes (STING)-cGAS impaired interferon signalling. Moreover, STING loss prevented the regression of abscopal tumours in the context of ionizing radiation and immune checkpoint blockade in vivo. These findings implicate temporal modulation of the cell cycle as an important consideration in the context of therapeutic strategies that combine genotoxic agents with immune checkpoint blockade.
C1 [Harding, Shane M.; Reenberg, Roger A. G.] Univ Penn, Dept Canc Biol, Basser Ctr BRCA, Abramson Family Canc Res Inst,Perelman Sch Med, 421 Curie Blvd, Philadelphia, PA 19104 USA.
   [Benci, Joseph L.; Minn, Andy J.] Univ Penn, Dept Radiat Oncol, Perelman Sch Med, Philadelphia, PA 19104 USA.
   [Benci, Joseph L.; Minn, Andy J.] Univ Penn, Inst Immunol, Perelman Sch Med, Philadelphia, PA 19104 USA.
   [Benci, Joseph L.; Minn, Andy J.] Univ Penn, Parker Inst Canc Immunotherapy, Perelman Sch Med, Philadelphia, PA 19104 USA.
   [Irianto, Jerome; Discher, Dennis E.] Univ Penn, Phys Sci Oncol Ctr Penn, 129 Towne Bldg, Philadelphia, PA 19104 USA.
   [Irianto, Jerome; Discher, Dennis E.] Univ Penn, Mol & Cell Biophys Lab, 129 Towne Bldg, Philadelphia, PA 19104 USA.
   [Irianto, Jerome; Discher, Dennis E.] Univ Penn, Grad Grp, Dept Phys & Astron, 129 Towne Bldg, Philadelphia, PA 19104 USA.
C3 University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania
RP Reenberg, RAG (corresponding author), Univ Penn, Dept Canc Biol, Basser Ctr BRCA, Abramson Family Canc Res Inst,Perelman Sch Med, 421 Curie Blvd, Philadelphia, PA 19104 USA.
EM rogergr@mail.med.upenn.edu
FU NIH [CA17494, GM101149, CA138835]; PSOC [U54-CA193417]; Basser Center; National Cancer Institute [R01CA138835, R01CA174904] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [R01HL124106] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM101149] Funding Source: NIH RePORTER
NR 34
TC 1177
Z9 1354
U1 4
U2 228
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 24
PY 2017
VL 548
IS 7668
BP 466
EP +
DI 10.1038/nature23470
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FE5VI
UT WOS:000408279000041
PM 28759889
DA 2026-03-09
ER

PT J
AU Bradlyn, B
   Elcoro, L
   Cano, J
   Vergniory, MG
   Wang, ZJ
   Felser, C
   Aroyo, MI
   Bernevig, BA
AF Bradlyn, Barry
   Elcoro, L.
   Cano, Jennifer
   Vergniory, M. G.
   Wang, Zhijun
   Felser, C.
   Aroyo, M. I. .
   Bernevig, B. Andrei
TI Topological quantum chemistry
SO NATURE
LA English
DT Article
ID single dirac cone; band representations; wannier functions; energy-bands; space-groups; semimetal; surface; solids; phase
AB Since the discovery of topological insulators and semimetals, there has been much research into predicting and experimentally discovering distinct classes of these materials, in which the topology of electronic states leads to robust surface states and electromagnetic responses. This apparent success, however, masks a fundamental shortcoming: topological insulators represent only a few hundred of the 200,000 stoichiometric compounds in material databases. However, it is unclear whether this low number is indicative of the esoteric nature of topological insulators or of a fundamental problem with the current approaches to finding them. Here we propose a complete electronic band theory, which builds on the conventional band theory of electrons, highlighting the link between the topology and local chemical bonding. This theory of topological quantum chemistry provides a description of the universal (across materials), global properties of all possible band structures and (weakly correlated) materials, consisting of a graph-theoretic description of momentum (reciprocal) space and a complementary group-theoretic description in real space. For all 230 crystal symmetry groups, we classify the possible band structures that arise from local atomic orbitals, and show which are topologically nontrivial. Our electronic band theory sheds new light on known topological insulators, and can be used to predict many more.
C1 [Bradlyn, Barry; Cano, Jennifer] Princeton Univ, Princeton Ctr Theoret Sci, Princeton, NJ 08544 USA.
   [Elcoro, L.; Aroyo, M. I. .] Univ Basque Country, UPV EHU, Dept Condensed Matter Phys, Apartado 644, Bilbao 48080, Spain.
   [Vergniory, M. G.; Bernevig, B. Andrei] Donostia Int Phys Ctr, P Manuel de Lardizabal 4, Donostia San Sebastian 20018, Spain.
   [Vergniory, M. G.] Univ Basque Country, UPV EHU, Dept Appl Phys 2, Apartado 644, Bilbao 48080, Spain.
   [Vergniory, M. G.] Max Planck Inst Solid State Res, Heisenbergstr 1, D-70569 Stuttgart, Germany.
   [Wang, Zhijun; Bernevig, B. Andrei] Princeton Univ, Dept Phys, Princeton, NJ 08544 USA.
   [Felser, C.] Max Planck Inst Chem Phys Solids, D-01187 Dresden, Germany.
   [Bernevig, B. Andrei] Univ Paris 06, Sorbonne Univ, Univ Paris Diderot,CNRS,Sorbonne Paris Cite, Lab Pierre Aigrain,Ecole Normale Super,PSL Res Un, 24 Rue Lhomond, F-75231 Paris 05, France.
   [Bernevig, B. Andrei] UPMC Univ Paris 06, Sorbonne Univ, UMR 7589, LPTHE, F-75005 Paris, France.
C3 Princeton University; University of Basque Country; University of Basque Country; Max Planck Society; Princeton University; Max Planck Society; Universite Paris Cite; Centre National de la Recherche Scientifique (CNRS); Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Physics (INP); Sorbonne Universite
RP Bernevig, BA (corresponding author), Donostia Int Phys Ctr, P Manuel de Lardizabal 4, Donostia San Sebastian 20018, Spain.; Bernevig, BA (corresponding author), Princeton Univ, Dept Phys, Princeton, NJ 08544 USA.; Bernevig, BA (corresponding author), Univ Paris 06, Sorbonne Univ, Univ Paris Diderot,CNRS,Sorbonne Paris Cite, Lab Pierre Aigrain,Ecole Normale Super,PSL Res Un, 24 Rue Lhomond, F-75231 Paris 05, France.; Bernevig, BA (corresponding author), UPMC Univ Paris 06, Sorbonne Univ, UMR 7589, LPTHE, F-75005 Paris, France.
EM bernevig@princeton.edu
FU Ecole Normale Superieure; Laboratoire de Physique Theorique et Hautes Energies; Spanish MINECO [FIS2016-75862-P, FIS2013-48286-C2-1-P]; Government of the Basque Country [IT779-13]; Spanish Ministry of Economy and Competitiveness; FEDER funds [MAT2015-66441-P]; Department of Energy [de-sc0016239]; Simons Investigator Award; Packard Foundation; Schmidt Fund for Innovative Research; NSF EAGER [DMR-1643312, ONR N00014-14-1-0330]; NSF-MRSEC [DMR-1420541]; National Cancer Institute [R01CA159859] Funding Source: NIH RePORTER
NR 47
TC 1213
Z9 1299
U1 18
U2 485
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 20
PY 2017
VL 547
IS 7663
BP 298
EP 305
DI 10.1038/nature23268
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB0OR
UT WOS:000405844900024
PM 28726818
DA 2026-03-09
ER

PT J
AU Kues, M
   Reimer, C
   Roztocki, P
   Cortés, LR
   Sciara, S
   Wetzel, B
   Zhang, YB
   Cino, A
   Chu, ST
   Little, BE
   Moss, DJ
   Caspani, L
   Azaña, J
   Morandotti, R
AF Kues, Michael
   Reimer, Christian
   Roztocki, Piotr
   Cortes, Luis Romero
   Sciara, Stefania
   Wetzel, Benjamin
   Zhang, Yanbing
   Cino, Alfonso
   Chu, Sai T.
   Little, Brent E.
   Moss, David J.
   Caspani, Lucia
   Azana, Jose
   Morandotti, Roberto
TI On-chip generation of high-dimensional entangled quantum states and their coherent control
SO NATURE
LA English
DT Article
ID silicon chip; photons; phase; computation; evolution; optics
AB Optical quantum states based on entangled photons are essential for solving questions in fundamental physics and are at the heart of quantum information science(1). Specifically, the realization of high-dimensional states (D-level quantum systems, that is, qudits, with D > 2) and their control are necessary for fundamental investigations of quantum mechanics(2), for increasing the sensitivity of quantum imaging schemes(3), for improving the robustness and key rate of quantum communication protocols(4), for enabling a richer variety of quantum simulations(5), and for achieving more efficient and error-tolerant quantum computation(6). Integrated photonics has recently become a leading platform for the compact, cost-efficient, and stable generation and processing of non-classical optical states(7). However, so far, integrated entangled quantum sources have been limited to qubits (D = 2)(8-11). Here we demonstrate on-chip generation of entangled qudit states, where the photons are created in a coherent superposition of multiple high-purity frequency modes. In particular, we confirm the realization of a quantum system with at least one hundred dimensions, formed by two entangled qudits with D = 10. Furthermore, using state-of-the-art, yet off-the-shelf telecommunications components, we introduce a coherent manipulation platform with which to control frequency-entangled states, capable of performing deterministic high-dimensional gate operations. We validate this platform by measuring Bell inequality violations and performing quantum state tomography. Our work enables the generation and processing of high-dimensional quantum states in a single spatial mode.
C1 [Kues, Michael; Reimer, Christian; Roztocki, Piotr; Cortes, Luis Romero; Sciara, Stefania; Wetzel, Benjamin; Zhang, Yanbing; Azana, Jose; Morandotti, Roberto] Ctr Energie Mat & Telecommun INRS EMT, Inst Natl Rech Sci, 1650 Blvd Lionel Boulet, Varennes, PQ J3X 1S2, Canada.
   [Kues, Michael] Univ Glasgow, Sch Engn, Rankine Bldg,Oakfield Ave, Glasgow G12 8LT, Lanark, Scotland.
   [Sciara, Stefania; Cino, Alfonso] Univ Palermo, Dept Energy Informat Engn & Math Models, Palermo, Italy.
   [Wetzel, Benjamin] Univ Sussex, Sch Math & Phys Sci, Brighton BN1 9RH, E Sussex, England.
   [Chu, Sai T.] City Univ Hong Kong, Dept Phys & Mat Sci, Tat Chee Ave, Hong Kong, Hong Kong, Peoples R China.
   [Little, Brent E.] Chinese Acad Sci, Xian Inst Opt & Precis Mech, State Key Lab Transient Opt & Photon, Xian, Peoples R China.
   [Moss, David J.] Swinburne Univ Technol, Ctr Micro Photon, Hawthorn, Vic 3122, Australia.
   [Caspani, Lucia] Univ Strathclyde, Inst Photon, Dept Phys, Glasgow G1 1RD, Lanark, Scotland.
   [Caspani, Lucia] Heriot Watt Univ, Inst Photon & Quantum Sci, Edinburgh EH14 4AS, Midlothian, Scotland.
   [Morandotti, Roberto] Univ Elect Sci & Technol China, Inst Fundamental & Frontier Sci, Chengdu 610054, Peoples R China.
   [Morandotti, Roberto] Natl Res Univ Informat Technol Mech & Opt, St Petersburg, Russia.
C3 University of Quebec; Institut national de la recherche scientifique (INRS); University of Glasgow; University of Palermo; University of Sussex; City University of Hong Kong; State Key Laboratory of Transient Optics & Photonics; Chinese Academy of Sciences; Xi'an Institute of Optics & Precision Mechanics, CAS; Swinburne University of Technology; University of Strathclyde; Heriot Watt University; University of Electronic Science & Technology of China; ITMO University
RP Kues, M; Morandotti, R (corresponding author), Ctr Energie Mat & Telecommun INRS EMT, Inst Natl Rech Sci, 1650 Blvd Lionel Boulet, Varennes, PQ J3X 1S2, Canada.; Kues, M (corresponding author), Univ Glasgow, Sch Engn, Rankine Bldg,Oakfield Ave, Glasgow G12 8LT, Lanark, Scotland.; Morandotti, R (corresponding author), Univ Elect Sci & Technol China, Inst Fundamental & Frontier Sci, Chengdu 610054, Peoples R China.; Morandotti, R (corresponding author), Natl Res Univ Informat Technol Mech & Opt, St Petersburg, Russia.
EM morandotti@emt.inrs.ca
FU Natural Sciences and Engineering Research Council of Canada (NSERC); MESI PSR-SIIRI Initiative in Quebec; Canada Research Chair Program; Australian Research Council [DP150104327]; NSERC Vanier Canada; European Union [656607]; CityU APRC programme [9610356]; Strategic Priority Research Program of the Chinese Academy of Sciences [XDB24030300]; People Programme (Marie Curie Actions) of the European Union [PIOF-GA-2013-625466]; People Programme (Marie Curie Actions) of the European Union under REA Grant [627478]; Government of the Russian Federation through ITMO Fellowship; 1000 Talents Sichuan Program;  [074-U 01]; Marie Curie Actions (MSCA) [656607] Funding Source: Marie Curie Actions (MSCA)
NR 45
TC 679
Z9 796
U1 7
U2 316
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 29
PY 2017
VL 546
IS 7660
BP 622
EP +
DI 10.1038/nature22986
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY9QB
UT WOS:000404332000041
PM 28658228
DA 2026-03-09
ER

PT J
AU Dalin, C
   Wada, Y
   Kastner, T
   Puma, MJ
AF Dalin, Carole
   Wada, Yoshihide
   Kastner, Thomas
   Puma, Michael J.
TI Groundwater depletion embedded in international food trade
SO NATURE
LA English
DT Article
ID water; transfers; aquifers
AB Recent hydrological modelling(1) and Earth observations(2,3) have located and quantified alarming rates of groundwater depletion worldwide. This depletion is primarily due to water withdrawals for irrigation(1,2,4), but its connection with the main driver of irrigation, global food consumption, has not yet been explored. Here we show that approximately eleven per cent of non-renewable groundwater use for irrigation is embedded in international food trade, of which two-thirds are exported by Pakistan, the USA and India alone. Our quantification of groundwater depletion embedded in the world's food trade is based on a combination of global, crop-specific estimates of non-renewable groundwater abstraction and international food trade data. A vast majority of the world's population lives in countries sourcing nearly all their staple crop imports from partners who deplete groundwater to produce these crops, highlighting risks for global food and water security. Some countries, such as the USA, Mexico, Iran and China, are particularly exposed to these risks because they both produce and import food irrigated from rapidly depleting aquifers. Our results could help to improve the sustainability of global food production and groundwater resource management by identifying priority regions and agricultural products at risk as well as the end consumers of these products.
C1 [Dalin, Carole] UCL, Inst Sustainable Resources, 14 Upper Woburn Pl, London WC1H 0NN, England.
   [Wada, Yoshihide] Int Inst Appl Syst Anal, Schlosspl 1, A-2361 Laxenburg, Austria.
   [Wada, Yoshihide; Puma, Michael J.] Columbia Univ, Ctr Climate Syst Res, 2880 Broadway, New York, NY 10025 USA.
   [Wada, Yoshihide; Puma, Michael J.] NASA, Goddard Inst Space Studies, 2880 Broadway, New York, NY 10025 USA.
   [Wada, Yoshihide] Univ Utrecht, Dept Phys Geog, Heidelberglaan 2, NL-3584 CS Utrecht, Netherlands.
   [Kastner, Thomas] Alpen Adria Univ Klagenfurt, Inst Social Ecol, Schottenfeldgasse 29, A-1070 Vienna, Austria.
   [Kastner, Thomas] Senckenberg Biodivers & Climate Res Ctr BiK F, Senckenberganlage 25, D-60325 Frankfurt, Germany.
   [Puma, Michael J.] Columbia Univ, Ctr Climate & Life, 61 Route 9W, Palisades, NY 10964 USA.
C3 University of London; University College London; International Institute for Applied Systems Analysis (IIASA); Columbia University; National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center; Goddard Institute for Space Studies; Utrecht University; University of Klagenfurt; Senckenberg Biodiversitat & Klima- Forschungszentrum (BiK-F); Leibniz Association; Senckenberg Gesellschaft fur Naturforschung (SGN); Columbia University
RP Dalin, C (corresponding author), UCL, Inst Sustainable Resources, 14 Upper Woburn Pl, London WC1H 0NN, England.
EM c.dalin@ucl.ac.uk
FU Belmont Forum (SAHEWS project) [NERC NE/L008785/1]; Economic and Social Research Council through the Centre for Climate Change Economics and Policy; Natural Environment Research Council Fellowship [NERC NE/N01524X/1]; European Research Council Starting Grant LUISE [263522]; Swedish Research Council Formas [231-2014-1181]; Columbia University Center for Climate and Life; Japan Society for the Promotion of Science (JSPS) [JSPS-2014-878]; OECD; NERC [NE/N01524X/1] Funding Source: UKRI; European Research Council (ERC) [263522] Funding Source: European Research Council (ERC); Natural Environment Research Council [NE/L008785/1, NE/N01524X/1] Funding Source: researchfish
NR 30
TC 664
Z9 750
U1 17
U2 620
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 30
PY 2017
VL 543
IS 7647
BP 700
EP +
DI 10.1038/nature21403
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EP8IS
UT WOS:000397619700052
PM 28358074
DA 2026-03-09
ER

PT J
AU Campbell, JE
   Berry, JA
   Seibt, U
   Smith, SJ
   Montzka, SA
   Launois, T
   Belviso, S
   Bopp, L
   Laine, M
AF Campbell, J. E.
   Berry, J. A.
   Seibt, U.
   Smith, S. J.
   Montzka, S. A.
   Launois, T.
   Belviso, S.
   Bopp, L.
   Laine, M.
TI Large historical growth in global terrestrial gross primary production
SO NATURE
LA English
DT Article
ID atmospheric carbonyl sulfide; forest productivity; co2; model; cycle; uncertainty; enhancement; variability; feedbacks; earth
AB Growth in terrestrial gross primary production (GPP)-the amount of carbon dioxide that is 'fixed' into organic material through the photosynthesis of land plants-may provide a negative feedback for climate change(1,2). It remains uncertain, however, to what extent biogeochemical processes can suppress global GPP growth(3). As a consequence, modelling estimates of terrestrial carbon storage, and of feedbacks between the carbon cycle and climate, remain poorly constrained(4). Here we present a global, measurement-based estimate of GPP growth during the twentieth century that is based on long-term atmospheric carbonyl sulfide (COS) records, derived from ice-core, firn and ambient air samples(5). We interpret these records using a model that simulates changes in COS concentration according to changes in its sources and sinks-including a large sink that is related to GPP. We find that the observation-based COS record is most consistent with simulations of climate and the carbon cycle that assume large GPP growth during the twentieth century (31% +/- 5% growth; mean +/- 95% confidence interval). Although this COS analysis does not directly constrain models of future GPP growth, it does provide a global-scale benchmark for historical carbon-cycle simulations.
C1 [Campbell, J. E.] Univ Calif Merced, Sierra Nevada Res Inst, Merced, CA 95343 USA.
   [Berry, J. A.] Carnegie Inst Sci, Dept Global Ecol, Stanford, CA 94305 USA.
   [Seibt, U.] Univ Calif Los Angeles, Dept Atmospher & Ocean Sci, Los Angeles, CA 90095 USA.
   [Smith, S. J.] Joint Global Change Res Inst, Pacific Northwest Natl Lab, College Pk, MD 20740 USA.
   [Montzka, S. A.] NOAA, Earth Syst Res Lab, Boulder, CO 80305 USA.
   [Launois, T.; Belviso, S.; Bopp, L.] UVSQ, CEA, CNRS, IPSL,Lab Sci Climat & Environm, F-91191 Gif Sur Yvette, France.
   [Laine, M.] Finnish Meteorol Inst, Helsinki 00560, Finland.
   [Launois, T.] INRA, UMR 1391, ISPA, F-33140 Villenave Dornon, France.
   [Bopp, L.] UMPC, ENS, CNRS, IPSL,Lab Meteorol Dynam,X, F-75005 Paris, France.
C3 University of California System; University of California Merced; Carnegie Institution for Science; University of California System; University of California Los Angeles; United States Department of Energy (DOE); Pacific Northwest National Laboratory; National Oceanic Atmospheric Admin (NOAA) - USA; Universite Paris Cite; Universite Paris Saclay; Centre National de la Recherche Scientifique (CNRS); CEA; Finnish Meteorological Institute; INRAE; Universite PSL; Ecole Normale Superieure (ENS); Institut Polytechnique de Paris; Ecole Polytechnique; Universite Paris Cite; Centre National de la Recherche Scientifique (CNRS); Sorbonne Universite
RP Campbell, JE (corresponding author), Univ Calif Merced, Sierra Nevada Res Inst, Merced, CA 95343 USA.
EM ecampbell3@ucmerced.edu
FU US Department of Energy, Office of Science, Office of Terrestrial Ecosystem Sciences [DE-SC0011999]; National Oceanic and Atmospheric Administration (NOAA) Climate Program Office's AC4 program; Academy of Finland as part of the INQUIRE project [267442]; H2020 project CRESCENDO [641816]; European Research Council (ERC) early career starting grant SOLCA [338264]; European Research Council (ERC) [338264] Funding Source: European Research Council (ERC); U.S. Department of Energy (DOE) [DE-SC0011999] Funding Source: U.S. Department of Energy (DOE)
CR Andreae MO, 1992, GLOBAL BIOGEOCHEM CY, V6, P175, DOI 10.1029/91GB02809
   ANDREAE MO, 1984, MAR CHEM, V14, P267, DOI 10.1016/0304-4203(84)90047-1
   Arneth A, 2010, NAT GEOSCI, V3, P525, DOI 10.1038/NGEO905
   Aydin M, 2016, J GEOPHYS RES-ATMOS, V121, P1943, DOI 10.1002/2015JD024235
   Beer C, 2010, SCIENCE, V329, P834, DOI 10.1126/science.1184984
   Berry J, 2013, J GEOPHYS RES-BIOGEO, V118, P842, DOI 10.1002/jgrg.20068
   Campbell JE, 2008, SCIENCE, V322, P1085, DOI 10.1126/science.1164015
   Campbell JE, 2015, GEOPHYS RES LETT, V42, P3004, DOI 10.1002/2015GL063445
   Commane R, 2015, P NATL ACAD SCI USA, V112, P14162, DOI 10.1073/pnas.1504131112
   Drake JE, 2011, ECOL LETT, V14, P349, DOI 10.1111/j.1461-0248.2011.01593.x
   Ehlers I, 2015, P NATL ACAD SCI USA, V112, P15585, DOI 10.1073/pnas.1504493112
   Field CB, 2007, ANNU REV ENV RESOUR, V32, P1, DOI 10.1146/annurev.energy.32.053006.141119
   Friedlingstein P, 2014, J CLIMATE, V27, P511, DOI 10.1175/JCLI-D-12-00579.1
   Hansen J, 2013, ENVIRON RES LETT, V8, P0, DOI 10.1088/1748-9326/8/1/011006
   Hilton TW, 2015, TELLUS B CHEM PHYS M, V0, P0
   Launois T, 2015, ATMOS CHEM PHYS, V15, P2295, DOI 10.5194/acp-15-2295-2015
   Lejeune B, 2017, J QUANT SPECTROSC RA, V186, P81, DOI 10.1016/j.jqsrt.2016.06.001
   Li W, 2016, P NATL ACAD SCI USA, V113, P13104, DOI 10.1073/pnas.1603956113
   Mahieu E, 1997, J ATMOS CHEM, V28, P227, DOI 10.1023/A:1005854926740
   Maseyk K, 2014, P NATL ACAD SCI USA, V111, P9064, DOI 10.1073/pnas.1319132111
   Montzka SA, 2007, J GEOPHYS RES-ATMOS, V112, P0, DOI 10.1029/2006JD007665
   Montzka SA, 2004, J GEOPHYS RES-ATMOS, V109, P0, DOI 10.1029/2004JD004686
   Norby RJ, 2010, P NATL ACAD SCI USA, V107, P19368, DOI 10.1073/pnas.1006463107
   Rinsland CP, 2008, J QUANT SPECTROSC RA, V109, P2679, DOI 10.1016/j.jqsrt.2008.07.008
   Sandoval-Soto L, 2005, BIOGEOSCIENCES, V2, P125, DOI 10.5194/bg-2-125-2005
   Schimel D, 2015, P NATL ACAD SCI USA, V112, P436, DOI 10.1073/pnas.1407302112
   Smith WK, 2016, NAT CLIM CHANGE, V6, P306, DOI 10.1038/nclimate2879
   Stimler K, 2010, NEW PHYTOL, V186, P869, DOI 10.1111/j.1469-8137.2010.03218.x
   Welp LR, 2011, NATURE, V477, P579, DOI 10.1038/nature10421
   Wenzel S, 2016, NATURE, V538, P499, DOI 10.1038/nature19772
   Whelan ME, 2016, ATMOS CHEM PHYS, V16, P3711, DOI 10.5194/acp-16-3711-2016
   Wohlfahrt G, 2012, PLANT CELL ENVIRON, V35, P657, DOI 10.1111/j.1365-3040.2011.02451.x
   Zhu ZC, 2016, NAT CLIM CHANGE, V6, P791, DOI 10.1038/nclimate3004
NR 33
TC 238
Z9 263
U1 16
U2 464
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 6
PY 2017
VL 544
IS 7648
BP 84
EP 87
DI 10.1038/nature22030
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EQ8GQ
UT WOS:000398323300037
PM 28382993
DA 2026-03-09
ER

PT J
AU Manguso, RT
   Pope, HW
   Zimmer, MD
   Brown, FD
   Yates, KB
   Miller, BC
   Collins, NB
   Bi, K
   Lafleur, MW
   Juneja, VR
   Weiss, SA
   Lo, J
   Fisher, DE
   Miao, D
   Van Allen, E
   Root, DE
   Sharpe, AH
   Doench, JG
   Haining, WN
AF Manguso, Robert T.
   Pope, Hans W.
   Zimmer, Margaret D.
   Brown, Flavian D.
   Yates, Kathleen B.
   Miller, Brian C.
   Collins, Natalie B.
   Bi, Kevin
   Lafleur, Martin W.
   Juneja, Vikram R.
   Weiss, Sarah A.
   Lo, Jennifer
   Fisher, David E.
   Miao, Diana
   Van Allen, Eliezer
   Root, David E.
   Sharpe, Arlene H.
   Doench, John G.
   Haining, W. Nicholas
TI In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target
SO NATURE
LA English
DT Article
ID hla-e; gene; expression; blockade; cells; cd94/nkg2a; pd-1
AB Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-gamma signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-kappa B signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-gamma-mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways.
C1 [Manguso, Robert T.; Pope, Hans W.; Zimmer, Margaret D.; Brown, Flavian D.; Yates, Kathleen B.; Miller, Brian C.; Collins, Natalie B.; Bi, Kevin; Lafleur, Martin W.; Weiss, Sarah A.; Haining, W. Nicholas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA.
   [Manguso, Robert T.; Brown, Flavian D.; Lafleur, Martin W.; Miao, Diana; Van Allen, Eliezer] Harvard Med Sch, Div Med Sci, Boston, MA 02115 USA.
   [Manguso, Robert T.; Pope, Hans W.; Zimmer, Margaret D.; Yates, Kathleen B.; Miller, Brian C.; Collins, Natalie B.; Bi, Kevin; Miao, Diana; Van Allen, Eliezer; Root, David E.; Doench, John G.; Haining, W. Nicholas] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA.
   [Miller, Brian C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.
   [Collins, Natalie B.; Sharpe, Arlene H.; Haining, W. Nicholas] Childrens Hosp, Div Pediat Hematol & Oncol, 300 Longwood Ave, Boston, MA 02115 USA.
   [Juneja, Vikram R.] Harvard Med Sch, Dept Microbiol & Immunol, Boston, MA 02115 USA.
   [Lo, Jennifer; Fisher, David E.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Bldg 149,13th St, Charlestown, MA 02129 USA.
   [Lo, Jennifer; Fisher, David E.] Harvard Med Sch, Bldg 149,13th St, Charlestown, MA 02129 USA.
   [Sharpe, Arlene H.] Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA.
C3 Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School
RP Haining, WN (corresponding author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA.; Haining, WN (corresponding author), Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA.; Haining, WN (corresponding author), Childrens Hosp, Div Pediat Hematol & Oncol, 300 Longwood Ave, Boston, MA 02115 USA.
EM Nicholas_Haining@dfci.harvard.edu
FU Broad Institute of Harvard; MIT; NIGMS [T32GM007753]; National Institute of General Medical Sciences [T32GM007753] Funding Source: NIH RePORTER
NR 35
TC 892
Z9 1100
U1 7
U2 370
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 27
PY 2017
VL 547
IS 7664
BP 413
EP +
DI 10.1038/nature23270
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB7ZK
UT WOS:000406358300027
PM 28723893
DA 2026-03-09
ER

PT J
AU Tillotson, R
   Selfridge, J
   Koerner, MV
   Gadalla, KKE
   Guy, J
   De Sousa, D
   Hector, RD
   Cobb, SR
   Bird, A
AF Tillotson, Rebekah
   Selfridge, Jim
   Koerner, Martha V.
   Gadalla, Kamal K. E.
   Guy, Jacky
   De Sousa, Dina
   Hector, Ralph D.
   Cobb, Stuart R.
   Bird, Adrian
TI Radically truncated MeCP2 rescues Rett syndromelike neurological defects
SO NATURE
LA English
DT Article
ID cpg binding domain; methyl-cpg; dna methylation; chromosomal-protein; phenotypic severity; missense mutations; dendritic growth; molecular-basis; phosphorylation; complex
AB Heterozygous mutations in the X-linked MECP2 gene cause the neurological disorder Rett syndrome1. The methyl-CpG-binding protein 2 (MeCP2) protein is an epigenetic reader whose binding to chromatin primarily depends on 5-methylcytosine(2,3). Functionally, MeCP2 has been implicated in several cellular processes on the basis of its reported interaction with more than 40 binding partners(4), including transcriptional co-repressors (for example, the NCoR/SMRT complex5), transcriptional activators(6), RNA(7), chromatin remodellers8,9, microRNA-processing proteins(10) and splicing factors(11). Accordingly, MeCP2 has been cast as a multi-functional hub that integrates diverse processes that are essential in mature neurons(12). At odds with the concept of broad functionality, missense mutations that cause Rett syndrome are concentrated in two discrete clusters coinciding with interaction sites for partner macromolecules: the methyl-CpG binding domain(13) and the NCoR/SMRT interaction domain(5). Here we test the hypothesis that the single dominant function of MeCP2 is to physically connect DNA with the NCoR/ SMRT complex, by removing almost all amino-acid sequences except the methyl-CpG binding and NCoR/SMRT interaction domains. We find that mice expressing truncated MeCP2 lacking both the N-and C-terminal regions (approximately half of the native protein) are phenotypically near-normal; and those expressing a minimal MeCP2 additionally lacking a central domain survive for over one year with only mild symptoms. This minimal protein is able to prevent or reverse neurological symptoms when introduced into MeCP2-deficient mice by genetic activation or virus-mediated delivery to the brain. Thus, despite evolutionary conservation of the entire MeCP2 protein sequence, the DNA and co-repressor binding domains alone are sufficient to avoid Rett syndrome-like defects and may therefore have therapeutic utility.
C1 [Tillotson, Rebekah; Selfridge, Jim; Koerner, Martha V.; Guy, Jacky; De Sousa, Dina; Bird, Adrian] Univ Edinburgh, Wellcome Ctr Cell Biol, Michael Swann Bldg,Kings Bldg, Edinburgh EH9 3BF, Midlothian, Scotland.
   [Gadalla, Kamal K. E.; Hector, Ralph D.; Cobb, Stuart R.] Univ Glasgow, Inst Neurosci & Psychol, Coll Med Vet & Life Sci, Glasgow G12 8QQ, Lanark, Scotland.
   [Gadalla, Kamal K. E.] Tanta Univ, Pharmacol Dept, Fac Med, Tanta 31527, Egypt.
C3 University of Edinburgh; University of Glasgow; Egyptian Knowledge Bank (EKB); Tanta University
RP Bird, A (corresponding author), Univ Edinburgh, Wellcome Ctr Cell Biol, Michael Swann Bldg,Kings Bldg, Edinburgh EH9 3BF, Midlothian, Scotland.
EM a.bird@ed.ac.uk
FU Rett Syndrome Research Trust; Wellcome; Sylvia Aitken Charitable Trust; Biotechnology and Biological Sciences Research Council Doctoral Training Partnership studentship; Biotechnology and Biological Sciences Research Council [1272176] Funding Source: researchfish; Medical Research Council [G0800401] Funding Source: researchfish
NR 37
TC 117
Z9 150
U1 0
U2 42
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 19
PY 2017
VL 550
IS 7676
BP 398
EP 401
DI 10.1038/nature24058
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK1NF
UT WOS:000413247900061
PM 29019980
DA 2026-03-09
ER

PT J
AU Xiang, Y
   Laurent, B
   Hsu, CH
   Nachtergaele, S
   Lu, ZK
   Sheng, WQ
   Xu, CY
   Hen, HC
   Jian, OY
   Wang, SQ
   Ling, D
   Hsu, PH
   Zou, L
   Jambhekar, A
   Iie, C
   Shi, Y
AF Xiang, Yang
   Laurent, Benoit
   Hsu, Chih-Hung
   Nachtergaele, Sigrid
   Lu, Zhike
   Sheng, Wanqiang
   Xu, Chuanyun
   Hen, Hao C.
   Jian, Ouyang
   Wang, Siqing
   Ling, Dominic
   Hsu, Pang-Hung
   Zou, Lee
   Jambhekar, Ashwini
   IIe, Chuan
   Shi, Yang
TI RNA m6A methylation regulates the ultraviolet-induced DNA damage response
SO NATURE
LA English
DT Article
ID nuclear-rna; polymerase-kappa; human-cells; pol-kappa; n-6-methyladenosine; repair; n6-methyladenosine; mouse; transcription; localization
AB Cell proliferation and survival require the faithful maintenance and propagation of genetic information, which are threatened by the ubiquitous sources of DNA damage present intracellularly and in the external environment. A system of DNA repair, called the DNA damage response, detects and repairs damaged DNA and prevents cell division until the repair is complete. Here we report that methylation at the 6 position of adenosine (m(6)A) in RNA is rapidly (within 2 min) and transiently induced at DNA damage sites in response to ultraviolet irradiation. This modification occurs on numerous poly(A)+ transcripts and is regulated by the methyltransferase METTL3 (methyltransferase-like 3) 1 and the demethylase FTO (fat mass and obesity-associated protein) 2. In the absence of METTL3 catalytic activity, cells showed delayed repair of ultraviolet-induced cyclobutane pyrimidine adducts and elevated sensitivity to ultraviolet, demonstrating the importance of m(6)A in the ultraviolet-responsive DNA damage response. Multiple DNA polymerases are involved in the ultraviolet response, some of which resynthesize DNA after the lesion has been excised by the nucleotide excision repair pathway3, while others participate in trans-lesion synthesis to allow replication past damaged lesions in S phase(4). DNA polymerase. (Pol.), which has been implicated in both nucleotide excision repair and trans-lesion synthesis(5,6), required the catalytic activity of METTL3 for immediate localization to ultravioletinduced DNA damage sites. Importantly, Pol. overexpression qualitatively suppressed the cyclobutane pyrimidine removal defect associated with METTL3 loss. Thus, we have uncovered a novel function for RNA m(6)A modification in the ultraviolet-induced DNA damage response, and our findings collectively support a model in which m(6)A RNA serves as a beacon for the selective, rapid recruitment of Pol. to damage sites to facilitate repair and cell survival.
C1 [Xiang, Yang; Laurent, Benoit; Hsu, Chih-Hung; Sheng, Wanqiang; Xu, Chuanyun; Hen, Hao C.; Wang, Siqing; Ling, Dominic; Jambhekar, Ashwini; Shi, Yang] Boston Childrens Hosp, Dept Med, Div Newborn Med & Epigenet Program, Boston, MA 02115 USA.
   [Xiang, Yang; Laurent, Benoit; Hsu, Chih-Hung; Sheng, Wanqiang; Xu, Chuanyun; Hen, Hao C.; Wang, Siqing; Ling, Dominic; Jambhekar, Ashwini; Shi, Yang] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
   [Nachtergaele, Sigrid; Lu, Zhike; IIe, Chuan] Univ Chicago, Dept Chem, Chicago, IL 60637 USA.
   [Nachtergaele, Sigrid; Lu, Zhike; IIe, Chuan] Univ Chicago, Inst Biophys Dynam, 929 East 57th St, Chicago, IL 60637 USA.
   [Nachtergaele, Sigrid; Lu, Zhike; IIe, Chuan] Univ Chicago, Howard Hughes Med Inst, 929 East 57th St, Chicago, IL 60637 USA.
   [Jian, Ouyang; Zou, Lee] Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Boston, MA 02109 USA.
   [Jian, Ouyang; Zou, Lee] Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Dept Pathol, Boston, MA 02109 USA.
   [Hsu, Pang-Hung] Natl Taiwan Ocean Univ, Dept Biosci & Biotechnol, Keelung 202, Taiwan.
   [Wang, Siqing] Fudan Univ, Inst Biomed Sci, Shanghai 200433, Peoples R China.
C3 Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; University of Chicago; University of Chicago; University of Chicago; Howard Hughes Medical Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; National Taiwan Ocean University; Fudan University
RP Xiang, Y; Laurent, B; Hsu, CH (corresponding author), Boston Childrens Hosp, Dept Med, Div Newborn Med & Epigenet Program, Boston, MA 02115 USA.; Xiang, Y; Laurent, B; Hsu, CH (corresponding author), Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
EM yshi@hms.harvard.edu
FU Association pour la Recherche sur le Cancer (ARC) (France); National Institutes of Health [4 T32 HD 7466-20, R01 CA118487]; Boston Children's Hospital
NR 35
TC 753
Z9 849
U1 1
U2 287
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 23
PY 2017
VL 543
IS 7646
BP 573
EP +
DI 10.1038/nature21671
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EO9OM
UT WOS:000397018000056
PM 28297716
DA 2026-03-09
ER

PT J
AU Nesbitt, SJ
   Butler, RJ
   Ezcurra, MD
   Barrett, PM
   Stocker, MR
   Angielczyk, KD
   Smith, RMH
   Sidor, CA
   Niedzwiedzki, G
   Sennikov, AG
   Charig, AJ
AF Nesbitt, Sterling J.
   Butler, Richard J.
   Ezcurra, Martin D.
   Barrett, Paul M.
   Stocker, Michelle R.
   Angielczyk, Kenneth D.
   Smith, Roger M. H.
   Sidor, Christian A.
   Niedzwiedzki, Grzegorz
   Sennikov, Andrey G.
   Charig, Alan J.
TI The earliest bird-line archosaurs and the assembly of the dinosaur body plan
SO NATURE
LA English
DT Article
ID evolutionary radiation; origin; karoo
AB The relationship between dinosaurs and other reptiles is well established(1-4), but the sequence of acquisition of dinosaurian features has been obscured by the scarcity of fossils with transitional morphologies. The closest extinct relatives of dinosaurs either have highly derived morphologies(5-7) or are known from poorly preserved(8,9) or incomplete material(10,11). Here we describe one of the stratigraphically lowest and phylogenetically earliest members of the avian stem lineage (Avemetatarsalia), Teleocrater rhadinus gen. et sp. nov., from the Middle Triassic epoch. The anatomy of T. rhadinus provides key information that unites several enigmatic taxa from across Pangaea into a previously unrecognized clade, Aphanosauria. This clade is the sister taxon of Ornithodira (pterosaurs and birds) and shortens the ghost lineage inferred at the base of Avemetatarsalia. We demonstrate that several anatomical features long thought to characterize Dinosauria and dinosauriforms evolved much earlier, soon after the bird-crocodylian split, and that the earliest avemetatarsalians retained the crocodylian-like ankle morphology and hindlimb proportions of stem archosaurs and early pseudosuchians. Early avemetatarsalians were substantially more species-rich, widely geographically distributed and morphologically diverse than previously recognized. Moreover, several early dinosauromorphs that were previously used as models to understand dinosaur origins may represent specialized forms rather than the ancestral avemetatarsalian morphology.
C1 [Nesbitt, Sterling J.; Stocker, Michelle R.] Virginia Tech, Dept Geosci, Blacksburg, VA 24061 USA.
   [Butler, Richard J.; Ezcurra, Martin D.] Univ Birmingham, Sch Geog Earth & Environm Sci, Birmingham B15 2TT, W Midlands, England.
   [Ezcurra, Martin D.] Museo Argentino Ciencias Nat Bernardino Rivadavia, CONICET, Secc Paleontol Vertebrados, Buenos Aires, DF, Argentina.
   [Barrett, Paul M.; Charig, Alan J.] Nat Hist Museum, Dept Earth Sci, Cromwell Rd, London SW7 5BD, England.
   [Angielczyk, Kenneth D.] Field Museum Nat Hist, Integrat Res Ctr, 1400 South Lake Shore Dr, Chicago, IL 60605 USA.
   [Smith, Roger M. H.] Univ Witwatersrand, Evolutionary Studies Inst, PO Wits 2050, Johannesburg, South Africa.
   [Smith, Roger M. H.] Iziko South African Museum, POB 61, Cape Town, South Africa.
   [Sidor, Christian A.] Univ Washington, Burke Museum, Seattle, WA 98195 USA.
   [Sidor, Christian A.] Univ Washington, Dept Biol, Seattle, WA 98195 USA.
   [Niedzwiedzki, Grzegorz] Uppsala Univ, Dept Organismal Biol, Norbyvagen 18A, S-75236 Uppsala, Sweden.
   [Sennikov, Andrey G.] Russian Acad Sci, Borissiak Paleontol Inst, Profsoyuznaya 123, Moscow 117997, Russia.
   [Sennikov, Andrey G.] Kazan Fed Univ, Kremlyovskaya Ul 18, Kazan 420008, Russia.
C3 Virginia Polytechnic Institute & State University; University of Birmingham; Museo Argentino de Ciencias Naturales Bernardino Rivadavia (MACN); Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); Natural History Museum London; Field Museum of Natural History (Chicago); University of Witwatersrand; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Uppsala University; Russian Academy of Sciences; Paleontological Institute of the Russian Academy of Sciences; Kazan Federal University
RP Nesbitt, SJ (corresponding author), Virginia Tech, Dept Geosci, Blacksburg, VA 24061 USA.
EM sjn2104@vt.edu
FU National Geographic Society Research Exploration [9606-14]; National Science Foundation [EAR-1337569, EAR-1337291]; Marie Curie Career Integration Grant [630123]; National Geographic Society Young Explorers grant [9467-14]; Russian Government Program of Competitive Growth of Kazan Federal University; RFBR [14-04-00185, 17-04-00410]; Division Of Earth Sciences; Directorate For Geosciences [1337291] Funding Source: National Science Foundation; Division Of Earth Sciences; Directorate For Geosciences [1337569] Funding Source: National Science Foundation
CR Unknown -, 2013, R LANG ENV STAT COMP, V0, P0
   BAKKER RT, 1974, NATURE, V248, P168, DOI 10.1038/248168a0
   Benton MJ, 1988, SYSTEMATICS ASSOCIATION SPECIAL VOLUME SERIES, V0, P295
   Benton MJ, 2010, EARTH ENV SCI T R SO, V101, P285, DOI 10.1017/S1755691011020081
   Benton MJ, 1999, PHILOS T ROY SOC B, V354, P1423, DOI 10.1098/rstb.1999.0489
   Brusatte SL, 2008, SCIENCE, V321, P1485, DOI 10.1126/science.1161833
   Brusatte SL, 2010, EARTH ENV SCI T R SO, V101, P367, DOI 10.1017/S1755691011020056
   Brusatte SL, 2010, EARTH-SCI REV, V101, P68, DOI 10.1016/j.earscirev.2010.04.001
   Butler RJ, 2014, BMC EVOL BIOL, V14, P0, DOI 10.1186/1471-2148-14-128
   Butler RJ, 2011, PLOS ONE, V6, P0, DOI 10.1371/journal.pone.0025693
   Close RA, 2015, CURR BIOL, V25, P2137, DOI 10.1016/j.cub.2015.06.047
   Dzik J, 2003, J VERTEBR PALEONTOL, V23, P556, DOI 10.1671/A1097
   Ezcurra MD, 2016, PEERJ, V4, P0, DOI 10.7717/peerj.1778
   Gauthier J, 1986, MEMOIRS OF THE CALIFORNIA ACADEMY OF SCIENCES, V0, P1
   Goloboff P, 2008, CLADISTICS, V24, P91
   Goloboff PA, 2016, CLADISTICS, V32, P221, DOI 10.1111/cla.12160
   Hamilton N, 2016, GGTERN: AN EXTENSION TO "GGPLOT2", V0, P0
   Irmis RB, 2007, SCIENCE, V317, P358, DOI 10.1126/science.1143325
   Kubo T, 2012, PALEOBIOLOGY, V38, P474, DOI 10.1666/11015.1
   Lamm ET, 2013, BONE HISTOLOGY OF FOSSIL TETRAPODS: ADVANCING METHODS, V0, P0
   Langer MC, 2006, J SYST PALAEONTOL, V4, P309, DOI 10.1017/S1477201906001970
   Langer MC, 2010, BIOL REV, V85, P55, DOI 10.1111/j.1469-185X.2009.00094.x
   Lloyd GT, 2016, BIOL J LINN SOC, V118, P131, DOI 10.1111/bij.12746
   Nesbitt SJ, 2013, BIOL LETTERS, V9, P0, DOI 10.1098/rsbl.2012.0949
   Nesbitt SJ, 2011, B AM MUS NAT HIST, V0, PP1, DOI 10.1206/352.1
   Nesbitt SJ, 2010, NATURE, V464, P95, DOI 10.1038/nature08718
   Niedzwiedzki G, 2016, HIST BIOL, V28, P550, DOI 10.1080/08912963.2014.992017
   Padian K, 2004, J VERTEBR PALEONTOL, V24, P555, DOI 10.1671/0272-4634(2004)024[0555:GISDAP]2.0.CO;2
   Rubidge BS, 2005, S AFR J GEOL, V108, P135, DOI 10.2113/108.1.135
   Sereno PC, 1991, JOURNAL OF VERTEBRATE PALEONTOLOGY, V11, P1
   Sereno Paul C, 1993, JOURNAL OF VERTEBRATE PALEONTOLOGY, V13, P385
   Sereno PC, 1999, SCIENCE, V284, P2137, DOI 10.1126/science.284.5423.2137
   SERENO PC, 1994, J VERTEBR PALEONTOL, V14, P53, DOI 10.1080/02724634.1994.10011538
   Sidor CA, 2013, P NATL ACAD SCI USA, V110, P8129, DOI 10.1073/pnas.1302323110
   Wopfner H, 2002, J AFR EARTH SCI, V34, P167, DOI 10.1016/S0899-5362(02)00016-7
NR 36
TC 167
Z9 180
U1 2
U2 73
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 27
PY 2017
VL 544
IS 7651
BP 484
EP +
DI 10.1038/nature22037
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET1TN
UT WOS:000400051900044
PM 28405026
DA 2026-03-09
ER

PT J
AU Tobler, R
   Rohrlach, A
   Soubrier, J
   Bover, P
   Llamas, B
   Tuke, J
   Bean, N
   Abdullah-Highfold, A
   Agius, S
   O'Donoghue, A
   O'Loughlin, I
   Sutton, P
   Zilio, F
   Walshe, K
   Williams, AN
   Turney, CSM
   Williams, M
   Richards, SM
   Mitchell, RJ
   Kowal, E
   Stephen, JR
   Williams, L
   Haak, W
   Cooper, A
AF Tobler, Ray
   Rohrlach, Adam
   Soubrier, Julien
   Bover, Pere
   Llamas, Bastien
   Tuke, Jonathan
   Bean, Nigel
   Abdullah-Highfold, Ali
   Agius, Shane
   O'Donoghue, Amy
   O'Loughlin, Isabel
   Sutton, Peter
   Zilio, Fran
   Walshe, Keryn
   Williams, Alan N.
   Turney, Chris S. M.
   Williams, Matthew
   Richards, Stephen M.
   Mitchell, Robert J.
   Kowal, Emma
   Stephen, John R.
   Williams, Lesley
   Haak, Wolfgang
   Cooper, Alan
TI Aboriginal mitogenomes reveal 50,000 years of regionalism in Australia
SO NATURE
LA English
DT Article
ID human occupation site; paleoenvironmental change; devils-lair; ancient; megafauna; colonization; pleistocene; calibration; archaeology; settlement
AB Aboriginal Australians represent one of the longest continuous cultural complexes known. Archaeological evidence indicates that Australia and New Guinea were initially settled approximately 50 thousand years ago (ka); however, little is known about the processes underlying the enormous linguistic and phenotypic diversity within Australia. Here we report 111 mitochondrial genomes (mitogenomes) from historical Aboriginal Australian hair samples, whose origins enable us to reconstruct Australian phylogeographic history before European settlement. Marked geographic patterns and deep splits across the major mitochondrial haplogroups imply that the settlement of Australia comprised a single, rapid migration along the east and west coasts that reached southern Australia by 49-45 ka. After continent-wide colonization, strong regional patterns developed and these have survived despite substantial climatic and cultural change during the late Pleistocene and Holocene epochs. Remarkably, we find evidence for the continuous presence of populations in discrete geographic areas dating back to around 50 ka, in agreement with the notable Aboriginal Australian cultural attachment to their country.
C1 [Tobler, Ray; Soubrier, Julien; Bover, Pere; Llamas, Bastien; Williams, Matthew; Richards, Stephen M.; Haak, Wolfgang; Cooper, Alan] Univ Adelaide, Sch Biol Sci, Australian Ctr Ancient DNA, Adelaide, SA 5005, Australia.
   [Rohrlach, Adam; Tuke, Jonathan; Bean, Nigel] Univ Adelaide, Sch Math Sci, Adelaide, SA 5005, Australia.
   [Rohrlach, Adam; Tuke, Jonathan; Bean, Nigel] Univ Adelaide, ARC Ctr Excellence Math & Stat Frontiers, Adelaide, SA 5005, Australia.
   [Soubrier, Julien] SA Pathol, Genet & Mol Pathol, Adelaide, SA 5000, Australia.
   [Abdullah-Highfold, Ali; Agius, Shane; O'Donoghue, Amy; O'Loughlin, Isabel; Sutton, Peter; Zilio, Fran; Walshe, Keryn] South Australian Museum, Adelaide, SA 5005, Australia.
   [Sutton, Peter] Univ Adelaide, Sch Biol Sci, Adelaide, SA 5005, Australia.
   [Turney, Chris S. M.] Univ New South Wales, Sch Biol Earth & Environm Sci, Palaeontol Geobiol & Earth Arch Res Ctr, Sydney, NSW 2052, Australia.
   [Turney, Chris S. M.] Univ New South Wales, Sch Biol Earth & Environm Sci, Climate Change Res Ctr, Sydney, NSW 2052, Australia.
   [Williams, Matthew] Australian Natl Univ, Coll Arts & Social Sci, Sch Archaeol & Anthropol, Canberra, ACT 0200, Australia.
   [Mitchell, Robert J.] La Trobe Univ, Dept Biochem & Genet, Bundoora, Vic 3086, Australia.
   [Kowal, Emma] Deakin Univ, Alfred Deakin Inst, Melbourne, Vic 3125, Australia.
   [Stephen, John R.] Waite Res Precinct, Australian Genome Res Facil, Adelaide, SA 5064, Australia.
   [Williams, Lesley] Commun Elder & Cultural Advisor, Cherbourg, Qld, Australia.
   [Haak, Wolfgang] Max Planck Inst Sci Human Hist, Dept Archeogenet, D-07745 Jena, Germany.
   [Cooper, Alan] Univ Adelaide, Inst Environm, Adelaide, SA 5005, Australia.
C3 Adelaide University; University of Adelaide; Adelaide University; University of Adelaide; Adelaide University; University of Adelaide; SA Pathology; South Australian Museum; Adelaide University; University of Adelaide; University of New South Wales Sydney; University of New South Wales Sydney; Australian National University; La Trobe University; Deakin University; Adelaide University; University of Adelaide
RP Cooper, A (corresponding author), Univ Adelaide, Sch Biol Sci, Australian Ctr Ancient DNA, Adelaide, SA 5005, Australia.; Cooper, A (corresponding author), Univ Adelaide, Inst Environm, Adelaide, SA 5005, Australia.
EM alan.cooper@adelaide.edu.au
FU South Australian Museum; Australian Research Council; University of Adelaide Environment Institute; Genographic Project; Bioplatforms Australia; University of Adelaide Human Research Ethics Committee [H-2014-252]
NR 78
TC 155
Z9 167
U1 0
U2 56
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 13
PY 2017
VL 544
IS 7649
BP 180
EP +
DI 10.1038/nature21416
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ER6EK
UT WOS:000398897900027
PM 28273067
DA 2026-03-09
ER

PT J
AU Liao, KB
   Pickel, TC
   Oyarskikh, VB
   Acsa, JB
   Usaev, DGM
   Davies, HML
AF Liao, Kuangbiao
   Pickel, Thomas C.
   Oyarskikh, Vyacheslav B.
   Acsa, John B.
   Usaev, Djamaladdin G. M.
   Davies, Huw M. L.
TI Site-selective and stereoselective functionalization of non-activated tertiary C-H bonds
SO NATURE
LA English
DT Article
ID diazoesters; derivatives; activation; complexes; catalysts; insertion; alkanes
AB The synthesis of complex organic compounds usually relies on controlling the reactions of the functional groups. In recent years, it has become possible to carry out reactions directly on the C-H bonds, previously considered to be unreactive(1-3). One of the major challenges is to control the site-selectivity because most organic compounds have many similar C-H bonds. The most well developed procedures so far rely on the use of substrate control, in which the substrate has one inherently more reactive C-H bond(4) or contains a directing group(5,6) or the reaction is conducted intramolecularly(7) so that a specific C-H bond is favoured. A more versatile but more challenging approach is to use catalysts to control which site in the substrate is functionalized. p450 enzymes exhibit C-H oxidation site-selectivity, in which the enzyme scaffold causes a specific C-H bond to be functionalized by placing it close to the iron-oxo haem complex(8). Several studies have aimed to emulate this enzymatic site-selectivity with designed transition-metal catalysts but it is difficult to achieve exceptionally high levels of site-selectivity(9-11). Recently, we reported a dirhodium catalyst for the site-selective functionalization of the most accessible nonactivated (that is, not next to a functional group) secondary C-H bonds by means of rhodium-carbene-induced C-H insertion(12). Here we describe another dirhodium catalyst that has a very different reactivity profile. Instead of the secondary C-H bond(12), the new catalyst is capable of precise site-selectivity at the most accessible tertiary C-H bonds. Using this catalyst, we modify several natural products, including steroids and a vitamin E derivative, indicating the applicability of this method of synthesis to the late-stage functionalization of complex molecules. These studies show it is possible to achieve site-selectivity at different positions within a substrate simply by selecting the appropriate catalyst. We hope that this work will inspire the design of even more sophisticated catalysts, such that catalyst-controlled C-H functionalization becomes a broadly applied strategy for the synthesis of complex molecules.
C1 [Liao, Kuangbiao; Pickel, Thomas C.; Oyarskikh, Vyacheslav B.; Acsa, John B.; Davies, Huw M. L.] Emory Univ, Dept Chem, 1515 Dickey Dr, Atlanta, GA 30322 USA.
   [Usaev, Djamaladdin G. M.] Emory Univ, Cherry L Emerson Ctr Sci Computat, 1521 Dickey Dr, Atlanta, GA 30322 USA.
C3 Emory University; Emory University
RP Davies, HML (corresponding author), Emory Univ, Dept Chem, 1515 Dickey Dr, Atlanta, GA 30322 USA.
EM hmdavie@emory.edu
FU NSF under CCI Center [CHE-1700982]; Novartis; AbbVie; NSF MRI-R2 grant [CHE-0958205]; National Science Foundation [CHE 1531620, CHE 1626172]; Direct For Mathematical & Physical Scien; Division Of Chemistry [1531620] Funding Source: National Science Foundation
NR 32
TC 245
Z9 290
U1 10
U2 275
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 30
PY 2017
VL 551
IS 7682
BP 609
EP 613
DI 10.1038/nature24641
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FO1KW
UT WOS:000416520400039
PM 29156454
DA 2026-03-09
ER

PT J
AU Cohen, LJ
   Esterhazy, D
   Kim, SH
   Lemetre, C
   Aguilar, RR
   Gordon, EA
   Pickard, AJ
   Cross, JR
   Emiliano, AB
   Han, SM
   Chu, J
   Vila-Farres, X
   Kaplitt, J
   Rogoz, A
   Calle, PY
   Hunter, C
   Bitok, JK
   Brady, SF
AF Cohen, Louis J.
   Esterhazy, Daria
   Kim, Seong-Hwan
   Lemetre, Christophe
   Aguilar, Rhiannon R.
   Gordon, Emma A.
   Pickard, Amanda J.
   Cross, Justin R.
   Emiliano, Ana B.
   Han, Sun M.
   Chu, John
   Vila-Farres, Xavier
   Kaplitt, Jeremy
   Rogoz, Aneta
   Calle, Paula Y.
   Hunter, Craig
   Bitok, J. Kipchirchir
   Brady, Sean F.
TI Commensal bacteria make GPCR ligands that mimic human signalling molecules
SO NATURE
LA English
DT Article
ID protein-coupled receptor; glucagon-like peptide-1; glycemic control; gpr119 agonist; activation; g2a; oleoylethanolamide; microbiota; secretion; discovery
AB Commensal bacteria are believed to have important roles in human health. The mechanisms by which they affect mammalian physiology remain poorly understood, but bacterial metabolites are likely to be key components of host interactions. Here we use bioinformatics and synthetic biology to mine the human microbiota for N-acyl amides that interact with G-protein-coupled receptors (GPCRs). We found that N-acyl amide synthase genes are enriched in gastrointestinal bacteria and the lipids that they encode interact with GPCRs that regulate gastrointestinal tract physiology. Mouse and cell-based models demonstrate that commensal GPR119 agonists regulate metabolic hormones and glucose homeostasis as efficiently as human ligands, although future studies are needed to define their potential physiological role in humans. Our results suggest that chemical mimicry of eukaryotic signalling molecules may be common among commensal bacteria and that manipulation of microbiota genes encoding metabolites that elicit host cellular responses represents a possible small-molecule therapeutic modality (microbiome-biosynthetic gene therapy).
C1 [Cohen, Louis J.; Kim, Seong-Hwan; Lemetre, Christophe; Aguilar, Rhiannon R.; Gordon, Emma A.; Han, Sun M.; Chu, John; Vila-Farres, Xavier; Kaplitt, Jeremy; Calle, Paula Y.; Bitok, J. Kipchirchir; Brady, Sean F.] Rockefeller Univ, Lab Genetically Encoded Small Mol, New York, NY 10065 USA.
   [Cohen, Louis J.] Icahn Sch Med Mt Sinai, Dept Med, Div Gastroenterol, New York, NY 10029 USA.
   [Esterhazy, Daria; Rogoz, Aneta] Rockefeller Univ, Lab Mucosal Immunol, New York, NY 10065 USA.
   [Pickard, Amanda J.; Cross, Justin R.] Mem Sloan Kettering Canc Ctr, Donald B & Catherine C Marron Canc Metab Ctr, New York, NY 10065 USA.
   [Emiliano, Ana B.] Rockefeller Univ, Mol Genet Lab, New York, NY 10065 USA.
   [Hunter, Craig] Rockefeller Univ, Comparat Biosci Ctr, New York, NY 10065 USA.
C3 Rockefeller University; Icahn School of Medicine at Mount Sinai; Rockefeller University; Memorial Sloan Kettering Cancer Center; Rockefeller University; Rockefeller University
RP Brady, SF (corresponding author), Rockefeller Univ, Lab Genetically Encoded Small Mol, New York, NY 10065 USA.
EM sbrady@rockefeller.edu
FU Robertson Foundation; Center for Basic and Translational Research on Disorders of the Digestive System; Leona M. and Harry B. Helmsley Charitable Trust; Rainin Foundation [U01 GM110714-1A1, GM122559-01]; Crohn's and Colitis Foundation Career Development Award; NIDDK [K08 DK109287-01]; National Institute of General Medical Sciences [R35GM122559] Funding Source: NIH RePORTER
NR 44
TC 370
Z9 433
U1 5
U2 210
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 7
PY 2017
VL 549
IS 7670
BP 48
EP +
DI 10.1038/nature23874
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG0DH
UT WOS:000409388700030
PM 28854168
DA 2026-03-09
ER

PT J
AU Hite, RK
   Tao, X
   MacKinnon, R
AF Hite, Richard K.
   Tao, Xiao
   MacKinnon, Roderick
TI Structural basis for gating the high-conductance Ca2+-activated K+ channel
SO NATURE
LA English
DT Article
ID activated potassium channels; planar lipid bilayers; bk channels; skeletal-muscle; voltage sensor; electron cryomicroscopy; quaternary ammonium; ca-2&-activated k; kinetic structure; ca2+ binding
AB The precise control of an ion channel gate by environmental stimuli is crucial for the fulfilment of its biological role. The gate in Slo1 K+ channels is regulated by two separate stimuli, intracellular Ca2+ concentration and membrane voltage. Slo1 is thus central to understanding the relationship between intracellular Ca2+ and membrane excitability. Here we present the Slo1 structure from Aplysia californica in the absence of Ca2+ and compare it with the Ca2+-bound channel. We show that Ca2+ binding at two unique binding sites per subunit stabilizes an expanded conformation of the Ca2+ sensor gating ring. These conformational changes are propagated from the gating ring to the pore through covalent linkers and through protein interfaces formed between the gating ring and the voltage sensors. The gating ring and the voltage sensors are directly connected through these interfaces, which allow membrane voltage to regulate gating of the pore by influencing the Ca2+ sensors.
C1 [Hite, Richard K.; Tao, Xiao; MacKinnon, Roderick] Rockefeller Univ, 1230 York Ave, New York, NY 10065 USA.
   [Hite, Richard K.; Tao, Xiao; MacKinnon, Roderick] Howard Hughes Med Inst, 1230 York Ave, New York, NY 10065 USA.
C3 Rockefeller University; Howard Hughes Medical Institute
RP MacKinnon, R (corresponding author), Rockefeller Univ, 1230 York Ave, New York, NY 10065 USA.; MacKinnon, R (corresponding author), Howard Hughes Med Inst, 1230 York Ave, New York, NY 10065 USA.
EM mackinn@mail.rockefeller.edu
FU [GM43949]; National Institute of General Medical Sciences [R01GM043949] Funding Source: NIH RePORTER
NR 52
TC 153
Z9 174
U1 0
U2 67
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 5
PY 2017
VL 541
IS 7635
BP 52
EP +
DI 10.1038/nature20775
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6NA
UT WOS:000396119500027
PM 27974801
DA 2026-03-09
ER

PT J
AU Arif, A
   Terenzi, F
   Potdar, AA
   Jia, J
   Sacks, J
   China, A
   Halawani, D
   Vasu, K
   Li, XX
   Brown, JM
   Chen, J
   Kozma, SC
   Thomas, G
   Fox, PL
AF Arif, Abul
   Terenzi, Fulvia
   Potdar, Alka A.
   Jia, Jie
   Sacks, Jessica
   China, Arnab
   Halawani, Dalia
   Vasu, Kommireddy
   Li, Xiaoxia
   Brown, J. Mark
   Chen, Jie
   Kozma, Sara C.
   Thomas, George
   Fox, Paul L.
TI EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice
SO NATURE
LA English
DT Article
ID acid transport protein-1; transfer-rna synthetase; diet-induced obesity; translational control; skeletal-muscle; ppar-gamma; noncanonical function; s6 phosphorylation; cholesteryl esters; insulin-resistance
AB Metabolic pathways that contribute to adiposity and ageing are activated by the mammalian target of rapamycin complex 1 (mTORC1) and p70 ribosomal protein S6 kinase 1 (S6K1) axis(1-3). However, known mTORC1-S6K1 targets do not account for observed loss-of-function phenotypes, suggesting that there are additional downstream effectors of this pathway(4-6). Here we identify glutamylprolyl-tRNA synthetase (EPRS) as an mTORC1-S6K1 target that contributes to adiposity and ageing. Phosphorylation of EPRS at Ser999 by mTORC1-S6K1 induces its release from the aminoacyl tRNA multisynthetase complex, which is required for execution of noncanonical functions of EPRS beyond protein synthesis(7,8). To investigate the physiological function of EPRS phosphorylation, we generated Eprs knock-in mice bearing phospho-deficient Ser999-to-Ala (S999A) and phospho-mimetic (S999D) mutations. Homozygous S999A mice exhibited low body weight, reduced adipose tissue mass, and increased lifespan, similar to S6K1-deficient mice(9-11) and mice with adipocyte-specific deficiency of raptor, an mTORC1 constituent(12). Substitution of the Eprs(S999D) allele in S6K1-deficient mice normalized body mass and adiposity, indicating that EPRS phosphorylation mediates S6K1-dependent metabolic responses. In adipocytes, insulin stimulated S6K1-dependent EPRS phosphorylation and release from the multisynthetase complex. Interaction screening revealed that phospho-EPRS binds SLC27A1 (that is, fatty acid transport protein 1, FATP1)(13-15), inducing its translocation to the plasma membrane and long-chain fatty acid uptake. Thus, EPRS and FATP1 are terminal mTORC1-S6K1 axis effectors that are critical for metabolic phenotypes.
C1 [Arif, Abul; Terenzi, Fulvia; Jia, Jie; Sacks, Jessica; China, Arnab; Halawani, Dalia; Vasu, Kommireddy; Brown, J. Mark; Fox, Paul L.] Cleveland Clin, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44195 USA.
   [Potdar, Alka A.] Cedars Sinai Med Ctr, F Widjaja Fdn Inflammatory Bowel & Immunobiol Res, Los Angeles, CA 90048 USA.
   [Li, Xiaoxia] Cleveland Clin, Lerner Res Inst, Dept Immunol, Cleveland, OH 44195 USA.
   [Chen, Jie] Univ Illinois, Dept Cell & Dev Biol, Urbana, IL 61801 USA.
   [Kozma, Sara C.; Thomas, George] IDIBELL, Bellvitge Biomed Res Inst, ICO, Catalan Inst Oncol, Barcelona, Spain.
   [Kozma, Sara C.; Thomas, George] Univ Barcelona, Fac Med, Dept Physiol Sci 2, Barcelona 08908, Spain.
   [Thomas, George] Univ Cincinnati, Coll Med, Dept Internal Med, Div Hematol & Oncol, Cincinnati, OH USA.
C3 Cleveland Clinic Foundation; Cedars Sinai Medical Center; Cleveland Clinic Foundation; University of Illinois System; University of Illinois Urbana-Champaign; Institut d'Investigacio Biomedica de Bellvitge (IDIBELL); Institut Catala d'Oncologia; University of Barcelona; University of Barcelona; University System of Ohio; University of Cincinnati
RP Fox, PL (corresponding author), Cleveland Clin, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44195 USA.
EM foxp@ccf.org
FU NIH [P01HL029582, P01HL076491, R01GM086430, R01GM115476, P50CA150964, R01AR048914, R01GM089771, R01CA158768]; AHA SDG [10SDG3930003]; CIHR fellowship; AHA fellowship; Spanish Ministry [BFU2012-38867, SAF2011-24967]; Fundacio La Marato de TV3 [174/U/2016]; CIG European Commission [PCIG10-GA-2011-304160]; National Cancer Institute [P50CA150964] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM089771] Funding Source: NIH RePORTER; American Heart Association (AHA) [10SDG3930003] Funding Source: American Heart Association (AHA)
NR 54
TC 106
Z9 122
U1 1
U2 34
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 16
PY 2017
VL 542
IS 7641
BP 357
EP +
DI 10.1038/nature21380
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2LQ
UT WOS:000394451600039
PM 28178239
DA 2026-03-09
ER

PT J
AU Grilli, J
   Barabás, G
   Michalska-Smith, MJ
   Allesina, S
AF Grilli, Jacopo
   Barabas, Gyorgy
   Michalska-Smith, Matthew J.
   Allesina, Stefano
TI Higher-order interactions stabilize dynamics in competitive network models
SO NATURE
LA English
DT Article
ID optimal strategy; stable strategy; game; coexistence; biodiversity; community; paper
AB Ecologists have long sought a way to explain how the remarkable biodiversity observed in nature is maintained. On the one hand, simple models of interacting competitors cannot produce the stable persistence of very large ecological communities(1-5). On the other hand, neutral models(6-9), in which species do not interact and diversity is maintained by immigration and speciation, yield unrealistically small fluctuations in population abundance(10), and a strong positive correlation between a species' abundance and its age(11), contrary to empirical evidence. Models allowing for the robust persistence of large communities of interacting competitors are lacking. Here we show that very diverse communities could persist thanks to the stabilizing role of higher-order interactions(12,13), in which the presence of a species influences the interaction between other species. Although higher-order interactions have been studied for decades(14-16), their role in shaping ecological communities is still unclear(5). The inclusion of higher-order interactions in competitive network models stabilizes dynamics, making species coexistence robust to the perturbation of both population abundance and parameter values. We show that higher-order interactions have strong effects in models of closed ecological communities, as well as of open communities in which new species are constantly introduced. In our framework, higher-order interactions are completely defined by pairwise interactions, facilitating empirical parameterization and validation of our models.
C1 [Grilli, Jacopo; Barabas, Gyorgy; Michalska-Smith, Matthew J.; Allesina, Stefano] Univ Chicago, Ecol & Evolut, 1101 East 57th St, Chicago, IL 60637 USA.
   [Allesina, Stefano] Univ Chicago, Computat Inst, Chicago, IL 60637 USA.
   [Allesina, Stefano] Northwestern Univ, Northwestern Inst Complex Syst, Evanston, IL 60208 USA.
C3 University of Chicago; University of Chicago; Northwestern University
RP Allesina, S (corresponding author), Univ Chicago, Ecol & Evolut, 1101 East 57th St, Chicago, IL 60637 USA.; Allesina, S (corresponding author), Univ Chicago, Computat Inst, Chicago, IL 60637 USA.; Allesina, S (corresponding author), Northwestern Univ, Northwestern Inst Complex Syst, Evanston, IL 60208 USA.
EM sallesina@uchicago.edu
FU Human Frontier Science Program; NSF [DEB-1148867]; US Department of Education [P200A150101]; Division Of Environmental Biology; Direct For Biological Sciences [1148867] Funding Source: National Science Foundation
NR 30
TC 505
Z9 554
U1 20
U2 277
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 10
PY 2017
VL 548
IS 7666
BP 210
EP +
DI 10.1038/nature23273
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD1GB
UT WOS:000407284300043
PM 28746307
DA 2026-03-09
ER

PT J
AU Kim, HK
   Fuchs, G
   Wang, SC
   Wei, W
   Zhang, Y
   Park, H
   Roy-Chaudhuri, B
   Li, P
   Xu, JP
   Chu, K
   Zhang, FJ
   Chua, MS
   So, S
   Zhang, QC
   Sarnow, P
   Kay, MA
AF Kim, Hak Kyun
   Fuchs, Gabriele
   Wang, Shengchun
   Wei, Wei
   Zhang, Yue
   Park, Hyesuk
   Roy-Chaudhuri, Biswajoy
   Li, Pan
   Xu, Jianpeng
   Chu, Kirk
   Zhang, Feijie
   Chua, Mei-Sze
   So, Samuel
   Zhang, Qiangfeng Cliff
   Sarnow, Peter
   Kay, Mark A.
TI A transfer-RNA-derived small RNA regulates ribosome biogenesis
SO NATURE
LA English
DT Article
ID diamond-blackfan anemia; cell-proliferation; nucleic-acid; fragments; reveals; gene; expression; proteins; maturation; efficient
AB Transfer-RNA-derived small RNAs (tsRNAs; also called tRNA-derived fragments) are an abundant class of small non-coding RNAs whose biological roles are not well understood. Here we show that inhibition of a specific tsRNA, LeuCAG3'tsRNA, induces apoptosis in rapidly dividing cells in vitro and in a patient-derived orthotopic hepatocellular carcinoma model in mice. This tsRNA binds at least two ribosomal protein mRNAs (RPS28 and RPS15) to enhance their translation. A decrease in translation of RPS28 mRNA blocks pre-18S ribosomal RNA processing, resulting in a reduction in the number of 40S ribosomal subunits. These data establish a post-transcriptional mechanism that can fine-tune gene expression during different physiological states and provide a potential new target for treating cancer.
C1 [Kim, Hak Kyun; Wang, Shengchun; Zhang, Yue; Park, Hyesuk; Roy-Chaudhuri, Biswajoy; Xu, Jianpeng; Chu, Kirk; Zhang, Feijie; Kay, Mark A.] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA.
   [Kim, Hak Kyun; Wang, Shengchun; Zhang, Yue; Park, Hyesuk; Roy-Chaudhuri, Biswajoy; Xu, Jianpeng; Chu, Kirk; Zhang, Feijie; Kay, Mark A.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
   [Fuchs, Gabriele; Sarnow, Peter] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA.
   [Wei, Wei; Chua, Mei-Sze; So, Samuel] Stanford Univ, Dept Surg, Asian Liver Ctr, Sch Med, Stanford, CA 94305 USA.
   [Li, Pan; Zhang, Qiangfeng Cliff] Tsinghua Univ, Tsinghua Peking Joint Ctr Life Sci, Ctr Synthet & Syst Biol,MOE Key Lab Bioinformat, Beijing Adv Innovat Ctr Struct Biol,Sch Life Sci, Beijing 100084, Peoples R China.
   [Fuchs, Gabriele] SUNY Albany, RNA Inst, 1400 Washington Ave, Albany, NY 12222 USA.
   [Fuchs, Gabriele] SUNY Albany, Dept Biol Sci, 1400 Washington Ave, Albany, NY 12222 USA.
   [Wang, Shengchun] Medtron Vasc, 3576 Unocal Pl, Santa Rosa, CA 95403 USA.
   [Zhang, Yue] Stanford Ctr Genom & Personalized Med, 3165 Porter Dr, Palo Alto, CA 94304 USA.
   [Roy-Chaudhuri, Biswajoy] Impossible Foods Inc, 525 Chesapeake Dr, Redwood City, CA 94063 USA.
C3 Stanford University; Stanford University; Stanford University; Stanford University; Tsinghua University; State University of New York (SUNY) System; University at Albany, SUNY; State University of New York (SUNY) System; University at Albany, SUNY; Impossible Foods Inc.
RP Kay, MA (corresponding author), Stanford Univ, Dept Pediat, Stanford, CA 94305 USA.; Kay, MA (corresponding author), Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
EM markay@stanford.edu
FU National Institutes of Health [R01AI071068, R01DK114483]; Stanford Cancer Institute; CJ Huang Foundation; TS Kwok Liver Cancer Foundation
NR 45
TC 424
Z9 469
U1 6
U2 104
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 7
PY 2017
VL 552
IS 7683
BP 57
EP +
DI 10.1038/nature25005
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FP4BA
UT WOS:000417560500042
PM 29186115
DA 2026-03-09
ER

PT J
AU Halpern, KB
   Shenhav, R
   Matcovitch-Natan, O
   Tóth, B
   Lemze, D
   Golan, M
   Massasa, EE
   Baydatch, S
   Landen, S
   Moor, AE
   Brandis, A
   Giladi, A
   Stokar-Avihail, A
   David, E
   Amit, I
   Itzkovitz, S
AF Halpern, Keren Bahar
   Shenhav, Rom
   Matcovitch-Natan, Orit
   Toth, Beata
   Lemze, Doron
   Golan, Matan
   Massasa, Efi E.
   Baydatch, Shaked
   Landen, Shanie
   Moor, Andreas E.
   Brandis, Alexander
   Giladi, Amir
   Stokar-Avihail, Avigail
   David, Eyal
   Amit, Ido
   Itzkovitz, Shalev
TI Single-cell spatial reconstruction reveals global division of labour in the mammalian liver
SO NATURE
LA English
DT Article
ID zonal gene-expression; messenger-rna; zonation; tissue; seq; metabolism; energy
AB The mammalian liver consists of hexagon-shaped lobules that are radially polarized by blood flow and morphogens(1-4). Key liver genes have been shown to be differentially expressed along the lobule axis, a phenomenon termed zonation(5,6), but a detailed genome-wide reconstruction of this spatial division of labour has not been achieved. Here we measure the entire transcriptome of thousands of mouse liver cells and infer their lobule coordinates on the basis of a panel of zonated landmark genes, characterized with single-molecule fluorescence in situ hybridization(7). Using this approach, we obtain the zonation profiles of all liver genes with high spatial resolution. We find that around 50% of liver genes are significantly zonated and uncover abundant non-monotonic profiles that peak at the mid-lobule layers. These include a spatial order of bile acid biosynthesis enzymes that matches their position in the enzymatic cascade. Our approach can facilitate the reconstruction of similar spatial genomic blueprints for other mammalian organs.
C1 [Halpern, Keren Bahar; Shenhav, Rom; Toth, Beata; Lemze, Doron; Golan, Matan; Massasa, Efi E.; Baydatch, Shaked; Landen, Shanie; Moor, Andreas E.; Stokar-Avihail, Avigail; Itzkovitz, Shalev] Weizmann Inst Sci, Dept Mol Cell Biol, Rehovot, Israel.
   [Matcovitch-Natan, Orit; Giladi, Amir; David, Eyal; Amit, Ido] Weizmann Inst Sci, Dept Immunol, Rehovot, Israel.
   [Brandis, Alexander] Weizmann Inst Sci, Biol Serv, Rehovot, Israel.
C3 Weizmann Institute of Science; Weizmann Institute of Science; Weizmann Institute of Science
RP Itzkovitz, S (corresponding author), Weizmann Inst Sci, Dept Mol Cell Biol, Rehovot, Israel.; Amit, I (corresponding author), Weizmann Inst Sci, Dept Immunol, Rehovot, Israel.
EM ido.amit@weizmann.ac.il; shalev.itzkovitz@weizmann.ac.il
FU European Research Council [309788]; Israel Science Foundation; Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine; Helen and Martin Kimmel award; Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; Leir Charitable Foundations; Richard Jakubskind Laboratory of Systems Biology; Cymerman-Jakubskind Prize; Lord Sieff of Brimpton Memorial Fund; I-CORE program of the Planning and Budgeting Committee; Israel Science Foundation [1902/12, 1796/12, 1486/16]; EMBO Young Investigator Program; European Research Council under the European Union/ERC [335122]; European Research Council (ERC) [309788, 335122] Funding Source: European Research Council (ERC)
NR 38
TC 772
Z9 937
U1 7
U2 213
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 16
PY 2017
VL 542
IS 7641
BP 352
EP +
DI 10.1038/nature21065
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2LQ
UT WOS:000394451600038
PM 28166538
DA 2026-03-09
ER

PT J
AU Yang, HW
   Chung, M
   Kudo, T
   Meyer, T
AF Yang, Hee Won
   Chung, Mingyu
   Kudo, Takamasa
   Meyer, Tobias
TI Competing memories of mitogen and p53 signalling control cell-cycle entry
SO NATURE
LA English
DT Article
ID proliferation-quiescence decision; dna-damage response; replication stress; d1; p21; inhibition; activation; expression; radiation; p21(cip1)
AB Regulation of cell proliferation is necessary for immune responses, tissue repair, and upkeep of organ function to maintain human health(1). When proliferating cells complete mitosis, a fraction of newly born daughter cells immediately enter the next cell cycle, while the remaining cells in the same population exit to a transient or persistent quiescent state(2). Whether this choice between two cell-cycle pathways is due to natural variability in mitogen signalling or other underlying causes is unknown. Here we show that human cells make this fundamental cell-cycle entry or exit decision based on competing memories of variable mitogen and stress signals. Rather than erasing their signalling history at cell-cycle checkpoints before mitosis, mother cells transmit DNA damage-induced p53 protein and mitogen-induced cyclin D1 (CCND1) mRNA to newly born daughter cells. After mitosis, the transferred CCND1 mRNA and p53 protein induce variable expression of cyclin D1 and the CDK inhibitor p21 that almost exclusively determines cell-cycle commitment in daughter cells. We find that stoichiometric inhibition of cyclin D1-CDK4 activity by p21 controls the retinoblastoma (Rb) and E2F transcription program in an ultrasensitive manner. Thus, daughter cells control the proliferation-quiescence decision by converting the memories of variable mitogen and stress signals into a competition between cyclin D1 and p21 expression. We propose a cell-cycle control principle based on natural variation, memory and competition that maximizes the health of growing cell populations.
C1 [Yang, Hee Won; Chung, Mingyu; Kudo, Takamasa; Meyer, Tobias] Stanford Univ, Dept Chem & Syst Biol, Sch Med, Stanford, CA 94305 USA.
C3 Stanford University
RP Yang, HW; Meyer, T (corresponding author), Stanford Univ, Dept Chem & Syst Biol, Sch Med, Stanford, CA 94305 USA.
EM heewony@stanford.edu; tobias1@stanford.edu
FU National Research Foundation of Korea (NRF) - Ministry of Education [2013R1A6A3A03025832]; NIGMS [GM11837, GM063702, PGM107615]
NR 26
TC 166
Z9 205
U1 1
U2 47
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 21
PY 2017
VL 549
IS 7672
BP 404
EP +
DI 10.1038/nature23880
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FH7PB
UT WOS:000411381300039
PM 28869970
DA 2026-03-09
ER

PT J
AU Moysiuk, J
   Smith, MR
   Caron, JB
AF Moysiuk, Joseph
   Smith, Martin R.
   Caron, Jean-Bernard
TI Hyoliths are Palaeozoic lophophorates
SO NATURE
LA English
DT Article
ID burgess shale; shelled brachiopods; canadian rocky; south-australia; assemblage; biology; china
AB Hyoliths are abundant and globally distributed 'shelly' fossils that appear early in the Cambrian period and can be found throughout the 280 million year span of Palaeozoic strata(1,2). The ecological and evolutionary importance of this group has remained unresolved, largely because of their poorly constrained soft anatomy and idiosyncratic scleritome, which comprises an operculum, a conical shell and, in some taxa, a pair of lateral spines (helens)(3-5). Since their first description over 175 years ago, hyoliths have most often been regarded as incertae sedis(4,6), related to molluscs(7,8) or assigned to their own phylum(1,2). Here we examine over 1,500 specimens of the mid-Cambrian hyolith Haplophrentis from the Burgess Shale and Spence Shale Lagerstatten. We reconstruct Haplophrentis as a semi-sessile, epibenthic suspension feeder that could use its helens to elevate its tubular body above the sea floor(3,9-12). Exceptionally preserved soft tissues include an extendable, gullwing-shaped, tentacle-bearing organ surrounding a central mouth, which we interpret as a lophophore, and a U-shaped digestive tract ending in a dorsolateral anus. Together with opposing bilateral sclerites and a deep ventral visceral cavity, these features indicate an affinity with the lophophorates (brachiopods, phoronids and tommotiids), substantially increasing the morphological disparity of this prominent group.
C1 [Moysiuk, Joseph; Caron, Jean-Bernard] Univ Toronto, Dept Ecol & Evolutionary Biol & Earth Sci, 25 Willcocks St, Toronto, ON M5S 3B2, Canada.
   [Smith, Martin R.] Univ Cambridge, Dept Earth Sci, Downing St, Cambridge CB2 3EQ, England.
   [Smith, Martin R.] Univ Durham, Dept Earth Sci, Mountjoy Site,South Rd, Durham DH1 3LE, England.
   [Caron, Jean-Bernard] Royal Ontario Museum, Dept Nat Hist, 100 Queens Pk, Toronto, ON M5S 2C6, Canada.
C3 University of Toronto; University of Cambridge; Durham University; Royal Ontario Museum
RP Moysiuk, J; Caron, JB (corresponding author), Univ Toronto, Dept Ecol & Evolutionary Biol & Earth Sci, 25 Willcocks St, Toronto, ON M5S 3B2, Canada.; Caron, JB (corresponding author), Royal Ontario Museum, Dept Nat Hist, 100 Queens Pk, Toronto, ON M5S 2C6, Canada.
EM joe.moysiuk@mail.utoronto.ca; jcaron@rom.on.ca
FU University of Toronto [EEB299Y]; Royal Ontario Museum; NSERC [341944]; Clare College, Cambridge; Malacological Society of London; Royal Ontario Museum Burgess Shale project [70]
NR 31
TC 91
Z9 108
U1 3
U2 36
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 19
PY 2017
VL 541
IS 7637
BP 394
EP +
DI 10.1038/nature20804
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6QP
UT WOS:000396128800042
PM 28077871
DA 2026-03-09
ER

PT J
AU Vasiliauskaité-Brooks, I
   Sounier, R
   Rochaix, P
   Bellot, G
   Fortier, M
   Hoh, F
   De Colibus, L
   Bechara, C
   Saied, EM
   Arenz, C
   Leyrat, C
   Granier, S
AF Vasiliauskaite-Brooks, Ieva
   Sounier, Remy
   Rochaix, Pascal
   Bellot, Gaetan
   Fortier, Mathieu
   Hoh, Francois
   De Colibus, Luigi
   Bechara, Cherine
   Saied, Essa M.
   Arenz, Christoph
   Leyrat, Cedric
   Granier, Sebastien
TI Structural insights into adiponectin receptors suggest ceramidase activity
SO NATURE
LA English
DT Article
ID additive force-field; molecular-dynamics method; macromolecular crystallography; intramembrane proteolysis; accurate docking; protein; simulations; validation; hydrolases; database
AB Adiponectin receptors (ADIPORs) are integral membrane proteins that control glucose and lipid metabolism by mediating, at least in part, a cellular ceramidase activity1 that catalyses the hydrolysis of ceramide to produce sphingosine and a free fatty acid (FFA). The crystal structures of the two receptor subtypes, ADIPOR1 and ADIPOR2, show a similar overall seven-transmembrane-domain architecture with large unoccupied cavities and a zinc binding site within the seven transmembrane domain2. However, the molecular mechanisms by which ADIPORs function are not known. Here we describe the crystal structure of ADIPOR2 bound to a FFA molecule and show that ADIPOR2 possesses intrinsic basal ceramidase activity that is enhanced by adiponectin. We also identify a ceramide binding pose and propose a possible mechanism for the hydrolytic activity of ADIPOR2 using computational approaches. In molecular dynamics simulations, the side chains of residues coordinating the zinc rearrange quickly to promote the nucleophilic attack of a zinc-bound hydroxide ion onto the ceramide amide carbonyl. Furthermore, we present a revised ADIPOR1 crystal structure exhibiting a seven-transmembranedomain architecture that is clearly distinct from that of ADIPOR2. In this structure, no FFA is observed and the ceramide binding pocket and putative zinc catalytic site are exposed to the inner membrane leaflet. ADIPOR1 also possesses intrinsic ceramidase activity, so we suspect that the two distinct structures may represent key steps in the enzymatic activity of ADIPORs. The ceramidase activity is low, however, and further studies will be required to characterize fully the enzymatic parameters and substrate specificity of ADIPORs. These insights into ADIPOR function will enable the structure-based design of potent modulators of these clinically relevant enzymes.
C1 [Vasiliauskaite-Brooks, Ieva; Sounier, Remy; Rochaix, Pascal; Bellot, Gaetan; Fortier, Mathieu; Leyrat, Cedric; Granier, Sebastien] Univ Montpellier, CNRS UMR 5203, INSERM U1191, Inst Genom Fonct, F-34094 Montpellier, France.
   [Hoh, Francois] Univ Montpellier, CNRS UMR 5048, Ctr Biochim Struct, INSERM 1054, 29 Rue Navacelles, F-34090 Montpellier, France.
   [De Colibus, Luigi] Univ Oxford, Div Struct Biol, Oxford, England.
   [Bechara, Cherine] Univ Montpellier, CNRS UMR5235, Dynam Interact Membranaires Norm & Patholog, F-34095 Montpellier, France.
   [Saied, Essa M.; Arenz, Christoph] Humboldt Univ, Inst Chem, Brook Taylor Str 2, D-12489 Berlin, Germany.
   [Saied, Essa M.] Suez Canal Univ, Fac Sci, Dept Chem, Ismailia 41522, Egypt.
C3 Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Montpellier; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite de Montpellier; Institut National de la Sante et de la Recherche Medicale (Inserm); University of Oxford; Universite de Montpellier; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Humboldt University of Berlin; Egyptian Knowledge Bank (EKB); Suez Canal University
RP Leyrat, C (corresponding author), Univ Montpellier, CNRS UMR 5203, INSERM U1191, Inst Genom Fonct, F-34094 Montpellier, France.
EM cedric.leyrat@igf.cnrs.fr; sebastien.granier@igf.cnrs.fr
FU European Research Council (ERC) under the European Union [647687]; European Research Council (ERC) [647687] Funding Source: European Research Council (ERC)
NR 50
TC 178
Z9 191
U1 1
U2 95
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 6
PY 2017
VL 544
IS 7648
BP 120
EP +
DI 10.1038/nature21714
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EQ8GQ
UT WOS:000398323300045
PM 28329765
DA 2026-03-09
ER

PT J
AU Li, X
   Kim, Y
   Sang, EKT
   Davis, JR
   Damani, FN
   Hiang, CC
   Hess, GT
   Zappala, Z
   Strober, BJ
   Scott, AJ
   Li, A
   Ganna, A
   Assik, MCB
   Merker, JD
   Hall, IM
   Attle, AB
   Montgomery, SB
AF Li, Xin
   Kim, Yungil
   Sang, Emily K. T.
   Davis, Joe R. .
   Damani, Farhan N.
   Hiang, Colby C.
   Hess, Gaelen T. .
   Zappala, Zachary
   Strober, Benjamin J.
   Scott, Alexandra J.
   Li, Amy
   Ganna, Andrea
   Assik, Michael C. . B.
   Merker, Jason D.
   Hall, Ira M.
   Attle, Alexis B.
   Montgomery, Stephen B. .
TI The impact of rare variation on gene expression across tissues
SO NATURE
LA English
DT Article
ID variants; pathogenicity; architecture; evolution; selection; elements; growth
AB Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk(1-4). While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants(1,5). Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles(1,6,7), but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues(8-11), but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype Tissue Expression (GTEx) project v6p release(12). We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes.
C1 [Li, Xin; Sang, Emily K. T.; Davis, Joe R. .; Zappala, Zachary; Merker, Jason D.; Montgomery, Stephen B. .] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA.
   [Kim, Yungil; Damani, Farhan N.; Attle, Alexis B.] Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA.
   [Sang, Emily K. T.] Stanford Univ, Biomed Informat Program, Stanford, CA 94305 USA.
   [Davis, Joe R. .; Hess, Gaelen T. .; Zappala, Zachary; Li, Amy; Assik, Michael C. . B.; Montgomery, Stephen B. .] Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
   [Hiang, Colby C.; Scott, Alexandra J.; Hall, Ira M.] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO 63108 USA.
   [Strober, Benjamin J.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA.
   [Ganna, Andrea] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
   [Ganna, Andrea] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA.
   [Ganna, Andrea] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA.
   [Hall, Ira M.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA.
   [Hall, Ira M.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA.
C3 Stanford University; Johns Hopkins University; Stanford University; Stanford University; Washington University (WUSTL); Johns Hopkins University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Washington University (WUSTL); Washington University (WUSTL)
RP Montgomery, SB (corresponding author), Stanford Univ, Dept Pathol, Stanford, CA 94305 USA.; Attle, AB (corresponding author), Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA.; Montgomery, SB (corresponding author), Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
EM ajbattle@cs.jhu.edu; smontgom@stanford.edu
FU Common Fund of the Office of the Director of the National Institutes of Health (NIH); National Cancer Institute; National Human Genome Research Institute (NHGRI); National Heart, Lung, and Blood Institute: National Institute on Drug Abuse; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; Leidos Biomedical, Inc. (Leidos) [10XS170, 10XS171]; LDACC [HHSN268201000029C]; Leidos subcontract [105-F1035]; University of Miami [DA006227]; Hewlett-Packard Stanford Graduate Fellowship; Natural Science and Engineering Council of Canada; Lucille P Markey Biomedical Research Stanford Graduate Fellowship; Stanford Genome Training Program (SGTP) [NHGRI T32HG000044]; National Science Foundation GRFP [DGE-114747]; Joseph C. Pistritto Research Fellowship; NIH training grant [T32 GM007057]; Mr and Mrs Spencer T. Olin Fellowship for Women in Graduate Study; Searle Scholars Program; NIH [1 R01MH109905-01, R01MH101814, R01HG008150]; NHGRI [U01HG007436, U01HG009080]; National Cancer Institute [T32CA096520] Funding Source: NIH RePORTER; National Human Genome Research Institute [T32HG000044] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007057] Funding Source: NIH RePORTER
NR 48
TC 168
Z9 216
U1 0
U2 41
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 12
PY 2017
VL 550
IS 7675
BP 239
EP +
DI 10.1038/nature24267
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FJ5YG
UT WOS:000412829500045
PM 29022581
DA 2026-03-09
ER

PT J
AU Han, G
   Mao, FY
   Bi, SD
   Wang, YQ
   Meng, J
AF Han, Gang
   Mao, Fangyuan
   Bi, Shundong
   Wang, Yuanqing
   Meng, Jin
TI A Jurassic gliding euharamiyidan mammal with an ear of five auditory bones
SO NATURE
LA English
DT Article
ID middle-ear; evolution; jaw; affinity; divergence; phylogeny; radiation
AB Gliding is a distinctive locomotion type that has been identified in only three mammal species from the Mesozoic era. Here we describe another Jurassic glider that belongs to the euharamiyidan mammals and shows hair details on its gliding membrane that are highly similar to those of extant gliding mammals. This species possesses a five-boned auditory apparatus consisting of the stapes, incus, malleus, ectotympanic and surangular, representing, to our knowledge, the earliest known definitive mammalian middle ear. The surangular has not been previously identified in any mammalian middle ear, and the morphology of each auditory bone differs from those of known mammals and their kin. We conclude that gliding locomotion was probably common in euharamiyidans, which lends support to idea that there was a major adaptive radiation of mammals in the mid-Jurassic period. The acquisition of the auditory bones in euharamiyidans was related to the formation of the dentary-squamosal jaw joint, which allows a posterior chewing movement, and must have evolved independently from the middle ear structures of monotremes and therian mammals.
C1 [Han, Gang] Bohai Univ, Paleontol Ctr, Jinzhou 121013, Liaoning, Peoples R China.
   [Han, Gang] Hainan Trop Ocean Univ, Sanya 572022, Hainan, Peoples R China.
   [Mao, Fangyuan; Wang, Yuanqing] Chinese Acad Sci, Inst Vertebrate Paleontol & Paleoanthropol, Key Lab Evolutionary Systemat Vertebrates, POB 643, Beijing 100044, Peoples R China.
   [Bi, Shundong] Indiana Univ Penn, Dept Biol, Indiana, PA 15705 USA.
   [Meng, Jin] Amer Museum Nat Hist, Div Paleontol, New York, NY 10024 USA.
C3 Bohai University; Hainan Tropical Ocean University; Chinese Academy of Sciences; Institute of Vertebrate Paleontology & Paleoanthropology, CAS; Pennsylvania State System of Higher Education (PASSHE); Indiana University of Pennsylvania; American Museum of Natural History (AMNH)
RP Mao, FY (corresponding author), Chinese Acad Sci, Inst Vertebrate Paleontol & Paleoanthropol, Key Lab Evolutionary Systemat Vertebrates, POB 643, Beijing 100044, Peoples R China.; Meng, J (corresponding author), Amer Museum Nat Hist, Div Paleontol, New York, NY 10024 USA.
EM maofangyuan@ivpp.ac.cn; jmeng@amnh.org
FU National Natural Science Foundation of China [41688103, 41404022]; Strategic Priority Research Program (B) of the Chinese Academy of Sciences [XDB18000000]
NR 72
TC 74
Z9 84
U1 1
U2 66
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 23
PY 2017
VL 551
IS 7681
BP 451
EP +
DI 10.1038/nature24483
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FN5JO
UT WOS:000416043700035
PM 29132143
DA 2026-03-09
ER

PT J
AU Dong, D
   Guo, MH
   Wang, SH
   Zhu, YW
   Wang, S
   Xiong, Z
   Yang, JZ
   Xu, ZL
   Huang, ZW
AF Dong, De
   Guo, Minghui
   Wang, Sihan
   Zhu, Yuwei
   Wang, Shuo
   Xiong, Zhi
   Yang, Jianzheng
   Xu, Zengliang
   Huang, Zhiwei
TI Structural basis of CRISPR-SpyCas9 inhibition by an anti-CRISPR protein
SO NATURE
LA English
DT Article
ID target dna recognition; adaptive immunity; nuclease specificity; bacterial immunity; cas systems; rna; complex; prokaryotes; archaea; endonuclease
AB CRISPR-Cas9 systems are bacterial adaptive immune systems that defend against infection by phages. Through the RNA-guided endonuclease activity of Cas9 they degrade double-stranded DNA with a protospacer adjacent motif (PAM) and sequences complementary to the guide RNA(1-5). Recently, two anti-CRISPR proteins (AcrIIA2 and AcrIIA4 from Listeria monocytogenes prophages) were identified, both of which inhibit Streptococcus pyogenes Cas9 (SpyCas9) and L. monocytogenes Cas9 activity in bacteria and human cells(6). However, the mechanism of AcrIIA2- or AcrIIA4-mediated Cas9 inhibition remains unknown. Here we report a crystal structure of SpyCas9 in complex with a single-guide RNA (sgRNA) and AcrIIA4. Our data show that AcrIIA2 and AcrIIA4 interact with SpyCas9 in a sgRNA-dependent manner. The structure reveals that AcrIIA4 inhibits SpyCas9 activity by structurally mimicking the PAM to occupy the PAM-interacting site in the PAM-interacting domain, thereby blocking recognition of double-stranded DNA substrates by SpyCas9. AcrIIA4 further inhibits the endonuclease activity of SpyCas9 by shielding its RuvC active site. Structural comparison reveals that formation of the AcrIIA4-binding site of SpyCas9 is induced by sgRNA binding. Our study reveals the mechanism of SpyCas9 inhibition by AcrIIA4, providing a structural basis for developing 'off-switch' tools for SpyCas9 to avoid unwanted genome edits within cells and tissues.
C1 [Dong, De; Guo, Minghui; Wang, Sihan; Zhu, Yuwei; Wang, Shuo; Xiong, Zhi; Yang, Jianzheng; Xu, Zengliang; Huang, Zhiwei] Harbin Inst Technol, Sch Life Sci & Technol, HIT Ctr Life Sci, Harbin 150080, Peoples R China.
C3 Harbin Institute of Technology
RP Huang, ZW (corresponding author), Harbin Inst Technol, Sch Life Sci & Technol, HIT Ctr Life Sci, Harbin 150080, Peoples R China.
EM huangzhiwei@hit.edu.cn
FU National Natural Science Foundation of China [31422014, 31450001, 31300605]
NR 35
TC 166
Z9 199
U1 4
U2 171
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 15
PY 2017
VL 546
IS 7658
BP 436
EP +
DI 10.1038/nature22377
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EX5BK
UT WOS:000403250900041
PM 28448066
DA 2026-03-09
ER

PT J
AU Choi, J
   Huebner, AJ
   Clement, K
   Walsh, RM
   Savol, A
   Lin, KX
   Gu, HC
   Di Stefano, B
   Brumbaugh, J
   Kim, SY
   Sharif, J
   Rose, CM
   Mohammad, A
   Odajima, J
   Charron, J
   Shioda, T
   Gnirke, A
   Gygi, S
   Koseki, H
   Adreyev, RIS
   Xiao, A
   Meissner, A
   Hochedlinger, K
AF Choi, Jiho
   Huebner, Aaron J.
   Clement, Kendell
   Walsh, Ryan M.
   Savol, Andrej
   Lin, Kaixuan
   Gu, Hongcang
   Di Stefano, Bruno
   Brumbaugh, Justin
   Kim, Sang-Yong
   Sharif, Jafar
   Rose, Christopher M.
   Mohammad, Arman
   Odajima, Junko
   Charron, Jean
   Shioda, Toshi
   Gnirke, Andreas
   Gygi, Steven
   Koseki, Haruhiko
   Adreyev, Ruslan I. S.
   Xiao, Andrew
   Meissner, Alexander
   Hochedlinger, Konrad
TI Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells
SO NATURE
LA English
DT Article
ID ground-state pluripotency; differential expression analysis; dna hypomethylation; genomic stability; self-renewal; demethylation; inhibition; mice; bioconductor; maintenance
AB Concomitant activation of the Wnt pathway and suppression of Mapk signalling by two small molecule inhibitors (2i) in the presence of leukaemia inhibitory factor (LIF) (hereafter termed 2i/L) induces a naive state in mouse embryonic stem (ES) cells that resembles the inner cell mass (ICM) of the pre-implantation embryo(1). Since the ICM exists only transiently in vivo, it remains unclear how sustained propagation of naive ES cells in vitro affects their stability and functionality. Here we show that prolonged culture of male mouse ES cells in 2i/L results in irreversible epigenetic and genomic changes that impair their developmental potential. Furthermore, we find that female ES cells cultured in conventional serum plus LIF medium phenocopy male ES cells cultured in 2i/L. Mechanistically, we demonstrate that the inhibition of Mek1/2 is predominantly responsible for these effects, in part through the downregulation of DNA methyltransferases and their cofactors. Finally, we show that replacement of the Mek1/2 inhibitor with a Src inhibitor preserves the epigenetic and genomic integrity as well as the developmental potential of ES cells. Taken together, our data suggest that, although short-term suppression of Mek1/2 in ES cells helps to maintain an ICM-like epigenetic state, prolonged suppression results in irreversible changes that compromise their developmental potential.
C1 [Choi, Jiho; Huebner, Aaron J.; Walsh, Ryan M.; Savol, Andrej; Di Stefano, Bruno; Brumbaugh, Justin; Adreyev, Ruslan I. S.; Hochedlinger, Konrad] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.
   [Choi, Jiho; Huebner, Aaron J.; Walsh, Ryan M.; Di Stefano, Bruno; Brumbaugh, Justin; Odajima, Junko; Shioda, Toshi; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA.
   [Choi, Jiho; Huebner, Aaron J.; Walsh, Ryan M.; Di Stefano, Bruno; Brumbaugh, Justin; Odajima, Junko; Shioda, Toshi; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.
   [Choi, Jiho; Huebner, Aaron J.; Clement, Kendell; Walsh, Ryan M.; Di Stefano, Bruno; Brumbaugh, Justin; Meissner, Alexander; Hochedlinger, Konrad] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.
   [Choi, Jiho; Huebner, Aaron J.; Clement, Kendell; Walsh, Ryan M.; Di Stefano, Bruno; Brumbaugh, Justin; Meissner, Alexander; Hochedlinger, Konrad] Harvard Stem Cell Inst, 1350 Massachusetts Ave, Cambridge, MA 02138 USA.
   [Clement, Kendell; Gu, Hongcang; Mohammad, Arman; Gnirke, Andreas; Meissner, Alexander] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Lin, Kaixuan; Xiao, Andrew] Yale Univ, Sch Med, Dept Genet, 10 Amistad St, New Haven, CT 06519 USA.
   [Kim, Sang-Yong] NYU, Langone Med Ctr, New York, NY 10016 USA.
   [Sharif, Jafar; Koseki, Haruhiko] RIKEN, Natl Res & Dev Agcy, Ctr Integrat Med Sci, Tsurumi Ku, 1-7-22 Suehiuro Cho, Yokohama, Kanagawa 2300045, Japan.
   [Rose, Christopher M.; Gygi, Steven] Harvard Med Sch, Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 USA.
   [Charron, Jean] Univ Laval, Ctr Rech Canc, CRCHU Quebec, Hotel Dieu Quebec, 9 Rue McMahon, Quebec City, PQ G1R 2J6, Canada.
C3 Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Yale University; New York University; NYU Langone Medical Center; RIKEN; Harvard University; Harvard Medical School; Laval University; Laval University Hospital
RP Hochedlinger, K (corresponding author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Hochedlinger, K (corresponding author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA.; Hochedlinger, K (corresponding author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.; Hochedlinger, K (corresponding author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.; Hochedlinger, K (corresponding author), Harvard Stem Cell Inst, 1350 Massachusetts Ave, Cambridge, MA 02138 USA.
EM khochedlinger@mgh.harvard.edu
FU NIH [P30 CA006973, R21ES024861, 1P50HG006193, R01 HD058013-06]; American Cancer Society-New England Division-Ellison Foundation Postdoctoral Fellowship [PF-15-130-01-DDC]; EMBO [ALTF 1143-2015]; New York Stem Cell Foundation; MGH; HHMI; Gerald and Darlene Jordan Chair in Regenerative Medicine; National Cancer Institute [P30CA006973] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK040561] Funding Source: NIH RePORTER; Grants-in-Aid for Scientific Research [16H02622] Funding Source: KAKEN
NR 49
TC 141
Z9 160
U1 1
U2 50
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 10
PY 2017
VL 548
IS 7666
BP 219
EP +
DI 10.1038/nature23274
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD1GB
UT WOS:000407284300045
PM 28746311
DA 2026-03-09
ER

PT J
AU Skrott, Z
   Mistrik, M
   Andersen, KK
   Friis, S
   Majera, D
   Gursky, J
   Ozdian, T
   Bartkova, J
   Turi, Z
   Moudry, P
   Kraus, M
   Michalova, M
   Vaclavkova, J
   Dzubak, P
   Vrobel, I
   Pouckova, P
   Sedlacek, J
   Miklovicova, A
   Kutt, A
   Li, J
   Mattova, J
   Driessen, C
   Dou, QP
   Olsen, J
   Hajduch, M
   Cvek, B
   Deshaies, RJ
   Bartek, J
AF Skrott, Zdenek
   Mistrik, Martin
   Andersen, Klaus Kaae
   Friis, Soren
   Majera, Dusana
   Gursky, Jan
   Ozdian, Tomas
   Bartkova, Jirina
   Turi, Zsofia
   Moudry, Pavel
   Kraus, Marianne
   Michalova, Martina
   Vaclavkova, Jana
   Dzubak, Petr
   Vrobel, Ivo
   Pouckova, Pavla
   Sedlacek, Jindrich
   Miklovicova, Andrea
   Kutt, Anne
   Li, Jing
   Mattova, Jana
   Driessen, Christoph
   Dou, Q. Ping
   Olsen, Jorgen
   Hajduch, Marian
   Cvek, Boris
   Deshaies, Raymond J.
   Bartek, Jiri
TI Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4
SO NATURE
LA English
DT Article
ID valosin-containing protein; breast-cancer; antialcoholism drug; proteasome activity; poor-prognosis; cell-death; aaa-atpase; inhibition; expression; degradation
AB Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb-copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram's tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.
C1 [Skrott, Zdenek; Mistrik, Martin; Majera, Dusana; Gursky, Jan; Ozdian, Tomas; Turi, Zsofia; Moudry, Pavel; Michalova, Martina; Vaclavkova, Jana; Dzubak, Petr; Vrobel, Ivo; Hajduch, Marian] Palacky Univ, Inst Mol & Translat Med, Fac Med & Dent, Olomouc, Czech Republic.
   [Andersen, Klaus Kaae; Friis, Soren; Bartkova, Jirina; Kutt, Anne; Olsen, Jorgen; Bartek, Jiri] Danish Canc Soc, Res Ctr, DK-2100 Copenhagen, Denmark.
   [Bartkova, Jirina; Bartek, Jiri] Karolinska Inst, Dept Med Biochem & Biophys, Div Genome Biol, Sci Life Lab, Stockholm, Sweden.
   [Kraus, Marianne; Driessen, Christoph] Kantonsspital St Gallen, Dept Oncol Hematol, St Gallen, Switzerland.
   [Pouckova, Pavla; Mattova, Jana] Charles Univ Prague, Inst Biophys & Informat, Fac Med 1, Prague 12000 2, Czech Republic.
   [Sedlacek, Jindrich; Cvek, Boris] Palacky Univ, Dept Cell Biol & Genet, Olomouc, Czech Republic.
   [Miklovicova, Andrea] Psychiat Hosp, Sternberk 78501, Czech Republic.
   [Li, Jing; Deshaies, Raymond J.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
   [Dou, Q. Ping] Wayne State Univ, Sch Med, Barbara Ann Karmanos Canc Inst, Detroit, MI USA.
   [Dou, Q. Ping] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI USA.
   [Dou, Q. Ping] Guangzhou Med Univ, Sch Basic Med Sci, Affiliated Tumor Hosp, Guangzhou 511436, Guangdong, Peoples R China.
   [Deshaies, Raymond J.] CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA.
   [Cvek, Boris] Palacky Univ, Olomouc Univ, Social Hlth Inst, Olomouc, Czech Republic.
   [Deshaies, Raymond J.] Amgen Inc, Thousand Oaks, CA 91320 USA.
C3 Palacky University Olomouc; Danish Cancer Society; Karolinska Institutet; Kantonsspital St. Gallen; Charles University Prague; Palacky University Olomouc; California Institute of Technology; Wayne State University; Barbara Ann Karmanos Cancer Institute; Wayne State University; Guangzhou Medical University; California Institute of Technology; Howard Hughes Medical Institute; Palacky University Olomouc; Amgen
RP Bartek, J (corresponding author), Danish Canc Soc, Res Ctr, DK-2100 Copenhagen, Denmark.; Bartek, J (corresponding author), Karolinska Inst, Dept Med Biochem & Biophys, Div Genome Biol, Sci Life Lab, Stockholm, Sweden.; Cvek, B (corresponding author), Palacky Univ, Dept Cell Biol & Genet, Olomouc, Czech Republic.; Deshaies, RJ (corresponding author), CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.; Deshaies, RJ (corresponding author), CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA.
EM cvekb@seznam.cz; deshaies@caltech.edu; jb@cancer.dk
FU Kellner Family Foundation; Czech National Program of Sustainability; Grant Agency of the Czech Republic; MEYS CR project Czech-BioImaging; Czech Health Research Council; Danish Cancer Society; Danish National Research Foundation (project CARD); Danish Council for Independent Research; Novo Nordisk Foundation; Czech Cancer League; Swedish Research Council; Cancerfonden of Sweden; European Commission (EATRIS); Czech Ministry of Education, youth and sports (OPVKCZ); Cancer Research Czech Republic; Howard Hughes Medical Institute; Lundbeck Foundation [R93-2011-8990] Funding Source: researchfish
NR 53
TC 678
Z9 746
U1 9
U2 545
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 14
PY 2017
VL 552
IS 7684
BP 194
EP +
DI 10.1038/nature25016
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ0FK
UT WOS:000418029500035
PM 29211715
DA 2026-03-09
ER

PT J
AU Schwalm, CR
   Anderegg, WRL
   Michalak, AM
   Fisher, JB
   Biondi, F
   Koch, G
   Litvak, M
   Ogle, K
   Shaw, JD
   Wolf, A
   Huntzinger, DN
   Schaefer, K
   Cook, R
   Wei, YX
   Fang, YY
   Hayes, D
   Huang, MY
   Jain, A
   Tian, HQ
AF Schwalm, Christopher R.
   Anderegg, William R. L.
   Michalak, Anna M.
   Fisher, Joshua B.
   Biondi, Franco
   Koch, George
   Litvak, Marcy
   Ogle, Kiona
   Shaw, John D.
   Wolf, Adam
   Huntzinger, Deborah N.
   Schaefer, Kevin
   Cook, Robert
   Wei, Yaxing
   Fang, Yuanyuan
   Hayes, Daniel
   Huang, Maoyi
   Jain, Atul
   Tian, Hanqin
TI Global patterns of drought recovery
SO NATURE
LA English
DT Article
ID model intercomparison project; program multiscale synthesis; land-use; forest ecosystems; climate extremes; biodiversity; resistance; reduction; diversity
AB Drought, a recurring phenomenon with major impacts on both human and natural systems(1-3), is the most widespread climatic extreme that negatively affects the land carbon sink(2,4). Although twentieth-century trends in drought regimes are ambiguous(5-7), across many regions more frequent and severe droughts are expected in the twenty-first century(3,7-9). Recovery time-how long an ecosystem requires to revert to its pre-drought functional state-is a critical metric of drought impact. Yet the factors influencing drought recovery and its spatiotemporal patterns at the global scale are largely unknown. Here we analyse three independent datasets of gross primary productivity and show that, across diverse ecosystems, drought recovery times are strongly associated with climate and carbon cycle dynamics, with biodiversity and CO2 fertilization as secondary factors. Our analysis also provides two key insights into the spatiotemporal patterns of drought recovery time: first, that recovery is longest in the tropics and high northern latitudes (both vulnerable areas of Earth's climate system(10)) and second, that drought impacts(11) (assessed using the area of ecosystems actively recovering and time to recovery) have increased over the twentieth century. If droughts become more frequent, as expected, the time between droughts may become shorter than drought recovery time, leading to permanently damaged ecosystems and widespread degradation of the land carbon sink.
C1 [Schwalm, Christopher R.] Woods Hole Res Ctr, Falmouth, MA 02540 USA.
   [Schwalm, Christopher R.; Koch, George] No Arizona Univ, Ctr Ecosyst Sci & Soc, Flagstaff, AZ 86011 USA.
   [Anderegg, William R. L.] Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA.
   [Michalak, Anna M.; Fang, Yuanyuan] Carnegie Inst Sci, Dept Global Ecol, Stanford, CA 94305 USA.
   [Fisher, Joshua B.] CALTECH, Jet Prop Lab, 4800 Oak Grove Dr, Pasadena, CA 91109 USA.
   [Biondi, Franco] Univ Nevada, EECB, DendroLab & Grad Program, Reno, NV 89557 USA.
   [Litvak, Marcy] Univ New Mexico, Dept Biol, Albuquerque, NM 87131 USA.
   [Ogle, Kiona] No Arizona Univ, Informat & Comp Program, Flagstaff, AZ 86011 USA.
   [Shaw, John D.] US Forest Serv, Rocky Mt Res Stn, Ogden, UT 84401 USA.
   [Wolf, Adam] Arable Labs Inc, 40 North Tulane St, Princeton, NJ 08542 USA.
   [Huntzinger, Deborah N.] No Arizona Univ, Sch Earth Sci & Environm Sustainabil, Flagstaff, AZ 86011 USA.
   [Schaefer, Kevin] Natl Snow & Ice Data Ctr, Boulder, CO 80309 USA.
   [Cook, Robert; Wei, Yaxing] Oak Ridge Natl Lab, Environm Sci Div, Oak Ridge, TN 37831 USA.
   [Hayes, Daniel] Univ Maine, Sch Forest Resources, Orono, ME 04469 USA.
   [Huang, Maoyi] Pacific Northwest Natl Lab, Atmospher Sci & Global Change Div, Richland, WA 99354 USA.
   [Jain, Atul] Univ Illinois, Dept Atmospher Sci, Urbana, IL 61801 USA.
   [Tian, Hanqin] Auburn Univ, Int Ctr Climate & Global Change Res, Auburn, AL 36849 USA.
   [Tian, Hanqin] Auburn Univ, Sch Forestry & Wildlife Sci, Auburn, AL 36849 USA.
C3 Woodwell Climate Research Center; Northern Arizona University; Utah System of Higher Education; University of Utah; Carnegie Institution for Science; National Aeronautics & Space Administration (NASA); NASA Jet Propulsion Laboratory (JPL); California Institute of Technology; Nevada System of Higher Education (NSHE); University of Nevada Reno; University of New Mexico; Northern Arizona University; United States Department of Agriculture (USDA); United States Forest Service; Northern Arizona University; United States Department of Energy (DOE); Oak Ridge National Laboratory; University of Maine System; University of Maine Orono; United States Department of Energy (DOE); Pacific Northwest National Laboratory; University of Illinois System; University of Illinois Urbana-Champaign; Auburn University System; Auburn University; Auburn University System; Auburn University
RP Schwalm, CR (corresponding author), Woods Hole Res Ctr, Falmouth, MA 02540 USA.; Schwalm, CR (corresponding author), No Arizona Univ, Ctr Ecosyst Sci & Soc, Flagstaff, AZ 86011 USA.
EM schwalm.christopher@gmail.com
FU National Science Foundation (NSF) [DEB EF-1340270]; National Aeronautics and Space Administration (NASA) [NNX12AK12G, NNX12AP74G, NNX10AG01A, NNX11AO08A]; NASA; NASA [NNX10AG01A, NNN13D504T, NNN13D202T, NNN13D503T, NNH10AN681]; Directorate For Geosciences; Div Atmospheric & Geospace Sciences [1243071] Funding Source: National Science Foundation; Emerging Frontiers; Direct For Biological Sciences [1602131] Funding Source: National Science Foundation
NR 44
TC 772
Z9 892
U1 48
U2 997
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 10
PY 2017
VL 548
IS 7666
BP 202
EP +
DI 10.1038/nature23021
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD1GB
UT WOS:000407284300041
PM 28796213
DA 2026-03-09
ER

PT J
AU Fica, SM
   Oubridge, C
   Galej, WP
   Wilkinson, ME
   Bai, XC
   Newman, AJ
   Nagai, K
AF Fica, Sebastian M.
   Oubridge, Chris
   Galej, Wojciech P.
   Wilkinson, Max E.
   Bai, Xiao-Chen
   Newman, Andrew J.
   Nagai, Kiyoshi
TI Structure of a spliceosome remodelled for exon ligation
SO NATURE
LA English
DT Article
ID pre-messenger-rna; cryo-em structure; angstrom resolution; splicing factor; electron cryomicroscopy; functional interactions; crystal-structure; catalytic center; site choice; 2nd step
AB The spliceosome excises introns from pre-mRNAs in two sequential transesterifications-branching and exon ligation(1)-catalysed at a single catalytic metal site in U6 small nuclear RNA (snRNA)(2,3). Recently reported structures of the spliceosomal C complex(4,5) with the cleaved 5' exon and lariat-3'-exon bound to the catalytic centre revealed that branching-specific factors such as Cwc25 lock the branch helix into position for nucleophilic attack of the branch adenosine at the 5' splice site. Furthermore, the ATPase Prp16 is positioned to bind and translocate the intron downstream of the branch point to destabilize branching-specific factors and release the branch helix from the active site(4). Here we present, at 3.8 angstrom resolution, the cryo-electron microscopy structure of a Saccharomyces cerevisiae spliceosome stalled after Prp16-mediated remodelling but before exon ligation. While the U6 snRNA catalytic core remains firmly held in the active site cavity of Prp8 by proteins common to both steps, the branch helix has rotated by 75 degrees compared to the C complex and is stabilized in a new position by Prp17, Cef1 and the reoriented Prp8 RNase H-like domain. This rotation of the branch helix removes the branch adenosine from the catalytic core, creates a space for 3' exon docking, and restructures the pairing of the 5' splice site with the U6 snRNA ACAGAGA region. Slu7 and Prp18, which promote exon ligation, bind together to the Prp8 RNase H-like domain. The ATPase Prp22, bound to Prp8 in place of Prp16, could interact with the 3' exon, suggesting a possible basis for mRNA release after exon ligation(6,7). Together with the structure of the C complex(4), our structure of the C* complex reveals the two major conformations of the spliceosome during the catalytic stages of splicing.
C1 [Fica, Sebastian M.; Oubridge, Chris; Galej, Wojciech P.; Wilkinson, Max E.; Bai, Xiao-Chen; Newman, Andrew J.; Nagai, Kiyoshi] MRC, Mol Biol Lab, Francis Crick Ave, Cambridge CB2 0QH, England.
   [Galej, Wojciech P.] EMBL Grenoble, CS 90181, 71 Ave Martyrs, F-38042 Grenoble 9, France.
C3 MRC Laboratory Molecular Biology; European Molecular Biology Laboratory (EMBL)
RP Fica, SM; Nagai, K (corresponding author), MRC, Mol Biol Lab, Francis Crick Ave, Cambridge CB2 0QH, England.
EM sfica@mrc-lmb.cam.ac.uk; kn@mrc-lmb.cam.ac.uk
FU Medical Research Council [MC_U105184330]; European Research Council [693087 - SPLICE3D]; EMBO; Marie Sklodowska-Curie fellowship; Rutherford Memorial Cambridge Scholarship; MRC [MC_U105184330] Funding Source: UKRI; Medical Research Council [MC_U105184330] Funding Source: researchfish
NR 55
TC 136
Z9 162
U1 0
U2 51
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 16
PY 2017
VL 542
IS 7641
BP 377
EP +
DI 10.1038/nature21078
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2LQ
UT WOS:000394451600043
PM 28076345
DA 2026-03-09
ER

PT J
AU Jackson, MG
   Konter, JG
   Becker, TW
AF Jackson, M. G.
   Konter, J. G.
   Becker, T. W.
TI Primordial helium entrained by the hottest mantle plumes
SO NATURE
LA English
DT Article
ID high he-3/he-4 ratios; ocean island basalts; rare-gas systematics; mid-atlantic ridge; isotope geochemistry; yellowstone plume; himu reservoir; volcanic-rocks; loihi seamount; noble-gases
AB Helium isotopes provide an important tool for tracing early-Earth, primordial reservoirs that have survived in the planet's interior(1-3). Volcanic hotspot lavas, like those erupted at Hawaii and Iceland, can host rare, high He-3/He-4 isotopic ratios (up to 50 times(4) the present atmospheric ratio, Ra) compared to the lower He-3/He-4 ratios identified in mid-ocean-ridge basalts that form by melting the upper mantle (about 8Ra; ref. 5). A long-standing hypothesis maintains that the high-He-3/He-4 domain resides in the deep mantle(6-8), beneath the upper mantle sampled by mid-ocean-ridge basalts, and that buoyantly upwelling plumes from the deep mantle transport high-He-3/He-4 material to the shallow mantle beneath plume-fed hotspots. One problem with this hypothesis is that, while some hotspots have He-3/He-4 values ranging from low to high, other hotspots exhibit only low He-3/He-4 ratios. Here we show that, among hotspots suggested to overlie mantle plumes(9,10), those with the highest maximum He-3/He-4 ratios have high hotspot buoyancy fluxes and overlie regions with seismic low-velocity anomalies in the upper mantle(11), unlike plume-fed hotspots with only low maximum He-3/He-4 ratios. We interpret the relationships between He-3/He-4 values, hotspot buoyancy flux, and upper-mantle shear wave velocity to mean that hot plumes-which exhibit seismic low-velocity anomalies at depths of 200 kilometres-are more buoyant and entrain both high-He-3/He-4 and low-He-3/He-4 material. In contrast, cooler, less buoyant plumes do not entrain this high-He-3/He-4 material. This can be explained if the high-He-3/He-4 domain is denser than low-He-3/He-4 mantle components hosted in plumes, and if high-He-3/He-4 material is entrained from the deep mantle only by the hottest, most buoyant plumes(12). Such a dense, deep-mantle high-He-3/He-4 domain could remain isolated from the convecting mantle(13,14), which may help to explain the preservation of early Hadean (>4.5 billion years ago) geochemical anomalies in lavas sampling this reservoir(1-3).
C1 [Jackson, M. G.] Univ Calif Santa Barbara, Dept Earth Sci, Santa Barbara, CA 93106 USA.
   [Konter, J. G.] Univ Hawaii Manoa, Sch Ocean & Earth Sci & Technol, Dept Geol & Geophys, 1680 East West Rd, Honolulu, HI 96822 USA.
   [Becker, T. W.] Univ Texas Austin, Jackson Sch Geosci, 1 Univ Stn,C1160, Austin, TX 78712 USA.
C3 University of California System; University of California Santa Barbara; University of Hawaii System; University of Hawaii Manoa; University of Texas System; University of Texas Austin
RP Jackson, MG (corresponding author), Univ Calif Santa Barbara, Dept Earth Sci, Santa Barbara, CA 93106 USA.
EM jackson@geol.ucsb.edu
FU NSF [EAR-1347377, EAR-1624840];  [EAR-1460479];  [EAR-1338329];  [OCE-1538121]; Directorate For Geosciences; Division Of Earth Sciences [1135452] Funding Source: National Science Foundation; Division Of Earth Sciences; Directorate For Geosciences [1347377] Funding Source: National Science Foundation
NR 106
TC 123
Z9 147
U1 4
U2 111
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 16
PY 2017
VL 542
IS 7641
BP 340
EP +
DI 10.1038/nature21023
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2LQ
UT WOS:000394451600035
PM 28166539
DA 2026-03-09
ER

PT J
AU Ovadnevaite, J
   Zuend, A
   Laaksonen, A
   Sanchez, KJ
   Roberts, G
   Ceburnis, D
   Decesari, S
   Rinaldi, M
   Hodas, N
   Facchini, MC
   Seinfeld, JH
   O'Dowd, C
AF Ovadnevaite, Jurgita
   Zuend, Andreas
   Laaksonen, Ari
   Sanchez, Kevin J.
   Roberts, Greg
   Ceburnis, Darius
   Decesari, Stefano
   Rinaldi, Matteo
   Hodas, Natasha
   Facchini, Maria Cristina
   Seinfeld, John H.
   O'Dowd, Colin
TI Surface tension prevails over solute effect in organic-influenced cloud droplet activation
SO NATURE
LA English
DT Article
ID thermodynamic model; hygroscopic growth; coastal aerosol; particles; nucleus; impact; ccn
AB The spontaneous growth of cloud condensation nuclei (CCN) into cloud droplets under supersaturated water vapour conditions is described by classic Kohler theory(1,2). This spontaneous activation of CCN depends on the interplay between the Raoult effect, whereby activation potential increases with decreasing water activity or increasing solute concentration, and the Kelvin effect, whereby activation potential decreases with decreasing droplet size or increases with decreasing surface tension, which is sensitive to surfactants(1). Surface tension lowering caused by organic surfactants, which diminishes the Kelvin effect, is expected to be negated by a concomitant reduction in the Raoult effect, driven by the displacement of surfactant molecules from the droplet bulk to the droplet-vapour interface(3,4). Here we present observational and theoretical evidence illustrating that, in ambient air, surface tension lowering can prevail over the reduction in the Raoult effect, leading to substantial increases in cloud droplet concentrations. We suggest that consideration of liquid-liquid phase separation, leading to complete or partial engulfing of a hygroscopic particle core by a hydrophobic organic-rich phase, can explain the lack of concomitant reduction of the Raoult effect, while maintaining substantial lowering of surface tension, even for partial surface coverage. Apart from the importance of particle size and composition in droplet activation, we show by observation and modelling that incorporation of phase-separation effects into activation thermodynamics can lead to a CCN number concentration that is up to ten times what is predicted by climate models, changing the properties of clouds. An adequate representation of the CCN activation process is essential to the prediction of clouds in climate models, and given the effect of clouds on the Earth's energy balance, improved prediction of aerosol-cloud-climate interactions is likely to result in improved assessments of future climate change.
C1 [Ovadnevaite, Jurgita; Ceburnis, Darius; O'Dowd, Colin] Natl Univ Ireland Galway, Sch Phys, Galway, Ireland.
   [Ovadnevaite, Jurgita; Ceburnis, Darius; O'Dowd, Colin] Natl Univ Ireland Galway, Ctr Climate & Air Pollut Studies, Galway, Ireland.
   [Zuend, Andreas] McGill Univ, Dept Atmospher & Ocean Sci, Montreal, PQ, Canada.
   [Laaksonen, Ari] Finnish Meteorol Inst, Helsinki, Finland.
   [Laaksonen, Ari] Univ Eastern Finland, Dept Appl Phys, Kuopio, Finland.
   [Sanchez, Kevin J.; Roberts, Greg] Ctr Natl Rech Meteorol, 42 Ave Gaspard Coriolis, F-31057 Toulouse, France.
   [Roberts, Greg] Scripps Inst Oceanog, 9500 Gilman Dr,0221, La Jolla, CA 92093 USA.
   [Decesari, Stefano; Rinaldi, Matteo; Facchini, Maria Cristina] CNR, Inst Sci Atmosfera, I-40129 Bologna, Italy.
   [Hodas, Natasha; Seinfeld, John H.] CALTECH, Div Chem & Chem Engn, Mail Code 210-41, Pasadena, CA 91125 USA.
   [Hodas, Natasha] Portland State Univ, Dept Environm Sci & Management, Portland, OR 97201 USA.
C3 Ollscoil na Gaillimhe-University of Galway; Ollscoil na Gaillimhe-University of Galway; McGill University; Finnish Meteorological Institute; University of Eastern Finland; University of California System; University of California San Diego; Scripps Institution of Oceanography; Consiglio Nazionale delle Ricerche (CNR); California Institute of Technology; Portland State University
RP O'Dowd, C (corresponding author), Natl Univ Ireland Galway, Sch Phys, Galway, Ireland.; O'Dowd, C (corresponding author), Natl Univ Ireland Galway, Ctr Climate & Air Pollut Studies, Galway, Ireland.
EM colin.odowd@nuigalway.ie
FU European Union [603445]; Irish Environmental Protection Agency; HEA PRTLI4 project; Academy of Finland Center of Excellence programme [272041]; CNR (Italy) under AirSEaLab: Progetto Laboratori Congiunti; US Office of Naval Research; Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN/04315-2014]; National Science Foundation Atmospheric and Geospace Sciences Postdoctoral Research Fellowship [14433246]; Directorate For Geosciences; ICER [1450554] Funding Source: National Science Foundation; Directorate For Geosciences; ICER [1450657] Funding Source: National Science Foundation
NR 31
TC 261
Z9 293
U1 5
U2 329
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 29
PY 2017
VL 546
IS 7660
BP 637
EP 641
DI 10.1038/nature22806
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY9QB
UT WOS:000404332000044
PM 28636594
DA 2026-03-09
ER

PT J
AU Shan, JJ
   Li, MW
   Allard, LF
   Lee, SS
   Flytzani-Stephanopoulos, M
AF Shan, Junjun
   Li, Mengwei
   Allard, Lawrence F.
   Lee, Sungsik
   Flytzani-Stephanopoulos, Maria
TI Mild oxidation of methane to methanol or acetic acid on supported isolated rhodium catalysts
SO NATURE
LA English
DT Article
ID exchanged zeolites; carbon-monoxide; conversion; oxygen; zsm-5; co; carbonylation; temperature; selectivity; mordenite
AB An efficient and direct method of catalytic conversion of methane to liquid methanol and other oxygenates would be of considerable practical value. However, it remains an unsolved problem in catalysis, as typically it involves expensive(1-4) or corrosive oxidants or reaction media(5-8) that are not amenable to commercialization. Although methane can be directly converted to methanol using molecular oxygen under mild conditions in the gas phase, the process is either stoichiometric (and therefore requires a water extraction step)(9-15) or is too slow and low-yielding(16) to be practical. Methane could, in principle, also be transformed through direct oxidative carbonylation to acetic acid, which is commercially obtained through methane steam reforming, methanol synthesis, and subsequent methanol carbonylation on homogeneous catalysts(17,18). However, an effective catalyst for the direct carbonylation of methane to acetic acid, which might enable the economical small-scale utilization of natural gas that is currently flared or stranded, has not yet been reported. Here we show that mononuclear rhodium species, anchored on a zeolite or titanium dioxide support suspended in aqueous solution, catalyse the direct conversion of methane to methanol and acetic acid, using oxygen and carbon monoxide under mild conditions. We find that the two products form through independent pathways, which allows us to tune the conversion: three-hour-long batch-reactor tests conducted at 150 degrees Celsius, using either the zeolitesupported or the titanium-dioxide-supported catalyst, yield around 22,000 micromoles of acetic acid per gram of catalyst, or around 230 micromoles of methanol per gram of catalyst, respectively, with selectivities of 60-100 per cent. We anticipate that these unusually high activities, despite still being too low for commercial application, may guide the development of optimized catalysts and practical processes for the direct conversion of methane to methanol, acetic acid and other useful chemicals.
C1 [Shan, Junjun; Li, Mengwei; Flytzani-Stephanopoulos, Maria] Tufts Univ, Dept Chem & Biol Engn, Medford, MA 02155 USA.
   [Allard, Lawrence F.] Oak Ridge Natl Lab, Mat Sci & Technol Div, Oak Ridge, TN 37831 USA.
   [Lee, Sungsik] Argonne Natl Lab, Xray Sci Div, 9700 South Cass Ave, Argonne, IL 60439 USA.
   [Shan, Junjun] NICE Amer Res Inc, Mountain View, CA 94043 USA.
C3 Tufts University; United States Department of Energy (DOE); Oak Ridge National Laboratory; United States Department of Energy (DOE); Argonne National Laboratory
RP Flytzani-Stephanopoulos, M (corresponding author), Tufts Univ, Dept Chem & Biol Engn, Medford, MA 02155 USA.
EM maria.flytzani-stephanopoulos@tufts.edu
FU Department of Energy, DOE/ARPA-e from MIT [DE-AR0000433]; DOE Office of Science [DE-AC02-06CH11357]; US Department of Energy, Office of Energy Efficiency and Renewable Energy, Vehicle Technologies Office
NR 40
TC 658
Z9 738
U1 48
U2 1203
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 30
PY 2017
VL 551
IS 7682
BP 605
EP +
DI 10.1038/nature24640
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FO1KW
UT WOS:000416520400038
PM 29189776
DA 2026-03-09
ER

PT J
AU Zhao, D
   Lu, X
   Wang, GC
   Lan, ZD
   Liao, WT
   Li, J
   Liang, X
   Chen, JR
   Shah, S
   Shang, XY
   Tang, M
   Deng, PN
   Dey, P
   Chakravarti, D
   Chen, PW
   Spring, DJ
   Navone, NM
   Troncoso, P
   Zhang, JH
   Wang, YA
   DePinho, RA
AF Zhao, Di
   Lu, Xin
   Wang, Guocan
   Lan, Zhengdao
   Liao, Wenting
   Li, Jun
   Liang, Xin
   Chen, Jasper Robin
   Shah, Sagar
   Shang, Xiaoying
   Tang, Ming
   Deng, Pingna
   Dey, Prasenjit
   Chakravarti, Deepavali
   Chen, Peiwen
   Spring, Denise J.
   Navone, Nora M.
   Troncoso, Patricia
   Zhang, Jianhua
   Wang, Y. Alan
   DePinho, Ronald A.
TI Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer
SO NATURE
LA English
DT Article
ID prostate-cancer; beta-trcp; mutant-cells; vulnerability; phosphorylation; deletion
AB Synthetic lethality and collateral lethality are two well-validated conceptual strategies for identifying therapeutic targets in cancers with tumour-suppressor gene deletions(1-3). Here, we explore an approach to identify potential synthetic-lethal interactions by screening mutually exclusive deletion patterns in cancer genomes. We sought to identify 'synthetic-essential' genes: those that are occasionally deleted in some cancers but are almost always retained in the context of a specific tumour-suppressor deficiency. We also posited that such synthetic-essential genes would be therapeutic targets in cancers that harbour specific tumour-suppressor deficiencies. In addition to known synthetic-lethal interactions, this approach uncovered the chromatin helicase DNA-binding factor CHD1 as a putative synthetic-essential gene in PTEN-deficient cancers. In PTEN-deficient prostate and breast cancers, CHD1 depletion profoundly and specifically suppressed cell proliferation, cell survival and tumorigenic potential. Mechanistically, functional PTEN stimulates the GSK3 beta-mediated phosphorylation of CHD1 degron domains, which promotes CHD1 degradation via the beta-TrCP-mediated ubiquitination-proteasome pathway. Conversely, PTEN deficiency results in stabilization of CHD1, which in turn engages the trimethyl lysine-4 histone H3 modification to activate transcription of the pro-tumorigenic TNF-NF-kappa B gene network. This study identifies a novel PTEN pathway in cancer and provides a framework for the discovery of 'trackable' targets in cancers that harbour specific tumour-suppressor deficiencies.
C1 [Zhao, Di; Lu, Xin; Wang, Guocan; Lan, Zhengdao; Liao, Wenting; Liang, Xin; Chen, Jasper Robin; Shah, Sagar; Shang, Xiaoying; Deng, Pingna; Dey, Prasenjit; Chakravarti, Deepavali; Chen, Peiwen; Spring, Denise J.; Wang, Y. Alan; DePinho, Ronald A.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA.
   [Li, Jun; Tang, Ming; Zhang, Jianhua] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA.
   Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77054 USA.
   [Navone, Nora M.] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA.
   [Troncoso, Patricia] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA.
C3 University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center
RP Wang, YA (corresponding author), Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA.
EM yalanwang@mdanderson.org; rdepinho@mdanderson.org
FU University of Texas [MDACC 600649-80-116647-21]; DOD [W81XWH-14-1-0576]; NIH-NCI [1K99CA194289]; DOD PCRP [W81XWH-14-1-0429]; CPRIT [RP140106-DC]; NIH [P01 CA117969, R01 CA084628]; National Cancer Institute [P01CA117969, P30CA016672] Funding Source: NIH RePORTER
NR 30
TC 173
Z9 202
U1 3
U2 48
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 23
PY 2017
VL 542
IS 7642
BP 484
EP +
DI 10.1038/nature21357
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1RG
UT WOS:000395094100038
PM 28166537
DA 2026-03-09
ER

PT J
AU Camp, JG
   Sekine, K
   Gerber, T
   Loeffler-Wirth, H
   Binder, H
   Gac, M
   Kanton, S
   Kageyama, J
   Damm, G
   Seehofer, D
   Belicova, L
   Bickle, M
   Barsacchi, R
   Okuda, R
   Yoshizawa, E
   Kimura, M
   Ayabe, H
   Taniguchi, H
   Takebe, T
   Treutlein, B
AF Camp, J. Gray
   Sekine, Keisuke
   Gerber, Tobias
   Loeffler-Wirth, Henry
   Binder, Hans
   Gac, Malgorzata
   Kanton, Sabina
   Kageyama, Jorge
   Damm, Georg
   Seehofer, Daniel
   Belicova, Lenka
   Bickle, Marc
   Barsacchi, Rico
   Okuda, Ryo
   Yoshizawa, Emi
   Kimura, Masaki
   Ayabe, Hiroaki
   Taniguchi, Hideki
   Takebe, Takanori
   Treutlein, Barbara
TI Multilineage communication regulates human liver bud development from pluripotency
SO NATURE
LA English
DT Article
ID functional human liver; expression; signals; cells; generation; tissue
AB Conventional two-dimensional differentiation from pluripotency fails to recapitulate cell interactions occurring during organogenesis. Three-dimensional organoids generate complex organ-like tissues(1); however, it is unclear how heterotypic interactions affect lineage identity. Here we use single-cell RNA sequencing(2,3) to reconstruct hepatocyte-like lineage progression from pluripotency in two-dimensional culture. We then derive three-dimensional liver bud organoids(4) by reconstituting hepatic, stromal, and endothelial interactions, and deconstruct heterogeneity during liver bud development. We find that liver bud hepatoblasts diverge from the two-dimensional lineage, and express epithelial migration signatures characteristic of organ budding. We benchmark three-dimensional liver buds against fetal and adult human liver single-cell RNA sequencing data, and find a striking correspondence between the three-dimensional liver bud and fetal liver cells. We use a receptor-ligand pairing analysis and a high-throughput inhibitor assay to interrogate signalling in liver buds, and show that vascular endothelial growth factor (VEGF) crosstalk potentiates endothelial network formation and hepatoblast differentiation. Our molecular dissection reveals interlineage communication regulating organoid development, and illuminates previously inaccessible aspects of human liver development.
C1 [Camp, J. Gray; Gerber, Tobias; Gac, Malgorzata; Kanton, Sabina; Kageyama, Jorge; Treutlein, Barbara] Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, Deutsch Pl 6, D-04103 Leipzig, Germany.
   [Sekine, Keisuke; Okuda, Ryo; Yoshizawa, Emi; Kimura, Masaki; Ayabe, Hiroaki; Taniguchi, Hideki; Takebe, Takanori] Yokohama City Univ, Grad Sch Med, Dept Regenerat Med, Kanazawa Ku, 3-9 Fukuura, Yokohama, Kanagawa 2360004, Japan.
   [Loeffler-Wirth, Henry; Binder, Hans] Univ Leipzig, Interdisciplinary Ctr Bioinformat, 16 Hartelstr, D-04107 Leipzig, Germany.
   [Damm, Georg; Seehofer, Daniel] Univ Hosp Leipzig, Dept Hepatobiliary & Transplantat Surg, Liebigstr 20, D-04103 Leipzig, Germany.
   [Damm, Georg; Seehofer, Daniel] Univ Leipzig, Saxonian Incubator Clin Translat SIKT, 55 Philipp Rosenthal Str, D-04103 Leipzig, Germany.
   [Belicova, Lenka; Bickle, Marc; Barsacchi, Rico; Treutlein, Barbara] Max Planck Inst Mol Cell Biol & Genet, 108 Pfotenhauerstr, D-01307 Dresden, Germany.
   [Takebe, Takanori] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Dept Pediat, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
C3 Max Planck Society; Yokohama City University; Leipzig University; Leipzig University; Leipzig University; Max Planck Society; Cincinnati Children's Hospital Medical Center; University System of Ohio; University of Cincinnati
RP Treutlein, B (corresponding author), Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, Deutsch Pl 6, D-04103 Leipzig, Germany.; Sekine, K; Takebe, T (corresponding author), Yokohama City Univ, Grad Sch Med, Dept Regenerat Med, Kanazawa Ku, 3-9 Fukuura, Yokohama, Kanagawa 2360004, Japan.; Treutlein, B (corresponding author), Max Planck Inst Mol Cell Biol & Genet, 108 Pfotenhauerstr, D-01307 Dresden, Germany.; Takebe, T (corresponding author), Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Dept Pediat, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
EM ksekine@yokohama-cu.ac.jp; Takanori.Takebe@cchmc.org; barbara_treutlein@eva.mpg.de
FU Max Planck Society; PRESTO Japan Science and Technology Agency; Ministry of Education Culture and Sports of Japan [15H04922, 15KK0314]; AMED Research Center Network for Realization of Regenerative Medicine; Grants-in-Aid for Scientific Research [15H05677, 15H04922, 16K15597, 16KT0073, 15KK0314] Funding Source: KAKEN
NR 46
TC 460
Z9 533
U1 8
U2 214
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 22
PY 2017
VL 546
IS 7659
BP 533
EP +
DI 10.1038/nature22796
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY2QK
UT WOS:000403814100039
PM 28614297
DA 2026-03-09
ER

PT J
AU Otis, JM
   Namboodiri, VMK
   Matan, AM
   Voets, ES
   Mohorn, EP
   Kosyk, O
   McHenry, JA
   Robinson, JE
   Resendez, SL
   Rossi, MA
   Stuber, GD
AF Otis, James M.
   Namboodiri, Vijay M. K.
   Matan, Ana M.
   Voets, Elisa S.
   Mohorn, Emily P.
   Kosyk, Oksana
   McHenry, Jenna A.
   Robinson, J. Elliott
   Resendez, Shanna L.
   Rossi, Mark A.
   Stuber, Garret D.
TI Prefrontal cortex output circuits guide reward seeking through divergent cue encoding
SO NATURE
LA English
DT Article
ID cocaine-induced reinstatement; nucleus-accumbens; in-vivo; projections; neurons; rat; behavior; inhibition; attention; dopamine
AB The prefrontal cortex is a critical neuroanatomical hub for controlling motivated behaviours across mammalian species(1-3). In addition to intra-cortical connectivity, prefrontal projection neurons innervate subcortical structures that contribute to reward-seeking behaviours, such as the ventral striatum and midline thalamus(4). While connectivity among these structures contributes to appetitive behaviours(5-13), how projection-specific prefrontal neurons encode reward-relevant information to guide reward seeking is unknown. Here we use in vivo two-photon calcium imaging to monitor the activity of dorsomedial prefrontal neurons in mice during an appetitive Pavlovian conditioning task. At the population level, these neurons display diverse activity patterns during the presentation of reward-predictive cues. However, recordings from prefrontal neurons with resolved projection targets reveal that individual corticostriatal neurons show response tuning to reward-predictive cues, such that excitatory cue responses are amplified across learning. By contrast, corticothalamic neurons gradually develop new, primarily inhibitory responses to reward-predictive cues across learning. Furthermore, bidirectional optogenetic manipulation of these neurons reveals that stimulation of corticostriatal neurons promotes conditioned reward-seeking behaviour after learning, while activity in corticothalamic neurons suppresses both the acquisition and expression of conditioned reward seeking. These data show how prefrontal circuitry can dynamically control rewardseeking behaviour through the opposing activities of projection-specific cell populations.
C1 [Otis, James M.; Namboodiri, Vijay M. K.; Matan, Ana M.; Voets, Elisa S.; Mohorn, Emily P.; Kosyk, Oksana; McHenry, Jenna A.; Robinson, J. Elliott; Resendez, Shanna L.; Rossi, Mark A.; Stuber, Garret D.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA.
   [Namboodiri, Vijay M. K.; Stuber, Garret D.] Univ N Carolina, Ctr Neurosci, Chapel Hill, NC 27599 USA.
   [Robinson, J. Elliott; Stuber, Garret D.] Univ N Carolina, Neurosci Curriculum, Chapel Hill, NC 27599 USA.
   [Stuber, Garret D.] Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA.
C3 University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill
RP Stuber, GD (corresponding author), Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA.; Stuber, GD (corresponding author), Univ N Carolina, Ctr Neurosci, Chapel Hill, NC 27599 USA.; Stuber, GD (corresponding author), Univ N Carolina, Neurosci Curriculum, Chapel Hill, NC 27599 USA.; Stuber, GD (corresponding author), Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA.
EM gstuber@med.unc.edu
FU National Institutes of Health [NIDA: F32-DA041184, R01-DA032750, R01-DA038168, NICHD: T32-HD079124, NIMH: T32-MH093315]; Brain and Behavior Research Foundation; Children's Tumor Foundation [016-01-006]; Foundation of Hope; UNC Neuroscience Center (Helen Lyng White Fellowship); UNC Neuroscience Center Microscopy Core [P30 NS045892]; UNC Department of Psychiatry; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK056350] Funding Source: NIH RePORTER; National Institute of Mental Health [T32MH093315] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [P30NS045892] Funding Source: NIH RePORTER; National Institute on Drug Abuse [R37DA032750, R01DA038168] Funding Source: NIH RePORTER; National Institute on Drug Abuse; National Institute of Neurological Disorders and Stroke [T32NS007431] Funding Source: NIH RePORTER
NR 40
TC 288
Z9 363
U1 3
U2 89
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 2
PY 2017
VL 543
IS 7643
BP 103
EP +
DI 10.1038/nature21376
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0AA
UT WOS:000395671500041
PM 28225752
DA 2026-03-09
ER

PT J
AU Quadrato, G
   Nguyen, T
   Macosko, EZ
   Sherwood, JL
   Yang, SM
   Berger, DR
   Maria, N
   Scholvin, J
   Goldman, M
   Kinney, JP
   Boyden, ES
   Lichtman, JW
   Williams, ZM
   McCarroll, SA
   Arlotta, P
AF Quadrato, Giorgia
   Tuan Nguyen
   Macosko, Evan Z.
   Sherwood, John L.
   Yang, Sung Min
   Berger, Daniel R.
   Maria, Natalie
   Scholvin, Jorg
   Goldman, Melissa
   Kinney, Justin P.
   Boyden, Edward S.
   Lichtman, Jeff W.
   Williams, Ziv M. .
   McCarroll, Steven A.
   Arlotta, Paola
TI Cell diversity and network dynamics in photosensitive human brain organoids
SO NATURE
LA English
DT Article
ID subtype-specific genes; cerebral organoids; transcriptome; expression; neurons; reconstruction; astrocytes; generation; receptor; database
AB In vitro models of the developing brain such as three-dimensional brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, the cells generated within organoids and the extent to which they recapitulate the regional complexity, cellular diversity and circuit functionality of the brain remain undefined. Here we analyse gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina. Organoids could be developed over extended periods (more than 9 months), allowing for the establishment of relatively mature features, including the formation of dendritic spines and spontaneously active neuronal networks. Finally, neuronal activity within organoids could be controlled using light stimulation of photosensitive cells, which may offer a way to probe the functionality of human neuronal circuits using physiological sensory stimuli.
C1 [Quadrato, Giorgia; Tuan Nguyen; Sherwood, John L.; Yang, Sung Min; Maria, Natalie; Arlotta, Paola] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.
   [Quadrato, Giorgia; Tuan Nguyen; Macosko, Evan Z.; Sherwood, John L.; McCarroll, Steven A.; Arlotta, Paola] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA.
   [Macosko, Evan Z.; Goldman, Melissa; McCarroll, Steven A.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.
   [Berger, Daniel R.; Lichtman, Jeff W.] Harvard Univ, Dept Cellular & Mol Biol, Cambridge, MA 02138 USA.
   [Berger, Daniel R.; Lichtman, Jeff W.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA.
   [Scholvin, Jorg; Boyden, Edward S.] MIT, Dept Biol Engn, MIT Media Lab, Cambridge, MA 02139 USA.
   [Scholvin, Jorg; Boyden, Edward S.] MIT, Dept Brain & Cognit Sci, MIT Media Lab, Cambridge, MA 02139 USA.
   [Scholvin, Jorg; Boyden, Edward S.] MIT, McGovern Inst, Cambridge, MA 02139 USA.
   [Kinney, Justin P.] LeafLabs LLC, Cambridge, MA 02139 USA.
   [Williams, Ziv M. .] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA.
C3 Harvard University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Harvard University; Harvard University; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital
RP Quadrato, G; Arlotta, P (corresponding author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.; Quadrato, G; Arlotta, P (corresponding author), Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA.
EM giorgia_quadrato@harvard.edu; paola_arlotta@harvard.edu
FU Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; Star Family Award of Harvard University; NIH [1DP1NS087724]; IARPA; Conte; MURI Army Research Office; National Institute of Mental Health [P50MH094271] Funding Source: NIH RePORTER
NR 44
TC 931
Z9 1117
U1 11
U2 302
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 4
PY 2017
VL 545
IS 7652
BP 48
EP +
DI 10.1038/nature22047
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET7MK
UT WOS:000400480400028
PM 28445462
DA 2026-03-09
ER

PT J
AU Li, HB
   Tong, JY
   Zhu, S
   Batista, PJ
   Duffy, EE
   Zhao, J
   Bailis, W
   Cao, GC
   Kroehling, L
   Chen, YY
   Wang, G
   Broughton, JP
   Chen, YG
   Kluger, Y
   Simon, MD
   Chang, HY
   Yin, ZN
   Flavell, RA
AF Li, Hua-Bing
   Tong, Jiyu
   Zhu, Shu
   Batista, Pedro J.
   Duffy, Erin E.
   Zhao, Jun
   Bailis, Will
   Cao, Guangchao
   Kroehling, Lina
   Chen, Yuanyuan
   Wang, Geng
   Broughton, James P.
   Chen, Y. Grace
   Kluger, Yuval
   Simon, Matthew D.
   Chang, Howard Y.
   Yin, Zhinan
   Flavell, Richard A.
TI m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways
SO NATURE
LA English
DT Article
ID degradation dynamics; n-6-methyladenosine; naive; resolution
AB N-6-methyladenosine (m(6)A) is the most common and abundant messenger RNA modification, modulated by 'writers', 'erasers' and 'readers' of this mark(1,2). In vitro data have shown that m(6)A influences all fundamental aspects of mRNA metabolism, mainly mRNA stability, to determine stem cell fates(3,4). However, its in vivo physiological function in mammals and adult mammalian cells is still unknown. Here we show that the deletion of m(6)A 'writer' protein METTL3 in mouse T cells disrupts T cell homeostasis and differentiation. In a lymphopaenic mouse adoptive transfer model, naive Mettl3-deficient T cells failed to undergo homeostatic expansion and remained in the naive state for up to 12 weeks, thereby preventing colitis. Consistent with these observations, the mRNAs of SOCS family genes encoding the STAT signalling inhibitory proteins SOCS1, SOCS3 and CISH were marked by m(6)A, exhibited slower mRNA decay and showed increased mRNAs and levels of protein expression in Mettl3-deficient naive T cells. This increased SOCS family activity consequently inhibited IL-7-mediated STAT5 activation and T cell homeostatic proliferation and differentiation. We also found that m(6)A has important roles for inducible degradation of Socs mRNAs in response to IL-7 signalling in order to reprogram naive T cells for proliferation and differentiation. Our study elucidates for the first time, to our knowledge, the in vivo biological role of m(6)A modification in T-cell-mediated pathogenesis and reveals a novel mechanism of T cell homeostasis and signal-dependent induction of mRNA degradation.
C1 [Li, Hua-Bing; Tong, Jiyu; Zhu, Shu; Zhao, Jun; Bailis, Will; Cao, Guangchao; Kroehling, Lina; Chen, Yuanyuan; Wang, Geng; Flavell, Richard A.] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA.
   [Tong, Jiyu; Cao, Guangchao; Yin, Zhinan] Jinan Univ, Biomed Translat Res Inst, Affiliated Hosp 1, Guangzhou 510632, Guangdong, Peoples R China.
   [Tong, Jiyu; Cao, Guangchao; Yin, Zhinan] Jinan Univ, Guangdong Prov Key Lab Mol Immunol & Antibody Eng, Guangzhou 510632, Guangdong, Peoples R China.
   [Batista, Pedro J.; Broughton, James P.; Chen, Y. Grace; Chang, Howard Y.] Stanford Univ, Ctr Dynam Regulomes, Stanford, CA 94305 USA.
   [Duffy, Erin E.; Simon, Matthew D.] Yale Univ, Dept Mol Biophys & Biochem, POB 6666, New Haven, CT 06511 USA.
   [Duffy, Erin E.; Simon, Matthew D.] Yale Univ, Inst Chem Biol, West Haven, CT 06516 USA.
   [Zhao, Jun; Kluger, Yuval] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA.
   [Chen, Yuanyuan] Third Mil Med Univ, Inst Surg Res, Daping Hosp, Chongqing 400038, Peoples R China.
   [Flavell, Richard A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
C3 Yale University; Jinan University; Jinan University; Stanford University; Yale University; Yale University; Yale University; Army Medical University; Howard Hughes Medical Institute
RP Li, HB; Flavell, RA (corresponding author), Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA.; Yin, ZN (corresponding author), Jinan Univ, Biomed Translat Res Inst, Affiliated Hosp 1, Guangzhou 510632, Guangdong, Peoples R China.; Yin, ZN (corresponding author), Jinan Univ, Guangdong Prov Key Lab Mol Immunol & Antibody Eng, Guangzhou 510632, Guangdong, Peoples R China.; Flavell, RA (corresponding author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
EM huabing.li@yale.edu; zhinan.yin@yale.edu; richard.flavell@yale.edu
FU NIH [T32 2T32DK007356]; Helen Hay Whitney Foundation-Howard Hughes Medical Institute; Howard Hughes Medical Institute; NSF Major International Joint Research Program of China [31420103901]; '111' project [R01-HG004361]; NIH New Innovator Award [DP2 HD083992-01]; Searle scholarship; National Center for Advancing Translational Sciences [UL1TR001863] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [T32DK007356] Funding Source: NIH RePORTER
NR 43
TC 777
Z9 883
U1 9
U2 244
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 17
PY 2017
VL 548
IS 7667
BP 338
EP +
DI 10.1038/nature23450
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD8AU
UT WOS:000407748400034
PM 28792938
DA 2026-03-09
ER

PT J
AU Falgarone, E
   Zwaan, MA
   Odard, BG
   Bergin, E
   Ivison, RJ
   Andreani, PM
   Bournaud, F
   Bussmann, RS
   Elbaz, D
   Omont, A
   Oteo, I
   Walter, F
AF Falgarone, E.
   Zwaan, M. A.
   Odard, B. G.
   Bergin, E.
   Ivison, R. J.
   Andreani, P. M.
   Bournaud, F.
   Bussmann, R. S.
   Elbaz, D.
   Omont, A.
   Oteo, I.
   Walter, F.
TI Large turbulent reservoirs of cold molecular gas around high-redshift starburst galaxies
SO NATURE
LA English
DT Article
ID interstellar-medium; submillimeter galaxy; star-formation; outflows; spectra; models; bright; shocks
AB Starburst galaxies at the peak of cosmic star formation(1) are among the most extreme star-forming engines in the Universe, producing stars over about 100 million years (ref. 2). The star-formation rates of these galaxies, which exceed 100 solar masses per year, require large reservoirs of cold molecular gas(3) to be delivered to their cores, despite strong feedback from stars or active galactic nuclei(4,5). Consequently, starburst galaxies are ideal for studying the interplay between this feedback and the growth of a galaxy(6). The methylidyne cation, CH+, is a most useful molecule for such studies because it cannot form in cold gas without suprathermal energy input, so its presence indicates dissipation of mechanical energy(7-9) or strong ultraviolet irradiation(10,11). Here we report the detection of CH+ (J = 1-0) emission and absorption lines in the spectra of six lensed starburst galaxies(12-15) at redshifts near 2.5. This line has such a high critical density for excitation that it is emitted only in very dense gas, and is absorbed in low-density gas(10). We find that the CH+ emission lines, which are broader than 1,000 kilometres per second, originate in dense shock waves powered by hot galactic winds. The CH+ absorption lines reveal highly turbulent reservoirs of cool (about 100 kelvin), low-density gas, extending far (more than 10 kiloparsecs) outside the starburst galaxies (which have radii of less than 1 kiloparsec). We show that the galactic winds sustain turbulence in the 10-kiloparsec-scale environments of the galaxies, processing these environments into multiphase, gravitationally bound reservoirs. However, the mass outflow rates are found to be insufficient to balance the star-formation rates. Another mass input is therefore required for these reservoirs, which could be provided by ongoing mergers(16) or cold-stream accretion(17,18). Our results suggest that galactic feedback, coupled jointly to turbulence and gravity, extends the starburst phase of a galaxy instead of quenching it.
C1 [Falgarone, E.; Odard, B. G.] UPMC Univ Paris 06, LERMA LRA, Observ Paris, PSL Res Univ,CNRS,Sorbonne Univ,Ecole Normale Sup, F-75005 Paris, France.
   [Zwaan, M. A.; Ivison, R. J.; Andreani, P. M.; Oteo, I.] European Southern Observ, Karl Schwarzschild Str 2, D-85748 Garching, Germany.
   [Bergin, E.] Univ Michigan, Ann Arbor, MI 48109 USA.
   [Ivison, R. J.; Oteo, I.] Univ Edinburgh, Inst Astron, Blackford Hill, Edinburgh EH9 3HJ, Midlothian, Scotland.
   [Bournaud, F.; Elbaz, D.] CEA AIM, Saclay, France.
   [Bussmann, R. S.] Cornell Univ, Cornell, NY USA.
   [Omont, A.] UPMC Univ Paris 06, Sorbonne Univ, CNRS, IAP, F-75014 Paris, France.
   [Walter, F.] Max Planck Inst Astron, Heidelberg, Germany.
C3 Universite PSL; Ecole Normale Superieure (ENS); Observatoire de Paris; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); European Southern Observatory; University of Michigan System; University of Michigan; University of Edinburgh; Universite Paris Cite; Cornell University; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); Max Planck Society
RP Falgarone, E (corresponding author), UPMC Univ Paris 06, LERMA LRA, Observ Paris, PSL Res Univ,CNRS,Sorbonne Univ,Ecole Normale Sup, F-75005 Paris, France.
EM edith.falgarone@ens.fr
FU ERC [321302]; national CNRS programme Physique et Chimie du Milieu Interstellaire (PCMI); Science and Technology Facilities Council [ST/M001229/1] Funding Source: researchfish; European Research Council (ERC) [321302] Funding Source: European Research Council (ERC)
NR 53
TC 69
Z9 78
U1 0
U2 12
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 24
PY 2017
VL 548
IS 7668
BP 430
EP +
DI 10.1038/nature23298
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FE5VI
UT WOS:000408279000033
PM 28813416
DA 2026-03-09
ER

PT J
AU Kassem, S
   Lee, ATL
   Leigh, DA
   Marcos, V
   Palmer, LI
   Pisano, S
AF Kassem, Salma
   Lee, Alan T. L.
   Leigh, David A.
   Marcos, Vanesa
   Palmer, Leoni I.
   Pisano, Simone
TI Stereodivergent synthesis with a programmable molecular machine
SO NATURE
LA English
DT Article
ID dynamic control; chemistry; rise
AB It has been convincingly argued(1-3) that molecular machines that manipulate individual atoms, or highly reactive clusters of atoms, with Angstrom precision are unlikely to be realized. However, biological molecular machines routinely position rather less reactive substrates in order to direct chemical reaction sequences, from sequence-specific synthesis by the ribosome(4) to polyketide synthases(5-7), where tethered molecules are passed from active site to active site in multi-enzyme complexes. Artificial molecular machines(8-12) have been developed for tasks that include sequence-specific oligomer synthesis(13-15) and the switching of product chirality(16-19), a photo-responsive host molecule has been described that is able to mechanically twist a bound molecular guest(20), and molecular fragments have been selectively transported in either direction between sites on a molecular platform through a ratchet mechanism(21). Here we detail an artificial molecular machine that moves a substrate between different activating sites to achieve different product outcomes from chemical synthesis. This molecular robot can be programmed to stereoselectively produce, in a sequential one-pot operation, an excess of any one of four possible diastereoisomers from the addition of a thiol and an alkene to an alpha,beta-unsaturated aldehyde in a tandem reaction process. The stereodivergent synthesis includes diastereoisomers that cannot be selectively synthesized(22) through conventional iminium-enamine organocatalysis. We anticipate that future generations of programmable molecular machines may have significant roles in chemical synthesis and molecular manufacturing.
C1 [Kassem, Salma; Lee, Alan T. L.; Leigh, David A.; Marcos, Vanesa; Palmer, Leoni I.; Pisano, Simone] Univ Manchester, Sch Chem, Oxford Rd, Oxford M13 9PL, England.
C3 University of Manchester
RP Leigh, DA (corresponding author), Univ Manchester, Sch Chem, Oxford Rd, Oxford M13 9PL, England.
EM david.leigh@manchester.ac.uk
FU Engineering and Physical Sciences Research Council (EPSRC) [EP/H021620/1, EP/H021620/2]; European Research Council (ERC) [339019]; EPSRC [EP/H021620/1, EP/P001386/1, EP/H021620/2] Funding Source: UKRI; Engineering and Physical Sciences Research Council [EP/H021620/1, EP/P001386/1, EP/H021620/2] Funding Source: researchfish
NR 30
TC 148
Z9 165
U1 1
U2 183
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 21
PY 2017
VL 549
IS 7672
BP 374
EP 378
DI 10.1038/nature23677
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FH7PB
UT WOS:000411381300033
PM 28933436
DA 2026-03-09
ER

PT J
AU Cao, YL
   Meng, SX
   Chen, Y
   Feng, JX
   Gu, DD
   Yu, B
   Li, YJ
   Yang, JY
   Liao, S
   Chan, DC
   Gao, S
AF Cao, Yu-Lu
   Meng, Shuxia
   Chen, Yang
   Feng, Jian-Xiong
   Gu, Dong-Dong
   Yu, Bing
   Li, Yu-Jie
   Yang, Jin-Yu
   Liao, Shuang
   Chan, David C.
   Gao, Song
TI MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion
SO NATURE
LA English
DT Article
ID crystal-structure; fission; oligomerization; morphology; mitofusins; curvature; mechanism; dynamics; insights; system
AB Mitochondria are double-membraned organelles with variable shapes influenced by metabolic conditions, developmental stage, and environmental stimuli(1-4). Their dynamic morphology is a result of regulated and balanced fusion and fission processes(5,6). Fusion is crucial for the health and physiological functions of mitochondria, including complementation of damaged mitochondrial DNAs and the maintenance of membrane potential(6-8). Mitofusins are dynamin-related GTPases that are essential for mitochondrial fusion(9,10). They are embedded in the mitochondrial outer membrane and thought to fuse adjacent mitochondria via combined oligomerization and GTP hydrolysis(11-13). However, the molecular mechanisms of this process remain unknown. Here we present crystal structures of engineered human MFN1 containing the GTPase domain and a helical domain during different stages of GTP hydrolysis. The helical domain is composed of elements from widely dispersed sequence regions of MFN1 and resembles the 'neck' of the bacterial dynamin-like protein. The structures reveal unique features of its catalytic machinery and explain how GTP binding induces conformational changes to promote GTPase domain dimerization in the transition state. Disruption of GTPase domain dimerization abolishes the fusogenic activity of MFN1. Moreover, a conserved aspartate residue trigger was found to affect mitochondrial elongation in MFN1, probably through a GTP-loading-dependent domain rearrangement. Thus, we propose a mechanistic model for MFN1-mediated mitochondrial tethering, and our results shed light on the molecular basis of mitochondrial fusion and mitofusin-related human neuromuscular disorders(14).
C1 [Cao, Yu-Lu; Chen, Yang; Feng, Jian-Xiong; Gu, Dong-Dong; Yu, Bing; Li, Yu-Jie; Yang, Jin-Yu; Liao, Shuang; Gao, Song] Sun Yat Sen Univ, Ctr Canc, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Guangzhou 510060, Guangdong, Peoples R China.
   [Meng, Shuxia; Chan, David C.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
C3 State Key Lab Oncology South China; Sun Yat Sen University; California Institute of Technology
RP Gao, S (corresponding author), Sun Yat Sen Univ, Ctr Canc, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Guangzhou 510060, Guangdong, Peoples R China.
EM gaosong@sysucc.org.cn
FU National Basic Research Program of China [2013CB910500]; National Natural Science Foundation of China [31200553]; Natural Science Foundation of Guangdong Province [2014TQ01R584, 20144030312015]; New Century Excellent Talents in University [NCET-12-0567]; Recruitment Program of Global Youth Experts; National Institutes of Health [GM110039, GM119388]
NR 51
TC 260
Z9 319
U1 4
U2 105
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 16
PY 2017
VL 542
IS 7641
BP 372
EP +
DI 10.1038/nature21077
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2LQ
UT WOS:000394451600042
PM 28114303
DA 2026-03-09
ER

PT J
AU Bridwell-Rabb, J
   Zhong, AS
   Sun, HG
   Drennan, CL
   Liu, HW
AF Bridwell-Rabb, Jennifer
   Zhong, Aoshu
   Sun, He G.
   Drennan, Catherine L.
   Liu, Hung-wen
TI A B12-dependent radical SAM enzyme involved in oxetanocin A biosynthesis
SO NATURE
LA English
DT Article
ID dependent methionine synthase; x-ray-structure; crystal-structure; methyl transfer; mechanism; methyltransferase; superfamily; fosfomycin; chemistry; catalysis
AB Oxetanocin A (OXT-A) is a potent antitumour, antiviral and antibacterial compound. Biosynthesis of OXT-A has been linked to a plasmid-borne Bacillus megaterium gene cluster that contains four genes: oxsA, oxsB, oxrA and oxrB. Here we show that both the oxsA and oxsB genes are required for the production of OXT-A. Biochemical analysis of the encoded proteins, a cobalamin (Cbl)-dependent S-adenosylmethionine (AdoMet) radical enzyme, OxsB, and an HD-domain phosphohydrolase, OxsA, reveals that OXT-A is derived from a 2'-deoxyadenosine phosphate in an OxsB-catalysed ring contraction reaction initiated by hydrogen atom abstraction from C2'. Hence, OxsB represents the first biochemically characterized non-methylating Cbl-dependent AdoMet radical enzyme. X-ray analysis of OxsB reveals the fold of a Cbl-dependent AdoMet radical enzyme, a family of enzymes with an estimated 7,000 members. Overall, this work provides a framework for understanding the interplay of AdoMet and Cbl cofactors and expands the catalytic repertoire of Cbl-dependent AdoMet radical enzymes.
C1 [Bridwell-Rabb, Jennifer; Drennan, Catherine L.] MIT, Howard Hughes Med Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Bridwell-Rabb, Jennifer; Drennan, Catherine L.] MIT, Dept Chem, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Bridwell-Rabb, Jennifer; Drennan, Catherine L.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Zhong, Aoshu; Sun, He G.; Liu, Hung-wen] Univ Texas Austin, Coll Pharm, Div Chem Biol & Med Chem, Austin, TX 78712 USA.
   [Zhong, Aoshu; Sun, He G.; Liu, Hung-wen] Univ Texas Austin, Dept Chem, Austin, TX 78712 USA.
C3 Howard Hughes Medical Institute; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); University of Texas System; University of Texas Austin; University of Texas System; University of Texas Austin
RP Drennan, CL (corresponding author), MIT, Howard Hughes Med Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Drennan, CL (corresponding author), MIT, Dept Chem, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Drennan, CL (corresponding author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Liu, HW (corresponding author), Univ Texas Austin, Coll Pharm, Div Chem Biol & Med Chem, Austin, TX 78712 USA.; Liu, HW (corresponding author), Univ Texas Austin, Dept Chem, Austin, TX 78712 USA.
EM cdrennan@mit.edu; h.w.liu@mail.utexas.edu
FU National Institute of Health [F32-GM108189, GM035906]; Welch Foundation [F-1511]; National Institute of General Medical Sciences from the National Institutes of Health [P41 GM103403]; NIH-ORIP HEI grant [S10 RR029205]; DOE Office of Science [DE-AC02-06CH11357]; National Institute of General Medical Sciences [R01GM035906] Funding Source: NIH RePORTER
NR 44
TC 87
Z9 103
U1 2
U2 102
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 20
PY 2017
VL 544
IS 7650
BP 322
EP U321
DI 10.1038/nature21689
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ES4SG
UT WOS:000399524400031
PM 28346939
DA 2026-03-09
ER

PT J
AU Morishima, K
   Kuno, M
   Nishio, A
   Kitagawa, N
   Manabe, Y
   Moto, M
   Takasaki, F
   Fujii, H
   Satoh, K
   Kodama, H
   Hayashi, K
   Odaka, S
   Procureur, S
   Attié, D
   Bouteille, S
   Calvet, D
   Filosa, C
   Magnier, P
   Mandjavidze, I
   Riallot, M
   Marini, B
   Gable, P
   Date, Y
   Sugiura, M
   Elshayeb, Y
   Elnady, T
   Ezzy, M
   Guerriero, E
   Steiger, V
   Serikoff, N
   Mouret, JB
   Charles, B
   Helal, H
   Tayoubi, M
AF Morishima, Kunihiro
   Kuno, Mitsuaki
   Nishio, Akira
   Kitagawa, Nobuko
   Manabe, Yuta
   Moto, Masaki
   Takasaki, Fumihiko
   Fujii, Hirofumi
   Satoh, Kotaro
   Kodama, Hideyo
   Hayashi, Kohei
   Odaka, Shigeru
   Procureur, Sebastien
   Attie, David
   Bouteille, Simon
   Calvet, Denis
   Filosa, Christopher
   Magnier, Patrick
   Mandjavidze, Irakli
   Riallot, Marc
   Marini, Benoit
   Gable, Pierre
   Date, Yoshikatsu
   Sugiura, Makiko
   Elshayeb, Yasser
   Elnady, Tamer
   Ezzy, Mustapha
   Guerriero, Emmanuel
   Steiger, Vincent
   Serikoff, Nicolas
   Mouret, Jean-Baptiste
   Charles, Bernard
   Helal, Hany
   Tayoubi, Mehdi
TI Discovery of a big void in Khufu's Pyramid by observation of cosmic-ray muons
SO NATURE
LA English
DT Article
ID nuclear-emulsion; micromegas; detector; chamber
AB The Great Pyramid, or Khufu's Pyramid, was built on the Giza plateau in Egypt during the fourth dynasty by the pharaoh Khufu (Cheops)(1), who reigned from 2509 BC to 2483 BC. Despite being one of the oldest and largest monuments on Earth, there is no consensus about how it was built(2,3). To understand its internal structure better, we imaged the pyramid using muons, which are by-products of cosmic rays that are only partially absorbed by stone(4-6). The resulting cosmic-ray muon radiography allows us to visualize the known and any unknown voids in the pyramid in a non-invasive way. Here we report the discovery of a large void (with a cross-section similar to that of the Grand Gallery and a minimum length of 30 metres) situated above the Grand Gallery. This constitutes the first major inner structure found in the Great Pyramid since the nineteenth century(1). The void, named ScanPyramids' Big Void, was first observed with nuclear emulsion films(7-9) installed in the Queen's chamber, then confirmed with scintillator hodoscopes(10,11) set up in the same chamber and finally re-confirmed with gas detectors(12) outside the pyramid. This large void has therefore been detected with high confidence by three different muon detection technologies and three independent analyses. These results constitute a breakthrough for the understanding of the internal structure of Khufu's Pyramid. Although there is currently no information about the intended purpose of this void, these findings show how modern particle physics can shed new light on the world's archaeological heritage.
C1 [Morishima, Kunihiro; Kuno, Mitsuaki; Nishio, Akira; Kitagawa, Nobuko; Manabe, Yuta; Moto, Masaki] Nagoya Univ, F Lab, Chikusa Ku, Furo Cho, Nagoya, Aichi 4648602, Japan.
   [Takasaki, Fumihiko; Fujii, Hirofumi; Satoh, Kotaro; Kodama, Hideyo; Hayashi, Kohei; Odaka, Shigeru] High Energy Accelerator Res Org KEK, 1-1 Oho, Tsukuba, Ibaraki 3050801, Japan.
   [Procureur, Sebastien; Attie, David; Bouteille, Simon; Calvet, Denis; Filosa, Christopher; Magnier, Patrick; Mandjavidze, Irakli; Riallot, Marc] Univ Paris Saclay, Commissariat Energie Atom & Energies Alternat CEA, IRFU, F-91191 Gif Sur Yvette, France.
   [Marini, Benoit; Steiger, Vincent; Serikoff, Nicolas; Helal, Hany; Tayoubi, Mehdi] HIP Inst, 50 Rue Rome, F-75008 Paris, France.
   [Gable, Pierre; Guerriero, Emmanuel] Emissive, 71 Rue Provence, F-75009 Paris, France.
   [Date, Yoshikatsu] NHK Enterprises Inc NEP, Shibuya Ku, 4-14 Kamiyama Cho, Tokyo 1500047, Japan.
   [Sugiura, Makiko] Suave Images, Meguro Ku, N-2 Maison Shino,3-30-8 Kamineguro, Tokyo 1530051, Japan.
   [Elshayeb, Yasser; Ezzy, Mustapha] Cairo Univ, 9 Al Gameya, Oula, Giza Governorat, Egypt.
   [Elnady, Tamer] Ain Shams Univ, Cairo, Egypt.
   [Mouret, Jean-Baptiste] Inria, F-54600 Villers Les Nancy, France.
   [Mouret, Jean-Baptiste] CNRS, F-54500 Vandoeuvre Les Nancy, France.
   [Mouret, Jean-Baptiste] Univ Lorraine, F-54500 Vandoeuvre Les Nancy, France.
   [Charles, Bernard; Tayoubi, Mehdi] Dassault Syst, 10 Rue Marcel Dassault, F-78140 Velizy Villacoublay, France.
C3 Nagoya University; High Energy Accelerator Research Organization (KEK); Universite Paris Saclay; CEA; Egyptian Knowledge Bank (EKB); Cairo University; Egyptian Knowledge Bank (EKB); Ain Shams University; Inria; Centre National de la Recherche Scientifique (CNRS); Universite de Lorraine; Universite de Lorraine; Dassault Systemes
RP Morishima, K (corresponding author), Nagoya Univ, F Lab, Chikusa Ku, Furo Cho, Nagoya, Aichi 4648602, Japan.; Tayoubi, M (corresponding author), HIP Inst, 50 Rue Rome, F-75008 Paris, France.; Tayoubi, M (corresponding author), Dassault Syst, 10 Rue Marcel Dassault, F-78140 Velizy Villacoublay, France.
EM morishima@flab.phys.nagoya-u.ac.jp; tayoubi@hip.institute
FU NHK; La Fondation Dassault Systemes; Suez; IceWatch; le Groupe Dassault; Batscop; Itekube; Parrot; ILP; Kurtzdev; Gen-G; Schneider Electric; JSPS KAKENHI [JP15H04241]; Region Ile-de-France; P2IO LabEx [ANR-10-LABX-0038, ANR-11-IDEX-0003-01]; JST-SENTAN Program from the Japan Science and Technology Agency; Grants-in-Aid for Scientific Research [16J11975, 15H04241] Funding Source: KAKEN
NR 45
TC 288
Z9 364
U1 22
U2 172
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 21
PY 2017
VL 552
IS 7685
BP 386
EP +
DI 10.1038/nature24647
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ7RI
UT WOS:000418559800055
PM 29160306
DA 2026-03-09
ER

PT J
AU Spaulding, CN
   Klein, RD
   Ruer, S
   Kau, AL
   Schreiber, HL
   Cusumano, ZT
   Dodson, KW
   Pinkner, JS
   Fremont, DH
   Janetka, JW
   Remaut, H
   Gordon, JI
   Hultgren, SJ
AF Spaulding, Caitlin N.
   Klein, Roger D.
   Ruer, Segolene
   Kau, Andrew L.
   Schreiber, Henry L.
   Cusumano, Zachary T.
   Dodson, Karen W.
   Pinkner, Jerome S.
   Fremont, Daved H.
   Janetka, James W.
   Remaut, Han
   Gordon, Jeffrey I.
   Hultgren, Scott J.
TI Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist
SO NATURE
LA English
DT Article
ID escherichia-coli; mouse model; urinary; microbiota; sequence; binding; optimization; community; infection; bacteria
AB Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) affect 150 million people annually(1,2). Despite effective antibiotic therapy, 30-50% of patients experience recurrent UTIs(1). In addition, the growing prevalence of UPEC that are resistant to last-line antibiotic treatments, and more recently to carbapenems and colistin, make UTI a prime example of the antibiotic-resistance crisis and emphasize the need for new approaches to treat and prevent bacterial infections(3-5). UPEC strains establish reservoirs in the gut from which they are shed in the faeces, and can colonize the periurethral area or vagina and subsequently ascend through the urethra to the urinary tract, where they cause UTIs(6). UPEC isolates encode up to 16 distinct chaperone-usher pathway pili, and each pilus type may enable colonization of a habitat in the host or environment(7). For example, the type 1 pilus adhesin FimH binds mannose on the bladder surface, and mediates colonization of the bladder. However, little is known about the mechanisms underlying UPEC persistence in the gut(5). Here, using a mouse model, we show that F17-like and type 1 pili promote intestinal colonization and show distinct binding to epithelial cells distributed along colonic crypts. Phylogenomic and structural analyses reveal that F17-like pili are closely related to pilus types carried by intestinal pathogens, but are restricted to extra-intestinal pathogenic E. coli. Moreover, we show that targeting FimH with M4284, a high-affinity inhibitory mannoside, reduces intestinal colonization of genetically diverse UPEC isolates, while simultaneously treating UTI, without notably disrupting the structural configuration of the gut microbiota. By selectively depleting intestinal UPEC reservoirs, mannosides could markedly reduce the rate of UTIs and recurrent UTIs.
C1 [Spaulding, Caitlin N.; Klein, Roger D.; Schreiber, Henry L.; Cusumano, Zachary T.; Dodson, Karen W.; Pinkner, Jerome S.; Fremont, Daved H.; Hultgren, Scott J.] Washington Univ, Dept Mol Microbiol, St Louis, MO 63110 USA.
   [Spaulding, Caitlin N.; Klein, Roger D.; Kau, Andrew L.; Schreiber, Henry L.; Cusumano, Zachary T.; Dodson, Karen W.; Pinkner, Jerome S.; Janetka, James W.; Hultgren, Scott J.] Washington Univ, CWIDR, St Louis, MO 63110 USA.
   [Ruer, Segolene; Remaut, Han] VIB, Struct & Mol Microbiol, VIB Ctr Struct Biol, Pl Laan 2, B-1050 Brussels, Belgium.
   [Ruer, Segolene; Remaut, Han] Vrije Univ Brussel, Struct Biol Brussels, Pl Laan 2, B-1050 Brussels, Belgium.
   [Kau, Andrew L.] Washington Univ, Dept Med, St Louis, MO 63110 USA.
   [Schreiber, Henry L.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Fremont, Daved H.] Washington Univ, Dept Pathol & Immunol, St Louis, MO 63110 USA.
   [Fremont, Daved H.; Janetka, James W.] Washington Univ, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA.
   [Gordon, Jeffrey I.] Washington Univ, Ctr Genome Sci & Syst Biol, St Louis, MO 63110 USA.
   [Gordon, Jeffrey I.] Washington Univ, Ctr Gut Microbiome & Nutr Res, St Louis, MO 63110 USA.
C3 Washington University (WUSTL); Washington University (WUSTL); Flanders Institute for Biotechnology (VIB); Vrije Universiteit Brussel; Washington University (WUSTL); Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL)
RP Hultgren, SJ (corresponding author), Washington Univ, Dept Mol Microbiol, St Louis, MO 63110 USA.; Hultgren, SJ (corresponding author), Washington Univ, CWIDR, St Louis, MO 63110 USA.
EM hultgren@wustl.edu
FU NIH [K08AI113184, RO1DK051406, R01AI048689, P50DK064540, RC1DK086378, DK30292, 1F31DK107057]; FWO-Flanders [G030411N]; Hercules Foundation [UABR/09/005]; VIB PRJ9; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK051406, R01DK030292] Funding Source: NIH RePORTER
NR 46
TC 239
Z9 288
U1 4
U2 155
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 22
PY 2017
VL 546
IS 7659
BP 528
EP +
DI 10.1038/nature22972
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY2QK
UT WOS:000403814100038
PM 28614296
DA 2026-03-09
ER

PT J
AU Melentijevic, I
   Toth, ML
   Arnold, ML
   Guasp, RJ
   Harinath, G
   Nguyen, KC
   Taub, D
   Parker, JA
   Neri, C
   Gabel, CV
   Hall, DH
   Driscoll, M
AF Melentijevic, Ilija
   Toth, Marton L.
   Arnold, Meghan L.
   Guasp, Ryan J.
   Harinath, Girish
   Nguyen, Ken C.
   Taub, Daniel
   Parker, J. Alex
   Neri, Christian
   Gabel, Christopher V.
   Hall, David H.
   Driscoll, Monica
TI C-elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress
SO NATURE
LA English
DT Article
ID tunneling nanotubes; transmission; expression; exosm; mutant; cells; ced-1; gene; rnai
AB The toxicity of misfolded proteins and mitochondrial dysfunction are pivotal factors that promote age-associated functional neuronal decline and neurodegenerative disease(1,2). Accordingly, neurons invest considerable cellular resources in chaperones, protein degradation, autophagy and mitophagy to maintain proteostasis and mitochondrial quality(3,4). Complicating the challenges of neuroprotection, misfolded human disease proteins and mitochondria can move into neighbouring cells via unknown mechanisms, which may promote pathological spread(5,6). Here we show that adult neurons from Caenorhabditis elegans extrude large (approximately 4 mu m) membrane-surrounded vesicles called exophers that can contain protein aggregates and organelles. Inhibition of chaperone expression, autophagy or the proteasome, in addition to compromising mitochondrial quality, enhances the production of exophers. Proteotoxically stressed neurons that generate exophers subsequently function better than similarly stressed neurons that did not produce exophers. The extruded exopher transits through surrounding tissue in which some contents appear degraded, but some non-degradable materials can subsequently be found in more remote cells, suggesting secondary release. Our observations suggest that exopher-genesis is a potential response to rid cells of neurotoxic components when proteostasis and organelle function are challenged. We propose that exophers are components of a conserved mechanism that constitutes a fundamental, but formerly unrecognized, branch of neuronal proteostasis and mitochondrial quality control, which, when dysfunctional or diminished with age, might actively contribute to pathogenesis in human neurodegenerative disease and brain ageing.
C1 [Melentijevic, Ilija; Toth, Marton L.; Arnold, Meghan L.; Guasp, Ryan J.; Harinath, Girish; Driscoll, Monica] Rutgers State Univ, Nelson Biol Labs, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA.
   [Nguyen, Ken C.; Hall, David H.] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA.
   [Taub, Daniel; Gabel, Christopher V.] Boston Univ, Sch Med, Dept Physiol & Biophys, Boston, MA 02118 USA.
   [Taub, Daniel; Gabel, Christopher V.] Boston Univ, Photon Ctr, Boston, MA 02215 USA.
   [Parker, J. Alex] Univ Montreal, CRCHUM, Dept Neurosci, Montreal, PQ H2X 0A9, Canada.
   [Neri, Christian] CNRS, UMR 8256, Brain Team C, Paris, France.
   [Neri, Christian] Univ Pierre & Marie Curie UPMC Univ Paris 06, Sorbonnes Univ, Paris, France.
C3 Rutgers University System; Rutgers University New Brunswick; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Boston University; Boston University; Universite de Montreal; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Sorbonne Universite
RP Driscoll, M (corresponding author), Rutgers State Univ, Nelson Biol Labs, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA.
EM driscoll@dls.rutgers.edu
FU National Institutes of Health [1R01NS086064, 1R01AG046358]; National Institute of General Medical Sciences [T32 GM008339]; NIH [0010943]; Core EM facilities; NICHD [P30 HD71593]; NIH Office of Research Infrastructure Programs [P40 00010440]; National Institute on Aging [R01AG047101] Funding Source: NIH RePORTER; NIH Office of the Director [R24OD010943] Funding Source: NIH RePORTER; NIH Office of the Director; National Institute of General Medical Sciences [P40OD010440] Funding Source: NIH RePORTER
NR 49
TC 341
Z9 398
U1 7
U2 127
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 16
PY 2017
VL 542
IS 7641
BP 367
EP +
DI 10.1038/nature21362
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2LQ
UT WOS:000394451600041
PM 28178240
DA 2026-03-09
ER

PT J
AU Yin, JA
   Gao, G
   Liu, XJ
   Hao, ZQ
   Li, K
   Kang, XL
   Li, H
   Shan, YH
   Hu, WL
   Li, HP
   Cai, SQ
AF Yin, Jiang-An
   Gao, Ge
   Liu, Xi-Juan
   Hao, Zi-Qian
   Li, Kai
   Kang, Xin-Lei
   Li, Hong
   Shan, Yuan-Hong
   Hu, Wen-Li
   Li, Hai-Peng
   Cai, Shi-Qing
TI Genetic variation in glia-neuron signalling modulates ageing rate
SO NATURE
LA English
DT Article
ID caenorhabditis-elegans; life-span; neuropeptide-y; longevity; expression; selection; behavior; food; mutations; extension
AB The rate of behavioural decline in the ageing population is remarkably variable among individuals. Despite the considerable interest in studying natural variation in ageing rate to identify factors that control healthy ageing, no such factor has yet been found. Here we report a genetic basis for variation in ageing rates in Caenorhabditis elegans. We find that C. elegans isolates show diverse lifespan and age-related declines in virility, pharyngeal pumping, and locomotion. DNA polymorphisms in a novel peptide-coding gene, named regulatory-gene-for-behavioural-ageing-1 (rgba-1), and the neuropeptide receptor gene npr-28 influence the rate of age-related decline of worm mating behaviour; these two genes might have been subjected to recent selective sweeps. Glia-derived RGBA-1 activates NPR-28 signalling, which acts in serotonergic and dopaminergic neurons to accelerate behavioural deterioration. This signalling involves the SIR-2.1-dependent activation of the mitochondrial unfolded protein response, a pathway that modulates ageing. Thus, natural variation in neuropeptide-mediated glia-neuron signalling modulates the rate of ageing in C. elegans.
C1 [Yin, Jiang-An; Gao, Ge; Liu, Xi-Juan; Li, Kai; Kang, Xin-Lei; Cai, Shi-Qing] Chinese Acad Sci, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci, Shanghai 200031, Peoples R China.
   [Yin, Jiang-An; Gao, Ge; Liu, Xi-Juan; Li, Kai; Kang, Xin-Lei; Cai, Shi-Qing] Chinese Acad Sci, CAS Ctr Excellence Brain Sci & Intelligence Techn, State Key Lab Neurosci, Shanghai 200031, Peoples R China.
   [Gao, Ge; Hao, Zi-Qian] Univ Chinese Acad Sci, Beijing 100049, Peoples R China.
   [Hao, Zi-Qian; Li, Hai-Peng] Chinese Acad Sci, Shanghai Inst Biol Sci, CAS MPG Partner Inst Computat Biol, CAS Key Lab Computat Biol, Shanghai 200031, Peoples R China.
   [Li, Hong] Chinese Acad Sci, Inst Biochem & Cell Biol, Core Facil Mol Biol, Shanghai 200031, Peoples R China.
   [Shan, Yuan-Hong] Chinese Acad Sci, Core Facil Ctr, Shanghai 200032, Peoples R China.
C3 Chinese Academy of Sciences; Center for Excellence in Brain Science and Intelligence Technology, CAS; Chinese Academy of Sciences; Center for Excellence in Brain Science and Intelligence Technology, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; Max Planck Society; Chinese Academy of Sciences; Center for Excellence in Molecular Cell Science, CAS; Chinese Academy of Sciences
RP Cai, SQ (corresponding author), Chinese Acad Sci, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci, Shanghai 200031, Peoples R China.; Cai, SQ (corresponding author), Chinese Acad Sci, CAS Ctr Excellence Brain Sci & Intelligence Techn, State Key Lab Neurosci, Shanghai 200031, Peoples R China.
EM sqcai@ion.ac.cn
FU Strategic Priority Research Program of the Chinese Academy of Sciences [XDB 13000000]; National Natural Science Foundation of China [31471149, 81527901]
NR 71
TC 59
Z9 72
U1 2
U2 93
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 9
PY 2017
VL 551
IS 7679
BP 198
EP +
DI 10.1038/nature24463
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM1KF
UT WOS:000414734200041
PM 29120414
DA 2026-03-09
ER

PT J
AU Sugiura, A
   Mattie, S
   Prudent, J
   McBride, HM
AF Sugiura, Ayumu
   Mattie, Sevan
   Prudent, Julien
   McBride, Heidi M.
TI Newly born peroxisomes are a hybrid of mitochondrial and ER-derived pre-peroxisomes
SO NATURE
LA English
DT Article
ID membrane-proteins; endoplasmic-reticulum; pex3; biogenesis; pathway; import; maintenance; evolution; transport; vesicles
AB Peroxisomes function together with mitochondria in a number of essential biochemical pathways, from bile acid synthesis to fatty acid oxidation(1). Peroxisomes grow and divide from preexisting organelles(2), but can also emerge de novo in the cell(3). The physiological regulation of de novo peroxisome biogenesis remains unclear, and it is thought that peroxisomes emerge from the endoplasmic reticulum in both mammalian and yeast cells'. However, in contrast to the yeast system(5-8), a number of integral peroxisomal membrane proteins are imported into mitochondria in mammalian cells in the absence of peroxisomes, including Pex3, Pex12, Pex13, Pex14, Pex26, PMP34 and ALDP(9-15). Overall, the mitochondrial localization of peroxisomal membrane proteins in mammalian cells has largely been considered a mis-targeting artefact in which de novo biogenesis occurs exclusively from endoplasmic reticulum-targeted peroxins(16). Here, in following the generation of new peroxisomes within human patient fibroblasts lacking peroxisomes, we show that the essential import receptors Pex3 and Pex14 target mitochondria, where they are selectively released into vesicular pre-peroxisomal structures. Maturation of pre-peroxisomes containing Pex3 and Pex14 requires fusion with endoplasmic reticulum-derived vesicles carrying Pex16, thereby providing full import competence. These findings demonstrate the hybrid nature of newly born peroxisomes, expanding their functional links to mitochondria.
C1 [Sugiura, Ayumu; Mattie, Sevan; Prudent, Julien; McBride, Heidi M.] McGill Univ, Montreal Neurol Inst, 3801 Univ Ave, Montreal, PQ H3A 2B4, Canada.
C3 McGill University
RP McBride, HM (corresponding author), McGill Univ, Montreal Neurol Inst, 3801 Univ Ave, Montreal, PQ H3A 2B4, Canada.
EM heidi.mcbride@mcgill.ca
FU CIHR grant MOP [133549]; Canada Research Chair; JSPS Postdoctoral Fellowship for Research Abroad; Quebec FRQS Studentship; CIHR [MFE-140925]
NR 29
TC 308
Z9 357
U1 6
U2 122
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 9
PY 2017
VL 542
IS 7640
BP 251
EP 254
DI 10.1038/nature21375
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK2DJ
UT WOS:000393737500045
PM 28146471
DA 2026-03-09
ER

PT J
AU Ortiz, JL
   Santos-Sanz, P
   Sicardy, B
   Benedetti-Rossi, G
   Bérard, D
   Morales, N
   Duffard, R
   Braga-Ribas, F
   Hopp, U
   Ries, C
   Nascimbeni, V
   Marzari, F
   Granata, V
   Pál, A
   Kiss, C
   Pribulla, T
   Komzík, R
   Hornoch, K
   Pravec, P
   Bacci, P
   Maestripieri, M
   Nerli, L
   Mazzei, L
   Bachini, M
   Martinelli, F
   Succi, G
   Ciabattari, F
   Mikuz, H
   Carbognani, A
   Gaehrken, B
   Mottola, S
   Hellmich, S
   Rommel, FL
   Fernández-Valenzuela, E
   Bagatin, AC
   Cikota, S
   Ikota, AC
   Lecacheux, J
   Vieira-Martins, R
   Camargo, JIB
   Assafin, M
   Colas, F
   Behrend, R
   Desmars, J
   Meza, E
   Alvarez-Candal, A
   Beisker, W
   Gomes, AR
   Morgado, BE
   Roques, F
   Vachier, F
   Berthier, J
   Mueller, TG
   Madiedo, JM
   Unsalan, O
   Sonbas, E
   Karaman, N
   Erece, O
   Koseoglu, DT
   Ozisik, T
   Kalkan, S
   Guney, Y
   Niaei, S
   Satir, O
   Yesilyaprak, C
   Puskullu, C
   Kabas, A
   Demircan, O
   Alikakos, J
   Charmandaris, V
   Leto, G
   Ohlert, J
   Christille, JM
   Szakáts, R
   Farkas, AT
   Varga-Verebélyi, E
   Marton, G
   Marciniak, A
   Bartczak, P
   Santana-Ros, T
   Utkiewicz-Bak, MB
   Dudzinski, G
   Alí-Lagoa, V
   Gazeas, K
   Zouganatos, LT
   Paschalis, N
   Tsamis, V
   Sánchez-Lavega, A
   Pérez-Hoyos, S
   Hueso, R
   Guirado, JC
   Peris, V
   Iglesias-Marzoa, R
AF Ortiz, J. L.
   Santos-Sanz, P.
   Sicardy, B.
   Benedetti-Rossi, G.
   Berard, D.
   Morales, N.
   Duffard, R.
   Braga-Ribas, F.
   Hopp, U.
   Ries, C.
   Nascimbeni, V.
   Marzari, F.
   Granata, V.
   Pal, A.
   Kiss, C.
   Pribulla, T.
   Komzik, R.
   Hornoch, K.
   Pravec, P.
   Bacci, P.
   Maestripieri, M.
   Nerli, L.
   Mazzei, L.
   Bachini, M.
   Martinelli, F.
   Succi, G.
   Ciabattari, F.
   Mikuz, H.
   Carbognani, A.
   Gaehrken, B.
   Mottola, S.
   Hellmich, S.
   Rommel, F. L.
   Fernandez-Valenzuela, E.
   Campo Bagatin, A.
   Cikota, S.
   Cikota, A.
   Lecacheux, J.
   Vieira-Martins, R.
   Camargo, J. I. B.
   Assafin, M.
   Colas, F.
   Behrend, R.
   Desmars, J.
   Meza, E.
   Alvarez-Candal, A.
   Beisker, W.
   Gomes-Junior, A. R. .
   Morgado, B. E. .
   Roques, F.
   Vachier, F.
   Berthier, J.
   Mueller, T. G.
   Madiedo, J. M.
   Unsalan, O.
   Sonbas, E.
   Karaman, N.
   Erece, O.
   Koseoglu, D. T. .
   Ozisik, T.
   Kalkan, S.
   Guney, Y.
   Niaei, S.
   Satir, O.
   Yesilyaprak, C.
   Puskullu, C.
   Kabas, A.
   Demircan, O.
   Alikakos, J.
   Charmandaris, V.
   Leto, G.
   Ohlert, J.
   Christille, J. M.
   Szakats, R.
   Farkas, A. Takacsne
   Varga-Verebelyi, E.
   Marton, G.
   Marciniak, A.
   Bartczak, P.
   Santana-Ros, T.
   Utkiewicz-Bak, M. B.
   Dudzinski, G.
   Ali-Lagoa, V.
   Gazeas, K.
   Zouganatos, L. T.
   Paschalis, N.
   Tsamis, V.
   Sanchez-Lavega, A.
   Perez-Hoyos, S.
   Hueso, R.
   Guirado, J. C. .
   Peris, V.
   Iglesias-Marzoa, R.
TI The size, shape, density and ring of the dwarf planet Haumea from a stellar occultation
SO NATURE
LA English
DT Article
ID photometric-observations; 2003 el61; object; albedo; satellites; body
AB Haumea-one of the four known trans-Neptunian dwarf planets is a very elongated and rapidly rotating body(1-3). In contrast to other dwarf planets(4-6), its size, shape, albedo and density are not well constrained. The Centaur Chariklo was the first body other than a giant planet known to have a ring system(7), and the Centaur Chiron was later found to possess something similar to Chariklo's rings(8,9). Here we report observations from multiple Earth-based observatories of Haumea passing in front of a distant star (a multi chord stellar occultation). Secondary events observed around the main body of Haumea are consistent with the presence of a ring with an opacity of 0.5, width of 70 kilometres and radius of about 2,287 kilometres. The ring is coplanar with both Haumea's equator and the orbit of its satellite Hi'iaka. The radius of the ring places it close to the 3:1 mean-motion resonance with Haumea's spin period-that is, Haumea rotates three times on its axis in the time that a ring particle completes one revolution. The occultation by the main body provides an instantaneous elliptical projected shape with axes of about 1,704 kilometres and 1,138 kilometres. Combined with rotational light curves, the occultation constrains the three-dimensional orientation of Haumea and its triaxial shape, which is inconsistent with a homogeneous body in hydrostatic equilibrium. Haumea's largest axis is at least 2,322 kilometres, larger than previously thought, implying an upper limit for its density of 1,885 kilograms per cubic metre and a geometric albedo of 0.51, both smaller than previous estimates(1,10,11). In addition, this estimate of the density of Haumea is closer to that of Pluto than are previous estimates, in line with expectations. No global nitrogen- or methane-dominated atmosphere was detected.
C1 [Ortiz, J. L.; Santos-Sanz, P.; Morales, N.; Duffard, R.; Fernandez-Valenzuela, E.] CSIC, Inst Astrofis Andalucia, Glorieta Astron S-N, E-18008 Granada, Spain.
   [Sicardy, B.; Berard, D.; Lecacheux, J.; Desmars, J.; Meza, E.; Roques, F.] Sorbonne Univ, UPMC Univ Paris 6, Univ Paris Diderot,Sorbonne Paris Cite, LESIA,Observ Paris,PSL Res Univ,CNRS,, Paris, France.
   [Benedetti-Rossi, G.; Braga-Ribas, F.; Vieira-Martins, R.; Camargo, J. I. B.; Alvarez-Candal, A.; Morgado, B. E. .] MCTIC, Observ Nacl, Rua Gen Jose Cristino 77, BR-20921400 Rio De Janeiro, Brazil.
   [Braga-Ribas, F.; Rommel, F. L.] Fed Univ Technol Parana UTFPR DAFIS, Rua Sete Setembro 3165, BR-80230901 Curitiba, Parana, Brazil.
   [Hopp, U.; Ries, C.] Univ Sternwarte Munchen, Scheiner Str 1, D-81679 Munich, Germany.
   [Hopp, U.; Mueller, T. G.; Ali-Lagoa, V.] Max Planck Inst Extraterr Phys, D-85741 Garching, Germany.
   [Nascimbeni, V.; Granata, V.] Univ Padua, Dipartimento Fis & Astron G Galilei, Vicolo Osservatorio 3, I-35122 Padua, Italy.
   [Nascimbeni, V.; Granata, V.] Osserv Astron Padova, INAF, Vicolo Osservatorio 3, I-35122 Padua, Italy.
   [Marzari, F.] Univ Padua, Dipartimento Fis, Via Marzolo 8, I-35131 Padua, Italy.
   [Pal, A.; Kiss, C.; Szakats, R.; Farkas, A. Takacsne; Varga-Verebelyi, E.; Marton, G.] Hungarian Acad Sci, Konkoly Observ, Res Ctr Astron & Earth Sci, Konkoly Thege 15-17, H-1121 Budapest, Hungary.
   [Pribulla, T.; Komzik, R.] Slovak Acad Sci, Astron Inst, Tatranska Lomnica 05960, Slovakia.
   [Hornoch, K.; Pravec, P.] Acad Sci Czech Republ, Astron Inst, Fricova 298, Ondrejov 25165, Czech Republic.
   [Bacci, P.; Maestripieri, M.; Nerli, L.; Mazzei, L.] Astron Observ San Marcello Pistoiese CARA Project, San Marcello Pistoiese, Pistoia, Italy.
   [Bachini, M.; Succi, G.] Osservatorio Astron Tavolaia, Santa Maria A Monte, Italy.
   [Bachini, M.; Martinelli, F.; Succi, G.] Lajatico Astron Ctr, Via Mulini A Vento 9 Orciatico, I-56030 Lajatico, Italy.
   [Ciabattari, F.] Osservatorio Astron Monte Agliale, Via Cune Motrone, I-55023 Borgo A Mozzano, Italy.
   [Mikuz, H.] Crni Vrh Observ, Predgrize 29A, Crni Vrh Nad Idrijo 5274, Slovenia.
   [Carbognani, A.; Christille, J. M.] Astron Observ Autonomous Reg Aosta Valley OAVdA, I-11020 Nus, Italy.
   [Gaehrken, B.] Bayer Volkssternwarte Munchen, Rosenheimer Str 145th, D-81671 Munich, Germany.
   [Mottola, S.; Hellmich, S.] German Aerosp Ctr DLR, Inst Planetary Res, Rutherfordstr 2, D-12489 Berlin, Germany.
   [Campo Bagatin, A.] Univ Alicante, Dept Fis Ingn Sistemas & Teoria Senal, POB 99, E-03080 Alicante, Spain.
   [Campo Bagatin, A.] Univ Alicante, Inst Univ Fis Aplicada Ciencias & Tecnol, POB 99, E-03080 Alicante, Spain.
   [Cikota, S.] Univ Zagreb, Fac Elect Engn & Comp, Dept Appl Phys, Unska 3, Zagreb 10000, Croatia.
   [Cikota, S.] Rudjer Boskovic Inst, Bijenicka Cesta 54, Zagreb 10000, Croatia.
   [Cikota, A.] European Southern Observ, Karl Schwarzschild Str 2, D-85748 Garching, Germany.
   [Vieira-Martins, R.; Colas, F.; Vachier, F.; Berthier, J.] Observ Paris, IMCCE, 77 Ave Denfert Rochereau, F-75014 Paris, France.
   [Vieira-Martins, R.; Camargo, J. I. B.] Lab Interinst & Astron LIneA, Rua Gen Jose Cristino 77, BR-20921400 Rio De Janeiro, Brazil.
   [Vieira-Martins, R.; Assafin, M.; Gomes-Junior, A. R. .] Univ Fed Rio de Janeiro, Observ Valongo, Ladeira Pedro Antonio 43, BR-20080090 Rio de Janeiro, Brazil.
   [Behrend, R.] Observ Geneva, CH-1290 Sauverny, Switzerland.
   [Beisker, W.] IOTA ES, Bartold Knausstr 8, D-30459 Hannover, Germany.
   [Madiedo, J. M.] Univ Huelva, Fac Ciencias Expt, Ave Fuerzas Armadas, Huelva 21071, Spain.
   [Unsalan, O.] Ege Univ, Fac Sci, Dept Phys, TR-35100 Izmir, Turkey.
   [Sonbas, E.; Karaman, N.] Adiyaman Univ, Dept Phys, TR-02040 Adiyaman, Turkey.
   [Erece, O.; Koseoglu, D. T. .; Ozisik, T.] TUBITAK Natl Observ TUG, Akdeniz Univ Campus, TR-07058 Antalya, Turkey.
   [Kalkan, S.] Ondokuz Mayis Univ Observ, Space Res Ctr, TR-55200 Kurupelit, Turkey.
   [Guney, Y.] Ataturk Univ, Fac Sci, Dept Phys, TR-25240 Erzurum, Turkey.
   [Niaei, S.; Satir, O.; Yesilyaprak, C.] Ataturk Univ, Astrophys Res & Applicat Ctr ATASAM, TR-25240 Erzurum, Turkey.
   [Yesilyaprak, C.] Ataturk Univ, Fac Sci, Dept Astron & Astrophys, TR-25240 Erzurum, Turkey.
   [Puskullu, C.; Kabas, A.; Demircan, O.] Canakkale Onsekiz Mart Univ, ARC, Canakkale, Turkey.
   [Puskullu, C.; Kabas, A.; Demircan, O.] Ulupinar Observ UPO, Canakkale, Turkey.
   [Alikakos, J.; Charmandaris, V.] Natl Observ Athens, Inst Astron Astrophys Space Applicat & Remote Sen, GR-15236 Penteli, Greece.
   [Charmandaris, V.] Univ Crete, Dept Phys, GR-71003 Iraklion, Greece.
   [Leto, G.] INAF Catania Astrophys Observ, Via Santa Sofia 78, I-95123 Catania, Italy.
   [Ohlert, J.] Astron Stiftung Trebur, Michael Adrian Observatorium, Fichtenstr 7, D-65468 Trebur, Germany.
   [Ohlert, J.] Univ Appl Sci, Tech Hsch Mittelhessen, Wilhelm Leuschner Str 13, D-61169 Friedberg, Germany.
   [Marciniak, A.; Bartczak, P.; Santana-Ros, T.; Utkiewicz-Bak, M. B.; Dudzinski, G.] Adam Mickiewicz Univ, Fac Phys, Astron Observ Inst, Sloneczna 36, PL-60286 Poznan, Poland.
   [Gazeas, K.; Zouganatos, L. T.] Natl & Kapodistrian Univ Athens, Dept Phys, Sect Astrophys Astron & Mech, GR-15784 Athens, Greece.
   [Paschalis, N.] Nunki Observ, Skiathos Isl 37002, Greece.
   [Tsamis, V.] Ellinogermaniki Agogi Observ, Dimitriou Panagea St, GR-15351 Athens, Greece.
   [Sanchez-Lavega, A.; Perez-Hoyos, S.; Hueso, R.] Univ Pais Vasco UPV EHU, Escuela Ingn Bilbao, Dept Fis Aplicada 1, Plaza Torres Quevedo 1, Bilbao 48013, Spain.
   [Guirado, J. C. .; Peris, V.] Univ Valencia, Observ Astron, Catedrat Jose Beltran 2, Paterna 46980, Spain.
   [Guirado, J. C. .] Univ Valencia, Dept Astron & Astrofis, Calle Dr Moliner 50, E-46100 Burjassot, Spain.
   [Iglesias-Marzoa, R.] Ctr Estudios Fis Cosmos Aragon, Plaza San Juan 1,2 Planta, Teruel 44001, Spain.
   [Iglesias-Marzoa, R.] Univ La Laguna, Dept Astrofis, Ave Astrofis Fco Sanchez, San Cristobal la Laguna 38200, Spain.
C3 Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Astrofisica de Andalucia (IAA); Universite PSL; Observatoire de Paris; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); Universite Paris Cite; Ministerio da Ciencia, Tecnologia e Inovacao (MCTIC); University of Munich; Max Planck Society; University of Padua; Istituto Nazionale Astrofisica (INAF); University of Padua; University of Padua; Hungarian Academy of Sciences; HUN-REN; HUN-REN Research Centre for Astronomy & Earth Sciences; Konkoly Thege Miklos Astronomical Institute; Slovak Academy of Sciences; Astronomical Institute, SAS; Czech Academy of Sciences; Astronomical Institute of the Czech Academy of Sciences; Helmholtz Association; German Aerospace Centre (DLR); Universitat d'Alacant; Universitat d'Alacant; University of Zagreb; Rudjer Boskovic Institute; European Southern Observatory; Sorbonne Universite; Universite PSL; Observatoire de Paris; Laboratorio Interinstitucional de e-Astronomia (LINEA); Universidade Federal do Rio de Janeiro; University of Geneva; Universidad de Huelva; Ege University; Adiyaman University; Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK); Akdeniz University; Ataturk University; Ataturk University; Ataturk University; Canakkale Onsekiz Mart University; National Observatory of Athens; University of Crete; Istituto Nazionale Astrofisica (INAF); Adam Mickiewicz University; National & Kapodistrian University of Athens; University of Basque Country; University of Valencia; University of Valencia; Universidad de la Laguna
RP Ortiz, JL (corresponding author), CSIC, Inst Astrofis Andalucia, Glorieta Astron S-N, E-18008 Granada, Spain.
EM ortiz@iaa.es
FU Spanish and Andalusian grants [MINECO AYA-2014-56637-C2-1-P, 2012-FQM1776]; FEDER funds; European Union's Horizon 2020 Research and Innovation Programme [687378]; French grants 'Beyond Neptune' [ANR-08-BLAN-0177]; French grants 'Beyond Neptune II' [ANR-11-1S56-0002]; European Research Council under the European Community's H2020 [669416]; Hungarian Academy of Sciences [LP2012-31]; National Research, Development and Innovation Office (NKFIH) [K-125015]; CAPES; CNPq; FAPERJ; Generalitat Valenciana [PROMETEOII/2014/057]; Shoemaker NEO Grant from The Planetary Society; Fondazione CRT; Slovakian project ITMS [26220120029];  [AYA2015-63939-C2-2-P];  [RVO:67985815]; European Research Council (ERC) [669416] Funding Source: European Research Council (ERC); Agence Nationale de la Recherche (ANR) [ANR-08-BLAN-0177] Funding Source: Agence Nationale de la Recherche (ANR)
NR 46
TC 193
Z9 218
U1 6
U2 57
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 12
PY 2017
VL 550
IS 7675
BP 219
EP +
DI 10.1038/nature24051
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FJ5YG
UT WOS:000412829500041
PM 29022593
DA 2026-03-09
ER

PT J
AU Peng, Y
   Zhang, M
   Zheng, LJ
   Liang, Q
   Li, HZ
   Chen, JT
   Guo, HY
   Oshina, SY
   Chen, YZ
   Zhao, X
   Wu, XQ
   Liu, B
   Mitani, S
   Yu, JS
   Xue, D
AF Peng, Yu
   Zhang, Man
   Zheng, Lingjun
   Liang, Qian
   Li, Hanzeng
   Chen, Jeng-Ting
   Guo, Hongyan
   Oshina, Sawako Y.
   Chen, Yu-Zen
   Zhao, Xiang
   Wu, Xiaoqi
   Liu, Bin
   Mitani, Shohei
   Yu, Jau-Song
   Xue, Ding
TI Cysteine protease cathepsin B mediates radiation-induced bystander effects
SO NATURE
LA English
DT Article
ID damage-induced apoptosis; caenorhabditis-elegans; c-elegans; cancer-therapy; dna-damage; life-span; p53; homolog; proliferation; irradiation
AB The radiation-induced bystander effect (RIBE) refers to a unique process in which factors released by irradiated cells or tissues exert effects on other parts of the animal not exposed to radiation, causing genomic instability, stress responses and altered apoptosis or cell proliferation(1-3). Although RIBEs have important implications for radioprotection, radiation safety and radiotherapy, the molecular identities of RIBE factors and their mechanisms of action remain poorly understood. Here we use Caenorhabditis elegans as a model in which to study RIBEs, and identify the cysteine protease CPR4, a homologue of human cathepsin B, as the first RIBE factor in nematodes, to our knowledge. CPR-4 is secreted from animals irradiated with ultraviolet or ionizing gamma rays, and is the major factor in the conditioned medium that leads to the inhibition of cell death and increased embryonic lethality in unirradiated animals. Moreover, CPR-4 causes these effects and stress responses at unexposed sites distal to the irradiated tissue. The activity of CPR-4 is regulated by the p53 homologue CEP-1 in response to radiation, and CPR-4 seems to exert RIBEs by acting through the insulin-like growth factor receptor DAF-2. Our study provides crucial insights into RIBEs, and will facilitate the identification of additional RIBE factors and their mechanisms of action.
C1 [Peng, Yu; Zhang, Man; Liang, Qian; Guo, Hongyan; Zhao, Xiang; Xue, Ding] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China.
   [Peng, Yu; Zhang, Man; Liang, Qian; Guo, Hongyan; Zhao, Xiang; Xue, Ding] Tsinghua Univ, Collaborat Innovat Ctr Diag & Treatment Infect Di, Beijing 100084, Peoples R China.
   [Zheng, Lingjun; Li, Hanzeng; Chen, Yu-Zen; Wu, Xiaoqi; Xue, Ding] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA.
   [Zheng, Lingjun; Wu, Xiaoqi; Liu, Bin] Fujian Agr & Forestry Univ, Coll Food Sci, Fuzhou 350002, Fujian, Peoples R China.
   [Chen, Jeng-Ting; Yu, Jau-Song] Chang Gung Univ, Coll Med, Grad Inst Biomed Sci, Taoyuan 333, Taiwan.
   [Chen, Jeng-Ting; Yu, Jau-Song] Chang Gung Mem Hosp Linkou, Liver Res Ctr, Taoyuan 333, Taiwan.
   [Oshina, Sawako Y.; Mitani, Shohei] Tokyo Womens Med Univ, Sch Med, Dept Physiol, Tokyo 1628666, Japan.
   [Oshina, Sawako Y.; Mitani, Shohei] Japan Sci & Technol Agcy JST, CREST, Tokyo 1628666, Japan.
C3 Tsinghua University; Collaborative Innovation Center for Diagnosis & Treatment of Infectious Diseases; Tsinghua University; University of Colorado System; University of Colorado Boulder; Fujian Agriculture & Forestry University; Chang Gung University; Chang Gung Memorial Hospital; Tokyo Women's Medical University; Japan Science & Technology Agency (JST)
RP Xue, D (corresponding author), Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China.; Xue, D (corresponding author), Tsinghua Univ, Collaborat Innovat Ctr Diag & Treatment Infect Di, Beijing 100084, Peoples R China.; Xue, D (corresponding author), Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA.
EM ding.xue@colorado.edu
FU National Basic Research Program of China [2013CB945602]; National Scientific and Technological Major Project of China [2013ZX10002-002]; China Scholarship Council; Fujian Agriculture and Forestry University; Tsinghua University-Peking University Center for Life Sciences; NIH [R35 GM118188]; Grants-in-Aid for Scientific Research [17K18135, 16H05123] Funding Source: KAKEN; National Institute of General Medical Sciences [R35GM118188] Funding Source: NIH RePORTER
NR 39
TC 62
Z9 77
U1 7
U2 163
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 27
PY 2017
VL 547
IS 7664
BP 458
EP +
DI 10.1038/nature23284
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB7ZK
UT WOS:000406358300037
PM 28723894
DA 2026-03-09
ER

PT J
AU Farnung, L
   Vos, SM
   Wigge, C
   Cramer, P
AF Farnung, Lucas
   Vos, Seychelle M.
   Wigge, Christoph
   Cramer, Patrick
TI Nucleosome-Chd1 structure and implications for chromatin remodelling
SO NATURE
LA English
DT Article
ID recombinant histones; chd1; complex; translocation; binding; protein; chromodomain; mechanisms; contains; biology
AB Chromatin-remodelling factors change nucleosome positioning and facilitate DNA transcription, replication, and repair(1). The conserved remodelling factor chromodomain-helicase-DNA binding protein 1 (Chd1)(2) can shift nucleosomes and induce regular nucleosome spacing(3-5). Chd1 is required for the passage of RNA polymerase II through nucleosomes(6) and for cellular pluripotency(7). Chd1 contains the DNA-binding domains SANT and SLIDE, a bilobal motor domain that hydrolyses ATP, and a regulatory double chromodomain. Here we report the cryo-electron microscopy structure of Chd1 from the yeast Saccharomyces cerevisiae bound to a nucleosome at a resolution of 4.8 angstrom. Chd1 detaches two turns of DNA from the histone octamer and binds between the two DNA gyres in a state poised for catalysis. The SANT and SLIDE domains contact detached DNA around superhelical location (SHL) -7 of the first DNA gyre. The ATPase motor binds the second DNA gyre at SHL +2 and is anchored to the N-terminal tail of histone H4, as seen in a recent nucleosome-Snf2 ATPase structure(8). Comparisons with published results(9) reveal that the double chromodomain swings towards nucleosomal DNA at SHL +1, resulting in ATPase closure. The ATPase can then promote translocation of DNA towards the nucleosome dyad, thereby loosening the first DNA gyre and remodelling the nucleosome. Translocation may involve ratcheting of the two lobes of the ATPase, which is trapped in a pre-or post-translocation state in the absence(8) or presence, respectively, of transition state-mimicking compounds.
C1 [Farnung, Lucas; Vos, Seychelle M.; Wigge, Christoph; Cramer, Patrick] Max Planck Inst Biophys Chem, Dept Mol Biol, Fassberg 11, D-37077 Gottingen, Germany.
C3 Max Planck Society
RP Cramer, P (corresponding author), Max Planck Inst Biophys Chem, Dept Mol Biol, Fassberg 11, D-37077 Gottingen, Germany.
EM pcramer@mpibpc.mpg.de
FU EMBO Long-Term-Fellowship [ALTF 745-2014]; Deutsche Forschungsgemeinschaft [SFB860, SPP1935]; European Research Council Advanced Investigator Grant TRANSREGULON [693023]; Volkswagen Foundation
NR 52
TC 187
Z9 221
U1 2
U2 42
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 26
PY 2017
VL 550
IS 7677
BP 539
EP +
DI 10.1038/nature24046
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK7OW
UT WOS:000413697800047
PM 29019976
DA 2026-03-09
ER

PT J
AU Maddocks, ODK
   Athineos, D
   Cheung, EC
   Lee, P
   Zhang, T
   van den Broek, NJF
   Mackay, GM
   Labuschagne, CF
   Gay, D
   Kruiswijk, F
   Blagih, J
   Vincent, DF
   Campbell, KJ
   Ceteci, F
   Sansom, OJ
   Blyth, K
   Vousden, KH
AF Maddocks, Oliver D. K.
   Athineos, Dimitris
   Cheung, Eric C.
   Lee, Pearl
   Zhang, Tong
   van den Broek, Niels J. F.
   Mackay, Gillian M.
   Labuschagne, Christiaan F.
   Gay, David
   Kruiswijk, Flore
   Blagih, Julianna
   Vincent, David F.
   Campbell, Kirsteen J.
   Ceteci, Fatih
   Sansom, Owen J.
   Blyth, Karen
   Vousden, Karen H.
TI Modulating the therapeutic response of tumours to dietary serine and glycine starvation
SO NATURE
LA English
DT Article
ID multiple intestinal neoplasia; pyruvate-kinase m2; cell lung-cancer; pancreatic-cancer; metabolism; metformin; proliferation; tigar; mice; ros
AB The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis(2-4), many others rely on exogenous serine for optimal growth(5-7). Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models(7,8). Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.
C1 [Maddocks, Oliver D. K.; Athineos, Dimitris; Cheung, Eric C.; Lee, Pearl; van den Broek, Niels J. F.; Mackay, Gillian M.; Labuschagne, Christiaan F.; Gay, David; Kruiswijk, Flore; Blagih, Julianna; Vincent, David F.; Campbell, Kirsteen J.; Ceteci, Fatih; Sansom, Owen J.; Blyth, Karen; Vousden, Karen H.] Canc Res UK, Beatson Inst, Switchback Rd, Glasgow G61 1BD, Lanark, Scotland.
   [Maddocks, Oliver D. K.; Zhang, Tong; Sansom, Owen J.] Univ Glasgow, Inst Canc Sci, Switchback Rd, Glasgow G61 1QH, Lanark, Scotland.
   [Lee, Pearl] Abrahamson Family Canc Res Inst, 421 Curie Blvd, Philadelphia, PA 19104 USA.
   [Ceteci, Fatih] Georg Speyer Haus, Inst Tumor Biol & Expt Therapy, Paul Ehrlich Str 42-44, D-60596 Frankfurt, Germany.
   [Vousden, Karen H.] Crick Inst, 1 Midland Rd, London NW1 1AT, England.
C3 Beatson Institute; Cancer Research UK; University of Glasgow; Octapharma; Francis Crick Institute
RP Maddocks, ODK; Vousden, KH (corresponding author), Canc Res UK, Beatson Inst, Switchback Rd, Glasgow G61 1BD, Lanark, Scotland.
EM oliver.maddocks@glasgow.ac.uk; karen.vousden@crick.ac.uk
FU Cancer Research UK [C596/A10419]; ERC [322842-METABOp53, 311301]; CRUK Career Development Fellowship [C53309/A19702]; CRUK; Cancer Research UK [18274, 22311] Funding Source: researchfish; The Francis Crick Institute [10557] Funding Source: researchfish; Versus Arthritis; Cancer Research UK [21139] Funding Source: researchfish; Versus Arthritis; Cancer Research UK [19702] Funding Source: researchfish; European Research Council (ERC) [311301] Funding Source: European Research Council (ERC)
NR 44
TC 471
Z9 551
U1 8
U2 171
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 20
PY 2017
VL 544
IS 7650
BP 372
EP +
DI 10.1038/nature22056
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ES4SG
UT WOS:000399524400041
PM 28425994
DA 2026-03-09
ER

PT J
AU Wylie, AA
   Schoepfer, J
   Jahnke, W
   Cowan-Jacob, SW
   Loo, A
   Furet, P
   Marzinzik, AL
   Pelle, X
   Donovan, J
   Zhu, WJ
   Buonamici, S
   Hassan, AQ
   Lombardo, F
   Iyer, V
   Palmer, M
   Berellini, G
   Dodd, S
   Thohan, S
   Bitter, H
   Branford, S
   Ross, DM
   Hughes, TP
   Petruzzelli, L
   Vanasse, KG
   Warmuth, M
   Hofmann, F
   Keen, NJ
   Sellers, WR
AF Wylie, Andrew A.
   Schoepfer, Joseph
   Jahnke, Wolfgang
   Cowan-Jacob, Sandra W.
   Loo, Alice
   Furet, Pascal
   Marzinzik, Andreas L.
   Pelle, Xavier
   Donovan, Jerry
   Zhu, Wenjing
   Buonamici, Silvia
   Hassan, A. Quamrul
   Lombardo, Franco
   Iyer, Varsha
   Palmer, Michael
   Berellini, Giuliano
   Dodd, Stephanie
   Thohan, Sanjeev
   Bitter, Hans
   Branford, Susan
   Ross, David M.
   Hughes, Timothy P.
   Petruzzelli, Lilli
   Vanasse, K. Gary
   Warmuth, Markus
   Hofmann, Francesco
   Keen, Nicholas J.
   Sellers, William R.
TI The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1
SO NATURE
LA English
DT Article
ID chronic myeloid-leukemia; bcr-abl; imatinib; therapy; binding; cml
AB Chronic myeloid leukaemia (CML) is driven by the activity of the BCR-ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of patients treated with imatinib surviving for more than 10 years(1). Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML2. Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR-ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment(3,4). Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib. Consistent with this profile, acquired resistance was observed with single-agent therapy in mice; however, the combination of ABL001 and nilotinib led to complete disease control and eradicated CML xenograft tumours without recurrence after the cessation of treatment.
C1 [Wylie, Andrew A.; Loo, Alice; Donovan, Jerry; Zhu, Wenjing; Buonamici, Silvia; Hassan, A. Quamrul; Lombardo, Franco; Palmer, Michael; Berellini, Giuliano; Dodd, Stephanie; Thohan, Sanjeev; Bitter, Hans; Petruzzelli, Lilli; Vanasse, K. Gary; Warmuth, Markus; Keen, Nicholas J.; Sellers, William R.] Novartis Inst BioMed Res, Cambridge, MA 02139 USA.
   [Schoepfer, Joseph; Jahnke, Wolfgang; Cowan-Jacob, Sandra W.; Furet, Pascal; Marzinzik, Andreas L.; Pelle, Xavier; Iyer, Varsha; Hofmann, Francesco] Novartis Inst BioMed Res, Basel, Switzerland.
   [Branford, Susan] SA Pathol, Ctr Canc Biol, Adelaide, SA 5000, Australia.
   [Branford, Susan] Univ South Australia, Adelaide, SA 5000, Australia.
   [Ross, David M.] SA Pathol, Haematol Directorate, POB 14,Rundle Mall, Adelaide, SA 5000, Australia.
   [Hughes, Timothy P.] SAHMRI, North Terrace, Adelaide, SA 5000, Australia.
   [Buonamici, Silvia; Warmuth, Markus] H3 Biomed Target Biol, 300 Technol Sq, Cambridge, MA 02139 USA.
C3 Novartis; Novartis USA; Novartis; SA Pathology; Centre for Cancer Biology; Adelaide University; University of South Australia; SA Pathology; South Australian Health & Medical Research Institute (SAHMRI)
RP Wylie, AA (corresponding author), Novartis Inst BioMed Res, Cambridge, MA 02139 USA.
EM andrew.wylie@novartis.com
NR 20
TC 480
Z9 550
U1 3
U2 157
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 30
PY 2017
VL 543
IS 7647
BP 733
EP +
DI 10.1038/nature21702
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EP8IS
UT WOS:000397619700059
PM 28329763
DA 2026-03-09
ER

PT J
AU He, KM
   Marsland, R
   Upadhyayula, S
   Song, E
   Dang, S
   Capraro, BR
   Wang, WM
   Skillern, W
   Gaudin, R
   Ma, MH
   Kirchhausen, T
AF He, Kangmin
   Marsland, Robert, III
   Upadhyayula, Srigokul
   Song, Eli
   Dang, Song
   Capraro, Benjamin R.
   Wang, Weiming
   Skillern, Wesley
   Gaudin, Raphael
   Ma, Minghe
   Kirchhausen, Tom
TI Dynamics of phosphoinositide conversion in clathrin-mediated endocytic traffic
SO NATURE
LA English
DT Article
ID phosphatidylinositol 4-phosphate; lowe-syndrome; coated pits; auxilin; cell; recruitment; reveals; 5-phosphatase; 3-phosphate; metabolism
AB Vesicular carriers transport proteins and lipids from one organelle to another, recognizing specific identifiers for the donor and acceptor membranes. Two important identifiers are phosphoinositides and GTP-bound GTPases, which provide well-defined but mutable labels. Phosphatidylinositol and its phosphorylated derivatives are present on the cytosolic faces of most cellular membranes(1,2). Reversible phosphorylation of its headgroup produces seven distinct phosphoinositides. In endocytic traffic, phosphatidylinositol-4,5-biphosphate marks the plasma membrane, and phosphatidylinositol-3-phosphate and phosphatidylinositol-4-phosphate mark distinct endosomal compartments(2,3). It is unknown what sequence of changes in lipid content confers on the vesicles their distinct identity at each intermediate step. Here we describe 'coincidence-detecting' sensors that selectively report the phosphoinositide composition of clathrin-associated structures, and the use of these sensors to follow the dynamics of phosphoinositide conversion during endocytosis. The membrane of an assembling coated pit, in equilibrium with the surrounding plasma membrane, contains phosphatidylinositol-4,5-biphosphate and a smaller amount of phosphatidylinositol-4-phosphate. Closure of the vesicle interrupts free exchange with the plasma membrane. A substantial burst of phosphatidylinositol-4-phosphate immediately after budding coincides with a burst of phosphatidylinositol-3-phosphate, distinct from any later encounter with the phosphatidylinositol-3-phosphate pool in early endosomes; phosphatidylinositol-3,4-biphosphate and the GTPase Rab5 then appear and remain as the uncoating vesicles mature into Rab5-positive endocytic intermediates. Our observations show that a cascade of molecular conversions, made possible by the separation of a vesicle from its parent membrane, can label membrane-traffic intermediates and determine their destinations.
C1 [He, Kangmin; Upadhyayula, Srigokul; Capraro, Benjamin R.; Wang, Weiming; Gaudin, Raphael; Kirchhausen, Tom] Harvard Med Sch, Dept Cell Biol, 200 Longwood Ave, Boston, MA 02115 USA.
   [He, Kangmin; Upadhyayula, Srigokul; Song, Eli; Dang, Song; Capraro, Benjamin R.; Wang, Weiming; Skillern, Wesley; Gaudin, Raphael; Ma, Minghe; Kirchhausen, Tom] Boston Childrens Hosp, Program Cellular & Mol Med, 200 Longwood Ave, Boston, MA 02115 USA.
   [He, Kangmin; Upadhyayula, Srigokul; Kirchhausen, Tom] Harvard Med Sch, Dept Pediat, 200 Longwood Ave, Boston, MA 02115 USA.
   [Marsland, Robert, III] MIT, Phys Living Syst Grp, 400 Technol Sq, Cambridge, MA 02139 USA.
   [Marsland, Robert, III] Boston Univ, Dept Phys, 590 Commonwealth Ave, Boston, MA 02215 USA.
   [Song, Eli] Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Natl Lab Biomacromol, Beijing 100101, Peoples R China.
   [Gaudin, Raphael] INSERM, U1110, Inst Viral & Liver Dis, 3 Rue Koeberle, F-67000 Strasbourg, France.
C3 Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Program in Cellular & Molecular Medicine (PCMM); Harvard University; Harvard Medical School; Massachusetts Institute of Technology (MIT); Boston University; Chinese Academy of Sciences; Institute of Biophysics, CAS; Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Institut National de la Sante et de la Recherche Medicale (Inserm)
RP He, KM; Kirchhausen, T (corresponding author), Harvard Med Sch, Dept Cell Biol, 200 Longwood Ave, Boston, MA 02115 USA.; He, KM; Kirchhausen, T (corresponding author), Boston Childrens Hosp, Program Cellular & Mol Med, 200 Longwood Ave, Boston, MA 02115 USA.; He, KM; Kirchhausen, T (corresponding author), Harvard Med Sch, Dept Pediat, 200 Longwood Ave, Boston, MA 02115 USA.
EM Kangmin.He@childrens.harvard.edu; kirchhausen@crystal.harvard.edu
FU National Defense Science and Engineering Graduate (NDSEG) Fellowship from the DoD Air Force Office of Scientific Research; National Natural Science Foundation of China [31770900, 31270884, 30900268]; Beijing Natural Science Foundation [5122026, 5092017]; Youth Innovation Promotion Association of the Chinese Academy of Sciences [2011087]; NIH [GM103792, NIH R01 GM075252]; Janelia Visitor Program; Biogen; Ionis Pharmaceuticals
NR 47
TC 115
Z9 132
U1 2
U2 92
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 21
PY 2017
VL 552
IS 7685
BP 410
EP +
DI 10.1038/nature25146
PG 28
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ7RI
UT WOS:000418559800060
PM 29236694
DA 2026-03-09
ER

PT J
AU Dodd, D
   Spitzer, MH
   Van Treuren, W
   Merrill, BD
   Hryckowian, AJ
   Higginbottom, SK
   Le, A
   Cowan, TM
   Nolan, GP
   Fischbach, MA
   Sonnenburg, JL
AF Dodd, Dylan
   Spitzer, Matthew H.
   Van Treuren, William
   Merrill, Bryan D.
   Hryckowian, Andrew J.
   Higginbottom, Steven K.
   Le, Anthony
   Cowan, Tina M.
   Nolan, Garry P.
   Fischbach, Michael A.
   Sonnenburg, Justin L.
TI A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites
SO NATURE
LA English
DT Article
ID mass cytometry; immune
AB The human gut microbiota produces dozens of metabolites that accumulate in the bloodstream(1,2), where they can have systemic effects on the host. Although these small molecules commonly reach concentrations similar to those achieved by pharmaceutical agents, remarkably little is known about the microbial metabolic pathways that produce them. Here we use a combination of genetics and metabolic profiling to characterize a pathway from the gut symbiont Clostridium sporogenes that generates aromatic amino acid metabolites. Our results reveal that this pathway produces twelve compounds, nine of which are known to accumulate in host serum. All three aromatic amino acids (tryptophan, phenylalanine and tyrosine) serve as substrates for the pathway, and it involves branching and alternative reductases for specific intermediates. By genetically manipulating C. sporogenes, we modulate serum levels of these metabolites in gnotobiotic mice, and show that in turn this affects intestinal permeability and systemic immunity. This work has the potential to provide the basis of a systematic effort to engineer the molecular output of the gut bacterial community.
C1 [Dodd, Dylan; Spitzer, Matthew H.; Le, Anthony; Cowan, Tina M.] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA.
   [Dodd, Dylan; Spitzer, Matthew H.; Van Treuren, William; Merrill, Bryan D.; Hryckowian, Andrew J.; Higginbottom, Steven K.; Nolan, Garry P.; Sonnenburg, Justin L.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA.
   [Fischbach, Michael A.] Univ Calif San Francisco, California Inst Quantitat Biosci, San Francisco, CA 94143 USA.
   [Fischbach, Michael A.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA.
   [Spitzer, Matthew H.] Univ Calif San Francisco, Parker Inst Canc Immunotherapy, Helen Diller Family Comprehens Canc Ctr, Dept Microbiol & Immunol, San Francisco, CA 94143 USA.
   [Fischbach, Michael A.] Stanford Univ, Dept Bioengn & ChEM H, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; Stanford University
RP Sonnenburg, JL (corresponding author), Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA.; Fischbach, MA (corresponding author), Univ Calif San Francisco, California Inst Quantitat Biosci, San Francisco, CA 94143 USA.; Fischbach, MA (corresponding author), Stanford Univ, Dept Bioengn & ChEM H, Stanford, CA 94305 USA.
EM fischbach@fischbachgroup.org; jsonnenburg@stanford.edu
FU National Institutes of Health NIDDK [R01-DK101674]; NIH [DP2-OD006515, U19AI057229, U19AI100627, R33CA183654, R33CA0183692, R01GM10983601, R01CA184968, R01CA19665701, R21CA183660, R01NS08953301, 5UH2AR067676, R01HL120724, DP5-OD023056]; FDA [BAA-12-00118]; Department of Defence [OC110674, W81XWH-14-1-0 180]; Gates Foundation [OPP1113682, DP1 DK113598, R01 DK110174]; HHMI-Simons Faculty Scholars Award; Byers Award in Basic Science; David and Lucile Packard Foundation; BASF research grant; Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease Awards; NIH postdoctoral NRSA [T32-AI007328]; National Science Foundation [DGE-114747]; National Institute of Allergy and Infectious Diseases [U19AI100627, T32AI007328] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK085025, R01DK101674] Funding Source: NIH RePORTER
NR 26
TC 1042
Z9 1191
U1 28
U2 569
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 30
PY 2017
VL 551
IS 7682
BP 648
EP +
DI 10.1038/nature24661
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FO1KW
UT WOS:000416520400047
PM 29168502
DA 2026-03-09
ER

PT J
AU Usinowicz, J
   Chang-Yang, CH
   Chen, YY
   Clark, JS
   Fletcher, C
   Garwood, NC
   Hao, ZQ
   Johnstone, J
   Lin, YC
   Metz, MR
   Masaki, T
   Nakashizuka, T
   Sun, IF
   Valencia, R
   Wang, YY
   Zimmerman, JK
   Ives, AR
   Wright, SJ
AF Usinowicz, Jacob
   Chang-Yang, Chia-Hao
   Chen, Yu-Yun
   Clark, James S.
   Fletcher, Christine
   Garwood, Nancy C.
   Hao, Zhanqing
   Johnstone, Jill
   Lin, Yiching
   Metz, Margaret R.
   Masaki, Takashi
   Nakashizuka, Tohru
   Sun, I-Fang
   Valencia, Renato
   Wang, Yunyun
   Zimmerman, Jess K.
   Ives, Anthony R.
   Wright, S. Joseph
TI Temporal coexistence mechanisms contribute to the latitudinal gradient in forest diversity
SO NATURE
LA English
DT Article
ID neotropical rain-forest; species-diversity; tropical forests; seed production; maintenance; predictions; competition; community; richness; dynamics
AB The tropical forests of Borneo and Amazonia may each contain more tree species diversity in half a square kilometre than do all the temperate forests of Europe, North America, and Asia combined(1). Biologists have long been fascinated by this disparity, using it to investigate potential drivers of biodiversity(2). Latitudinal variation in many of these drivers is expected to create geographic differences in ecological(2-4) and evolutionary processes(4,5), and evidence increasingly shows that tropical ecosystems have higher rates of diversification, clade origination, and clade dispersal(5,6). However, there is currently no evidence to link gradients in ecological processes within communities at a local scale directly to the geographic gradient in biodiversity. Here, we show geographic variation in the storage effect, an ecological mechanism that reduces the potential for competitive exclusion more strongly in the tropics than it does in temperate and boreal zones, decreasing the ratio of interspecific-to-intraspecific competition by 0.25% for each degree of latitude that an ecosystem is located closer to the Equator. Additionally, we find evidence that latitudinal variation in climate underpins these differences; longer growing seasons in the tropics reduce constraints on the seasonal timing of reproduction, permitting lower recruitment synchrony between species and thereby enhancing niche partitioning through the storage effect. Our results demonstrate that the strength of the storage effect, and therefore its impact on diversity within communities, varies latitudinally in association with climate. This finding highlights the importance of biotic interactions in shaping geographic diversity patterns, and emphasizes the need to understand the mechanisms underpinning ecological processes in greater detail than has previously been appreciated.
C1 [Usinowicz, Jacob; Ives, Anthony R.] Univ Wisconsin, Dept Integrat Biol, Madison, WI 53706 USA.
   [Chang-Yang, Chia-Hao; Chen, Yu-Yun; Sun, I-Fang] Natl Doug Hwa Univ, Dept Nat Resources & Environm Studies, Hualien, Taiwan.
   [Clark, James S.] Duke Univ, Nicholas Sch Environm, Durham, NC 27708 USA.
   [Fletcher, Christine] Forest Res Inst Malaysia, Kuala Lumpur, Malaysia.
   [Garwood, Nancy C.] Southern Illinois Univ, Dept Plant Biol, Carbondale, IL USA.
   [Hao, Zhanqing; Wang, Yunyun] Chinese Acad Sci, Inst Appl Ecol, Inst CAS Key Lab Forest Ecol & Management, Shenyang, Liaoning, Peoples R China.
   [Johnstone, Jill] Univ Alaska Fairbanks, Inst Arctic Biol, Fairbanks, AK USA.
   [Lin, Yiching] Tunghai Univ, Dept Life Sci, Taichung, Taiwan.
   [Metz, Margaret R.] Lewis & Clark Coll, Dept Biol, Portland, OR 97219 USA.
   [Masaki, Takashi] Forestry & Forest Prod Res Inst, Tsukuba, Ibaraki, Japan.
   [Nakashizuka, Tohru] Tohoku Univ, Grad Sch Life Sci, Sendai, Miyagi, Japan.
   [Nakashizuka, Tohru] Res Inst Humanity & Nat, Kyoto, Japan.
   [Valencia, Renato] Pontificia Univ Catolica Ecuador, Herbario QCA, Lab Ecol Plantas, Quito, Ecuador.
   [Zimmerman, Jess K.; Wright, S. Joseph] Univ Puerto Rico Rio Piedras, Dept Environm Sci, San Juan, PR USA.
   [Wright, S. Joseph] Smithsonian Trop Res Inst, Apartado 0843-03092, Balboa, Panama.
C3 University of Wisconsin System; University of Wisconsin Madison; Duke University; Institute Penyelidikan Perhutanan Malaysia; Southern Illinois University System; Southern Illinois University; Chinese Academy of Sciences; Shenyang Institute of Applied Ecology, CAS; University of Alaska System; University of Alaska Fairbanks; Tunghai University; Lewis & Clark College; Forestry & Forest Products Research Institute - Japan; Tohoku University; Research Institute for Humanity & Nature (RIHN); Pontificia Universidad Catolica del Ecuador; University of Puerto Rico; University of Puerto Rico Rio Piedras; Smithsonian Institution; Smithsonian Tropical Research Institute
RP Usinowicz, J (corresponding author), Univ Wisconsin, Dept Integrat Biol, Madison, WI 53706 USA.
EM jacob.usinwicz@usys.ethz.ch
FU Andrew M. Mellon Foundation; Center for Tropical Forest Science; Environment Research and Technology Development Fund of the Japan Ministry of the Environment; JSPS KAKENHI; National Key Research and Development Program of China; National Natural Science Foundation of China; National Science Foundation of the United States (DDIG); National Science Foundation of the United States (IGERT); National Science Foundation of the United States (LTER); National Science Foundation of the United States (LTREB); Natural Environment Research Council of the UK; Natural History Museum of London; Smithsonian Tropical Research Institute; Taiwan Forestry Bureau; Taiwan Forestry Research Institute; Taiwan Ministry of Science and Technology; USDA Forest Service; Grants-in-Aid for Scientific Research [15H04517] Funding Source: KAKEN; Direct For Biological Sciences; Division Of Environmental Biology [1122325, 1122634] Funding Source: National Science Foundation; Direct For Biological Sciences; Emerging Frontiers [1550911] Funding Source: National Science Foundation; Emerging Frontiers; Direct For Biological Sciences [1550907] Funding Source: National Science Foundation
NR 36
TC 100
Z9 121
U1 2
U2 220
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 5
PY 2017
VL 550
IS 7674
BP 105
EP +
DI 10.1038/nature24038
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI7XU
UT WOS:000412214100054
PM 28953870
DA 2026-03-09
ER

PT J
AU Zabala-Letona, A
   Arruabarrena-Aristorena, A
   Martín-Martín, N
   Fernandez-Ruiz, S
   Sutherland, JD
   Clasquin, M
   Tomas-Cortazar, J
   Jimenez, J
   Torres, I
   Quang, P
   Ximenez-Embun, P
   Bago, R
   Galde-Olano, AU
   Oizaga-Iriarte, AL
   Acasa-Viscasillas, IL
   Nda, MU
   Torrano, V
   Cabrera, D
   van Liempd, SM
   Cendon, Y
   Castro, E
   Murray, S
   Revandkar, A
   Alimonti, A
   Zhang, YN
   Barnett, A
   Lein, G
   Pirman, D
   Cortazar, AR
   Arreal, L
   Prudkin, L
   Astobiza, I
   Valcarcel-Jimenez, L
   Zuñiga-García, P
   Fernandez-Dominguez, I
   Piva, M
   Caro-Maldonado, A
   Sánchez-Mosquera, P
   Castillo-Martín, M
   Serra, V
   Beraza, N
   Gentilella, A
   Thomas, G
   Azkargorta, M
   Elortza, F
   Farràs, R
   Olmos, D
   Efeyan, A
   Anguita, J
   Muñoz, J
   Falcón-Pérez, JM
   Barrio, R
   Macarulla, T
   Mato, JM
   Martinez-Chantar, ML
   Cordon-Cardo, C
   Aransay, AM
   Marks, K
   Baselga, J
   Tabernero, J
   Nuciforo, P
   Manning, BD
   Marjon, K
   Carracedo, A
AF Zabala-Letona, Amaia
   Arruabarrena-Aristorena, Amaia
   Martin-Martin, Natalia
   Fernandez-Ruiz, Sonia
   Sutherland, James D.
   Clasquin, Michelle
   Tomas-Cortazar, Julen
   Jimenez, Jose
   Torres, Ines
   Phong Quang
   Ximenez-Embun, Pilar
   Bago, Ruzica
   Galde-Olano, Aitziber U.
   Oizaga-Iriarte, Ana L.
   Acasa-Viscasillas, Isabel L.
   Nda, Miguel U.
   Torrano, Veronica
   Cabrera, Diana
   van Liempd, Sebastiaan M.
   Cendon, Ylenia
   Castro, Elena
   Murray, Stuart
   Revandkar, Ajinkya
   Alimonti, Andrea
   Zhang, Yinan
   Barnett, Amelia
   Lein, Gina
   Pirman, David
   Cortazar, Ana R.
   Arreal, Leire
   Prudkin, Ludmila
   Astobiza, Ianire
   Valcarcel-Jimenez, Lorea
   Zuniga-Garcia, Patricia
   Fernandez-Dominguez, Itziar
   Piva, Marco
   Caro-Maldonado, Alfredo
   Sanchez-Mosquera, Pilar
   Castillo-Martin, Mireia
   Serra, Violeta
   Beraza, Naiara
   Gentilella, Antonio
   Thomas, George
   Azkargorta, Mikel
   Elortza, Felix
   Farras, Rosa
   Olmos, David
   Efeyan, Alejo
   Anguita, Juan
   Munoz, Javier
   Falcon-Perez, Juan M.
   Barrio, Rosa
   Macarulla, Teresa
   Mato, Jose M.
   Martinez-Chantar, Maria L.
   Cordon-Cardo, Carlos
   Aransay, Ana M.
   Marks, Kevin
   Baselga, Jose
   Tabernero, Josep
   Nuciforo, Paolo
   Manning, Brendan D.
   Marjon, Katya
   Carracedo, Arkaitz
TI mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer
SO NATURE
LA English
DT Article
ID s-adenosylmethionine decarboxylase; solid tumors; phase-i; biosynthesis inhibitor; cellular senescence; pten; pathway; cells; growth; leads
AB Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation(1,2). Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model(3) and human biopsies(4) of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus(5) exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.
C1 [Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Martin-Martin, Natalia; Fernandez-Ruiz, Sonia; Sutherland, James D.; Tomas-Cortazar, Julen; Torrano, Veronica; Cabrera, Diana; van Liempd, Sebastiaan M.; Cortazar, Ana R.; Arreal, Leire; Astobiza, Ianire; Valcarcel-Jimenez, Lorea; Zuniga-Garcia, Patricia; Fernandez-Dominguez, Itziar; Piva, Marco; Caro-Maldonado, Alfredo; Sanchez-Mosquera, Pilar; Beraza, Naiara; Azkargorta, Mikel; Elortza, Felix; Anguita, Juan; Falcon-Perez, Juan M.; Barrio, Rosa; Mato, Jose M.; Martinez-Chantar, Maria L.; Aransay, Ana M.; Carracedo, Arkaitz] CIC bioGUNE, Bizkaia Technology Pk,801 Bldg, Derio 48160, Spain.
   [Zabala-Letona, Amaia; Martin-Martin, Natalia; Fernandez-Ruiz, Sonia; Macarulla, Teresa; Tabernero, Josep; Carracedo, Arkaitz] Inst Salud Carlos III, CIBERONC, C Monforte Lemos 3-5,Pabellon 11,Planta 0, Madrid 28029, Spain.
   [Clasquin, Michelle; Phong Quang; Murray, Stuart; Barnett, Amelia; Lein, Gina; Pirman, David; Marjon, Katya] AGIOS Pharmaceut, Cambridge, MA 02139 USA.
   [Jimenez, Jose; Prudkin, Ludmila; Serra, Violeta; Macarulla, Teresa; Tabernero, Josep; Nuciforo, Paolo] Univ Autonoma Barcelona, VHIO, Barcelona 08035, Spain.
   [Torres, Ines] Univ Autonoma Barcelona, ValldHebron Hosp, Dept Pathol, Barcelona 08035, Spain.
   [Ximenez-Embun, Pilar; Cendon, Ylenia; Castro, Elena; Olmos, David; Efeyan, Alejo; Munoz, Javier] Spanish Natl Canc Res Ctr CNIO, Madrid 28029, Spain.
   [Bago, Ruzica] Univ Dundee, Coll Life Sci, MRC Prot Phosphorylat & Ubiquitylat Unit, Dow St, Dundee DD1 5EH, Scotland.
   [Galde-Olano, Aitziber U.] Basurto Univ Hosp, Dept Pathol, Bilbao 48013, Spain.
   [Oizaga-Iriarte, Ana L.; Acasa-Viscasillas, Isabel L.; Nda, Miguel U.] Basurto Univ Hosp, Dept Urol, Bilbao 48013, Spain.
   [Cendon, Ylenia] Univ Autonoma Madrid, Sch Med, Madrid 28049, Spain.
   [Revandkar, Ajinkya; Alimonti, Andrea] IOR, CH-6500 Bellinzona, Switzerland.
   [Revandkar, Ajinkya; Alimonti, Andrea] Oncol Inst Southern Switzerland IOSI, CH-6500 Bellinzona, Switzerland.
   [Alimonti, Andrea] Univ Lausanne UNIL, Fac Biol & Med, CH-1011 Lausanne, Switzerland.
   [Zhang, Yinan; Manning, Brendan D.] Harvard Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA.
   [Castillo-Martin, Mireia; Cordon-Cardo, Carlos] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA.
   [Castillo-Martin, Mireia] Fundacao Champalimaud, Dept Pathol, P-1400038 Lisbon, Portugal.
   [Gentilella, Antonio; Thomas, George] Catalan Inst Oncol, ICO, Bellvitge Biomed Res Inst, IDIBELL,Lab Metab & Canc, Barcelona 08908, Spain.
   [Gentilella, Antonio] Univ Barcelona, Fac Pharm, Dept Biochem & Physiol, Barcelona 08028, Catalunya, Spain.
   [Azkargorta, Mikel; Elortza, Felix] Inst Salud Carlos III, Carlos Networked Prote Platform ProteoRed ISCIII, C Monforte Lemos 3-5,Pabellon 11,Planta 0, Madrid 28029, Spain.
   [Elortza, Felix; Falcon-Perez, Juan M.; Mato, Jose M.; Martinez-Chantar, Maria L.; Aransay, Ana M.] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, C Monforte Lemos 3-5,Pabellon 11,Planta 0, Madrid 28029, Spain.
   [Farras, Rosa] Ctr Invest Principe Felipe, Eduardo Primo Yufera 3, Valencia 46012, Spain.
   [Olmos, David] Hosp Univ Virgen de la Victoria & Reg Malaga, Med Oncol Dept, CNIO IBIMA Genitourinary Canc Unit, Malaga 29010, Spain.
   [Anguita, Juan; Falcon-Perez, Juan M.; Carracedo, Arkaitz] Ikerbasque, Basque Fdn Sci, Bilbao 48011, Spain.
   [Baselga, Jose] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA.
   [Carracedo, Arkaitz] Univ Basque Country UPV EHU, Biochem & Mol Biol Dept, Bilbao 48940, Spain.
   [Beraza, Naiara] Inst Food Res, Gut Hlth & Food Safety Programme, Norwich Res Pk, Norwich NR4 7UA, Norfolk, England.
C3 CIC bioGUNE; Instituto de Salud Carlos III; CIBER - Centro de Investigacion Biomedica en Red; CIBERONC; Agios Pharmaceuticals; Autonomous University of Barcelona; Vall d'Hebron Institut d'Oncologia (VHIO); Autonomous University of Barcelona; Centro Nacional de Investigaciones Oncologicas (CNIO); University of Dundee; Basurto Hospital; Basurto Hospital; Autonomous University of Madrid; Universita della Svizzera Italiana; Institute of Oncology Research (IOR); Institute of Oncology Research (IOR); University of Lausanne; Harvard University; Harvard T.H. Chan School of Public Health; Icahn School of Medicine at Mount Sinai; Fundacao Champalimaud; University of Barcelona; Institut Catala d'Oncologia; Institut d'Investigacio Biomedica de Bellvitge (IDIBELL); University of Barcelona; Instituto de Salud Carlos III; Instituto de Salud Carlos III; CIBER - Centro de Investigacion Biomedica en Red; CIBEREHD; Prince Felipe Research Center; IBIMA Plataforma BIONAND, Instituto de Investigacion Biomedica de Malaga; Basque Foundation for Science; Memorial Sloan Kettering Cancer Center; University of Basque Country; University of East Anglia; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); Quadram Institute
RP Carracedo, A (corresponding author), CIC bioGUNE, Bizkaia Technology Pk,801 Bldg, Derio 48160, Spain.; Carracedo, A (corresponding author), Inst Salud Carlos III, CIBERONC, C Monforte Lemos 3-5,Pabellon 11,Planta 0, Madrid 28029, Spain.; Carracedo, A (corresponding author), Ikerbasque, Basque Fdn Sci, Bilbao 48011, Spain.; Carracedo, A (corresponding author), Univ Basque Country UPV EHU, Biochem & Mol Biol Dept, Bilbao 48940, Spain.
EM acarracedo@cicbiogune.es
FU Ramon y Cajal award; Juan de la Cierva; BFU grant [BFU2014-52282-P, BFU2011-25986]; SAF grant (FEDER/EU) [SAF2016-79381-R]; SAF grant from Spanish Ministry of Economy, Industry and Competitiveness (MINECO) [SAF2014-54658-R, SAF2015-66312, SAF 2014-52097R, SAF2015-67538-R, SAF2015-65327R, SAF2011-24967]; European Union [ERC-StG-336343, PoC754627, CIG 660191, 602272, ERC-2014-STG-638891]; Basque Government Department of Health [2016111109, 2015111149]; Department of Education [PI2012/03, IKERTALDE I.T.1106-16, PI2012/42]; PhD grants; AECC; ISCIII [PI10/01484, PI13/00031, PT13/0001, PI15/209, PI13/01714, CP14/00228]; Ramon Areces foundation; Basque Department of Industry, Tourism and Trade (Etortek); FERO Foundation; Fundacion Vasca de Innovacion e Investigacion Sanitarias; BIOEF [BIO15/CA/052]; BBVA Foundation; National Institutes of Health [P01CA087497, R01AT001576]; Fundacion CRIS contra el Cancer; Stewart Rahr Young Investigator Award from Prostate Cancer Foundation; FPU predoctoral fellowship [15/05126]; Catalan Agency AGAUR [2014 SGR 1331]; Medical Research Council [MC_UU_12016/2]; FEDER funds; MRC [MC_UU_12016/2] Funding Source: UKRI; National Cancer Institute [R35CA197459, P01CA087497, P30CA008748] Funding Source: NIH RePORTER; Medical Research Council [MC_UU_12016/2] Funding Source: researchfish
NR 49
TC 161
Z9 190
U1 0
U2 85
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 6
PY 2017
VL 547
IS 7661
BP 109
EP +
DI 10.1038/nature22964
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EZ6PM
UT WOS:000404839900040
PM 28658205
DA 2026-03-09
ER

PT J
AU Zhang, Q
   Jiang, XJ
   Tong, D
   Davis, SJ
   Zhao, HY
   Geng, GN
   Feng, T
   Zheng, B
   Lu, ZF
   Streets, DG
   Ni, RJ
   Brauer, M
   van Donkelaar, A
   Martin, RV
   Huo, H
   Liu, Z
   Pan, D
   Kan, HD
   Yan, YY
   Lin, JT
   He, KB
   Guan, DB
AF Zhang, Qiang
   Jiang, Xujia
   Tong, Dan
   Davis, Steven J.
   Zhao, Hongyan
   Geng, Guannan
   Feng, Tong
   Zheng, Bo
   Lu, Zifeng
   Streets, David G.
   Ni, Ruijing
   Brauer, Michael
   van Donkelaar, Aaron
   Martin, Randall V.
   Huo, Hong
   Liu, Zhu
   Pan, Da
   Kan, Haidong
   Yan, Yingying
   Lin, Jintai
   He, Kebin
   Guan, Dabo
TI Transboundary health impacts of transported global air pollution and international trade
SO NATURE
LA English
DT Article
ID fine particulate matter; intercontinental transport; burden; disease; ozone; mortality; exposure; quality
AB Millions of people die every year from diseases caused by exposure to outdoor air pollution(1-5). Some studies have estimated premature mortality related to local sources of air pollution(6,7), but local air quality can also be affected by atmospheric transport of pollution from distant sources(8-18). International trade is contributing to the globalization of emission and pollution as a result of the production of goods (and their associated emissions) in one region for consumption in another region(14,19-22). The effects of international trade on air pollutant emissions(23), air quality(14) and health(24) have been investigated regionally, but a combined, global assessment of the health impacts related to international trade and the transport of atmospheric air pollution is lacking. Here we combine four global models to estimate premature mortality caused by fine particulate matter (PM2.5) pollution as a result of atmospheric transport and the production and consumption of goods and services in different world regions. We find that, of the 3.45 million premature deaths related to PM2.5 pollution in 2007 worldwide, about 12 per cent (411,100 deaths) were related to air pollutants emitted in a region of the world other than that in which the death occurred, and about 22 per cent (762,400 deaths) were associated with goods and services produced in one region for consumption in another. For example, PM2.5 pollution produced in China in 2007 is linked to more than 64,800 premature deaths in regions other than China, including more than 3,100 premature deaths in western Europe and the USA; on the other hand, consumption in western Europe and the USA is linked to more than 108,600 premature deaths in China. Our results reveal that the transboundary health impacts of PM2.5 pollution associated with international trade are greater than those associated with long-distance atmospheric pollutant transport.
C1 [Zhang, Qiang; Tong, Dan; Davis, Steven J.; Zhao, Hongyan; Geng, Guannan; Feng, Tong; He, Kebin; Guan, Dabo] Tsinghua Univ, Dept Earth Syst Sci, Key Lab Earth Syst Modeling, Minist Educ, Beijing 100084, Peoples R China.
   [Jiang, Xujia; Zheng, Bo; He, Kebin] Tsinghua Univ, Sch Environm, State Key Joint Lab Environm Simulat & Pollut Con, Beijing 100084, Peoples R China.
   [Davis, Steven J.] Univ Calif Irvine, Dept Earth Syst Sci, Irvine, CA 92697 USA.
   [Lu, Zifeng; Streets, David G.] Argonne Natl Lab, Div Energy Syst, 9700 S Cass Ave, Argonne, IL 60439 USA.
   [Ni, Ruijing; Yan, Yingying; Lin, Jintai] Peking Univ, Lab Climate & Ocean Atmosphere Studies, Dept Atmospher & Ocean Sci, Sch Phys, Beijing 100871, Peoples R China.
   [Brauer, Michael] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V6T 1Z3, Canada.
   [van Donkelaar, Aaron; Martin, Randall V.] Dalhousie Univ, Dept Phys & Atmospher Sci, Halifax, NS B3H 4R2, Canada.
   [Martin, Randall V.] Harvard Smithsonian Ctr Astrophys, Smithsonian Astrophys Observ, 60 Garden St, Cambridge, MA 02138 USA.
   [Huo, Hong] Tsinghua Univ, Inst Energy Environm & Econ, Beijing 100084, Peoples R China.
   [Liu, Zhu] CALTECH, Resnick Sustainabil Inst, Pasadena, CA 91125 USA.
   [Pan, Da] Princeton Univ, Dept Civil & Environm Engn, Princeton, NJ 08544 USA.
   [Kan, Haidong] Fudan Univ, Sch Publ Hlth, Shanghai, Peoples R China.
   [He, Kebin] State Environm Protect Key Lab Sources & Control, Beijing 100084, Peoples R China.
   [Guan, Dabo] Univ East Anglia, Sch Int Dev, Norwich NR4 7TJ, Norfolk, England.
C3 Tsinghua University; Tsinghua University; University of California System; University of California Irvine; United States Department of Energy (DOE); Argonne National Laboratory; Peking University; University of British Columbia; Dalhousie University; Smithsonian Astrophysical Observatory; Smithsonian Institution; Harvard University; Tsinghua University; California Institute of Technology; Princeton University; Fudan University; University of East Anglia
RP Zhang, Q; Davis, SJ; He, KB (corresponding author), Tsinghua Univ, Dept Earth Syst Sci, Key Lab Earth Syst Modeling, Minist Educ, Beijing 100084, Peoples R China.; He, KB (corresponding author), Tsinghua Univ, Sch Environm, State Key Joint Lab Environm Simulat & Pollut Con, Beijing 100084, Peoples R China.; Davis, SJ (corresponding author), Univ Calif Irvine, Dept Earth Syst Sci, Irvine, CA 92697 USA.; Lin, JT (corresponding author), Peking Univ, Lab Climate & Ocean Atmosphere Studies, Dept Atmospher & Ocean Sci, Sch Phys, Beijing 100871, Peoples R China.; He, KB (corresponding author), State Environm Protect Key Lab Sources & Control, Beijing 100084, Peoples R China.
EM qiangzhang@tsinghua.edu.cn; sjdavis@uci.edu; linjt@pku.edu.cn; hekb@tsinghua.edu.cn
FU National Natural Science Foundation of China [41625020, 41629501, 41422502, 41222036, 41541039, 71322304, 41501605]; China's National Basic Research Program [2014CB441301, 2014CB441303]; Collaborative Innovation Center for Regional Environmental Quality; Cyrus Tang Foundation; National Key R&D Program of China [2016YFA0602604]; UK Economic and Social Research Council [ES/L016028/1]; UK Natural Environment Research Council [NE/N00714X/1]; British Academy [AF150310]; Economic and Social Research Council [ES/L016028/1] Funding Source: researchfish; Natural Environment Research Council [NE/N00714X/1] Funding Source: researchfish; ESRC [ES/L016028/1] Funding Source: UKRI; NERC [NE/N00714X/1] Funding Source: UKRI
NR 33
TC 861
Z9 946
U1 42
U2 1322
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 30
PY 2017
VL 543
IS 7647
BP 705
EP +
DI 10.1038/nature21712
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EP8IS
UT WOS:000397619700053
PM 28358094
DA 2026-03-09
ER

PT J
AU Blees, A
   Januliene, D
   Hofmann, T
   Koller, N
   Schmidt, C
   Trowitzsch, S
   Moeller, A
   Tampé, R
AF Blees, Andreas
   Januliene, Dovile
   Hofmann, Tommy
   Koller, Nicole
   Schmidt, Carla
   Trowitzsch, Simon
   Moeller, Arne
   Tampe, Robert
TI Structure of the human MHC-I peptide-loading complex
SO NATURE
LA English
DT Article
ID major histocompatibility complex; molecular architecture; tapasin; tap; calreticulin; binding; erp57; visualization; purification; transporters
AB The peptide-loading complex (PLC) is a transient, multisubunit membrane complex in the endoplasmic reticulum that is essential for establishing a hierarchical immune response. The PLC coordinates peptide translocation into the endoplasmic reticulum with loading and editing of major histocompatibility complex class I (MHC-I) molecules. After final proofreading in the PLC, stable peptide-MHC-I complexes are released to the cell surface to evoke a T-cell response against infected or malignant cells(1,2). Sampling of different MHC-I allomorphs requires the precise coordination of seven different subunits in a single macromolecular assembly, including the transporter associated with antigen processing (TAP1 and TAP2, jointly referred to as TAP), the oxidoreductase ERp57, the MHC-I heterodimer, and the chaperones tapasin and calreticulin(3,4). The molecular organization of and mechanistic events that take place in the PLC are unknown owing to the heterogeneous composition and intrinsically dynamic nature of the complex. Here, we isolate human PLC from Burkitt's lymphoma cells using an engineered viral inhibitor as bait and determine the structure of native PLC by electron cryo-microscopy. Two endoplasmic reticulum-resident editing modules composed of tapasin, calreticulin, ERp57, and MHC-I are centred around TAP in a pseudo-symmetric orientation. A multivalent chaperone network within and across the editing modules establishes the proofreading function at two lateral binding platforms for MHC-I molecules. The lectin-like domain of calreticulin senses the MHC-I glycan, whereas the P domain reaches over the MHC-I peptide-binding pocket towards ERp57. This arrangement allows tapasin to facilitate peptide editing by clamping MHC-I. The translocation pathway of TAP opens out into a large endoplasmic reticulum lumenal cavity, confined by the membrane entry points of tapasin and MHC-I. Two lateral windows channel the antigenic peptides to MHC-I. Structures of PLC captured at distinct assembly states provide mechanistic insight into the recruitment and release of MHC-I. Our work defines the molecular symbiosis of an ABC transporter and an endoplasmic reticulum chaperone network in MHC-I assembly and provides insight into the onset of the adaptive immune response.
C1 [Blees, Andreas; Koller, Nicole; Trowitzsch, Simon; Tampe, Robert] Goethe Univ Frankfurt, Bioctr, Inst Biochem, Max von Laue Str 9, D-60438 Frankfurt, Germany.
   [Januliene, Dovile; Moeller, Arne] Max Planck Inst Biophys, Dept Struct Biol, Max von Laue Str 3, D-60438 Frankfurt, Germany.
   [Hofmann, Tommy; Schmidt, Carla] Martin Luther Univ Halle Wittenberg, Interdisciplinary Res Ctr HALOmen, Kurt Mothes Str 3, D-06120 Halle, Germany.
C3 Goethe University Frankfurt; Max Planck Society; Martin Luther University Halle Wittenberg
RP Trowitzsch, S; Tampé, R (corresponding author), Goethe Univ Frankfurt, Bioctr, Inst Biochem, Max von Laue Str 9, D-60438 Frankfurt, Germany.; Moeller, A (corresponding author), Max Planck Inst Biophys, Dept Struct Biol, Max von Laue Str 3, D-60438 Frankfurt, Germany.
EM trowitzsch@biochem.uni-frankfurt.de; arne.moeller@biophys.mpg.de; tampe@em.uni-frankfurt.de
FU German Research Foundation [SFB 807, GRK 1986]; Federal Ministry for Education and Research (BMBF, ZIK) [03Z22HN22]; European Regional Development Funds (EFRE) [ZS/2016/04/78115]; MLU Halle-Wittenberg
NR 60
TC 294
Z9 346
U1 10
U2 128
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 23
PY 2017
VL 551
IS 7681
BP 525
EP +
DI 10.1038/nature24627
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FN5JO
UT WOS:000416043700050
PM 29107940
DA 2026-03-09
ER

PT J
AU Green, J
   Adachi, A
   Shah, KK
   Hirokawa, JD
   Magani, PS
   Maimon, G
AF Green, Jonathan
   Adachi, Atsuko
   Shah, Kunal K.
   Hirokawa, Jonathan D.
   Magani, Pablo S.
   Maimon, Gaby
TI A neural circuit architecture for angular integration in Drosophila
SO NATURE
LA English
DT Article
ID head-direction cells; freely moving rats; path-integration; protocerebral bridge; representation; orientation; postsubiculum; dynamics; velocity; position
AB Many animals keep track of their angular heading over time while navigating through their environment. However, a neural-circuit architecture for computing heading has not been experimentally defined in any species. Here we describe a set of clockwise-and anticlockwise-shifting neurons in the Drosophila central complex whose wiring and physiology provide a means to rotate an angular heading estimate based on the fly's angular velocity. We show that each class of shifting neurons exists in two subtypes, with spatiotemporal activity profiles that suggest different roles for each subtype at the start and end of tethered-walking turns. Shifting neurons are required for the heading system to properly track the fly's heading in the dark, and stimulation of these neurons induces predictable shifts in the heading signal. The central features of this biological circuit are analogous to those of computational models proposed for head-direction cells in rodents and may shed light on how neural systems, in general, perform integration.
C1 [Green, Jonathan; Adachi, Atsuko; Shah, Kunal K.; Hirokawa, Jonathan D.; Magani, Pablo S.; Maimon, Gaby] Rockefeller Univ, Lab Integrat Brain Funct, New York, NY 10065 USA.
C3 Rockefeller University
RP Maimon, G (corresponding author), Rockefeller Univ, Lab Integrat Brain Funct, New York, NY 10065 USA.
EM maimon@rockefeller.edu
FU New York Stem Cell Foundation [NYSCF-R-NI13]; Searle Scholars Foundation [12-SSP-153]; McKnight Foundation; National Institute on Drug Abuse of the NIH [DP2DA035148]; National Institute of General Medical Sciences; National Institute of Neurological Disorders and Stroke; NIH Office of the Director; Eunice Kennedy Shriver National Institute of Child Health and Human Development [P40OD018537] Funding Source: NIH RePORTER
NR 45
TC 226
Z9 267
U1 3
U2 69
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 1
PY 2017
VL 546
IS 7656
BP 101
EP +
DI 10.1038/nature22343
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW3CR
UT WOS:000402372800036
PM 28538731
DA 2026-03-09
ER

PT J
AU Kurnosov, A
   Marquardt, H
   Frost, DJ
   Ballaran, TB
   Ziberna, L
AF Kurnosov, A.
   Marquardt, H.
   Frost, D. J.
   Ballaran, T. Boffa
   Ziberna, L.
TI Evidence for a Fe3+-rich pyrolitic lower mantle from (Al,Fe)-bearing bridgmanite elasticity data
SO NATURE
LA English
DT Article
ID equation-of-state; single-crystal elasticity; earths lower mantle; high-pressure; mgsio3 perovskite; brillouin-scattering; sound velocity; ferric iron; temperature; gpa
AB The chemical composition of Earth's lower mantle can be constrained by combining seismological observations with mineral physics elasticity measurements(1-3). However, the lack of laboratory data for Earth's most abundant mineral, (Mg, Fe, Al)(Si, Al, Fe)O-3 bridgmanite (also known as silicate perovskite), has hampered any conclusive result. Here we report single-crystal elasticity data on (Al, Fe)-bearing bridgmanite (Mg0.9Fe0.1Si0.9Al0.1)O-3 measured using high-pressure Brillouin spectroscopy and X-ray diffraction. Our measurements show that the elastic behaviour of (Al, Fe)-bearing bridgmanite is markedly different from the behaviour of the MgSiO3 endmember2,4. We use our data to model seismic wave velocities in the top portion of the lower mantle, assuming a pyrolitic(5) mantle composition and accounting for depth-dependent changes in iron partitioning between bridgmanite and ferropericlase(6,7). We find excellent agreement between our mineral physics predictions and the seismic Preliminary Reference Earth Model(8) down to at least 1,200 kilometres depth, indicating chemical homogeneity of the upper and shallow lower mantle. A high Fe3+/Fe2+ ratio of about two in shallow-lower-mantle bridgmanite is required to match seismic data, implying the presence of metallic iron in an isochemical mantle. Our calculated velocities are in increasingly poor agreement with those of the lower mantle at depths greater than 1,200 kilometres, indicating either a change in bridgmanite cation ordering or a decrease in the ferric iron content of the lower mantle.
C1 [Kurnosov, A.; Marquardt, H.; Frost, D. J.; Ballaran, T. Boffa; Ziberna, L.] Univ Bayreuth, Bayer Geoinst BGI, D-95440 Bayreuth, Germany.
   [Ziberna, L.] Univ Bristol, Sch Earth Sci, Bristol BS8 1RJ, Avon, England.
C3 University of Bayreuth; University of Bristol
RP Marquardt, H (corresponding author), Univ Bayreuth, Bayer Geoinst BGI, D-95440 Bayreuth, Germany.
EM hauke.marquardt@uni-bayreuth.de
FU projects 'GeoMaX' under Emmy-Noether Program of the German Science Foundation [MA4534/3-1]; ERC through EU [227893]; Bavarian Academy of Sciences;  [INST 91/315-1 FUGG]; European Research Council (ERC) [227893] Funding Source: European Research Council (ERC)
NR 54
TC 87
Z9 101
U1 0
U2 110
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 23
PY 2017
VL 543
IS 7646
BP 543
EP +
DI 10.1038/nature21390
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EO9OM
UT WOS:000397018000049
PM 28289289
DA 2026-03-09
ER

PT J
AU Hoch, NC
   Hanzlikova, H
   Rulten, SL
   Tétreault, M
   Komulainen, E
   Ju, LM
   Hornyak, P
   Zeng, ZH
   Gittens, W
   Rey, SA
   Staras, K
   Mancini, GMS
   McKinnon, PJ
   Wang, ZQ
   Wagner, JD
   Yoon, G
   Caldecott, KW
AF Hoch, Nicolas C.
   Hanzlikova, Hana
   Rulten, Stuart L.
   Tetreault, Martine
   Komulainen, Emilia
   Ju, Limei
   Hornyak, Peter
   Zeng, Zhihong
   Gittens, William
   Rey, Stephanie A.
   Staras, Kevin
   Mancini, Grazia M. S.
   McKinnon, Peter J.
   Wang, Zhao-Qi
   Wagner, Justin D.
   Yoon, Grace
   Caldecott, Keith W.
TI XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia
SO NATURE
LA English
DT Article
ID strand break repair; base excision-repair; poly(adp-ribose) polymerase; spinocerebellar ataxia; dna; cells; gene; replication; disease; rates
AB XRCC1 is a molecular scaffold protein that assembles multiprotein complexes involved in DNA single-strand break repair(1,2). Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP3-5 and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.
C1 [Hoch, Nicolas C.; Hanzlikova, Hana; Rulten, Stuart L.; Komulainen, Emilia; Ju, Limei; Hornyak, Peter; Zeng, Zhihong; Gittens, William; Caldecott, Keith W.] Univ Sussex, Genome Damage & Stabil Ctr, Sch Life Sci, Brighton BN1 9RH, E Sussex, England.
   [Hoch, Nicolas C.] Minist Educ Brazil, CAPES Fdn, BR-70040020 Brasilia, DF, Brazil.
   [Tetreault, Martine] McGill Univ, Dept Human Genet, Montreal, PQ H3A OG4, Canada.
   [Tetreault, Martine] Genome Quebec Innovat Ctr, Montreal, PQ H3A OG4, Canada.
   [Rey, Stephanie A.; Staras, Kevin] Univ Sussex, Sch Life Sci, Neurosci, Brighton BN1 9QG, E Sussex, England.
   [Mancini, Grazia M. S.] Erasmus MC, Dept Clin Genet, POB 2040, NL-3000 CA Rotterdam, Netherlands.
   [McKinnon, Peter J.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA.
   [Wang, Zhao-Qi] Fritz Lipmann Inst, Leibniz Inst Age Res, Jena, Germany.
   [Wagner, Justin D.] Childrens Hosp, Eastern Ontario Res Inst, Ottawa, ON K1L 8H1, Canada.
   [Yoon, Grace] Univ Toronto, Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada.
   [Yoon, Grace] Univ Toronto, Hosp Sick Children, Div Neurol, Toronto, ON M5G 1X8, Canada.
C3 University of Sussex; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); McGill University; University of Sussex; Erasmus University Rotterdam; Erasmus MC; St Jude Children's Research Hospital; Leibniz Association; Leibniz Institut fur Alternsforschung - Fritz-Lipmann-Institut (FLI); University of Ottawa; Children's Hospital of Eastern Ontario; University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; Hospital for Sick Children (SickKids)
RP Caldecott, KW (corresponding author), Univ Sussex, Genome Damage & Stabil Ctr, Sch Life Sci, Brighton BN1 9RH, E Sussex, England.; Yoon, G (corresponding author), Univ Toronto, Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada.; Yoon, G (corresponding author), Univ Toronto, Hosp Sick Children, Div Neurol, Toronto, ON M5G 1X8, Canada.
EM grace.yoon@utoronto.ca; k.w.caldecott@sussex.ac.uk
FU MRC [MR/J006750/1, MR/P010121/1]; CAPES Foundation, Ministry of Education, Brazil [BEX9769-13-7]; Genome Canada; Canadian Institutes of Health Research; Ontario Genomics Institute; Ontario Research Fund; Genome Quebec; Children's Hospital of Eastern Ontario Foundation; Hospital for Sick Children; BBSRC [BB/K019015/1]; National Institutes of Health [NS-37956, CA-21765]; CCSG [P30 CA21765]; American Lebanese and Syrian Associated Charities of St. Jude Children's Research Hospital; Biotechnology and Biological Sciences Research Council [BB/K019015/1] Funding Source: researchfish; Cancer Research UK [16771] Funding Source: researchfish; Medical Research Council [MR/P010121/1, MR/J006750/1] Funding Source: researchfish; National Cancer Institute [P01CA096832, P30CA021765] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [R01NS037956] Funding Source: NIH RePORTER; BBSRC [BB/K019015/1] Funding Source: UKRI; MRC [MR/J006750/1, MR/P010121/1] Funding Source: UKRI
NR 26
TC 212
Z9 242
U1 0
U2 25
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 5
PY 2017
VL 541
IS 7635
BP 87
EP +
DI 10.1038/nature20790
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6NA
UT WOS:000396119500034
PM 28002403
DA 2026-03-09
ER

PT J
AU Lu, NP
   Zhang, PF
   Zhang, QH
   Qiao, RM
   He, Q
   Li, HB
   Wang, YJ
   Guo, JW
   Zhang, D
   Duan, Z
   Li, ZL
   Wang, M
   Yang, SZ
   Yan, MZ
   Arenholz, E
   Zhou, SY
   Yang, WL
   Gu, L
   Nan, CW
   Wu, J
   Tokura, Y
   Yu, P
AF Lu, Nianpeng
   Zhang, Pengfei
   Zhang, Qinghua
   Qiao, Ruimin
   He, Qing
   Li, Hao-Bo
   Wang, Yujia
   Guo, Jingwen
   Zhang, Ding
   Duan, Zheng
   Li, Zhuolu
   Wang, Meng
   Yang, Shuzhen
   Yan, Mingzhe
   Arenholz, Elke
   Zhou, Shuyun
   Yang, Wanli
   Gu, Lin
   Nan, Ce-Wen
   Wu, Jian
   Tokura, Yoshinori
   Yu, Pu
TI Electric-field control of tri-state phase transformation with a selective dual-ion switch
SO NATURE
LA English
DT Article
ID epitaxial thin-films; room-temperature; liquid water; oxide; transition; metal; insulator; cobalt; vo2; semiconductor
AB Materials can be transformed from one crystalline phase to another by using an electric field to control ion transfer, in a process that can be harnessed in applications such as batteries(1), smart windows(2) and fuel cells(3). Increasing the number of transferrable ion species and of accessible crystalline phases could in principle greatly enrich material functionality. However, studies have so far focused mainly on the evolution and control of single ionic species (for example, oxygen, hydrogen or lithium ions(4-10)). Here we describe the reversible and non-volatile electric-field control of dual-ion (oxygen and hydrogen) phase transformations, with associated electrochromic(2) and magnetoelectric(11) effects. We show that controlling the insertion and extraction of oxygen and hydrogen ions independently of each other can direct reversible phase transformations among three different material phases: the perovskite SrCoO3-delta (ref. 12), the brownmillerite SrCoO2.5 (ref. 13), and a hitherto-unexplored phase, HSrCoO2.5. By analysing the distinct optical absorption properties of these phases, we demonstrate selective manipulation of spectral transparency in the visible-light and infrared regions, revealing a dual-band electrochromic effect that could see application in smart windows(2,9). Moreover, the starkly different magnetic and electric properties of the three phases-HSrCoO2.5 is a weakly ferromagnetic insulator, SrCoO3-delta is a ferromagnetic metal(12), and SrCoO2.5 is an antiferromagnetic insulator(13)-enable an unusual form of magnetoelectric coupling, allowing electric-field control of three different magnetic ground states. These findings open up opportunities for the electric-field control of multistate phase transformations with rich functionalities.
C1 [Lu, Nianpeng; Zhang, Pengfei; Li, Hao-Bo; Wang, Yujia; Guo, Jingwen; Zhang, Ding; Duan, Zheng; Li, Zhuolu; Wang, Meng; Yang, Shuzhen; Yan, Mingzhe; Zhou, Shuyun; Wu, Jian; Yu, Pu] Tsinghua Univ, State Key Lab Low Dimens Quantum Phys, Beijing 100084, Peoples R China.
   [Lu, Nianpeng; Zhang, Pengfei; Li, Hao-Bo; Wang, Yujia; Guo, Jingwen; Zhang, Ding; Duan, Zheng; Li, Zhuolu; Wang, Meng; Yang, Shuzhen; Yan, Mingzhe; Zhou, Shuyun; Wu, Jian; Yu, Pu] Tsinghua Univ, Dept Phys, Beijing 100084, Peoples R China.
   [Zhang, Qinghua; Gu, Lin] Chinese Acad Sci, Beijing Natl Lab Condensed Matter Phys, Inst Phys, Beijing 100190, Peoples R China.
   [Zhang, Qinghua; Nan, Ce-Wen] Tsinghua Univ, Sch Mat Sci & Engn, State Key Lab New Ceram & Fine Proc, Beijing 100084, Peoples R China.
   [Qiao, Ruimin; Arenholz, Elke; Yang, Wanli] Lawrence Berkeley Natl Lab, Adv Light Source, Berkeley, CA 94720 USA.
   [He, Qing] Univ Durham, Dept Phys, Durham DH1 3LE, England.
   [Zhou, Shuyun; Gu, Lin; Wu, Jian; Yu, Pu] Collaborat Innovat Ctr Quantum Matter, Beijing 100084, Peoples R China.
   [Tokura, Yoshinori; Yu, Pu] RIKEN, Ctr Emergent Matter Sci, Wako, Saitama 351198, Japan.
C3 Tsinghua University; Tsinghua University; Chinese Academy of Sciences; Institute of Physics, CAS; Tsinghua University; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; Durham University; Peking University; Tsinghua University; Collaborative Innovation Center of Quantum Matter; RIKEN
RP Wu, J; Yu, P (corresponding author), Tsinghua Univ, State Key Lab Low Dimens Quantum Phys, Beijing 100084, Peoples R China.; Wu, J; Yu, P (corresponding author), Tsinghua Univ, Dept Phys, Beijing 100084, Peoples R China.; Wu, J; Yu, P (corresponding author), Collaborat Innovat Ctr Quantum Matter, Beijing 100084, Peoples R China.; Yu, P (corresponding author), RIKEN, Ctr Emergent Matter Sci, Wako, Saitama 351198, Japan.
EM wu@tsinghua.edu.cn; yupu@tsinghua.edu.cn
FU National Basic Research Program of China [2015CB921700, 2016YFA0301004, 2015CB921002]; National Natural Science Foundation of China [11274194, 51561145005, 51332001, 11334006, 51522212, 51421002, 51672307]; Initiative Research Projects of Tsinghua University [20141081116]; Beijing Advanced Innovation Center for Future Chip (ICFC); National Program on Key Basic Research Project [2014CB921002]; Strategic Priority Research Program of Chinese Academy of Sciences [XDB07030200]; US Department of Energy [DE-AC02-05CH11231]; Engineering and Physical Sciences Research Council [EP/N016718/1] Funding Source: researchfish; EPSRC [EP/N016718/1] Funding Source: UKRI
NR 50
TC 689
Z9 744
U1 39
U2 1819
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 1
PY 2017
VL 546
IS 7656
BP 124
EP +
DI 10.1038/nature22389
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW3CR
UT WOS:000402372800040
PM 28569818
DA 2026-03-09
ER

PT J
AU Shimokawa, M
   Ohta, Y
   Nishikori, S
   Matano, M
   Takano, A
   Fujii, M
   Date, S
   Sugimoto, S
   Kanai, T
   Sato, T
AF Shimokawa, Mariko
   Ohta, Yuki
   Nishikori, Shingo
   Matano, Mami
   Takano, Ai
   Fujii, Masayuki
   Date, Shoichi
   Sugimoto, Shinya
   Kanai, Takanori
   Sato, Toshiro
TI Visualization and targeting of LGR5+ human colon cancer stem cells
SO NATURE
LA English
DT Article
ID plasticity; crypt; heterogeneity; intestine; mouse; niche
AB The cancer stem cell (CSC) theory highlights a self-renewing subpopulation of cancer cells that fuels tumour growth. The existence of human CSCs is mainly supported by xenotransplantation of prospectively isolated cells, but their clonal dynamics and plasticity remain unclear. Here, we show that human LGR5(+) colorectal cancer cells serve as CSCs in growing cancer tissues. Lineage-tracing experiments with a tamoxifen-inducible Cre knock-in allele of LGR5 reveal the self-renewal and differentiation capacity of LGR5(+) tumour cells. Selective ablation of LGR5(+) CSCs in LGR5-iCaspase9 knock-in organoids leads to tumour regression, followed by tumour regrowth driven by re-emerging LGR5(+) CSCs. KRT20 knock-in reporter marks differentiated cancer cells that constantly diminish in tumour tissues, while reverting to LGR5(+) CSCs and contributing to tumour regrowth after LGR5(+) CSC ablation. We also show that combined chemotherapy potentiates targeting of LGR5(+) CSCs. These data provide insights into the plasticity of CSCs and their potential as a therapeutic target in human colorectal cancer.
C1 [Shimokawa, Mariko; Ohta, Yuki; Nishikori, Shingo; Matano, Mami; Takano, Ai; Fujii, Masayuki; Date, Shoichi; Sugimoto, Shinya; Kanai, Takanori; Sato, Toshiro] Keio Univ, Sch Med, Dept Gastroenterol, Tokyo, Japan.
   [Nishikori, Shingo; Date, Shoichi] Otsuka Pharmaceut Co Ltd, Fujii Mem Res Inst, Otsu, Shiga, Japan.
C3 Keio University; Otsuka Pharmaceutical
RP Sato, T (corresponding author), Keio Univ, Sch Med, Dept Gastroenterol, Tokyo, Japan.
EM t.sato@keio.jp
FU Japan Agency for Medical Research and Development (AMED); Ministry of Education, Culture, Sports, Science and Technology of Japan; Japan Society for the Promotion of Science Research Fellowships for Young Scientists; Grants-in-Aid for Scientific Research [17J04827, 26115007, 15J00981, 16J06433, 17K09395, 15K08974, 15K15297, 15J06065] Funding Source: KAKEN
CR Asfaha S, 2015, CELL STEM CELL, V16, P627, DOI 10.1016/j.stem.2015.04.013
   Barker N, 2007, GASTROENTEROLOGY, V133, P1755, DOI 10.1053/j.gastro.2007.10.029
   Basak O, 2017, CELL STEM CELL, V20, P177, DOI 10.1016/j.stem.2016.11.001
   Bolte S, 2006, J MICROSC-OXFORD, V224, P213, DOI 10.1111/j.1365-2818.2006.01706.x
   Brooks MD, 2015, CELL STEM CELL, V17, P260, DOI 10.1016/j.stem.2015.08.014
   Buczacki SJA, 2013, NATURE, V495, P65, DOI 10.1038/nature11965
   Cernat L, 2014, PLOS ONE, V9, P0, DOI 10.1371/journal.pone.0104284
   Chaffer CL, 2013, CELL, V154, P61, DOI 10.1016/j.cell.2013.06.005
   Dalerba P, 2011, NAT BIOTECHNOL, V29, P1120, DOI 10.1038/nbt.2038
   Driessens G, 2012, NATURE, V488, P527, DOI 10.1038/nature11344
   Fujii M, 2016, CELL STEM CELL, V18, P827, DOI 10.1016/j.stem.2016.04.003
   Fujii M, 2015, NAT PROTOC, V10, P1474, DOI 10.1038/nprot.2015.088
   Gupta PB, 2011, CELL, V146, P633, DOI 10.1016/j.cell.2011.07.026
   Ito M, 2002, BLOOD, V100, P3175, DOI 10.1182/blood-2001-12-0207
   Junttila MR, 2015, SCI TRANSL MED, V7, P0, DOI 10.1126/scitranslmed.aac7433
   Kaiser J, 2015, SCIENCE, V347, P226, DOI 10.1126/science.347.6219.226
   Kemper K, 2012, STEM CELLS, V30, P2378, DOI 10.1002/stem.1233
   Kemper K, 2012, APOPTOSIS, V17, P528, DOI 10.1007/s10495-011-0692-z
   Kobayashi S, 2012, STEM CELLS, V30, P2631, DOI 10.1002/stem.1257
   Kreso A, 2014, CELL STEM CELL, V14, P275, DOI 10.1016/j.stem.2014.02.006
   LAPIDOT T, 1994, NATURE, V367, P645, DOI 10.1038/367645a0
   Matano M, 2015, NAT MED, V21, P256, DOI 10.1038/nm.3802
   Merlos-Suárez A, 2011, CELL STEM CELL, V8, P511, DOI 10.1016/j.stem.2011.02.020
   Metcalfe C, 2014, CELL STEM CELL, V14, P149, DOI 10.1016/j.stem.2013.11.008
   Muñoz J, 2012, EMBO J, V31, P3079, DOI 10.1038/emboj.2012.166
   Nassar D, 2016, ANNU REV PATHOL-MECH, V11, P47, DOI 10.1146/annurev-pathol-012615-044438
   Nguyen LV, 2012, NAT REV CANCER, V12, P133, DOI 10.1038/nrc3184
   OBrien CA, 2007, NATURE, V445, P106, DOI 10.1038/nature05372
   Plaks V, 2015, CELL STEM CELL, V16, P225, DOI 10.1016/j.stem.2015.02.015
   Ran FA, 2013, NAT PROTOC, V8, P2281, DOI 10.1038/nprot.2013.143
   Ricci-Vitiani L, 2007, NATURE, V445, P111, DOI 10.1038/nature05384
   Sato T, 2011, NATURE, V469, P415, DOI 10.1038/nature09637
   Schepers AG, 2012, SCIENCE, V337, P730, DOI 10.1126/science.1224676
   Schindelin J, 2012, NAT METHODS, V9, P676, DOI 10.1038/NMETH.2019
   Snippert HJ, 2010, CELL, V143, P134, DOI 10.1016/j.cell.2010.09.016
   Takebe N, 2015, NAT REV CLIN ONCOL, V12, P445, DOI 10.1038/nrclinonc.2015.61
   Tetteh PW, 2016, CELL STEM CELL, V18, P203, DOI 10.1016/j.stem.2016.01.001
   Tian H, 2011, NATURE, V478, P255, DOI 10.1038/nature10408
   Todaro M, 2008, CELL CYCLE, V7, P309, DOI 10.4161/cc.7.3.5389
   van Es JH, 2012, NAT CELL BIOL, V14, P1099, DOI 10.1038/ncb2581
   Vermeulen L, 2010, NAT CELL BIOL, V12, P468, DOI 10.1038/ncb2048
   Zeuner A, 2014, CELL STEM CELL, V15, P692, DOI 10.1016/j.stem.2014.11.012
NR 42
TC 576
Z9 648
U1 3
U2 185
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 11
PY 2017
VL 545
IS 7653
BP 187
EP +
DI 10.1038/nature22081
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EU3XG
UT WOS:000400963800027
PM 28355176
DA 2026-03-09
ER

PT J
AU Huttlin, EL
   Bruckner, RJ
   Paulo, JA
   Cannon, JR
   Ting, L
   Baltier, K
   Colby, G
   Gebreab, F
   Gygi, MP
   Parzen, H
   Szpyt, J
   Tam, S
   Zarraga, G
   Pontano-Vaites, L
   Swarup, S
   White, AE
   Schweppe, DK
   Rad, R
   Erickson, BK
   Obar, RA
   Guruharsha, KG
   Li, K
   Rtavanis-Tsakonas, SA
   Gygi, SP
   Harper, JW
AF Huttlin, Edward L.
   Bruckner, Raphael J.
   Paulo, Joao A. .
   Cannon, Joe R.
   Ting, Lily
   Baltier, Kurt
   Colby, Greg
   Gebreab, Fana
   Gygi, Melanie P.
   Parzen, Hannah
   Szpyt, John
   Tam, Stanley
   Zarraga, Gabriela
   Pontano-Vaites, Laura
   Swarup, Sharan
   White, Anne E.
   Schweppe, Devin K.
   Rad, Ramin
   Erickson, Brian K.
   Obar, Robert A. .
   Guruharsha, K. G.
   Li, Kejie
   Rtavanis-Tsakonas, Spyros A.
   Gygi, Steven P.
   Harper, J. Wade
TI Architecture of the human interactome defines protein communities and disease networks
SO NATURE
LA English
DT Article
ID scale map; regulators; landscape; complexes; peptides
AB The physiology of a cell can be viewed as the product of thousands of proteins acting in concert to shape the cellular response. Coordination is achieved in part through networks of protein-protein interactions that assemble functionally related proteins into complexes, organelles, and signal transduction pathways. Understanding the architecture of the human proteome has the potential to inform cellular, structural, and evolutionary mechanisms and is critical to elucidating how genome variation contributes to disease(1-3). Here we present BioPlex 2.0 (Biophysical Interactions of ORFeome-derived complexes), which uses robust affinity purification-mass spectrometry methodology(4) to elucidate protein interaction networks and co-complexes nucleated by more than 25% of protein-coding genes from the human genome, and constitutes, to our knowledge, the largest such network so far. With more than 56,000 candidate interactions, BioPlex 2.0 contains more than 29,000 previously unknown co-associations and provides functional insights into hundreds of poorly characterized proteins while enhancing network-based analyses of domain associations, subcellular localization, and co-complex formation. Unsupervised Markov clustering(5) of interacting proteins identified more than 1,300 protein communities representing diverse cellular activities. Genes essential for cell fitness(6,7) are enriched within 53 communities representing central cellular functions. Moreover, we identified 442 communities associated with more than 2,000 disease annotations, placing numerous candidate disease genes into a cellular framework. BioPlex 2.0 exceeds previous experimentally derived interaction networks in depth and breadth, and will be a valuable resource for exploring the biology of incompletely characterized proteins and for elucidating larger-scale patterns of proteome organization.
C1 [Huttlin, Edward L.; Bruckner, Raphael J.; Paulo, Joao A. .; Cannon, Joe R.; Ting, Lily; Baltier, Kurt; Colby, Greg; Gebreab, Fana; Gygi, Melanie P.; Parzen, Hannah; Szpyt, John; Tam, Stanley; Zarraga, Gabriela; Pontano-Vaites, Laura; Swarup, Sharan; White, Anne E.; Schweppe, Devin K.; Rad, Ramin; Erickson, Brian K.; Rtavanis-Tsakonas, Spyros A.; Gygi, Steven P.; Harper, J. Wade] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
   [Obar, Robert A. .; Guruharsha, K. G.; Li, Kejie; Rtavanis-Tsakonas, Spyros A.] Biogen Inc, 250 Binney St, Cambridge, MA 02142 USA.
C3 Harvard University; Harvard Medical School; Biogen
RP Huttlin, EL; Gygi, SP; Harper, JW (corresponding author), Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
EM edward_huttlin@hms.harvard.edu; steven_gygi@hms.harvard.edu; wade_harper@hms.harvard.edu
FU National Institutes of Health [U41 HG006673]; Biogen; Canadian Institutes for Health Research;  [K01DK098285]
NR 50
TC 1082
Z9 1294
U1 1
U2 229
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 25
PY 2017
VL 545
IS 7655
BP 505
EP +
DI 10.1038/nature22366
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV6TH
UT WOS:000401906500057
PM 28514442
DA 2026-03-09
ER

PT J
AU Luongo, TS
   Lambert, JP
   Gross, P
   Nwokedi, M
   Lombardi, AA
   Shanmughapriya, S
   Carpenter, AC
   Kolmetzky, D
   Gao, EH
   van Berlo, JH
   Tsai, EJ
   Molkentin, JD
   Chen, XW
   Madesh, M
   Houser, SR
   Elrod, JW
AF Luongo, Timothy S.
   Lambert, Jonathan P.
   Gross, Polina
   Nwokedi, Mary
   Lombardi, Alyssa A.
   Shanmughapriya, Santhanam
   Carpenter, April C.
   Kolmetzky, Devin
   Gao, Erhe
   van Berlo, Jop H.
   Tsai, Emily J.
   Molkentin, Jeffery D.
   Chen, Xiongwen
   Madesh, Muniswamy
   Houser, Steven R.
   Elrod, John W.
TI The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability
SO NATURE
LA English
DT Article
ID calcium uniporter; essential component; heart-failure; mice lacking; permeability transition; cardiac myocytes; mouse; survival; protein; mcu
AB Mitochondrial calcium (Ca-m(2+)) has a central role in both metabolic regulation and cell death signalling, however its role in homeostatic function and disease is controversial(1). Slc8b1 encodes the mitochondrial Na+/Ca2+ exchanger (NCLX), which is proposed to be the primary mechanism for mCa2+ extrusion in excitable cells(2,3). Here we show that tamoxifen-induced deletion of Slc8b1 in adult mouse hearts causes sudden death, with less than 13% of affected mice surviving after 14 days. Lethality correlated with severe myocardial dysfunction and fulminant heart failure. Mechanistically, cardiac pathology was attributed to mCa(2+) overload driving increased generation of superoxide and necrotic cell death, which was rescued by genetic inhibition of mitochondrial permeability transition pore activation. Corroborating these findings, overexpression of NCLX in the mouse heart by conditional transgenesis had the beneficial effect of augmenting mCa(2+) clearance, preventing permeability transition and protecting against ischaemia-induced cardiomyocyte necrosis and heart failure. These results demonstrate the essential nature of mCa(2+) efflux in cellular function and suggest that augmenting mCa(2+) efflux may be a viable therapeutic strategy in disease.
C1 [Luongo, Timothy S.; Lambert, Jonathan P.; Nwokedi, Mary; Lombardi, Alyssa A.; Shanmughapriya, Santhanam; Kolmetzky, Devin; Gao, Erhe; Madesh, Muniswamy; Elrod, John W.] Temple Univ, Sch Med, Ctr Translat Med, Dept Pharmacol, Philadelphia, PA 19140 USA.
   [Gross, Polina; Chen, Xiongwen; Houser, Steven R.] Temple Univ, Sch Med, Cardiovasc Res Ctr, Dept Physiol, Philadelphia, PA 19140 USA.
   [Carpenter, April C.] Ursinus Coll, Dept Hlth & Exercise Physiol, Collegeville, PA 19426 USA.
   [van Berlo, Jop H.] Univ Minnesota, Dept Med, Box 736 UMHC, Minneapolis, MN 55455 USA.
   [Tsai, Emily J.] Columbia Univ, Coll Phys & Surg, Dept Med, Div Cardiol, New York, NY 10032 USA.
   [Molkentin, Jeffery D.] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Howard Hughes Med Inst, Dept Pediat, Cincinnati, OH 45229 USA.
C3 Pennsylvania Commonwealth System of Higher Education (PCSHE); Temple University; Pennsylvania Commonwealth System of Higher Education (PCSHE); Temple University; University of Minnesota System; University of Minnesota Twin Cities; Columbia University; University System of Ohio; University of Cincinnati; Cincinnati Children's Hospital Medical Center; Howard Hughes Medical Institute
RP Elrod, JW (corresponding author), Temple Univ, Sch Med, Ctr Translat Med, Dept Pharmacol, Philadelphia, PA 19140 USA.
EM elrod@temple.edu
FU NIH [R01 HL123966, P01 DA037830 sub-8614]; AHA [14SDG18910041, 15PRE25080299, 16PRE31030038, 17PRE33460423]; National Heart Lung and Blood Institute [R01HL132831] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM109882] Funding Source: NIH RePORTER; American Heart Association (AHA) [16PRE31030038, 17PRE33460423, 15PRE25080299, 14SDG18910041] Funding Source: American Heart Association (AHA)
NR 36
TC 323
Z9 362
U1 1
U2 57
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 4
PY 2017
VL 545
IS 7652
BP 93
EP +
DI 10.1038/nature22082
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET7MK
UT WOS:000400480400037
PM 28445457
DA 2026-03-09
ER

PT J
AU Acerce, M
   Akdogan, EK
   Chhowalla, M
AF Acerce, Muharrem
   Akdogan, E. Koray
   Chhowalla, Manish
TI Metallic molybdenum disulfide nanosheet-based electrochemical actuators
SO NATURE
LA English
DT Article
ID artificial muscles; large-strain; intercalation; polypyrrole; elastomers; chemistry; devices; driven; redox; mos2
AB Actuators that convert electrical energy to mechanical energy are useful in a wide variety of electromechanical systems and in robotics(1-6), with applications such as steerable catheters(7), adaptive wings for aircraft and drag-reducing wind turbines(8). Actuation systems can be based on various stimuli, such as heat, solvent adsorption/desorption(4,9), or electrochemical action (in systems such as carbon nanotube electrodes(1,10), graphite electrodes(11), polymer electrodes(6,12-14) and metals(15)). Here we demonstrate that the dynamic expansion and contraction of electrode films formed by restacking chemically exfoliated nanosheets of two-dimensional metallic molybdenum disulfide (MoS2) on thin plastic substrates can generate substantial mechanical forces. These films are capable of lifting masses that are more than 150 times that of the electrode over several millimetres and for hundreds of cycles. Specifically, the MoS2 films are able to generate mechanical stresses of about 17 megapascals-higher than mammalian muscle (about 0.3 megapascals) 3 and comparable to ceramic piezoelectric actuators (about 40 megapascals)-and strains of about 0.6 per cent, operating at frequencies up to 1 hertz. The actuation performance is attributed to the high electrical conductivity of the metallic 1T phase of MoS2 nanosheets, the elastic modulus of restacked MoS2 layers (2 to 4 gigapascals) and fast proton diffusion between the nanosheets. These results could lead to new electrochemical actuators for high-strain and high-frequency applications.
C1 [Acerce, Muharrem; Akdogan, E. Koray; Chhowalla, Manish] Rutgers State Univ, Mat Sci & Engn, 607 Taylor Rd, Piscataway, NJ 08854 USA.
C3 Rutgers University System; Rutgers University New Brunswick
RP Chhowalla, M (corresponding author), Rutgers State Univ, Mat Sci & Engn, 607 Taylor Rd, Piscataway, NJ 08854 USA.
EM manish1@soe.rutgers.edu
FU Turkish Ministry of Education; NSF [ECCS 1128335]; Rutgers MSE Department
NR 43
TC 254
Z9 269
U1 9
U2 609
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 21
PY 2017
VL 549
IS 7672
BP 370
EP +
DI 10.1038/nature23668
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FH7PB
UT WOS:000411381300032
PM 28854166
DA 2026-03-09
ER

PT J
AU Houle, D
   Bolstad, GH
   van der Linde, K
   Hansen, TF
AF Houle, David
   Bolstad, Geir H.
   van der Linde, Kim
   Hansen, Thomas F.
TI Mutation predicts 40 million years of fly wing evolution
SO NATURE
LA English
DT Article
ID genetic principal components; divergence times; molecular phylogeny; drosophila; covariance; evolvability; constraint; patterns; selection; rates
AB Mutation enables evolution, but the idea that adaptation is also shaped by mutational variation is controversial(1-4). Simple evolutionary hypotheses predict such a relationship if the supply of mutations constrains evolution(5,6), but it is not clear that constraints exist, and, even if they do, they may be overcome by long-term natural selection(7). Quantification of the relationship between mutation and phenotypic divergence among species will help to resolve these issues. Here we use precise data on over 50,000 Drosophilid fly wings to demonstrate unexpectedly strong positive relationships between variation produced by mutation, standing genetic variation, and the rate of evolution over the last 40 million years. Our results are inconsistent with simple constraint hypotheses because the rate of evolution is very low relative to what both mutational and standing variation could allow. In principle, the constraint hypothesis could be rescued if the vast majority of mutations are so deleterious that they cannot contribute to evolution, but this also requires the implausible assumption that deleterious mutations have the same pattern of effects as potentially advantageous ones. Our evidence for a strong relationship between mutation and divergence in a slowly evolving structure challenges the existing models of mutation in evolution.
C1 [Houle, David; Bolstad, Geir H.; van der Linde, Kim] Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA.
   [Bolstad, Geir H.] Norwegian Inst Nat Res NINA, NO-7485 Trondheim, Norway.
   [van der Linde, Kim] Anim Genet Inc, 1336 Timberlane Rd, Tallahassee, FL 32312 USA.
   [Hansen, Thomas F.] Univ Oslo, Dept Biol, CEES, N-0316 Oslo, Norway.
   [Hansen, Thomas F.] Univ Oslo, EVOGENE, N-0316 Oslo, Norway.
C3 State University System of Florida; Florida State University; Norwegian Institute Nature Research; University of Oslo; University of Oslo
RP Houle, D (corresponding author), Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA.
EM dhoule@bio.fsu.edu
FU US NSF DEB [0129219, 0950002]; NSERC
NR 62
TC 137
Z9 149
U1 2
U2 94
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 24
PY 2017
VL 548
IS 7668
BP 447
EP +
DI 10.1038/nature23473
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FE5VI
UT WOS:000408279000037
PM 28792935
DA 2026-03-09
ER

PT J
AU Ma, C
   Meyers, SR
   Sageman, BB
AF Ma, Chao
   Meyers, Stephen R.
   Sageman, Bradley B.
TI Theory of chaotic orbital variations confirmed by Cretaceous geological evidence
SO NATURE
LA English
DT Article
ID western interior basin; insolation quantity; coniacian; biostratigraphy; milankovitch; behavior; cycles; earth
AB Variations in the Earth's orbit and spin vector are a primary control on insolation and climate; their recognition in the geological record has revolutionized our understanding of palaeoclimate dynamics(1), and has catalysed improvements in the accuracy and precision of the geological timescale(2). Yet the secular evolution of the planetary orbits beyond 50 million years ago remains highly uncertain, and the chaotic dynamical nature of the Solar System predicted by theoretical models has yet to be rigorously confirmed by well constrained (radioisotopically calibrated and anchored) geological data(2-4). Here we present geological evidence for a chaotic resonance transition associated with interactions between the orbits of Mars and the Earth, using an integrated radioisotopic and astronomical timescale from the Cretaceous Western Interior Basin of what is now North America(5). This analysis confirms the predicted chaotic dynamical behaviour of the Solar System, and provides a constraint for refining numerical solutions for insolation, which will enable a more precise and accurate geological timescale to be produced.
C1 [Ma, Chao; Meyers, Stephen R.] Univ Wisconsin, Dept Geosci, Madison, WI 53706 USA.
   [Sageman, Bradley B.] Northwestern Univ, Dept Earth & Planetary Sci, Evanston, IL USA.
C3 University of Wisconsin System; University of Wisconsin Madison; Northwestern University
RP Meyers, SR (corresponding author), Univ Wisconsin, Dept Geosci, Madison, WI 53706 USA.
EM smeyers@geology.wisc.edu
FU NSF [EAR-1151438, EAR-0959108]; Directorate For Geosciences; Division Of Earth Sciences [1151438] Funding Source: National Science Foundation
NR 37
TC 106
Z9 124
U1 1
U2 73
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 23
PY 2017
VL 542
IS 7642
BP 468
EP +
DI 10.1038/nature21402
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1RG
UT WOS:000395094100034
PM 28230127
DA 2026-03-09
ER

PT J
AU Mordmüller, B
   Surat, G
   Lagler, H
   Chakravarty, S
   Ishizuka, AS
   Lalremruata, A
   Gmeiner, M
   Campo, JJ
   Esen, M
   Ruben, AJ
   Held, J
   Calle, CL
   Mengue, JB
   Gebru, T
   Ibáñez, J
   Sulyok, M
   James, ER
   Billingsley, PF
   Kc, N
   Manoj, A
   Murshedkar, T
   Gunasekera, A
   Appen, AGE
   Li, T
   Stafford, RE
   Li, ML
   Felgner, PL
   Seder, RA
   Richie, TL
   Sim, BKL
   Hoffman, SL
   Kremsner, PG
AF Mordmueller, Benjamin
   Surat, Guezin
   Lagler, Heimo
   Chakravarty, Sumana
   Ishizuka, Andrew S.
   Lalremruata, Albert
   Gmeiner, Markus
   Campo, Joseph J.
   Esen, Meral
   Ruben, Adam J.
   Held, Jana
   Calle, Carlos Lamsfus
   Mengue, Juliana B.
   Gebru, Tamirat
   Ibanez, Javier
   Sulyok, Mihaly
   James, Eric R.
   Billingsley, Peter F.
   Kc, Natasha
   Manoj, Anita
   Murshedkar, Tooba
   Gunasekera, Anusha
   Appen, Abraham G. E.
   Li, Tao
   Stafford, Richard E.
   Li, Minglin
   Felgner, Phil L.
   Seder, Robert A.
   Richie, Thomas L.
   Sim, B. Kim Lee
   Hoffman, Stephen L.
   Kremsner, Peter G.
TI Sterile protection against human malaria by chemoattenuated PfSPZ vaccine
SO NATURE
LA English
DT Article
ID plasmodium-falciparum sporozoites; direct venous inoculation; cd8+ t-cells; liver-stage; chloroquine prophylaxis; human volunteers; immunization; immunity; infection; antibody
AB A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites(1). A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (PfSPZ) inoculated by mosquitoes(2-4); by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ ('PfSPZ Vaccine')(5,6); or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine(7-10) or mefloquine(11) (chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ ('PfSPZ Challenge'(12,13)) to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac)(14). Three doses of 5.12 x 10(4) PfSPZ of PfSPZ Challenge(12,13) at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 x 10(3) (group I) or 1.28 x 10(4) (group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 x 10(4) PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas.
C1 [Mordmueller, Benjamin; Surat, Guezin; Lagler, Heimo; Lalremruata, Albert] Univ Tubingen, Inst Trop Med, Partner Site, D-72074 Tubingen, Germany.
   [Gmeiner, Markus; Held, Jana; Gebru, Tamirat; James, Eric R.] German Ctr Infect Res, Partner Site, D-72074 Tubingen, Germany.
   [Chakravarty, Sumana; Billingsley, Peter F.; Murshedkar, Tooba; Hoffman, Stephen L.] Med Univ Vienna, Div Infect Dis & Trop Med, Dept Med, A-1090 Vienna, Austria.
   [Seder, Robert A.] Sanaria Inc, Rockville, MD 20850 USA.
   [Gmeiner, Markus; Ibanez, Javier; James, Eric R.; Kc, Natasha] NIAID, NIH, Vaccine Res Ctr VRC, Bethesda, MD 20892 USA.
   [Billingsley, Peter F.; Kc, Natasha] Antigen Discovery Inc, Irvine, CA 92618 USA.
   [Campo, Joseph J.; Mengue, Juliana B.; James, Eric R.; Manoj, Anita] Protein Potential LLC, Rockville, MD 20850 USA.
   [Ishizuka, Andrew S.; Calle, Carlos Lamsfus; Appen, Abraham G. E.; Li, Tao] Univ Calif Irvine, Dept Med, Irvine, CA 92697 USA.
C3 Eberhard Karls University of Tubingen; German Center for Infection Research; Medical University of Vienna; Sanaria Inc.; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); University of California System; University of California Irvine
RP Hoffman, SL (corresponding author), Med Univ Vienna, Div Infect Dis & Trop Med, Dept Med, A-1090 Vienna, Austria.
EM slhoffman@sanaria.com
FU German Federal Ministry of Education and Research (BMBF) through the German Center for Infection Research (DZIF); National Institute of Allergy and Infectious Diseases of the National Institutes of Health under SBIR [5R44AI058375, 5R44AI055229]; intramural research program of the VRC, NIAID, NIH; NIAID SBIR [5R44AI066791]; Bill & Melinda Gates Foundation; National Institute of Allergy and Infectious Diseases [ZIAAI005107] Funding Source: NIH RePORTER
NR 45
TC 325
Z9 355
U1 1
U2 56
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 23
PY 2017
VL 542
IS 7642
BP 445
EP +
DI 10.1038/nature21060
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1RG
UT WOS:000395094100029
PM 28199305
DA 2026-03-09
ER

PT J
AU Flyamer, IM
   Gassler, J
   Imakaev, M
   Brandao, HB
   Ulianov, SV
   Abdennur, N
   Razin, SV
   Mirny, LA
   Tachibana-Konwalski, K
AF Flyamer, Ilya M.
   Gassler, Johanna
   Imakaev, Maxim
   Brandao, Hugo B.
   Ulianov, Sergey V.
   Abdennur, Nezar
   Razin, Sergey V.
   Mirny, Leonid A.
   Tachibana-Konwalski, Kikue
TI Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition
SO NATURE
LA English
DT Article
ID differential transcriptional activity; chromosome conformation capture; genome organization; domains; cohesin; architecture; configuration; principles; landscape; map
AB Chromatin is reprogrammed after fertilization to produce a totipotent zygote with the potential to generate a new organism(1). The maternal genome inherited from the oocyte and the paternal genome provided by sperm coexist as separate haploid nuclei in the zygote. How these two epigenetically distinct genomes are spatially organized is poorly understood. Existing chromosome conformation capture-based methods(2-5) are not applicable to oocytes and zygotes owing to a paucity of material. To study three-dimensional chromatin organization in rare cell types, we developed a single-nucleus Hi-C (high-resolution chromosome conformation capture) protocol that provides greater than tenfold more contacts per cell than the previous method(2). Here we show that chromatin architecture is uniquely reorganized during the oocyte-to-zygote transition in mice and is distinct in paternal and maternal nuclei within single-cell zygotes. Features of genomic organization including compartments, topologically associating domains (TADs) and loops are present in individual oocytes when averaged over the genome, but the presence of each feature at a locus varies between cells. At the sub-megabase level, we observed stochastic clusters of contacts that can occur across TAD boundaries but average into TADs. Notably, we found that TADs and loops, but not compartments, are present in zygotic maternal chromatin, suggesting that these are generated by different mechanisms. Our results demonstrate that the global chromatin organization of zygote nuclei is fundamentally different from that of other interphase cells. An understanding of this zygotic chromatin 'ground state' could potentially provide insights into reprogramming cells to a state of totipotency.
C1 [Flyamer, Ilya M.; Gassler, Johanna; Tachibana-Konwalski, Kikue] Austrian Acad Sci, Vienna Bioctr VBC, IMBA Inst Mol Biotechnol, Dr Bohr Gasse 3, A-1030 Vienna, Austria.
   [Flyamer, Ilya M.; Ulianov, Sergey V.; Razin, Sergey V.] Russian Acad Sci, Inst Gene Biol, Moscow 119334, Russia.
   [Flyamer, Ilya M.; Ulianov, Sergey V.; Razin, Sergey V.] Lomonosov Moscow State Univ, Fac Biol, Moscow 119234, Russia.
   [Imakaev, Maxim; Mirny, Leonid A.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA.
   [Imakaev, Maxim; Mirny, Leonid A.] MIT, Dept Phys, Cambridge, MA 02139 USA.
   [Brandao, Hugo B.; Mirny, Leonid A.] Harvard Univ, Harvard Program Biophys, Cambridge, MA 02138 USA.
   [Abdennur, Nezar] MIT, Computat & Syst Biol Program, Cambridge, MA 02139 USA.
   [Flyamer, Ilya M.] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland.
C3 Austrian Academy of Sciences; Vienna Biocenter (VBC); Institute of Molecular Biotechnology (IMBA); Russian Academy of Sciences; Institute of Gene Biology (IGB) of Russian Academy of Sciences; Lomonosov Moscow State University; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Harvard University; Massachusetts Institute of Technology (MIT); University of Edinburgh
RP Mirny, LA (corresponding author), MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA.; Mirny, LA (corresponding author), MIT, Dept Phys, Cambridge, MA 02139 USA.; Mirny, LA (corresponding author), Harvard Univ, Harvard Program Biophys, Cambridge, MA 02138 USA.
EM leonid@mit.edu; kikue.tachibana@imba.oeaw.ac.at
FU Austrian Science Fund (FWF) [W1238-B20]; Natural Sciences and Engineering Research Council of Canada, PGS-D; Austrian Academy of Sciences; European Research Council [ERC-StG-336460 ChromHeritance]; Russian Science Foundation [14-24-00022]; National Institute of Health [R01 GM114190, U54 DK107980]; National Science Foundation [1504942]; Russian Science Foundation [17-24-00005] Funding Source: Russian Science Foundation; National Institute of General Medical Sciences [R01GM114190] Funding Source: NIH RePORTER; Austrian Science Fund (FWF) [W1238] Funding Source: Austrian Science Fund (FWF)
NR 40
TC 578
Z9 685
U1 0
U2 128
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 6
PY 2017
VL 544
IS 7648
BP 110
EP +
DI 10.1038/nature21711
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EQ8GQ
UT WOS:000398323300043
PM 28355183
DA 2026-03-09
ER

PT J
AU Ni, JD
   Baik, LS
   Holmes, TC
   Montell, C
AF Ni, Jinfei D.
   Baik, Lisa S.
   Holmes, Todd C.
   Montell, Craig
TI A rhodopsin in the brain functions in circadian photoentrainment in Drosophila
SO NATURE
LA English
DT Article
ID r8 photoreceptor cells; pacemaker neurons; lateral neurons; visual-system; clock neurons; gene; melanogaster; cryptochrome; rhythm; r7
AB Animals partition their daily activity rhythms through their internal circadian clocks, which are synchronized by oscillating day-night cycles of light. The fruitfly Drosophila melanogaster senses day-night cycles in part through rhodopsin-dependent light reception in the compound eye and photoreceptor cells in the Hofbauer-Buchner eyelet(1). A more noteworthy light entrainment pathway is mediated by central pacemaker neurons in the brain. The Drosophila circadian clock is extremely sensitive to light. However, the only known light sensor in pacemaker neurons, the flavoprotein cryptochrome (Cry)(2,3), responds only to high levels of light in vitro(4). These observations indicate that there is an additional light-sensing pathway in fly pacemaker neurons(5). Here we describe a previously uncharacterized rhodopsin, Rh7, which contributes to circadian light entrainment by circadian pacemaker neurons in the brain. The pacemaker neurons respond to violet light, and this response depends on Rh7. Loss of either cry or rh7 caused minor defects in photoentrainment, whereas loss of both caused profound impairment. The circadian photoresponse to constant light was impaired in rh7 mutant flies, especially under dim light. The demonstration that Rh7 functions in circadian pacemaker neurons represents, to our knowledge, the first role for an opsin in the central brain.
C1 [Ni, Jinfei D.; Montell, Craig] Univ Calif Santa Barbara, Neurosci Res Inst, Santa Barbara, CA 93106 USA.
   [Ni, Jinfei D.; Montell, Craig] Univ Calif Santa Barbara, Dept Mol Cellular & Dev Biol, Santa Barbara, CA 93106 USA.
   [Ni, Jinfei D.] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA.
   [Baik, Lisa S.; Holmes, Todd C.] Univ Calif Irvine, Dept Physiol & Biophys, Irvine, CA 92697 USA.
   [Holmes, Todd C.] Univ Calif San Diego, Ctr Circadian Biol, La Jolla, CA 92093 USA.
C3 University of California System; University of California Santa Barbara; University of California System; University of California Santa Barbara; Johns Hopkins University; University of California System; University of California Irvine; University of California System; University of California San Diego
RP Montell, C (corresponding author), Univ Calif Santa Barbara, Neurosci Res Inst, Santa Barbara, CA 93106 USA.; Montell, C (corresponding author), Univ Calif Santa Barbara, Dept Mol Cellular & Dev Biol, Santa Barbara, CA 93106 USA.
EM craig.montell@lifesci.ucsb.edu
FU National Eye Institute [EY008117]; National Institute on Deafness and other Communication Disorders [DC007864]; National Institute of General Medical Sciences [GM102965, GM107405]; National Eye Institute [R01EY008117] Funding Source: NIH RePORTER; National Institute on Deafness and Other Communication Disorders [R01DC007864] Funding Source: NIH RePORTER
NR 46
TC 112
Z9 143
U1 1
U2 78
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 18
PY 2017
VL 545
IS 7654
BP 340
EP +
DI 10.1038/nature22325
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV0WF
UT WOS:000401466500061
PM 28489826
DA 2026-03-09
ER

PT J
AU Castrillo, G
   Teixeira, PJPL
   Paredes, SH
   Law, TF
   de Lorenzo, L
   Feltcher, ME
   Finkel, OM
   Breakfield, NW
   Mieczkowski, P
   Jones, CD
   Paz-Ares, J
   Dangl, JL
AF Castrillo, Gabriel
   Teixeira, Paulo Jose Pereira Lima
   Paredes, Sur Herrera
   Law, Theresa F.
   de Lorenzo, Laura
   Feltcher, Meghan E.
   Finkel, Omri M.
   Breakfield, Natalie W.
   Mieczkowski, Piotr
   Jones, Corbin D.
   Paz-Ares, Javier
   Dangl, Jeffery L.
TI Root microbiota drive direct integration of phosphate stress and immunity
SO NATURE
LA English
DT Article
ID differential expression analysis; rna-seq experiments; plant; arabidopsis; starvation; responses; identification; colonization; degradation; deficiency
AB Plants live in biogeochemically diverse soils with diverse microbiota. Plant organs associate intimately with a subset of these microbes, and the structure of the microbial community can be altered by soil nutrient content. Plant-associated microbes can compete with the plant and with each other for nutrients, but may also carry traits that increase the productivity of the plant. It is unknown how the plant immune system coordinates microbial recognition with nutritional cues during microbiome assembly. Here we establish that a genetic network controlling the phosphate stress response influences the structure of the root microbiome community, even under non-stress phosphate conditions. We define a molecular mechanism regulating coordination between nutrition and defence in the presence of a synthetic bacterial community. We further demonstrate that the master transcriptional regulators of phosphate stress response in Arabidopsis thaliana also directly repress defence, consistent with plant prioritization of nutritional stress over defence. Our work will further efforts to define and deploy useful microbes to enhance plant performance.
C1 [Castrillo, Gabriel; Teixeira, Paulo Jose Pereira Lima; Paredes, Sur Herrera; Law, Theresa F.; Feltcher, Meghan E.; Finkel, Omri M.; Breakfield, Natalie W.; Jones, Corbin D.; Dangl, Jeffery L.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA.
   [Castrillo, Gabriel; Teixeira, Paulo Jose Pereira Lima; Paredes, Sur Herrera; Law, Theresa F.; Feltcher, Meghan E.; Finkel, Omri M.; Breakfield, Natalie W.; Dangl, Jeffery L.] Univ N Carolina, Howard Hughes Med Inst, Chapel Hill, NC 27599 USA.
   [Paredes, Sur Herrera; Jones, Corbin D.; Dangl, Jeffery L.] Univ N Carolina, Curriculum Bioinformat & Comp Biol, Chapel Hill, NC 27599 USA.
   [de Lorenzo, Laura; Paz-Ares, Javier] CNB CSIC, Dept Plant Mol Genet, Darwin 3, E-28049 Madrid, Spain.
   [Mieczkowski, Piotr; Jones, Corbin D.; Dangl, Jeffery L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA.
   [Mieczkowski, Piotr; Jones, Corbin D.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA.
   [Mieczkowski, Piotr; Jones, Corbin D.; Dangl, Jeffery L.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA.
   [Jones, Corbin D.; Dangl, Jeffery L.] Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA.
   [Dangl, Jeffery L.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA.
   [de Lorenzo, Laura; Breakfield, Natalie W.] NewLeaf Symbiot, St Louis, MO 63132 USA.
C3 University of North Carolina; University of North Carolina Chapel Hill; Howard Hughes Medical Institute; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Centro Nacional de Biotecnologia (CNB); University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill
RP Dangl, JL (corresponding author), Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA.; Dangl, JL (corresponding author), Univ N Carolina, Howard Hughes Med Inst, Chapel Hill, NC 27599 USA.; Dangl, JL (corresponding author), Univ N Carolina, Curriculum Bioinformat & Comp Biol, Chapel Hill, NC 27599 USA.; Dangl, JL (corresponding author), Univ N Carolina, Dept Genet, Chapel Hill, NC USA.; Dangl, JL (corresponding author), Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA.; Dangl, JL (corresponding author), Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA.; Dangl, JL (corresponding author), Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA.
EM dangl@email.unc.edu
FU NSF INSPIRE grant [IOS-1343020]; DOE-USDA [DE-SC001043]; NIH [T32 GM067553-06]; Pew Latin American Fellows Program in the Biomedical Sciences; HHMI; Gordon and Betty Moore Foundation [GBMF3030]; NIH NRSA [F32-GM112345-02, F32-GM117758-01]; NIH NRSA Fellowship [F32-GM103156]; Spanish Ministry of Economy and Competitiveness (MINECO) [BIO2014-60453-R, EUI2008-03748]; National Institute of Environmental Health Sciences [P30ES010126] Funding Source: NIH RePORTER; Direct For Biological Sciences; Division Of Integrative Organismal Systems [1343020] Funding Source: National Science Foundation
NR 55
TC 694
Z9 819
U1 29
U2 1105
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 23
PY 2017
VL 543
IS 7646
BP 513
EP +
DI 10.1038/nature21417
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EO9OM
UT WOS:000397018000043
PM 28297714
DA 2026-03-09
ER

PT J
AU Hon, CC
   Ramilowski, JA
   Harshbarger, J
   Bertin, N
   Rackham, OJL
   Gough, J
   Denisenko, E
   Schmeier, S
   Poulsen, TM
   Severin, J
   Lizio, M
   Kawaji, H
   Kasukawa, T
   Itoh, M
   Burroughs, AM
   Noma, S
   Djebali, S
   Alam, T
   Medvedeva, YA
   Testa, AC
   Lipovich, L
   Yip, CW
   Abugessaisa, I
   Mendez, M
   Hasegawa, A
   Tang, D
   Lassmann, T
   Heutink, P
   Babina, M
   Wells, CA
   Kojima, S
   Nakamura, Y
   Suzuki, H
   Daub, CO
   de Hoon, MJL
   Arner, E
   Hayashizaki, Y
   Carninci, P
   Forrest, ARR
AF Hon, Chung-Chau
   Ramilowski, Jordan A.
   Harshbarger, Jayson
   Bertin, Nicolas
   Rackham, Owen J. L.
   Gough, Julian
   Denisenko, Elena
   Schmeier, Sebastian
   Poulsen, Thomas M.
   Severin, Jessica
   Lizio, Marina
   Kawaji, Hideya
   Kasukawa, Takeya
   Itoh, Masayoshi
   Burroughs, A. Maxwell
   Noma, Shohei
   Djebali, Sarah
   Alam, Tanvir
   Medvedeva, Yulia A.
   Testa, Alison C.
   Lipovich, Leonard
   Yip, Chi-Wai
   Abugessaisa, Imad
   Mendez, Mickael
   Hasegawa, Akira
   Tang, Dave
   Lassmann, Timo
   Heutink, Peter
   Babina, Magda
   Wells, Christine A.
   Kojima, Soichi
   Nakamura, Yukio
   Suzuki, Harukazu
   Daub, Carsten O.
   de Hoon, Michiel J. L.
   Arner, Erik
   Hayashizaki, Yoshihide
   Carninci, Piero
   Forrest, Alistair R. R.
TI An atlas of human long non-coding RNAs with accurate 5′ ends
SO NATURE
LA English
DT Article
ID genome-wide association; gene-expression; transcription; architecture; annotation; landscape; evolution; database; lncrna; quantification
AB Long non-coding RNAs (lncRNAs) are largely heterogeneous and functionally uncharacterized. Here, using FANTOM5 cap analysis of gene expression (CAGE) data, we integrate multiple transcript collections to generate a comprehensive atlas of 27,919 human lncRNA genes with high-confidence 5' ends and expression profiles across 1,829 samples from the major human primary cell types and tissues. Genomic and epigenomic classification of these lncRNAs reveals that most intergenic lncRNAs originate from enhancers rather than from promoters. Incorporating genetic and expression data, we show that lncRNAs overlapping trait-associated single nucleotide polymorphisms are specifically expressed in cell types relevant to the traits, implicating these lncRNAs in multiple diseases. We further demonstrate that lncRNAs overlapping expression quantitative trait loci (eQTL)-associated single nucleotide polymorphisms of messenger RNAs are co-expressed with the corresponding messenger RNAs, suggesting their potential roles in transcriptional regulation. Combining these findings with conservation data, we identify 19,175 potentially functional lncRNAs in the human genome.
C1 [Hon, Chung-Chau; Ramilowski, Jordan A.; Harshbarger, Jayson; Severin, Jessica; Lizio, Marina; Kawaji, Hideya; Kasukawa, Takeya; Itoh, Masayoshi; Burroughs, A. Maxwell; Noma, Shohei; Yip, Chi-Wai; Abugessaisa, Imad; Mendez, Mickael; Hasegawa, Akira; Tang, Dave; Lassmann, Timo; Heutink, Peter; Suzuki, Harukazu; Daub, Carsten O.; de Hoon, Michiel J. L.; Arner, Erik; Carninci, Piero; Forrest, Alistair R. R.] RIKEN, Ctr Life Sci Technol, Div Gen Technol, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan.
   [Ramilowski, Jordan A.; Harshbarger, Jayson; Bertin, Nicolas; Severin, Jessica; Lizio, Marina; Kawaji, Hideya; Itoh, Masayoshi; Burroughs, A. Maxwell; Noma, Shohei; Mendez, Mickael; Hasegawa, Akira; Tang, Dave; Lassmann, Timo; Suzuki, Harukazu; Daub, Carsten O.; de Hoon, Michiel J. L.; Arner, Erik; Hayashizaki, Yoshihide; Carninci, Piero; Forrest, Alistair R. R.] RIKEN, Omics Sci Ctr, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan.
   [Bertin, Nicolas] Natl Univ Singapore, Ctr Translat Med, Canc Sci Inst Singapore, 14 Med Dr 12-01, Singapore 117599, Singapore.
   [Rackham, Owen J. L.; Gough, Julian] Univ Bristol, Dept Comp Sci, Life Sci Bldg,24 Tyndall Ave, Bristol BS8 1TQ, Avon, England.
   [Rackham, Owen J. L.] Duke NUS Med Sch, Program Cardiovasc & Metab Disorders, 8 Coll Rd, Singapore 169857, Singapore.
   [Denisenko, Elena; Schmeier, Sebastian] Massey Univ Auckland, Inst Nat & Math Sci, Albany 0632, New Zealand.
   [Poulsen, Thomas M.] Natl Inst Adv Ind Sci & Technol, Biotechnol Res Inst Drug Discovery BRD, Tsukuba Cent 2,1-1-1 Umezono, Tsukuba, Ibaraki 3058568, Japan.
   [Kawaji, Hideya; Itoh, Masayoshi; Hayashizaki, Yoshihide] RIKEN, Prevent Med & Diag Innovat Program, 2-1 Hirosawa, Wako, Saitama 3510198, Japan.
   [Burroughs, A. Maxwell] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA.
   [Djebali, Sarah] Barcelona Inst Sci & Technol, Ctr Gen Regulat CRG, Dr Aiguader 88, Barcelona 08003, Spain.
   [Djebali, Sarah] UPF, Barcelona Biomed Res Pk PRBB, Dr Aiguader 88, Barcelona 08003, Spain.
   [Alam, Tanvir] KAUST, Computat Biosci Res Ctr, Comp Elect & Math Sci & Engn Div, Thuwal 239556900, Saudi Arabia.
   [Medvedeva, Yulia A.] RAS, Biotechnol Res Ctr, Inst Bioengn, Moscow 119071, Russia.
   [Medvedeva, Yulia A.] RAS, Vavilov Inst Gen Genet, Moscow 119991, Russia.
   [Testa, Alison C.; Forrest, Alistair R. R.] Univ Western Australia, QEII Med Ctr, Harry Perkins Inst Med Res, Nedlands, WA 6009, Australia.
   [Testa, Alison C.; Forrest, Alistair R. R.] Univ Western Australia, Med Res Ctr, Nedlands, WA 6009, Australia.
   [Lipovich, Leonard] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA.
   [Lipovich, Leonard] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA.
   [Tang, Dave; Lassmann, Timo] Univ Western Australia, Telethon Kids Inst, 100 Roberts Rd, Subiaco, WA 6008, Australia.
   [Heutink, Peter] German Ctr Neurodegenerat Dis DZNE, D-72076 Tubingen, Germany.
   [Babina, Magda] Charite, Dept Dermatol & Allergy, D-10117 Berlin, Germany.
   [Wells, Christine A.] Univ Queensland, Australian Inst Bioengn & Nanotechnol, Brisbane, Qld 4072, Australia.
   [Wells, Christine A.] Univ Melbourne, Fac Med, Dept Anat & Neurosci, Melbourne, Vic 3010, Australia.
   [Kojima, Soichi] RIKEN, CLST Div Biofunct Dynam Imaging, Wako, Saitama 3510198, Japan.
   [Nakamura, Yukio] RIKEN, BioResource Ctr, Cell Engn Div, Tsukuba, Ibaraki 3050074, Japan.
   [Nakamura, Yukio] Univ Tsukuba, Fac Med, Tsukuba, Ibaraki 3058577, Japan.
   [Daub, Carsten O.] Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.
   [Bertin, Nicolas] Human Longev Singapore Pte Ltd, Singapore, Singapore.
   [Djebali, Sarah] Univ Toulouse, INRA, INPT, ENVT,GenPhySE, Castanet Tolosan, France.
   [Mendez, Mickael] Univ Toronto, Dept Comp Sci, Toronto, ON, Canada.
C3 RIKEN; RIKEN; National University of Singapore; University of Bristol; National University of Singapore; Massey University; National Institute of Advanced Industrial Science & Technology (AIST); RIKEN; National Institutes of Health (NIH) - USA; NIH National Library of Medicine (NLM); Barcelona Institute of Science & Technology; Pompeu Fabra University; Centre de Regulacio Genomica (CRG); Pompeu Fabra University; Barcelona Biomedical Research Park; King Abdullah University of Science & Technology; Research Center of Biotechnology RAS; Russian Academy of Sciences; Russian Academy of Sciences; Vavilov Institute of General Genetics; Queen Elizabeth II Medical Centre; Harry Perkins Institute of Medical Research; University of Western Australia; University of Western Australia; Wayne State University; Wayne State University; The Kids Research Institute Australia; University of Western Australia; Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE); Eberhard Karls University of Tubingen; Eberhard Karls University Hospital; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; University of Queensland; University of Melbourne; RIKEN; RIKEN; University of Tsukuba; Karolinska Institutet; Universite Federale Toulouse Midi-Pyrenees (ComUE); Universite de Toulouse; Institut National Polytechnique de Toulouse; Ecole Nationale Veterinaire de Toulouse; INRAE; University of Toronto
RP Carninci, P; Forrest, ARR (corresponding author), RIKEN, Ctr Life Sci Technol, Div Gen Technol, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan.; Carninci, P; Forrest, ARR (corresponding author), RIKEN, Omics Sci Ctr, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan.; Forrest, ARR (corresponding author), Univ Western Australia, QEII Med Ctr, Harry Perkins Inst Med Res, Nedlands, WA 6009, Australia.; Forrest, ARR (corresponding author), Univ Western Australia, Med Res Ctr, Nedlands, WA 6009, Australia.
EM carninci@riken.jp; alistair.forrest@gmail.com
FU MEXT; MEXT, Japan; Cancer Research Trust; MACA Ride to Conquer Cancer; Australian Research Council [DP160101960]; National Human Genome Research Institute of the National Institutes of Health [U54HG007004]; Ministry of Economy and Competitiveness (MINECO) [BIO2011-26205]; Spanish Ministry of Economy and Competitiveness [SEV-2012-0208]; Russian Science Foundation [15-14-30002]; BBSRC [BB/G022771/1] Funding Source: UKRI; Russian Science Foundation [15-14-30002] Funding Source: Russian Science Foundation; Biotechnology and Biological Sciences Research Council [BB/G022771/1] Funding Source: researchfish; National Cancer Institute [P30CA022453] Funding Source: NIH RePORTER
NR 68
TC 762
Z9 879
U1 1
U2 211
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 9
PY 2017
VL 543
IS 7644
BP 199
EP +
DI 10.1038/nature21374
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0GQ
UT WOS:000395688700030
PM 28241135
DA 2026-03-09
ER

PT J
AU Dong, XC
   Zhao, B
   Iacob, RE
   Zhu, JH
   Koksal, AC
   Lu, CF
   Engen, JR
   Springer, TA
AF Dong, Xianchi
   Zhao, Bo
   Iacob, Roxana E.
   Zhu, Jianghai
   Koksal, Adem C.
   Lu, Chafen
   Engen, John R.
   Springer, Timothy A.
TI Force interacts with macromolecular structure in activation of TGF-β
SO NATURE
LA English
DT Article
ID crystal-structure; integrin; scattering; fibronectin; ligand
AB Integrins are adhesion receptors that transmit force across the plasma membrane between extracellular ligands and the actin cytoskeleton. In activation of the transforming growth factor-beta 1 precursor (pro-TGF-beta 1), integrins bind to the prodomain, apply force, and release the TGF-beta growth factor. However, we know little about how integrins bind macromolecular ligands in the extracellular matrix or transmit force to them. Here we show how integrin alpha(V)beta(6) binds pro-TGF-beta 1 in an orientation biologically relevant for force-dependent release of TGF-beta from latency. The conformation of the prodomain integrin-binding motif differs in the presence and absence of integrin binding; differences extend well outside the interface and illustrate how integrins can remodel extracellular matrix. Remodelled residues outside the interface stabilize the integrin-bound conformation, adopt a conformation similar to earlier-evolving family members, and show how macromolecular components outside the binding motif contribute to integrin recognition. Regions in and outside the highly interdigitated interface stabilize a specific integrin/pro-TGF-beta orientation that defines the pathway through these macromolecules which actin-cytoskeleton-generated tensile force takes when applied through the integrin beta-subunit. Simulations of force-dependent activation of TGF-beta demonstrate evolutionary specializations for force application through the TGF-beta prodomain and through the beta- and not alpha-subunit of the integrin.
C1 [Dong, Xianchi; Zhao, Bo; Zhu, Jianghai; Koksal, Adem C.; Lu, Chafen; Springer, Timothy A.] Harvard Med Sch, Childrens Hosp Boston, Boston, MA 02115 USA.
   [Dong, Xianchi; Zhao, Bo; Zhu, Jianghai; Koksal, Adem C.; Lu, Chafen; Springer, Timothy A.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.
   [Iacob, Roxana E.; Engen, John R.] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA.
C3 Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Northeastern University
RP Springer, TA (corresponding author), Harvard Med Sch, Childrens Hosp Boston, Boston, MA 02115 USA.; Springer, TA (corresponding author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.
EM timothy.springer@childrens.harvard.edu
FU National Institutes of Health [R01AR067288]; Charles A. King Trust; Bank of America, N.A.; Waters Corporation
NR 26
TC 234
Z9 278
U1 1
U2 87
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 2
PY 2017
VL 542
IS 7639
BP 55
EP +
DI 10.1038/nature21035
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6MY
UT WOS:000396119300031
PM 28117447
DA 2026-03-09
ER

PT J
AU Wilck, N
   Matus, MG
   Kearney, SM
   Olesen, SW
   Forslund, K
   Bartolomaeus, H
   Haase, S
   Mähler, A
   Balogh, A
   Markó, L
   Vedenskaya, OV
   Kleiner, FH
   Tsvetkov, D
   Klug, L
   Costea, PI
   Sunagawa, S
   Maier, L
   Rakova, N
   Schatz, V
   Neubert, P
   Frätzer, C
   Krannich, A
   Gollasch, M
   Grohme, DA
   Côrte-Real, BF
   Gerlach, RG
   Basic, M
   Typas, A
   Wu, C
   Titze, JM
   Jantsch, J
   Boschmann, M
   Dechend, R
   Kleinewietfeld, M
   Kempa, S
   Bork, P
   Linker, RA
   Alm, EJ
   Müller, DN
AF Wilck, Nicola
   Matus, Mariana G.
   Kearney, Sean M.
   Olesen, Scott W.
   Forslund, Kristoffer
   Bartolomaeus, Hendrik
   Haase, Stefanie
   Maehler, Anja
   Balogh, Andras
   Marko, Lajos
   Vedenskaya, Olga V.
   Kleiner, Friedrich H.
   Tsvetkov, Dmitry
   Klug, Lars
   Costea, Paul I.
   Sunagawa, Shinichi
   Maier, Lisa
   Rakova, Natalia
   Schatz, Valentin
   Neubert, Patrick
   Fraetzer, Christian
   Krannich, Alexander
   Gollasch, Maik
   Grohme, Diana A.
   Corte-Real, Beatriz F.
   Gerlach, Roman G.
   Basic, Marijana
   Typas, Athanasios
   Wu, Chuan
   Titze, Jens M.
   Jantsch, Jonathan
   Boschmann, Michael
   Dechend, Ralf
   Kleinewietfeld, Markus
   Kempa, Stefan
   Bork, Peer
   Linker, Ralf A.
   Alm, Eric J.
   Mueller, Dominik N.
TI Salt-responsive gut commensal modulates TH17 axis and disease
SO NATURE
LA English
DT Article
ID aryl-hydrocarbon receptor; ii-induced hypertension; blood-pressure; sodium-intake; t-cell; microbiota; lactobacilli; community; impact; homeostasis
AB A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (T(H)17) cells, which can also contribute to hypertension. Induction of T(H)17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating T(H)17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased T(H)17 cells and increased blood pressure. Our results connect high salt intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.
C1 [Wilck, Nicola; Bartolomaeus, Hendrik; Maehler, Anja; Balogh, Andras; Kleiner, Friedrich H.; Tsvetkov, Dmitry; Rakova, Natalia; Gollasch, Maik; Boschmann, Michael; Dechend, Ralf; Mueller, Dominik N.] Max Delbruck Ctr Mol Med, Expt & Clin Res Ctr, D-13125 Berlin, Germany.
   [Wilck, Nicola; Bartolomaeus, Hendrik; Maehler, Anja; Balogh, Andras; Kleiner, Friedrich H.; Tsvetkov, Dmitry; Rakova, Natalia; Gollasch, Maik; Boschmann, Michael; Dechend, Ralf; Mueller, Dominik N.] Charite Univ Med Berlin, D-13125 Berlin, Germany.
   [Wilck, Nicola; Bartolomaeus, Hendrik; Balogh, Andras; Marko, Lajos; Tsvetkov, Dmitry; Gollasch, Maik; Dechend, Ralf; Mueller, Dominik N.] Charite Univ Med Berlin, D-10117 Berlin, Germany.
   [Wilck, Nicola; Bartolomaeus, Hendrik; Balogh, Andras; Marko, Lajos; Vedenskaya, Olga V.; Gollasch, Maik; Dechend, Ralf; Kempa, Stefan; Bork, Peer; Mueller, Dominik N.] Max Delbruck Ctr Mol Med, Helmholtz Assoc, D-13125 Berlin, Germany.
   [Wilck, Nicola; Bartolomaeus, Hendrik; Balogh, Andras; Marko, Lajos; Mueller, Dominik N.] DZHK German Ctr Cardiovasc Res, Partner Site Berlin, Berlin, Germany.
   [Wilck, Nicola; Bartolomaeus, Hendrik; Balogh, Andras; Marko, Lajos; Mueller, Dominik N.] BIH, Berlin, Germany.
   [Matus, Mariana G.; Kearney, Sean M.; Olesen, Scott W.; Alm, Eric J.] MIT, Ctr Microbiome Informat & Therapeut, Cambridge, MA 02139 USA.
   [Matus, Mariana G.; Kearney, Sean M.; Olesen, Scott W.; Alm, Eric J.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA.
   [Matus, Mariana G.] MIT, Computat & Syst Biol Program, Cambridge, MA 02139 USA.
   [Forslund, Kristoffer; Costea, Paul I.; Sunagawa, Shinichi] European Mol Biol Lab, Struct & Computat Biol Unit, D-69117 Heidelberg, Germany.
   [Haase, Stefanie] Friedrich Alexander Univ Erlangen Nuremberg, Dept Neurol, D-91054 Erlangen, Germany.
   [Vedenskaya, Olga V.; Kempa, Stefan] Inst Med Syst Biol BIMSB, Integrat Prote & Metabol Platform, D-13125 Berlin, Germany.
   [Vedenskaya, Olga V.] Charite Univ Med Berlin, Berlin Sch Integrat Oncol, Berlin, Germany.
   [Sunagawa, Shinichi] Swiss Fed Inst Technol, Inst Microbiol, CH-8092 Zurich, Switzerland.
   [Maier, Lisa] European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany.
   [Schatz, Valentin; Neubert, Patrick] Univ Regensburg, Univ Hosp Regensburg, Inst Clin Microbiol & Hyg, D-93053 Regensburg, Germany.
   [Fraetzer, Christian] Lipidomix GmbH, D-13125 Berlin, Germany.
   [Grohme, Diana A.] Tech Univ Dresden, Med Fac Carl Gustav Carus, Dept Clin Pathobiochem, Translat Immunol, D-01307 Dresden, Germany.
   [Corte-Real, Beatriz F.] Hasselt Univ, VIB Ctr Inflammat Res IRC, VIB Lab Translat Immunomodulat, Campus Diepenbeek, B-3590 Diepenbeek, Belgium.
   [Gerlach, Roman G.] Robert Koch Inst, Project Grp 5, D-38855 Wernigerode, Germany.
   [Basic, Marijana] Inst Lab Anim Sci, Hannover Med Sch, D-30625 Hannover, Germany.
   [Basic, Marijana] Cent Anim Facil, D-30625 Hannover, Germany.
   [Wu, Chuan] US Natl Inst Hlth, Natl Canc Inst, Exp Immunol Branch, Bethesda, MD USA.
   [Titze, Jens M.] Vanderbilt Univ, Sch Med, Div Clin Pharmacol, Nashville, TN 37212 USA.
   [Kleinewietfeld, Markus] Ctr Regenerat Therapies Dresden CRTD, D-01307 Dresden, Germany.
   [Bork, Peer] Heidelberg Univ, Mol Med Partnership Unit, D-69120 Heidelberg, Germany.
   [Bork, Peer] Univ Wurzburg, Dept Bioinformat, Bioctr, D-970740 Wurzburg, Germany.
C3 Helmholtz Association; Max Delbruck Center for Molecular Medicine; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Helmholtz Association; Max Delbruck Center for Molecular Medicine; German Centre for Cardiovascular Research; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); European Molecular Biology Laboratory (EMBL); University of Erlangen Nuremberg; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Swiss Federal Institutes of Technology Domain; ETH Zurich; European Molecular Biology Laboratory (EMBL); University of Regensburg; Technische Universitat Dresden; Carl Gustav Carus University Hospital; Flanders Institute for Biotechnology (VIB); Hasselt University; Robert Koch Institute; Hannover Medical School; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Vanderbilt University; Technische Universitat Dresden; Ruprecht Karls University Heidelberg; University of Wurzburg
RP Müller, DN (corresponding author), Max Delbruck Ctr Mol Med, Expt & Clin Res Ctr, D-13125 Berlin, Germany.; Alm, EJ (corresponding author), MIT, Ctr Microbiome Informat & Therapeut, Cambridge, MA 02139 USA.
EM ejalm@mit.edu; dominik.mueller@mdc-berlin.de
FU German Centre for Cardiovascular Research (DZHK) [BER 1.1 VD]; Center for Microbiome Informatics and Therapeutics; MetaCardis consortium; German Research Foundation (DFG); Novartis Pharma; European Research Council (ERC) under the European Union [640116]; government of Flanders, Belgium; Research Foundation Flanders (FWO), Belgium; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK043351] Funding Source: NIH RePORTER
NR 78
TC 1030
Z9 1201
U1 8
U2 395
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 30
PY 2017
VL 551
IS 7682
BP 585
EP +
DI 10.1038/nature24628
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FO1KW
UT WOS:000416520400034
PM 29143823
DA 2026-03-09
ER

PT J
AU Busslinger, GA
   Stocsits, RR
   van der Lelij, P
   Axelsson, E
   Tedeschi, A
   Galjart, N
   Peters, JM
AF Busslinger, Georg A.
   Stocsits, Roman R.
   van der Lelij, Petra
   Axelsson, Elin
   Tedeschi, Antonio
   Galjart, Niels
   Peters, Jan-Michael
TI Cohesin is positioned in mammalian genomes by transcription, CTCF and Wapl
SO NATURE
LA English
DT Article
ID differential expression analysis; gene-expression; sister chromatids; generation; domains; complex; sites
AB Mammalian genomes are spatially organized by CCCTC-binding factor (CTCF) and cohesin into chromatin loops(1,2) and topologically associated domains(3-6), which have important roles in gene regulation(1,2,4,5,7) and recombination(7-9). By binding to specific sequences(10), CTCF defines contact points for cohesin-mediated long-range chromosomal cis-interactions(1,2,4-7,11). Cohesin is also present at these sites(12,13), but has been proposed to be loaded onto DNA elsewhere(14,15) and to extrude chromatin loops until it encounters CTCF bound to DNA(16-19). How cohesin is recruited to CTCF sites, according to this or other models, is unknown. Here we show that the distribution of cohesin in the mouse genome depends on transcription, CTCF and the cohesin release factor Wings apart-like (Wapl). In CTCF-depleted fibroblasts, cohesin cannot be properly recruited to CTCF sites but instead accumulates at transcription start sites of active genes, where the cohesin-loading complex is located(14,15). In the absence of both CTCF and Wapl, cohesin accumulates in up to 70 kilobase-long regions at 3'-ends of active genes, in particular if these converge on each other. Changing gene expression modulates the position of these 'cohesin islands'. These findings indicate that transcription can relocate mammalian cohesin over long distances on DNA, as previously reported for yeast cohesin(20-23), that this translocation contributes to positioning cohesin at CTCF sites, and that active genes can be freed from cohesin either by transcription-mediated translocation or by Wapl-mediated release.
C1 [Busslinger, Georg A.; Stocsits, Roman R.; van der Lelij, Petra; Axelsson, Elin; Tedeschi, Antonio; Peters, Jan-Michael] Vienna Bioctr VBC, Res Inst Mol Pathol IMP, Campus Vienna Bioctr 1, A-1030 Vienna, Austria.
   [Galjart, Niels] Erasmus MC, Dept Cell Biol & Genet, NL-3000 CA Rotterdam, Netherlands.
   [Busslinger, Georg A.] Hubrecht Inst, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands.
   [Axelsson, Elin] Gregor Mendel Inst Mol Plant Biol, Dr Bohr Gasse 3, A-1030 Vienna, Austria.
   [Tedeschi, Antonio] Francis Crick Inst, 1 Midland Rd, London NW1 1AT, England.
C3 Vienna Biocenter (VBC); Research Institute of Molecular Pathology (IMP); Erasmus University Rotterdam; Erasmus MC; Royal Netherlands Academy of Arts & Sciences; Hubrecht Institute (KNAW); Austrian Academy of Sciences; Vienna Biocenter (VBC); Gregor Mendel Institute of Molecular Plant Biology (GMI); Francis Crick Institute
RP Peters, JM (corresponding author), Vienna Bioctr VBC, Res Inst Mol Pathol IMP, Campus Vienna Bioctr 1, A-1030 Vienna, Austria.
EM peters@imp.ac.at
FU Boehringer Ingelheim; Austrian Science Fund [SFB-F34]; Austrian Science Fund (Wittgenstein award) [Z196-B20]; Austrian Research Promotion Agency [FFG-834223, FFG-852936]; Austrian Research Promotion Agency (Laura Bassi Centre for Optimized Structural Studies grant) [FFG-840283]
NR 50
TC 328
Z9 395
U1 0
U2 65
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 27
PY 2017
VL 544
IS 7651
BP 503
EP +
DI 10.1038/nature22063
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET1TN
UT WOS:000400051900048
PM 28424523
DA 2026-03-09
ER

PT J
AU Shipman, SL
   Nivala, J
   Macklis, JD
   Church, GM
AF Shipman, Seth L. .
   Nivala, Jeff
   Macklis, Jeffrey D.
   Church, George M.
TI CRISPR-Cas encoding of a digital movie into the genomes of a population of living bacteria
SO NATURE
LA English
DT Article
ID information-storage; dna; adaptation; generation; resistance; immunity; elements
AB DNA is an excellent medium for archiving data. Recent efforts have illustrated the potential for information storage in DNA using synthesized oligonucleotides assembled in vitro(1-6). A relatively unexplored avenue of information storage in DNA is the ability to write information into the genome of a living cell by the addition of nucleotides over time. Using the Cas1-Cas2 integrase, the CRISPR-Cas microbial immune system stores the nucleotide content of invading viruses to confer adaptive immunity(7). When harnessed, this system has the potential to write arbitrary information into the genome(8). Here we use the CRISPR-Cas system to encode the pixel values of black and white images and a short movie into the genomes of a population of living bacteria. In doing so, we push the technical limits of this information storage system and optimize strategies to minimize those limitations. We also uncover underlying principles of the CRISPR-Cas adaptation system, including sequence determinants of spacer acquisition that are relevant for understanding both the basic biology of bacterial adaptation and its technological applications. This work demonstrates that this system can capture and stably store practical amounts of real data within the genomes of populations of living cells.
C1 [Shipman, Seth L. .; Nivala, Jeff; Church, George M.] Harvard Med Sch, Dept Genet, 77 Ave Louis Pasteur, Boston, MA 02115 USA.
   [Shipman, Seth L. .; Macklis, Jeffrey D.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Ctr Brain Sci, Cambridge, MA 02138 USA.
   [Shipman, Seth L. .; Macklis, Jeffrey D.] Harvard Univ, Harvard Stem Cell Inst, Bauer Lab 103, Cambridge, MA 02138 USA.
   [Shipman, Seth L. .; Nivala, Jeff; Church, George M.] Harvard Univ, Wyss Inst Biol Inspired Engn, Cambridge, MA 02138 USA.
C3 Harvard University; Harvard Medical School; Harvard University; Harvard University; Harvard University
RP Church, GM (corresponding author), Harvard Med Sch, Dept Genet, 77 Ave Louis Pasteur, Boston, MA 02115 USA.; Church, GM (corresponding author), Harvard Univ, Wyss Inst Biol Inspired Engn, Cambridge, MA 02138 USA.
EM gchurch@genetics.med.harvard.edu
FU National Institute of Mental Health [5R01MH103910]; National Human Genome Research Institute [5RM1HG008525]; Simons Foundation Autism Research Initiative [368485]; National Institute of Neurological Disorders and Stroke [5R01NS045523]; Paul G. Allen Frontiers Group; National Institute on Aging [T32AG000222] Funding Source: NIH RePORTER
NR 30
TC 258
Z9 335
U1 9
U2 286
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 20
PY 2017
VL 547
IS 7663
BP 345
EP +
DI 10.1038/nature23017
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB0OR
UT WOS:000405844900033
PM 28700573
DA 2026-03-09
ER

PT J
AU Petrenko, VV
   Mith, AMS
   Chaefer, HS
   Riedel, K
   Brook, E
   Baggenstos, D
   Harth, C
   Hua, Q
   Buizert, C
   Schilt, A
   Fain, X
   Mitchell, L
   Bauska, T
   Orsi, A
   Weiss, RF
   Everinghaus, JPS
AF Petrenko, Vasilii V.
   Mith, Andrew M. S.
   Chaefer, Hinrich S.
   Riedel, Katja
   Brook, Edward
   Baggenstos, Daniel
   Harth, Christina
   Hua, Quan
   Buizert, Christo
   Schilt, Adrian
   Fain, Xavier
   Mitchell, Logan
   Bauska, Thomas
   Orsi, Anais
   Weiss, Ray F.
   Everinghaus, Jeffrey P. S.
TI Minimal geological methane emissions during the Younger Dryas-Preboreal abrupt warming event
SO NATURE
LA English
DT Article
ID situ cosmogenic (ch4)-c-14; atmospheric ch4; taylor glacier; fossil-fuel; ice; c-14; (co)-c-14; climate; record; lakes
AB Methane (CH4) is a powerful greenhouse gas and plays a key part in global atmospheric chemistry. Natural geological emissions (fossil methane vented naturally from marine and terrestrial seeps and mud volcanoes) are thought to contribute around 52 teragrams of methane per year to the global methane source, about 10 per cent of the total, but both bottom-up methods (measuring emissions)(1) and top-down approaches (measuring atmospheric mole fractions and isotopes)(2) for constraining these geological emissions have been associated with large uncertainties. Here we use ice core measurements to quantify the absolute amount of radiocarbon-containing methane ((CH4)-C-14) in the past atmosphere and show that geological methane emissions were no higher than 15.4 teragrams per year (95 per cent confidence), averaged over the abrupt warming event that occurred between the Younger Dryas and Preboreal intervals, approximately 11,600 years ago. Assuming that past geological methane emissions were no lower than today(3,4), our results indicate that current estimates of today's natural geological methane emissions (about 52 teragrams per year)(1,2) are too high and, by extension, that current estimates of anthropogenic fossil methane emissions(2) are too low. Our results also improve on and confirm earlier findings(5-7) that the rapid increase of about 50 per cent in mole fraction of atmospheric methane at the Younger Dryas-Preboreal event was driven by contemporaneous methane from sources such as wetlands; our findings constrain the contribution from old carbon reservoirs (marine methane hydrates(8), permafrost(9) and methane trapped under ice(10)) to 19 per cent or less (95 per cent confidence). To the extent that the characteristics of the most recent deglaciation and the Younger Dryas-Preboreal warming are comparable to those of the current anthropogenic warming, our measurements suggest that large future atmospheric releases of methane from old carbon sources are unlikely to occur.
C1 [Petrenko, Vasilii V.] Univ Rochester, Dept Earth & Environm Sci, 601 Elmwood Ave, Rochester, NY 14627 USA.
   [Mith, Andrew M. S.; Hua, Quan] ANSTO, Locked Bag 2001, Kirrawee Dc, NSW 2232, Australia.
   [Chaefer, Hinrich S.; Riedel, Katja] Natl Inst Water & Atmospher Res NIWA, POB 14901,301 Evans Bay Parade, Wellington, New Zealand.
   [Brook, Edward; Buizert, Christo; Schilt, Adrian; Mitchell, Logan; Bauska, Thomas] Oregon State Univ, Coll Earth Ocean & Atmospher Sci, Corvallis, OR 97331 USA.
   [Baggenstos, Daniel; Harth, Christina; Orsi, Anais; Weiss, Ray F.; Everinghaus, Jeffrey P. S.] Univ Calif San Diego, Scripps Inst Oceanog, La Jolla, CA 92093 USA.
   [Baggenstos, Daniel] Univ Bern, Inst Phys, CH-3012 Bern, Switzerland.
   [Fain, Xavier] Univ Grenoble Alpes, CNRS, LGGE, UMR 5183, F-38041 Grenoble, France.
   [Mitchell, Logan] Univ Utah, Dept Atmospher Sci, Salt Lake City, UT 84112 USA.
   [Bauska, Thomas] Univ Cambridge, Dept Earth Sci, Cambridge CB2 3EQ, England.
   [Orsi, Anais] Univ Paris Saclay, Lab Sci Climat & Environm, LSCE IPSL, CEA CNRS UVSQ, F-91198 Gif Sur Yvette, France.
C3 University of Rochester; Australian Nuclear Science & Technology Organisation; Earth Sciences New Zealand; National Institute of Water & Atmospheric Research (NIWA) - New Zealand; Oregon State University; University of California System; University of California San Diego; Scripps Institution of Oceanography; University of Bern; Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Centre National de la Recherche Scientifique (CNRS); Utah System of Higher Education; University of Utah; University of Cambridge; CEA; Universite Paris Saclay
RP Petrenko, VV (corresponding author), Univ Rochester, Dept Earth & Environm Sci, 601 Elmwood Ave, Rochester, NY 14627 USA.
EM vpetrenk@ur.rochester.edu
FU US National Science Foundation [0839031, 0838936, 1245659]; National Oceanic and Atmospheric Administration Climate and Global Change Postdoctoral Fellowship; Packard Fellowship for Science and Engineering; Marsden Fund Council from New Zealand Government; ANSTO Isotopes in Climate Change and Atmospheric Systems project; NIWA under Climate and Atmosphere Research Programme [CAAC1504 (2014/15 SCI)]; Australian Government for the Centre for Accelerator Science at ANSTO through the National Collaborative Research Infrastructure Strategy; Directorate For Geosciences; Office of Polar Programs (OPP) [1245821] Funding Source: National Science Foundation; Directorate For Geosciences; Office of Polar Programs (OPP) [1246148, 1245659] Funding Source: National Science Foundation
NR 33
TC 84
Z9 95
U1 2
U2 89
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 24
PY 2017
VL 548
IS 7668
BP 443
EP 446
DI 10.1038/nature23316
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FE5VI
UT WOS:000408279000036
PM 28836593
DA 2026-03-09
ER

PT J
AU Cooney, CR
   Bright, JA
   Capp, EJR
   Chira, AM
   Hughes, EC
   Moody, CJA
   Nouri, LO
   Varley, ZK
   Thomas, GH
AF Cooney, Christopher R.
   Bright, Jen A.
   Capp, Elliot J. R.
   Chira, Angela M.
   Hughes, Emma C.
   Moody, Christopher J. A.
   Nouri, Lara O.
   Varley, Zoe K.
   Thomas, Gavin H.
TI Mega-evolutionary dynamics of the adaptive radiation of birds
SO NATURE
LA English
DT Article
ID principal components; r package; diversification; diversity; speciation; models; reveals; tree
AB The origin and expansion of biological diversity is regulated by both developmental trajectories(1,2) and limits on available ecological niches(3-7). As lineages diversify, an early and often rapid phase of species and trait proliferation gives way to evolutionary slow-downs as new species pack into ever more densely occupied regions of ecological niche space(6,8). Small clades such as Darwin's finches demonstrate that natural selection is the driving force of adaptive radiations, but how microevolutionary processes scale up to shape the expansion of phenotypic diversity over much longer evolutionary timescales is unclear(9). Here we address this problem on a global scale by analysing a crowdsourced dataset of three-dimensional scanned bill morphology from more than 2,000 species. We find that bill diversity expanded early in extant avian evolutionary history, before transitioning to a phase dominated by packing of morphological space. However, this early phenotypic diversification is decoupled from temporal variation in evolutionary rate: rates of bill evolution vary among lineages but are comparatively stable through time. We find that rare, but major, discontinuities in phenotype emerge from rapid increases in rate along single branches, sometimes leading to depauperate clades with unusual bill morphologies. Despite these jumps between groups, the major axes of within-group bill-shape evolution are remarkably consistent across birds. We reveal that macroevolutionary processes underlying global-scale adaptive radiations support Darwinian(9) and Simpsonian(4) ideas of microevolution within adaptive zones and accelerated evolution between distinct adaptive peaks.
C1 [Cooney, Christopher R.; Bright, Jen A.; Capp, Elliot J. R.; Chira, Angela M.; Hughes, Emma C.; Moody, Christopher J. A.; Nouri, Lara O.; Varley, Zoe K.; Thomas, Gavin H.] Univ Sheffield, Dept Anim & Plant Sci, Sheffield S10 2TN, S Yorkshire, England.
   [Bright, Jen A.] Univ S Florida, Sch Geosci, Tampa, FL 33620 USA.
   [Bright, Jen A.] Univ S Florida, Ctr Virtualizat & Appl Spatial Technol, Tampa, FL 33620 USA.
   [Thomas, Gavin H.] Nat Hist Museum, Dept Life Sci, Bird Grp, Tring, Herts, England.
C3 University of Sheffield; State University System of Florida; University of South Florida; State University System of Florida; University of South Florida; Natural History Museum London
RP Thomas, GH (corresponding author), Univ Sheffield, Dept Anim & Plant Sci, Sheffield S10 2TN, S Yorkshire, England.; Thomas, GH (corresponding author), Nat Hist Museum, Dept Life Sci, Bird Grp, Tring, Herts, England.
EM gavin.thomas@sheffield.ac.uk
FU European Research Council [615709]; Royal Society University Research Fellowship [UF120016]; Royal Society [UF120016] Funding Source: Royal Society; European Research Council (ERC) [615709] Funding Source: European Research Council (ERC)
NR 46
TC 265
Z9 300
U1 7
U2 250
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 16
PY 2017
VL 542
IS 7641
BP 344
EP +
DI 10.1038/nature21074
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2LQ
UT WOS:000394451600036
PM 28146475
DA 2026-03-09
ER

PT J
AU Ahmadi, M
   Alves, BXR
   Baker, CJ
   Bertsche, W
   Butler, E
   Capra, A
   Carruth, C
   Cesar, CL
   Charlton, M
   Cohen, S
   Collister, R
   Eriksson, S
   Evans, A
   Evetts, N
   Fajans, J
   Friesen, T
   Fujiwara, MC
   Gill, DR
   Gutierrez, A
   Hangst, JS
   Hardy, WN
   Hayden, ME
   Isaac, CA
   Ishida, A
   Johnson, MA
   Jones, SA
   Jonsell, S
   Kurchaninov, L
   Madsen, N
   Mathers, M
   Maxwell, D
   McKenna, JTK
   Menary, S
   Michan, JM
   Momose, T
   Munich, JJ
   Nolan, P
   Olchanski, K
   Olin, A
   Pusa, P
   Rasmussen, CO
   Robicheaux, F
   Sacramento, RL
   Sameed, M
   Sarid, E
   Silveira, DM
   Stracka, S
   Stutter, G
   So, C
   Tharp, TD
   Thompson, JE
   Thompson, RI
   van der Werf, DP
   Wurtele, JS
AF Ahmadi, M.
   Alves, B. X. R.
   Baker, C. J.
   Bertsche, W.
   Butler, E.
   Capra, A.
   Carruth, C.
   Cesar, C. L.
   Charlton, M.
   Cohen, S.
   Collister, R.
   Eriksson, S.
   Evans, A.
   Evetts, N.
   Fajans, J.
   Friesen, T.
   Fujiwara, M. C.
   Gill, D. R.
   Gutierrez, A.
   Hangst, J. S.
   Hardy, W. N.
   Hayden, M. E.
   Isaac, C. A.
   Ishida, A.
   Johnson, M. A.
   Jones, S. A.
   Jonsell, S.
   Kurchaninov, L.
   Madsen, N.
   Mathers, M.
   Maxwell, D.
   McKenna, J. T. K.
   Menary, S.
   Michan, J. M.
   Momose, T.
   Munich, J. J.
   Nolan, P.
   Olchanski, K.
   Olin, A.
   Pusa, P.
   Rasmussen, C. O.
   Robicheaux, F.
   Sacramento, R. L.
   Sameed, M.
   Sarid, E.
   Silveira, D. M.
   Stracka, S.
   Stutter, G.
   So, C.
   Tharp, T. D.
   Thompson, J. E.
   Thompson, R. I.
   van der Werf, D. P.
   Wurtele, J. S.
TI Observation of the 1S-2S transition in trapped antihydrogen
SO NATURE
LA English
DT Article
ID cold antihydrogen; charge; spectroscopy; limit
AB The spectrum of the hydrogen atom has played a central part in fundamental physics over the past 200 years. Historical examples of its importance include the wavelength measurements of absorption lines in the solar spectrum by Fraunhofer, the identification of transition lines by Balmer, Lyman and others, the empirical description of allowed wavelengths by Rydberg, the quantum model of Bohr, the capability of quantum electrodynamics to precisely predict transition frequencies, and modern measurements of the 1S-2S transition by Hansch1 to a precision of a few parts in 10(15). Recent technological advances have allowed us to focus on antihydrogen-the antimatter equivalent of hydrogen(2-4). The Standard Model predicts that there should have been equal amounts of matter and antimatter in the primordial Universe after the Big Bang, but today's Universe is observed to consist almost entirely of ordinary matter. This motivates the study of antimatter, to see if there is a small asymmetry in the laws of physics that govern the two types of matter. In particular, the CPT (charge conjugation, parity reversal and time reversal) theorem, a cornerstone of the Standard Model, requires that hydrogen and antihydrogen have the same spectrum. Here we report the observation of the 1S-2S transition in magnetically trapped atoms of antihydrogen. We determine that the frequency of the transition, which is driven by two photons from a laser at 243 nanometres, is consistent with that expected for hydrogen in the same environment. This laser excitation of a quantum state of an atom of antimatter represents the most precise measurement performed on an anti-atom. Our result is consistent with CPT invariance at a relative precision of about 2 x 10(-10).
C1 [Ahmadi, M.; Nolan, P.; Pusa, P.] Univ Liverpool, Dept Phys, Liverpool L69 7ZE, Merseyside, England.
   [Alves, B. X. R.; Friesen, T.; Hangst, J. S.; Rasmussen, C. O.; Stutter, G.] Aarhus Univ, Dept Phys & Astron, DK-8000 Aarhus C, Denmark.
   [Baker, C. J.; Charlton, M.; Eriksson, S.; Isaac, C. A.; Jones, S. A.; Madsen, N.; Maxwell, D.; Sameed, M.; van der Werf, D. P.] Swansea Univ, Dept Phys, Coll Sci, Swansea SA2 8PP, W Glam, Wales.
   [Bertsche, W.; Johnson, M. A.] Univ Manchester, Sch Phys & Astron, Manchester M12 9PL, Lancs, England.
   [Bertsche, W.; Johnson, M. A.] Sci Tech Daresbury, Cockcroft Inst, Warrington WA4 4AD, Cheshire, England.
   [Butler, E.] CERN, Phys Dept, CH-1211 Geneva 23, Switzerland.
   [Capra, A.; Collister, R.; Fujiwara, M. C.; Gill, D. R.; Kurchaninov, L.; McKenna, J. T. K.; Michan, J. M.; Olchanski, K.; Olin, A.] TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada.
   [Carruth, C.; Fajans, J.; Wurtele, J. S.] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Cesar, C. L.; Sacramento, R. L.; Silveira, D. M.] Univ Fed Rio de Janeiro, Inst Fis, BR-21941 Rio De Janeiro, Brazil.
   [Cohen, S.] Ben Gurion Univ Negev, Dept Phys, IL-84105 Beer Sheva, Israel.
   [Evans, A.; So, C.; Thompson, R. I.] Univ Calgary, Dept Phys & Astron, Calgary, AB T2N 1N4, Canada.
   [Evetts, N.; Hardy, W. N.; Momose, T.] Univ British Columbia, Dept Phys & Astron, Vancouver, BC V6T 1Z1, Canada.
   [Gutierrez, A.] UCL, Dept Med Phys & Biomed Engn, London WC1E 6BT, England.
   [Hayden, M. E.; Munich, J. J.] Simon Fraser Univ, Dept Phys, Burnaby, BC V5A 1S6, Canada.
   [Ishida, A.] Univ Tokyo, Dept Phys, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
   [Jonsell, S.] Stockholm Univ, Dept Phys, SE-10691 Stockholm, Sweden.
   [Mathers, M.; Menary, S.; Thompson, J. E.] York Univ, Dept Phys & Astron, Toronto, ON M3J 1P3, Canada.
   [Michan, J. M.] Ecole Polytech Fed Lausanne, Swiss Plasma Ctr, CH-1015 Lausanne, Switzerland.
   [Olin, A.] Univ Victoria, Dept Phys & Astron, Victoria, BC V8P 5C2, Canada.
   [Robicheaux, F.] Purdue Univ, Dept Phys & Astron, W Lafayette, IN 47907 USA.
   [Sarid, E.] Soreq NRC, IL-81800 Yavne, Israel.
   [Stracka, S.] Univ Pisa, Largo Pontecorvo 3, I-56127 Pisa, Italy.
   [Stracka, S.] Sez INFN Pisa, Largo Pontecorvo 3, I-56127 Pisa, Italy.
   [Tharp, T. D.] Marquette Univ, Dept Phys, POB 1881, Milwaukee, WI 53201 USA.
   [van der Werf, D. P.] CEA Saclay, IRFU, F-91191 Gif Sur Yvette, France.
C3 University of Liverpool; Aarhus University; Swansea University; University of Manchester; STFC Daresbury Laboratory; European Organization for Nuclear Research (CERN); University of British Columbia; University of California System; University of California Berkeley; Universidade Federal do Rio de Janeiro; Ben-Gurion University of the Negev; University of Calgary; University of British Columbia; University of London; University College London; Simon Fraser University; University of Tokyo; Stockholm University; York University - Canada; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; University of Victoria; Purdue University System; Purdue University; University of Pisa; Istituto Nazionale di Fisica Nucleare (INFN); Marquette University; Universite Paris Saclay; CEA
RP Hangst, JS (corresponding author), Aarhus Univ, Dept Phys & Astron, DK-8000 Aarhus C, Denmark.
EM jeffrey.hangst@cern.ch
FU European Research Council; CNPq (Brazil); FAPERJ (Brazil); RENAFAE (Brazil); NSERC (Canada); NRC/TRIUMF (Canada); EHPDS/EHDRS (Canada); FQRNT (Canada); FNU (Nice Centre) (Denmark); Carlsberg Foundation (Denmark); JSPS Postdoctoral Fellowships for Research Abroad (Japan); ISF (Israel); STFC (UK); EPSRC (UK); Royal Society (UK); Leverhulme Trust (UK); DOE (USA); NSF (USA); VR (Sweden); EPSRC [EP/K040235/1, EP/F033885/1, EP/L014769/1, EP/L014734/1, EP/P024785/1, EP/L014718/1, EP/I005692/1, EP/P024769/1, EP/D040108/1, EP/K017373/1, EP/H02431X/1, EP/E048951/1, EP/L005522/1, EP/H026932/1, EP/E016332/1, EP/G068968/1] Funding Source: UKRI; STFC [1686188] Funding Source: UKRI; Engineering and Physical Sciences Research Council [EP/P024769/1, EP/K017373/1, EP/G068968/1, EP/L014734/1, EP/K040235/1, EP/F033885/1, EP/L005522/1, EP/H026932/1, EP/I005692/1, EP/L014718/1, EP/D040108/1, 1422853, EP/L014769/1, EP/E048951/1, EP/P024785/1, EP/H02431X/1, EP/E016332/1] Funding Source: researchfish; Science and Technology Facilities Council [1686188] Funding Source: researchfish; Direct For Mathematical & Physical Scien; Division Of Physics [1500538, 1500470] Funding Source: National Science Foundation
NR 26
TC 123
Z9 149
U1 0
U2 71
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 26
PY 2017
VL 541
IS 7638
BP 
EP 
DI 10.1038/nature21040
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6LX
UT WOS:000396116600045
PM 28005057
DA 2026-03-09
ER

PT J
AU Zerkle, AL
   Poulton, SW
   Newton, RJ
   Mettam, C
   Claire, MW
   Bekker, A
   Junium, CK
AF Zerkle, Aubrey L.
   Poulton, Simon W.
   Newton, Robert J.
   Mettam, Colin
   Claire, Mark W.
   Bekker, Andrey
   Junium, Christopher K.
TI Onset of the aerobic nitrogen cycle during the Great Oxidation Event
SO NATURE
LA English
DT Article
ID isotopic composition; natural gases; fractionation; transvaal; oxygen; evolution; sediments; anammox; ratios; carbon
AB The rise of oxygen on the early Earth (about 2.4 billion years ago)(1) caused a reorganization of marine nutrient cycles(2,3), including that of nitrogen, which is important for controlling global primary productivity. However, current geochemical records(4) lack the temporal resolution to address the nature and timing of the biogeochemical response to oxygenation directly. Here we couple records of ocean redox chemistry with nitrogen isotope (N-15/N-14) values from approximately 2.31-billion-year-old shales(5) of the Rooihoogte and Timeball Hill formations in South Africa, deposited during the early stages of the first rise in atmospheric oxygen on the Earth (the Great Oxidation Event)(6). Our data fill a gap of about 400 million years in the temporal N-15/N-14 record(4) and provide evidence for the emergence of a pervasive aerobic marine nitrogen cycle. The interpretation of our nitrogen isotope data in the context of iron speciation and carbon isotope data suggests biogeochemical cycling across a dynamic redox boundary, with primary productivity fuelled by chemoautotrophic production and a nitrogen cycle dominated by nitrogen loss processes using newly available marine oxidants. This chemostratigraphic trend constrains the onset of widespread nitrate availability associated with ocean oxygenation. The rise of marine nitrate could have allowed for the rapid diversification and proliferation of nitrate-using cyanobacteria and, potentially, eukaryotic phytoplankton.
C1 [Zerkle, Aubrey L.; Mettam, Colin; Claire, Mark W.] Univ St Andrews, Sch Earth & Environm Sci, St Andrews KY16 9AL, Fife, Scotland.
   [Zerkle, Aubrey L.; Mettam, Colin; Claire, Mark W.] Univ St Andrews, Ctr Exoplanet Sci, St Andrews KY16 9AL, Fife, Scotland.
   [Poulton, Simon W.; Newton, Robert J.] Univ Leeds, Sch Earth & Environm, Leeds LS2 9JT, W Yorkshire, England.
   [Claire, Mark W.] Blue Marble Space Inst Sci, POB 88561, Seattle, WA 98145 USA.
   [Bekker, Andrey] Univ Calif Riverside, Dept Earth Sci, Riverside, CA 92521 USA.
   [Junium, Christopher K.] Syracuse Univ, Dept Earth Sci, Syracuse, NY 13244 USA.
C3 University of St Andrews; University of St Andrews; University of Leeds; University of California System; University of California Riverside; Syracuse University
RP Zerkle, AL (corresponding author), Univ St Andrews, Sch Earth & Environm Sci, St Andrews KY16 9AL, Fife, Scotland.; Zerkle, AL (corresponding author), Univ St Andrews, Ctr Exoplanet Sci, St Andrews KY16 9AL, Fife, Scotland.
EM az29@st-andrews.ac.uk
FU Natural Environment Research Council [NE/H016805]; NERC [NE/H016805/2, NE/H016805/1] Funding Source: UKRI; Natural Environment Research Council [NE/H016805/1, NE/H016805/2] Funding Source: researchfish; Division Of Earth Sciences; Directorate For Geosciences [1455258] Funding Source: National Science Foundation
NR 43
TC 114
Z9 125
U1 3
U2 264
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 23
PY 2017
VL 542
IS 7642
BP 465
EP +
DI 10.1038/nature20826
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1RG
UT WOS:000395094100033
PM 28166535
DA 2026-03-09
ER

PT J
AU Zhao, BXS
   Wang, X
   Beadell, AV
   Lu, ZK
   Shi, HL
   Kuuspalu, A
   Ho, RK
   He, C
AF Zhao, Boxuan Simen
   Wang, Xiao
   Beadell, Alana V.
   Lu, Zhike
   Shi, Hailing
   Kuuspalu, Adam
   Ho, Robert K.
   He, Chuan
TI m6A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition
SO NATURE
LA English
DT Article
ID embryonic stem-cells; nuclear-rna; methylation; transcriptome; reveals
AB The maternal-to-zygotic transition (MZT) is one of the most profound and tightly orchestrated processes during the early life of embryos, yet factors that shape the temporal pattern of vertebrate MZT are largely unknown. Here we show that over one-third of zebrafish maternal messenger RNAs (mRNAs) can be N-6-methyladenosine (m(6)A) modified, and the clearance of these maternal mRNAs is facilitated by an m(6)A-binding protein, Ythdf2. Removal of Ythdf2 in zebrafish embryos decelerates the decay of m(6)A-modified maternal mRNAs and impedes zygotic genome activation. These embryos fail to initiate timely MZT, undergo cell-cycle pause, and remain developmentally delayed throughout larval life. Our study reveals m(6)A-dependent RNA decay as a previously unidentified maternally driven mechanism that regulates maternal mRNA clearance during zebrafish MZT, highlighting the critical role of m(6)A mRNA methylation in transcriptome switching and animal development.
C1 [Zhao, Boxuan Simen; Wang, Xiao; Lu, Zhike; Shi, Hailing; He, Chuan] Univ Chicago, Dept Chem & Inst Biophys Dynam, 929 East 57th St, Chicago, IL 60637 USA.
   [Zhao, Boxuan Simen; Wang, Xiao; Lu, Zhike; Shi, Hailing; He, Chuan] Univ Chicago, Howard Hughes Med Inst, 929 East 57th St, Chicago, IL 60637 USA.
   [Beadell, Alana V.; Kuuspalu, Adam; Ho, Robert K.] Univ Chicago, Dept Organismal Biol & Anat, 1027 East 57th St, Chicago, IL 60637 USA.
   [He, Chuan] Univ Chicago, Dept Biochem & Mol Biol, 929 East 57th St, Chicago, IL 60637 USA.
C3 University of Chicago; Howard Hughes Medical Institute; University of Chicago; University of Chicago; University of Chicago
RP He, C (corresponding author), Univ Chicago, Dept Chem & Inst Biophys Dynam, 929 East 57th St, Chicago, IL 60637 USA.; He, C (corresponding author), Univ Chicago, Howard Hughes Med Inst, 929 East 57th St, Chicago, IL 60637 USA.; He, C (corresponding author), Univ Chicago, Dept Biochem & Mol Biol, 929 East 57th St, Chicago, IL 60637 USA.
EM chuanhe@uchicago.edu
FU National Institutes of Health [HG008688, GM113194, HD072598]; National Science Foundation [CHE-1048528]; National Institute of General Medical Sciences [R01GM113194] Funding Source: NIH RePORTER
NR 36
TC 469
Z9 566
U1 6
U2 187
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 23
PY 2017
VL 542
IS 7642
BP 475
EP +
DI 10.1038/nature21355
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1RG
UT WOS:000395094100036
PM 28192787
DA 2026-03-09
ER

PT J
AU Winkler, PA
   Huang, YH
   Sun, WN
   Du, J
   Lü, W
AF Winkler, Paige A.
   Huang, Yihe
   Sun, Weinan
   Du, Juan
   Lu, Wei
TI Electron cryo-microscopy structure of a human TRPM4 channel
SO NATURE
LA English
DT Article
ID nonselective cation channel; cryo-em structure; vanilloid receptor; activation; expression; reveals; domain; gene; identification; validation
AB Ca2+-activated, non-selective (CAN) ion channels sense increases of the intracellular Ca2+ concentration, producing a flux of Na+ and/or K+ ions that depolarizes the cell, thus modulating cellular Ca2+ entry. CAN channels are involved in cellular responses such as neuronal bursting activity and cardiac rhythm. Here we report the electron cryo-microscopy structure of the most widespread CAN channel, human TRPM4, bound to the agonist Ca2+ and the modulator decavanadate. Four cytosolic C-terminal domains form an umbrella-like structure with a coiled-coil domain for the 'pole' and four helical 'ribs' spanning the N-terminal TRPM homology regions (MHRs), thus holding four subunits in a crown-like architecture. We observed two decavanadate-binding sites, one in the C-terminal domain and another in the intersubunit MHR interface. A glutamine in the selectivity filter may be an important determinant of monovalent selectivity. Our structure provides new insights into the function and pharmacology of both the CAN and the TRPM families.
C1 [Winkler, Paige A.; Huang, Yihe; Du, Juan; Lu, Wei] Van Andel Inst, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA.
   [Sun, Weinan] Janelia Res Campus,19700 Helix Dr, Ashburn, VA 20147 USA.
C3 Van Andel Institute
RP Lü, W (corresponding author), Van Andel Inst, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA.
EM wei.lu@vai.org
FU VARI
NR 59
TC 149
Z9 165
U1 0
U2 60
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 14
PY 2017
VL 552
IS 7684
BP 200
EP +
DI 10.1038/nature24674
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ0FK
UT WOS:000418029500036
PM 29211723
DA 2026-03-09
ER

PT J
AU Saw, TB
   Doostmohammadi, A
   Nier, V
   Kocgozlu, L
   Thampi, S
   Toyama, Y
   Marcq, P
   Lim, CT
   Yeomans, JM
   Ladoux, B
AF Saw, Thuan Beng
   Doostmohammadi, Amin
   Nier, Vincent
   Kocgozlu, Leyla
   Thampi, Sumesh
   Toyama, Yusuke
   Marcq, Philippe
   Lim, Chwee Teck
   Yeomans, Julia M.
   Ladoux, Benoit
TI Topological defects in epithelia govern cell death and extrusion
SO NATURE
LA English
DT Article
ID forces; competition; transition; drosophila; mechanics; inference; dynamics; yap/taz; stress; growth
AB Epithelial tissues (epithelia) remove excess cells through extrusion, preventing the accumulation of unnecessary or pathological cells. The extrusion process can be triggered by apoptotic signalling(1), oncogenic transformation(2,3) and overcrowding of cells(4-6). Despite the important linkage of cell extrusion to developmental(7), homeostatic(5) and pathological processes(2,8) such as cancer metastasis, its underlying mechanism and connections to the intrinsic mechanics of the epithelium are largely unexplored. We approach this problem by modelling the epithelium as an active nematic liquid crystal (that has a long range directional order), and comparing numerical simulations to strain rate and stress measurements within monolayers of MDCK (Madin Darby canine kidney) cells. Here we show that apoptotic cell extrusion is provoked by singularities in cell alignments(9,10) in the form of comet-shaped topological defects. We find a universal correlation between extrusion sites and positions of nematic defects in the cell orientation field in different epithelium types. The results confirm the active nematic nature of epithelia, and demonstrate that defect-induced isotropic stresses are the primary precursors of mechanotransductive responses in cells, including YAP (Yes-associated protein) transcription factor activity(11), caspase-3-mediated cell death, and extrusions. Importantly, the defectdriven extrusion mechanism depends on intercellular junctions, because the weakening of cell-cell interactions in an a-catenin knockdown monolayer reduces the defect size and increases both the number of defects and extrusion rates, as is also predicted by our model. We further demonstrate the ability to control extrusion hotspots by geometrically inducing defects through microcontact printing of patterned monolayers. On the basis of these results, we propose a mechanism for apoptotic cell extrusion: spontaneously formed topological defects in epithelia govern cell fate. This will be important in predicting extrusion hotspots and dynamics in vivo, with potential applications to tissue regeneration and the suppression of metastasis. Moreover, we anticipate that the analogy between the epithelium and active nematic liquid crystals will trigger further investigations of the link between cellular processes and the material properties of epithelia.
C1 [Saw, Thuan Beng; Kocgozlu, Leyla; Toyama, Yusuke; Lim, Chwee Teck; Ladoux, Benoit] Mechanobiol Inst, T Lab, Singapore 117411, Singapore.
   [Saw, Thuan Beng; Lim, Chwee Teck] Natl Univ Singapore, Grad Sch Integrat Sci & Engn NGS, Ctr Life Sci CeLS, Singapore 117456, Singapore.
   [Doostmohammadi, Amin; Thampi, Sumesh; Yeomans, Julia M.] Univ Oxford, Rudolf Peierls Ctr Theoret Phys, Oxford OX1 3NP, England.
   [Nier, Vincent; Marcq, Philippe] Univ Paris 06, Inst Curie, CNRS, UMR 168,UPMC,Sorbonne Univ,Lab Phys Chim Curie, F-75005 Paris, France.
   [Thampi, Sumesh] Indian Inst Technol, Dept Chem Engn, Madras 600036, Tamil Nadu, India.
   [Toyama, Yusuke] Natl Univ Singapore, Dept Biol Sci, Singapore 117543, Singapore.
   [Toyama, Yusuke] Natl Univ Singapore, Temasek Life Sci Lab, Singapore 117604, Singapore.
   [Ladoux, Benoit] Univ Paris Diderot, CNRS, UMR 7592, IJM, F-75013 Paris, France.
C3 National University of Singapore; Center Life Science - NUS; University of Oxford; Universite PSL; UNICANCER; Institut Curie; Centre National de la Recherche Scientifique (CNRS); Sorbonne Universite; CNRS - Institute of Chemistry (INC); Indian Institute of Technology System (IIT System); Indian Institute of Technology (IIT) - Madras; National University of Singapore; National University of Singapore; Universite Paris Cite; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB)
RP Lim, CT; Ladoux, B (corresponding author), Mechanobiol Inst, T Lab, Singapore 117411, Singapore.; Lim, CT (corresponding author), Natl Univ Singapore, Grad Sch Integrat Sci & Engn NGS, Ctr Life Sci CeLS, Singapore 117456, Singapore.; Yeomans, JM (corresponding author), Univ Oxford, Rudolf Peierls Ctr Theoret Phys, Oxford OX1 3NP, England.; Ladoux, B (corresponding author), Univ Paris Diderot, CNRS, UMR 7592, IJM, F-75013 Paris, France.
EM ctlim@nus.edu.sg; Julia.Yeomans@physics.ox.ac.uk; benoit.ladoux@ijm.fr
FU MBI Microfabrication core; MBI Microscopy core; MBI Science Communication core; European Research Council under the European Union [617233, 291234]; Mechanobiology Institute; NGS scholarship; European Research Council (ERC) [291234, 617233] Funding Source: European Research Council (ERC)
NR 63
TC 637
Z9 724
U1 12
U2 359
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 13
PY 2017
VL 544
IS 7649
BP 212
EP +
DI 10.1038/nature21718
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ER6EK
UT WOS:000398897900033
PM 28406198
DA 2026-03-09
ER

PT J
AU Nishimura, Y
   Gautam, R
   Chun, TW
   Sadjadpour, R
   Foulds, KE
   Shingai, M
   Klein, F
   Gazumyan, A
   Golijanin, J
   Donaldson, M
   Donau, OK
   Plishka, RJ
   Buckler-White, A
   Seaman, MS
   Lifson, JD
   Koup, RA
   Fauci, AS
   Nussenzweig, MC
   Martin, MA
AF Nishimura, Yoshiaki
   Gautam, Rajeev
   Chun, Tae-Wook
   Sadjadpour, Reza
   Foulds, Kathryn E.
   Shingai, Masashi
   Klein, Florian
   Gazumyan, Anna
   Golijanin, Jovana
   Donaldson, Mitzi
   Donau, Olivia K.
   Plishka, Ronald J.
   Buckler-White, Alicia
   Seaman, Michael S.
   Lifson, Jeffrey D.
   Koup, Richard A. .
   Fauci, Anthony S.
   Nussenzweig, Michel C. .
   Martin, Malcolm A.
TI Early antibody therapy can induce long-lasting immunity to SHIV
SO NATURE
LA English
DT Article
ID broadly neutralizing antibody; simian/human immunodeficiency virus; active antiretroviral therapy; primary hiv-1 infection; cd4(+) t-cells; monoclonal-antibody; humanized mice; rhesus-monkeys; in-vivo; macaques
AB Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans(1-12). In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant longterm infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074 (refs 13, 14)). Viraemia remained undetectable for 56-177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4(+) T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8 beta monoclonal antibody to the controller animals led to a specific decline in levels of CD8(+) T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8(+) T-cell immunity able to durably suppress virus replication.
C1 [Nishimura, Yoshiaki; Gautam, Rajeev; Sadjadpour, Reza; Shingai, Masashi; Donau, Olivia K.; Plishka, Ronald J.; Buckler-White, Alicia; Martin, Malcolm A.] Natl Inst Allergy & Infect Dis, Lab Mol Microbiol, Natl Inst Hlth, Bethesda, MD 20892 USA.
   [Chun, Tae-Wook; Fauci, Anthony S.] Natl Inst Allergy & Infect Dis, Lab Immunoregulat, Natl Inst Hlth, Bethesda, MD 20892 USA.
   [Foulds, Kathryn E.; Donaldson, Mitzi; Koup, Richard A. .] Natl Inst Allergy & Infect Dis, Vaccine Res Ctr, Natl Inst Hlth, Bethesda, MD 20892 USA.
   [Klein, Florian] Univ Cologne, Inst Virol, D-50931 Cologne, Germany.
   [Klein, Florian] Univ Cologne, CMMC, D-50931 Cologne, Germany.
   [Gazumyan, Anna; Golijanin, Jovana; Nussenzweig, Michel C. .] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA.
   [Seaman, Michael S.] Ctr Virol & Vaccine Res, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA.
   [Lifson, Jeffrey D.] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD 21702 USA.
   [Nussenzweig, Michel C. .] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); University of Cologne; University of Cologne; Rockefeller University; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; Howard Hughes Medical Institute; Rockefeller University
RP Martin, MA (corresponding author), Natl Inst Allergy & Infect Dis, Lab Mol Microbiol, Natl Inst Hlth, Bethesda, MD 20892 USA.; Nussenzweig, MC (corresponding author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA.; Nussenzweig, MC (corresponding author), Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA.
EM nussen@rockefeller.edu; malm@nih.gov
FU National Institutes of Health (NIH) Nonhuman Primate Reagent Resource [HHSN272200900037C, OD10976]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIH); Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIH); National Cancer Institute (NIH) [HHSN261200800001E]; Collaboration for AIDS Vaccine Discovery grant [OPP1033115]; NIH Clinical and Translational Science Award (CTSA) program; NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) [1UM1 AI100663-01]; Bill and Melinda Gates Foundation [OPP1092074, OPP1124068]; NIH HIVRAD [P01 AI100148]; Robertson Foundation; National Institute of Allergy and Infectious Diseases [ZIAAI001213, ZIAAI005014, P01AI100148] Funding Source: NIH RePORTER; NIH Office of the Director; National Institute of Allergy and Infectious Diseases [ZIAAI000851] Funding Source: NIH RePORTER; Bill and Melinda Gates Foundation [OPP1092074, OPP1033115, OPP1124068] Funding Source: Bill and Melinda Gates Foundation
NR 36
TC 254
Z9 288
U1 0
U2 45
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 23
PY 2017
VL 543
IS 7646
BP 559
EP +
DI 10.1038/nature21435
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EO9OM
UT WOS:000397018000053
PM 28289286
DA 2026-03-09
ER

PT J
AU Dingle, EH
   Attal, M
   Sinclair, HD
AF Dingle, Elizabeth H.
   Attal, Mikael
   Sinclair, Hugh D.
TI Abrasion-set limits on Himalayan gravel flux
SO NATURE
LA English
DT Article
ID foreland basin; grain-size; sand transitions; river gravels; taiwan; landslides; morphology; deposits; history; erosion
AB Rivers sourced in the Himalayan mountain range carry some of the largest sediment loads on the planet(1), yet coarse gravel in these rivers vanishes within approximately 10-40 kilometres on entering the Ganga Plain (the part of the North Indian River Plain containing the Ganges River). Understanding the fate of gravel is important for forecasting the response of rivers to large influxes of sediment triggered by earthquakes or storms. Rapid increase in gravel flux and subsequent channel bed aggradation (that is, sediment deposition by a river) following the 1999 Chi-Chi and 2008 Wenchuan earthquakes(2-7) reduced channel capacity and increased flood inundation(3). Here we present an analysis of fan geometry, sediment grain size and lithology in the Ganga Basin. We find that the gravel fluxes from rivers draining the central Himalayan mountains, with upstream catchment areas ranging from about 350 to 50,000 square kilometres, are comparable. Our results show that abrasion of gravel during fluvial transport can explain this observation; most of the gravel sourced more than 100 kilometres upstream is converted into sand by the time it reaches the Ganga Plain. These findings indicate that earthquake-induced sediment pulses sourced from the Greater Himalayas, such as that following the 2015 Gorkha earthquake(8), are unlikely to drive increased gravel aggradation at the mountain front. Instead, we suggest that the sediment influx should result in an elevated sand flux, leading to distinct patterns of aggradation and flood risk in the densely populated, low-relief Ganga Plain.
C1 [Dingle, Elizabeth H.; Attal, Mikael; Sinclair, Hugh D.] Univ Edinburgh, Sch GeoSci, Drummond St, Edinburgh EH8 9XP, Midlothian, Scotland.
C3 University of Edinburgh
RP Dingle, EH (corresponding author), Univ Edinburgh, Sch GeoSci, Drummond St, Edinburgh EH8 9XP, Midlothian, Scotland.
EM elizabeth.dingle@ed.ac.uk
FU International Association of Sedimentologists; British Society for Geomorphology; Edinburgh University Club of Toronto; Natural Environment Research Council (NERC) [NE/L501566/1]; Natural Environment Research Council [1364253] Funding Source: researchfish; NERC [NE/L501566/1] Funding Source: UKRI
NR 37
TC 68
Z9 72
U1 2
U2 64
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 27
PY 2017
VL 544
IS 7651
BP 471
EP +
DI 10.1038/nature22039
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET1TN
UT WOS:000400051900041
PM 28447640
DA 2026-03-09
ER

PT J
AU Gao, X
   Wang, KL
AF Gao, Xiang
   Wang, Kelin
TI Rheological separation of the megathrust seismogenic zone and episodic tremor and slip
SO NATURE
LA English
DT Article
ID san-andreas-fault; low-frequency earthquakes; hikurangi subduction zone; 1944 tonankai earthquake; term slow slip; new-zealand; heat-flow; accretionary prism; crustal structure; southwest japan
AB Episodic tremor and accompanying slow slip, together called ETS, is most often observed in subduction zones of young and warm subducting slabs(1-3). ETS should help us to understand the mechanics of subduction megathrusts(3,4), but its mechanism is still unclear. It is commonly assumed that ETS represents a transition from seismic to aseismic behaviour of the megathrust with increasing depth, but this assumption is in contradiction with an observed spatial separation between the seismogenic zone and the ETS zone(5-8). Here we propose a unifying model for the necessary geological condition of ETS that explains the relationship between the two zones. By developing numerical thermal models, we examine the governing role of thermopetrologically controlled fault zone rheology (frictional versus viscous shear). High temperatures in the warm-slab environment(9) cause the megathrust seismogenic zone to terminate before reaching the depth of the intersection of the continental Mohorovicic discontinuity (Moho) and the subduction interface, called the mantle wedge corner. High pore-fluid pressures around the mantle wedge corner(10) give rise to an isolated friction zone responsible for ETS. Separating the two zones is a segment of semi-frictional or viscous behaviour. The new model reconciles a wide range of seemingly disparate observations and defines a conceptual framework for the study of slip behaviour and the seismogenesis of major faults.
C1 [Gao, Xiang] Chinese Acad Sci, Inst Oceanol, Key Lab Marine Geol & Environm, 7 Nanhai Rd, Qingdao 266071, Peoples R China.
   [Gao, Xiang] Qingdao Natl Lab Marine Sci & Technol, Lab Marine Geol, 1 Wenhai Rd, Qingdao 266061, Peoples R China.
   [Wang, Kelin] Nat Resources Canada, Geol Survey Canada, Pacific Geosci Ctr, 9860 West Saanich Rd, Sidney, BC V8L 4B2, Canada.
   [Wang, Kelin] Univ Victoria, Sch Earth & Ocean Sci, Victoria, BC V8P 5C2, Canada.
C3 Chinese Academy of Sciences; Institute of Oceanology, CAS; Laoshan Laboratory; Natural Resources Canada; Lands & Minerals Sector - Natural Resources Canada; Geological Survey of Canada; University of Victoria
RP Wang, KL (corresponding author), Nat Resources Canada, Geol Survey Canada, Pacific Geosci Ctr, 9860 West Saanich Rd, Sidney, BC V8L 4B2, Canada.; Wang, KL (corresponding author), Univ Victoria, Sch Earth & Ocean Sci, Victoria, BC V8P 5C2, Canada.
EM kelin.wang@canada.ca
FU Chinese Academy of Sciences' Strategic Priority Research Program [XDA11030102]; National Natural Science Foundation of China [41406063]; Geological Survey of Canada; Natural Sciences and Engineering Research Council of Canada through the University of Victoria
NR 112
TC 196
Z9 226
U1 4
U2 153
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 16
PY 2017
VL 543
IS 7645
BP 416
EP +
DI 10.1038/nature21389
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN9RN
UT WOS:000396337400049
PM 28264194
DA 2026-03-09
ER

PT J
AU Wagenbauer, KF
   Sigl, C
   Dietz, H
AF Wagenbauer, Klaus F.
   Sigl, Christian
   Dietz, Hendrik
TI Gigadalton-scale shape-programmable DNA assemblies
SO NATURE
LA English
DT Article
ID computational design; protein complexes; nanoscale shapes; accurate design; folding dna; origami; virus; architecture; resolution; state
AB Natural biomolecular assemblies such as molecular motors, enzymes, viruses and subcellular structures often form by self-limiting hierarchical oligomerization of multiple subunits(1-3). Large structures can also assemble efficiently from a few components by combining hierarchical assembly and symmetry, a strategy exemplified by viral capsids(4). De novo protein design(5-9) and RNA(10,11) and DNA nanotechnology(12-14) aim to mimic these capabilities, but the bottom-up construction of artificial structures with the dimensions and complexity of viruses and other subcellular components remains challenging. Here we show that natural assembly principles can be combined with the methods of DNA origami(15-24) to produce gigadalton-scale structures with controlled sizes. DNA sequence information is used to encode the shapes of individual DNA origami building blocks, and the geometry and details of the interactions between these building blocks then control their copy numbers, positions and orientations within higher-order assemblies. We illustrate this strategy by creating planar rings of up to 350 nanometres in diameter and with atomic masses of up to 330 megadaltons, micrometre-long, thick tubes commensurate in size to some bacilli, and three-dimensional polyhedral assemblies with sizes of up to 1.2 gigadaltons and 450 nanometres in diameter. We achieve efficient assembly, with yields of up to 90 per cent, by using building blocks with validated structure and sufficient rigidity, and an accurate design with interaction motifs that ensure that hierarchical assembly is self-limiting and able to proceed in equilibrium to allow for error correction. We expect that our method, which enables the self-assembly of structures with sizes approaching that of viruses and cellular organelles, can readily be used to create a range of other complex structures with well defined sizes, by exploiting the modularity and high degree of addressability of the DNA origami building blocks used.
C1 [Wagenbauer, Klaus F.; Sigl, Christian; Dietz, Hendrik] Tech Univ Munich, Dept Phys, Coulombwall 4a, D-85748 Garching, Germany.
   [Wagenbauer, Klaus F.; Sigl, Christian; Dietz, Hendrik] Tech Univ Munich, Inst Adv Study, Coulombwall 4a, D-85748 Garching, Germany.
C3 Technical University of Munich; Technical University of Munich
RP Dietz, H (corresponding author), Tech Univ Munich, Dept Phys, Coulombwall 4a, D-85748 Garching, Germany.; Dietz, H (corresponding author), Tech Univ Munich, Inst Adv Study, Coulombwall 4a, D-85748 Garching, Germany.
EM dietz@tum.de
FU European Research Council Starting Grant [256270]; Deutsche Forschungsgemeinschaft within Gottfried-Wilhelm-Leibniz Program; Excellence Clusters CIPSM (Center for Integrated Protein Science Munich); NIM (Nanosystems Initiative Munich); Technische Universitat Munchen (TUM) Institute for Advanced Study; Bosch Forschungsstiftung; European Research Council (ERC) [256270] Funding Source: European Research Council (ERC)
CR Bai XC, 2012, P NATL ACAD SCI USA, V109, P20012, DOI 10.1073/pnas.1215713109
   Bale JB, 2016, SCIENCE, V353, P389, DOI 10.1126/science.aaf8818
   BAN N, 1995, NAT STRUCT BIOL, V2, P882, DOI 10.1038/nsb1095-882
   Benson E, 2015, NATURE, V523, P441, DOI 10.1038/nature14586
   BOOY FP, 1994, P NATL ACAD SCI USA, V91, P5652, DOI 10.1073/pnas.91.12.5652
   CASPAR DLD, 1962, COLD SPRING HARB SYM, V27, P1, DOI 10.1101/sqb.1962.027.001.005
   Dietz H, 2009, SCIENCE, V325, P725, DOI 10.1126/science.1174251
   Douglas SM, 2009, NUCLEIC ACIDS RES, V37, P5001, DOI 10.1093/nar/gkp436
   Douglas SM, 2009, NATURE, V459, P414, DOI 10.1038/nature08016
   Funke JJ, 2016, NAT NANOTECHNOL, V11, P47, DOI 10.1038/NNANO.2015.240
   Furini S, 2008, BIOPHYS J, V95, P2265, DOI 10.1529/biophysj.107.127019
   Geary C, 2014, SCIENCE, V345, P799, DOI 10.1126/science.1253920
   Gerling T, 2015, SCIENCE, V347, P1446, DOI 10.1126/science.aaa5372
   Guo PX, 2010, NAT NANOTECHNOL, V5, P833, DOI 10.1038/NNANO.2010.231
   Iinuma R, 2014, SCIENCE, V344, P65, DOI 10.1126/science.1250944
   Jones MR, 2015, SCIENCE, V347, P0, DOI 10.1126/science.1260901
   King NP, 2014, NATURE, V510, P103, DOI 10.1038/nature13404
   Konijnenberg A, 2015, PROTEIN SCI, V24, P1292, DOI 10.1002/pro.2703
   Lai YT, 2014, NAT CHEM, V6, P1065, DOI 10.1038/NCHEM.2107
   Lanci CJ, 2012, P NATL ACAD SCI USA, V109, P7304, DOI 10.1073/pnas.1112595109
   Leung C, 2014, ELIFE, V3, P0, DOI 10.7554/eLife.04247
   Perlmutter JD, 2015, ANNU REV PHYS CHEM, V66, P217, DOI 10.1146/annurev-physchem-040214-121637
   Rothemund PWK, 2006, NATURE, V440, P297, DOI 10.1038/nature04586
   Stock D, 1999, SCIENCE, V286, P1700, DOI 10.1126/science.286.5445.1700
   Su T, 2017, ELIFE, V6, P0, DOI 10.7554/eLife.25642
   Thomson AR, 2014, SCIENCE, V346, P485, DOI 10.1126/science.1257452
   Tian C, 2014, ANGEW CHEM INT EDIT, V53, P8041, DOI 10.1002/anie.201400377
   Veneziano R, 2016, SCIENCE, V352, P0, DOI 10.1126/science.aaf4388
   Wagenbauer KF, 2017, CHEMBIOCHEM, V18, P1873, DOI 10.1002/cbic.201700377
   Wei B, 2012, NATURE, V485, P623, DOI 10.1038/nature11075
NR 30
TC 377
Z9 439
U1 7
U2 282
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 7
PY 2017
VL 552
IS 7683
BP 78
EP 83
DI 10.1038/nature24651
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FP4BA
UT WOS:000417560500046
PM 29219966
DA 2026-03-09
ER

PT J
AU Poran, A
   Nötzel, C
   Aly, O
   Mencia-Trinchant, N
   Harris, CT
   Guzman, ML
   Hassane, DC
   Lemento, OE
   Kafsack, BFC
AF Poran, Asaf
   Notzel, Christopher
   Aly, Omar
   Mencia-Trinchant, Nuria
   Harris, Chantal T.
   Guzman, Monica L.
   Hassane, Duane C.
   Lemento, Olivier E.
   Kafsack, Bjorn F. C.
TI Single-cell RNA sequencing reveals a signature of sexual commitment in malaria parasites
SO NATURE
LA English
DT Article
ID plasmodium-falciparum; antigenic variation; bistable switch; differentiation; gametocytes; mechanisms; dynamics; patterns
AB Pathogens have to balance transmission with persistence. For Plasmodium falciparum, the most widespread and virulent malaria parasite, persistence within its human host requires continuous asexual replication within red blood cells, while its mosquito-borne transmission depends on intra-erythrocytic differentiation into non-replicating sexual stages called gametocytes(1). Commitment to either fate is determined during the preceding cell cycle that begins with invasion by a single, asexually committed merozoite and ends, 48 hours later, with a schizont releasing newly formed merozoites, all committed to either continued asexual replication or differentiation into gametocytes(2,3). Sexual commitment requires the transcriptional activation of ap2-g (PF3D7_1222600)(4,5), the master regulator of sexual development, from an epigenetically silenced state during asexual replication(6,7). AP2-G expression during this 'commitment cycle' prepares gene expression in nascent merozoites to initiate sexual development through a hitherto unknown mechanism(2,4). To maintain a persistent infection, the expression of ap2-g is limited to a sub-population of parasites (1-30%, depending on genetic background and growth conditions). As sexually committed schizonts comprise only a sub-population and are morphologically indistinguishable from their asexually committed counterparts, defining their characteristic gene expression has been difficult using traditional, bulk transcriptome profiling(8). Here we use highly parallel, single-cell RNA sequencing(9) of malaria cultures undergoing sexual commitment to determine the transcriptional changes induced by AP2-G within this sub-population. By analysing more than 18,000 single parasite transcriptomes from a conditional AP2-G knockdown line and NF54 wild-type parasites at multiple stages of development, we show that sexually committed, AP2-G(+) mature schizonts specifically upregulate additional regulators of gene expression, including other AP2 transcription factors, histonemodifying enzymes, and regulators of nucleosome positioning. These epigenetic regulators may act to facilitate the expression and/or repression of genes that are necessary for the initiation of gametocyte development in the subsequent cell cycle.
C1 [Poran, Asaf; Aly, Omar; Hassane, Duane C.; Lemento, Olivier E.] Weill Cornell Med, Dept Physiol & Biophys, Inst Computat Biomed, New York, NY 10065 USA.
   [Poran, Asaf; Aly, Omar; Lemento, Olivier E.] Weill Cornell Med, Caryl & Israel Englander Inst Precis Med, New York, NY 10065 USA.
   [Poran, Asaf] Weill Cornell Med, Physiol Biophys & Syst Biol Grad Program, New York, NY 10065 USA.
   [Notzel, Christopher] Weill Cornell Med, Biochem Cell & Mol Biol Grad Program, New York, NY 10065 USA.
   [Notzel, Christopher; Harris, Chantal T.; Kafsack, Bjorn F. C.] Weill Cornell Med, Dept Microbiol & Immunol, New York, NY 10065 USA.
   [Mencia-Trinchant, Nuria; Guzman, Monica L.; Hassane, Duane C.] Weill Cornell Med, Div Hematol & Med Oncol, Dept Med, New York, NY 10065 USA.
   [Harris, Chantal T.] Weill Cornell Med, Immunol & Microbial Pathogenesis Grad Program, New York, NY 10065 USA.
C3 Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine
RP Lemento, OE (corresponding author), Weill Cornell Med, Dept Physiol & Biophys, Inst Computat Biomed, New York, NY 10065 USA.; Lemento, OE (corresponding author), Weill Cornell Med, Caryl & Israel Englander Inst Precis Med, New York, NY 10065 USA.; Kafsack, BFC (corresponding author), Weill Cornell Med, Dept Microbiol & Immunol, New York, NY 10065 USA.
EM ole2001@med.cornell.edu; bjk2007@med.cornell.edu
FU WCM internal startup funds; NSF CAREER award [DBI-10549646]; LLS SCOR [7006-13, 7012016]; Hirschl Trust Award; Starr Cancer Consortium [I6-A618]; NIH [1R01CA194547]; WCM graduate fellowships
NR 35
TC 162
Z9 197
U1 0
U2 42
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 2
PY 2017
VL 551
IS 7678
BP 95
EP +
DI 10.1038/nature24280
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FL4SY
UT WOS:000414222900052
PM 29094698
DA 2026-03-09
ER

PT J
AU García-López, V
   Chen, F
   Nilewski, LG
   Duret, G
   Aliyan, A
   Kolomeisky, AB
   Robinson, JT
   Wang, GF
   Pal, R
   Tour, JM
AF Garcia-Lopez, Victor
   Chen, Fang
   Nilewski, Lizanne G.
   Duret, Guillaume
   Aliyan, Amir
   Kolomeisky, Anatoly B.
   Robinson, Jacob T.
   Wang, Gufeng
   Pal, Robert
   Tour, James M.
TI Molecular machines open cell membranes
SO NATURE
LA English
DT Article
ID prostate-cancer; optical control; identification; apoptosis; poration; dynamics; vesicles; bilayers; rupture; fusion
AB Beyond the more common chemical delivery strategies, several physical techniques are used to open the lipid bilayers of cellular membranes(1). These include using electric(2) and magnetic(3) fields, temperature(4), ultrasound(5) or light(6) to introduce compounds into cells, to release molecular species from cells or to selectively induce programmed cell death (apoptosis) or uncontrolled cell death (necrosis). More recently, molecular motors and switches that can change their conformation in a controlled manner in response to external stimuli have been used to produce mechanical actions on tissue for biomedical applications(7-9). Here we show that molecular machines can drill through cellular bilayers using their molecular-scale actuation, specifically nanomechanical action. Upon physical adsorption of the molecular motors onto lipid bilayers and subsequent activation of the motors using ultraviolet light, holes are drilled in the cell membranes. We designed molecular motors and complementary experimental protocols that use nanomechanical action to induce the diffusion of chemical species out of synthetic vesicles, to enhance the diffusion of traceable molecular machines into and within live cells, to induce necrosis and to introduce chemical species into live cells. We also show that, by using molecular machines that bear short peptide addends, nanomechanical action can selectively target specific cell-surface recognition sites. Beyond the in vitro applications demonstrated here, we expect that molecular machines could also be used in vivo, especially as their design progresses to allow two-photon, near-infrared and radio-frequency activation(10).
C1 [Garcia-Lopez, Victor; Nilewski, Lizanne G.; Aliyan, Amir; Kolomeisky, Anatoly B.; Tour, James M.] Rice Univ, Dept Chem, POB 1892, Houston, TX 77005 USA.
   [Garcia-Lopez, Victor; Nilewski, Lizanne G.; Tour, James M.] Rice Univ, Smalley Curl Inst & NanoCarbon Ctr, Houston, TX 77005 USA.
   [Chen, Fang; Wang, Gufeng] North Carolina State Univ, Dept Chem, Raleigh, NC 27695 USA.
   [Duret, Guillaume; Robinson, Jacob T.] Rice Univ, Dept Elect & Comp Engn, Houston, TX 77005 USA.
   [Pal, Robert] Univ Durham, Dept Chem, South Rd, Durham DH1 3LE, England.
   [Tour, James M.] Rice Univ, Dept Mat Sci & NanoEngn, Houston, TX 77005 USA.
C3 Rice University; Rice University; North Carolina State University; Rice University; Durham University; Rice University
RP Tour, JM (corresponding author), Rice Univ, Dept Chem, POB 1892, Houston, TX 77005 USA.; Tour, JM (corresponding author), Rice Univ, Smalley Curl Inst & NanoCarbon Ctr, Houston, TX 77005 USA.; Wang, GF (corresponding author), North Carolina State Univ, Dept Chem, Raleigh, NC 27695 USA.; Robinson, JT (corresponding author), Rice Univ, Dept Elect & Comp Engn, Houston, TX 77005 USA.; Pal, R (corresponding author), Univ Durham, Dept Chem, South Rd, Durham DH1 3LE, England.; Tour, JM (corresponding author), Rice Univ, Dept Mat Sci & NanoEngn, Houston, TX 77005 USA.
EM jtrobinson@rice.edu; gufeng_wang@ncsu.edu; robert.pal@dur.ac.uk; tour@rice.edu
FU North Carolina State University; FRPD Award; Royal Society; BSI Durham; National Science Foundation [CHE-1007483]; Integrated Microscopy Core at Baylor College of Medicine; NIH [DK56338, CA125123]; CPRIT [RP150578]; Dan L. Duncan Comprehensive Cancer Center; John S. Dunn Gulf Coast Consortium for Chemical Genomics; EPSRC [EP/P025684/1] Funding Source: UKRI; Engineering and Physical Sciences Research Council [EP/P025684/1] Funding Source: researchfish
NR 30
TC 282
Z9 311
U1 4
U2 414
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 31
PY 2017
VL 548
IS 7669
BP 567
EP 572
DI 10.1038/nature23657
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FF2BO
UT WOS:000408703100035
PM 28858304
DA 2026-03-09
ER

PT J
AU Raven, A
   Lu, WY
   Man, TY
   Ferreira-Gonzalez, S
   O'Duibhir, E
   Dwyer, BJ
   Thomson, JP
   Meehan, RR
   Bogorad, R
   Koteliansky, V
   Kotelevtsev, Y
   Ffrench-Constant, C
   Boulter, L
   Forbes, SJ
AF Raven, Alexander
   Lu, Wei-Yu
   Man, Tak Yung
   Ferreira-Gonzalez, Sofia
   O'Duibhir, Eoghan
   Dwyer, Benjamin J.
   Thomson, John P.
   Meehan, Richard R.
   Bogorad, Roman
   Koteliansky, Victor
   Kotelevtsev, Yuri
   Ffrench-Constant, Charles
   Boulter, Luke
   Forbes, Stuart J.
TI Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration
SO NATURE
LA English
DT Article
ID hepatic progenitor cells; injury; mice; beta-1-integrin; activation; fibrosis; ablation; diseases; origin
AB After liver injury, regeneration occurs through self-replication of hepatocytes. In severe liver injury, hepatocyte proliferation is impaired-a feature of human chronic liver disease(1,2). It is unclear whether other liver cell types can regenerate hepatocytes(3-5). Here we use two independent systems to impair hepatocyte proliferation during liver injury to evaluate the contribution of non-hepatocytes to parenchymal regeneration. First, loss of beta 1-integrin in hepatocytes with liver injury triggered a ductular reaction of cholangiocyte origin, with approximately 25% of hepatocytes being derived from a non-hepatocyte origin. Second, cholangiocytes were lineage traced with concurrent inhibition of hepatocyte proliferation by beta 1-integrin knockdown or p21 overexpression, resulting in the significant emergence of cholangiocyte-derived hepatocytes. We describe a model of combined liver injury and inhibition of hepatocyte proliferation that causes physiologically significant levels of regeneration of functional hepatocytes from biliary cells.
C1 [Raven, Alexander; Lu, Wei-Yu; Man, Tak Yung; Ferreira-Gonzalez, Sofia; O'Duibhir, Eoghan; Dwyer, Benjamin J.; Ffrench-Constant, Charles; Forbes, Stuart J.] Univ Edinburgh, MRC Ctr Regenerat Med, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland.
   [Thomson, John P.; Meehan, Richard R.; Boulter, Luke] Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland.
   [Bogorad, Roman] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Koteliansky, Victor; Kotelevtsev, Yuri] Skolkovo Inst Sci & Technol, Funct Genom & RNAi Therapy CREI, 3 Nobel St, Skolkovo 143026, Moscow Region, Russia.
C3 University of Edinburgh; University of Edinburgh; Massachusetts Institute of Technology (MIT); Skolkovo Institute of Science & Technology
RP Forbes, SJ (corresponding author), Univ Edinburgh, MRC Ctr Regenerat Med, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland.
EM stuart.forbes@ed.ac.uk
FU UK Medical Research Council (MRC) [MC_PC_U127574433]; MRC [MR/L012766/1, MR/K017047/1]; UK Regenerative Medicine Platform [MR/K026666/1]; MRC [MR/L012766/1, MR/K026666/1, MC_PC_U127574433, MR/K017047/1] Funding Source: UKRI; Medical Research Council [1356047, MR/L012766/1, MR/K017047/1, MR/K026666/1, G0700711B, 1802904, MC_PC_U127574433] Funding Source: researchfish
NR 27
TC 435
Z9 481
U1 5
U2 141
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 20
PY 2017
VL 547
IS 7663
BP 350
EP +
DI 10.1038/nature23015
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB0OR
UT WOS:000405844900034
PM 28700576
DA 2026-03-09
ER

PT J
AU Ma, H
   Marti-Gutierrez, N
   Park, SW
   Wu, J
   Lee, Y
   Suzuki, K
   Koski, A
   Ji, DM
   Hayama, T
   Ahmed, R
   Darby, H
   Van Dyken, C
   Li, Y
   Kang, E
   Park, AR
   Kim, D
   Kim, ST
   Gong, JH
   Gu, Y
   Xu, X
   Battaglia, D
   Krieg, SA
   Lee, DM
   Wu, DH
   Wolf, DP
   Heitner, SB
   Belmonte, JCI
   Mato, PA
   Kim, JS
   Kaul, S
   Mitalipov, S
AF Ma, Hong
   Marti-Gutierrez, Nuria
   Park, Sang-Wook
   Wu, Jun
   Lee, Yeonmi
   Suzuki, Keiichiro
   Koski, Amy
   Ji, Dongmei
   Hayama, Tomonari
   Ahmed, Riffat
   Darby, Hayley
   Van Dyken, Crystal
   Li, Ying
   Kang, Eunju
   Park, A. -Reum
   Kim, Daesik
   Kim, Sang-Tae
   Gong, Jianhui
   Gu, Ying
   Xu, Xun
   Battaglia, David
   Krieg, Sacha A.
   Lee, David M.
   Wu, Diana H.
   Wolf, Don P.
   Heitner, Stephen B.
   Belmonte, Juan Carlos Izpisua
   Mato, Paula A.
   Kim, Jin-Soo
   Kaul, Sanjiv
   Mitalipov, Shoukhrat
TI Correction of a pathogenic gene mutation in human embryos (Publication with Expression of Concern)
SO NATURE
LA English
DT Article; Publication with Expression of Concern
ID rna-guided endonucleases; human-cells; primate embryos; digenome-seq; cas9; crispr-cas9; nucleases; mouse; dna; zygotes
AB Genome editing has potential for the targeted correction of germline mutations. Here we describe the correction of the heterozygous MYBPC3 mutation in human preimplantation embryos with precise CRISPR-Cas9-based targeting accuracy and high homology-directed repair efficiency by activating an endogenous, germline-specific DNA repair response. Induced double-strand breaks (DSBs) at the mutant paternal allele were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template. By modulating the cell cycle stage at which the DSB was induced, we were able to avoid mosaicism in cleaving embryos and achieve a high yield of homozygous embryos carrying the wild-type MYBPC3 gene without evidence of off-target mutations. The efficiency, accuracy and safety of the approach presented suggest that it has potential to be used for the correction of heritable mutations in human embryos by complementing preimplantation genetic diagnosis. However, much remains to be considered before clinical applications, including the reproducibility of the technique with other heterozygous mutations.
C1 [Ma, Hong; Marti-Gutierrez, Nuria; Lee, Yeonmi; Koski, Amy; Ji, Dongmei; Hayama, Tomonari; Ahmed, Riffat; Darby, Hayley; Van Dyken, Crystal; Li, Ying; Kang, Eunju; Battaglia, David; Wolf, Don P.; Mato, Paula A.; Mitalipov, Shoukhrat] Oregon Hlth & Sci Univ, Ctr Embryon Cell & Gene Therapy, 3303 Southwest,Bond Ave, Portland, OR 97239 USA.
   [Park, Sang-Wook; Park, A. -Reum; Kim, Sang-Tae; Kim, Jin-Soo] Inst for Basic Sci Korea, Ctr Genome Engn, 70 Yuseong Daero 1689 Gil, Daejeon 34047, South Korea.
   [Wu, Jun; Suzuki, Keiichiro; Belmonte, Juan Carlos Izpisua] Salk Inst Biol Studies, Gene Express Lab, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA.
   [Kim, Daesik; Kim, Jin-Soo] Seoul Natl Univ, Dept Chem, 599 Gwanak Ro, Seoul 151747, South Korea.
   [Gong, Jianhui; Gu, Ying; Xu, Xun] BGI Shenzhen, Bldg 11, Shenzhen 518083, Peoples R China.
   [Gong, Jianhui; Gu, Ying; Xu, Xun] BGI Shenzhen, China Natl GeneBank, Jinsha Rd, Shenzhen 518210, Peoples R China.
   [Gong, Jianhui; Gu, Ying; Xu, Xun] BGI Qingdao, 2877 Tuanjie Rd,Sino German Ecopk, Qingdao 266000, Peoples R China.
   [Gong, Jianhui] BGI Shenzhen, Shenzhen Engn Lab Innovat Mol Diagnost, Bldg 11, Shenzhen 518083, Peoples R China.
   [Battaglia, David; Krieg, Sacha A.; Lee, David M.; Wu, Diana H.; Mato, Paula A.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, 3303 Southwest,Bond Ave, Portland, OR 97239 USA.
   [Heitner, Stephen B.; Kaul, Sanjiv; Mitalipov, Shoukhrat] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, 3181 Southwest,Sam Jackson Pk Rd, Portland, OR 97239 USA.
C3 Oregon Health & Science University; Institute for Basic Science - Korea (IBS); Salk Institute; Seoul National University (SNU); Beijing Genomics Institute (BGI); Beijing Genomics Institute (BGI); Beijing Genomics Institute (BGI); Beijing Genomics Institute (BGI); Oregon Health & Science University; Oregon Health & Science University
RP Mato, PA; Mitalipov, S (corresponding author), Oregon Hlth & Sci Univ, Ctr Embryon Cell & Gene Therapy, 3303 Southwest,Bond Ave, Portland, OR 97239 USA.; Kim, JS (corresponding author), Inst for Basic Sci Korea, Ctr Genome Engn, 70 Yuseong Daero 1689 Gil, Daejeon 34047, South Korea.; Belmonte, JCI (corresponding author), Salk Inst Biol Studies, Gene Express Lab, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA.; Kim, JS (corresponding author), Seoul Natl Univ, Dept Chem, 599 Gwanak Ro, Seoul 151747, South Korea.; Mato, PA (corresponding author), Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, 3303 Southwest,Bond Ave, Portland, OR 97239 USA.; Kaul, S; Mitalipov, S (corresponding author), Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, 3181 Southwest,Sam Jackson Pk Rd, Portland, OR 97239 USA.
EM belmonte@salk.edu; amatop@ohsu.edu; jskim01@snu.ac.kr; kauls@ohsu.edu; mitalipo@ohsu.edu
FU OHSU institutional funds; Institute for Basic Science [IBS-R021-D1]; G. Harold and Leila Y. Mathers Charitable Foundation; Moxie Foundation; Leona M. and Harry B. Helmsley Charitable Trust; Shenzhen Municipal Government of China [DRC-SZ [2016] 884]
NR 48
TC 701
Z9 838
U1 12
U2 811
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 24
PY 2017
VL 548
IS 7668
BP 413
EP +
DI 10.1038/nature23305
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FE5VI
UT WOS:000408279000030
PM 28783728
DA 2026-03-09
ER

PT J
AU Bendixen, M
   Iversen, LL
   Bjork, AA
   Elberling, B
   Westergaard-Nielsen, A
   Overeem, I
   Barnhart, KR
   Khan, SA
   Box, JE
   Abermann, J
   Langley, K
   Kroon, A
AF Bendixen, Mette
   Iversen, Lars Lonsmann
   Bjork, Anders Anker
   Elberling, Bo
   Westergaard-Nielsen, Andreas
   Overeem, Irina
   Barnhart, Katy R.
   Khan, Shfaqat Abbas
   Box, Jason E.
   Abermann, Jakob
   Langley, Kirsty
   Kroon, Aart
TI Delta progradation in Greenland driven by increasing glacial mass loss
SO NATURE
LA English
DT Article
ID ice-sheet; sea-ice; arctic amplification; coastal erosion; climate model; fluctuations; rates
AB Climate changes are pronounced in Arctic regions and increase the vulnerability of the Arctic coastal zone(1). For example, increases in melting of the Greenland Ice Sheet and reductions in sea ice and permafrost distribution are likely to alter coastal morphodynamics. The deltas of Greenland are largely unaffected by human activity, but increased freshwater runoff and sediment fluxes may increase the size of the deltas, whereas increased wave activity in ice-free periods could reduce their size, with the net impact being unclear until now. Here we show that southwestern Greenland deltas were largely stable from the 1940s to 1980s, but prograded (that is, sediment deposition extended the delta into the sea) in a warming Arctic from the 1980s to 2010s. Our results are based on the areal changes of 121 deltas since the 1940s, assessed using newly discovered aerial photographs and remotely sensed imagery. We find that delta progradation was driven by high freshwater runoff from the Greenland Ice Sheet coinciding with periods of open water. Progradation was controlled by the local initial environmental conditions (that is, accumulated air temperatures above 0 degrees C per year, freshwater runoff and sea ice in the 1980s) rather than by local changes in these conditions from the 1980s to 2010s at each delta. This is in contrast to a dominantly eroding trend of Arctic sedimentary coasts along the coastal plains of Alaska(2), Siberia(3) and western Canada(4), and to the spatially variable patterns of erosion and accretion along the large deltas of the main rivers in the Arctic5-7. Our results improve the understanding of Arctic coastal evolution in a changing climate, and reveal the impacts on coastal areas of increasing ice mass loss and the associated freshwater runoff and lengthening of open-water periods.
C1 [Bendixen, Mette; Elberling, Bo; Westergaard-Nielsen, Andreas; Kroon, Aart] Univ Copenhagen, Ctr Permafrost CENPERM, DK-1350 Copenhagen, Denmark.
   [Iversen, Lars Lonsmann] Univ Copenhagen, Dept Biol, Freshwater Biol, DK-2100 Copenhagen, Denmark.
   [Bjork, Anders Anker] Univ Copenhagen, Ctr GeoGenet, Nat Hist Museum Denmark, DK-1350 Copenhagen, Denmark.
   [Bjork, Anders Anker] Univ Calif Irvine, Dept Earth Syst Sci, Irvine, CA 92697 USA.
   [Bjork, Anders Anker] NASA, Jet Prop Lab, Pasadena, CA 91109 USA.
   [Overeem, Irina] Univ Colorado, Inst Arctic & Alpine Res, Boulder, CO 80309 USA.
   [Barnhart, Katy R.] Univ Colorado, Cooperat Inst Res Environm Sci, Boulder, CO 80309 USA.
   [Barnhart, Katy R.] Univ Colorado, Dept Geol Sci, Boulder, CO 80309 USA.
   [Khan, Shfaqat Abbas] Tech Univ Denmark, DTU Space, Natl Space Inst, DK-2800 Lyngby, Denmark.
   [Box, Jason E.] Geol Survey Denmark & Greenland GEUS, DK-1350 Copenhagen, Denmark.
   [Abermann, Jakob; Langley, Kirsty] Asiaq Greenland Survey, Postbox 1003, Nuuk 3900, Greenland.
C3 University of Copenhagen; University of Copenhagen; University of Copenhagen; University of California System; University of California Irvine; National Aeronautics & Space Administration (NASA); NASA Jet Propulsion Laboratory (JPL); University of Colorado System; University of Colorado Boulder; University of Colorado System; University of Colorado Boulder; University of Colorado System; University of Colorado Boulder; Technical University of Denmark; Geological Survey Of Denmark & Greenland
RP Bendixen, M (corresponding author), Univ Copenhagen, Ctr Permafrost CENPERM, DK-1350 Copenhagen, Denmark.
EM mette.bendixen@ign.ku.dk
FU Danish National Research Foundation [CENPERM DNRF100]; Carlsberg Foundation [0604-02230B]; Danish Council for Independent Research [DFF-610800469, DFF-4181-00126]; Inge Lehmann Scholarship from the Royal Danish Academy of Science and Letters; US National Science Foundation (NSF) Office of Polar Programs [ARC-0909349]; INSTAAR; Annenberg Public Policy Center; NSF SI2-SSI Award [1450409]; Asiaq Greenland Survey
NR 54
TC 74
Z9 82
U1 2
U2 65
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 5
PY 2017
VL 550
IS 7674
BP 101
EP +
DI 10.1038/nature23873
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI7XU
UT WOS:000412214100053
PM 28980627
DA 2026-03-09
ER

PT J
AU Taylor, CM
   Belusic, D
   Guichard, F
   Arker, DJP
   Vischel, T
   Bock, O
   Harris, PP
   Janicot, S
   Klein, C
   Panthou, G
AF Taylor, Christopher M.
   Belusic, Danijel
   Guichard, Francoise
   Arker, Douglas J. P.
   Vischel, Theo
   Bock, Olivier
   Harris, Phil P.
   Janicot, Serge
   Klein, Cornelia
   Panthou, Geremy
TI Frequency of extreme Sahelian storms tripled since 1982 in satellite observations
SO NATURE
LA English
DT Article
ID precipitation extremes; future changes; climate; rainfall; temperatures; variability; intensity; trends; dry
AB The hydrological cycle is expected to intensify under global warming(1), with studies reporting more frequent extreme rain events in many regions of the world(2-4), and predicting increases in future flood frequency(5). Such early, predominantly mid-latitude observations are essential because of shortcomings within climate models in their depiction of convective rainfall(6,7). A globally important group of intense storms-mesoscale convective systems (MCSs) 8-poses a particular challenge, because they organize dynamically on spatial scales that cannot be resolved by conventional climate models. Here, we use 35 years of satellite observations from the West African Sahel to reveal a persistent increase in the frequency of the most intense MCSs. Sahelian storms are some of the most powerful on the planet(9), and rain gauges in this region have recorded a rise in 'extreme'(17) daily rainfall totals. We find that intense MCS frequency is only weakly related to the multidecadal recovery of Sahel annual rainfall, but is highly correlated with global land temperatures. Analysis of trends across Africa reveals that MCS intensification is limited to a narrow band south of the Sahara desert. During this period, wet-season Sahelian temperatures have not risen, ruling out the possibility that rainfall has intensified in response to locally warmer conditions. On the other hand, the meridional temperature gradient spanning the Sahel has increased in recent decades, consistent with anthropogenic forcing driving enhanced Saharan warming(10). We argue that Saharan warming intensifies convection within Sahelian MCSs through increased wind shear and changes to the Saharan air layer. The meridional gradient is projected to strengthen throughout the twenty-first century, suggesting that the Sahel will experience particularly marked increases in extreme rain. The remarkably rapid intensification of Sahelian MCSs since the 1980s sheds new light on the response of organized tropical convection to global warming, and challenges conventional projections made by general circulation models.
C1 [Taylor, Christopher M.; Belusic, Danijel; Harris, Phil P.; Klein, Cornelia] Ctr Ecol & Hydrol, Wallingford OX10 8BB, Oxon, England.
   [Taylor, Christopher M.; Harris, Phil P.] Natl Ctr Earth Observat, Wallingford OX10 8BB, Oxon, England.
   [Belusic, Danijel] Swedish Meteorol & Hydrol Inst, SE-60176 Norrkoping, Sweden.
   [Guichard, Francoise] CNRS, UMR 3589, CNRM, F-31057 Toulouse, France.
   [Guichard, Francoise] Meteo France, F-31057 Toulouse, France.
   [Arker, Douglas J. P.] Univ Leeds, Sch Earth & Environm, Leeds LS2 9JT, W Yorkshire, England.
   [Vischel, Theo; Panthou, Geremy] Univ Grenoble Alpes, IRD, CNRS, Inst Engn,Univ Grenoble Alpes G INP,IGE, F-38000 Grenoble, France.
   [Bock, Olivier] Univ Paris Diderot, Sorbonne Paris Cite, Lab Rech Geodesie LAREG, Inst Natl Informat Geog & Forestiere IGN, F-75205 Paris, France.
   [Janicot, Serge] UPMC, CNRS, IRD, MNHN,Sorbonne Univ,LOCEAN,UMR7159, F-75252 Paris, France.
C3 UK Centre for Ecology & Hydrology (UKCEH); Swedish Meteorological & Hydrological Institute; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); University of Leeds; Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Centre National de la Recherche Scientifique (CNRS); Institut de Recherche pour le Developpement (IRD); Universite Paris Cite; Universite Gustave-Eiffel; Sorbonne Universite; Museum National d'Histoire Naturelle (MNHN); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Institut de Recherche pour le Developpement (IRD)
RP Taylor, CM (corresponding author), Ctr Ecol & Hydrol, Wallingford OX10 8BB, Oxon, England.; Taylor, CM (corresponding author), Natl Ctr Earth Observat, Wallingford OX10 8BB, Oxon, England.
EM cmt@ceh.ac.uk
FU UK's National Environment Research Council (NERC)/Department for International Development (DFID) Future Climate For Africa programme under AMMA-2050 project [NE/M020428/1, NE/M019969/1, NE/M019950/1, NE/M020126/1, NE/M019934/1]; Royal Society Wolfson Research Merit Award; NERC [NE/B505554/1, NE/M020428/1, NE/G018499/1, nceo020006, NE/M019950/1, NE/M020126/1] Funding Source: UKRI; Natural Environment Research Council [NE/B505554/1, NE/M020428/1, NE/M019969/1, NE/M019950/1, NE/G018499/1, NE/M019934/1, nceo020006, NE/M020126/1] Funding Source: researchfish
NR 45
TC 324
Z9 357
U1 4
U2 167
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 27
PY 2017
VL 544
IS 7651
BP 475
EP +
DI 10.1038/nature22069
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET1TN
UT WOS:000400051900042
PM 28447639
DA 2026-03-09
ER

PT J
AU Wenthur, CJ
   Zhou, B
   Janda, KD
AF Wenthur, Cody J.
   Zhou, Bin
   Janda, Kim D.
TI Vaccine-driven pharmacodynamic dissection and mitigation of fenethylline psychoactivity
SO NATURE
LA English
DT Article
ID metabolic-fate; designer drugs; methamphetamine; amphetamine; fenetylline; abuse; derivatives; rat
AB Fenethylline, also known by the trade name Captagon, is a synthetic psychoactive stimulant that has recently been linked to a substanceuse disorder and 'pharmacoterrorism' in the Middle East(1-4). Although fenethylline shares a common phenethylamine core with other amphetamine-type stimulants, it also incorporates a covalently linked xanthine moiety into its parent structure(5,6). These independently active pharmacophores are liberated during metabolism, resulting in the release of a structurally diverse chemical mixture into the central nervous system(7-9). Although the psychoactive properties of fenethylline have been reported to differ from those of other synthetic stimulants, the in vivo chemical complexity it manifests upon ingestion has impeded efforts to unambiguously identify the specific species responsible for these effects(10,11). Here we develop a 'dissection through vaccination' approach, called DISSECTIV, to mitigate the psychoactive effects of fenethylline and show that its rapid-onset and distinct psychoactive properties are facilitated by functional synergy between theophylline and amphetamine. Our results demonstrate that incremental vaccination against a single chemical species within a multi-component mixture can be used to uncover emergent properties arising from polypharmacological activity. We anticipate that DISSECTIV will be used to expose unidentified active chemical species and resolve pharmacodynamic interactions within other chemically complex systems, such as those found in counterfeit or illegal drug preparations, post-metabolic tissue samples and natural product extracts.
C1 [Wenthur, Cody J.; Zhou, Bin; Janda, Kim D.] Scripps Res Inst, Dept Chem, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA.
   [Wenthur, Cody J.; Zhou, Bin; Janda, Kim D.] Scripps Res Inst, Dept Immunol, WIRM Inst Res & Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA.
C3 Scripps Research Institute; Scripps Research Institute
RP Janda, KD (corresponding author), Scripps Res Inst, Dept Chem, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA.; Janda, KD (corresponding author), Scripps Res Inst, Dept Immunol, WIRM Inst Res & Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA.
EM kdjanda@scripps.edu
FU NIH [DA024705-06]
NR 30
TC 11
Z9 14
U1 0
U2 19
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 24
PY 2017
VL 548
IS 7668
BP 476
EP +
DI 10.1038/nature23464
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FE5VI
UT WOS:000408279000043
PM 28813419
DA 2026-03-09
ER

PT J
AU Arcavi, I
   Hosseinzadeh, G
   Howell, DA
   McCully, C
   Poznanski, D
   Kasen, D
   Barnes, J
   Zaltzman, M
   Vasylyev, S
   Maoz, D
   Valenti, S
AF Arcavi, Iair
   Hosseinzadeh, Griffin
   Howell, D. Andrew
   McCully, Curtis
   Poznanski, Dovi
   Kasen, Daniel
   Barnes, Jennifer
   Zaltzman, Michael
   Vasylyev, Sergiy
   Maoz, Dan
   Valenti, Stefano
TI Optical emission from a kilonova following a gravitational-wave-detected neutron-star merger
SO NATURE
LA English
DT Article
ID gamma-ray bursts; nucleosynthesis
AB The merger of two neutron stars has been predicted to produce an optical-infrared transient (lasting a few days) known as a 'kilonova', powered by the radioactive decay of neutron-rich species synthesized in the merger(1-5). Evidence that short gamma-ray bursts also arise from neutron-star mergers has been accumulating(6-8). In models(2,9) of such mergers, a small amount of mass (10(-4)-10(-2) solar masses) with a low electron fraction is ejected at high velocities (0.1-0.3 times light speed) or carried out by winds from an accretion disk formed around the newly merged object(10,11). This mass is expected to undergo rapid neutron capture (r-process) nucleosynthesis, leading to the formation of radioactive elements that release energy as they decay, powering an electromagnetic transient(1-3,9-14). A large uncertainty in the composition of the newly synthesized material leads to various expected colours, durations and luminosities for such transients(11-14). Observational evidence for kilonovae has so far been inconclusive because it was based on cases(15-19) of moderate excess emission detected in the afterglows of gamma-ray bursts. Here we report optical to near-infrared observations of a transient coincident with the detection of the gravitational-wave signature of a binary neutron-star merger and with a low-luminosity short-duration gamma-ray burst(20). Our observations, taken roughly every eight hours over a few days following the gravitational-wave trigger, reveal an initial blue excess, with fast optical fading and reddening. Using numerical models(21), we conclude that our data are broadly consistent with a light curve powered by a few hundredths of a solar mass of low-opacity material corresponding to lanthanide-poor (a fraction of 10(-4.5) by mass) ejecta.
C1 [Arcavi, Iair; Hosseinzadeh, Griffin; Howell, D. Andrew; McCully, Curtis; Vasylyev, Sergiy] Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA.
   [Arcavi, Iair; Hosseinzadeh, Griffin; Howell, D. Andrew; McCully, Curtis; Vasylyev, Sergiy] Las Cumbres Observ, 6740 Cortona Dr,Suite 102, Goleta, CA 93117 USA.
   [Poznanski, Dovi; Zaltzman, Michael; Maoz, Dan] Tel Aviv Univ, Sch Phys & Astron, IL-69978 Tel Aviv, Israel.
   [Kasen, Daniel] Lawrence Berkeley Natl Lab, Nucl Sci Div, Berkeley, CA 94720 USA.
   [Kasen, Daniel] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Kasen, Daniel] Univ Calif Berkeley, Dept Astron, 601 Campbell Hall, Berkeley, CA 94720 USA.
   [Barnes, Jennifer] Columbia Univ, Columbia Astrophys Lab, 538 W 120th St, New York, NY 10027 USA.
   [Valenti, Stefano] Univ Calif Davis, Dept Phys, 1 Shields Ave, Davis, CA 95616 USA.
C3 University of California System; University of California Santa Barbara; Tel Aviv University; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; University of California System; University of California Berkeley; University of California System; University of California Berkeley; Columbia University; University of California System; University of California Davis
RP Arcavi, I (corresponding author), Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA.; Arcavi, I (corresponding author), Las Cumbres Observ, 6740 Cortona Dr,Suite 102, Goleta, CA 93117 USA.
EM arcavi@gmail.com
FU National Aeronautics and Space Administration (NASA) through the Einstein Fellowship Program [PF6-170148, PF7-180162]; US National Science Foundation (NSF) [AST-1313484]; Israel Science Foundation [541/17]; Department of Energy (DOE) [DE-SC0008067]; DOE Office of Nuclear Physics [DE-S00017616]; DOE SciDAC [DE-SC0018297]; Office of Energy Research, Office of High Energy and Nuclear Physics, Divisions of Nuclear Physics, of the US Department of Energy [DE-AC02-05CH11231]; Office of Science of the US Department of Energy [DE-AC02-05CH11231]; Space Telescope Science Institute (STScI) under US Government [NAG W-2166]; UK Science and Engineering Research Council; U.S. Department of Energy (DOE) [DE-SC0008067] Funding Source: U.S. Department of Energy (DOE)
NR 64
TC 614
Z9 676
U1 2
U2 29
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 2
PY 2017
VL 551
IS 7678
BP 64
EP +
DI 10.1038/nature24291
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FL4SY
UT WOS:000414222900044
DA 2026-03-09
ER

PT J
AU Minarik, M
   Stundl, J
   Fabian, P
   Jandzik, D
   Metscher, BD
   Psenicka, M
   Gela, D
   Osorio-Pérez, A
   Arias-Rodriguez, L
   Horácek, I
   Cerny, R
AF Minarik, Martin
   Stundl, Jan
   Fabian, Peter
   Jandzik, David
   Metscher, Brian D.
   Psenicka, Martin
   Gela, David
   Osorio-Perez, Adriana
   Arias-Rodriguez, Lenin
   Horacek, Ivan
   Cerny, Robert
TI Pre-oral gut contributes to facial structures in non-teleost fishes
SO NATURE
LA English
DT Article
ID endoderm formation; vertebrate head; primary mouth; evolution; origin; region; morphology; zebrafish; cells; gene
AB Despite the wide variety of adaptive modifications in the oral and facial regions of vertebrates, their early oropharyngeal development is considered strictly uniform. It involves sequential formation of the mouth and pharyngeal pouches, with ectoderm outlining the outer surface and endoderm the inner surface, as a rule(1,2). At the extreme anterior domain of vertebrate embryos, the ectoderm and endoderm directly juxtapose and initial development of this earliest ecto-endoderm interface, the primary mouth(3), typically involves ectodermal stomodeal invagination that limits the anterior expansion of the foregut endoderm(3,4). Here we present evidence that in embryos of extant non-teleost fishes, oral (stomodeal) formation is preceded by the development of prominent pre-oral gut diverticula (POGD) between the forebrain and roof of the forming mouth. Micro-computed tomography (micro-CT) imaging of bichir, sturgeon and gar embryos revealed that foregut outpocketing at the pre-oral domain begins even before the sequential formation of pharyngeal pouches. The presence of foregut-derived cells in the front of the mouth was further confirmed by in vivo experiments that allowed specific tracing of the early endodermal lining. We show that POGD in sturgeons contribute to the orofacial surface of their larvae, comprising oral teeth, lips, and sensory barbels. To our knowledge, this is the first thorough evidence for endodermal origin of external craniofacial structures in any vertebrate. In bichir and gar embryos, POGD form prominent cranial adhesive organs that are characteristic of the ancient bauplan of free-living chordate larvae. POGD hence seem arguably to be ancestral for all ray-finned fishes, and their topology, pharyngeal-like morphogenesis and gene expression suggest that they are evolutionarily related to the foregut-derived diverticula of early chordate and hemichordate embryos. The formation of POGD might thus represent an ancestral developmental module with deep deuterostome origins.
C1 [Minarik, Martin; Stundl, Jan; Fabian, Peter; Horacek, Ivan; Cerny, Robert] Charles Univ Prague, Dept Zool, Prague, Czech Republic.
   [Stundl, Jan] Natl Museum, Dept Zool, Prague, Czech Republic.
   [Jandzik, David] Comenius Univ, Dept Zool, Bratislava, Slovakia.
   [Metscher, Brian D.] Univ Vienna, Dept Theoret Biol, Vienna, Austria.
   [Psenicka, Martin; Gela, David] Univ South Bohemia Ceske Budejovice, Fac Fisheries & Protect Waters, Res Inst Fish Culture & Hydrobiol, South Bohemian Res Ctr Aquaculture & Biodivers Hy, Vodnany, Austria.
   [Osorio-Perez, Adriana; Arias-Rodriguez, Lenin] Univ Juarez Autonoma Tabasco, Div Acad Ciencias Biol, Villahermosa, Mexico.
C3 Charles University Prague; National Museum; Comenius University Bratislava; University of Vienna; Universidad Juarez Autonoma de Tabasco
RP Cerny, R (corresponding author), Charles Univ Prague, Dept Zool, Prague, Czech Republic.
EM robert.cerny@natur.cuni.cz
FU European Molecular Biology Organization (EMBO); GACR [16-23836S]; Charles University [SVV 260 434 / 2017]; Charles University GA UK [220213, 726516, 1448514]; OeAD Aktion Osterreich-Tschechien scholarship; BMWFW Austria; Ministry of Education, Youth and Sports of the Czech Republic [CZ.1.05/2.1.00/01.0024, LO1205]
NR 36
TC 30
Z9 33
U1 1
U2 49
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 13
PY 2017
VL 547
IS 7662
BP 209
EP +
DI 10.1038/nature23008
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FA3AX
UT WOS:000405314500037
PM 28678781
DA 2026-03-09
ER

PT J
AU Faesen, AC
   Thanasoula, M
   Maffini, S
   Breit, C
   Müller, F
   van Gerwen, S
   Bange, T
   Musacchio, A
AF Faesen, Alex C.
   Thanasoula, Maria
   Maffini, Stefano
   Breit, Claudia
   Mueller, Franziska
   van Gerwen, Suzan
   Bange, Tanja
   Musacchio, Andrea
TI Basis of catalytic assembly of the mitotic checkpoint complex
SO NATURE
LA English
DT Article
ID spindle checkpoint; unattached kinetochores; chromosome biorientation; mad2 activation; cdc20; apc/c; protein; inhibitor; reveals; binding
AB In mitosis, for each daughter cell to inherit an accurate copy of the genome from the mother cell, sister chromatids in the mother cell must attach to microtubules emanating from opposite poles of the mitotic spindle, a process known as bi-orientation. A surveillance mechanism, termed the spindle assembly checkpoint (SAC), monitors the microtubule attachment process and can temporarily halt the separation of sister chromatids and the completion of mitosis until bi-orientation is complete(1). SAC failure results in abnormal chromosome numbers, termed aneuploidy, in the daughter cells, a hallmark of many tumours. The HORMA-domain-containing protein mitotic arrest deficient 2 (MAD2) is a subunit of the SAC effector mitotic checkpoint complex (MCC). Structural conversion from the open to the closed conformation of MAD2 is required for MAD2 to be incorporated into the MCC1. In vitro, MAD2 conversion and MCC assembly take several hours(2-4), but in cells the SAC response is established in a few minutes(5-7). Here, to address this discrepancy, we reconstituted a near-complete SAC signalling system with purified components and monitored assembly of the MCC in real time. A marked acceleration in MAD2 conversion and MCC assembly was observed when monopolar spindle 1 (MPS1) kinase phosphorylated the MAD1-MAD2 complex, triggering it to act as the template for MAD2 conversion and therefore contributing to the establishment of a physical platform for MCC assembly. Thus, catalytic activation of the SAC depends on regulated protein-protein interactions that accelerate the spontaneous but rate-limiting conversion of MAD2 required for MCC assembly.
C1 [Faesen, Alex C.; Thanasoula, Maria; Maffini, Stefano; Breit, Claudia; Mueller, Franziska; van Gerwen, Suzan; Bange, Tanja; Musacchio, Andrea] Max Planck Inst Mol Physiol, Dept Mech Cell Biol, Otto Hahn Str 11, D-44227 Dortmund, Germany.
   [Musacchio, Andrea] Univ Duisburg Essen, Ctr Med Biotechnol, Fac Biol, Univ Str, D-45141 Essen, Germany.
C3 Max Planck Society; University of Duisburg Essen
RP Faesen, AC; Musacchio, A (corresponding author), Max Planck Inst Mol Physiol, Dept Mech Cell Biol, Otto Hahn Str 11, D-44227 Dortmund, Germany.; Musacchio, A (corresponding author), Univ Duisburg Essen, Ctr Med Biotechnol, Fac Biol, Univ Str, D-45141 Essen, Germany.
EM alex.faesen@mpi-dortmund.mpg.de; andrea.musacchio@mpi-dortmund.mpg.de
FU EMBO [ALTF 1096-2012]; Marie Curie Intra-European Fellowship (IEF); Project MitoSys; Horizon 2020 ERC agreement RECEPIANCE; DFG's Collaborative Research Centre (CRC) [1093]
NR 42
TC 127
Z9 153
U1 0
U2 33
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 23
PY 2017
VL 542
IS 7642
BP 498
EP +
DI 10.1038/nature21384
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1RG
UT WOS:000395094100041
PM 28102834
DA 2026-03-09
ER

PT J
AU Banerjee, M
   Heiblum, M
   Rosenblatt, A
   Oreg, Y
   Feldman, DE
   Stern, A
   Umansky, V
AF Banerjee, Mitali
   Heiblum, Moty
   Rosenblatt, Amir
   Oreg, Yuval
   Feldman, Dima E.
   Stern, Ady
   Umansky, Vladimir
TI Observed quantization of anyonic heat flow
SO NATURE
LA English
DT Article
ID thermoelectric transport; thermal conductance; neutral-modes; quantum; scattering; noise
AB The quantum of thermal conductance of ballistic (collisionless) onedimensional channels is a unique fundamental constant1. Although the quantization of the electrical conductance of one-dimensional ballistic conductors has long been experimentally established2, demonstrating the quantization of thermal conductance has been challenging as it necessitated an accurate measurement of very small temperature increase. It has been accomplished for weakly interacting systems of phonons(3,4), photons(5) and electronic Fermi liquids(6-8); however, it should theoretically also hold in strongly interacting systems, such as those in which the fractional quantum Hall effect is observed. This effect describes the fractionalization of electrons into anyons and chargeless quasiparticles, which in some cases can be Majorana fermions(2). Because the bulk is incompressible in the fractional quantum Hall regime, it is not expected to contribute substantially to the thermal conductance, which is instead determined by chiral, one-dimensional edge modes. The thermal conductance thus reflects the topological properties of the fractional quantum Hall electronic system, to which measurements of the electrical conductance give no access(9-12). Here we report measurements of thermal conductance in particle-like (LaughlinJain series) states and the more complex (and less studied) hole-like states in a high-mobility two-dimensional electron gas in GaAsAlGaAs heterostructures. Hole-like states, which have fractional Landau-level fillings of 1/2 to 1, support downstream charged modes as well as upstream neutral modes(13), and are expected to have a thermal conductance that is determined by the net chirality of all of their downstream and upstream edge modes. Our results establish the universality of the quantization of thermal conductance for fractionally charged and neutral modes. Measurements of anyonic heat flow provide access to information that is not easily accessible from measurements of conductance.
C1 [Banerjee, Mitali; Heiblum, Moty; Rosenblatt, Amir; Oreg, Yuval; Stern, Ady; Umansky, Vladimir] Weizmann Inst Sci, Braun Ctr Submicron Res, Dept Condensed Matter Phys, IL-76100 Rehovot, Israel.
   [Feldman, Dima E.] Brown Univ, Dept Phys, Providence, RI 02912 USA.
C3 Weizmann Institute of Science; Brown University
RP Heiblum, M (corresponding author), Weizmann Inst Sci, Braun Ctr Submicron Res, Dept Condensed Matter Phys, IL-76100 Rehovot, Israel.
EM moty.heiblum@weizmann.ac.il
FU European Research Council under the European Community [339070]; Minerva Foundation [711752]; V.U.; German Israeli Foundation (GIF) [I-1241-303.10/2014]; Israeli Science Foundation (ISF); European Research Council under the European Community/ERC [339070]; Israeli Science Foundation, ISF [13335/16]; NSF [DMR-1205715]; European Research Council (ERC) [339070] Funding Source: European Research Council (ERC)
NR 29
TC 170
Z9 184
U1 2
U2 106
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 4
PY 2017
VL 545
IS 7652
BP 75
EP +
DI 10.1038/nature22052
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET7MK
UT WOS:000400480400033
PM 28424514
DA 2026-03-09
ER

PT J
AU Kou, BQ
   Cao, YX
   Li, JD
   Xia, CJ
   Li, ZF
   Dong, HP
   Zhang, A
   Zhang, J
   Kob, W
   Wang, YJ
AF Kou, Binquan
   Cao, Yixin
   Li, Jindong
   Xia, Chengjie
   Li, Zhifeng
   Dong, Haipeng
   Zhang, Ang
   Zhang, Jie
   Kob, Walter
   Wang, Yujie
TI Granular materials flow like complex fluids
SO NATURE
LA English
DT Article
ID anomalous diffusion; origin
AB Granular materials such as sand, powders and foams are ubiquitous in daily life and in industrial and geotechnical applications(1-4). These disordered systems form stable structures when unperturbed, but in the presence of external influences such as tapping or shear they 'relax', becoming fluid in nature. It is often assumed that the relaxation dynamics of granular systems is similar to that of thermal glass-forming systems(3,5). However, so far it has not been possible to determine experimentally the dynamic properties of three-dimensional granular systems at the particle level. This lack of experimental data, combined with the fact that the motion of granular particles involves friction (whereas the motion of particles in thermal glass-forming systems does not), means that an accurate description of the relaxation dynamics of granular materials is lacking. Here we use X-ray tomography to determine the microscale relaxation dynamics of hard granular ellipsoids subject to an oscillatory shear. We find that the distribution of the displacements of the ellipsoids is well described by a Gumbel law(6) (which is similar to a Gaussian distribution for small displacements but has a heavier tail for larger displacements), with a shape parameter that is independent of the amplitude of the shear strain and of the time. Despite this universality, the mean squared displacement of an individual ellipsoid follows a power law as a function of time, with an exponent that does depend on the strain amplitude and time. We argue that these results are related to microscale relaxation mechanisms that involve friction and memory effects (whereby the motion of an ellipsoid at a given point in time depends on its previous motion). Our observations demonstrate that, at the particle level, the dynamic behaviour of granular systems is qualitatively different from that of thermal glass-forming systems, and is instead more similar to that of complex fluids. We conclude that granular materials can relax even when the driving strain is weak.
C1 [Kou, Binquan; Cao, Yixin; Li, Jindong; Xia, Chengjie; Li, Zhifeng; Zhang, Jie; Wang, Yujie] Shanghai Jiao Tong Univ, Sch Phys & Astron, 800 Dong Chuan Rd, Shanghai 200240, Peoples R China.
   [Dong, Haipeng; Zhang, Ang] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Radiol, Shanghai 200025, Peoples R China.
   [Zhang, Jie] Shanghai Jiao Tong Univ, Inst Nat Sci, Shanghai 200240, Peoples R China.
   [Kob, Walter] Univ Montpellier, Lab Charles Coulomb, F-34095 Montpellier, France.
   [Kob, Walter] CNRS, UMR 5221, F-34095 Montpellier, France.
   [Wang, Yujie] Shanghai Jiao Tong Univ, Mat Genome Initiat Ctr, 800 Dong Chuan Rd, Shanghai 200240, Peoples R China.
   [Wang, Yujie] Nanjing Univ, Collaborat Innovat Ctr Adv Microstruct, Nanjing 210093, Jiangsu, Peoples R China.
C3 Shanghai Jiao Tong University; Shanghai Jiao Tong University; Shanghai Jiao Tong University; Universite de Montpellier; Universite de Montpellier; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Physics (INP); Shanghai Jiao Tong University; Nanjing University; Collaborative Innovation Center of Advanced Microstructures (CICAM)
RP Wang, YJ (corresponding author), Shanghai Jiao Tong Univ, Sch Phys & Astron, 800 Dong Chuan Rd, Shanghai 200240, Peoples R China.; Kob, W (corresponding author), Univ Montpellier, Lab Charles Coulomb, F-34095 Montpellier, France.; Kob, W (corresponding author), CNRS, UMR 5221, F-34095 Montpellier, France.; Wang, YJ (corresponding author), Shanghai Jiao Tong Univ, Mat Genome Initiat Ctr, 800 Dong Chuan Rd, Shanghai 200240, Peoples R China.; Wang, YJ (corresponding author), Nanjing Univ, Collaborat Innovat Ctr Adv Microstruct, Nanjing 210093, Jiangsu, Peoples R China.
EM walter.kob@umontpellier.fr; yujiewang@sjtu.edu.cn
FU National Natural Science Foundation of China [11175121, 11675110, U1432111]; Specialized Research Fund for the Doctoral Program of Higher Education of China [20110073120073];  [ANR-15-CE30-0003-02]
NR 36
TC 179
Z9 220
U1 10
U2 319
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 16
PY 2017
VL 551
IS 7680
BP 360
EP +
DI 10.1038/nature24062
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM8UK
UT WOS:000415365500038
PM 29088704
DA 2026-03-09
ER

PT J
AU Bernien, H
   Schwartz, S
   Keesling, A
   Levine, H
   Omran, A
   Pichler, H
   Choi, SW
   Zibrov, AS
   Endres, M
   Greiner, M
   Vuletic, V
   Lukin, MD
AF Bernien, Hannes
   Schwartz, Sylvain
   Keesling, Alexander
   Levine, Harry
   Omran, Ahmed
   Pichler, Hannes
   Choi, Soonwon
   Zibrov, Alexander S.
   Endres, Manuel
   Greiner, Markus
   Vuletic, Vladan
   Lukin, Mikhail D.
TI Probing many-body dynamics on a 51-atom quantum simulator
SO NATURE
LA English
DT Article
ID range interactions
AB Controllable, coherent many-body systems can provide insights into the fundamental properties of quantum matter, enable the realization of new quantum phases and could ultimately lead to computational systems that outperform existing computers based on classical approaches. Here we demonstrate a method for creating controlled many-body quantum matter that combines deterministically prepared, reconfigurable arrays of individually trapped cold atoms with strong, coherent interactions enabled by excitation to Rydberg states. We realize a programmable Ising-type quantum spin model with tunable interactions and system sizes of up to 51 qubits. Within this model, we observe phase transitions into spatially ordered states that break various discrete symmetries, verify the high-fidelity preparation of these states and investigate the dynamics across the phase transition in large arrays of atoms. In particular, we observe robust manybody dynamics corresponding to persistent oscillations of the order after a rapid quantum quench that results from a sudden transition across the phase boundary. Our method provides a way of exploring many-body phenomena on a programmable quantum simulator and could enable realizations of new quantum algorithms.
C1 [Bernien, Hannes; Schwartz, Sylvain; Keesling, Alexander; Levine, Harry; Omran, Ahmed; Pichler, Hannes; Choi, Soonwon; Zibrov, Alexander S.; Greiner, Markus; Lukin, Mikhail D.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.
   [Schwartz, Sylvain; Vuletic, Vladan] MIT, Dept Phys, Cambridge, MA 02139 USA.
   [Schwartz, Sylvain; Vuletic, Vladan] MIT, Res Lab Elect, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Pichler, Hannes] Harvard Smithsonian Ctr Astrophys, Inst Theoret Atom Mol & Opt Phys, 60 Garden St, Cambridge, MA 02138 USA.
   [Endres, Manuel] CALTECH, Div Phys Math & Astron, Pasadena, CA 91125 USA.
C3 Harvard University; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Smithsonian Astrophysical Observatory; Smithsonian Institution; Harvard University; California Institute of Technology
RP Greiner, M; Lukin, MD (corresponding author), Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.; Vuletic, V (corresponding author), MIT, Dept Phys, Cambridge, MA 02139 USA.; Vuletic, V (corresponding author), MIT, Res Lab Elect, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
EM greiner@physics.harvard.edu; vuletic@mit.edu; lukin@fas.harvard.edu
FU NSF; CUA; ARO; Vannevar Bush Faculty Fellowship; Netherlands Organization for Scientific Research (NWO); German Research Foundation (DFG); European Union under the Marie Sklodowska Curie Individual Fellowship Programme [658253]; National Science Foundation (NSF) through Institute for Theoretical Atomic Molecular and Optical Physics (ITAMP) at Harvard University; Smithsonian Astrophysical Observatory; National Defense Science and Engineering Graduate (NDSEG) Fellowship; Marie Curie Actions (MSCA) [658253] Funding Source: Marie Curie Actions (MSCA); Direct For Mathematical & Physical Scien; Division Of Physics [1506284, 1521560] Funding Source: National Science Foundation
NR 62
TC 1994
Z9 2249
U1 15
U2 224
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 30
PY 2017
VL 551
IS 7682
BP 579
EP +
DI 10.1038/nature24622
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FO1KW
UT WOS:000416520400033
PM 29189778
DA 2026-03-09
ER

PT J
AU Orr, BO
   Fetter, RD
   Davis, GW
AF Orr, Brian O.
   Fetter, Richard D.
   Davis, Graeme W.
TI Retrograde semaphorin-plexin signalling drives homeostatic synaptic plasticity
SO NATURE
LA English
DT Article
ID expression; receptor; neurons; actin; brain; transmitter; refinement; modulation; mechanisms; guidance
AB Homeostatic signalling systems ensure stable but flexible neural activity and animal behaviour(1-4). Presynaptic homeostatic plasticity is a conserved form of neuronal homeostatic signalling that is observed in organisms ranging from Drosophila to human(1,5). Defining the underlying molecular mechanisms of neuronal homeostatic signalling will be essential in order to establish clear connections to the causes and progression of neurological disease. During neural development, semaphorin-plexin signalling instructs axon guidance and neuronal morphogenesis(6-10). However, semaphorins and plexins are also expressed in the adult brain(11-16). Here we show that semaphorin 2b (Sema2b) is a target-derived signal that acts upon presynaptic plexin B (PlexB) receptors to mediate the retrograde, homeostatic control of presynaptic neurotransmitter release at the neuromuscular junction in Drosophila. Further, we show that Sema2b-PlexB signalling regulates presynaptic homeostatic plasticity through the cytoplasmic protein Mical and the oxoreductase-dependent control of presynaptic actin. We propose that semaphorin-plexin signalling is an essential platform for the stabilization of synaptic transmission throughout the developing and mature nervous system. These findings may be relevant to the aetiology and treatment of diverse neurological and psychiatric diseases that are characterized by altered or inappropriate neural function and behaviour.
C1 [Orr, Brian O.; Fetter, Richard D.; Davis, Graeme W.] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94153 USA.
C3 University of California System; University of California San Francisco
RP Davis, GW (corresponding author), Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94153 USA.
EM graeme.davis@ucsf.edu
FU NIH [R01NS39313, R35NS097212]; National Institute of Neurological Disorders and Stroke [R35NS097212] Funding Source: NIH RePORTER
NR 35
TC 87
Z9 100
U1 0
U2 28
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 5
PY 2017
VL 550
IS 7674
BP 109
EP +
DI 10.1038/nature24017
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI7XU
UT WOS:000412214100055
PM 28953869
DA 2026-03-09
ER

PT J
AU Holen, SR
   Demere, TA
   Fisher, DC
   Fullagar, R
   Paces, JB
   Jefferson, GT
   Beeton, JM
   Cerutti, RA
   Rountrey, AN
   Vescera, L
   Holen, KA
AF Holen, Steven R.
   Demere, Thomas A.
   Fisher, Daniel C.
   Fullagar, Richard
   Paces, James B.
   Jefferson, George T.
   Beeton, Jared M.
   Cerutti, Richard A.
   Rountrey, Adam N.
   Vescera, Lawrence
   Holen, Kathleen A.
TI A 130,000-year- old archaeological site in southern California, USA
SO NATURE
LA English
DT Article
ID olduvai gorge; hammerstone percussion; bone; age; constraints; frequency; butchery
AB The earliest dispersal of humans into North America is a contentious subject, and proposed early sites are required to meet the following criteria for acceptance: (1) archaeological evidence is found in a clearly defined and undisturbed geologic context; (2) age is determined by reliable radiometric dating; (3) multiple lines of evidence from interdisciplinary studies provide consistent results; and (4) unquestionable artefacts are found in primary context(1,2). Here we describe the Cerutti Mastodon (CM) site, an archaeological site from the early late Pleistocene epoch, where in situ hammerstones and stone anvils occur in spatio-temporal association with fragmentary remains of a single mastodon (Mammut americanum). The CM site contains spiral-fractured bone and molar fragments, indicating that breakage occured while fresh. Several of these fragments also preserve evidence of percussion. The occurrence and distribution of bone, molar and stone refits suggest that breakage occurred at the site of burial. Five large cobbles (hammerstones and anvils) in the CM bone bed display use-wear and impact marks, and are hydraulically anomalous relative to the low-energy context of the enclosing sandy silt stratum. Th-230/U radiometric analysis of multiple bone specimens using diffusion-adsorption-decay dating models indicates a burial date of 130.7 +/- 9.4 thousand years ago. These findings confirm the presence of an unidentified species of Homo at the CM site during the last interglacial period (MIS 5e; early late Pleistocene), indicating that humans with manual dexterity and the experiential knowledge to use hammerstones and anvils processed mastodon limb bones for marrow extraction and/or raw material for tool production. Systematic proboscidean bone reduction, evident at the CM site, fits within a broader pattern of Palaeolithic bone percussion technology in Africa(3-6), Eurasia(7-9) and North America(10-12). The CM site is, to our knowledge, the oldest in situ, well-documented archaeological site in North America and, as such, substantially revises the timing of arrival of Homo into the Americas.
C1 [Holen, Steven R.; Holen, Kathleen A.] Ctr Amer Paleolith Res, 27930 Cascade Rd, Hot Springs, SD 57747 USA.
   [Holen, Steven R.; Demere, Thomas A.; Cerutti, Richard A.; Holen, Kathleen A.] San Diego Nat Hist Museum, Dept Palaeontol, San Diego, CA 92101 USA.
   [Fisher, Daniel C.; Rountrey, Adam N.] Univ Michigan, Museum Paleontol, Ann Arbor, MI 48109 USA.
   [Fisher, Daniel C.] Univ Michigan, Dept Earth & Environm Sci, Ann Arbor, MI 48109 USA.
   [Fullagar, Richard] Univ Wollongong, Fac Sci Med & Hlth, Sch Earth & Environm Sci, Ctr Archaeol Sci, Wollongong, NSW, Australia.
   [Paces, James B.] US Geol Survey, Geosci & Environm Change Sci Ctr, Box 25046, Denver, CO 80225 USA.
   [Jefferson, George T.; Vescera, Lawrence] Calif Dept Pk & Recreat, Colorado Desert Dist Stout Res Ctr, Borrego Springs, CA USA.
   [Beeton, Jared M.] Adams State Univ, Dept Earth Sci, Alamosa, CO USA.
C3 University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Wollongong; United States Department of the Interior; United States Geological Survey; Adams State University
RP Holen, SR (corresponding author), Ctr Amer Paleolith Res, 27930 Cascade Rd, Hot Springs, SD 57747 USA.; Holen, SR; Demere, TA (corresponding author), San Diego Nat Hist Museum, Dept Palaeontol, San Diego, CA 92101 USA.
EM sholen@goldenwest.net; tdemere@sdnhm.org
FU Caltrans-District 11; The James Hervey Johnson Charitable Educational Trust; National Geographic Society [4971-93]; Walton Family Foundation
NR 50
TC 114
Z9 148
U1 2
U2 69
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 27
PY 2017
VL 544
IS 7651
BP 479
EP +
DI 10.1038/nature22065
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET1TN
UT WOS:000400051900043
PM 28447646
DA 2026-03-09
ER

PT J
AU Castellano, JM
   Mosher, KI
   Abbey, RJ
   McBride, AA
   James, ML
   Berdnik, D
   Shen, JC
   Zou, BD
   Xie, XMS
   Tingle, M
   Hinkson, IV
   Angst, MS
   Wyss-Coray, T
AF Castellano, Joseph M.
   Mosher, Kira I.
   Abbey, Rachelle J.
   McBride, Alisha A.
   James, Michelle L.
   Berdnik, Daniela
   Shen, Jadon C.
   Zou, Bende
   Xie, Xinmin S.
   Tingle, Martha
   Hinkson, Izumi V.
   Angst, Martin S.
   Wyss-Coray, Tony
TI Human umbilical cord plasma proteins revitalize hippocampal function in aged mice
SO NATURE
LA English
DT Article
ID long-term potentiation; synaptic plasticity; tissue inhibitor; cognitive impairment; vivo stability; messenger-rna; dentate gyrus; aging brain; expression; deficits
AB Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation(1), an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation(2-4) and downregulated in the aged brain(5-8). In addition to revitalizing other aged tissues(9-13), exposure to factors in young blood counteracts age-related changes in these central nervous system parameters(14-16), although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown(17). We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of such plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing-or disease-associated hippocampal dysfunction.
C1 [Castellano, Joseph M.; Mosher, Kira I.; Abbey, Rachelle J.; McBride, Alisha A.; James, Michelle L.; Berdnik, Daniela; Shen, Jadon C.; Hinkson, Izumi V.; Wyss-Coray, Tony] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA.
   [Castellano, Joseph M.; Mosher, Kira I.; Abbey, Rachelle J.; McBride, Alisha A.; Berdnik, Daniela; Shen, Jadon C.; Hinkson, Izumi V.; Wyss-Coray, Tony] Stanford Univ, Sch Med, Paul F Glenn Ctr Biol Aging, Stanford, CA 94305 USA.
   [Mosher, Kira I.; Wyss-Coray, Tony] Stanford Univ, Sch Med, Neurosci Grad Program, Stanford, CA 94305 USA.
   [Abbey, Rachelle J.; McBride, Alisha A.; Berdnik, Daniela; Shen, Jadon C.; Hinkson, Izumi V.; Wyss-Coray, Tony] VA Palo Alto Healthcare Syst, Ctr Tissue Regenerat Repair & Restorat, Palo Alto, CA 94304 USA.
   [James, Michelle L.] Stanford Univ, Sch Med, Mol Imaging Program Stanford, Radiol, Stanford, CA 94305 USA.
   [Zou, Bende; Xie, Xinmin S.] AfaSci Res Labs, Redwood City, CA 94063 USA.
   [Xie, Xinmin S.; Tingle, Martha; Angst, Martin S.] Stanford Univ, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; Stanford University; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Palo Alto Health Care System; Stanford University; Stanford University
RP Wyss-Coray, T (corresponding author), Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA.; Wyss-Coray, T (corresponding author), Stanford Univ, Sch Med, Paul F Glenn Ctr Biol Aging, Stanford, CA 94305 USA.; Wyss-Coray, T (corresponding author), Stanford Univ, Sch Med, Neurosci Grad Program, Stanford, CA 94305 USA.; Wyss-Coray, T (corresponding author), VA Palo Alto Healthcare Syst, Ctr Tissue Regenerat Repair & Restorat, Palo Alto, CA 94304 USA.
EM twc@stanford.edu
FU Jane Coffin Childs Postdoctoral Fellowship-Simons Foundation; Veterans Affairs; Glenn Foundation for Medical Research; Stanford Brain Rejuvenation Project; National Institute on Aging [K99AG051711, AG045034, DP1AG053015, AG040877]
NR 51
TC 336
Z9 412
U1 4
U2 138
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 27
PY 2017
VL 544
IS 7651
BP 488
EP +
DI 10.1038/nature22067
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET1TN
UT WOS:000400051900045
PM 28424512
DA 2026-03-09
ER

PT J
AU Kammertoens, T
   Friese, C
   Arina, A
   Idel, C
   Briesemeister, D
   Rothe, M
   Ivanov, A
   Szymborska, A
   Patone, G
   Kunz, S
   Sommermeyer, D
   Engels, B
   Leisegang, M
   Textor, A
   Fehling, HJ
   Fruttiger, M
   Lohoff, M
   Herrmann, A
   Yu, H
   Weichselbaum, R
   Uckert, W
   Hübner, N
   Gerhardt, H
   Beule, D
   Schreiber, H
   Blankenstein, T
AF Kammertoens, Thomas
   Friese, Christian
   Arina, Ainhoa
   Idel, Christian
   Briesemeister, Dana
   Rothe, Michael
   Ivanov, Andranik
   Szymborska, Anna
   Patone, Giannino
   Kunz, Severine
   Sommermeyer, Daniel
   Engels, Boris
   Leisegang, Matthias
   Textor, Ana
   Fehling, Hans Joerg
   Fruttiger, Marcus
   Lohoff, Michael
   Herrmann, Andreas
   Yu, Hua
   Weichselbaum, Ralph
   Uckert, Wolfgang
   Huebner, Norbert
   Gerhardt, Holger
   Beule, Dieter
   Schreiber, Hans
   Blankenstein, Thomas
TI Tumour ischaemia by interferon-γ resembles physiological blood vessel regression
SO NATURE
LA English
DT Article
ID t-cells; in-vivo; endothelial-cells; cre-recombinase; necrosis-factor; expression; rejection; angiogenesis; cancer; mice
AB The relative contribution of the effector molecules produced by T cells to tumour rejection is unclear, but interferon-gamma (IFN gamma) is critical in most of the analysed models(1). Although IFN gamma can impede tumour growth by acting directly on cancer cells(2,3), it must also act on the tumour stroma for effective rejection of large, established tumours(4,5). However, which stroma cells respond to IFN gamma and by which mechanism IFN gamma contributes to tumour rejection through stromal targeting have remained unknown. Here we use a model of IFN gamma induction and an IFN gamma-GFP fusion protein in large, vascularized tumours growing in mice that express the IFN gamma receptor exclusively in defined cell types. Responsiveness to IFN gamma by myeloid cells and other haematopoietic cells, including T cells or fibroblasts, was not sufficient for IFN gamma-induced tumour regression, whereas responsiveness of endothelial cells to IFN gamma was necessary and sufficient. Intravital microscopy revealed IFN gamma induced regression of the tumour vasculature, resulting in arrest of blood flow and subsequent collapse of tumours, similar to nonhaemorrhagic necrosis in ischaemia and unlike haemorrhagic necrosis induced by tumour necrosis factor. The early events of IFN gamma-induced tumour ischaemia resemble non-apoptotic blood vessel regression during development, wound healing or IFN gamma-mediated, pregnancy-induced remodelling of uterine arteries(6-8). A better mechanistic understanding of how solid tumours are rejected may aid the design of more effective protocols for adoptive T-cell therapy.
C1 [Kammertoens, Thomas; Friese, Christian; Briesemeister, Dana; Rothe, Michael; Leisegang, Matthias; Textor, Ana; Schreiber, Hans; Blankenstein, Thomas] Inst Immunol, Charite Campus Buch, D-13125 Berlin, Germany.
   [Kammertoens, Thomas; Friese, Christian; Briesemeister, Dana; Rothe, Michael; Szymborska, Anna; Patone, Giannino; Kunz, Severine; Sommermeyer, Daniel; Engels, Boris; Leisegang, Matthias; Textor, Ana; Uckert, Wolfgang; Huebner, Norbert; Gerhardt, Holger; Beule, Dieter; Blankenstein, Thomas] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany.
   [Arina, Ainhoa; Weichselbaum, Ralph] Univ Chicago, Ludwig Ctr Metastasis Res, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA.
   [Idel, Christian; Schreiber, Hans] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA.
   [Ivanov, Andranik; Uckert, Wolfgang; Gerhardt, Holger; Beule, Dieter; Schreiber, Hans; Blankenstein, Thomas] Berlin Inst Hlth, D-10117 Berlin, Germany.
   [Ivanov, Andranik; Huebner, Norbert] Charite, D-10117 Berlin, Germany.
   [Fehling, Hans Joerg] Univ Clin Ulm, Inst Immunol, D-89081 Ulm, Germany.
   [Fruttiger, Marcus] UCL, Inst Ophthalmol, London EC1V 9EL, England.
   [Lohoff, Michael] Univ Marburg, Inst Med Microbiol, D-35032 Marburg, Germany.
   [Herrmann, Andreas; Yu, Hua] Beckman Res Inst, Comprehens Canc Ctr City Hope, Los Angeles, CA 91010 USA.
   [Huebner, Norbert; Gerhardt, Holger] DZHK German Ctr Cardiovasc Res, Partner Site Berlin, D-13347 Berlin, Germany.
   [Idel, Christian] Univ Lubeck, Dept Otorhinolaryngol, D-23562 Lubeck, Germany.
C3 Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Helmholtz Association; Max Delbruck Center for Molecular Medicine; University of Chicago; University of Chicago; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Ulm University; University of London; University College London; Philipps University Marburg; German Centre for Cardiovascular Research; University of Lubeck
RP Blankenstein, T (corresponding author), Inst Immunol, Charite Campus Buch, D-13125 Berlin, Germany.; Blankenstein, T (corresponding author), Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany.; Blankenstein, T (corresponding author), Berlin Inst Hlth, D-10117 Berlin, Germany.
EM tblanke@mdc-berlin.de
FU DFG [SFB-TR36]; Einstein Stiftung Berlin; NIH [RO1-CA37156, RO1-CA22677]; Rhon-Klinikum-AG; National Cancer Institute [R01CA022677] Funding Source: NIH RePORTER
NR 41
TC 214
Z9 252
U1 0
U2 58
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 4
PY 2017
VL 545
IS 7652
BP 98
EP +
DI 10.1038/nature22311
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET7MK
UT WOS:000400480400038
PM 28445461
DA 2026-03-09
ER

PT J
AU Yan, G
   Vértes, PE
   Towlson, EK
   Chew, YL
   Walker, DS
   Schafer, WR
   Barabási, AL
AF Yan, Gang
   Vertes, Petra E.
   Towlson, Emma K.
   Chew, Yee Lian
   Walker, Denise S.
   Schafer, William R.
   Barabasi, Albert-Laszlo
TI Network control principles predict neuron function in the Caenorhabditis elegans connectome
SO NATURE
LA English
DT Article
ID locomotion; circuit
AB Recent studies on the controllability of complex systems offer a powerful mathematical framework to systematically explore the structure-function relationship in biological, social, and technological networks(1-3). Despite theoretical advances, we lack direct experimental proof of the validity of these widely used control principles. Here we fill this gap by applying a control framework to the connectome of the nematode Caenorhabditis elegans(4-6), allowing us to predict the involvement of each C. elegans neuron in locomotor behaviours. We predict that control of the muscles or motor neurons requires 12 neuronal classes, which include neuronal groups previously implicated in locomotion by laser ablation(7-13), as well as one previously uncharacterized neuron, PDB. We validate this prediction experimentally, finding that the ablation of PDB leads to a significant loss of dorsoventral polarity in large body bends. Importantly, control principles also allow us to investigate the involvement of individual neurons within each neuronal class. For example, we predict that, within the class of DD motor neurons, only three (DD04, DD05, or DD06) should affect locomotion when ablated individually. This prediction is also confirmed; single cell ablations of DD04 or DD05 specifically affect posterior body movements, whereas ablations of DD02 or DD03 do not. Our predictions are robust to deletions of weak connections, missing connections, and rewired connections in the current connectome, indicating the potential applicability of this analytical framework to larger and less well-characterized connectomes.
C1 [Yan, Gang; Towlson, Emma K.; Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA.
   [Yan, Gang; Towlson, Emma K.; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Boston, MA 02115 USA.
   [Yan, Gang] Tongji Univ, Sch Phys Sci & Engn, Shanghai 200092, Peoples R China.
   [Vertes, Petra E.] Univ Cambridge, Behav & Clin Neurosci Inst, Dept Psychiat, Cambridge CB2 0SZ, England.
   [Chew, Yee Lian; Walker, Denise S.; Schafer, William R.] MRC Lab Mol Biol, Div Neurobiol, Cambridge Biomed Campus,Francis Crick Ave, Cambridge CB2 0QH, England.
   [Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA.
   [Barabasi, Albert-Laszlo] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA.
   [Barabasi, Albert-Laszlo] Cent European Univ, Ctr Network Sci, H-1051 Budapest, Hungary.
C3 Northeastern University; Northeastern University; Tongji University; University of Cambridge; MRC Laboratory Molecular Biology; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; Central European University
RP Barabási, AL (corresponding author), Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA.; Barabási, AL (corresponding author), Northeastern Univ, Dept Phys, Boston, MA 02115 USA.; Barabási, AL (corresponding author), Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA.; Barabási, AL (corresponding author), Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA.; Barabási, AL (corresponding author), Cent European Univ, Ctr Network Sci, H-1051 Budapest, Hungary.
EM alb@neu.edu
FU National Institutes of Health Office of Research Infrastructure Programs [P40 OD010440]; John Templeton Foundation: Mathematical and Physical Sciences grant [PFI-777]; European Commission [641191]; Medical Research Council [MC-A023-5PB91, MR/K020706/1]; Wellcome Trust [WT103784MA]; EMBO Long Term Fellowship; Wellcome Trust [103784/Z/14/Z] Funding Source: Wellcome Trust; Medical Research Council [MC_U105185857, MR/K020706/1] Funding Source: researchfish; Wellcome Trust [103784/Z/14/Z] Funding Source: researchfish; National Institute of General Medical Sciences; NIH Office of the Director [P40OD010440] Funding Source: NIH RePORTER; MRC [MC_U105185857, MR/K020706/1] Funding Source: UKRI
NR 30
TC 262
Z9 312
U1 2
U2 182
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 26
PY 2017
VL 550
IS 7677
BP 519
EP +
DI 10.1038/nature24056
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK7OW
UT WOS:000413697800043
PM 29045391
DA 2026-03-09
ER

PT J
AU Nengo, I
   Tafforeau, P
   Gilbert, CC
   Fleagle, JG
   Miller, ER
   Feibel, C
   Fox, DL
   Feinberg, J
   Pugh, KD
   Berruyer, C
   Mana, S
   Engle, Z
   Spoor, F
AF Nengo, Isaiah
   Tafforeau, Paul
   Gilbert, Christopher C.
   Fleagle, John G.
   Miller, Ellen R.
   Feibel, Craig
   Fox, David L.
   Feinberg, Josh
   Pugh, Kelsey D.
   Berruyer, Camille
   Mana, Sara
   Engle, Zachary
   Spoor, Fred
TI New infant cranium from the African Miocene sheds light on ape evolution
SO NATURE
LA English
DT Article
ID old-world monkeys; middle-miocene; tugen hills; origin; geochronology; kipsaramon; hominids; history; bearing; size
AB The evolutionary history of extant hominoids (humans and apes) remains poorly understood. The African fossil record during the crucial time period, the Miocene epoch, largely comprises isolated jaws and teeth, and little is known about ape cranial evolution. Here we report on the, to our knowledge, most complete fossil ape cranium yet described, recovered from the 13 million-year-old Middle Miocene site of Napudet, Kenya. The infant specimen, KNM-NP 59050, is assigned to a new species of Nyanzapithecus on the basis of its unerupted permanent teeth, visualized by synchrotron imaging. Its ear canal has a fully ossified tubular ectotympanic, a derived feature linking the species with crown catarrhines. Although it resembles some hylobatids in aspects of its morphology and dental development, it possesses no definitive hylobatid synapomorphies. The combined evidence suggests that nyanzapithecines were stem hominoids close to the origin of extant apes, and that hylobatid-like facial features evolved multiple times during catarrhine evolution.
C1 [Nengo, Isaiah] De Anza Coll, Dept Anthropol, Cupertino, CA 95104 USA.
   [Nengo, Isaiah] SUNY Stony Brook, Turkana Basin Inst, Social & Behav Sci Bldg N-507, Stony Brook, NY 11794 USA.
   [Tafforeau, Paul; Berruyer, Camille] European Synchrotron Radiat Facil, CS-40220, F-38043 Grenoble 09, France.
   [Gilbert, Christopher C.] CUNY Hunter Coll, Dept Anthropol, 695 Pk Ave, New York, NY 10065 USA.
   [Gilbert, Christopher C.; Pugh, Kelsey D.] CUNY, Grad Ctr, 365 5th Ave, New York, NY 10016 USA.
   [Gilbert, Christopher C.; Pugh, Kelsey D.] New York Consortium Evolutionary Primatol, New York, NY USA.
   [Fleagle, John G.] SUNY Stony Brook, Hlth Sci Ctr, Dept Anat Sci, Stony Brook, NY 11794 USA.
   [Miller, Ellen R.] Wake Forest Univ, Dept Anthropol, Winston Salem, NC 27109 USA.
   [Feibel, Craig] Rutgers State Univ, Dept Anthropol, New Brunswick, NJ 08901 USA.
   [Feibel, Craig; Engle, Zachary] Rutgers State Univ, Dept Earth & Planetary Sci, Piscataway, NJ 08854 USA.
   [Fox, David L.; Feinberg, Josh] Univ Minnesota, Dept Earth Sci, Minneapolis, MN 55455 USA.
   [Mana, Sara] Salem State Univ, Dept Geol Sci, Salem, MA 01970 USA.
   [Spoor, Fred] UCL, Dept Cell & Dev Biol, London WC1E 6BT, England.
   [Spoor, Fred] Max Planck Inst Evolutionary Anthropol, Dept Human Evolut, D-04103 Leipzig, Germany.
C3 De Anza College; State University of New York (SUNY) System; Stony Brook University; European Synchrotron Radiation Facility (ESRF); City University of New York (CUNY) System; Hunter College (CUNY); City University of New York (CUNY) System; State University of New York (SUNY) System; Stony Brook University; Wake Forest University; Rutgers University System; Rutgers University New Brunswick; Rutgers University System; Rutgers University New Brunswick; University of Minnesota System; University of Minnesota Twin Cities; Massachusetts System of Public Higher Education; Salem State University; University of London; University College London; Max Planck Society
RP Nengo, I (corresponding author), De Anza Coll, Dept Anthropol, Cupertino, CA 95104 USA.; Nengo, I (corresponding author), SUNY Stony Brook, Turkana Basin Inst, Social & Behav Sci Bldg N-507, Stony Brook, NY 11794 USA.
EM Isaiah.Nengo@stonybrook.edu
FU Leakey Foundation; Foothill-De Anza Foundation; De Anza College Design and Manufacturing Technologies Department; National Geographic Society; European Synchrotron Radiation Facility; Max Planck Society
CR Alba DM, 2015, SCIENCE, V350, P0, DOI 10.1126/science.aab2625
   Begun DR, 2015, HANDBOOK OF PALEOANTHROPOLOGY, V0, PP1261, DOI 10.1007/978-3-642-39979-4_32
   Begun DR, 2012, EVOL ANTHROPOL, V21, P10, DOI 10.1002/evan.20329
   Begun David R, 1997, P389, V0, P0
   Begun DR, 2001, HOM EVOLUT CLIMAT CH, V2, P231
   Behrensmeyer AK, 2002, J HUM EVOL, V42, P11, DOI 10.1006/jhev.2001.0519
   Benefit BR, 1998, AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, V26, P109
   BENEFIT BR, 1993, FOLIA PRIMATOL, V60, P133, DOI 10.1159/000156682
   BENEFIT BR, 1993, AM J PHYS ANTHROPOL, V92, P329, DOI 10.1002/ajpa.1330920307
   Bernor RL, 2007, P NATL ACAD SCI USA, V104, P19661
   Bromage TG, 2009, CALCIFIED TISSUE INT, V84, P388, DOI 10.1007/s00223-009-9221-2
   Cameron DW, 1997, J HUM EVOL, V33, P449, DOI 10.1006/jhev.1997.0145
   Dalrymple GB, 1981, 1176 US GEOL SURV, V0, P0
   DALRYMPLE GB, 1993, J GEOPHYS RES-PLANET, V98, P13085, DOI 10.1029/93JE01222
   Dirks W, 2007, J HUM EVOL, V53, P309, DOI 10.1016/j.jhevol.2007.04.007
   Dodson RG, 1971, 87 GEOL SURV KEN, V0, P0
   Fleagle JG, 2013, PRIMATE ADAPTATION AND EVOLUTION, V0, P1
   Gilbert CC, 2011, J HUM EVOL, V60, P731, DOI 10.1016/j.jhevol.2011.01.005
   Gilbert CC, 2010, J HUM EVOL, V59, P465, DOI 10.1016/j.jhevol.2010.05.005
   Gonzales LA, 2015, NAT COMMUN, V6, P0, DOI 10.1038/ncomms8580
   Hammer Oyvind, 2001, PALAEONTOLOGIA ELECTRONICA, V4, P0
   Harrison T, 2002, CAM S BIO EVOL ANTHR, V33, P311
   HARRISON T, 1986, AM J PHYS ANTHROPOL, V71, P265, DOI 10.1002/ajpa.1330710303
   Harrison Terry, 1997, P327, V0, P0
   Harrison Terry, 2010, P429, V0, P0
   Hilgen FJ, 2012, GEOLOGIC TIME SCALE 2012, VOLS 1 & 2, P923, DOI 10.1016/B978-0-444-59425-9.00029-9
   HILL A, 1988, YEARB PHYS ANTHROPOL, V31, P49
   Isler K, 2008, J HUM EVOL, V55, P967, DOI 10.1016/j.jhevol.2008.08.004
   Kelley J, 2002, J HUM EVOL, V42, P39, DOI 10.1006/jhev.2001.0504
   Kuiper KF, 2008, SCIENCE, V320, P500, DOI 10.1126/science.1154339
   Lebatard AE, 2008, P NATL ACAD SCI USA, V105, P3226, DOI 10.1073/pnas.0708015105
   MARTIN L, 1985, NATURE, V314, P260, DOI 10.1038/314260a0
   MCCROSSIN ML, 1992, INT J PRIMATOL, V13, P659, DOI 10.1007/BF02551258
   Morley CK, 1999, GEOSCIENCE RIFT SYST, V0, PP19, DOI 10.1306/ST44623C2
   Olejniczak AJ, 2006, THESIS, V0, P0
   Pickford M, 2005, ANTHROPOL SCI, V113, P189, DOI 10.1537/ase.113.189
   Rae TC, 1999, FOLIA PRIMATOL, V70, P125, DOI 10.1159/000021685
   RAFFERTY KL, 1995, AM J PHYS ANTHROPOL, V97, P391, DOI 10.1002/ajpa.1330970406
   Rossie JB, 2006, J HUM EVOL, V50, P568, DOI 10.1016/j.jhevol.2005.12.007
   Ryan TM, 2012, P ROY SOC B-BIOL SCI, V279, P3467, DOI 10.1098/rspb.2012.0939
   Smith RJ, 1997, J HUM EVOL, V32, P523, DOI 10.1006/jhev.1996.0122
   Smith TM, 2008, EVOL ANTHROPOL, V17, P213, DOI 10.1002/evan.20176
   Smith TM, 2010, P NATL ACAD SCI USA, V107, P20923, DOI 10.1073/pnas.1010906107
   SOLA SM, 1995, J HUM EVOL, V29, P101, DOI 10.1006/jhev.1995.1049
   SPOOR CF, 1993, THESIS, V0, P0
   Spoor F, 1998, YEARB PHYS ANTHROPOL, V41, P211
   Spoor F, 2007, P NATL ACAD SCI USA, V104, P10808, DOI 10.1073/pnas.0704250104
   STEIGER RH, 1977, EARTH PLANET SC LETT, V36, P359, DOI 10.1016/0012-821X(77)90060-7
   Stevens NJ, 2013, NATURE, V497, P611, DOI 10.1038/nature12161
   Tafforeau P, 2006, APPL PHYS A-MATER, V83, P195, DOI 10.1007/s00339-006-3507-2
   Tafforeau P, 2008, J HUM EVOL, V54, P272, DOI 10.1016/j.jhevol.2007.09.018
   Ward SC, 2002, CAM S BIO EVOL ANTHR, V33, P385
   Wiens JJ, 2000, SM S COMP E, V0, P115
NR 54
TC 63
Z9 77
U1 0
U2 138
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 10
PY 2017
VL 548
IS 7666
BP 169
EP +
DI 10.1038/nature23456
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD1GB
UT WOS:000407284300035
PM 28796200
DA 2026-03-09
ER

PT J
AU Liu, XY
   Li, MJ
   Xia, X
   Li, XM
   Chen, ZC
AF Liu, Xiaoyu
   Li, Meijing
   Xia, Xian
   Li, Xueming
   Chen, Zhucheng
TI Mechanism of chromatin remodelling revealed by the Snf2-nucleosome structure
SO NATURE
LA English
DT Article
ID nucleosome core particle; electron-microscopy; dna translocation; cryo-em; complex; swi/snf; iswi; visualization; architecture; resolution
AB Chromatin remodellers are helicase-like, ATP-dependent enzymes that alter chromatin structure and nucleosome positions to allow regulatory proteins access to DNA. Here we report the cryo-electron microscopy structure of chromatin remodeller Switch/sucrose non-fermentable (SWI2/SNF2) from Saccharomyces cerevisiae bound to the nucleosome. The structure shows that the two core domains of Snf2 are realigned upon nucleosome binding, suggesting activation of the enzyme. The core domains contact each other through two induced Brace helices, which are crucial for coupling ATP hydrolysis to chromatin remodelling. Snf2 binds to the phosphate backbones of one DNA gyre of the nucleosome mainly through its helicase motifs within the major domain cleft, suggesting a conserved mechanism of substrate engagement across different remodellers. Snf2 contacts the second DNA gyre via a positively charged surface, providing a mechanism to anchor the remodeller at a fixed position of the nucleosome. Snf2 locally deforms nucleosomal DNA at the site of binding, priming the substrate for the remodelling reaction. Together, these findings provide mechanistic insights into chromatin remodelling.
C1 [Liu, Xiaoyu; Li, Meijing; Xia, Xian; Li, Xueming; Chen, Zhucheng] Tsinghua Univ, Minist Educ, Key Lab Prot Sci, Beijing 100084, Peoples R China.
   [Liu, Xiaoyu; Li, Meijing; Xia, Xian; Li, Xueming; Chen, Zhucheng] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China.
   [Liu, Xiaoyu; Li, Meijing; Li, Xueming] Tsinghua Peking Joint Ctr Life Sci, Beijing 100084, Peoples R China.
C3 Tsinghua University; Tsinghua University
RP Li, XM; Chen, ZC (corresponding author), Tsinghua Univ, Minist Educ, Key Lab Prot Sci, Beijing 100084, Peoples R China.; Li, XM; Chen, ZC (corresponding author), Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China.; Li, XM (corresponding author), Tsinghua Peking Joint Ctr Life Sci, Beijing 100084, Peoples R China.
EM lixueming@mail.tsinghua.edu.cn; Zhucheng_chen@tsinghua.edu.cn
FU National Key Research and Development Program [2014CB910100, 2016YFA0501102, 2016YFA0501902]; National Natural Science Foundation of China [31570731, 31270762, 31630046, 31570730]; Advanced Innovation Center for Structural Biology; Tsinghua-Peking Joint Center for Life Sciences; 'Junior One Thousand Talents' program
NR 44
TC 181
Z9 222
U1 0
U2 123
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 27
PY 2017
VL 544
IS 7651
BP 440
EP +
DI 10.1038/nature22036
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET1TN
UT WOS:000400051900035
PM 28424519
DA 2026-03-09
ER

PT J
AU Scoles, DR
   Meera, P
   Schneider, MD
   Paul, S
   Dansithong, W
   Figueroa, KP
   Hung, GN
   Rigo, F
   Bennett, CF
   Otis, TS
   Pulst, SM
AF Scoles, Daniel R.
   Meera, Pratap
   Schneider, Matthew D.
   Paul, Sharan
   Dansithong, Warunee
   Figueroa, Karla P.
   Hung, Gene
   Rigo, Frank
   Bennett, C. Frank
   Otis, Thomas S.
   Pulst, Stefan M.
TI Antisense oligonucleotide therapy for spinocerebellar ataxia type 2
SO NATURE
LA English
DT Article
ID metabotropic glutamate receptors; expression; disease; mouse; mice; neurodegeneration; pathogenesis; model; sca2
AB There are no disease-modifying treatments for adult human neurodegenerative diseases. Here we test RNA-targeted therapies(1) in two mouse models of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant polyglutamine disease(2). Both models recreate the progressive adult-onset dysfunction and degeneration of a neuronal network that are seen in patients, including decreased firing frequency of cerebellar Purkinje cells and a decline in motor function(3,4). We developed a potential therapy directed at the ATXN2 gene by screening 152 antisense oligonucleotides (ASOs). The most promising oligonucleotide, ASO7, downregulated ATXN2 mRNA and protein, which resulted in delayed onset of the SCA2 phenotype. After delivery by intracerebroventricular injection to ATXN2-Q127 mice, ASO7 localized to Purkinje cells, reduced cerebellar ATXN2 expression below 75% for more than 10 weeks without microglial activation, and reduced the levels of cerebellar ATXN2. Treatment of symptomatic mice with ASO7 improved motor function compared to saline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model, and in both mouse models it normalized protein levels of several SCA2-related proteins expressed in Purkinje cells, including Rgs8, Pcp2, Pcp4, Homer3, Cep76 and Fam107b. Notably, the firing frequency of Purkinje cells returned to normal even when treatment was initiated more than 12 weeks after the onset of the motor phenotype in BAC-Q72 mice. These findings support ASOs as a promising approach for treating some human neurodegenerative diseases.
C1 [Scoles, Daniel R.; Schneider, Matthew D.; Paul, Sharan; Dansithong, Warunee; Figueroa, Karla P.; Pulst, Stefan M.] Univ Utah, Dept Neurol, 175 North Med Dr East,5th Floor, Salt Lake City, UT 84132 USA.
   [Meera, Pratap; Otis, Thomas S.] Univ Calif Los Angeles, Dept Neurobiol, Los Angeles, CA 90095 USA.
   [Hung, Gene; Rigo, Frank; Bennett, C. Frank] Ionis Pharmaceut, 2855 Gazelle Court, Carlsbad, CA 92010 USA.
   [Otis, Thomas S.] Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev Neurosci Ophthalmol, Grenzacherstr 124, CH-4070 Basel, Switzerland.
C3 Utah System of Higher Education; University of Utah; University of California System; University of California Los Angeles; Ionis Pharmaceuticals, Inc.; Roche Holding
RP Scoles, DR; Pulst, SM (corresponding author), Univ Utah, Dept Neurol, 175 North Med Dr East,5th Floor, Salt Lake City, UT 84132 USA.
EM Daniel.Scoles@hsc.utah.edu; Stefan.Pulst@hsc.utah.edu
FU National Institutes of Neurological Disorders and Stroke (NINDS) [R01NS33123, R56NS33123, R37NS033123]; Noorda foundation; NINDS [RC4NS073009, R21NS081182, NS090930]; Target ALS Foundation
NR 31
TC 241
Z9 287
U1 2
U2 88
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 20
PY 2017
VL 544
IS 7650
BP 362
EP +
DI 10.1038/nature22044
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ES4SG
UT WOS:000399524400039
PM 28405024
DA 2026-03-09
ER

PT J
AU Inoue, A
   Jiang, L
   Lu, FL
   Suzuki, T
   Zhang, Y
AF Inoue, Azusa
   Jiang, Lan
   Lu, Falong
   Suzuki, Tsukasa
   Zhang, Yi
TI Maternal H3K27me3 controls DNA methylation-independent imprinting
SO NATURE
LA English
DT Article
ID sequencing-based identification; repressive histone methylation; mouse; chromatin; placenta; gene; landscape; genome; domain; locus
AB Mammalian sperm and oocytes have different epigenetic landscapes and are organized in different fashions. After fertilization, the initially distinct parental epigenomes become largely equalized with the exception of certain loci, including imprinting control regions. How parental chromatin becomes equalized and how imprinting control regions escape from this reprogramming is largely unknown. Here we profile parental allele-specific DNase I hypersensitive sites in mouse zygotes and morula embryos, and investigate the epigenetic mechanisms underlying these allelic sites. Integrated analyses of DNA methylome and tri-methylation at lysine 27 of histone H3 (H3K27me3) chromatin immunoprecipitation followed by sequencing identify 76 genes with paternal allele-specific DNase I hypersensitive sites that are devoid of DNA methylation but harbour maternal allele-specific H3K27me3. Interestingly, these genes are paternally expressed in preimplantation embryos, and ectopic removal of H3K27me3 induces maternal allele expression. H3K27me3-dependent imprinting is largely lost in the embryonic cell lineage, but at least five genes maintain their imprinted expression in the extra-embryonic cell lineage. The five genes include all paternally expressed autosomal imprinted genes previously demonstrated to be independent of oocyte DNA methylation. Thus, our study identifies maternal H3K27me3 as a DNA methylation-independent imprinting mechanism.
C1 [Inoue, Azusa; Jiang, Lan; Lu, Falong; Suzuki, Tsukasa; Zhang, Yi] Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA.
   [Inoue, Azusa; Jiang, Lan; Lu, Falong; Suzuki, Tsukasa; Zhang, Yi] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.
   [Inoue, Azusa; Jiang, Lan; Lu, Falong; Suzuki, Tsukasa; Zhang, Yi] Boston Childrens Hosp, Div Hematol Oncol, Dept Pediat, Boston, MA 02115 USA.
   [Zhang, Yi] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.
   [Zhang, Yi] Harvard Stem Cell Inst, Boston, MA 02115 USA.
   [Lu, Falong] Chinese Acad Sci, Inst Genet & Dev Biol, State Key Lab Mol Dev Biol, Beijing 100101, Peoples R China.
C3 Howard Hughes Medical Institute; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Program in Cellular & Molecular Medicine (PCMM); Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Harvard University; Chinese Academy of Sciences; Institute of Genetics & Developmental Biology, CAS
RP Zhang, Y (corresponding author), Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA.; Zhang, Y (corresponding author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Zhang, Y (corresponding author), Boston Childrens Hosp, Div Hematol Oncol, Dept Pediat, Boston, MA 02115 USA.; Zhang, Y (corresponding author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.; Zhang, Y (corresponding author), Harvard Stem Cell Inst, Boston, MA 02115 USA.
EM yzhang@genetics.med.harvard.edu
FU Howard Hughes Medical Institute; Charles A. King Trust Postdoctoral Research Fellowship
NR 52
TC 361
Z9 420
U1 1
U2 122
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 27
PY 2017
VL 547
IS 7664
BP 419
EP +
DI 10.1038/nature23262
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB7ZK
UT WOS:000406358300028
PM 28723896
DA 2026-03-09
ER

PT J
AU Liddelow, SA
   Guttenplan, KA
   Larke, LEC
   Bennett, FC
   Bohlen, CJ
   Schirmer, L
   Bennett, ML
   Münch, AE
   Chung, WS
   Peterson, TC
   Wilton, DK
   Frouin, A
   Napier, BA
   Panicker, N
   Kumar, M
   Buckwalter, MS
   Rowitch, DH
   Dawson, VL
   Dawson, TM
   Stevens, B
   Barres, B
AF Liddelow, Shane A.
   Guttenplan, Kevin A.
   Larke, Laura E. C.
   Bennett, Frederick C.
   Bohlen, Christopher J.
   Schirmer, Lucas
   Bennett, Mariko L.
   Munch, Alexandra E.
   Chung, Won-Suk
   Peterson, Todd C.
   Wilton, Daniel K.
   Frouin, Arnaud
   Napier, Brooke A.
   Panicker, Nikhil
   Kumar, Manoj
   Buckwalter, Marion S.
   Rowitch, David H.
   Dawson, Valina L.
   Dawson, Ted M.
   Stevens, Beth
   Barres, Ben A.
TI Neurotoxic reactive astrocytes are induced by activated microglia
SO NATURE
LA English
DT Article
ID secreted proteins; scar formation; neurons; inflammation; brain; cells; transcriptome; degeneration; purification; ablation
AB Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1 alpha, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer's, Huntington's and Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases.
C1 [Liddelow, Shane A.; Guttenplan, Kevin A.; Larke, Laura E. C.; Bennett, Frederick C.; Bennett, Mariko L.; Munch, Alexandra E.; Barres, Ben A.] Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA.
   [Liddelow, Shane A.; Bohlen, Christopher J.] Univ Melbourne, Dept Pharmacol & Therapeut, Parkville, Vic 3010, Australia.
   [Bennett, Frederick C.] Stanford Univ, Dept Psychiat & Behav Sci, Sch Med, Stanford, CA 94305 USA.
   [Schirmer, Lucas] Univ Calif San Francisco, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA.
   [Schirmer, Lucas] Tech Univ Munich, Dept Neurol, Klinikum Rechts Isar, D-81675 Munich, Germany.
   [Chung, Won-Suk] Korea Adv Inst Sci & Technol, Dept Biol Sci, Daejeon 34141, South Korea.
   [Peterson, Todd C.; Buckwalter, Marion S.] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA.
   [Wilton, Daniel K.; Frouin, Arnaud; Stevens, Beth] Boston Childrens Hosp, Dept Neurol, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA.
   [Napier, Brooke A.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA.
   [Panicker, Nikhil; Kumar, Manoj; Dawson, Valina L.; Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Neuroregenerat Program, Inst Cell Engn, Baltimore, MD 21205 USA.
   [Panicker, Nikhil; Kumar, Manoj; Dawson, Valina L.; Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Stem Cell Program, Inst Cell Engn, Baltimore, MD 21205 USA.
   [Panicker, Nikhil; Kumar, Manoj; Dawson, Valina L.; Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA.
   [Panicker, Nikhil; Kumar, Manoj; Dawson, Valina L.; Dawson, Ted M.] Adrienne Helis Malvin Med Res Fdn, New Orleans, LA 70130 USA.
   [Rowitch, David H.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA.
   [Rowitch, David H.] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA.
   [Rowitch, David H.] Univ Cambridge, Dept Paediat, Cambridge CB2, England.
   [Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA.
   [Dawson, Valina L.; Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA.
   [Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA.
C3 Stanford University; University of Melbourne; Stanford University; University of California System; University of California San Francisco; Technical University of Munich; Korea Advanced Institute of Science & Technology (KAIST); Stanford University; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Stanford University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of Cambridge; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University
RP Liddelow, SA (corresponding author), Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA.
EM liddelow@stanford.edu
FU National Institutes of Health [R01 AG048814, RO1 DA15043, P50 NS38377]; Christopher and Dana Reeve Foundation; Novartis Institute for Biomedical Research; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; JPB Foundation; Cure Alzheimer's Fund; Glenn Foundation; Esther B O'Keeffe Charitable Foundation; Maryland Stem Cell Research Fund [2013-MSCRFII-0105-00, 2012-MSCRFII-0268-00, 2014-MSCRFF-0665]; Australian National Health and Medical Research Council [GNT1052961]; Glenn Foundation Glenn Award; Merck Research Laboratories postdoctoral fellowship; NEI [K99EY024690]; Damon Runyon Cancer Research Foundation [DRG-2125-12]; German Research Foundation (DFG) [SCHI 1330/1-1]; Foundation's Parkinson's Disease Program [M-2014]; Stanford Alzheimer's disease research Centre [AG047366]; Stanford Health Care Brain Bank; Multiple Sclerosis Society of Great Britain and Northern Ireland [207495]; Parkinson&apos;s UK [J-1402] Funding Source: researchfish; National Institute of Neurological Disorders and Stroke [R37NS067525] Funding Source: NIH RePORTER
NR 33
TC 5827
Z9 6081
U1 40
U2 1545
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 26
PY 2017
VL 541
IS 7638
BP 481
EP 487
DI 10.1038/nature21029
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6LX
UT WOS:000396116600041
PM 28099414
DA 2026-03-09
ER

PT J
AU Zhang, J
   Pagano, G
   Hess, PW
   Kyprianidis, A
   Ecker, PB
   Kaplan, H
   Gorshkov, AV
   Gong, ZX
   Monroe, C
AF Zhang, J.
   Pagano, G.
   Hess, P. W.
   Kyprianidis, A.
   Ecker, P. B.
   Kaplan, H.
   Gorshkov, A. V.
   Gong, Z. -X.
   Monroe, C.
TI Observation of a many-body dynamical phase transition with a 53-qubit quantum simulator
SO NATURE
LA English
DT Article
ID propagation; systems; ions
AB A quantum simulator is a type of quantum computer that controls the interactions between quantum bits (or qubits) in a way that can be mapped to certain quantum many-body problems(1,2). As it becomes possible to exert more control over larger numbers of qubits, such simulators will be able to tackle a wider range of problems, such as materials design and molecular modelling, with the ultimate limit being a universal quantum computer that can solve general classes of hard problems(3). Here we use a quantum simulator composed of up to 53 qubits to study non-equilibrium dynamics in the transverse-field Ising model with long-range interactions. We observe a dynamical phase transition after a sudden change of the Hamiltonian, in a regime in which conventional statistical mechanics does not apply(4). The qubits are represented by the spins of trapped ions, which can be prepared in various initial pure states. We apply a global long-range Ising interaction with controllable strength and range, and measure each individual qubit with an efficiency of nearly 99 per cent. Such high efficiency means that arbitrary many-body correlations between qubits can be measured in a single shot, enabling the dynamical phase transition to be probed directly and revealing computationally intractable features that rely on the long-range interactions and high connectivity between qubits.
C1 [Zhang, J.; Pagano, G.; Hess, P. W.; Kyprianidis, A.; Ecker, P. B.; Kaplan, H.; Gorshkov, A. V.; Gong, Z. -X.; Monroe, C.] Univ Maryland, Joint Quantum Inst, Dept Phys, College Pk, MD 20742 USA.
   [Zhang, J.; Pagano, G.; Hess, P. W.; Kyprianidis, A.; Ecker, P. B.; Kaplan, H.; Gorshkov, A. V.; Gong, Z. -X.; Monroe, C.] Univ Maryland, Joint Ctr Quantum Informat & Comp Sci, Dept Phys, College Pk, MD 20742 USA.
   [Zhang, J.; Pagano, G.; Hess, P. W.; Kyprianidis, A.; Ecker, P. B.; Kaplan, H.; Gorshkov, A. V.; Gong, Z. -X.; Monroe, C.] Natl Inst Stand & Technol, College Pk, MD 20742 USA.
   [Monroe, C.] IonQ Inc, College Pk, MD 20740 USA.
   [Gong, Z. -X.] Colorado Sch Mines, Dept Phys, Golden, CO 80401 USA.
C3 University System of Maryland; University of Maryland College Park; University System of Maryland; University of Maryland College Park; National Institute of Standards & Technology (NIST) - USA; Colorado School of Mines
RP Zhang, J (corresponding author), Univ Maryland, Joint Quantum Inst, Dept Phys, College Pk, MD 20742 USA.; Zhang, J (corresponding author), Univ Maryland, Joint Ctr Quantum Informat & Comp Sci, Dept Phys, College Pk, MD 20742 USA.; Zhang, J (corresponding author), Natl Inst Stand & Technol, College Pk, MD 20742 USA.
EM jiehang.zhang@gmail.com
FU ARO and AFOSR Atomic and Molecular Physics Programs; AFOSR MURI; IARPA LogiQ programme; ARO MURI; ARL Center for Distributed Quantum Information; NSF Quantum Information Science programme; NSF Physics Frontier Center at JQI; IC Postdoctoral Research Fellowship Program; Direct For Mathematical & Physical Scien; Division Of Physics [1430094] Funding Source: National Science Foundation
NR 43
TC 887
Z9 1030
U1 2
U2 167
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 30
PY 2017
VL 551
IS 7682
BP 601
EP +
DI 10.1038/nature24654
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FO1KW
UT WOS:000416520400037
PM 29189781
DA 2026-03-09
ER

PT J
AU Zepeda-Ruiz, LA
   Stukowski, A
   Oppelstrup, T
   Bulatov, VV
AF Zepeda-Ruiz, Luis A.
   Stukowski, Alexander
   Oppelstrup, Tomas
   Bulatov, Vasily V.
TI Probing the limits of metal plasticity with molecular dynamics simulations
SO NATURE
LA English
DT Article
ID single-crystals; deformation; tantalum; dislocations; strain; flow; temperature; physics; stress
AB Ordinarily, the strength and plasticity properties of a metal are defined by dislocations-line defects in the crystal lattice whose motion results in material slippage along lattice planes(1). Dislocation dynamics models are usually used as mesoscale proxies for true atomistic dynamics, which are computationally expensive to perform routinely(2). However, atomistic simulations accurately capture every possible mechanism of material response, resolving every "jiggle and wiggle"(3) of atomic motion, whereas dislocation dynamics models do not. Here we present fully dynamic atomistic simulations of bulk single-crystal plasticity in the body-centred-cubic metal tantalum. Our goal is to quantify the conditions under which the limits of dislocation-mediated plasticity are reached and to understand what happens to the metal beyond any such limit. In our simulations, the metal is compressed at ultrahigh strain rates along its [001] crystal axis under conditions of constant pressure, temperature and strain rate. To address the complexity of crystal plasticity processes on the length scales (85-340 nm) and timescales (1 ns-1 mu s) that we examine, we use recently developed methods of in situ computational microscopy(4,5) to recast the enormous amount of transient trajectory data generated in our simulations into a form that can be analysed by a human. Our simulations predict that, on reaching certain limiting conditions of strain, dislocations alone can no longer relieve mechanical loads; instead, another mechanism, known as deformation twinning (the sudden re-orientation of the crystal lattice(6)), takes over as the dominant mode of dynamic response. Below this limit, the metal assumes a strain-path-independent steady state of plastic flow in which the flow stress and the dislocation density remain constant as long as the conditions of straining thereafter remain unchanged. In this distinct state, tantalum flows like a viscous fluid while retaining its crystal lattice and remaining a strong and stiff metal.
C1 [Zepeda-Ruiz, Luis A.; Oppelstrup, Tomas; Bulatov, Vasily V.] Lawrence Livermore Natl Lab, Livermore, CA 94550 USA.
   [Stukowski, Alexander] Tech Univ Darmstadt, Darmstadt, Germany.
C3 United States Department of Energy (DOE); Lawrence Livermore National Laboratory; Technical University of Darmstadt
RP Bulatov, VV (corresponding author), Lawrence Livermore Natl Lab, Livermore, CA 94550 USA.
EM bulatov1@llnl.gov
FU US Department of Energy by Lawrence Livermore National Laboratory [W-7405-Eng-48]; NNSA ASC programme
NR 38
TC 385
Z9 427
U1 18
U2 407
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 26
PY 2017
VL 550
IS 7677
BP 492
EP +
DI 10.1038/nature23472
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK7OW
UT WOS:000413697800037
PM 28953878
DA 2026-03-09
ER

PT J
AU Choi, S
   Choi, J
   Landig, R
   Kucsko, G
   Zhou, HY
   Isoya, J
   Jelezko, F
   Onoda, S
   Sumiya, H
   Khemani, V
   von Keyserlingk, C
   Yao, NY
   Demler, E
   Lukin, MD
AF Choi, Soonwon
   Choi, Joonhee
   Landig, Renate
   Kucsko, Georg
   Zhou, Hengyun
   Isoya, Junichi
   Jelezko, Fedor
   Onoda, Shinobu
   Sumiya, Hitoshi
   Khemani, Vedika
   von Keyserlingk, Curt
   Yao, Norman Y.
   Demler, Eugene
   Lukin, Mikhail D.
TI Observation of discrete time-crystalline order in a disordered dipolar many-body system
SO NATURE
LA English
DT Article
ID localization; thermalization; electron; diamond; spin
AB Understanding quantum dynamics away from equilibrium is an outstanding challenge in the modern physical sciences. Out-of-equilibrium systems can display a rich variety of phenomena, including self-organized synchronization and dynamical phase transitions(1,2). More recently, advances in the controlled manipulation of isolated many-body systems have enabled detailed studies of non-equilibrium phases in strongly interacting quantum matter(3-6); for example, the interplay between periodic driving, disorder and strong interactions has been predicted to result in exotic 'time-crystalline' phases(7), in which a system exhibits temporal correlations at integer multiples of the fundamental driving period, breaking the discrete time-translational symmetry of the underlying drive(8-12). Here we report the experimental observation of such discrete time-crystalline order in a driven, disordered ensemble of about one million dipolar spin impurities in diamond at room temperature(13-15). We observe long-lived temporal correlations, experimentally identify the phase boundary and find that the temporal order is protected by strong interactions. This order is remarkably stable to perturbations, even in the presence of slow thermalization(16,17). Our work opens the door to exploring dynamical phases of matter and controlling interacting, disordered many-body systems(18-20).
C1 [Choi, Soonwon; Choi, Joonhee; Landig, Renate; Kucsko, Georg; Zhou, Hengyun; Khemani, Vedika; Demler, Eugene; Lukin, Mikhail D.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.
   [Choi, Joonhee] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA.
   [Isoya, Junichi] Univ Tsukuba, Res Ctr Knowledge Commun, Tsukuba, Ibaraki 3058550, Japan.
   [Jelezko, Fedor] Univ Ulm, Inst Quantenopt, D-89081 Ulm, Germany.
   [Jelezko, Fedor] Univ Ulm, Ctr Integrated Quantum Sci & Technol, D-89081 Ulm, Germany.
   [Onoda, Shinobu] Takasaki Adv Radiat Res Inst, Natl Inst Quantum & Radiol Sci & Technol, 1233 Watanuki, Takasaki, Gunma 3701292, Japan.
   [Sumiya, Hitoshi] Sumitomo Elect Ind Ltd, Itami, Hyogo 6640016, Japan.
   [von Keyserlingk, Curt] Princeton Univ, Princeton Ctr Theoret Sci, Princeton, NJ 08544 USA.
   [Yao, Norman Y.] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
C3 Harvard University; Harvard University; University of Tsukuba; Ulm University; Ulm University; National Institutes for Quantum Science & Technology; Sumitomo Electric Industries; Princeton University; University of California System; University of California Berkeley
RP Lukin, MD (corresponding author), Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.
EM lukin@physics.harvard.edu
FU CUA; NSSEFF; ARO MURI; Moore Foundation; Harvard Society of Fellows; Princeton Center for Theoretical Science; Miller Institute for Basic Research in Science; Kwanjeong Educational Foundation; Samsung Fellowship; Purcell Fellowship; NSF [PHY-1506284, DMR-1308435]; Japan Society for the Promotion of Science KAKENHI [26246001]; LDRD Program of LBNL under US DOE [DE-AC02-05CH11231]; EU (FP7, Horizons, ERC); DFG; SNF; Volkswagenstiftung; BMBF; Direct For Mathematical & Physical Scien; Division Of Materials Research [1308435] Funding Source: National Science Foundation; Direct For Mathematical & Physical Scien; Division Of Physics [1506284] Funding Source: National Science Foundation; Division Of Physics; Direct For Mathematical & Physical Scien [1125846] Funding Source: National Science Foundation; Grants-in-Aid for Scientific Research [26246001] Funding Source: KAKEN
NR 31
TC 902
Z9 1006
U1 8
U2 212
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 9
PY 2017
VL 543
IS 7644
BP 221
EP +
DI 10.1038/nature21426
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0GQ
UT WOS:000395688700034
PM 28277511
DA 2026-03-09
ER

PT J
AU Schafer, S
   Viswanathan, S
   Widjaja, AA
   Lim, WW
   Moreno-Moral, A
   DeLaughter, DM
   Ng, B
   Patone, G
   Chow, K
   Khin, E
   Tan, J
   Chothani, SP
   Ye, L
   Rackham, OJL
   Ko, NSJ
   Sahib, NE
   Pua, CJ
   Zhen, NTG
   Xie, C
   Wang, M
   Maatz, H
   Lim, SQ
   Saar, K
   Blachut, S
   Petretto, E
   Schmidt, S
   Putoczki, T
   Guimaraes-Camboa, N
   Wakimoto, H
   van Heesch, S
   Sigmundsson, K
   Lim, SL
   Soon, JL
   Chao, VTT
   Chua, YL
   Tan, TE
   Evans, SM
   Loh, YJ
   Jamal, MH
   Ong, KK
   Chua, KC
   Ong, BH
   Chakaramakkil, MJ
   Seidman, JG
   Seidman, CE
   Hubner, N
   Sin, KYK
   Cook, SA
AF Schafer, Sebastian
   Viswanathan, Sivakumar
   Widjaja, Anissa A.
   Lim, Wei-Wen
   Moreno-Moral, Aida
   DeLaughter, Daniel M.
   Ng, Benjamin
   Patone, Giannino
   Chow, Kingsley
   Khin, Ester
   Tan, Jessie
   Chothani, Sonia P.
   Ye, Lei
   Rackham, Owen J. L.
   Ko, Nicole S. J.
   Sahib, Norliza E.
   Pua, Chee Jian
   Zhen, Nicole T. G.
   Xie, Chen
   Wang, Mao
   Maatz, Henrike
   Lim, Shiqi
   Saar, Kathrin
   Blachut, Susanne
   Petretto, Enrico
   Schmidt, Sabine
   Putoczki, Tracy
   Guimaraes-Camboa, Nuno
   Wakimoto, Hiroko
   van Heesch, Sebastiaan
   Sigmundsson, Kristmundur
   Lim, See L.
   Soon, Jia L.
   Chao, Victor T. T.
   Chua, Yeow L.
   Tan, Teing E.
   Evans, Sylvia M.
   Loh, Yee J.
   Jamal, Muhammad H.
   Ong, Kim K.
   Chua, Kim C.
   Ong, Boon-Hean
   Chakaramakkil, Mathew J.
   Seidman, Jonathan G.
   Seidman, Christine E.
   Hubner, Norbert
   Sin, Kenny Y. K.
   Cook, Stuart A.
TI IL-11 is a crucial determinant of cardiovascular fibrosis
SO NATURE
LA English
DT Article
ID interleukin-11; fibroblasts; mechanisms; mutation; pathway; heart; mice
AB Fibrosis is a common pathology in cardiovascular disease(1). In the heart, fibrosis causes mechanical and electrical dysfunction(1,2) and in the kidney, it predicts the onset of renal failure(3). Transforming growth factor beta 1 (TGF beta 1) is the principal pro-fibrotic factor(4,5), but its inhibition is associated with side effects due to its pleiotropic roles(6,7). We hypothesized that downstream effectors of TGF beta 1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGF beta 1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.
C1 [Schafer, Sebastian; Lim, Wei-Wen; Ng, Benjamin; Chow, Kingsley; Tan, Jessie; Ye, Lei; Pua, Chee Jian; Zhen, Nicole T. G.; Xie, Chen; Lim, Shiqi; Lim, See L.; Soon, Jia L.; Chao, Victor T. T.; Chua, Yeow L.; Tan, Teing E.; Loh, Yee J.; Jamal, Muhammad H.; Ong, Kim K.; Chua, Kim C.; Ong, Boon-Hean; Chakaramakkil, Mathew J.; Sin, Kenny Y. K.; Cook, Stuart A.] Natl Heart Ctr Singapore, Singapore, Singapore.
   [Schafer, Sebastian; Viswanathan, Sivakumar; Widjaja, Anissa A.; Moreno-Moral, Aida; Khin, Ester; Chothani, Sonia P.; Rackham, Owen J. L.; Ko, Nicole S. J.; Sahib, Norliza E.; Wang, Mao; Petretto, Enrico; Sigmundsson, Kristmundur; Soon, Jia L.; Chao, Victor T. T.; Sin, Kenny Y. K.; Cook, Stuart A.] Duke Natl Univ Singapore, Sch Med, Singapore, Singapore.
   [DeLaughter, Daniel M.; Wakimoto, Hiroko; Seidman, Jonathan G.; Seidman, Christine E.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.
   [Patone, Giannino; Maatz, Henrike; Saar, Kathrin; Blachut, Susanne; Schmidt, Sabine; van Heesch, Sebastiaan; Hubner, Norbert] Helmholtz Assoc MDC, Max Delbruck Ctr Mol Med, Cardiovasc & Metab Sci, Robert Rossle Str 10, D-13125 Berlin, Germany.
   [Putoczki, Tracy] Walter & Eliza Hall Inst Med Res, Inflammat Div, Parkville, Vic 3052, Australia.
   [Putoczki, Tracy] Univ Melbourne, Dept Med Biol, Parkville, Vic 3050, Australia.
   [Guimaraes-Camboa, Nuno; Evans, Sylvia M.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA.
   [Evans, Sylvia M.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA.
   [Evans, Sylvia M.] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA.
   [Loh, Yee J.; Ong, Kim K.] Kandang Kerbau Womens & Childrens Hosp, Singapore, Singapore.
   [Seidman, Christine E.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA.
   [Seidman, Christine E.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
   [Hubner, Norbert] DZHK German Ctr Cardiovasc Res, Partner Site, Berlin, Germany.
   [Hubner, Norbert] Charite, Berlin, Germany.
   [Hubner, Norbert] Berlin Inst Hlth BIH, Berlin, Germany.
   [Cook, Stuart A.] Imperial Coll London, Natl Heart & Lung Inst, London, England.
   [Cook, Stuart A.] MRC London Inst Med Sci, Hammersmith Hosp Campus,Du Cane Rd, London W12 0NN, England.
C3 National Heart Centre Singapore; National University of Singapore; Harvard University; Harvard Medical School; Helmholtz Association; Max Delbruck Center for Molecular Medicine; Walter & Eliza Hall Institute; University of Melbourne; University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Diego; KK Women's & Children's Hospital; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Howard Hughes Medical Institute; German Centre for Cardiovascular Research; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Imperial College London
RP Cook, SA (corresponding author), Natl Heart Ctr Singapore, Singapore, Singapore.; Cook, SA (corresponding author), Duke Natl Univ Singapore, Sch Med, Singapore, Singapore.; Cook, SA (corresponding author), Imperial Coll London, Natl Heart & Lung Inst, London, England.; Cook, SA (corresponding author), MRC London Inst Med Sci, Hammersmith Hosp Campus,Du Cane Rd, London W12 0NN, England.
EM stuart.cook@duke-nus.edu.sg
FU National Medical Research Council (NMRC) Singapore STaR award [NMRC/STaR/0011/2012]; NMRC Centre Grant; Goh Foundation; Tanoto Foundation; NHLBI [5R01HL080494]; HHMI; Fondation Leducq; MRC [MC_U120085815, MC_U120097112] Funding Source: UKRI; Medical Research Council [MC_U120097112, MC_U120085815] Funding Source: researchfish
NR 43
TC 516
Z9 598
U1 4
U2 164
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 7
PY 2017
VL 552
IS 7683
BP 110
EP +
DI 10.1038/nature24676
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FP4BA
UT WOS:000417560500053
PM 29160304
DA 2026-03-09
ER

PT J
AU Gordon, SR
   Aute, RLM
   Dulken, BW
   Hutter, G
   George, BM
   Ccracken, MNM
   Gupta, R
   Tsai, JM
   Sinha, R
   Corey, D
   Ring, AM
   Connolly, AJ
   Weissman, IL
AF Gordon, Sydney R.
   Aute, Roy L. M.
   Dulken, Ben W.
   Hutter, Gregor
   George, Benson M. .
   Ccracken, Melissa N. M.
   Gupta, Rohit
   Tsai, Jonathan M. .
   Sinha, Rahul
   Corey, Daniel
   Ring, Aaron M. .
   Connolly, Andrew J.
   Weissman, Irving L.
TI PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity
SO NATURE
LA English
DT Article
ID nf-kappa-b; anti-pd-1 antibody; pd-1/pd-l1 axis; cell; melanoma; receptor; pathway; safety; progression; population
AB Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance(1,2). Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system(3,4). Monoclonal antibodies that block the interaction between PD-1 and PD-L1, by binding to either the ligand or receptor, have shown notable clinical efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small-cell lung cancer and Hodgkin's lymphoma(5-9). Although it is well established that PD-1-PD-L1 blockade activates T cells, little is known about the role that this pathway may have in tumour-associated macrophages (TAMs). Here we show that both mouse and human TAMs express PD-1. TAM PD-1 expression increases over time in mouse models of cancer and with increasing disease stage in primary human cancers. TAM PD-1 expression correlates negatively with phagocytic potency against tumour cells, and blockade of PD-1-PD-L1 in vivo increases macrophage phagocytosis, reduces tumour growth and lengthens the survival of mice in mouse models of cancer in a macrophage-dependent fashion. This suggests that PD-1-PD-L1 therapies may also function through a direct effect on macrophages, with substantial implications for the treatment of cancer with these agents.
C1 [Gordon, Sydney R.; Aute, Roy L. M.; Dulken, Ben W.; Hutter, Gregor; George, Benson M. .; Ccracken, Melissa N. M.; Tsai, Jonathan M. .; Sinha, Rahul; Corey, Daniel; Weissman, Irving L.] Stanford Univ, Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA.
   [Gordon, Sydney R.] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA USA.
   [Gordon, Sydney R.; Aute, Roy L. M.; George, Benson M. .; Ccracken, Melissa N. M.; Tsai, Jonathan M. .; Sinha, Rahul; Corey, Daniel; Weissman, Irving L.] Stanford Univ, Sch Med, Ludwig Ctr Canc Stem Cell Res & Med, Stanford, CA 94305 USA.
   [Gordon, Sydney R.; Aute, Roy L. M.; George, Benson M. .; Ccracken, Melissa N. M.; Tsai, Jonathan M. .; Sinha, Rahul; Corey, Daniel; Weissman, Irving L.] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA.
   [Gordon, Sydney R.; Aute, Roy L. M.; George, Benson M. .; Ccracken, Melissa N. M.; Tsai, Jonathan M. .; Sinha, Rahul; Corey, Daniel; Connolly, Andrew J.; Weissman, Irving L.] Stanford Univ, Med Ctr, Dept Pathol, Stanford, CA 94305 USA.
   [Dulken, Ben W.] Stanford Univ, Stanford Med Scientist Training Program, Stanford, CA 94305 USA.
   [Hutter, Gregor] Stanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USA.
   [Hutter, Gregor] Univ Hosp Basel, Dept Neurosurg, CH-4031 Basel, Switzerland.
   [Gupta, Rohit] Stanford Univ, Sch Med, Human Immune Monitoring Ctr Biobank, Palo Alto, CA 94304 USA.
   [Ring, Aaron M. .] Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06519 USA.
C3 Stanford University; Stanford University; Stanford University; Stanford University; Stanford Cancer Institute; Stanford University; Stanford University; Stanford University; University of Basel; Stanford University; Yale University
RP Weissman, IL (corresponding author), Stanford Univ, Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA.; Weissman, IL (corresponding author), Stanford Univ, Sch Med, Ludwig Ctr Canc Stem Cell Res & Med, Stanford, CA 94305 USA.; Weissman, IL (corresponding author), Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA.; Weissman, IL (corresponding author), Stanford Univ, Med Ctr, Dept Pathol, Stanford, CA 94305 USA.
EM irv@stanford.edu
FU D. K. Ludwig Fund for Cancer Research; A.P. Giannini Foundation; Stanford Dean's Fellowship; Stanford Medical Scientist Training Program [NIH-GM07365]; Cancer Research Institute Irvington Fellowship; Swiss National Science Foundation [P300P3_155336]; ARRA Award from the National Center for Research Resources (NCRR) [1S10RR026780-01]; National Cancer Institute [P30CA124435] Funding Source: NIH RePORTER; National Institute of Arthritis and Musculoskeletal and Skin Diseases [T32AR050942] Funding Source: NIH RePORTER; National Institute on Aging [T32AG047126] Funding Source: NIH RePORTER; Swiss National Science Foundation (SNF) [P300P3_155336] Funding Source: Swiss National Science Foundation (SNF)
NR 32
TC 1810
Z9 2014
U1 16
U2 729
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 25
PY 2017
VL 545
IS 7655
BP 495
EP +
DI 10.1038/nature22396
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV6TH
UT WOS:000401906500055
PM 28514441
DA 2026-03-09
ER

PT J
AU Pfeifer, M
   Lefebvre, V
   Peres, CA
   Banks-Leite, C
   Wearn, OR
   Marsh, CJ
   Butchart, SHM
   Arroyo-Rodríguez, V
   Barlow, J
   Cerezo, A
   Cisneros, L
   D'Cruze, N
   Faria, D
   Hadley, A
   Harris, SM
   Klingbeil, BT
   Kormann, U
   Lens, L
   Medina-Rangel, GF
   Morante-Filho, JC
   Olivier, P
   Peters, SL
   Pidgeon, A
   Ribeiro, DB
   Scherber, C
   Schneider-Maunoury, L
   Struebig, M
   Urbina-Cardona, N
   Watling, JI
   Willig, MR
   Wood, EM
   Ewers, RM
AF Pfeifer, M.
   Lefebvre, V.
   Peres, C. A.
   Banks-Leite, C.
   Wearn, O. R.
   Marsh, C. J.
   Butchart, S. H. M.
   Arroyo-Rodriguez, V.
   Barlow, J.
   Cerezo, A.
   Cisneros, L.
   D'Cruze, N.
   Faria, D.
   Hadley, A.
   Harris, S. M.
   Klingbeil, B. T.
   Kormann, U.
   Lens, L.
   Medina-Rangel, G. F.
   Morante-Filho, J. C.
   Olivier, P.
   Peters, S. L.
   Pidgeon, A.
   Ribeiro, D. B.
   Scherber, C.
   Schneider-Maunoury, L.
   Struebig, M.
   Urbina-Cardona, N.
   Watling, J. I.
   Willig, M. R.
   Wood, E. M.
   Ewers, R. M.
TI Creation of forest edges has a global impact on forest vertebrates
SO NATURE
LA English
DT Article
ID extinction risk; rain-forest; body-size; habitat fragmentation; tropical forest; plantation forests; species richness; thermal ecology; biodiversity; landscape
AB Forest edges influence more than half of the world's forests and contribute to worldwide declines in biodiversity and ecosystem functions. However, predicting these declines is challenging in heterogeneous fragmented landscapes. Here we assembled a global dataset on species responses to fragmentation and developed a statistical approach for quantifying edge impacts in heterogeneous landscapes to quantify edge-determined changes in abundance of 1,673 vertebrate species. We show that the abundances of 85% of species are affected, either positively or negatively, by forest edges. Species that live in the centre of the forest (forest core), that were more likely to be listed as threatened by the International Union for Conservation of Nature (IUCN), reached peak abundances only at sites farther than 200-400 m from sharp high-contrast forest edges. Smaller-bodied amphibians, larger reptiles and medium-sized non-volant mammals experienced a larger reduction in suitable habitat than other forest-core species. Our results highlight the pervasive ability of forest edges to restructure ecological communities on a global scale.
C1 [Pfeifer, M.] Newcastle Univ, Sch Biol, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England.
   [Pfeifer, M.; Lefebvre, V.; Banks-Leite, C.; Ewers, R. M.] Imperial Coll London, Silwood Pk Campus,Buckhurst Rd, Ascot SL5 7PY, Berks, England.
   [Lefebvre, V.] Flowminder Fdn, Roslagsgatan 17, SE-11355 Stockholm, Sweden.
   [Peres, C. A.] Univ East Anglia, Sch Environm Sci, Norwich NR4 7TJ, Norfolk, England.
   [Wearn, O. R.] Zool Soc London, Inst Zool, Regents Pk, London NW1 4RY, England.
   [Marsh, C. J.] Nat Hist Museum, Dept Life Sci, Cromwell Rd, London SW7 5BD, England.
   [Butchart, S. H. M.] BirdLife Int, David Attenborough Bldg,Pembroke St, Cambridge CB2 3QZ, England.
   [Butchart, S. H. M.] Univ Cambridge, Dept Zool, Downing St, Cambridge CB2 3EJ, England.
   [Arroyo-Rodriguez, V.] Univ Nacl Autonoma Mexico, Inst Invest Ecosistemas & Sustentabilidad, Morelia 58190, Michoacan, Mexico.
   [Barlow, J.] Univ Lancaster, Lancaster Environm Ctr, Lancaster LA1 4YQ, England.
   [Cerezo, A.] Fdn Ecodesarrollo & Conservac FUNDAECO, 25 Calle,2-53,Zona 1, Guatemala City 0101, Guatemala.
   [Cisneros, L.] Univ Connecticut, Dept Nat Resources & Environm, Storrs, CT 06269 USA.
   [D'Cruze, N.] Univ Oxford, Dept Zool, Wildlife Conservat Res Unit, Tubney OX13 5QL, England.
   [Faria, D.; Morante-Filho, J. C.] Univ Estadual Santa Cruz, Appl Conservat Ecol Lab, Programa Posgrad Ecol & Conservacao Biodiversidad, Km16, BR-45662000 Ilheus, Bahia, Brazil.
   [Hadley, A.; Kormann, U.] Oregon State Univ, Forest Biodivers Res Network, Forest Ecosyst & Soc, Corvallis, OR 97331 USA.
   [Harris, S. M.] Univ Liverpool, Seabird Ecol Grp, Liverpool L69 7ZX, Merseyside, England.
   [Klingbeil, B. T.; Willig, M. R.] Univ Connecticut, Ctr Environm Sci & Engn, Dept Ecol & Evolutionary Biol, Storrs, CT 06269 USA.
   [Lens, L.] Univ Ghent, Dept Biol, Ledeganckstr 35, B-9000 Ghent, Belgium.
   [Medina-Rangel, G. F.] Univ Nacl Colombia, Inst Ciencias Natur, Grp Biodiversidad & Conservac, Ciudad Univ,Edificio 425, Bogota, Colombia.
   [Olivier, P.] Univ Pretoria, Dept Zool & Entomol, Conservat Ecol Res Unit, ZA-0083 Pretoria, South Africa.
   [Peters, S. L.] Univ Western Ontario, Dept Biol, London N6A 4B8, ON, Canada.
   [Pidgeon, A.] Univ Wisconsin Madison, Dept Forest & Wildlife Ecol, Madison, WI 53706 USA.
   [Ribeiro, D. B.] Univ Fed Mato Grosso do Sul, Biol & Hlth Sci Ctr, Campo Grande, MS, Brazil.
   [Scherber, C.] Univ Munster, Inst Landscape Ecol, Heisenbergstr 2, D-48149 Munster, Germany.
   [Schneider-Maunoury, L.] Museum Natl Hist Nat, F-75005 Paris, France.
   [Struebig, M.] Univ Kent, Sch Anthropol & Conservat, Durrell Inst Conservat & Ecol, Canterbury CT2 7NZ, Kent, England.
   [Urbina-Cardona, N.] Pontificia Univ Javeriana, Fac Rural & Environm Studies, Dept Ecol & Terr, Bogota 110231594, Colombia.
   [Watling, J. I.] John Carroll Univ, Dept Biol, University Hts, OH USA.
   [Wood, E. M.] Calif State Univ Los Angeles, Dept Biol Sci, Los Angeles, CA 90032 USA.
C3 Newcastle University - UK; Imperial College London; University of East Anglia; Zoological Society of London; Natural History Museum London; BirdLife International; University of Cambridge; Universidad Nacional Autonoma de Mexico; Lancaster University; University of Connecticut; University of Oxford; Universidade Estadual de Santa Cruz; Oregon State University; University of Liverpool; University of Connecticut; Ghent University; Universidad Nacional de Colombia; University of Pretoria; Western University (University of Western Ontario); University of Wisconsin System; University of Wisconsin Madison; Universidade Federal de Mato Grosso do Sul; University of Munster; Museum National d'Histoire Naturelle (MNHN); University of Kent; Pontificia Universidad Javeriana; University System of Ohio; John Carroll University; California State University System; California State University Los Angeles
RP Pfeifer, M (corresponding author), Newcastle Univ, Sch Biol, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England.; Pfeifer, M (corresponding author), Imperial Coll London, Silwood Pk Campus,Buckhurst Rd, Ascot SL5 7PY, Berks, England.
EM marion.pfeifer@newcastle.ac.uk
FU European Research Council [281986]; Division Of Environmental Biology; Direct For Biological Sciences [1546686] Funding Source: National Science Foundation; NERC [NE/K016393/1] Funding Source: UKRI; Natural Environment Research Council [NE/K016393/1] Funding Source: researchfish
NR 125
TC 386
Z9 443
U1 32
U2 467
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 9
PY 2017
VL 551
IS 7679
BP 187
EP +
DI 10.1038/nature24457
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM1KF
UT WOS:000414734200039
PM 29088701
DA 2026-03-09
ER

PT J
AU Chabera, P
   Liu, YZ
   Prakash, O
   Thyrhaug, E
   El Nahhas, A
   Honarfar, A
   Essén, S
   Fredin, LA
   Harlang, TCB
   Kjær, KS
   Handrup, K
   Ericson, F
   Tatsuno, H
   Morgan, K
   Schnadt, J
   Häggström, L
   Ericsson, T
   Sobkowiak, A
   Lidin, S
   Huang, P
   Styring, S
   Uhlig, J
   Bendix, J
   Lomoth, R
   Sundström, V
   Persson, P
   Wärnmark, K
AF Chabera, Pavel
   Liu, Yizhu
   Prakash, Om
   Thyrhaug, Erling
   El Nahhas, Amal
   Honarfar, Alireza
   Essen, Sofia
   Fredin, Lisa A.
   Harlang, Tobias C. B.
   Kjaer, Kasper S.
   Handrup, Karsten
   Ericson, Fredric
   Tatsuno, Hideyuki
   Morgan, Kelsey
   Schnadt, Joachim
   Haggstrom, Lennart
   Ericsson, Tore
   Sobkowiak, Adam
   Lidin, Sven
   Huang, Ping
   Styring, Stenbjorn
   Uhlig, Jens
   Bendix, Jesper
   Lomoth, Reiner
   Sundstrom, Villy
   Persson, Petter
   Warnmark, Kenneth
TI A low-spin Fe(III) complex with 100-ps ligand-to-metal charge transfer photoluminescence
SO NATURE
LA English
DT Article
ID excited-states; iron(ii); lifetime; light; photosensitizer; absorption; dynamics; row
AB Transition-metal complexes are used as photosensitizers(1), in light-emitting diodes, for biosensing and in photocatalysis(2). A key feature in these applications is excitation from the ground state to a charge-transfer state(3,4); the long charge-transfer-state lifetimes typical for complexes of ruthenium(5) and other precious metals are often essential to ensure high performance. There is much interest in replacing these scarce elements with Earth-abundant metals, with iron(6) and copper(7) being particularly attractive owing to their low cost and non-toxicity. But despite the exploration of innovative molecular designs(6,8-10), it remains a formidable scientific challenge(11) to access Earth-abundant transition-metal complexes with long-lived charge-transfer excited states. No known iron complexes are considered(12) photoluminescent at room temperature, and their rapid excited-state deactivation precludes their use as photosensitizers(13-15). Here we present the iron complex [Fe(btz)(3)](3+) (where btz is 3,3'-dimethyl-1,1'-bis(p-tolyl)-4,4'-bis(1,2,3-triazol-5-ylidene)), and show that the superior sigma-donor and pi-acceptor electron properties of the ligand stabilize the excited state sufficiently to realize a long charge-transfer lifetime of 100 picoseconds (ps) and room-temperature photoluminescence. This species is a low-spin Fe(III) d(5) complex, and emission occurs from a long-lived doublet ligand-to-metal charge-transfer ((LMCT)-L-2) state that is rarely seen for transition-metal complexes(4,16,17). The absence of intersystem crossing, which often gives rise to large excited-state energy losses in transition-metal complexes, enables the observation of spin-allowed emission directly to the ground state and could be exploited as an increased driving force in photochemical reactions on surfaces. These findings suggest that appropriate design strategies can deliver new iron-based materials for use as light emitters and photosensitizers.
C1 [Chabera, Pavel; Thyrhaug, Erling; El Nahhas, Amal; Honarfar, Alireza; Harlang, Tobias C. B.; Kjaer, Kasper S.; Tatsuno, Hideyuki; Uhlig, Jens; Sundstrom, Villy] Lund Univ, Dept Chem, Div Phys Chem, Box 124, SE-22100 Lund, Sweden.
   [Liu, Yizhu; Prakash, Om; Essen, Sofia; Lidin, Sven; Warnmark, Kenneth] Lund Univ, Dept Chem, CAS, Box 124, SE-22100 Lund, Sweden.
   [Fredin, Lisa A.; Ericson, Fredric; Persson, Petter] Lund Univ, Dept Chem, Div Theoret Chem, Box 124, SE-22100 Lund, Sweden.
   [Harlang, Tobias C. B.; Kjaer, Kasper S.] Tech Univ Denmark, Dept Phys, DK-2800 Lyngby, Denmark.
   [Handrup, Karsten; Schnadt, Joachim] Lund Univ, Dept Phys, Div Synchrotron Radiat Res, Box 118, SE-22100 Lund, Sweden.
   [Morgan, Kelsey] NIST, Boulder, CO 80305 USA.
   [Haggstrom, Lennart; Ericsson, Tore; Sobkowiak, Adam] Uppsala Univ, Dept Chem, Angstrom Lab, Box 538, SE-75121 Uppsala, Sweden.
   [Huang, Ping; Styring, Stenbjorn; Lomoth, Reiner] Uppsala Univ, Dept Chem, Angstrom Lab, Box 523, SE-75120 Uppsala, Sweden.
   [Bendix, Jesper] Univ Copenhagen, Dept Chem, Univ Pk 5, DK-2100 Copenhagen, Denmark.
C3 Lund University; Lund University; Lund University; Technical University of Denmark; Lund University; National Institute of Standards & Technology (NIST) - USA; Uppsala University; Uppsala University; University of Copenhagen
RP Wärnmark, K (corresponding author), Lund Univ, Dept Chem, CAS, Box 124, SE-22100 Lund, Sweden.
EM kenneth.warnmark@chem.lu.se
FU Knut och Alice Wallenbergs Stiftelse; Danish Research Council for Independent Research [12-125226]; Swedish Energy Agency (Energimyndigheten); Crafoord Foundation; Swedish National Infrastructure Committee (SNIC); Stiftelsen Olle Engkvist Byggmastare; Sten K. Johnsons Stiftelse
NR 49
TC 337
Z9 373
U1 19
U2 414
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 30
PY 2017
VL 543
IS 7647
BP 695
EP +
DI 10.1038/nature21430
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EP8IS
UT WOS:000397619700051
PM 28358064
DA 2026-03-09
ER

PT J
AU Venegas, C
   Kumar, S
   Franklin, BS
   Dierkes, T
   Brinkschulte, R
   Tejera, D
   Vieira-Saecker, A
   Schwartz, S
   Santarelli, F
   Kummer, MP
   Griep, A
   Gelpi, E
   Beilharz, M
   Riedel, D
   Golenbock, DT
   Geyer, M
   Walter, J
   Latz, E
   Heneka, MT
AF Venegas, Carmen
   Kumar, Sathish
   Franklin, Bernardo S.
   Dierkes, Tobias
   Brinkschulte, Rebecca
   Tejera, Dario
   Vieira-Saecker, Ana
   Schwartz, Stephanie
   Santarelli, Francesco
   Kummer, Markus P.
   Griep, Angelika
   Gelpi, Ellen
   Beilharz, Michael
   Riedel, Dietmar
   Golenbock, Douglas T.
   Geyer, Matthias
   Walter, Jochen
   Latz, Eicke
   Heneka, Michael T.
TI Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease
SO NATURE
LA English
DT Article
ID nlrp3 inflammasome; in-vivo; activation; protein; signal; mice; presenilin-1; pyroptosome; mechanism; peptide
AB The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-beta is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-beta and increase the formation of amyloid-beta oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-beta pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-beta pathology in transgenic double-mutant APP(Swe)PSEN1(dE9) mice. By contrast, homogenates from brains of APP(Swe)PSEN1(dE9) mice failed to induce seeding and spreading of amyloid-beta pathology in ASC-deficient APP(Swe)PSEN1(dE9) mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-beta pathology in APP(Swe)PSEN1(dE9) mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-beta pathology in patients with Alzheimer's disease.
C1 [Venegas, Carmen; Dierkes, Tobias; Tejera, Dario; Vieira-Saecker, Ana; Schwartz, Stephanie; Santarelli, Francesco; Kummer, Markus P.; Griep, Angelika; Heneka, Michael T.] Univ Bonn, Dept Neurodegenerat Dis & Gerontopsychiat, Sigmund Freud Str 25, D-53127 Bonn, Germany.
   [Kumar, Sathish; Walter, Jochen] Univ Bonn, Dept Neurol, D-53127 Bonn, Germany.
   [Franklin, Bernardo S.; Dierkes, Tobias; Brinkschulte, Rebecca; Beilharz, Michael; Geyer, Matthias; Latz, Eicke] Univ Bonn, Inst Innate Immun, D-53127 Bonn, Germany.
   [Gelpi, Ellen] Univ Barcelona, Hosp Clin, IDIBAPS, Neurol Tissue Bank, E-08036 Barcelona, Spain.
   [Riedel, Dietmar] Max Planck Inst Biophys Chem, Electron Microscopy Grp, D-37077 Gottingen, Germany.
   [Golenbock, Douglas T.; Latz, Eicke; Heneka, Michael T.] Univ Massachusetts, Sch Med, Dept Infect Dis & Immunol, Worcester, MA 01655 USA.
   [Latz, Eicke; Heneka, Michael T.] DZNE, D-53127 Bonn, Germany.
C3 University of Bonn; University of Bonn; University of Bonn; University of Barcelona; Hospital Clinic de Barcelona; IDIBAPS; Max Planck Society; University of Massachusetts System; University of Massachusetts Worcester; Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE)
RP Heneka, MT (corresponding author), Univ Bonn, Dept Neurodegenerat Dis & Gerontopsychiat, Sigmund Freud Str 25, D-53127 Bonn, Germany.; Heneka, MT (corresponding author), Univ Massachusetts, Sch Med, Dept Infect Dis & Immunol, Worcester, MA 01655 USA.; Heneka, MT (corresponding author), DZNE, D-53127 Bonn, Germany.
EM michael.heneka@ukbonn.de
FU Deutsche Forschungsgemeinschaft through Cluster of Excellence "Immunosensation"; Clinical Research Group [KFO177]; ERC InflammAct; ERC PLAT-IL-1; ERA-NET consortium TracInflam; JPND consortium InCure;  [SFB670];  [WA1477/6]
NR 33
TC 778
Z9 910
U1 0
U2 206
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 21
PY 2017
VL 552
IS 7685
BP 355
EP +
DI 10.1038/nature25158
PG 32
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ7RI
UT WOS:000418559800049
PM 29293211
DA 2026-03-09
ER

PT J
AU Liu, J
   Hu, QY
   Kim, DY
   Wu, ZQ
   Wang, WZ
   Xiao, YM
   Chow, P
   Meng, Y
   Prakapenka, VB
   Mao, HK
   Mao, WL
AF Liu, Jin
   Hu, Qingyang
   Kim, Duck Young
   Wu, Zhongqing
   Wang, Wenzhong
   Xiao, Yuming
   Chow, Paul
   Meng, Yue
   Prakapenka, Vitali B.
   Mao, Ho-Kwang
   Mao, Wendy L.
TI Hydrogen-bearing iron peroxide and the origin of ultralow-velocity zones
SO NATURE
LA English
DT Article
ID generalized gradient approximation; diamond-anvil cell; x-ray-diffraction; partial melt; earths; base; scattering; stability; system; top
AB Ultralow-velocity zones (ULVZs) at Earth's core-mantle boundary region have important implications for the chemical composition and thermal structure of our planet, but their origin has long been debated(1-3). Hydrogen-bearing iron peroxide (FeO2Hx) in the pyrite-type crystal structure was recently found to be stable under the conditions of the lowermost mantle(4-6). Using high-pressure experiments and theoretical calculations, we find that iron peroxide with a varying amount of hydrogen has a high density and high Poisson ratio as well as extremely low sound velocities consistent with ULVZs. Here we also report a reaction between iron and water at 86 gigapascals and 2,200 kelvin that produces FeO2Hx. This would provide a mechanism for generating the observed volume occupied by ULVZs through the reaction of about one-tenth the mass of Earth's ocean water in subducted hydrous minerals with the effectively unlimited reservoir of iron in Earth's core. Unlike other candidates for the composition of ULVZs(7-12), FeO2Hx synthesized from the superoxidation of iron by water would not require an extra transportation mechanism to migrate to the core-mantle boundary. These dense FeO2Hx-rich domains would be expected to form directly in the core-mantle boundary region and their properties would provide an explanation for the many enigmatic seismic features that are observed in ULVZs(1,13,14).
C1 [Liu, Jin; Hu, Qingyang; Mao, Wendy L.] Stanford Univ, Dept Geol Sci, Stanford, CA 94305 USA.
   [Hu, Qingyang; Kim, Duck Young; Mao, Ho-Kwang] Ctr High Pressure Sci & Technol Adv Res, Shanghai 201203, Peoples R China.
   [Wu, Zhongqing; Wang, Wenzhong] Univ Sci & Technol China, Sch Earth & Space Sci, Lab Seismol & Phys Earths Interior, Hefei, Anhui, Peoples R China.
   [Xiao, Yuming; Chow, Paul; Meng, Yue] Carnegie Inst Sci, High Pressure Collaborat Access Team, Geophys Lab, Argonne, IL 60439 USA.
   [Prakapenka, Vitali B.] Univ Chicago, Ctr Adv Radiat Sources, Chicago, IL 60437 USA.
   [Mao, Ho-Kwang] Carnegie Inst Sci, Geophys Lab, Washington, DC 20015 USA.
   [Mao, Wendy L.] SLAC Natl Accelerator Lab, Stanford Inst Mat & Energy Sci, Menlo Pk, CA 94025 USA.
C3 Stanford University; Chinese Academy of Sciences; University of Science & Technology of China, CAS; Carnegie Institution for Science; University of Chicago; Carnegie Institution for Science; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory
RP Mao, WL (corresponding author), Stanford Univ, Dept Geol Sci, Stanford, CA 94305 USA.; Mao, HK (corresponding author), Ctr High Pressure Sci & Technol Adv Res, Shanghai 201203, Peoples R China.; Mao, HK (corresponding author), Carnegie Inst Sci, Geophys Lab, Washington, DC 20015 USA.; Mao, WL (corresponding author), SLAC Natl Accelerator Lab, Stanford Inst Mat & Energy Sci, Menlo Pk, CA 94025 USA.
EM hmao@gl.ciw.edu; wmao@stanford.edu
FU Department of Energy (DOE)-NNSA [DE-NA0001974]; NSF; DOE-BES/DMSE [DE-FG02-99ER45775]; National Science Foundation (NSF)-Earth Sciences [EAR-1128799]; DOE Geosciences [DE-FG02-94ER14466]; US DOE, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; Geophysics Program by the NSF [EAR 1446969]; Deep Carbon Observatory; NSF [EAR-1345112, EAR-1447438]; National Natural Science Foundation of China [U1530402]; Natural Science Foundation of China [41590621]; State Key Development Program of Basic Research of China [2014CB845905]; Division Of Earth Sciences; Directorate For Geosciences [1446969] Funding Source: National Science Foundation
NR 55
TC 137
Z9 172
U1 5
U2 139
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 23
PY 2017
VL 551
IS 7681
BP 494
EP +
DI 10.1038/nature24461
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FN5JO
UT WOS:000416043700043
PM 29168804
DA 2026-03-09
ER

PT J
AU Gregorio, GG
   Masureel, M
   Hilger, D
   Terry, DS
   Juette, M
   Zhao, H
   Zhou, Z
   Perez-Aguilar, JM
   Hauge, M
   Mathiasen, S
   Javitch, JA
   Weinstein, H
   Kobilka, BK
   Blanchard, SC
AF Gregorio, G. Glenn
   Masureel, Matthieu
   Hilger, Daniel
   Terry, Daniel S.
   Juette, Manuel
   Zhao, Hong
   Zhou, Zhou
   Perez-Aguilar, Jose Manuel
   Hauge, Maria
   Mathiasen, Signe
   Javitch, Jonathan A.
   Weinstein, Harel
   Kobilka, Brian K.
   Blanchard, Scott C.
TI Single-molecule analysis of ligand efficacy in β2AR-G-protein activation
SO NATURE
LA English
DT Article
ID conformational dynamics; structural insights; nucleotide exchange; receptor; transducin; mechanism; gpcr; rhodopsin; agonists; beta(2)
AB G-protein-coupled receptor (GPCR)-mediated signal transduction is central to human physiology and disease intervention, yet the molecular mechanisms responsible for ligand-dependent signalling responses remain poorly understood. In class A GPCRs, receptor activation and G-protein coupling entail outward movements of transmembrane helix 6 (TM6). Here, using single-molecule fluorescence resonance energy transfer imaging, we examine TM6 movements in the beta(2) adrenergic receptor (beta(2)AR) upon exposure to orthosteric ligands with different efficacies, in the absence and presence of the G(s) heterotrimer. We show that partial and full agonists differentially affect TM6 motions to regulate the rate at which GDP-bound beta(2)AR-G(s) complexes are formed and the efficiency of nucleotide exchange leading to G(s) activation. These data also reveal transient nucleotide-bound beta(2)AR-G(s) species that are distinct from known structures, and provide single-molecule perspectives on the allosteric link between ligand-and nucleotide-binding pockets that shed new light on the G-protein activation mechanism.
C1 [Gregorio, G. Glenn; Terry, Daniel S.; Juette, Manuel; Zhao, Hong; Zhou, Zhou; Perez-Aguilar, Jose Manuel; Weinstein, Harel; Blanchard, Scott C.] Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.
   [Masureel, Matthieu; Hilger, Daniel; Kobilka, Brian K.] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
   [Hauge, Maria; Mathiasen, Signe; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Psychiat, 722 W 168th St, New York, NY 10032 USA.
   [Hauge, Maria; Mathiasen, Signe; Javitch, Jonathan A.] New York State Psychiat Inst & Hosp, Div Mol Therapeut, New York, NY 10032 USA.
   [Hauge, Maria] Univ Copenhagen, Dept Neurosci & Pharmacol, Lab Mol Pharmacol, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
   [Hauge, Maria] Univ Copenhagen, NNF Ctr Basic Metab Res, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
   [Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Pharmacol, 630 W 168th St, New York, NY 10032 USA.
   [Weinstein, Harel] Cornell Univ, Weill Cornell Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10021 USA.
   [Perez-Aguilar, Jose Manuel] IBM Thomas J Watson Res Ctr, Yorktown Hts, NY USA.
C3 Cornell University; Weill Cornell Medicine; Stanford University; Columbia University; New York State Psychiatry Institute; University of Copenhagen; University of Copenhagen; Columbia University; Cornell University; Weill Cornell Medicine; International Business Machines (IBM); IBM USA
RP Blanchard, SC (corresponding author), Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.; Kobilka, BK (corresponding author), Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
EM kobilka@stanford.edu; scb2005@med.cornell.edu
FU University of Texas at Austin [TG MCB120008]; Oak Ridge Leadership Computing Facility (ALCC) at the Oak Ridge National Laboratory by Office of Science of the US Department of Energy [BIP109, DE-AC05-00OR22725]; National Institutes of Health (NIH) [GM098859, R21DA0354585, K05DA022413, R01 MH54137, R01GM083118, R01NS028471, U54GM087519]; German Academic Exchange Service (DAAD); American Heart Association [15POST22700020]; Novo Nordisk Foundation Center for Basic Metabolic Research; American Heart Association (AHA) [15POST22700020] Funding Source: American Heart Association (AHA); National Institute of General Medical Sciences [R01GM083118] Funding Source: NIH RePORTER; National Institute of Mental Health [R01MH054137] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [R01NS028471] Funding Source: NIH RePORTER; NNF Center for Basic Metabolic Research [Schwartz Group] Funding Source: researchfish
NR 34
TC 267
Z9 305
U1 3
U2 155
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 6
PY 2017
VL 547
IS 7661
BP 68
EP +
DI 10.1038/nature22354
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EZ6PM
UT WOS:000404839900032
PM 28607487
DA 2026-03-09
ER

PT J
AU Lee, C
   Guo, JT
   Zeng, WZ
   Kim, S
   She, J
   Cang, CL
   Ren, DJ
   Jiang, YX
AF Lee, Changkeun
   Guo, Jiangtao
   Zeng, Weizhong
   Kim, Sunghoon
   She, Ji
   Cang, Chunlei
   Ren, Dejian
   Jiang, Youxing
TI The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture
SO NATURE
LA English
DT Article
ID k+ channel; crystal-structure; atomic-structure; selectivity; transport; proteins; disease; complex; shaker; na+
AB TMEM175 is a lysosomal K+ channel that is important for maintaining the membrane potential and pH stability in lysosomes(1). It contains two homologous copies of a six-transmembrane-helix (6-TM) domain, which has no sequence homology to the canonical tetrameric K+ channels and lacks the TVGYG selectivity filter motif found in these channels2-4. The prokaryotic TMEM175 channel, which is present in a subset of bacteria and archaea, contains only a single 6-TM domain and functions as a tetramer. Here, we present the crystal structure of a prokaryotic TMEM175 channel from Chamaesiphon minutus, CmTMEM175, the architecture of which represents a completely different fold from that of canonical K+ channels. All six transmembrane helices of CmTMEM175 are tightly packed within each subunit without undergoing domain swapping. The highly conserved TM1 helix acts as the pore-lining inner helix, creating an hourglass-shaped ion permeation pathway in the channel tetramer. Three layers of hydrophobic residues on the carboxy-terminal half of the TM1 helices form a bottleneck along the ion conduction pathway and serve as the selectivity filter of the channel. Mutagenesis analysis suggests that the first layer of the highly conserved isoleucine residues in the filter is primarily responsible for channel selectivity. Thus, the structure of CmTMEM175 represents a novel architecture of a tetrameric cation channel whose ion selectivity mechanism appears to be distinct from that of the classical K+ channel family.
C1 [Lee, Changkeun; Guo, Jiangtao; Zeng, Weizhong; Kim, Sunghoon; She, Ji; Jiang, Youxing] Univ Texas Southwestern Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA.
   [Lee, Changkeun; Guo, Jiangtao; Zeng, Weizhong; Kim, Sunghoon; She, Ji; Jiang, Youxing] Univ Texas Southwestern Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA.
   [Lee, Changkeun; Zeng, Weizhong; Kim, Sunghoon; Jiang, Youxing] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
   [Cang, Chunlei; Ren, Dejian] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA.
C3 University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Howard Hughes Medical Institute; University of Pennsylvania
RP Jiang, YX (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA.; Jiang, YX (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA.; Jiang, YX (corresponding author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
EM youxing.jiang@utsouthwestern.edu
FU US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]; National Institutes of Health, National Institute of General Medical Sciences; Howard Hughes Medical Institute; Office of Science, Office of Basic Energy Sciences, of the US Department of Energy [DE-AC02-05CH11231]; National Institutes of Health [GM079179, NS055293, NS074257]; Welch Foundation [I-1578]
NR 41
TC 61
Z9 68
U1 1
U2 52
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 27
PY 2017
VL 547
IS 7664
BP 472
EP +
DI 10.1038/nature23269
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB7ZK
UT WOS:000406358300040
PM 28723891
DA 2026-03-09
ER

PT J
AU Hodaei, H
   Hassan, AU
   Wittek, S
   Garcia-Gracia, H
   El-Ganainy, R
   Christodoulides, DN
   Khajavikhan, M
AF Hodaei, Hossein
   Hassan, Absar U.
   Wittek, Steffen
   Garcia-Gracia, Hipolito
   El-Ganainy, Ramy
   Christodoulides, Demetrios N.
   Khajavikhan, Mercedeh
TI Enhanced sensitivity at higher-order exceptional points
SO NATURE
LA English
DT Article
ID parity-time symmetry; microring lasers; label-free; microcavity
AB Non-Hermitian degeneracies, also known as exceptional points, have recently emerged as a new way to engineer the response of open physical systems, that is, those that interact with the environment. They correspond to points in parameter space at which the eigenvalues of the underlying system and the corresponding eigenvectors simultaneously coalesce(1-3). In optics, the abrupt nature of the phase transitions that are encountered around exceptional points has been shown to lead to many intriguing phenomena, such as loss-induced transparency(4), unidirectional invisibility(5,6), band merging(7,8), topological chirality(9,10) and laser mode selectivity(11,12). Recently, it has been shown that the bifurcation properties of second-order non-Hermitian degeneracies can provide a means of enhancing the sensitivity (frequency shifts) of resonant optical structures to external perturbations(13). Of particular interest is the use of even higher-order exceptional points (greater than second order), which in principle could further amplify the effect of perturbations, leading to even greater sensitivity. Although a growing number of theoretical studies have been devoted to such higher-order degeneracies(14-16), their experimental demonstration in the optical domain has so far remained elusive. Here we report the observation of higher-order exceptional points in a coupled cavity arrangement-specifically, a ternary, parity-time-symmetric photonic laser molecule-with a carefully tailored gain-loss distribution. We study the system in the spectral domain and find that the frequency response associated with this system follows a cube-root dependence on induced perturbations in the refractive index. Our work paves the way for utilizing non-Hermitian degeneracies in fields including photonics, optomechanics(10), microwaves(9) and atomic physics(17,18).
C1 [Hodaei, Hossein; Hassan, Absar U.; Wittek, Steffen; Garcia-Gracia, Hipolito; Christodoulides, Demetrios N.; Khajavikhan, Mercedeh] Univ Cent Florida, CREOL, Coll Opt & Photon, Orlando, FL 32816 USA.
   [El-Ganainy, Ramy] Michigan Technol Univ, Dept Phys, Houghton, MI 49931 USA.
   [El-Ganainy, Ramy] Michigan Technol Univ, Henes Ctr Quantum Phenomena, Houghton, MI 49931 USA.
C3 State University System of Florida; University of Central Florida; Michigan Technological University; Michigan Technological University
RP Khajavikhan, M (corresponding author), Univ Cent Florida, CREOL, Coll Opt & Photon, Orlando, FL 32816 USA.
EM mercedeh@creol.ucf.edu
FU Office of Naval Research (ONR) [N00014-16-1-2640]; National Science Foundation (NSF) [ECCS-1454531, DMR-1420620]; Air force Office of Scientific Research (AFOSR) [FA9550-14-1-0037]; Army Research Office (ARO) [W911NF-16-1-0013]; Qatar National Research Fund [NPRP 9-020-1-006]; Henes Center for Quantum Phenomena at Michigan Tech University; Div Of Electrical, Commun & Cyber Sys; Directorate For Engineering [1454531] Funding Source: National Science Foundation
NR 37
TC 1528
Z9 1692
U1 33
U2 517
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 10
PY 2017
VL 548
IS 7666
BP 187
EP +
DI 10.1038/nature23280
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD1GB
UT WOS:000407284300038
PM 28796201
DA 2026-03-09
ER

PT J
AU Bendesky, A
   Kwon, YM
   Lassance, JM
   Lewarch, CL
   Yao, SQ
   Peterson, BK
   He, MX
   Dulac, C
   Hoekstra, HE
AF Bendesky, Andres
   Kwon, Young-Mi
   Lassance, Jean-Marc
   Lewarch, Caitlin L.
   Yao, Shenqin
   Peterson, Brant K.
   He, Meng Xiao
   Dulac, Catherine
   Hoekstra, Hopi E.
TI The genetic basis of parental care evolution in monogamous mice
SO NATURE
LA English
DT Article
ID medial preoptic area; maternal-behavior; deer mice; paraventricular nucleus; vasopressin; peromyscus; oxytocin; expression; chromosm; aggression
AB Parental care is essential for the survival of mammals, yet the mechanisms underlying its evolution remain largely unknown. Here we show that two sister species of mice, Peromyscus polionotus and Peromyscus maniculatus, have large and heritable differences in parental behaviour. Using quantitative genetics, we identify 12 genomic regions that affect parental care, 8 of which have sex-specific effects, suggesting that parental care can evolve independently in males and females. Furthermore, some regions affect parental care broadly, whereas others affect specific behaviours, such as nest building. Of the genes linked to differences in nest-building behaviour, vasopressin is differentially expressed in the hypothalamus of the two species, with increased levels associated with less nest building. Using pharmacology in Peromyscus and chemogenetics in Mus, we show that vasopressin inhibits nest building but not other parental behaviours. Together, our results indicate that variation in an ancient neuropeptide contributes to interspecific differences in parental care.
C1 [Bendesky, Andres; Kwon, Young-Mi; Lassance, Jean-Marc; Lewarch, Caitlin L.; Yao, Shenqin; Peterson, Brant K.; Dulac, Catherine; Hoekstra, Hopi E.] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA.
   [Bendesky, Andres; Kwon, Young-Mi; Lassance, Jean-Marc; Peterson, Brant K.; Hoekstra, Hopi E.] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA.
   [Bendesky, Andres; Lassance, Jean-Marc; Lewarch, Caitlin L.; Yao, Shenqin; Dulac, Catherine; Hoekstra, Hopi E.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA.
   [He, Meng Xiao; Hoekstra, Hopi E.] Harvard Univ, Grad Program Biophys, Cambridge, MA 02138 USA.
   [Dulac, Catherine; Hoekstra, Hopi E.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA.
   [Hoekstra, Hopi E.] Harvard Univ, Museum Comparat Zool, Cambridge, MA 02138 USA.
   [Yao, Shenqin] Allen Inst Brain Sci, Seattle, WA 98103 USA.
   [Peterson, Brant K.] Novartis Inst BioMed Res, Cambridge, MA 02139 USA.
C3 Howard Hughes Medical Institute; Harvard University; Harvard University; Harvard University; Harvard University; Harvard University; Harvard University; Allen Institute for Brain Science; Novartis; Novartis USA
RP Hoekstra, HE (corresponding author), Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA.; Hoekstra, HE (corresponding author), Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA.; Hoekstra, HE (corresponding author), Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA.; Hoekstra, HE (corresponding author), Harvard Univ, Grad Program Biophys, Cambridge, MA 02138 USA.; Hoekstra, HE (corresponding author), Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA.; Hoekstra, HE (corresponding author), Harvard Univ, Museum Comparat Zool, Cambridge, MA 02138 USA.
EM hoekstra@oeb.harvard.edu
FU Helen Hay Whitney Foundation; National Institutes of Health (NIH) [HD084732]; Harvard Museum of Comparative Zoology; Harvard Undergraduate Research Fellowships; European Molecular Biology Organization [ALTF 379-2011]; Human Frontier Science Program; Belgian American Educational Foundation; NIH [GM008313]; National Philanthropic Trust [RFP-12-03]; Harvard Mind Brain Behavior Award; Harvard Brain Science Initiative; Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD082131] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM008313] Funding Source: NIH RePORTER
NR 65
TC 180
Z9 224
U1 1
U2 155
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 27
PY 2017
VL 544
IS 7651
BP 434
EP +
DI 10.1038/nature22074
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET1TN
UT WOS:000400051900034
PM 28424518
DA 2026-03-09
ER

PT J
AU Ambrosi, G
   An, Q
   Asfandiyarov, R
   Azzarello, P
   Bernardini, P
   Bertucci, B
   Cai, MS
   Chang, J
   Chen, DY
   Chen, HF
   Chen, JL
   Chen, W
   Cui, MY
   Cui, TS
   D'Amone, A
   De Benedittis, A
   De Mitri, I
   Di Santo, M
   Dong, JN
   Dong, TK
   Dong, YF
   Dong, ZX
   Donvito, G
   Droz, D
   Duan, KK
   Duan, JL
   Duranti, M
   D'Urso, D
   Fan, RR
   Fan, YZ
   Fang, F
   Feng, CQ
   Feng, L
   Fusco, P
   Gallo, V
   Gan, FJ
   Gao, M
   Gao, SS
   Gargano, F
   Garrappa, S
   Gong, K
   Gong, YZ
   Guo, DY
   Guo, JH
   Hu, YM
   Huang, GS
   Huang, YY
   Ionica, M
   Jiang, D
   Jiang, W
   Jin, X
   Kong, J
   Lei, SJ
   Li, S
   Li, X
   Li, WL
   Li, Y
   Liang, YF
   Liang, YM
   Liao, NH
   Liu, H
   Liu, J
   Liu, SB
   Liu, WQ
   Liu, Y
   Loparco, F
   Ma, M
   Ma, PX
   Ma, SY
   Ma, T
   Ma, XQ
   Ma, XY
   Marsella, G
   Mazziotta, MN
   Mo, D
   Niu, XY
   Peng, XY
   Peng, WX
   Qiao, R
   Rao, JN
   Salinas, MM
   Shang, GZ
   Shen, WH
   Shen, ZQ
   Shen, ZT
   Song, JX
   Su, H
   Su, M
   Sun, ZY
   Surdo, A
   Teng, XJ
   Tian, XB
   Tykhonov, A
   Vagelli, V
   Vitillo, S
   Wang, C
   Wang, H
   Wang, HY
   Wang, JZ
   Wang, LG
   Wang, Q
   Wang, S
   Wang, XH
   Wang, XL
   Wang, YF
   Wang, YP
   Wang, YZ
   Wen, SC
   Wang, ZM
   Wei, DM
   Wei, JJ
   Wei, YF
   Wu, D
   Wu, J
   Wu, LB
   Wu, SS
   Wu, X
   Xi, K
   Xia, ZQ
   Xin, YL
   Xu, HT
   Xu, ZL
   Xu, ZZ
   Xue, GF
   Yang, HB
   Yang, P
   Yang, YQ
   Yang, ZL
   Yao, HJ
   Yu, YH
   Yuan, Q
   Yue, C
   Zang, JJ
   Zhang, C
   Zhang, DL
   Zhang, F
   Zhang, JB
   Zhang, JY
   Zhang, JZ
   Zhang, L
   Zhang, PF
   Zhang, SX
   Zhang, WZ
   Zhang, Y
   Zhang, YJ
   Zhang, YQ
   Zhang, YL
   Zhang, YP
   Zhang, Z
   Zhang, ZY
   Zhao, H
   Zhao, HY
   Zhao, XF
   Zhou, CY
   Zhou, Y
   Zhu, X
   Zhu, Y
   Zimmer, S
AF Ambrosi, G.
   An, Q.
   Asfandiyarov, R.
   Azzarello, P.
   Bernardini, P.
   Bertucci, B.
   Cai, M. S.
   Chang, J.
   Chen, D. Y.
   Chen, H. F.
   Chen, J. L.
   Chen, W.
   Cui, M. Y.
   Cui, T. S.
   D'Amone, A.
   De Benedittis, A.
   De Mitri, I.
   Di Santo, M.
   Dong, J. N.
   Dong, T. K.
   Dong, Y. F.
   Dong, Z. X.
   Donvito, G.
   Droz, D.
   Duan, K. K.
   Duan, J. L.
   Duranti, M.
   D'Urso, D.
   Fan, R. R.
   Fan, Y. Z.
   Fang, F.
   Feng, C. Q.
   Feng, L.
   Fusco, P.
   Gallo, V.
   Gan, F. J.
   Gao, M.
   Gao, S. S.
   Gargano, F.
   Garrappa, S.
   Gong, K.
   Gong, Y. Z.
   Guo, D. Y.
   Guo, J. H.
   Hu, Y. M.
   Huang, G. S.
   Huang, Y. Y.
   Ionica, M.
   Jiang, D.
   Jiang, W.
   Jin, X.
   Kong, J.
   Lei, S. J.
   Li, S.
   Li, X.
   Li, W. L.
   Li, Y.
   Liang, Y. F.
   Liang, Y. M.
   Liao, N. H.
   Liu, H.
   Liu, J.
   Liu, S. B.
   Liu, W. Q.
   Liu, Y.
   Loparco, F.
   Ma, M.
   Ma, P. X.
   Ma, S. Y.
   Ma, T.
   Ma, X. Q.
   Ma, X. Y.
   Marsella, G.
   Mazziotta, M. N.
   Mo, D.
   Niu, X. Y.
   Peng, X. Y.
   Peng, W. X.
   Qiao, R.
   Rao, J. N.
   Salinas, M. M.
   Shang, G. Z.
   Shen, W. H.
   Shen, Z. Q.
   Shen, Z. T.
   Song, J. X.
   Su, H.
   Su, M.
   Sun, Z. Y.
   Surdo, A.
   Teng, X. J.
   Tian, X. B.
   Tykhonov, A.
   Vagelli, V.
   Vitillo, S.
   Wang, C.
   Wang, H.
   Wang, H. Y.
   Wang, J. Z.
   Wang, L. G.
   Wang, Q.
   Wang, S.
   Wang, X. H.
   Wang, X. L.
   Wang, Y. F.
   Wang, Y. P.
   Wang, Y. Z.
   Wen, S. C.
   Wang, Z. M.
   Wei, D. M.
   Wei, J. J.
   Wei, Y. F.
   Wu, D.
   Wu, J.
   Wu, L. B.
   Wu, S. S.
   Wu, X.
   Xi, K.
   Xia, Z. Q.
   Xin, Y. L.
   Xu, H. T.
   Xu, Z. L.
   Xu, Z. Z.
   Xue, G. F.
   Yang, H. B.
   Yang, P.
   Yang, Y. Q.
   Yang, Z. L.
   Yao, H. J.
   Yu, Y. H.
   Yuan, Q.
   Yue, C.
   Zang, J. J.
   Zhang, C.
   Zhang, D. L.
   Zhang, F.
   Zhang, J. B.
   Zhang, J. Y.
   Zhang, J. Z.
   Zhang, L.
   Zhang, P. F.
   Zhang, S. X.
   Zhang, W. Z.
   Zhang, Y.
   Zhang, Y. J.
   Zhang, Y. Q.
   Zhang, Y. L.
   Zhang, Y. P.
   Zhang, Z.
   Zhang, Z. Y.
   Zhao, H.
   Zhao, H. Y.
   Zhao, X. F.
   Zhou, C. Y.
   Zhou, Y.
   Zhu, X.
   Zhu, Y.
   Zimmer, S.
TI Direct detection of a break in the teraelectronvolt cosmic-ray spectrum of electrons and positrons
SO NATURE
LA English
DT Article
ID particle dark-matter; propagation; candidates; signature; energy
AB High-energy cosmic-ray electrons and positrons (CREs), which lose energy quickly during their propagation, provide a probe of Galactic high-energy processes(1-7) and may enable the observation of phenomena such as dark-matter particle annihilation or decay(8-10). The CRE spectrum has been measured directly up to approximately 2 teraelectronvolts in previous balloon-or space-borne experiments(11-16), and indirectly up to approximately 5 teraelectronvolts using ground-based Cherenkov gamma-ray telescope arrays(17,18). Evidence for a spectral break in the teraelectronvolt energy range has been provided by indirect measurements(17,18), although the results were qualified by sizeable systematic uncertainties. Here we report a direct measurement of CREs in the energy range 25 gigaelectronvolts to 4.6 teraelectronvolts by the Dark Matter Particle Explorer (DAMPE)(19) with unprecedentedly high energy resolution and low background. The largest part of the spectrum can be well fitted by a 'smoothly broken power-law' model rather than a single power-law model. The direct detection of a spectral break at about 0.9 teraelectronvolts confirms the evidence found by previous indirect measurements(17,18), clarifies the behaviour of the CRE spectrum at energies above 1 teraelectronvolt and sheds light on the physical origin of the sub-teraelectronvolt CREs.
C1 [Ambrosi, G.; Bertucci, B.; Duranti, M.; D'Urso, D.; Garrappa, S.; Ionica, M.; Vagelli, V.] Ist Nazl Fis Nucl INFN, Sez Perugia, I-06123 Perugia, Italy.
   [An, Q.; Chen, H. F.; Dong, J. N.; Feng, C. Q.; Gan, F. J.; Gao, S. S.; Huang, G. S.; Jiang, D.; Jin, X.; Liu, S. B.; Ma, S. Y.; Shen, Z. T.; Wang, C.; Wang, Q.; Wang, X. L.; Wang, Y. F.; Wei, Y. F.; Wu, L. B.; Xu, Z. Z.; Zhang, D. L.; Zhang, J. B.; Zhang, Y. L.; Zhang, Z. Y.; Zhu, X.] Univ Sci & Technol China, State Key Lab Particle Detect & Elect, Hefei 230026, Anhui, Peoples R China.
   [An, Q.; Chen, H. F.; Dong, J. N.; Feng, C. Q.; Gan, F. J.; Gao, S. S.; Huang, G. S.; Jiang, D.; Jin, X.; Liu, S. B.; Ma, S. Y.; Shen, Z. T.; Wang, C.; Wang, Q.; Wang, X. L.; Wang, Y. F.; Wei, Y. F.; Wu, L. B.; Xu, Z. Z.; Zhang, D. L.; Zhang, J. B.; Zhang, Y. L.; Zhang, Z. Y.; Zhu, X.] Univ Sci & Technol China, Dept Modern Phys, Hefei 230026, Anhui, Peoples R China.
   [Asfandiyarov, R.; Azzarello, P.; Droz, D.; Gallo, V.; Salinas, M. M.; Tykhonov, A.; Vitillo, S.; Wu, X.; Zimmer, S.] Univ Geneva, Dept Nucl & Particle Phys, CH-1211 Geneva, Switzerland.
   [Bernardini, P.; D'Amone, A.; De Benedittis, A.; De Mitri, I.; Marsella, G.] Univ Salento, Dipartimento Matemat & Fis E De Giorgi, I-73100 Lecce, Italy.
   [Bernardini, P.; D'Amone, A.; De Benedittis, A.; De Mitri, I.; Marsella, G.] Ist Nazl Fis Nucl INFN, Sez Lecce, I-73100 Lecce, Italy.
   [Bertucci, B.; Duranti, M.; Garrappa, S.; Vagelli, V.] Univ Perugia, Dipartimento Fis & Geol, I-06123 Perugia, Italy.
   [Cai, M. S.; Chang, J.; Chen, D. Y.; Chen, W.; Cui, M. Y.; Dong, T. K.; Duan, K. K.; Fan, Y. Z.; Feng, L.; Gong, Y. Z.; Guo, J. H.; Hu, Y. M.; Huang, Y. Y.; Jiang, W.; Lei, S. J.; Li, S.; Li, X.; Liang, Y. F.; Liao, N. H.; Liu, H.; Liu, Y.; Ma, P. X.; Ma, T.; Peng, X. Y.; Shen, Z. Q.; Su, M.; Wang, S.; Wang, Y. P.; Wang, Y. Z.; Wen, S. C.; Wei, D. M.; Wei, J. J.; Wu, J.; Xia, Z. Q.; Xin, Y. L.; Xu, Z. L.; Yuan, Q.; Yue, C.; Zang, J. J.; Zhang, C.; Zhang, L.; Zhang, P. F.; Zhang, Y.; Zhang, Y. Q.; Zhang, Z.] Chinese Acad Sci, Purple Mt Observ, Key Lab Dark Matter & Space Astron, Nanjing 210008, Jiangsu, Peoples R China.
   [Cai, M. S.; Chang, J.; Fan, Y. Z.; Jiang, W.; Ma, P. X.; Wei, D. M.; Wu, J.; Xia, Z. Q.; Yuan, Q.] Univ Sci & Technol China, Sch Astron & Space Sci, Hefei 230026, Anhui, Peoples R China.
   [Chen, D. Y.; Chen, W.; Duan, K. K.; Li, S.; Liang, Y. F.; Shen, Z. Q.; Wang, S.; Wang, Y. P.; Wang, Y. Z.; Wen, S. C.; Xu, Z. L.; Yue, C.; Zhang, L.; Zhang, Y.; Zhang, Y. Q.] Univ Chinese Acad Sci, Yuquan Rd 19, Beijing 100049, Peoples R China.
   [Chen, J. L.; Duan, J. L.; Fang, F.; Kong, J.; Li, Y.; Liu, J.; Liu, W. Q.; Mo, D.; Niu, X. Y.; Su, H.; Sun, Z. Y.; Wang, X. H.; Wang, Z. M.; Xi, K.; Yang, H. B.; Yang, P.; Yang, Y. Q.; Yang, Z. L.; Yao, H. J.; Yu, Y. H.; Zhang, J. Z.; Zhang, S. X.; Zhang, Y. J.; Zhang, Y. P.; Zhao, H. Y.; Zhou, Y.] Chinese Acad Sci, Inst Modern Phys, Nanchang Rd 509, Lanzhou 730000, Gansu, Peoples R China.
   [Cui, T. S.; Dong, Z. X.; Li, W. L.; Liang, Y. M.; Ma, M.; Ma, X. Q.; Ma, X. Y.; Rao, J. N.; Shang, G. Z.; Shen, W. H.; Song, J. X.; Teng, X. J.; Tian, X. B.; Wang, H.; Wang, L. G.; Wu, S. S.; Xu, H. T.; Xue, G. F.; Zhang, W. Z.; Zhao, X. F.; Zhou, C. Y.; Zhu, Y.] Chinese Acad Sci, Natl Space Sci Ctr, Nanertiao 1, Beijing 100190, Peoples R China.
   [Dong, Y. F.; Fan, R. R.; Gao, M.; Gong, K.; Guo, D. Y.; Peng, W. X.; Qiao, R.; Wang, H. Y.; Wang, J. Z.; Wu, D.; Zhang, F.; Zhang, J. Y.; Zhao, H.] Chinese Acad Sci, Inst High Energy Phys, YuquanLu 19B, Beijing 100049, Peoples R China.
   [Donvito, G.; Fusco, P.; Gargano, F.; Loparco, F.; Mazziotta, M. N.] Ist Nazl Fis Nucl INFN, Sez Bari, I-70125 Bari, Italy.
   [D'Urso, D.] ASI Space Sci Data Ctr SSDC, I-00133 Rome, Italy.
   [Fusco, P.; Loparco, F.] Univ Politecn Bari, Dipartimento Fis M Merlin, I-70126 Bari, Italy.
   [Su, M.] Univ Hong Kong, Dept Phys, Pok Fu Lam, Hong Kong, Peoples R China.
   [Su, M.] Univ Hong Kong, Lab Space Res, Pok Fu Lam, Hong Kong, Peoples R China.
C3 Istituto Nazionale di Fisica Nucleare (INFN); Chinese Academy of Sciences; University of Science & Technology of China, CAS; Chinese Academy of Sciences; University of Science & Technology of China, CAS; University of Geneva; University of Salento; Istituto Nazionale di Fisica Nucleare (INFN); University of Perugia; Chinese Academy of Sciences; Nanjing Institute of Astronomical Optics & Technology, NAOC, CAS; Purple Mountain Observatory, CAS; Chinese Academy of Sciences; University of Science & Technology of China, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; Institute of Modern Physics, CAS; Chinese Academy of Sciences; National Space Science Center, CAS; Chinese Academy of Sciences; Institute of High Energy Physics, CAS; Istituto Nazionale di Fisica Nucleare (INFN); Politecnico di Bari; University of Hong Kong; University of Hong Kong
RP Ambrosi, G (corresponding author), Ist Nazl Fis Nucl INFN, Sez Perugia, I-06123 Perugia, Italy.
FU strategic priority science and technology projects in space science of the Chinese Academy of Sciences; National Key R&D Program of China [2016YFA0400200]; National Basic Research Program of China [2013CB837000]; National Natural Science Foundation of China [11525313, 11622327, U1738206]; 100 Talents Program of Chinese Academy of Sciences; Swiss National Science Foundation (SNSF), Switzerland; National Institute for Nuclear Physics (INFN), Italy
NR 38
TC 465
Z9 548
U1 1
U2 166
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 7
PY 2017
VL 552
IS 7683
BP 63
EP +
DI 10.1038/nature24475
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FP4BA
UT WOS:000417560500043
PM 29186110
DA 2026-03-09
ER

PT J
AU Wang, YP
   Gao, WQ
   Shi, XY
   Ding, JJ
   Liu, W
   He, HB
   Wang, K
   Shao, F
AF Wang, Yupeng
   Gao, Wenqing
   Shi, Xuyan
   Ding, Jingjin
   Liu, Wang
   He, Huabin
   Wang, Kun
   Shao, Feng
TI Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin
SO NATURE
LA English
DT Article
ID inflammatory caspases; dfna5 gene; gsdmd; methylation; receptors; mechanism
AB Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide(1-3). The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity(4-9). GSDMD belongs to a gasdermin family that shares the pore-forming domain(4,6,10). The functions and mechanisms of activation of other gasdermins are unknown. Here we show that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5)(11), can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis. After chemotherapy, cleavage of GSDME by caspase-3 induced pyroptosis in certain GSDME-expressing cancer cells. GSDME was silenced in most cancer cells but expressed in many normal tissues. Human primary cells exhibited GSDME-dependent pyroptosis upon activation of caspase-3 by chemotherapy drugs. Gsdme(-/-) (also known as Dfna5(-/-)) mice were protected from chemotherapy-induced tissue damage and weight loss. These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy.
C1 [Wang, Yupeng; Gao, Wenqing; Shi, Xuyan] China Agr Univ, Coll Biol Sci, Beijing 100094, Peoples R China.
   [Wang, Yupeng; Gao, Wenqing; Shi, Xuyan; Ding, Jingjin; Liu, Wang; He, Huabin; Wang, Kun; Shao, Feng] Natl Inst Biol Sci, Beijing 102206, Peoples R China.
   [Ding, Jingjin] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China.
   [Shao, Feng] Natl Inst Biol Sci, Collaborat Innovat Ctr Canc Med, Beijing 102206, Peoples R China.
C3 China Agricultural University; National Institute of Biological Sciences, Beijing; Chinese Academy of Sciences; Institute of Biophysics, CAS; National Institute of Biological Sciences, Beijing
RP Shao, F (corresponding author), Natl Inst Biol Sci, Beijing 102206, Peoples R China.; Shao, F (corresponding author), Natl Inst Biol Sci, Collaborat Innovat Ctr Canc Med, Beijing 102206, Peoples R China.
EM shaofeng@nibs.ac.cn
FU National Key Research and Development Project on Protein Machinery and Control and Regulation of Biological Processes [2016YFA0501500]; Strategic Priority Research Program of the Chinese Academy of Sciences [XDB08020202]
NR 28
TC 2605
Z9 2923
U1 49
U2 1202
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 6
PY 2017
VL 547
IS 7661
BP 99
EP +
DI 10.1038/nature22393
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EZ6PM
UT WOS:000404839900038
PM 28459430
DA 2026-03-09
ER

PT J
AU Frachetti, MD
   Smith, CE
   Traub, CM
   Williams, T
AF Frachetti, Michael D.
   Smith, C. Evan
   Traub, Cynthia M.
   Williams, Tim
TI Nomadic ecology shaped the highland geography of Asia's Silk Roads
SO NATURE
LA English
DT Article
ID mobile pastoralism; china; agriculture; patterns; states
AB There are many unanswered questions about the evolution of the ancient 'Silk Roads' across Asia. This is especially the case in their mountainous stretches, where harsh terrain is seen as an impediment to travel. Considering the ecology and mobility of inner Asian mountain pastoralists, we use 'flow accumulation' modelling to calculate the annual routes of nomadic societies (from 750 m to 4,000 m elevation). Aggregating 500 iterations of the model reveals a high-resolution flow network that simulates how centuries of seasonal nomadic herding could shape discrete routes of connectivity across the mountains of Asia. We then compare the locations of known high-elevation Silk Road sites with the geography of these optimized herding flows, and find a significant correspondence in mountainous regions. Thus, we argue that highland Silk Road networks (from 750 m to 4,000 m) emerged slowly in relation to long-established mobility patterns of nomadic herders in the mountains of inner Asia.
C1 [Frachetti, Michael D.; Smith, C. Evan] Washington Univ, Dept Anthropol, SAIE Lab, 1 Brookings Dr,CB 1114, St Louis, MO 63130 USA.
   [Traub, Cynthia M.] Washington Univ, Univ Lib, 1 Brookings Dr,CB 1061, St Louis, MO 63130 USA.
   [Williams, Tim] UCL, Inst Archaeol, 31-34 Gordon Sq, London WC1H 0PY, England.
C3 Washington University (WUSTL); Washington University (WUSTL); University of London; University College London
RP Frachetti, MD (corresponding author), Washington Univ, Dept Anthropol, SAIE Lab, 1 Brookings Dr,CB 1114, St Louis, MO 63130 USA.
EM frachetti@wustl.edu
FU Washington University in St. Louis
NR 48
TC 193
Z9 228
U1 13
U2 224
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 9
PY 2017
VL 543
IS 7644
BP 193
EP +
DI 10.1038/nature21696
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0GQ
UT WOS:000395688700029
PM 28277506
DA 2026-03-09
ER

PT J
AU Liu, ZQ
   Wang, L
   Welch, JD
   Ma, H
   Zhou, Y
   Vaseghi, HR
   Yu, S
   Wall, JB
   Alimohamadi, S
   Zheng, M
   Yin, CY
   Shen, WN
   Prins, JF
   Liu, JD
   Qian, L
AF Liu, Ziqing
   Wang, Li
   Welch, Joshua D.
   Ma, Hong
   Zhou, Yang
   Vaseghi, Haley Ruth
   Yu, Shuo
   Wall, Joseph Blake
   Alimohamadi, Sahar
   Zheng, Michael
   Yin, Chaoying
   Shen, Weining
   Prins, Jan F.
   Liu, Jiandong
   Qian, Li
TI Single-cell transcriptomics reconstructs fate conversion from fibroblast to cardiomyocyte
SO NATURE
LA English
DT Article
ID cardiac fibroblasts; in-vitro; expression
AB Direct lineage conversion offers a new strategy for tissue regeneration and disease modelling. Despite recent success in directly reprogramming fibroblasts into various cell types, the precise changes that occur as fibroblasts progressively convert to the target cell fates remain unclear. The inherent heterogeneity and asynchronous nature of the reprogramming process renders it difficult to study this process using bulk genomic techniques. Here we used single-cell RNA sequencing to overcome this limitation and analysed global transcriptome changes at early stages during the reprogramming of mouse fibroblasts into induced cardiomyocytes (iCMs)(1-4). Using unsupervised dimensionality reduction and clustering algorithms, we identified molecularly distinct subpopulations of cells during reprogramming. We also constructed routes of iCM formation, and delineated the relationship between cell proliferation and iCM induction. Further analysis of global gene expression changes during reprogramming revealed unexpected downregulation of factors involved in mRNA processing and splicing. Detailed functional analysis of the top candidate splicing factor, Ptbp1, revealed that it is a critical barrier for the acquisition of cardiomyocyte-specific splicing patterns in fibroblasts. Concomitantly, Ptbp1 depletion promoted cardiac transcriptome acquisition and increased iCM reprogramming efficiency. Additional quantitative analysis of our dataset revealed a strong correlation between the expression of each reprogramming factor and the progress of individual cells through the reprogramming process, and led to the discovery of new surface markers for the enrichment of iCMs. In summary, our single-cell transcriptomics approaches enabled us to reconstruct the reprogramming trajectory and to uncover intermediate cell populations, gene pathways and regulators involved in iCM induction.
C1 [Liu, Ziqing; Wang, Li; Ma, Hong; Zhou, Yang; Vaseghi, Haley Ruth; Yu, Shuo; Wall, Joseph Blake; Alimohamadi, Sahar; Zheng, Michael; Yin, Chaoying; Liu, Jiandong; Qian, Li] Univ North Carolina Chapel Hill, McAllister Heart Inst, Chapel Hill, NC 27599 USA.
   [Liu, Ziqing; Wang, Li; Ma, Hong; Zhou, Yang; Vaseghi, Haley Ruth; Yu, Shuo; Wall, Joseph Blake; Alimohamadi, Sahar; Zheng, Michael; Yin, Chaoying; Liu, Jiandong; Qian, Li] Univ North Carolina Chapel Hill, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA.
   [Welch, Joshua D.; Prins, Jan F.] Univ North Carolina Chapel Hill, Dept Comp Sci, Chapel Hill, NC 27599 USA.
   [Shen, Weining] Univ Calif Irvine, Dept Stat, Irvine, CA 92697 USA.
C3 University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of California System; University of California Irvine
RP Liu, JD; Qian, L (corresponding author), Univ North Carolina Chapel Hill, McAllister Heart Inst, Chapel Hill, NC 27599 USA.; Liu, JD; Qian, L (corresponding author), Univ North Carolina Chapel Hill, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA.
EM jiandong_liu@med.unc.edu; li_qian@med.unc.edu
FU NIH BD2K Fellowship [T32 CA201159]; NIH F31 Fellowship [HG008912]; NIH/NHLBI [R00 HL109079, R01HL128331]; American Heart Association (AHA) [15GRNT25530005, 13SDG17060010]; Ellison Medical Foundation (EMF) [AG-NS-1064-13]; NIH [HG06272]; National Heart Lung and Blood Institute [T32HL069768] Funding Source: NIH RePORTER; American Heart Association (AHA) [13SDG17060010] Funding Source: American Heart Association (AHA)
NR 42
TC 167
Z9 219
U1 0
U2 85
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 2
PY 2017
VL 551
IS 7678
BP 100
EP +
DI 10.1038/nature24454
PG 25
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FL4SY
UT WOS:000414222900053
PM 29072293
DA 2026-03-09
ER

PT J
AU Liu, YJ
   Lu, YQ
   Yang, XS
   Zheng, XL
   Wen, SH
   Wang, F
   Vidal, X
   Zhao, JB
   Liu, DM
   Zhou, ZG
   Ma, CS
   Zhou, JJ
   Piper, JA
   Xi, P
   Jin, DY
AF Liu, Yujia
   Lu, Yiqing
   Yang, Xusan
   Zheng, Xianlin
   Wen, Shihui
   Wang, Fan
   Vidal, Xavier
   Zhao, Jiangbo
   Liu, Deming
   Zhou, Zhiguang
   Ma, Chenshuo
   Zhou, Jiajia
   Piper, James A.
   Xi, Peng
   Jin, Dayong
TI Amplified stimulated emission in upconversion nanoparticles for super-resolution nanoscopy
SO NATURE
LA English
DT Article
ID resonance energy-transfer; photon-avalanche; sted microscopy; upconverting nanoparticles; nanocrystals; luminescence; laser; fluorescence; resolution; efficient
AB Lanthanide-doped glasses and crystals are attractive for laser applications because the metastable energy levels of the trivalent lanthanide ions facilitate the establishment of population inversion and amplified stimulated emission at relatively low pump power(1-3). At the nanometre scale, lanthanide-doped upconversion nanoparticles (UCNPs) can now be made with precisely controlled phase, dimension and doping level(4,5). When excited in the near-infrared, these UCNPs emit stable, bright visible luminescence at a variety of selectable wavelengths(6-9), with single-nanoparticle sensitivity(10-13), which makes them suitable for advanced luminescence microscopy applications. Here we show that UCNPs doped with high concentrations of thulium ions (Tm3+), excited at a wavelength of 980 nanometres, can readily establish a population inversion on their intermediate metastable H-3(4) level: the reduced inter-emitter distance at high Tm3+ doping concentration leads to intense cross-relaxation, inducing a photon-avalanche-like effect that rapidly populates the metastable H-3(4) level, resulting in population inversion relative to the H-3(6) ground level within a single nanoparticle. As a result, illumination by a laser at 808 nanometres, matching the upconversion band of the H-3(4)-> H-3(6) transition, can trigger amplified stimulated emission to discharge the H-3(4) intermediate level, so that the upconversion pathway to generate blue luminescence can be optically inhibited. We harness these properties to realize low-power super-resolution stimulated emission depletion (STED) microscopy and achieve nanometre-scale optical resolution (nanoscopy), imaging single UCNPs; the resolution is 28 nanometres, that is, 1/36th of the wavelength. These engineered nanocrystals offer saturation intensity two orders of magnitude lower than those of fluorescent probes currently employed in stimulated emission depletion microscopy, suggesting a new way of alleviating the square-root law that typically limits the resolution that can be practically achieved by such techniques.
C1 [Liu, Yujia; Lu, Yiqing; Zheng, Xianlin; Wen, Shihui; Wang, Fan; Vidal, Xavier; Zhao, Jiangbo; Liu, Deming; Zhou, Zhiguang; Ma, Chenshuo; Piper, James A.; Xi, Peng; Jin, Dayong] Macquarie Univ, ARC Ctr Excellence Nanoscale BioPhoton CNBP, Adv Cytometry Labs, Sydney, NSW 2109, Australia.
   [Liu, Yujia; Lu, Yiqing; Zheng, Xianlin; Wang, Fan; Vidal, Xavier; Zhao, Jiangbo; Liu, Deming; Piper, James A.; Jin, Dayong] Macquarie Univ, Dept Phys & Astron, Sydney, NSW 2109, Australia.
   [Liu, Yujia; Yang, Xusan; Xi, Peng] Peking Univ, Dept Biomed Engn, Coll Engn, Beijing 100871, Peoples R China.
   [Liu, Yujia] Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, Shanghai 200241, Peoples R China.
   [Wen, Shihui; Wang, Fan; Zhou, Zhiguang; Zhou, Jiajia; Jin, Dayong] Univ Technol Sydney, Fac Sci, IBMD, Sydney, NSW 2007, Australia.
C3 Macquarie University; Macquarie University; Peking University; Shanghai Jiao Tong University; University of Technology Sydney
RP Lu, YQ; Xi, P; Jin, DY (corresponding author), Macquarie Univ, ARC Ctr Excellence Nanoscale BioPhoton CNBP, Adv Cytometry Labs, Sydney, NSW 2109, Australia.; Lu, YQ; Jin, DY (corresponding author), Macquarie Univ, Dept Phys & Astron, Sydney, NSW 2109, Australia.; Xi, P (corresponding author), Peking Univ, Dept Biomed Engn, Coll Engn, Beijing 100871, Peoples R China.; Jin, DY (corresponding author), Univ Technol Sydney, Fac Sci, IBMD, Sydney, NSW 2007, Australia.
EM yiqing.lu@mq.edu.au; xipeng@pku.edu.cn; dayong.jin@uts.edu.au
FU Australian Research Council (ARC) [FT 130100517]; ARC Centre of Excellence for Nanoscale BioPhotonics [CE140100003]; Natural Science Foundation of China [61428501, 31327901, 61475010]; National Instrumentation Project of China [2013YQ03065102]; Macquarie University Research Fellowship
NR 36
TC 756
Z9 836
U1 28
U2 1675
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 9
PY 2017
VL 543
IS 7644
BP 229
EP +
DI 10.1038/nature21366
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0GQ
UT WOS:000395688700036
PM 28225761
DA 2026-03-09
ER

PT J
AU Laforest-Lapointe, I
   Paquette, A
   Messier, C
   Kembel, SW
AF Laforest-Lapointe, Isabelle
   Paquette, Alain
   Messier, Christian
   Kembel, Steven W.
TI Leaf bacterial diversity mediates plant diversity and ecosystem function relationships
SO NATURE
LA English
DT Article
ID biodiversity; microbiome; complementarity; gene; microorganisms; productivity; community; selection; fitness; field
AB Research on biodiversity and ecosystem functioning has demonstrated links between plant diversity and ecosystem functions such as productivity(1,2). At other trophic levels, the plant microbiome has been shown to influence host plant fitness and function(3,4), and host-associated microbes have been proposed to influence ecosystem function through their role in defining the extended phenotype of host organisms(5,6) However, the importance of the plant microbiome for ecosystem function has not been quantified in the context of the known importance of plant diversity and traits. Here, using a tree biodiversity-ecosystem functioning experiment, we provide strong support for the hypothesis that leaf bacterial diversity is positively linked to ecosystem productivity, even after accounting for the role of plant diversity. Our results also show that host species identity, functional identity and functional diversity are the main determinants of leaf bacterial community structure and diversity. Our study provides evidence of a positive correlation between plant-associated microbial diversity and terrestrial ecosystem productivity, and a new mechanism by which models of biodiversity-ecosystem functioning relationships can be improved.
C1 [Laforest-Lapointe, Isabelle; Paquette, Alain; Messier, Christian; Kembel, Steven W.] Univ Quebec, Dept Sci Biol, Montreal, PQ H3C 3P8, Canada.
   [Laforest-Lapointe, Isabelle; Paquette, Alain; Messier, Christian; Kembel, Steven W.] Univ Quebec, Ctr Etude Foret, Montreal, PQ H2X 3Y7, Canada.
   [Messier, Christian] Univ Quebec Outaouais, Inst Sci Foret Temp, Ripon, PQ J0V 1V0, Canada.
C3 University of Quebec; University of Quebec Montreal; University of Quebec; University of Quebec Montreal; University of Quebec; University Quebec Outaouais
RP Laforest-Lapointe, I (corresponding author), Univ Quebec, Dept Sci Biol, Montreal, PQ H3C 3P8, Canada.; Laforest-Lapointe, I (corresponding author), Univ Quebec, Ctr Etude Foret, Montreal, PQ H2X 3Y7, Canada.
EM isabelle.laforest.lapointe@gmail.com
FU McGill University
NR 50
TC 284
Z9 325
U1 11
U2 581
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 1
PY 2017
VL 546
IS 7656
BP 145
EP +
DI 10.1038/nature22399
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW3CR
UT WOS:000402372800045
PM 28538736
DA 2026-03-09
ER

PT J
AU Sivaramakrishnan, P
   Sepúlveda, LA
   Halliday, JA
   Liu, JJ
   Núñez, MAB
   Golding, I
   Rosenberg, SM
   Herman, C
AF Sivaramakrishnan, Priya
   Sepulveda, Leonardo A.
   Halliday, Jennifer A.
   Liu, Jingjing
   Nunez, Maria Angelica Bravo
   Golding, Ido
   Rosenberg, Susan M.
   Herman, Christophe
TI The transcription fidelity factor GreA impedes DNA break repair
SO NATURE
LA English
DT Article
ID recombination hotspot-chi; escherichia-coli-cells; rna-polymerase; recbcd enzyme; reca protein; regulatory sequence; nuclease activity; cleavage factors; ppgpp binding; in-vivo
AB Homologous recombination repairs DNA double-strand breaks and must function even on actively transcribed DNA. Because break repair prevents chromosome loss, the completion of repair is expected to outweigh the transcription of broken templates. However, the interplay between DNA break repair and transcription processivity is unclear. Here we show that the transcription factor GreA inhibits break repair in Escherichia coli. GreA restarts backtracked RNA polymerase and hence promotes transcription fidelity. We report that removal of GreA results in markedly enhanced break repair via the classic RecBCD-RecA pathway. Using a deep-sequencing method to measure chromosomal exonucleolytic degradation, we demonstrate that the absence of GreA limits RecBCD-mediated resection. Our findings suggest that increased RNA polymerase backtracking promotes break repair by instigating RecA loading by RecBCD, without the influence of canonical Chi signals. The idea that backtracked RNA polymerase can stimulate recombination presents a DNA transaction conundrum: a transcription fidelity factor that compromises genomic integrity.
C1 [Sivaramakrishnan, Priya; Halliday, Jennifer A.; Liu, Jingjing; Nunez, Maria Angelica Bravo; Rosenberg, Susan M.; Herman, Christophe] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.
   [Sepulveda, Leonardo A.; Golding, Ido; Rosenberg, Susan M.] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA.
   [Golding, Ido; Rosenberg, Susan M.; Herman, Christophe] Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.
   [Rosenberg, Susan M.; Herman, Christophe] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA.
C3 Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine
RP Herman, C (corresponding author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.; Herman, C (corresponding author), Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.; Herman, C (corresponding author), Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA.
EM herman@bcm.edu
FU National Institutes of Health (NIH) [R01-GM088653]; Dan L. Duncan Cancer Center; pilot grant [P30 CA125123]; W. M. Keck Foundation; NIH [R35-GM122598, DP1-CA174424, RO1-GM082837]; National Science Foundation [PHY 1147498, PHY 1430124, PHY 1427654]; Welch Foundation [Q-1759]; John S. Dunn Foundation; Division Of Physics; Direct For Mathematical & Physical Scien [1147498] Funding Source: National Science Foundation; National Cancer Institute [P30CA125123] Funding Source: NIH RePORTER
NR 44
TC 51
Z9 56
U1 1
U2 33
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 12
PY 2017
VL 550
IS 7675
BP 214
EP +
DI 10.1038/nature23907
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FJ5YG
UT WOS:000412829500040
PM 28976965
DA 2026-03-09
ER

PT J
AU Drané, P
   Brault, ME
   Cui, GF
   Meghani, K
   Chaubey, S
   Detappe, A
   Parnandi, N
   He, YZ
   Zheng, XF
   Botuyan, MV
   Kalousi, A
   Yewdell, WT
   Münch, C
   Harper, JW
   Chaudhuri, J
   Soutoglou, E
   Mer, G
   Chowdhury, D
AF Drane, Pascal
   Brault, Marie-Eve
   Cui, Gaofeng
   Meghani, Khyati
   Chaubey, Shweta
   Detappe, Alexandre
   Parnandi, Nishita
   He, Yizhou
   Zheng, Xiao-Feng
   Botuyan, Maria Victoria
   Kalousi, Alkmini
   Yewdell, William T.
   Muench, Christian
   Harper, J. Wade
   Chaudhuri, Jayanta
   Soutoglou, Evi
   Mer, Georges
   Chowdhury, Dipanjan
TI TIRR regulates 53BP1 by masking its histone methyl-lysine binding function
SO NATURE
LA English
DT Article
ID strand break repair; dna breaks; cytoplasmic domain; protein; recruitment; inhibitors; syndecan-4; resection; syndesmos; sites
AB P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.
C1 [Drane, Pascal; Brault, Marie-Eve; Meghani, Khyati; Chaubey, Shweta; Detappe, Alexandre; Parnandi, Nishita; He, Yizhou; Zheng, Xiao-Feng; Chowdhury, Dipanjan] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA.
   [Cui, Gaofeng; Botuyan, Maria Victoria; Mer, Georges] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN 55905 USA.
   [Kalousi, Alkmini; Soutoglou, Evi] IGBMC, F-67404 Illkirch Graffenstaden, France.
   [Yewdell, William T.; Chaudhuri, Jayanta] Mem Sloan Kettering Canc Ctr, Gerstner Sloan Kettering Grad Sch, Immunol Program, New York, NY 10065 USA.
   [Muench, Christian; Harper, J. Wade] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
   [Chaudhuri, Jayanta] Weill Cornell Med Sch, Immunol & Microbial Pathogenesis Program, New York, NY 10065 USA.
   [Chowdhury, Dipanjan] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.
   [Chowdhury, Dipanjan] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.
   [Muench, Christian] Goethe Univ, Sch Med, Inst Biochem 2, Theodor Stern Kai 7, D-60590 Frankfurt, Germany.
C3 Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Mayo Clinic; Institut National de la Sante et de la Recherche Medicale (Inserm); Memorial Sloan Kettering Cancer Center; Harvard University; Harvard Medical School; Cornell University; Weill Cornell Medicine; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Goethe University Frankfurt
RP Chowdhury, D (corresponding author), Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA.; Chowdhury, D (corresponding author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Chowdhury, D (corresponding author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.
EM dipanjan_chowdhury@dfci.harvard.edu
FU National Institute of Allergy and Infectious Diseases [R01 AI101897-01]; National Cancer Institute [R01CA142698-07, 4T32CA009149-40]; Leukemia and Lymphoma Society Scholar Grant; Claudia Adams Barr Program for Innovative Cancer Research; Department of Defense Ovarian Cancer Award; Breast SPORE Pilot Award; Robert and Deborah First Fund Award; National Institutes of Health [R01 CA132878, R01 GM116829]; Mayo Clinic Brain Cancer SPORE Program Pilot Award [P50 CA108961]; National Institutes of Health/National Institute of Allergy and Infectious Disease grants [1RO1AI072194, 1RO1AI124186]; National Cancer Institute Cancer Center Support grant [P30CA008748];  [AG011085]; National Cancer Institute [T32CA009149, P30CA008748] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [R01AI072194, R01AI124186] Funding Source: NIH RePORTER
NR 51
TC 109
Z9 135
U1 1
U2 29
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 9
PY 2017
VL 543
IS 7644
BP 211
EP +
DI 10.1038/nature21358
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0GQ
UT WOS:000395688700032
PM 28241136
DA 2026-03-09
ER

PT J
AU Mackenzie, KJ
   Carroll, P
   Martin, CA
   Murina, O
   Fluteau, A
   Impson, DJS
   Olova, N
   Sutcliffe, H
   Rainger, JK
   Leitch, A
   Osborn, RT
   Wheeler, AP
   Nowotny, M
   Gilbert, N
   Chandra, T
   Reijns, MAM
   Jackson, AP
AF Mackenzie, Karen J.
   Carroll, Paula
   Martin, Carol-Anne
   Murina, Olga
   Fluteau, Adeline
   Impson, Daniel J. S.
   Olova, Nelly
   Sutcliffe, Hannah
   Rainger, Jacqueline K.
   Leitch, Andrea
   Osborn, Ruby T.
   Wheeler, Ann P.
   Nowotny, Marcin
   Gilbert, Nick
   Chandra, Tamir
   Reijns, Martin A. M.
   Jackson, Andrew P.
TI cGAS surveillance of micronuclei links genome instability to innate immunity
SO NATURE
LA English
DT Article
ID gmp-amp synthase; cytosolic dna sensor; rna-seq; sensing pathway; cell-migration; 30 nm; nuclear; chromatin; envelope; cancer
AB DNA is strictly compartmentalized within the nucleus to prevent autoimmunity(1); despite this, cyclic GMP-AMP synthase (cGAS), a cytosolic sensor of double-stranded DNA, is activated in autoinflammatory disorders and by DNA damage(2-6). Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localizes to micronuclei arising from genome instability in a mouse model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. Such micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by its own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis(7), leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS is activated by chromatin, and consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA damage are cell-cycle dependent. By combining live-cell laser microdissection with single cell transcriptomics, we establish that interferon-stimulated gene expression is induced in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, recognition of micronuclei by cGAS may act as a cell-intrinsic immune surveillance mechanism that detects a range of neoplasia-inducing processes.
C1 [Mackenzie, Karen J.; Carroll, Paula; Martin, Carol-Anne; Murina, Olga; Fluteau, Adeline; Impson, Daniel J. S.; Olova, Nelly; Sutcliffe, Hannah; Rainger, Jacqueline K.; Leitch, Andrea; Osborn, Ruby T.; Wheeler, Ann P.; Gilbert, Nick; Chandra, Tamir; Reijns, Martin A. M.; Jackson, Andrew P.] Univ Edinburgh, MRC Human Genet Unit, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland.
   [Nowotny, Marcin] Int Inst Mol & Cell Biol, Lab Prot Struct, Warsaw, Poland.
C3 University of Edinburgh; Miedzynarodowy Instytut Biologii Molekularnej i Komorkowej
RP Reijns, MAM; Jackson, AP (corresponding author), Univ Edinburgh, MRC Human Genet Unit, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland.
EM martin.reijns@igmm.ed.ac.uk; Andrew.jackson@igmm.ed.ac.uk
FU Medical Research Council HGU core grant (MRC) [U127580972]; Newlife the Charity for Disabled Children; Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund 2; MRC [MC_PC_15075]; Howard Hughes Medical Institute; EMBO Long-Term Fellowship [ALTF 7-2015]; European Commission [GA-2013-609409]; Swiss National Science Foundation [P2ZHP3_158709]; Swiss National Science Foundation (SNF) [P2ZHP3_158709] Funding Source: Swiss National Science Foundation (SNF); MRC [MC_UU_12018/24, MC_PC_15075, MC_PC_U127580972, MR/K01563X/1, 1805075] Funding Source: UKRI; Medical Research Council [MR/K01563X/1, 1805075, MC_UU_12018/24, MC_PC_U127580972, MC_PC_15075] Funding Source: researchfish
CR Ablasser A, 2016, J MOL MED, V94, P1085, DOI 10.1007/s00109-016-1423-2
   Ablasser A, 2013, NATURE, V498, P380, DOI 10.1038/nature12306
   Aguilera A, 2008, NAT REV GENET, V9, P204, DOI 10.1038/nrg2268
   Ahn J, 2014, NAT COMMUN, V5, P0, DOI 10.1038/ncomms6166
   Baker SC, 2005, NAT METHODS, V2, P731, DOI 10.1038/nmeth1005-731
   Bakhoum SF, 2012, J CLIN INVEST, V122, P1138, DOI 10.1172/JCI59954
   Balmus G, 2015, NAT PROTOC, V10, P205, DOI 10.1038/nprot.2015.010
   Barber GN, 2015, NAT REV IMMUNOL, V15, P760, DOI 10.1038/nri3921
   Bridgeman A, 2015, SCIENCE, V349, P1228, DOI 10.1126/science.aab3632
   Chen Q, 2016, NAT IMMUNOL, V17, P1142, DOI 10.1038/ni.3558
   Ciccia A, 2010, MOL CELL, V40, P179, DOI 10.1016/j.molcel.2010.09.019
   Crasta K, 2012, NATURE, V482, P53, DOI 10.1038/nature10802
   Denais CM, 2016, SCIENCE, V352, P353, DOI 10.1126/science.aad7297
   Dobin A, 2013, BIOINFORMATICS, V29, P15, DOI 10.1093/bioinformatics/bts635
   Gao DX, 2015, P NATL ACAD SCI USA, V112, PE5699, DOI 10.1073/pnas.1516465112
   Gao P, 2013, CELL, V153, P1094, DOI 10.1016/j.cell.2013.04.046
   Gilbert N, 2004, CELL, V118, P555, DOI 10.1016/j.cell.2004.08.011
   Gilbert N, 2007, J CELL BIOL, V177, P401, DOI 10.1083/jcb.200607133
   Gisselsson D, 2001, AM J PATHOL, V158, P199, DOI 10.1016/S0002-9440(10)63958-2
   Green CM, 2002, EMBO REP, V3, P28, DOI 10.1093/embo-reports/kvf005
   Härtlova A, 2015, IMMUNITY, V42, P332, DOI 10.1016/j.immuni.2015.01.012
   Hatch E, 2014, J CELL BIOL, V205, P133, DOI 10.1083/jcb.201402003
   Hatch EM, 2013, CELL, V154, P47, DOI 10.1016/j.cell.2013.06.007
   Huynh VAT, 2005, J MOL BIOL, V345, P957, DOI 10.1016/j.jmb.2004.10.075
   JACKS T, 1994, CURR BIOL, V4, P1, DOI 10.1016/S0960-9822(00)00002-6
   Kharchenko PV, 2014, NAT METHODS, V11, P740, DOI 10.1038/NMETH.2967
   Kirschner K, 2017, CELL REP, V19, P1503, DOI 10.1016/j.celrep.2017.04.074
   Lan YY, 2014, CELL REP, V9, P180, DOI 10.1016/j.celrep.2014.08.074
   Lau L, 2015, SCIENCE, V350, P568, DOI 10.1126/science.aab3291
   Li X, 2013, IMMUNITY, V39, P1019, DOI 10.1016/j.immuni.2013.10.019
   Liao Y, 2013, NUCLEIC ACIDS RES, V41, P0, DOI 10.1093/nar/gkt214
   Maciejowski J, 2015, CELL, V163, P1641, DOI 10.1016/j.cell.2015.11.054
   Mackenzie KJ, 2016, EMBO J, V35, P831, DOI 10.15252/embj.201593339
   McCarthy DJ, 2017, BIOINFORMATICS, V33, P1179, DOI 10.1093/bioinformatics/btw777
   Micutkova L, 2012, INT J CANCER, V130, P1544, DOI 10.1002/ijc.26149
   Naughton C, 2010, MOL CELL, V40, P397, DOI 10.1016/j.molcel.2010.10.013
   Ohkuri T, 2014, CANCER IMMUNOL RES, V2, P1199, DOI 10.1158/2326-6066.CIR-14-0099
   Paludan SR, 2015, MICROBIOL MOL BIOL R, V79, P225, DOI 10.1128/MMBR.00061-14
   Pavlidis P, 2003, BIOINFORMATICS, V19, P295, DOI 10.1093/bioinformatics/19.2.295
   Picelli S, 2014, NAT PROTOC, V9, P171, DOI 10.1038/nprot.2014.006
   Pokatayev V, 2016, J EXP MED, V213, P329, DOI 10.1084/jem.20151464
   Raab M, 2016, SCIENCE, V352, P359, DOI 10.1126/science.aad7611
   Reijns MAM, 2012, CELL, V149, P0, DOI 10.1016/j.cell.2012.04.011
   Roers A, 2016, IMMUNITY, V44, P739, DOI 10.1016/j.immuni.2016.04.002
   Rogge RA, 2013, JOVE-J VIS EXP, V79, P50354
   Saleiro D, 2015, CELL REP, V11, P605, DOI 10.1016/j.celrep.2015.03.056
   Schoggins JW, 2014, NATURE, V505, P691, DOI 10.1038/nature12862
   Shen YJ, 2015, CELL REP, V11, P460, DOI 10.1016/j.celrep.2015.03.041
   Staresincic L, 2009, EMBO J, V28, P1111, DOI 10.1038/emboj.2009.49
   Sun LJ, 2013, SCIENCE, V339, P786, DOI 10.1126/science.1232458
   Swift S, 2001, CURR PROTOC IMMUNOL, VChapter 10, P0, DOI 10.1002/0471142735.im1017cs31
   Woo SR, 2014, IMMUNITY, V41, P830, DOI 10.1016/j.immuni.2014.10.017
   Xia TL, 2016, CELL REP, V14, P282, DOI 10.1016/j.celrep.2015.12.029
   Zhang CZ, 2015, NATURE, V522, P179, DOI 10.1038/nature14493
   Zhang X, 2014, CELL REP, V6, P421, DOI 10.1016/j.celrep.2014.01.003
NR 55
TC 1346
Z9 1544
U1 7
U2 242
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 24
PY 2017
VL 548
IS 7668
BP 461
EP +
DI 10.1038/nature23449
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FE5VI
UT WOS:000408279000040
PM 28738408
DA 2026-03-09
ER

PT J
AU Mauk, BH
   Haggerty, DK
   Aranicas, CP
   Clark, G
   Kollmann, P
   Rymer, AM
   Bolton, SJ
   Levin, SM
   Adriani, A
   Allegrini, F
   Bagenal, F
   Bonfond, B
   Connerney, JEP
   Gladstone, GR
   Kurth, WS
   McComas, DJ
   Valek, P
AF Mauk, B. H.
   Haggerty, D. K.
   Aranicas, C. P.
   Clark, G.
   Kollmann, P.
   Rymer, A. M.
   Bolton, S. J.
   Levin, S. M.
   Adriani, A.
   Allegrini, F.
   Bagenal, F.
   Bonfond, B.
   Connerney, J. E. P.
   Gladstone, G. R.
   Kurth, W. S.
   McComas, D. J.
   Valek, P.
TI Discrete and broadband electron acceleration in Jupiter's powerful aurora
SO NATURE
LA English
DT Article
ID magnetosphere; oval
AB The most intense auroral emissions from Earth's polar regions, called discrete for their sharply defined spatial configurations, are generated by a process involving coherent acceleration of electrons by slowly evolving, powerful electric fields directed along the magnetic field lines that connect Earth's space environment to its polar regions(1,2). In contrast, Earth's less intense auroras are generally caused by wave scattering of magnetically trapped populations of hot electrons (in the case of diffuse aurora) or by the turbulent or stochastic downward acceleration of electrons along magnetic field lines by waves during transitory periods (in the case of broadband or Alfvenic aurora)(3,4). Jupiter's relatively steady main aurora has a power density that is so much larger than Earth's that it has been taken for granted that it must be generated primarily by the discrete auroral process(5-7). However, preliminary in situ measurements of Jupiter's auroral regions yielded no evidence of such a process(8-10). Here we report observations of distinct, high-energy, downward, discrete electron acceleration in Jupiter's auroral polar regions. We also infer upward magnetic-field-aligned electric potentials of up to 400 kiloelectronvolts, an order of magnitude larger than the largest potentials observed at Earth(11). Despite the magnitude of these upward electric potentials and the expectations from observations at Earth, the downward energy flux from discrete acceleration is less at Jupiter than that caused by broadband or stochastic processes, with broadband and stochastic characteristics that are substantially different from those at Earth.
C1 [Mauk, B. H.; Haggerty, D. K.; Aranicas, C. P.; Clark, G.; Kollmann, P.; Rymer, A. M.] Johns Hopkins Univ, Appl Phys Lab, Laurel, MD 21218 USA.
   [Bolton, S. J.; Allegrini, F.; Gladstone, G. R.; McComas, D. J.; Valek, P.] Southwest Res Inst, San Antonio, TX USA.
   [Levin, S. M.] Jet Prop Lab, Pasadena, CA USA.
   [Adriani, A.] Inst Astofis & Planetol Spaziali, Inst Nazl Astrofis, Rome, Italy.
   [Allegrini, F.] Univ Texas San Antonio, Dept Phys & Astron, San Antonio, TX USA.
   [Bagenal, F.] Univ Colorado, Boulder, CO 80309 USA.
   [Bonfond, B.] Univ Liege, Technol & Astrophys Res Inst, Lab Phys Atmospher & Planetaire, Liege, Belgium.
   [Connerney, J. E. P.] NASA, Goddard Space Flight Ctr, Greenbelt, MD USA.
   [Kurth, W. S.] Univ Iowa, Iowa City, IA USA.
   [McComas, D. J.] Princeton Univ, Princeton, NJ 08544 USA.
C3 Johns Hopkins University; Johns Hopkins University Applied Physics Laboratory; Southwest Research Institute; National Aeronautics & Space Administration (NASA); NASA Jet Propulsion Laboratory (JPL); Istituto Nazionale Astrofisica (INAF); University of Texas System; University of Texas at San Antonio; University of Colorado System; University of Colorado Boulder; University of Liege; National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center; University of Iowa; Princeton University
RP Mauk, BH (corresponding author), Johns Hopkins Univ, Appl Phys Lab, Laurel, MD 21218 USA.
EM Barry.Mauk@jhuapl.edu
FU NASA's New Frontiers Program; Southwest Research Institute
NR 24
TC 95
Z9 109
U1 0
U2 22
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 7
PY 2017
VL 549
IS 7670
BP 66
EP +
DI 10.1038/nature23648
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG0DH
UT WOS:000409388700033
PM 28880294
DA 2026-03-09
ER

PT J
AU Bassat, E
   Mutlak, YE
   Genzelinakh, A
   Shadrin, IY
   Umansky, KB
   Yifa, O
   Kain, D
   Rajchman, D
   Leach, J
   Bassat, DR
   Udi, Y
   Sarig, R
   Sagi, I
   Martin, JF
   Bursac, N
   Cohen, S
   Tzahor, E
AF Bassat, Elad
   Mutlak, Yara Eid
   Genzelinakh, Alex
   Shadrin, Ilya Y.
   Umansky, Kfir Baruch
   Yifa, Oren
   Kain, David
   Rajchman, Dana
   Leach, John
   Bassat, Daria Riabov
   Udi, Yael
   Sarig, Rachel
   Sagi, Irit
   Martin, James F.
   Bursac, Nenad
   Cohen, Shenhav
   Tzahor, Eldad
TI The extracellular matrix protein agrin promotes heart regeneration in mice
SO NATURE
LA English
DT Article
ID receptor; cardiomyocytes; identification; proliferation; dystroglycan; maturation; binding
AB The adult mammalian heart is non-regenerative owing to the post-mitotic nature of cardiomyocytes. The neonatal mouse heart can regenerate, but only during the first week of life. Here we show that changes in the composition of the extracellular matrix during this week can affect cardiomyocyte growth and differentiation in mice. We identify agrin, a component of neonatal extracellular matrix, as required for the full regenerative capacity of neonatal mouse hearts. In vitro, recombinant agrin promotes the division of cardiomyocytes that are derived from mouse and human induced pluripotent stem cells through a mechanism that involves the disassembly of the dystrophin-glycoprotein complex, and Yap-and ERK-mediated signalling. In vivo, a single administration of agrin promotes cardiac regeneration in adult mice after myocardial infarction, although the degree of cardiomyocyte proliferation observed in this model suggests that there are additional therapeutic mechanisms. Together, our results uncover a new inducer of mammalian heart regeneration and highlight fundamental roles of the extracellular matrix in cardiac repair.
C1 [Bassat, Elad; Genzelinakh, Alex; Umansky, Kfir Baruch; Yifa, Oren; Kain, David; Rajchman, Dana; Sarig, Rachel; Tzahor, Eldad] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel.
   [Mutlak, Yara Eid; Cohen, Shenhav] Technion, Fac Biol, IL-32000 Haifa, Israel.
   [Shadrin, Ilya Y.; Bursac, Nenad] Duke Univ, Dept Biomed Engn, Durham, NC 27708 USA.
   [Leach, John; Martin, James F.] Baylor Coll Med, Houston, TX 77030 USA.
   [Leach, John; Martin, James F.] Texas Heart Inst, Houston, TX 77030 USA.
   [Bassat, Daria Riabov; Udi, Yael; Sagi, Irit] Weizmann Inst Sci, Dept Regulat Biol, IL-76100 Rehovot, Israel.
C3 Weizmann Institute of Science; Technion Israel Institute of Technology; Duke University; Baylor College of Medicine; Texas Heart Institute; Weizmann Institute of Science
RP Tzahor, E (corresponding author), Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel.
EM eldad.tzahor@weizmann.ac.il
FU European Research Council; Israel Science Foundation; Britain Israel Research and Academic Exchange (BIRAX); Foundation LeDucq; NIH; National Heart Lung and Blood Institute [U01HL134764] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007171] Funding Source: NIH RePORTER
NR 30
TC 532
Z9 636
U1 2
U2 181
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 13
PY 2017
VL 547
IS 7662
BP 179
EP +
DI 10.1038/nature22978
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FA3AX
UT WOS:000405314500031
PM 28581497
DA 2026-03-09
ER

PT J
AU Haber, AL
   Biton, M
   Rogel, N
   Herbst, RH
   Shekhar, K
   Smillie, C
   Burgin, G
   Delorey, TM
   Howitt, MR
   Katz, Y
   Tirosh, I
   Beyaz, S
   Dionne, D
   Zhang, M
   Raychowdhury, R
   Garrett, WS
   Rozenblatt-Rosen, O
   Shi, HN
   Yilmaz, O
   Xavier, RJ
   Regev, A
AF Haber, Adam L.
   Biton, Moshe
   Rogel, Noga
   Herbst, Rebecca H.
   Shekhar, Karthik
   Smillie, Christopher
   Burgin, Grace
   Delorey, Toni M.
   Howitt, Michael R.
   Katz, Yarden
   Tirosh, Itay
   Beyaz, Semir
   Dionne, Danielle
   Zhang, Mei
   Raychowdhury, Raktima
   Garrett, Wendy S.
   Rozenblatt-Rosen, Orit
   Shi, Hai Ning
   Yilmaz, Omer
   Xavier, Ramnik J.
   Regev, Aviv
TI A single-cell survey of the small intestinal epithelium
SO NATURE
LA English
DT Article
ID enterica serovar typhimurium; patch m-cells; rna-seq; stem-cells; tuft cells; inflammatory responses; mucosal immunity; peptide yy; differentiation; identification
AB Intestinal epithelial cells absorb nutrients, respond to microbes, function as a barrier and help to coordinate immune responses. Here we report profiling of 53,193 individual epithelial cells from the small intestine and organoids of mice, which enabled the identification and characterization of previously unknown subtypes of intestinal epithelial cell and their gene signatures. We found unexpected diversity in hormone-secreting enteroendocrine cells and constructed the taxonomy of newly identified subtypes, and distinguished between two subtypes of tuft cell, one of which expresses the epithelial cytokine Tslp and the pan-immune marker CD45, which was not previously associated with non-haematopoietic cells. We also characterized the ways in which cell-intrinsic states and the proportions of different cell types respond to bacterial and helminth infections: Salmonella infection caused an increase in the abundance of Paneth cells and enterocytes, and broad activation of an antimicrobial program; Heligmosomoides polygyrus caused an increase in the abundance of goblet and tuft cells. Our survey highlights previously unidentified markers and programs, associates sensory molecules with cell types, and uncovers principles of gut homeostasis and response to pathogens.
C1 [Haber, Adam L.; Biton, Moshe; Rogel, Noga; Herbst, Rebecca H.; Shekhar, Karthik; Smillie, Christopher; Burgin, Grace; Delorey, Toni M.; Tirosh, Itay; Dionne, Danielle; Raychowdhury, Raktima; Garrett, Wendy S.; Rozenblatt-Rosen, Orit; Yilmaz, Omer; Xavier, Ramnik J.; Regev, Aviv] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA.
   [Biton, Moshe; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA.
   [Herbst, Rebecca H.; Katz, Yarden] Harvard Med Sch, Dept Syst Biol, Boston, MA 02114 USA.
   [Delorey, Toni M.] Worcester Polytech Inst, Dept Biol & Biotechnol, Worcester, MA 01609 USA.
   [Howitt, Michael R.; Garrett, Wendy S.] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA.
   [Howitt, Michael R.; Garrett, Wendy S.] Harvard TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA.
   [Beyaz, Semir; Yilmaz, Omer] MIT, Dept Biol, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA.
   [Beyaz, Semir] Harvard Med Sch, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA.
   [Beyaz, Semir] Harvard Med Sch, Harvard Stem Cell Inst, Howard Hughes Med Inst, Dana Farber Canc Inst,Dept Pediat Oncol, Boston, MA 02115 USA.
   [Zhang, Mei; Shi, Hai Ning] Massachusetts Gen Hosp, Mucosal Immunol & Biol Res Ctr, Charlestown, MA 02129 USA.
   [Zhang, Mei; Shi, Hai Ning] Harvard Med Sch, Charlestown, MA 02129 USA.
   [Yilmaz, Omer] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.
   [Yilmaz, Omer] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA.
   [Yilmaz, Omer] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA.
   [Yilmaz, Omer] Harvard Med Sch, Boston, MA 02114 USA.
   [Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA.
   [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA.
   [Regev, Aviv] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02140 USA.
C3 Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Worcester Polytechnic Institute; Harvard University; Harvard T.H. Chan School of Public Health; Harvard University; Harvard T.H. Chan School of Public Health; Massachusetts Institute of Technology (MIT); Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Howard Hughes Medical Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Massachusetts Institute of Technology (MIT); Howard Hughes Medical Institute
RP Biton, M; Xavier, RJ; Regev, A (corresponding author), Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA.; Biton, M; Xavier, RJ (corresponding author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA.; Xavier, RJ (corresponding author), Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA.; Xavier, RJ (corresponding author), Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA.; Regev, A (corresponding author), MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02140 USA.
EM mbiton@broadinstitute.org; xavier@molbio.mgh.harvard.edu; aregev@broadinstitute.org
FU Klarman Cell Observatory at the Broad Institute, NIH [RC2DK114784]; HHMI; Food Allergy Science Initiative (FASI) at the Broad Institute; Broadnext10 award; Human Frontiers Science Program (HFSP); NIH [DK43351, DK097485]; Helmsley Charitable Trust; National Cancer Institute [R01CA211184, R01CA154426] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [K01DK113041, P30DK034854, R01DK097485, P30DK043351, RC2DK114784] Funding Source: NIH RePORTER
NR 67
TC 1250
Z9 1494
U1 17
U2 371
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 16
PY 2017
VL 551
IS 7680
BP 333
EP +
DI 10.1038/nature24489
PG 25
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM8UK
UT WOS:000415365500033
PM 29144463
DA 2026-03-09
ER

PT J
AU Ndeh, D
   Rogowski, A
   Cartmell, A
   Luis, AS
   Baslé, A
   Gray, J
   Venditto, I
   Briggs, J
   Zhang, XY
   Labourel, A
   Terrapon, N
   Buffetto, F
   Nepogodiev, S
   Xiao, Y
   Field, RA
   Zhu, YP
   O'Neill, MA
   Urbanowicz, BR
   York, WS
   Davies, GJ
   Abbott, DW
   Ralet, MC
   Martens, EC
   Henrissat, B
   Gilbert, HJ
AF Ndeh, Didier
   Rogowski, Artur
   Cartmell, Alan
   Luis, Ana S.
   Basle, Arnaud
   Gray, Joseph
   Venditto, Immacolata
   Briggs, Jonathon
   Zhang, Xiaoyang
   Labourel, Aurore
   Terrapon, Nicolas
   Buffetto, Fanny
   Nepogodiev, Sergey
   Xiao, Yao
   Field, Robert A.
   Zhu, Yanping
   O'Neill, Malcolm A.
   Urbanowicz, Breeanna R.
   York, William S.
   Davies, Gideon J.
   Abbott, D. Wade
   Ralet, Marie-Christine
   Martens, Eric C.
   Henrissat, Bernard
   Gilbert, Harry J.
TI Complex pectin metabolism by gut bacteria reveals novel catalytic functions
SO NATURE
LA English
DT Article
ID rhamnogalacturonan-ii; macromolecular crystallography; structural basis; side-chains; polysaccharide; mechanism; monosaccharide; identification; microbiota; fragments
AB The metabolism of carbohydrate polymers drives microbial diversity in the human gut microbiota. It is unclear, however, whether bacterial consortia or single organisms are required to depolymerize highly complex glycans. Here we show that the gut bacterium Bacteroides thetaiotaomicron uses the most structurally complex glycan known: the plant pectic polysaccharide rhamnogalacturonan-II, cleaving all but 1 of its 21 distinct glycosidic linkages. The deconstruction of rhamnogalacturonan-II side chains and backbone are coordinated to overcome steric constraints, and the degradation involves previously undiscovered enzyme families and catalytic activities. The degradation system informs revision of the current structural model of rhamnogalacturonan-II and highlights how individual gut bacteria orchestrate manifold enzymes to metabolize the most challenging glycan in the human diet.
C1 [Ndeh, Didier; Rogowski, Artur; Cartmell, Alan; Luis, Ana S.; Basle, Arnaud; Gray, Joseph; Venditto, Immacolata; Briggs, Jonathon; Zhang, Xiaoyang; Labourel, Aurore; Gilbert, Harry J.] Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
   [Terrapon, Nicolas; Henrissat, Bernard] Aix Marseille Univ, CNRS, Architecture & Fonct Macromol Biol, F-13288 Marseille, France.
   [Buffetto, Fanny; Ralet, Marie-Christine] INRA, UR Biopolymeres Interact Assemblages 1268, F-44300 Nantes, France.
   [Nepogodiev, Sergey; Field, Robert A.] John Innes Ctr, Dept Biol Chem, Norwich Res Pk, Norwich NR4 7UH, Norfolk, England.
   [Xiao, Yao; Martens, Eric C.] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA.
   [Zhu, Yanping; O'Neill, Malcolm A.; Urbanowicz, Breeanna R.; York, William S.] Univ Georgia, Complex Carbohydrate Res Ctr, 315 Riverbend Rd, Athens, GA 30602 USA.
   [Davies, Gideon J.] Univ York, Dept Chem, York YO10 5DD, N Yorkshire, England.
   [Abbott, D. Wade] Lethbridge Res Ctr, Lethbridge, AB T1J 4B1, Canada.
   [Henrissat, Bernard] INRA, USC AFMB 1408, F-13288 Marseille, France.
   [Henrissat, Bernard] King Abdulaziz Univ, Dept Biol Sci, Jeddah, Saudi Arabia.
   [Rogowski, Artur] Megazyme Bray Co, Wicklow A98 YV29, Ireland.
   [Buffetto, Fanny] Univ Stellenbosch, Dept Viticulture & Oenol, Inst Wine Biotechnol, ZA-7602 Matieland, South Africa.
C3 Newcastle University - UK; Aix-Marseille Universite; Centre National de la Recherche Scientifique (CNRS); INRAE; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); John Innes Centre; University of Michigan System; University of Michigan; University System of Georgia; University of Georgia; University of York - UK; INRAE; King Abdulaziz University; Stellenbosch University
RP Gilbert, HJ (corresponding author), Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
EM harry.gilbert@ncl.ac.uk
FU European Research Council [322820]; Agence Nationale de la Recherche [ANR 12-BIME-0006-01]; Biotechnology and Biological Research Council [BB/K020358/1, BB/K001949/1]; Wellcome Trust [WT097907MA]; European Union Seventh Framework Programme under the WallTraC project [263916]; Division of Chemical Sciences, Geosciences, and Biosciences, Office of Basic Energy Sciences of the US Department of Energy [DE-FG02-12ER16324]; Marie Sklodowska-Curie Fellowship [707922]; Beef and Cattle Research Council [FDE.15.13]; BBSRC [BBS/E/J/000PR9790, BBS/E/J/000C0618] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BBS/E/J/000C0618, BB/K001949/1, BBS/E/J/000PR9790, BB/K020358/1] Funding Source: researchfish; Marie Curie Actions (MSCA) [707922] Funding Source: Marie Curie Actions (MSCA); Agence Nationale de la Recherche (ANR) [ANR-12-BIME-0006] Funding Source: Agence Nationale de la Recherche (ANR)
NR 47
TC 497
Z9 569
U1 16
U2 622
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 6
PY 2017
VL 544
IS 7648
BP 65
EP +
DI 10.1038/nature21725
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EQ8GQ
UT WOS:000398323300033
PM 28329766
DA 2026-03-09
ER

PT J
AU Tashiro, T
   Ishida, A
   Hori, M
   Igisu, M
   Koike, M
   Méjean, P
   Takahata, N
   Sano, Y
   Komiya, T
AF Tashiro, Takayuki
   Ishida, Akizumi
   Hori, Masako
   Igisu, Motoko
   Koike, Mizuho
   Mejean, Pauline
   Takahata, Naoto
   Sano, Yuji
   Komiya, Tsuyoshi
TI Early trace of life from 3.95 Ga sedimentary rocks in Labrador, Canada
SO NATURE
LA English
DT Article
ID northern labrador; supracrustal rocks; gneiss complex; saglek block; carbon; graphite; isua; origin; geochemistry; greenland
AB The vestiges of life in Eoarchean rocks have the potential to elucidate the origin of life. However, gathering evidence from many terrains is not always possible(1-3), and biogenic graphite has thus far been found only in the 3.7-3.8 Ga (gigayears ago) Isua supracrustal belt(4-7). Here we present the total organic carbon contents and carbon isotope values of graphite (d13Corg) and carbonate (delta(13)Ccarb) in the oldest metasedimentary rocks from northern Labrador(8,9). Some pelitic rocks have low delta(13)Corg values of -28.2, comparable to the lowest value in younger rocks. The consistency between crystallization temperatures of the graphite and metamorphic temperature of the host rocks establishes that the graphite does not originate from later contamination. A clear correlation between the delta(13)Corg values and metamorphic grade indicates that variations in the delta(13)Corg values are due to metamorphism, and that the pre-metamorphic value was lower than the minimum value. We concluded that the large fractionation between the delta(13)Ccarb and delta(13)Corg values, up to 25%, indicates the oldest evidence of organisms greater than 3.95 Ga. The discovery of the biogenic graphite enables geochemical study of the biogenic materials themselves, and will provide insight into early life not only on Earth but also on other planets.
C1 [Tashiro, Takayuki; Komiya, Tsuyoshi] Univ Tokyo, Grad Sch Arts & Sci, Dept Earth Sci & Astron, Tokyo 1538902, Japan.
   [Ishida, Akizumi; Hori, Masako; Koike, Mizuho; Mejean, Pauline; Takahata, Naoto; Sano, Yuji] Univ Tokyo, Atmosphere & Ocean Res Inst, Chiba 2778564, Japan.
   [Ishida, Akizumi] Tohoku Univ, Inst Excellence Higher Educ, Sendai, Miyagi 9808576, Japan.
   [Hori, Masako] Osaka Kyoiku Univ, Dept Arts & Sci, Osaka 5828582, Japan.
   [Igisu, Motoko] Japan Agcy Marine Earth Sci & Technol JAMSTEC, Lab Ocean Earth Life Evolut Res, Yokosuka, Kanagawa 2370061, Japan.
C3 University of Tokyo; University of Tokyo; Tohoku University; Osaka University of Education; Japan Agency for Marine-Earth Science & Technology (JAMSTEC)
RP Komiya, T (corresponding author), Univ Tokyo, Grad Sch Arts & Sci, Dept Earth Sci & Astron, Tokyo 1538902, Japan.; Sano, Y (corresponding author), Univ Tokyo, Atmosphere & Ocean Res Inst, Chiba 2778564, Japan.
EM ysano@aori.u-tokyo.ac.jp; komiya@ea.c.u-tokyo.ac.jp
FU Ministry of Education, Culture, Sports, Science and Technology, Japan [23253007, 26220713, 24221002]; Mitsubishi Foundation; Grants-in-Aid for Scientific Research [26220713, 23253007, 16J07403, 15J40157, 26106005] Funding Source: KAKEN
NR 31
TC 155
Z9 180
U1 1
U2 99
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 28
PY 2017
VL 549
IS 7673
BP 516
EP +
DI 10.1038/nature24019
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI4GT
UT WOS:000411930000049
PM 28959955
DA 2026-03-09
ER

PT J
AU Kiziltan, B
   Baumgardt, H
   Loeb, A
AF Kiziltan, Bulent
   Baumgardt, Holger
   Loeb, Abraham
TI An intermediate-mass black hole in the centre of the globular cluster 47 Tucanae
SO NATURE
LA English
DT Article
ID millisecond pulsars; compact binary; winds driven; evolution; systems; stars; core; gas
AB Intermediate-mass black holes should help us to understand the evolutionary connection between stellar-mass and super-massive black holes(1). However, the existence of intermediate-mass black holes is still uncertain, and their formation process is therefore unknown(2). It has long been suspected that black holes with masses 100 to 10,000 times that of the Sun should form and reside in dense stellar systems(3-6). Therefore, dedicated observational campaigns have targeted globular clusters for many decades, searching for signatures of these elusive objects. All candidate signatures appear radio-dim and do not have the X-ray to radio flux ratios required for accreting black holes(7). Based on the lack of an electromagnetic counterpart, upper limits of 2,060 and 470 solar masses have been placed on the mass of a putative black hole in 47 Tucanae (NGC 104) from radio and X-ray observations, respectively(8,9). Here we show there is evidence for a central black hole in 47 Tucanae with a mass of 2, 200(-800)(+1,500) solar masses when the dynamical state of the globular cluster is probed with pulsars. The existence of an intermediate-mass black hole in the centre of one of the densest clusters with no detectable electromagnetic counterpart suggests that the black hole is not accreting at a sufficient rate to make it electromagnetically bright and therefore, contrary to expectations, is gas-starved. This intermediate-mass black hole might be a member of an electromagnetically invisible population of black holes that grow into supermassive black holes in galaxies.
C1 [Kiziltan, Bulent; Loeb, Abraham] Harvard Smithsonian Ctr Astrophys, 60 Garden St, Cambridge, MA 02138 USA.
   [Baumgardt, Holger] Univ Queensland, Sch Math & Phys, St Lucia, Qld 4068, Australia.
C3 Smithsonian Institution; Harvard University; Smithsonian Astrophysical Observatory; University of Queensland
RP Kiziltan, B (corresponding author), Harvard Smithsonian Ctr Astrophys, 60 Garden St, Cambridge, MA 02138 USA.
EM bkiziltan@cfa.harvard.edu
FU Black Hole Initiative at Harvard University through John Templeton Foundation
NR 30
TC 146
Z9 166
U1 0
U2 15
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 9
PY 2017
VL 542
IS 7640
BP 203
EP 205
DI 10.1038/nature21361
PG 3
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK2DJ
UT WOS:000393737500034
PM 28179649
DA 2026-03-09
ER

PT J
AU Shaffer, SM
   Dunagin, MC
   Torborg, SR
   Torre, EA
   Emert, B
   Krepler, C
   Beqiri, M
   Sproesser, K
   Brafford, PA
   Xiao, M
   Ggan, EE
   Anastopoulos, IN
   Vargas-Garcia, CA
   Singh, A
   Nathanson, KL
   Herlyn, M
   Raj, A
AF Shaffer, Sydney M.
   Dunagin, Margaret C.
   Torborg, Stefan R.
   Torre, Eduardo A.
   Emert, Benjamin
   Krepler, Clemens
   Beqiri, Marilda
   Sproesser, Katrin
   Brafford, Patricia A.
   Xiao, Min
   Ggan, Elliott E.
   Anastopoulos, Ioannis N.
   Vargas-Garcia, Cesar A.
   Singh, Abhyudai
   Nathanson, Katherine L.
   Herlyn, Meenhard
   Raj, Arjun
TI Rare cell variability and drug- induced reprogramming as a mode of cancer drug resistance
SO NATURE
LA English
DT Article
ID melanoma reveals; vemurafenib; inhibition; mechanisms; plasticity; mutations; chromatin; state
AB Therapies that target signalling molecules that are mutated in cancers can often have substantial short-term effects, but the emergence of resistant cancer cells is a major barrier to full cures(1,2). Resistance can result from secondary mutations(3,4), but in other cases there is no clear genetic cause, raising the possibility of non-genetic rare cell variability(5-11). Here we show that human melanoma cells can display profound transcriptional variability at the single-cell level that predicts which cells will ultimately resist drug treatment. This variability involves infrequent, semi-coordinated transcription of a number of resistance markers at high levels in a very small percentage of cells. The addition of drug then induces epigenetic reprogramming in these cells, converting the transient transcriptional state to a stably resistant state. This reprogramming begins with a loss of SOX10-mediated differentiation followed by activation of new signalling pathways, partially mediated by the activity of the transcription factors JUN and/ or AP-1 and TEAD. Our work reveals the multistage nature of the acquisition of drug resistance and provides a framework for understanding resistance dynamics in single cells. We find that other cell types also exhibit sporadic expression of many of these same marker genes, suggesting the existence of a general program in which expression is displayed in rare subpopulations of cells.
C1 [Shaffer, Sydney M.; Dunagin, Margaret C.; Torborg, Stefan R.; Torre, Eduardo A.; Raj, Arjun] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA.
   [Shaffer, Sydney M.; Torre, Eduardo A.; Emert, Benjamin; Ggan, Elliott E.; Anastopoulos, Ioannis N.; Nathanson, Katherine L.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA.
   [Torborg, Stefan R.] Univ Penn, Dept Biochem, Philadelphia, PA 19104 USA.
   [Emert, Benjamin] Univ Penn, Genom & Computat Biol Grp, Philadelphia, PA 19104 USA.
   [Krepler, Clemens; Beqiri, Marilda; Sproesser, Katrin; Brafford, Patricia A.; Xiao, Min] Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, Melanoma Res Ctr, Philadelphia, PA 19104 USA.
   [Vargas-Garcia, Cesar A.; Singh, Abhyudai] Univ Delaware, Elect & Comp Engn, Newark, DE 19716 USA.
   [Singh, Abhyudai] Univ Delaware, Biomed Engn, Newark, DE 19716 USA.
   [Raj, Arjun] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA.
C3 University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; The Wistar Institute; University of Delaware; University of Delaware; University of Pennsylvania
RP Raj, A (corresponding author), Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA.; Raj, A (corresponding author), Univ Penn, Dept Genet, Philadelphia, PA 19104 USA.
EM arjunraj@seas.upenn.edu
FU NIH [DP2 OD008514, R33 EB019767, P30 CA016520, F30 AI114475]; NIH/NCI PSOC [U54 CA193417]; NSF CAREER [1350601]; National Science Foundation [DMS-1312926]; SPORE [P50 CA174523]; Melanoma Research Foundation; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation;  [P01 CA114046];  [R01 CA047159]; National Cancer Institute [P01CA114046, P30CA010815, P30CA016520] Funding Source: NIH RePORTER; National Human Genome Research Institute [T32HG000046] Funding Source: NIH RePORTER; Division Of Mathematical Sciences; Direct For Mathematical & Physical Scien [1312926] Funding Source: National Science Foundation; Div Of Molecular and Cellular Bioscience; Direct For Biological Sciences [1350601] Funding Source: National Science Foundation
NR 35
TC 847
Z9 1043
U1 0
U2 146
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 15
PY 2017
VL 546
IS 7658
BP 431
EP +
DI 10.1038/nature22794
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EX5BK
UT WOS:000403250900040
PM 28607484
DA 2026-03-09
ER

PT J
AU Kobayashi, T
   Zhang, HX
   Tang, WWC
   Irie, N
   Withey, S
   Klisch, D
   Sybirna, A
   Dietmann, S
   Contreras, DA
   Webb, R
   Allegrucci, C
   Alberio, R
   Surani, MA
AF Kobayashi, Toshihiro
   Zhang, Haixin
   Tang, Walfred W. C.
   Irie, Naoko
   Withey, Sarah
   Klisch, Doris
   Sybirna, Anastasiya
   Dietmann, Sabine
   Contreras, David A.
   Webb, Robert
   Allegrucci, Cinzia
   Alberio, Ramiro
   Surani, M. Azim
TI Principles of early human development and germ cell program from conserved model systems
SO NATURE
LA English
DT Article
ID pluripotent stem-cells; in-vitro; definitive endoderm; fate; mouse; differentiation; mice; specification; induction; dynamics
AB Human primordial germ cells (hPGCs), the precursors of sperm and eggs, originate during weeks 2-3 of early post-implantation development(1). Using in vitro models of hPGC induction(2-4), recent studies have suggested that there are marked mechanistic differences in the specification of human and mouse PGCs(5). This may be due in part to the divergence in their pluripotency networks and early post-implantation development(6-8). As early human embryos are not accessible for direct study, we considered alternatives including porcine embryos that, as in humans, develop as bilaminar embryonic discs. Here we show that porcine PGCs originate from the posterior pre-primitive-streak competent epiblast by sequential upregulation of SOX17 and BLIMP1 in response to WNT and BMP signalling. We use this model together with human and monkey in vitro models simulating peri-gastrulation development to show the conserved principles of epiblast development for competency for primordial germ cell fate. This process is followed by initiation of the epigenetic program(9-11) and regulated by a balanced SOX17-BLIMP1 gene dosage. Our combinatorial approach using human, porcine and monkey in vivo and in vitro models provides synthetic insights into early human development.
C1 [Kobayashi, Toshihiro; Tang, Walfred W. C.; Irie, Naoko; Sybirna, Anastasiya; Dietmann, Sabine; Surani, M. Azim] Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Tennis Court Rd, Cambridge CB2 1QN, England.
   [Kobayashi, Toshihiro; Tang, Walfred W. C.; Irie, Naoko; Sybirna, Anastasiya; Surani, M. Azim] Univ Cambridge, Dept Physiol Dev & Neurosci, Downing St, Cambridge CB2 3DY, England.
   [Zhang, Haixin; Withey, Sarah; Klisch, Doris; Contreras, David A.; Webb, Robert; Alberio, Ramiro] Univ Nottingham, Sch Biosci, Loughborough LE12 5RD, Leics, England.
   [Sybirna, Anastasiya; Dietmann, Sabine] Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Tennis Court Rd, Cambridge CB2 1QR, England.
   [Allegrucci, Cinzia] Univ Nottingham, Sch Vet Med & Sci, Loughborough LE12 5RD, Leics, England.
   [Contreras, David A.] CEIEPAA FMVZ UNAM, Tequisquiapan 76790, Queretaro, Mexico.
C3 University of Cambridge; University of Cambridge; University of Nottingham; University of Cambridge; University of Nottingham
RP Surani, MA (corresponding author), Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Tennis Court Rd, Cambridge CB2 1QN, England.; Surani, MA (corresponding author), Univ Cambridge, Dept Physiol Dev & Neurosci, Downing St, Cambridge CB2 3DY, England.; Alberio, R (corresponding author), Univ Nottingham, Sch Biosci, Loughborough LE12 5RD, Leics, England.
EM Ramiro.Alberio@nottingham.ac.uk; a.surani@gurdon.cam.ac.uk
FU JSPS; Uehara Foundation; Kanae Foundation; CSC; CONACYT; BBSRC [BB/M001466/1]; Biotechnology and Biological Sciences Research Council [BB/M001466/1] Funding Source: researchfish; Medical Research Council [MC_PC_12009, MR/P009948/1] Funding Source: researchfish; Rosetrees [M603] Funding Source: researchfish; BBSRC [BB/M001466/1] Funding Source: UKRI; MRC [MR/P009948/1] Funding Source: UKRI
NR 39
TC 250
Z9 284
U1 0
U2 69
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 15
PY 2017
VL 546
IS 7658
BP 416
EP +
DI 10.1038/nature22812
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EX5BK
UT WOS:000403250900037
PM 28607482
DA 2026-03-09
ER

PT J
AU Takata, MA
   Gonçalves-Carneiro, D
   Zang, TM
   Soll, SJ
   York, A
   Blanco-Melo, D
   Bieniasz, PD
AF Takata, Matthew A.
   Goncalves-Carneiro, Daniel
   Zang, Trinity M.
   Soll, Steven J.
   York, Ashley
   Blanco-Melo, Daniel
   Bieniasz, Paul D.
TI CG dinucleotide suppression enables antiviral defence targeting non-self RNA
SO NATURE
LA English
DT Article
ID viral messenger-rnas; codon pair; binding-specificity; zap; virus; inhibition; replication; bias
AB Vertebrate genomes exhibit marked CG suppression-that is, lower than expected numbers of 5'-CG-3' dinucleotides(1). This feature is likely to be due to C-to-T mutations that have accumulated over hundreds of millions of years, driven by CG-specific DNA methyl transferases and spontaneous methyl-cytosine deamination. Many RNA viruses of vertebrates that are not substrates for DNA methyl transferases mimic the CG suppression of their hosts(2-4). This property of viral genomes is unexplained(4-6). Here we show, using synonymous mutagenesis, that CG suppression is essential for HIV-1 replication. The deleterious effect of CG dinucleotides on HIV-1 replication was cumulative, associated with cytoplasmic RNA depletion, and was exerted by CG dinucleotides in both translated and non-translated exonic RNA sequences. A focused screen using small inhibitory RNAs revealed that zinc-finger antiviral protein (ZAP) 7 inhibited virion production by cells infected with CG-enriched HIV-1. Crucially, HIV-1 mutants containing segments whose CG content mimicked random nucleotide sequence were defective in unmanipulated cells, but replicated normally in ZAP-deficient cells. Crosslinking-immunoprecipitation-sequencing assays demonstrated that ZAP binds directly and selectively to RNA sequences containing CG dinucleotides. These findings suggest that ZAP exploits host CG suppression to identify non-self RNA. The dinucleotide composition of HIV-1, and perhaps other RNA viruses, appears to have adapted to evade this host defence.
C1 [Takata, Matthew A.; Goncalves-Carneiro, Daniel; Zang, Trinity M.; Soll, Steven J.; York, Ashley; Blanco-Melo, Daniel; Bieniasz, Paul D.] Rockefeller Univ, Lab Retrovirol, 1230 York Ave, New York, NY 10021 USA.
   [Zang, Trinity M.; Soll, Steven J.; Bieniasz, Paul D.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA.
C3 Rockefeller University; Rockefeller University; Howard Hughes Medical Institute
RP Bieniasz, PD (corresponding author), Rockefeller Univ, Lab Retrovirol, 1230 York Ave, New York, NY 10021 USA.; Bieniasz, PD (corresponding author), Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA.
EM pbieniasz@rockefeller.edu
FU NIH [R01A150111, P50GM103297]; National Institute of Allergy and Infectious Diseases [R01AI050111] Funding Source: NIH RePORTER
NR 30
TC 326
Z9 384
U1 0
U2 48
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 5
PY 2017
VL 550
IS 7674
BP 124
EP +
DI 10.1038/nature24039
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI7XU
UT WOS:000412214100058
PM 28953888
DA 2026-03-09
ER

PT J
AU Wang, B
   Jie, ZL
   Joo, DH
   Ordureau, A
   Liu, P
   Gan, WJ
   Guo, JP
   Zhang, JF
   North, BJ
   Dai, XP
   Cheng, XH
   Bian, XW
   Zhang, LQ
   Harper, JW
   Sun, SC
   Wei, WY
AF Wang, Bin
   Jie, Zuliang
   Joo, Donghyun
   Ordureau, Alban
   Liu, Pengda
   Gan, Wenjian
   Guo, Jianping
   Zhang, Jinfang
   North, Brian J.
   Dai, Xiangpeng
   Cheng, Xuhong
   Bian, Xiuwu
   Zhang, Lingqiang
   Harper, J. Wade
   Sun, Shao-Cong
   Wei, Wenyi
TI TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling
SO NATURE
LA English
DT Article
ID rag gtpases; protein-phosphorylation; complex integrity; gap activity; cancer; raptor; akt; activation; growth; rictor
AB The mechanistic target of rapamycin (mTOR) has a key role in the integration of various physiological stimuli to regulate several cell growth and metabolic pathways(1). mTOR primarily functions as a catalytic subunit in two structurally related but functionally distinct multi-component kinase complexes, mTOR complex 1 (mTORC1) and mTORC2 (refs 1, 2). Dysregulation of mTOR signalling is associated with a variety of human diseases, including metabolic disorders and cancer(1). Thus, both mTORC1 and mTORC2 kinase activity is tightly controlled in cells. mTORC1 is activated by both nutrients(3-6) and growth factors(7), whereas mTORC2 responds primarily to extracellular cues such as growth-factor-triggered activation of PI3K signalling(8-10). Although both mTOR and G beta L (also known as MLST8) assemble into mTORC1 and mTORC2 (refs 11-15), it remains largely unclear what drives the dynamic assembly of these two functionally distinct complexes. Here we show, in humans and mice, that the K63-linked polyubiquitination status of G beta L dictates the homeostasis of mTORC2 formation and activation. Mechanistically, the TRAF2 E3 ubiquitin ligase promotes K63-linked polyubiquitination of G beta L, which disrupts its interaction with the unique mTORC2 component SIN1 (refs 12-14) to favour mTORC1 formation. By contrast, the OTUD7B deubiquitinase removes polyubiquitin chains from G beta L to promote G beta L interaction with SIN1, facilitating mTORC2 formation in response to various growth signals. Moreover, loss of critical ubiquitination residues in G beta L, by either K305R/K313R mutations or a melanoma-associated G beta L(Delta W297) truncation, leads to elevated mTORC2 formation, which facilitates tumorigenesis, in part by activating AKT oncogenic signalling. In support of a physiologically pivotal role for OTUD7B in the activation of mTORC2/AKT signalling, genetic deletion of Otud7b in mice suppresses Akt activation and Kras-driven lung tumorigenesis in vivo. Collectively, our study reveals a G beta L-ubiquitination-dependent switch that fine-tunes the dynamic organization and activation of the mTORC2 kinase under both physiological and pathological conditions.
C1 [Wang, Bin] Third Mil Med Univ, Daping Hosp, Inst Surg Res, Dept Gastroenterol, Chongqing 400042, Peoples R China.
   [Wang, Bin; Liu, Pengda; Gan, Wenjian; Guo, Jianping; Zhang, Jinfang; North, Brian J.; Dai, Xiangpeng; Wei, Wenyi] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA.
   [Jie, Zuliang; Joo, Donghyun; Cheng, Xuhong; Sun, Shao-Cong] Univ Texas MD Anderson Canc Ctr, Dept Immunol, 7455 Fannin St,Box 902, Houston, TX 77030 USA.
   [Ordureau, Alban; Harper, J. Wade] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
   [Bian, Xiuwu] Third Mil Med Univ, Southwest Hosp, Minist Educ China, Inst Pathol, Chongqing 400038, Peoples R China.
   [Bian, Xiuwu] Third Mil Med Univ, Southwest Hosp, Minist Educ China, Southwest Canc Ctr, Chongqing 400038, Peoples R China.
   [Bian, Xiuwu] Third Mil Med Univ, Southwest Hosp, Minist Educ China, Key Lab Tumor Immunopathol, Chongqing 400038, Peoples R China.
   [Zhang, Lingqiang] Beijing Inst Radiat Med, Collaborat Innovat Ctr Canc Med, Beijing Proteome Res Ctr, State Key Lab Prote, Beijing 100850, Peoples R China.
C3 Army Medical University; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard Medical School; University of Texas System; UTMD Anderson Cancer Center; Harvard University; Harvard Medical School; Army Medical University; Army Medical University; Army Medical University; Academy of Military Medical Sciences - China
RP Wei, WY (corresponding author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA.; Sun, SC (corresponding author), Univ Texas MD Anderson Canc Ctr, Dept Immunol, 7455 Fannin St,Box 902, Houston, TX 77030 USA.
EM ssun@mdanderson.org; wwei2@bidmc.harvard.edu
FU Edward R. and Anne G. Lefler Center; NIH [R01CA177910, R01GM094777, R37AI064639, R01GM084459, AG011085, GM095567]; National Natural Science Foundation of China [81472294, 81521064];  [ROOCA181342];  [1K99CA207867]; National Cancer Institute [R01CA177910] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [R37AI064639] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM084459] Funding Source: NIH RePORTER; National Institute on Aging [R01AG011085] Funding Source: NIH RePORTER
NR 45
TC 165
Z9 182
U1 1
U2 92
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 18
PY 2017
VL 545
IS 7654
BP 365
EP +
DI 10.1038/nature22344
PG 27
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV0WF
UT WOS:000401466500066
PM 28489822
DA 2026-03-09
ER

PT J
AU Luo, ZX
   Meng, QJ
   Grossnickle, DM
   Liu, D
   Neander, AI
   Zhang, YG
   Ji, Q
AF Luo, Zhe-Xi
   Meng, Qing-Jin
   Grossnickle, David M.
   Liu, Di
   Neander, April I.
   Zhang, Yu-Guang
   Ji, Qiang
TI New evidence for mammaliaform ear evolution and feeding adaptation in a Jurassic ecosystem
SO NATURE
LA English
DT Article
ID multituberculate mammals; diversification; fossil
AB Stem mammaliaforms are forerunners to modern mammals(1), and they achieved considerable ecomorphological diversity in their own right(2). Recent discoveries suggest that eleutherodontids, a subclade of Haramiyida, were more species-rich during the Jurassic period in Asia than previously recognized(3-12). Here we report a new Jurassic eleutherodontid mammaliaform with an unusual mosaic of highly specialized characteristics(1-6), and the results of phylogenetic analyses that support the hypothesis that haramiyidans are stem mammaliaforms. The new fossil shows fossilized skin membranes that are interpreted to be for gliding and a mandibular middle ear with a unique character combination previously unknown in mammaliaforms. Incisor replacement is prolonged until well after molars are fully erupted, a timing pattern unique to most other mammaliaforms. In situ molar occlusion and a functional analysis reveal a new mode of dental occlusion: dual mortar-pestle occlusion of opposing upper and lower molars, probably for dual crushing and grinding. This suggests that eleutherodontids are herbivorous, and probably specialized for granivory or feeding on soft plant tissues. The inferred dietary adaptation of eleutherodontid gliders represents a remarkable evolutionary convergence with herbivorous gliders in Theria. These Jurassic fossils represent volant, herbivorous stem mammaliaforms associated with pre-angiosperm plants that appear long before the later, iterative associations between angiosperm plants and volant herbivores in various therian clades.
C1 [Luo, Zhe-Xi; Neander, April I.] Univ Chicago, Dept Organismal Biol & Anat, 1025 E 57Th St, Chicago, IL 60637 USA.
   [Luo, Zhe-Xi; Grossnickle, David M.] Univ Chicago, Comm Evolutionary Biol, Chicago, IL 60637 USA.
   [Meng, Qing-Jin; Liu, Di; Zhang, Yu-Guang] Beijing Museum Nat Hist, Beijing 100050, Peoples R China.
   [Ji, Qiang] Hebei GEO Univ, Shijiazhuang 050031, Hebei, Peoples R China.
C3 University of Chicago; University of Chicago; Hebei GEO University
RP Luo, ZX (corresponding author), Univ Chicago, Dept Organismal Biol & Anat, 1025 E 57Th St, Chicago, IL 60637 USA.; Luo, ZX (corresponding author), Univ Chicago, Comm Evolutionary Biol, Chicago, IL 60637 USA.; Meng, QJ (corresponding author), Beijing Museum Nat Hist, Beijing 100050, Peoples R China.
EM zxluo@uchicago.edu; mengqingjin18@163.com
FU Beijing Scientific Commission; UChicago-BSD
CR Anders U, 2011, PALAEONTOL Z, V85, P321, DOI 10.1007/s12542-011-0098-9
   Averianov A O, 2011, DOKL BIOL SCI, V437, P103, DOI 10.1134/S0012496611020074
   Bi SD, 2014, NATURE, V514, P579, DOI 10.1038/nature13718
   Butler PM, 2000, ACTA PALAEONTOL POL, V45, P317
   Jackson SM, 2012, GLIDING MAMMALS OF THE WORLD INTERNET, V0, P0
   Jenkins FA, 1997, NATURE, V385, P715, DOI 10.1038/385715a0
   Kermack KA, 1998, ACTA PALAEONTOL POL, V43, P581
   Labandeira CC, 2010, ANN MO BOT GARD, V97, P469, DOI 10.3417/2010037
   Lazzari V, 2010, J MAMM EVOL, V17, P177, DOI 10.1007/s10914-010-9139-5
   Liao H- Y, 2014, ACTA PALAEONTOLOGICA, V53, P201
   Luo ZX, 2007, NATURE, V450, P1011, DOI 10.1038/nature06277
   Luo Zhe-Xi, 2004, BULLETIN OF CARNEGIE MUSEUM OF NATURAL HISTORY, V36, P159, DOI 10.2992/0145-9058(2004)36[159:EODRIM]2.0.CO;2
   Luo ZX, 2015, P NATL ACAD SCI USA, V112, PE7101, DOI 10.1073/pnas.1519387112
   Luo ZX, 2015, SCIENCE, V347, P760, DOI 10.1126/science.1260880
   Luo ZX, 2011, ANNU REV ECOL EVOL S, V42, P355, DOI 10.1146/annurev-ecolsys-032511-142302
   Martin Thomas, 2010, PALAEOBIODIVERSITY PALAEOENVIRONMENTS, V90, P295, DOI 10.1007/s12549-010-0030-4
   Meng J, 2011, NATURE, V472, P181, DOI 10.1038/nature09921
   Meng Q- J, 2017, NATURE, V0, P0
   Meng QJ, 2015, SCIENCE, V347, P764, DOI 10.1126/science.1260879
   OMeara RN, 2016, PALEOBIOLOGY, V42, P439, DOI 10.1017/pab.2015.51
   RADINSKY LB, 1968, J MORPHOL, V124, P167, DOI 10.1002/jmor.1051240204
   Rowe T, 1988, JOURNAL OF VERTEBRATE PALEONTOLOGY, V8, P241
   Santana SE, 2011, FUNCT ECOL, V25, P839, DOI 10.1111/j.1365-2435.2011.01832.x
   SUES H-D, 1986, BULLETIN OF THE MUSEUM OF COMPARATIVE ZOOLOGY, V151, P217
   Thorington RW Jr, 2005, J VERTEBR PALEONTOL, V25, P950, DOI 10.1671/0272-4634(2005)025[0950:TDOIFS]2.0.CO;2
   Wilson GP, 2012, NATURE, V483, P457, DOI 10.1038/nature10880
   Yuan CX, 2013, SCIENCE, V341, P779, DOI 10.1126/science.1237970
   Zheng XT, 2013, NATURE, V500, P199, DOI 10.1038/nature12353
   Zhou CF, 2013, NATURE, V500, P163, DOI 10.1038/nature12429
NR 30
TC 86
Z9 98
U1 0
U2 66
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 17
PY 2017
VL 548
IS 7667
BP 326
EP +
DI 10.1038/nature23483
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD8AU
UT WOS:000407748400031
PM 28792934
DA 2026-03-09
ER

PT J
AU Kim, S
   Kim, H
   Yim, YS
   Ha, S
   Atarashi, K
   Tan, TG
   Longman, RS
   Honda, K
   Littman, DR
   Choi, GB
   Huh, JR
AF Kim, Sangdoo
   Kim, Hyunju
   Yim, Yeong Shin
   Ha, Soyoung
   Atarashi, Koji
   Tan, Tze Guan
   Longman, Randy S. .
   Honda, Kenya
   Littman, Dan R.
   Choi, Gloria B. .
   Huh, Jun R.
TI Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring
SO NATURE
LA English
DT Article
ID autism spectrum disorders; immune activation; brain-development; dendritic cells; t(h)17 cells; microbiota; differentiation; infection; pregnancy; mice
AB Maternal immune activation (MIA) contributes to behavioural abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring(1-4). In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing autism spectrum disorder(5-7). In pregnant mice, interleukin-17a (IL-17a) produced by T helper 17 (T(H)17) cells (CD4(+) T helper effector cells involved in multiple inflammatory conditions) induces behavioural and cortical abnormalities in the offspring exposed to MIA(8). However, it is unclear whether other maternal factors are required to promote MIA-associated phenotypes. Moreover, the underlying mechanisms by which MIA leads to T cell activation with increased IL-17a in the maternal circulation are not well understood. Here we show that MIA phenotypes in offspring require maternal intestinal bacteria that promote T(H)17 cell differentiation. Pregnant mice that had been colonized with mouse commensal segmented filamentous bacteria or human commensal bacteria that induce intestinal T(H)17 cells were more likely to produce offspring with MIA-associated abnormalities. We also show that small intestine dendritic cells from pregnant, but not from non-pregnant, females secrete IL-1 beta, IL-23 and IL-6 and stimulate T cells to produce IL-17a upon exposure to MIA. Overall, our data suggest that defined gut commensal bacteria with a propensity to induce T(H)17 cells may increase the risk of neurodevelopmental disorders in the offspring of pregnant mothers undergoing immune system activation owing to infections or autoinflammatory syndromes.
C1 [Kim, Sangdoo; Kim, Hyunju; Ha, Soyoung; Huh, Jun R.] Univ Massachusetts, Med Sch, Div Infect Dis & Immunol, Worcester, MA 01605 USA.
   [Kim, Sangdoo; Kim, Hyunju; Ha, Soyoung; Huh, Jun R.] Univ Massachusetts, Med Sch, Dept Med, Program Innate Immun, Worcester, MA 01605 USA.
   [Yim, Yeong Shin; Choi, Gloria B. .] MIT, Dept Brain & Cognit Sci, McGovern Inst Brain Res, Cambridge, MA 02139 USA.
   [Atarashi, Koji; Honda, Kenya] Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo 1608582, Japan.
   [Tan, Tze Guan] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA.
   [Longman, Randy S. .] Weill Cornell Med, Div Gastroenterol & Hepatol, Jill Roberts Inst Res IBD, New York, NY 10021 USA.
   [Littman, Dan R.] NYU, Sch Med, Skirball Inst, Kimmel Ctr Biol & Med, New York, NY 10016 USA.
   [Littman, Dan R.] Howard Hughes Med Inst, New York, NY 10016 USA.
   [Huh, Jun R.] Harvard Med Sch, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA.
   [Huh, Jun R.] Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA.
   [Huh, Jun R.] Brigham & Womens Hosp, Boston, MA 02115 USA.
C3 University of Massachusetts System; University of Massachusetts Worcester; University of Massachusetts System; University of Massachusetts Worcester; Massachusetts Institute of Technology (MIT); Keio University; Harvard University; Harvard Medical School; Cornell University; Weill Cornell Medicine; New York University; Howard Hughes Medical Institute; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital
RP Huh, JR (corresponding author), Univ Massachusetts, Med Sch, Div Infect Dis & Immunol, Worcester, MA 01605 USA.; Huh, JR (corresponding author), Univ Massachusetts, Med Sch, Dept Med, Program Innate Immun, Worcester, MA 01605 USA.; Choi, GB (corresponding author), MIT, Dept Brain & Cognit Sci, McGovern Inst Brain Res, Cambridge, MA 02139 USA.; Huh, JR (corresponding author), Harvard Med Sch, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA.; Huh, JR (corresponding author), Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA.; Huh, JR (corresponding author), Brigham & Womens Hosp, Boston, MA 02115 USA.
EM gbchoi@mit.edu; jun_huh@hms.harvard.edu
FU Simons Foundation Autism Research Initiative [274443, 402005]; Simons Foundation; Hock E. Tan and K. Lisa Yang Center for Autism Research; Howard Hughes Medical Institute; Robert Buxton; National Research Foundation of Korea [MEST-35B-2011-1-E00012, NRF-2014R1A1A1006089]; Searle Scholars Program; Pew Scholar for Biomedical Sciences; Kenneth Rainin Foundation; National Institutes of Health [R01DK106351, R01DK110559]; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK110559] Funding Source: NIH RePORTER; National Institute of Mental Health [R01MH115037] Funding Source: NIH RePORTER; Grants-in-Aid for Scientific Research [15H05657] Funding Source: KAKEN
NR 30
TC 543
Z9 622
U1 2
U2 175
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 28
PY 2017
VL 549
IS 7673
BP 528
EP +
DI 10.1038/nature23910
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI4GT
UT WOS:000411930000052
PM 28902840
DA 2026-03-09
ER

PT J
AU Filer, D
   Thompson, MA
   Takhaveev, V
   Dobson, AJ
   Kotronaki, I
   Green, JWM
   Heinemann, M
   Tullet, JMA
   Alic, N
AF Filer, Danny
   Thompson, Maximillian A.
   Takhaveev, Vakil
   Dobson, Adam J.
   Kotronaki, Ilektra
   Green, James W. M.
   Heinemann, Matthias
   Tullet, Jennifer M. A.
   Alic, Nazif
TI RNA polymerase III limits longevity downstream of TORC1
SO NATURE
LA English
DT Article
ID life-span extension; drosophila; rapamycin; transcription; expression; system; yeast; acid; beta
AB Three distinct RNA polymerases transcribe different classes of genes in the eukaryotic nucleus(1). RNA polymerase (Pol) III is the essential, evolutionarily conserved enzyme that generates short, non-coding RNAs, including tRNAs and 5S rRNA(2). The historical focus on transcription of protein-coding genes has left the roles of Pol III in organismal physiology relatively unexplored. Target of rapamycin kinase complex 1 (TORC1) regulates Pol III activity, and is also an important determinant of longevity(3). This raises the possibility that Pol III is involved in ageing. Here we show that Pol III limits lifespan downstream of TORC1. We find that a reduction in Pol III extends chronological lifespan in yeast and organismal lifespan in worms and flies. Inhibiting the activity of Pol III in the gut of adult worms or flies is sufficient to extend lifespan; in flies, longevity can be achieved by Pol III inhibition specifically in intestinal stem cells. The longevity phenotype is associated with amelioration of age-related gut pathology and functional decline, dampened protein synthesis and increased tolerance of proteostatic stress. Pol III acts on lifespan downstream of TORC1, and limiting Pol III activity in the adult gut achieves the full longevity benefit of systemic TORC1 inhibition. Hence, Pol III is a pivotal mediator of this key nutrient-signalling network for longevity; the growth-promoting anabolic activity of Pol III mediates the acceleration of ageing by TORC1. The evolutionary conservation of Pol III affirms its potential as a therapeutic target.
C1 [Filer, Danny; Dobson, Adam J.; Kotronaki, Ilektra; Alic, Nazif] UCL, Inst Healthy Ageing, Dept Genet Evolut & Environm, Gower St, London WC1E 6BT, England.
   [Thompson, Maximillian A.; Green, James W. M.; Tullet, Jennifer M. A.] Univ Kent, Sch Biosci, Canterbury CT2 7NJ, Kent, England.
   [Takhaveev, Vakil; Heinemann, Matthias] Univ Groningen, Mol Syst Biol, Groningen Biomol Sci & Biotechnol Inst, NL-9747 AG Groningen, Netherlands.
C3 University of London; University College London; University of Kent; University of Groningen
RP Alic, N (corresponding author), UCL, Inst Healthy Ageing, Dept Genet Evolut & Environm, Gower St, London WC1E 6BT, England.; Tullet, JMA (corresponding author), Univ Kent, Sch Biosci, Canterbury CT2 7NJ, Kent, England.
EM j.m.a.tullet@kent.ac.uk; n.alic@ucl.ac.uk
FU NIH Office of Research Infrastructure Programs [P40 OD010440]; Biotechnology and Biological Sciences Research Council [BB/M029093/1]; Royal Society [RG140694, RG140122]; Medical Research Council [MR/L018802/1]; European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant [642738]; UCL Impact PhD studentship; BBSRC [BB/M029093/1] Funding Source: UKRI; MRC [MR/L018802/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/M029093/1] Funding Source: researchfish; Medical Research Council [MR/L018802/1] Funding Source: researchfish; National Institute of General Medical Sciences; NIH Office of the Director [P40OD010440] Funding Source: NIH RePORTER
NR 48
TC 85
Z9 96
U1 3
U2 41
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 14
PY 2017
VL 552
IS 7684
BP 263
EP +
DI 10.1038/nature25007
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ0FK
UT WOS:000418029500049
PM 29186112
DA 2026-03-09
ER

PT J
AU Jiang, SH
   Wang, H
   Wu, Y
   Liu, XJ
   Chen, HH
   Yao, MJ
   Gault, B
   Ponge, D
   Raabe, D
   Hirata, A
   Chen, MW
   Wang, YD
   Lu, ZP
AF Jiang, Suihe
   Wang, Hui
   Wu, Yuan
   Liu, Xiongjun
   Chen, Honghong
   Yao, Mengji
   Gault, Baptiste
   Ponge, Dirk
   Raabe, Dierk
   Hirata, Akihiko
   Chen, Mingwei
   Wang, Yandong
   Lu, Zhaoping
TI Ultrastrong steel via minimal lattice misfit and high-density nanoprecipitation
SO NATURE
LA English
DT Article
ID mechanical-property; atom-probe; microstructural evolution; precipitation; reconstruction; diffusion; strength; phase; cu
AB Next-generation high-performance structural materials are required for lightweight design strategies and advanced energy applications. Maraging steels, combining a martensite matrix with nanoprecipitates, are a class of high-strength materials with the potential for matching these demands(1-3). Their outstanding strength originates from semi-coherent precipitates(4,5), which unavoidably exhibit a heterogeneous distribution that creates large coherency strains, which in turn may promote crack initiation under load(6-8). Here we report a counterintuitive strategy for the design of ultrastrong steel alloys by high-density nanoprecipitation with minimal lattice misfit. We found that these highly dispersed, fully coherent precipitates (that is, the crystal lattice of the precipitates is almost the same as that of the surrounding matrix), showing very low lattice misfit with the matrix and high anti-phase boundary energy, strengthen alloys without sacrificing ductility. Such low lattice misfit (0.03 +/- 0.04 per cent) decreases the nucleation barrier for precipitation, thus enabling and stabilizing nanoprecipitates with an extremely high number density (more than 10(24) per cubic metre) and small size (about 2.7 +/- 0.2 nanometres). The minimized elastic misfit strain around the particles does not contribute much to the dislocation interaction, which is typically needed for strength increase. Instead, our strengthening mechanism exploits the chemical ordering effect that creates backstresses (the forces opposing deformation) when precipitates are cut by dislocations. We create a class of steels, strengthened by Ni(Al, Fe) precipitates, with a strength of up to 2.2 gigapascals and good ductility (about 8.2 per cent). The chemical composition of the precipitates enables a substantial reduction in cost compared to conventional maraging steels owing to the replacement of the essential but high-cost alloying elements cobalt and titanium with inexpensive and lightweight aluminium. Strengthening of this class of steel alloy is based on minimal lattice misfit to achieve maximal precipitate dispersion and high cutting stress (the stress required for dislocations to cut through coherent precipitates and thus produce plastic deformation), and we envisage that this lattice misfit design concept may be applied to many other metallic alloys.
C1 [Jiang, Suihe; Wang, Hui; Wu, Yuan; Liu, Xiongjun; Chen, Honghong; Wang, Yandong; Lu, Zhaoping] Univ Sci & Technol Beijing, State Key Lab Adv Met & Mat, Beijing 100083, Peoples R China.
   [Yao, Mengji; Gault, Baptiste; Ponge, Dirk; Raabe, Dierk] Max Planck Inst Eisenforsch GmbH, Dept Microstruct Phys & Alloy Design, Max Planck Str, D-40237 Dusseldorf, Germany.
   [Hirata, Akihiko; Chen, Mingwei] Tohoku Univ, WPI Adv Inst Mat Res, Sendai, Miyagi 9808577, Japan.
   [Hirata, Akihiko] Tohoku Univ, Math Adv Mat OIL, AIST, Sendai, Miyagi 9808577, Japan.
   [Chen, Mingwei] Johns Hopkins Univ, Dept Mat Sci & Engn, Baltimore, MD 21218 USA.
C3 University of Science & Technology Beijing; Max Planck Society; Tohoku University; National Institute of Advanced Industrial Science & Technology (AIST); Tohoku University; Johns Hopkins University
RP Lu, ZP (corresponding author), Univ Sci & Technol Beijing, State Key Lab Adv Met & Mat, Beijing 100083, Peoples R China.
EM luzp@ustb.edu.cn
FU National Natural Science Foundation of China [51531001, 51422101, 51671018, 51271212, 51371003]; 111 Project [B07003]; International S&T Cooperation Program of China [2015DFG52600]; Program for Changjiang Scholars and Innovative Research Team in University [IRT_14R05]; Projects of SKL-AMM-USTB [2016Z-04, 2016-09, 2016Z-16]; DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
NR 43
TC 1386
Z9 1513
U1 82
U2 2001
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 27
PY 2017
VL 544
IS 7651
BP 460
EP +
DI 10.1038/nature22032
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET1TN
UT WOS:000400051900039
PM 28397822
DA 2026-03-09
ER

PT J
AU Natchiar, SK
   Myasnikov, AG
   Kratzat, H
   Hazemann, I
   Klaholz, BP
AF Natchiar, S. Kundhavai
   Myasnikov, Alexander G.
   Kratzat, Hanna
   Hazemann, Isabelle
   Klaholz, Bruno P.
TI Visualization of chemical modifications in the human 80S ribosome structure
SO NATURE
LA English
DT Article
ID particle electron cryomicroscopy; cryo-em structure; rna modifications; posttranscriptional modifications; saccharomyces-cerevisiae; eukaryotic ribosome; angstrom resolution; escherichia-coli; xenopus-laevis; methyl-groups
AB Chemical modifications of human ribosomal RNA (rRNA) are introduced during biogenesis and have been implicated in the dysregulation of protein synthesis, as is found in cancer and other diseases. However, their role in this phenomenon is unknown. Here we visualize more than 130 individual rRNA modifications in the three-dimensional structure of the human ribosome, explaining their structural and functional roles. In addition to a small number of universally conserved sites, we identify many eukaryote-or human-specific modifications and unique sites that form an extended shell in comparison to bacterial ribosomes, and which stabilize the RNA. Several of the modifications are associated with the binding sites of three ribosome-targeting antibiotics, or are associated with degenerate states in cancer, such as keto alkylations on nucleotide bases reminiscent of specialized ribosomes. This high-resolution structure of the human 80S ribosome paves the way towards understanding the role of epigenetic rRNA modifications in human diseases and suggests new possibilities for designing selective inhibitors and therapeutic drugs.
C1 [Natchiar, S. Kundhavai; Myasnikov, Alexander G.; Kratzat, Hanna; Hazemann, Isabelle; Klaholz, Bruno P.] Univ Strasbourg, CNRS, INSERM,IGBMC, Ctr Integrat Biol CBI,Dept Integrated Struct Biol, 1 Rue Laurent Fries, F-67404 Illkirch Graffenstaden, France.
   [Natchiar, S. Kundhavai; Myasnikov, Alexander G.; Kratzat, Hanna; Hazemann, Isabelle; Klaholz, Bruno P.] Inst Genet & Mol & Cellular Biol IGBMC, 1 Rue Laurent Fries, Illkirch Graffenstaden, France.
   [Natchiar, S. Kundhavai; Myasnikov, Alexander G.; Kratzat, Hanna; Hazemann, Isabelle; Klaholz, Bruno P.] CNRS, UMR 7104, Illkirch Graffenstaden, France.
   [Natchiar, S. Kundhavai; Myasnikov, Alexander G.; Kratzat, Hanna; Hazemann, Isabelle; Klaholz, Bruno P.] INSERM, U964, Illkirch Graffenstaden, France.
   [Natchiar, S. Kundhavai; Myasnikov, Alexander G.; Kratzat, Hanna; Hazemann, Isabelle; Klaholz, Bruno P.] Univ Strasbourg, Illkirch Graffenstaden, France.
   [Kratzat, Hanna] Ludwig Maximilians Univ Munchen, Gene Ctr, Munich, Germany.
C3 Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Institut National de la Sante et de la Recherche Medicale (Inserm); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; University of Munich
RP Klaholz, BP (corresponding author), Univ Strasbourg, CNRS, INSERM,IGBMC, Ctr Integrat Biol CBI,Dept Integrated Struct Biol, 1 Rue Laurent Fries, F-67404 Illkirch Graffenstaden, France.; Klaholz, BP (corresponding author), Inst Genet & Mol & Cellular Biol IGBMC, 1 Rue Laurent Fries, Illkirch Graffenstaden, France.; Klaholz, BP (corresponding author), CNRS, UMR 7104, Illkirch Graffenstaden, France.
EM klaholz@igbmc.fr
FU CNRS; Association pour la Recherche sur le Cancer (ARC); Institut National du Cancer (INCa); Ligue nationale contre le cancer (Ligue); Agence National pour la Recherche (ANR) [ANR-10-LABX-0030-INRT, ANR-10-IDEX-0002-02]; Instruct-ULTRA as part of the European Union [731005]
NR 71
TC 276
Z9 322
U1 4
U2 56
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 23
PY 2017
VL 551
IS 7681
BP 472
EP +
DI 10.1038/nature24482
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FN5JO
UT WOS:000416043700038
PM 29143818
DA 2026-03-09
ER

PT J
AU Mosialou, I
   Shikhel, S
   Liu, JM
   Maurizi, A
   Luo, N
   He, ZY
   Huang, YR
   Zong, HH
   Friedman, RA
   Barasch, J
   Lanzano, P
   Deng, LY
   Leibel, RL
   Rubin, M
   Nicholas, T
   Chung, W
   Zeltser, LM
   Williams, KW
   Pessin, JE
   Kousteni, S
AF Mosialou, Ioanna
   Shikhel, Steven
   Liu, Jian-Min
   Maurizi, Antonio
   Luo, Na
   He, Zhenyan
   Huang, Yiru
   Zong, Haihong
   Friedman, Richard A.
   Barasch, Jonathan
   Lanzano, Patricia
   Deng, Liyong
   Leibel, Rudolph L.
   Rubin, Mishaela
   Nicholas, Thomas
   Chung, Wendy
   Zeltser, Lori M.
   Williams, Kevin W.
   Pessin, Jeffrey E.
   Kousteni, Stavroula
TI MC4R-dependent suppression of appetite by bone-derived lipocalin 2
SO NATURE
LA English
DT Article
ID green fluorescent protein; insulin-receptor; body-weight; energy-balance; neurons; osteoblasts; obesity; expression; mice; proopiomelanocortin
AB Bone has recently emerged as a pleiotropic endocrine organ that secretes at least two hormones, FGF23 and osteocalcin, which regulate kidney function and glucose homeostasis, respectively. These findings have raised the question of whether other bone-derived hormones exist and what their potential functions are. Here we identify, through molecular and genetic analyses in mice, lipocalin 2 (LCN2) as an osteoblast-enriched, secreted protein. Loss-and gain-of-function experiments in mice demonstrate that osteoblast-derived LCN2 maintains glucose homeostasis by inducing insulin secretion and improves glucose tolerance and insulin sensitivity. In addition, osteoblast-derived LCN2 inhibits food intake. LCN2 crosses the blood-brain barrier, binds to the melanocortin 4 receptor (MC4R) in the paraventricular and ventromedial neurons of the hypothalamus and activates an MC4R-dependent anorexigenic (appetite-suppressing) pathway. These results identify LCN2 as a bone-derived hormone with metabolic regulatory effects, which suppresses appetite in a MC4R-dependent manner, and show that the control of appetite is an endocrine function of bone.
C1 [Mosialou, Ioanna; Shikhel, Steven; Liu, Jian-Min; Maurizi, Antonio; Luo, Na; Kousteni, Stavroula] Columbia Univ, Coll Phys & Surg, Dept Physiol & Cellular Biophys, New York, NY 10032 USA.
   [He, Zhenyan; Huang, Yiru] Southern Med Univ, Zhujiang Hosp, Dept Neurosurg, Guangzhou 510515, Guangdong, Peoples R China.
   [He, Zhenyan; Huang, Yiru; Williams, Kevin W.] Univ Texas Southwestern Med Ctr Dallas, Div Hypothalam Res, Dallas, TX 75390 USA.
   [Zong, Haihong; Pessin, Jeffrey E.] Albert Einstein Coll Med, Dept Med & Mol Pharmacol, Bronx, NY 10461 USA.
   [Friedman, Richard A.] Columbia Univ, Coll Phys & Surg, Herbert Irving Comprehens Canc Ctr, Biomed Informat Shared Resource,Dept Biomed Infor, New York, NY 10032 USA.
   [Barasch, Jonathan] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY 10032 USA.
   [Lanzano, Patricia; Deng, Liyong; Leibel, Rudolph L.; Chung, Wendy] Columbia Univ, Coll Phys & Surg, Naomi Berrie Diabet Ctr, New York, NY 10032 USA.
   [Lanzano, Patricia; Deng, Liyong; Leibel, Rudolph L.; Chung, Wendy] Columbia Univ, Coll Phys & Surg, Div Mol Genet, Dept Pediat, New York, NY 10032 USA.
   [Rubin, Mishaela] Columbia Univ, Coll Phys & Surg, Metab Bone Dis Unit, Dept Med, New York, NY 10032 USA.
   [Nicholas, Thomas] Columbia Univ, Coll Phys & Surg, Dept Med Nephrol, New York, NY 10032 USA.
   [Zeltser, Lori M.] Columbia Univ, Naomi Berrie Diabet Ctr, New York, NY 10032 USA.
   [Zeltser, Lori M.] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA.
   [Liu, Jian-Min] Shanghai Jiao Tong Univ, Sch Med, Shanghai Rui Jin Hosp, Dept Endocrine & Metab Dis, Shanghai 200025, Peoples R China.
   [Maurizi, Antonio] Univ Aquila, Dept Biotechnol & Appl Clin Sci, I-67100 Laquila, Italy.
C3 Columbia University; Southern Medical University - China; University of Texas System; University of Texas Southwestern Medical Center; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Columbia University; Columbia University; Columbia University; Columbia University; Columbia University; Columbia University; Columbia University; Columbia University; Shanghai Jiao Tong University; University of L'Aquila
RP Kousteni, S (corresponding author), Columbia Univ, Coll Phys & Surg, Dept Physiol & Cellular Biophys, New York, NY 10032 USA.
EM sk2836@cumc.columbia.edu
FU National Institutes of Health [R01AR054447, P01AG032959, R01AR055931, R01DK100699, R01DK52431, P30DK26687, P30DK063608]; NOVO Nordisk; T32 Training Grant [DK07328]; National Institute of Diabetes and Digestive and Kidney Diseases [T32DK007328, P30DK063608, P30DK020541, P30DK026687] Funding Source: NIH RePORTER; National Institute on Aging [P01AG032959] Funding Source: NIH RePORTER
NR 51
TC 357
Z9 430
U1 3
U2 113
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 16
PY 2017
VL 543
IS 7645
BP 385
EP +
DI 10.1038/nature21697
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN9RN
UT WOS:000396337400043
PM 28273060
DA 2026-03-09
ER

PT J
AU Reinhard, CT
   Planavsky, NJ
   Gill, BC
   Ozaki, K
   Robbins, LJ
   Lyons, TW
   Fischer, WW
   Wang, CJ
   Cole, DB
   Konhauser, KO
AF Reinhard, Christopher T.
   Planavsky, Noah J.
   Gill, Benjamin C.
   Ozaki, Kazumi
   Robbins, Leslie J.
   Lyons, Timothy W.
   Fischer, Woodward W.
   Wang, Chunjiang
   Cole, Devon B.
   Konhauser, Kurt O.
TI Evolution of the global phosphorus cycle
SO NATURE
LA English
DT Article
ID middle proterozoic ocean; marine-sediments; organic-carbon; ferruginous conditions; dissolved phosphate; atmospheric oxygen; green rust; iron; redox; nitrogen
AB The macronutrient phosphorus is thought to limit primary productivity in the oceans on geological timescales(1). Although there has been a sustained effort to reconstruct the dynamics of the phosphorus cycle over the past 3.5 billion years(2-5), it remains uncertain whether phosphorus limitation persisted throughout Earth's history and therefore whether the phosphorus cycle has consistently modulated biospheric productivity and ocean-atmosphere oxygen levels over time. Here we present a compilation of phosphorus abundances in marine sedimentary rocks spanning the past 3.5 billion years. We find evidence for relatively low authigenic phosphorus burial in shallow marine environments until about 800 to 700 million years ago. Our interpretation of the database leads us to propose that limited marginal phosphorus burial before that time was linked to phosphorus biolimitation, resulting in elemental stoichiometries in primary producers that diverged strongly from the Redfield ratio (the atomic ratio of carbon, nitrogen and phosphorus found in phytoplankton). We place our phosphorus record in a quantitative biogeochemical model framework and find that a combination of enhanced phosphorus scavenging in anoxic, iron-rich oceans(6,7) and a nutrient-based bistability in atmospheric oxygen levels could have resulted in a stable low-oxygen world. The combination of these factors may explain the protracted oxygenation of Earth's surface over the last 3.5 billion years of Earth history(8). However, our analysis also suggests that a fundamental shift in the phosphorus cycle may have occurred during the late Proterozoic eon (between 800 and 635 million years ago), coincident with a previously inferred shift in marine redox states(9), severe perturbations to Earth's climate system(10), and the emergence of animals(11,12).
C1 [Reinhard, Christopher T.; Ozaki, Kazumi] Georgia Inst Technol, Sch Earth & Atmospher Sci, Atlanta, GA 30332 USA.
   [Planavsky, Noah J.; Cole, Devon B.] Yale Univ, Dept Geol & Geophys, POB 6666, New Haven, CT 06511 USA.
   [Gill, Benjamin C.] Virginia Tech, Dept Geosci, Blacksburg, VA 24061 USA.
   [Ozaki, Kazumi] Univ Tokyo, Ctr Earth Surface Syst Dynam, Kashiwanoha 2778561, Japan.
   [Robbins, Leslie J.; Konhauser, Kurt O.] Univ Alberta, Dept Earth & Atmospher Sci, Edmonton, AB T6G 2E3, Canada.
   [Lyons, Timothy W.] Univ Calif Riverside, Dept Earth Sci, Riverside, CA 92521 USA.
   [Fischer, Woodward W.] CALTECH, Div Geol & Planetary Sci, Pasadena, CA 91125 USA.
   [Wang, Chunjiang] China Univ Petr, State Key Lab Petr Resources & Prospecting, Beijing 102249, Peoples R China.
C3 University System of Georgia; Georgia Institute of Technology; Yale University; Virginia Polytechnic Institute & State University; University of Tokyo; University of Alberta; University of California System; University of California Riverside; California Institute of Technology; China University of Petroleum
RP Reinhard, CT (corresponding author), Georgia Inst Technol, Sch Earth & Atmospher Sci, Atlanta, GA 30332 USA.; Planavsky, NJ (corresponding author), Yale Univ, Dept Geol & Geophys, POB 6666, New Haven, CT 06511 USA.
EM chris.reinhard@eas.gatech.edu; noah.planavsky@yale.edu
FU NSF-EAR; NASA Astrobiology Institute; Alfred P. Sloan Foundation; JSPS KAKENHI; Division Of Earth Sciences; Directorate For Geosciences [1338810] Funding Source: National Science Foundation; Division Of Earth Sciences; Directorate For Geosciences [1338299] Funding Source: National Science Foundation
NR 85
TC 510
Z9 572
U1 70
U2 1130
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 19
PY 2017
VL 541
IS 7637
BP 386
EP +
DI 10.1038/nature20772
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6QP
UT WOS:000396128800040
PM 28002400
DA 2026-03-09
ER

PT J
AU Clark, JB
   Lecocq, F
   Simmonds, RW
   Aumentado, J
   Teufel, JD
AF Clark, Jeremy B.
   Lecocq, Florent
   Simmonds, Raymond W.
   Aumentado, Jose
   Teufel, John D.
TI Sideband cooling beyond the quantum backaction limit with squeezed light
SO NATURE
LA English
DT Article
ID mechanical oscillator; ground-state; cavity optomechanics; radiation pressure; noise reduction; vacuum; resonator; atoms
AB Quantum fluctuations of the electromagnetic vacuum produce measurable physical effects such as Casimir forces and the Lamb shift(1). They also impose an observable limit-known as the quantum backaction limit-on the lowest temperatures that can be reached using conventional laser cooling techniques(2,3). As laser cooling experiments continue to bring massive mechanical systems to unprecedentedly low temperatures(4,5), this seemingly fundamental limit is increasingly important in the laboratory(6). Fortunately, vacuum fluctuations are not immutable and can be 'squeezed', reducing amplitude fluctuations at the expense of phase fluctuations. Here we propose and experimentally demonstrate that squeezed light can be used to cool the motion of a macroscopic mechanical object below the quantum backaction limit. We first cool a microwave cavity optomechanical system using a coherent state of light to within 15 per cent of this limit. We then cool the system to more than two decibels below the quantum backaction limit using a squeezed microwave field generated by a Josephson parametric amplifier. From heterodyne spectroscopy of the mechanical sidebands, we measure a minimum thermal occupancy of 0.19 +/- 0.01 phonons. With our technique, even low-frequency mechanical oscillators can in principle be cooled arbitrarily close to the motional ground state, enabling the exploration of quantum physics in larger, more massive systems.
C1 [Clark, Jeremy B.; Lecocq, Florent; Simmonds, Raymond W.; Aumentado, Jose; Teufel, John D.] Natl Inst Stand & Technol, Boulder, CO 80305 USA.
C3 National Institute of Standards & Technology (NIST) - USA
RP Teufel, JD (corresponding author), Natl Inst Stand & Technol, Boulder, CO 80305 USA.
EM john.teufel@nist.gov
FU NIST; DARPA QuASAR program; NIST National Research Council Postdoctoral Research Associateship Program
NR 39
TC 244
Z9 266
U1 2
U2 156
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 12
PY 2017
VL 541
IS 7636
BP 191
EP +
DI 10.1038/nature20604
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6PI
UT WOS:000396125500035
PM 28079081
DA 2026-03-09
ER

PT J
AU Mendoza, A
   Fang, V
   Chen, C
   Serasinghe, M
   Verma, A
   Muller, J
   Chaluvadi, VS
   Dustin, ML
   Hla, T
   Elemento, O
   Chipuk, JE
   Schwab, SR
AF Mendoza, Alejandra
   Fang, Victoria
   Chen, Cynthia
   Serasinghe, Madhavika
   Verma, Akanksha
   Muller, James
   Chaluvadi, V. Sai
   Dustin, Michael L.
   Hla, Timothy
   Elemento, Olivier
   Chipuk, Jerry E.
   Schwab, Susan R.
TI Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells
SO NATURE
LA English
DT Article
ID sphingosine-1-phosphate transporter spns2; protein-coupled receptor; lymphocyte egress; homeostasis; trafficking; expression; apoptosis; thymus
AB Effective adaptive immune responses require a large repertoire of naive T cells that migrate throughout the body, rapidly identifying almost any foreign peptide(1). Because the production of T cells declines with age, naive T cells must be long-lived(2). However, it remains unclear how naive T cells survive for years while constantly travelling. The chemoattractant sphingosine 1-phosphate (S1P) guides T cell circulation among secondary lymphoid organs, including spleen, lymph nodes and Peyer's patches, where T cells search for antigens. The concentration of S1P is higher in circulatory fluids than in lymphoid organs, and the S1P(1) receptor (S1P(1)R) directs the exit of T cells from the spleen into blood, and from lymph nodes and Peyer's patches into lymph(3). Here we show that S1P is essential not only for the circulation of naive T cells, but also for their survival. Using transgenic mouse models, we demonstrate that lymphatic endothelial cells support the survival of T cells by secreting S1P via the transporter SPNS2, that this S1P signals through S1P(1)R on T cells, and that the requirement for S1P(1)R is independent of the established role of the receptor in guiding exit from lymph nodes. S1P signalling maintains the mitochondrial content of naive T cells, providing cells with the energy to continue their constant migration. The S1P signalling pathway is being targeted therapeutically to inhibit autoreactive T cell trafficking, and these findings suggest that it may be possible simultaneously to target autoreactive or malignant cell survival(4).
C1 [Mendoza, Alejandra; Fang, Victoria; Chen, Cynthia; Muller, James; Chaluvadi, V. Sai; Dustin, Michael L.; Schwab, Susan R.] NYU, Sch Med, Skirball Inst Biomol Med, New York, NY 10016 USA.
   [Serasinghe, Madhavika; Chipuk, Jerry E.] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA.
   [Verma, Akanksha; Elemento, Olivier] Weill Cornell Med Coll, Inst Computat Biomed, New York, NY 10021 USA.
   [Dustin, Michael L.] Univ Oxford, Kennedy Inst Rheumatol, Roosevelt Dr, Oxford OX3 7FY, England.
   [Hla, Timothy] Harvard Med Sch, Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA.
C3 New York University; Icahn School of Medicine at Mount Sinai; Cornell University; Weill Cornell Medicine; University of Oxford; Kennedy Institute for Rheumatology; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital
RP Schwab, SR (corresponding author), NYU, Sch Med, Skirball Inst Biomol Med, New York, NY 10016 USA.
EM susan.schwab@med.nyu.edu
FU National Institutes of Health (NIH) [R01 AI085166, AI123308]; NIH [R01 CA206005, R01 HL089934, R37 AI43542, T32 AI100853]; Tisch Cancer Institute Cancer Center Support Grant [P30 CA196521]; American Cancer Society; Leukemia & Lymphoma Society; US National Science Foundation [1054964]; NCI [R01 CA194547]; Wellcome Trust; Kennedy Trust for Rheumatology Research [PRF 100262Z/12/Z]; Kennedy Trust [KENN161702] Funding Source: researchfish; Wellcome Trust [100262/Z/12/Z] Funding Source: researchfish; National Cancer Institute [P30CA196521] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [T32AI100853, R01AI085166] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK020541] Funding Source: NIH RePORTER; Direct For Biological Sciences; Div Of Biological Infrastructure [1054964] Funding Source: National Science Foundation
NR 32
TC 158
Z9 178
U1 2
U2 21
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 1
PY 2017
VL 546
IS 7656
BP 158
EP +
DI 10.1038/nature22352
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW3CR
UT WOS:000402372800048
PM 28538737
DA 2026-03-09
ER

PT J
AU Kaiser-Bunbury, CN
   Mougal, J
   Whittington, AE
   Valentin, T
   Gabriel, R
   Olesen, JM
   Blüthgen, N
AF Kaiser-Bunbury, Christopher N.
   Mougal, James
   Whittington, Andrew E.
   Valentin, Terence
   Gabriel, Ronny
   Olesen, Jens M.
   Bluethgen, Nico
TI Ecosystem restoration strengthens pollination network resilience and function
SO NATURE
LA English
DT Article
ID alien plants; biodiversity; specialization; metaanalysis; mutualisms; tolerance; declines; impacts
AB Land degradation results in declining biodiversity and the disruption of ecosystem functioning worldwide, particularly in the tropics(1). Vegetation restoration is a common tool used to mitigate these impacts and increasingly aims to restore ecosystem functions rather than species diversity(2). However, evidence from community experiments on the effect of restoration practices on ecosystem functions is scarce(3). Pollination is an important ecosystem function and the global decline in pollinators attenuates the resistance of natural areas and agro-environments to disturbances(4). Thus, the ability of pollination functions to resist or recover from disturbance (that is, the functional resilience)(5,6) may be critical for ensuring a successful restoration process'. Here we report the use of a community field experiment to investigate the effects of vegetation restoration, specifically the removal of exotic shrubs, on pollination. We analyse 64 plant-pollinator networks and the reproductive performance of the ten most abundant plant species across four restored and four unrestored, disturbed mountaintop communities. Ecosystem restoration resulted in a marked increase in pollinator species, visits to flowers and interaction diversity. Interactions in restored networks were more generalized than in unrestored networks, indicating a higher functional redundancy in restored communities. Shifts in interaction patterns had direct and positive effects on pollination, especially on the relative and total fruit production of native plants. Pollinator limitation was prevalent at unrestored sites only, where the proportion of flowers producing fruit increased with pollinator visitation, approaching the higher levels seen in restored plant communities. Our results show that vegetation restoration can improve pollination, suggesting that the degradation of ecosystem functions is at least partially reversible. The degree of recovery may depend on the state of degradation before restoration intervention and the proximity to pollinator source populations in the surrounding landscape(5,8). We demonstrate that network structure is a suitable indicator for pollination quality, highlighting the usefulness of interaction networks in environmental management(6,9).
C1 [Kaiser-Bunbury, Christopher N.; Bluethgen, Nico] Tech Univ Darmstadt, Dept Biol, Ecol Networks, D-64287 Darmstadt, Germany.
   [Mougal, James; Valentin, Terence; Gabriel, Ronny] Seychelles Natl Pk Author, POB 1240, Mahe, Seychelles.
   [Whittington, Andrew E.] Bournemouth Univ, Dept Archaeol Anthropol & Forens Sci, Poole BH12 5BB, Dorset, England.
   [Olesen, Jens M.] Aarhus Univ, Dept Biosci, Ecol & Genet, DK-8000 Aarhus C, Denmark.
C3 Technical University of Darmstadt; Bournemouth University; Aarhus University
RP Kaiser-Bunbury, CN (corresponding author), Tech Univ Darmstadt, Dept Biol, Ecol Networks, D-64287 Darmstadt, Germany.
EM c.kaiserbunbury@gmail.com
FU German Research Foundation [KA 3349/2-1]
NR 31
TC 293
Z9 347
U1 10
U2 551
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 9
PY 2017
VL 542
IS 7640
BP 223
EP 227
DI 10.1038/nature21071
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK2DJ
UT WOS:000393737500039
PM 28135718
DA 2026-03-09
ER

PT J
AU Green, AA
   Kim, JM
   Ma, D
   Ilver, PAS
   Collins, JJ
   Yin, P
AF Green, Alexander A.
   Kim, Jongmin
   Ma, Duo
   Ilver, Pamela A. S.
   Collins, James J.
   Yin, Peng
TI Complex cellular logic computation using ribocomputing devices
SO NATURE
LA English
DT Article
ID dna strand displacement; mammalian-cells; gene-expression; living cells; circuits; gates; regulators; network
AB Synthetic biology aims to develop engineering-driven approaches to the programming of cellular functions that could yield transformative technologies(1). Synthetic gene circuits that combine DNA, protein, and RNA components have demonstrated a range of functions such as bistability(2), oscillation(3,4), feedback(5,6), and logic capabilities(7-15). However, it remains challenging to scale up these circuits owing to the limited number of designable, orthogonal, high-performance parts, the empirical and often tedious composition rules, and the requirements for substantial resources for encoding and operation. Here, we report a strategy for constructing RNA-only nanodevices to evaluate complex logic in living cells. Our 'ribocomputing' systems are composed of de-novo-designed parts and operate through predictable and designable base-pairing rules, allowing the effective in silico design of computing devices with prescribed configurations and functions in complex cellular environments. These devices operate at the post-transcriptional level and use an extended RNA transcript to co-localize all circuit sensing, computation, signal transduction, and output elements in the same self-assembled molecular complex, which reduces diffusion-mediated signal losses, lowers metabolic cost, and improves circuit reliability. We demonstrate that ribocomputing devices in Escherichia coli can evaluate two-input logic with a dynamic range up to 900-fold and scale them to four-input AND, six-input OR, and a complex 12-input expression (A1 AND A2 AND NOT A1*) OR (B1 AND B2 AND NOT B2*) OR (C1 AND C2) OR (D1 AND D2) OR (E1 AND E2). Successful operation of ribocomputing devices based on programmable RNA interactions suggests that systems employing the same design principles could be implemented in other host organisms or in extracellular settings.
C1 [Green, Alexander A.; Kim, Jongmin; Ilver, Pamela A. S.; Collins, James J.; Yin, Peng] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA.
   [Green, Alexander A.; Ma, Duo] Arizona State Univ, Biodesign Inst, Biodesign Ctr Mol Design & Biomimet, Tempe, AZ 85287 USA.
   [Green, Alexander A.; Ma, Duo] Arizona State Univ, Sch Mol Sci, Tempe, AZ 85287 USA.
   [Kim, Jongmin; Ilver, Pamela A. S.; Yin, Peng] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA.
   [Collins, James J.] MIT, Dept Biol Engn, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Collins, James J.] MIT, Synthet Biol Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Collins, James J.] Broad Inst & Harvard, Cambridge, MA 02142 USA.
C3 Harvard University; Arizona State University; Arizona State University-Tempe; Arizona State University; Arizona State University-Tempe; Harvard University; Harvard Medical School; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute
RP Green, AA; Yin, P (corresponding author), Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA.; Green, AA (corresponding author), Arizona State Univ, Biodesign Inst, Biodesign Ctr Mol Design & Biomimet, Tempe, AZ 85287 USA.; Green, AA (corresponding author), Arizona State Univ, Sch Mol Sci, Tempe, AZ 85287 USA.; Yin, P (corresponding author), Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA.
EM alexgreen@asu.edu; py@hms.harvard.edu
FU NIH Director's New Innovator and Transformative Research Awards [1DP2OD007292, 1R01EB018659]; ONR Young Investigator Program Award [N000141110914]; NSF [CCF1054898, CCF1317291]; Wyss Institute Molecular Robotics Initiative; DARPA Living Foundries grant [HR001112C0061]; ONR MURI Program grant; DTRA grant [HDTRA1-15-1-0040]; Paul G. Allen Frontiers Group funds; Arizona Biomedical Research Commission New Investigator Award; Alfred P. Sloan Research Fellowship [FG-2017-9108]; Arizona State University funds; Wyss Institute Director's Cross-Platform Fellowship;  [N000141010827];  [N000141310593];  [N000141410610];  [N000141612410];  [CCF1162459];  [ERASynBio 1540214]; Division of Computing and Communication Foundations; Direct For Computer & Info Scie & Enginr [1317694] Funding Source: National Science Foundation; Division of Computing and Communication Foundations; Direct For Computer & Info Scie & Enginr [1317291] Funding Source: National Science Foundation
NR 31
TC 297
Z9 378
U1 7
U2 409
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 3
PY 2017
VL 548
IS 7665
BP 117
EP +
DI 10.1038/nature23271
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FC4SU
UT WOS:000406831700048
PM 28746304
DA 2026-03-09
ER

PT J
AU Olmeda, D
   Cerezo-Wallis, D
   Riveiro-Falkenbach, E
   Pennacchi, PC
   Contreras-Alcalde, M
   Ibarz, N
   Cifdaloz, M
   Catena, X
   Calvo, TG
   Cañón, E
   Alonso-Curbelo, D
   Suarez, J
   Osterloh, L
   Graña, O
   Mulero, F
   Megías, D
   Cañamero, M
   Martínez-Torrecuadrada, JL
   Mondal, C
   Di Martino, J
   Lora, D
   Martinez-Corral, I
   Bravo-Cordero, JJ
   Muñoz, J
   Puig, S
   Ortiz-Romero, P
   Rodriguez-Peralto, JL
   Ortega, S
   Soengas, MS
AF Olmeda, David
   Cerezo-Wallis, Daniela
   Riveiro-Falkenbach, Erica
   Pennacchi, Paula C.
   Contreras-Alcalde, Marta
   Ibarz, Nuria
   Cifdaloz, Metehan
   Catena, Xavier
   Calvo, Tonantzin G.
   Canon, Estela
   Alonso-Curbelo, Direna
   Suarez, Javier
   Osterloh, Lisa
   Grana, Osvaldo
   Mulero, Francisca
   Megias, Diego
   Canamero, Marta
   Martinez-Torrecuadrada, Jorge L.
   Mondal, Chandrani
   Di Martino, Julie
   Lora, David
   Martinez-Corral, Ines
   Bravo-Cordero, J. Javier
   Munoz, Javier
   Puig, Susana
   Ortiz-Romero, Pablo
   Rodriguez-Peralto, Jose L.
   Ortega, Sagrario
   Soengas, Maria S.
TI Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine
SO NATURE
LA English
DT Article
ID lymph-node; lymphangiogenesis; expression; melanoma; gene; mechanisms; biomarker; vessels; cancer; mouse
AB Cutaneous melanoma is a type of cancer with an inherent potential for lymph node colonization, which is generally preceded by neolymphangiogenesis(1-3). However, sentinel lymph node removal does not necessarily extend the overall survival of patients with melanoma(4,5). Moreover, lymphatic vessels collapse and become dysfunctional as melanomas progress(6,7). Therefore, it is unclear whether (and how) lymphangiogenesis contributes to visceral metastasis. Soluble and vesicle-associated proteins secreted by tumours and/or their stroma have been proposed to condition pre-metastatic sites in patients with melanoma(8-14). Still, the identities and prognostic value of lymphangiogenic mediators remain unclear(2,14). Moreover, our understanding of lymphangiogenesis (in melanomas and other tumour types) is limited by the paucity of mouse models for live imaging of distal pre-metastatic niches(15). Injectable lymphatic tracers have been developed(7), but their limited diffusion precludes whole-body imaging at visceral sites(16). Vascular endothelial growth factor receptor 3 (VEGFR3) is an attractive 'lymphoreporter' 17 because its expression is strongly downregulated in normal adult lymphatic endothelial cells, but is activated in pathological situations such as inflammation and cancer(17,18). Here, we exploit this inducibility of VEGFR3 to engineer mouse melanoma models for whole-body imaging of metastasis generated by human cells, clinical biopsies or endogenously deregulated oncogenic pathways. This strategy revealed early induction of distal pre-metastatic niches uncoupled from lymphangiogenesis at primary lesions. Analyses of the melanoma secretome and validation in clinical specimens showed that the heparin-binding factor midkine is a systemic inducer of neo-lymphangiogenesis that defines patient prognosis. This role of midkine was linked to a paracrine activation of the mTOR pathway in lymphatic endothelial cells. These data support the use of VEGFR3 reporter mice as a 'MetAlert' discovery platform for drivers and inhibitors of metastasis.
C1 [Olmeda, David; Cerezo-Wallis, Daniela; Pennacchi, Paula C.; Contreras-Alcalde, Marta; Cifdaloz, Metehan; Catena, Xavier; Calvo, Tonantzin G.; Canon, Estela; Alonso-Curbelo, Direna; Suarez, Javier; Osterloh, Lisa; Soengas, Maria S.] Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.
   [Riveiro-Falkenbach, Erica; Rodriguez-Peralto, Jose L.] Univ Complutense Madrid, Inst I 12, Hosp Univ Octubre 12, Med Sch,Dept Pathol, Madrid 28041, Spain.
   [Ibarz, Nuria; Munoz, Javier] Spanish Natl Canc Res Ctr CNIO, Prote Unit, Biotechnol Programme, Madrid 28029, Spain.
   [Grana, Osvaldo] Spanish Natl Canc Res Ctr CNIO, Bioinformat Unit, Struct Biol & Biocomp Programme, Madrid 28029, Spain.
   [Mulero, Francisca] Spanish Natl Canc Res Ctr CNIO, Mol Imaging Unit, Biotechnol Programme, Madrid 28029, Spain.
   [Megias, Diego] Spanish Natl Canc Res Ctr CNIO, Confocal Microscopy Unit, Biotechnol Programme, Madrid 28029, Spain.
   [Canamero, Marta] Spanish Natl Canc Res Ctr CNIO, Histopathol Unit, Biotechnol Programme, Madrid 28029, Spain.
   [Martinez-Torrecuadrada, Jorge L.] Spanish Natl Canc Res Ctr CNIO, Crystallog & Prot Engn Unit, Biotechnol Programme, Madrid 28029, Spain.
   [Mondal, Chandrani; Di Martino, Julie; Bravo-Cordero, J. Javier] Icahn Sch Med Mt Sinai, Tisch Canc Inst, Div Hematol & Oncol, Dept Med, New York, NY 10029 USA.
   [Lora, David] Hosp Univ 12 Octubre, Inst I 12, CIBERESP, Madrid 28041, Spain.
   [Martinez-Corral, Ines; Ortega, Sagrario] Spanish Natl Canc Res Ctr CNIO, Transgen Mice Unit, Biotechnol Programme, Madrid 28029, Spain.
   [Puig, Susana] Hosp Clin Barcelona, Inst Invest Biomed August Pi & Sunyer, Melanoma Unit, Dermatol Dept, E-08036 Barcelona, Spain.
   [Ortiz-Romero, Pablo] Univ Complutense Madrid, Hosp Univ Octubre 12, Inst I 12, Dept Dermatol,Med Sch, Madrid 28041, Spain.
   [Alonso-Curbelo, Direna] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA.
   [Cifdaloz, Metehan] Roche Innovat Ctr Munich, Roche Pharma Res & Early Dev, D-82377 Penzberg, Germany.
   [Martinez-Corral, Ines] Uppsala Univ, Dept Immunol, Genet & Pathol & Rudbeck Lab, S-75185 Uppsala, Sweden.
C3 Centro Nacional de Investigaciones Oncologicas (CNIO); Hospital Universitario 12 de Octubre; Complutense University of Madrid; Centro Nacional de Investigaciones Oncologicas (CNIO); Centro Nacional de Investigaciones Oncologicas (CNIO); Centro Nacional de Investigaciones Oncologicas (CNIO); Centro Nacional de Investigaciones Oncologicas (CNIO); Centro Nacional de Investigaciones Oncologicas (CNIO); Centro Nacional de Investigaciones Oncologicas (CNIO); Icahn School of Medicine at Mount Sinai; CIBER - Centro de Investigacion Biomedica en Red; CIBERESP; Hospital Universitario 12 de Octubre; Centro Nacional de Investigaciones Oncologicas (CNIO); University of Barcelona; Hospital Clinic de Barcelona; IDIBAPS; Complutense University of Madrid; Hospital Universitario 12 de Octubre; Memorial Sloan Kettering Cancer Center; Uppsala University
RP Soengas, MS (corresponding author), Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.
EM msoengas@cnio.es
FU Spanish Ministry of Economy and Innovation [SAF2014-56868-R]; Asociacion Espanola Contra el Cancer (AECC); Worldwide Cancer Research, an Established Investigator Award from Melanoma Research Alliance (MRA); L'Oreal Paris USA-MRA Team Science Award for Woman in Scientific Research; MINECO [SAF2013-45504-R, SAF2013-44866-R]; Ramon y Cajal Programme (MINECO) [RYC-2012-10651]; Spanish Ministry of Health [FIS 2014/1737, 11/02568, FIS 2014/01784, 11/1759]; AMIT Project/CDTI/CENIT Programme (MICINN); NCI [K22CA196750]; TCI Young Scientist Cancer Research Award JJR Fund [P30 CA196521]; ARC Foundation; Fundacion Cientifica de la Asociacion Espanola Contra el Cancer; Fundacion La Caixa; Immutrain Marie Sklodowska-Curie ITN Grant;  [PT13/0001]; National Cancer Institute [P30CA196521] Funding Source: NIH RePORTER
NR 44
TC 125
Z9 141
U1 0
U2 40
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 29
PY 2017
VL 546
IS 7660
BP 676
EP +
DI 10.1038/nature22977
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY9QB
UT WOS:000404332000052
PM 28658220
DA 2026-03-09
ER

PT J
AU Karim, W
   Spreafico, C
   Kleibert, A
   Gobrecht, J
   VandeVondele, J
   Ekinci, Y
   van Bokhoven, JA
AF Karim, Waiz
   Spreafico, Clelia
   Kleibert, Armin
   Gobrecht, Jens
   VandeVondele, Joost
   Ekinci, Yasin
   van Bokhoven, Jeroen A.
TI Catalyst support effects on hydrogen spillover
SO NATURE
LA English
DT Article
ID excess electrons; atom spillover; gamma-alumina; anatase; tio2; dft; spectroscopy; adsorption; reduction; platinum
AB Hydrogen spillover(1) is the surface migration of activated hydrogen atoms from a metal catalyst particle, on which they are generated, onto the catalyst support(2). The phenomenon has been much studied(3-7) and its occurrence on reducible supports such as titanium oxide is established, yet questions remain about whether hydrogen spillover can take place on nonreducible supports such as aluminium oxide(8-13). Here we use the enhanced precision of top-down nanofabrication(14,15) to prepare controlled and precisely tunable model systems that allow us to quantify the efficiency and spatial extent of hydrogen spillover on both reducible and nonreducible supports. We place multiple pairs of iron oxide and platinum nanoparticles on titanium oxide and aluminium oxide supports, varying the distance between the pairs from zero to 45 nanometres with a precision of one nanometre. We then observe the extent of the reduction of the iron oxide particles by hydrogen atoms generated on the platinum using single-particle in situ X-ray absorption spectromicroscopy(14) applied simultaneously to all particle pairs. The data, in conjunction with density functional theory calculations(16,17), reveal fast hydrogen spillover on titanium oxide that reduces remote iron oxide nanoparticles via coupled proton-electron transfer. In contrast, spillover on aluminium oxide is mediated by three-coordinated aluminium centres that also interact with water and that give rise to hydrogen mobility competing with hydrogen desorption; this results in hydrogen spillover about ten orders of magnitude slower than on titanium oxide and restricted to very short distances from the platinum particle. We anticipate that these observations will improve our understanding of hydrogen storage(18,19) and catalytic reactions involving hydrogen(8,11-13), and that our approach to creating and probing model catalyst systems will provide opportunities for studying the origin of synergistic effects in supported catalysts that combine multiple functionalities.
C1 [Karim, Waiz; van Bokhoven, Jeroen A.] Swiss Fed Inst Technol, Inst Chem & Bioengn, CH-8093 Zurich, Switzerland.
   [Karim, Waiz; Gobrecht, Jens; Ekinci, Yasin] Paul Scherrer Inst, Lab Micro & Nanotechnol, CH-5232 Villigen, Switzerland.
   [Karim, Waiz; van Bokhoven, Jeroen A.] Paul Scherrer Inst, Lab Catalysis & Sustainable Chem, CH-5232 Villigen, Switzerland.
   [Spreafico, Clelia; VandeVondele, Joost] Swiss Fed Inst Technol, Dept Mat, Nanoscale Simulat, CH-8093 Zurich, Switzerland.
   [Kleibert, Armin] Paul Scherrer Inst, Swiss Light Source, CH-5232 Villigen, Switzerland.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich; Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute; Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute; Swiss Federal Institutes of Technology Domain; ETH Zurich; Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute
RP van Bokhoven, JA (corresponding author), Swiss Fed Inst Technol, Inst Chem & Bioengn, CH-8093 Zurich, Switzerland.; Ekinci, Y (corresponding author), Paul Scherrer Inst, Lab Micro & Nanotechnol, CH-5232 Villigen, Switzerland.; van Bokhoven, JA (corresponding author), Paul Scherrer Inst, Lab Catalysis & Sustainable Chem, CH-5232 Villigen, Switzerland.
EM yasin.ekinci@psi.ch; jeroen.vanbokhoven@chem.ethz.ch
FU Paul Scherrer Institute (PSI) Research Commission; European Union [277910]; Swiss National Supercomputer Center [ch5]
NR 58
TC 917
Z9 1011
U1 52
U2 1310
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 5
PY 2017
VL 541
IS 7635
BP 68
EP +
DI 10.1038/nature20782
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6NA
UT WOS:000396119500030
PM 28054605
DA 2026-03-09
ER

PT J
AU Chen, SY
   Zhu, B
   Yin, CQ
   Liu, W
   Han, CP
   Chen, BE
   Liu, TZ
   Li, X
   Chen, X
   Li, CY
   Hu, LM
   Zhou, J
   Xu, ZX
   Gao, XM
   Wu, X
   Goding, CR
   Cui, RT
AF Chen, Shuyang
   Zhu, Bo
   Yin, Chengqian
   Liu, Wei
   Han, Changpeng
   Chen, Baoen
   Liu, Tongzheng
   Li, Xin
   Chen, Xiang
   Li, Chunying
   Hu, Limin
   Zhou, Jun
   Xu, Zhi-Xiang
   Gao, Xiumei
   Wu, Xu
   Goding, Colin R.
   Cui, Rutao
TI Palmitoylation-dependent activation of MC1R prevents melanomagenesis
SO NATURE
LA English
DT Article
ID melanocortin 1 receptor; dna-damage; human melanocytes; uv exposure; risk; metaanalysis; association; population; regulator; phenotype
AB The melanocortin-1 receptor (MC1R), a G-protein-coupled receptor, has a crucial role in human and mouse pigmentation(1-8). Activation of MC1R in melanocytes by alpha-melanocyte-stimulating hormone (alpha-MSH)(9) stimulates cAMP signalling and melanin production and enhances DNA repair after ultraviolet irradiation(10-16). Individuals carrying MC1R variants, especially those associated with red hair colour, fair skin and poor tanning ability (denoted as RHC variants), are associated with higher risk of melanoma(5,17-20). However, how MC1R activity is modulated by ultraviolet irradiation, why individuals with red hair are more prone to developing melanoma, and whether the activity of RHC variants might be restored for therapeutic benefit are unknown. Here we demonstrate a potential MC1R-targeted intervention strategy in mice to rescue loss-of-function MC1R in MC1R RHC variants for therapeutic benefit by activating MC1R protein palmitoylation. MC1R palmitoylation, primarily mediated by the protein-acyl transferase ZDHHC13, is essential for activating MC1R signalling, which triggers increased pigmentation, ultraviolet-B-induced G1-like cell cycle arrest and control of senescence and melanomagenesis in vitro and in vivo. Using C57BL/6J-Mc1r(e/e)J mice, in which endogenous MC1R is prematurely terminated, expressing Mc1r RHC variants, we show that pharmacological activation of palmitoylation rescues the defects of Mc1r RHC variants and prevents melanomagenesis. The results highlight a central role for MC1R palmitoylation in pigmentation and protection against melanoma.
C1 [Chen, Shuyang; Zhu, Bo; Yin, Chengqian; Liu, Wei; Han, Changpeng; Li, Xin; Cui, Rutao] Boston Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02118 USA.
   [Chen, Baoen; Wu, Xu] Harvard Med Sch, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA.
   [Liu, Tongzheng] Jinan Univ, Inst Tumor Pharmacol, Guangzhou 510632, Guangdong, Peoples R China.
   [Chen, Xiang] Cent S Univ, Xiangya Hosp, Hunan Key Lab Skin Canc & Psoriasis, Dept Dermatol, Changsha 410008, Hunan, Peoples R China.
   [Li, Chunying] Fourth Mil Med Univ, Xijing Hosp, Dept Dermatol, Xian 710000, Shaanxi, Peoples R China.
   [Hu, Limin; Gao, Xiumei] Tianjin Univ Tradit Chinese Med, Tianjin State Key Lab Modern Chinese Med, Tianjin 300193, Peoples R China.
   [Zhou, Jun] Nankai Univ, Coll Life Sci, State Key Lab Med Chem Biol, Tianjin 300071, Peoples R China.
   [Xu, Zhi-Xiang] Univ Alabama Birmingham, Div Hematol & Oncol, Dept Med, Comprehens Canc Ctr, Birmingham, AL 35294 USA.
   [Goding, Colin R.] Univ Oxford, Ludwig Inst Canc Res, Oxford OX3 7DQ, England.
C3 Boston University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Jinan University; Central South University; Air Force Medical University; Tianjin University of Traditional Chinese Medicine; Nankai University; University of Alabama System; University of Alabama Birmingham; Ludwig Institute for Cancer Research; University of Oxford
RP Cui, RT (corresponding author), Boston Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02118 USA.
EM rutaocui@bu.edu
FU National Institutes of Health [R01CA137098, R01CA193913, R01CA196896]; Department of Defense [CA140020]; Melanoma Research Foundation; Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China [81428025]; National Natural Science Foundation of China [81630106]; Ludwig Institute for Cancer Research
NR 35
TC 186
Z9 217
U1 3
U2 102
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 21
PY 2017
VL 549
IS 7672
BP 399
EP +
DI 10.1038/nature23887
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FH7PB
UT WOS:000411381300038
PM 28869973
DA 2026-03-09
ER

PT J
AU Fadok, JP
   Krabbe, S
   Markovic, M
   Courtin, J
   Xu, C
   Massi, L
   Botta, P
   Bylund, K
   Müller, C
   Kovacevic, A
   Tovote, P
   Lüthi, A
AF Fadok, Jonathan P.
   Krabbe, Sabine
   Markovic, Milica
   Courtin, Julien
   Xu, Chun
   Massi, Lema
   Botta, Paolo
   Bylund, Kristine
   Mueller, Christian
   Kovacevic, Aleksandar
   Tovote, Philip
   Luthi, Andreas
TI A competitive inhibitory circuit for selection of active and passive fear responses
SO NATURE
LA English
DT Article
ID central amygdala; defensive behaviors; periaqueductal gray; projection neurons; conditioned fear; organization; anxiety; cells; rat; information
AB When faced with threat, the survival of an organism is contingent upon the selection of appropriate active or passive behavioural responses(1-3). Freezing is an evolutionarily conserved passive fear response that has been used extensively to study the neuronal mechanisms of fear and fear conditioning in rodents(4). However, rodents also exhibit active responses such as flight under natural conditions(2). The central amygdala (CEA) is a forebrain structure vital for the acquisition and expression of conditioned fear responses, and the role of specific neuronal sub-populations of the CEA in freezing behaviour is well-established(1,5-7). Whether the CEA is also involved in flight behaviour, and how neuronal circuits for active and passive fear behaviour interact within the CEA, are not yet understood. Here, using in vivo optogenetics and extracellular recordings of identified cell types in a behavioural model in which mice switch between conditioned freezing and flight, we show that active and passive fear responses are mediated by distinct and mutually inhibitory CEA neurons. Cells expressing corticotropin-releasing factor (CRF+) mediate conditioned flight, and activation of somatostatin-positive (SOM+) neurons initiates passive freezing behaviour. Moreover, we find that the balance between conditioned flight and freezing behaviour is regulated by means of local inhibitory connections between CRF+ and SOM+ neurons, indicating that the selection of appropriate behavioural responses to threat is based on competitive interactions between two defined populations of inhibitory neurons, a circuit motif allowing for rapid and flexible action selection.
C1 [Fadok, Jonathan P.; Krabbe, Sabine; Markovic, Milica; Courtin, Julien; Xu, Chun; Massi, Lema; Botta, Paolo; Bylund, Kristine; Mueller, Christian; Kovacevic, Aleksandar; Tovote, Philip; Luthi, Andreas] Friedrich Miescher Inst Biomed Res, Maulbeerstr 66, CH-4058 Basel, Switzerland.
   [Markovic, Milica; Botta, Paolo; Luthi, Andreas] Univ Basel, CH-4000 Basel, Switzerland.
   [Botta, Paolo] Champalimaud Ctr Unknown, P-1400038 Lisbon, Portugal.
C3 Friedrich Miescher Institute for Biomedical Research; University of Basel; Fundacao Champalimaud
RP Tovote, P; Lüthi, A (corresponding author), Friedrich Miescher Inst Biomed Res, Maulbeerstr 66, CH-4058 Basel, Switzerland.; Lüthi, A (corresponding author), Univ Basel, CH-4000 Basel, Switzerland.
EM philip.tovote@fmi.ch; andreas.luthi@fmi.ch
FU EMBO LTF [952-2011]; NARSAD Young Investigator Fellowship; EMBO ALTF [1579-2010]; National Center of Competences in Research: 'SYNAPSY - The Synaptic Bases of Mental Diseases' - Swiss National Science Foundation; SNSF; ERC; Novartis Research Foundation
NR 38
TC 320
Z9 391
U1 2
U2 113
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 2
PY 2017
VL 542
IS 7639
BP 96
EP +
DI 10.1038/nature21047
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6MY
UT WOS:000396119300038
PM 28117439
DA 2026-03-09
ER

PT J
AU Kawaguchi, K
   Kageyama, R
   Sano, M
AF Kawaguchi, Kyogo
   Kageyama, Ryoichiro
   Sano, Masaki
TI Topological defects control collective dynamics in neural progenitor cell cultures
SO NATURE
LA English
DT Article
ID giant number fluctuations; active nematics; migration; order; soft
AB Cultured stem cells have become a standard platform not only for regenerative medicine and developmental biology but also for biophysical studies. Yet, the characterization of cultured stem cells at the level of morphology and of the macroscopic patterns resulting from cell-to-cell interactions remains largely qualitative. Here we report on the collective dynamics of cultured murine neural progenitor cells (NPCs), which are multipotent stem cells that give rise to cells in the central nervous system(1). At low densities, NPCs moved randomly in an amoeba-like fashion. However, NPCs at high density elongated and aligned their shapes with one another, gliding at relatively high velocities. Although the direction of motion of individual cells reversed stochastically along the axes of alignment, the cells were capable of forming an aligned pattern up to length scales similar to that of the migratory stream observed in the adult brain(2). The two-dimensional order of alignment within the culture showed a liquid-crystalline pattern containing interspersed topological defects with winding numbers of +1/2 and -1/2 (half-integer due to the nematic feature that arises from the head-tail symmetry of cell-to-cell interaction). We identified rapid cell accumulation at +1/2 defects and the formation of three-dimensional mounds. Imaging at the single-cell level around the defects allowed us to quantify the velocity field and the evolving cell density; cells not only concentrate at +1/2 defects, but also escape from -1/2 defects. We propose a generic mechanism for the instability in cell density around the defects that arises from the interplay between the anisotropic friction and the active force field.
C1 [Kawaguchi, Kyogo; Sano, Masaki] Univ Tokyo, Dept Phys, Bunkyo Ku, Tokyo 1130033, Japan.
   [Kawaguchi, Kyogo] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA.
   [Kawaguchi, Kyogo; Sano, Masaki] Univ Tokyo, Universal Biol Inst, Bunkyo Ku, Tokyo 1130033, Japan.
   [Kageyama, Ryoichiro] Kyoto Univ, Inst Frontier Life & Med Sci, Sakyo Ku, Kyoto 6068507, Japan.
C3 University of Tokyo; Harvard University; Harvard Medical School; University of Tokyo; Kyoto University
RP Kawaguchi, K; Sano, M (corresponding author), Univ Tokyo, Dept Phys, Bunkyo Ku, Tokyo 1130033, Japan.; Kawaguchi, K (corresponding author), Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA.; Kawaguchi, K; Sano, M (corresponding author), Univ Tokyo, Universal Biol Inst, Bunkyo Ku, Tokyo 1130033, Japan.
EM kyogo_kawaguchi@hms.harvard.edu; sano@phys.s.u-tokyo.ac.jp
FU Core Research for Evolutional Science and Technology [JPMJCR12W2]; KAKENHI from MEXT, Japan [25103004, 16H06480]; Platform for Dynamic Approaches to Living Systems from MEXT, Japan;  [24-8031];  [28-908]; Grants-in-Aid for Scientific Research [25103004, 16H06480] Funding Source: KAKEN
NR 36
TC 344
Z9 393
U1 4
U2 176
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 18
PY 2017
VL 545
IS 7654
BP 327
EP +
DI 10.1038/nature22321
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV0WF
UT WOS:000401466500058
PM 28403137
DA 2026-03-09
ER

PT J
AU Carus-Cadavieco, M
   Gorbati, M
   Ye, L
   Bender, F
   van der Veldt, S
   Kosse, C
   Börgers, C
   Lee, SY
   Ramakrishnan, C
   Hu, YB
   Denisova, N
   Ramm, F
   Volitaki, E
   Burdakov, D
   Deisseroth, K
   Ponomarenko, A
   Korotkova, T
AF Carus-Cadavieco, Marta
   Gorbati, Maria
   Ye, Li
   Bender, Franziska
   van der Veldt, Suzanne
   Kosse, Christin
   Borgers, Christoph
   Lee, Soo Yeun
   Ramakrishnan, Charu
   Hu, Yubin
   Denisova, Natalia
   Ramm, Franziska
   Volitaki, Emmanouela
   Burdakov, Denis
   Deisseroth, Karl
   Ponomarenko, Alexey
   Korotkova, Tatiana
TI Gamma oscillations organize top-down signalling to hypothalamus and enable food seeking
SO NATURE
LA English
DT Article
ID working-memory; lateral septum; hippocampus; neurons; information; activation; frequency; responses; circuits; rhythms
AB Both humans and animals seek primary rewards in the environment, even when such rewards do not correspond to current physiological needs. An example of this is a dissociation between food-seeking behaviour and metabolic needs, a notoriously difficult-to treat symptom of eating disorders. Feeding relies on distinct cell groups in the hypothalamus(1-4), the activity of which also changes in anticipation of feeding onset(5-7). The hypothalamus receives strong descending inputs from the lateral septum, which is connected, in turn, with cortical networks', but cognitive regulation of feeding-related behaviours is not yet understood. Cortical cognitive processing(9,10) involves gamma oscillations(11-15), which support memory(16,17), attention(18), cognitive flexibility(19) and sensory responses(20). These functions contribute crucially to feeding behaviour by unknown neural mechanisms. Here we show that coordinated gamma (30-90 Hz) oscillations in the lateral hypothalamus and upstream brain regions organize food seeking behaviour in mice. Gamma-rhythmic input to the lateral hypothalamus from somatostatin-positive lateral septum cells evokes food approach without affecting food intake. Inhibitory inputs from the lateral septum enable separate signalling by lateral hypothalamus neurons according to their feeding-related activity, making them fire at distinct phases of the gamma oscillation. Upstream, medial prefrontal cortical projections provide gamma rhythmic inputs to the lateral septum; these inputs are causally associated with improved performance in a food-rewarded learning task. Overall, our work identifies a top-down pathway that uses gamma synchronization to guide the activity of subcortical networks and to regulate feeding behaviour by dynamic reorganization of functional cell groups in the hypothalamus.
C1 [Carus-Cadavieco, Marta; Gorbati, Maria; Bender, Franziska; van der Veldt, Suzanne; Hu, Yubin; Denisova, Natalia; Ramm, Franziska; Volitaki, Emmanouela; Ponomarenko, Alexey; Korotkova, Tatiana] Leibniz Inst Mol Pharmacol FMP, NeuroCure Cluster Excellence, Behav Neurodynam Grp, Berlin, Germany.
   [Ye, Li; Lee, Soo Yeun; Ramakrishnan, Charu; Deisseroth, Karl] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.
   [Ye, Li; Deisseroth, Karl] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Kosse, Christin; Burdakov, Denis] Francis Crick Inst, Mill Hill Lab, London NW7 1AA, England.
   [Borgers, Christoph] Tufts Univ, Dept Math, Medford, MA 02155 USA.
   [Deisseroth, Karl] Stanford Univ, Dept Psychiat & Behav Sci, W080 Clark Ctr,318 Campus Dr West, Stanford, CA 94305 USA.
C3 Leibniz Association; Leibniz Forschungsinstitut furr Molekulare Pharmakologie (FMP); Stanford University; Howard Hughes Medical Institute; Stanford University; Francis Crick Institute; Tufts University; Stanford University
RP Ponomarenko, A; Korotkova, T (corresponding author), Leibniz Inst Mol Pharmacol FMP, NeuroCure Cluster Excellence, Behav Neurodynam Grp, Berlin, Germany.
EM ponomarenko@fmp-berlin.de; korotkova@fmp-berlin.de
FU Human Frontier Science Program (HFSP) [RGY0076/2012]; Deutsche Forschungsgemeinschaft (DFG) [Exc 257 NeuroCure, SPP1665]; NIH (the Collaborative Research in Computational Neuroscience, CRCNS) [1R01 NS067199]; German-Israeli Foundation for Scientific Research and Development [GIF: I-1326-421.13/2015]; Medical Research Council [1363890] Funding Source: researchfish
NR 30
TC 102
Z9 118
U1 6
U2 58
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 9
PY 2017
VL 542
IS 7640
BP 232
EP 236
DI 10.1038/nature21066
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK2DJ
UT WOS:000393737500041
PM 28146472
DA 2026-03-09
ER

PT J
AU Dekker, J
   Belmont, AS
   Guttman, M
   Leshyk, VO
   Lis, JT
   Lomvardas, S
   Mirny, LA
   O'Shea, CC
   Park, PJ
   Ren, B
   Politz, JCR
   Shendure, J
   Zhong, S
   van den Berg, A
   Heckert, AB
   Bertero, A
   Bortnick, A
   Kukalev, A
   Moore, A
   Pombo, A
   Hansen, AS
   Chiariello, AM
   Sali, A
   Belmont, A
   Stephens, A
   Nand, A
   Valton, AL
   Goloborodko, A
   He, A
   van Steensel, B
   Webb, B
   Roscoe, B
   Li, B
   Ren, B
   Chait, B
   Blau, CA
   Annunziatella, C
   Ware, C
   Wei, CL
   Leemans, C
   Disteche, C
   Jarjour, C
   Thieme, C
   Murry, C
   Barcia, CT
   Trapnell, C
   Murre, C
   Peric-Hupkes, D
   Simon, D
   Bartlett, D
   Gao, D
   Plewczynski, D
   Gilbert, D
   Gorkin, D
   McSwiggen, D
   Lin, D
   Aghamirzaie, D
   Banigan, E
   Finn, E
   Sontheimer, E
   Cadete, FT
   Alber, F
   Mast, F
   Filippova, G
   Yardimci, GG
   Fudenberg, G
   Loof, G
   Bonora, G
   Pegoraro, G
   Caglio, G
   Polles, G
   Ozadam, H
   Shin, H
   Pliner, H
   Reinecke, H
   Li, HC
   Tjong, H
   Fang, H
   Marie-Nelly, H
   Belaghzal, H
   Brandao, H
   Zhao, HM
   Cissé, I
   Jung, IY
   Tasan, I
   Juric, I
   Andrews, JO
   Schreiber, J
   Spille, JH
   Zimmerman, J
   Shendure, J
   Dixon, J
   Ma, J
   Xu, J
   Sima, J
   Dekker, J
   Gibcus, J
   Nuebler, J
   Aitchison, J
   Marko, J
   Lam, J
   Mendieta, JAB
   Mulia, JCR
   Cayford, J
   Cook, K
   Mitzelfelt, K
   Parsi, KM
   Klein, K
   Brueckner, L
   Mirny, L
   Zhang, L
   Pabon, L
   Chen, L
   Carpp, L
   Yang, LY
   Pei, L
   Sander, M
   Imakaev, M
   Nicodemi, M
   Schueler, M
   Falk, M
   Denholtz, M
   Libbrecht, M
   Bolukbasi, MF
   Zhen, M
   Yu, M
   Rout, M
   Hu, M
   Mir, M
   Armani, N
   Hua, N
   Kubo, N
   Abdennur, N
   Krietenstein, N
   Khanna, N
   Dudko, O
   Rando, O
   Luo, O
   Chaturvedi, P
   Blainey, P
   Fields, P
   Wang, P
   Li, QJ
   Casellas, R
   Gudla, R
   Maeh, R
   Kempfer, R
   Beagrie, R
   Biggs, R
   Fang, RX
   Qiu, RL
   Genga, RMJ
   Srivatsan, S
   Kumar, S
   Wolfe, S
   Shaffer, S
   Kim, SS
   Shachar, S
   Bianco, S
   Jain, S
   Sasaki, T
   Isoda, T
   Misteli, T
   van Schaik, T
   Liu, T
   Hsieh, TH
   Ramani, V
   Agarwal, V
   Dileep, V
   Chandra, V
   Winick-Ng, W
   Li, WY
   Noble, W
   Darzacq, X
   Zhou, XHJ
   Deng, XX
   Xiong, X
   Yang, XL
   Yang, Y
   Zhang, Y
   Kou, Y
   Zhou, Y
   Ruan, YJ
   Chen, Y
   Wang, YC
   Qiu, YJ
   Duan, ZJ
   Tang, ZH
   Ozer, A
   Cote, A
   Tanay, A
   Chow, A
   Omer, AD
   Hwang, A
   Dudley, C
   Bartman, C
   Danko, C
   Varnai, C
   Aiden, EL
   Blobel, G
   Lin, HN
   Phillips-Cremins, J
   Lis, J
   Wang, J
   Ray, J
   Dunagin, M
   Arrastia, M
   Lai, M
   Curtis, M
   Kushner, M
   Pham, M
   Wang, M
   Yang, M
   Guttman, M
   Durand, NC
   Ollikainen, N
   Munn, P
   Fraser, P
   Ismagilov, R
   Hsu, S
   Bhardwaj, S
   Quinodoz, S
   Nagano, T
   Amarante, T
   Zipfel, W
   Baran, Y
   Lubling, Y
   Wang, Z
   Palla, A
   Muimbey-Wahula, A
   Vertii, A
   Moradian, A
   Larabell, C
   Brangwynne, C
   Lindsay, C
   Sanders, D
   Scalzo, D
   Cannavò, E
   McDermott, G
   Ozadam, H
   Ma, H
   Moresco, J
   Ritland, J
   Dekker, J
   Rinn, J
   Yates, J
   Zhu, J
   Roth, K
   Gerace, L
   Tait, L
   Brown, L
   Zhu, L
   Kordon, M
   Groudine, M
   Le Gros, M
   Escamilla, M
   Sweredoski, M
   Guttman, M
   Kaufman, P
   Maas, P
   Barutcu, R
   Amin, R
   Baboo, S
   Debartolome, SM
   Hess, S
   Lomvardas, S
   Pederson, T
   Szempruch, T
   Walkup, W
   Sun, XM
   Shin, YD
   Senecal, A
   Hansen, A
   Barentine, A
   Spakowitz, A
   Gustavsson, AK
   Tangara, A
   Rieger, B
   Nijmeijer, B
   Lim, B
   English, B
   Barton, C
   Kenworthy, C
   Carroll, C
   O'Shea, C
   Boassa, D
   Baddeley, D
   Grunwald, D
   Birney, E
   Chuang, F
   Castillon, G
   Wang, HF
   Grabmayr, H
   Chen, HT
   Ou, H
   Ellenberg, J
   Liphardt, J
   Soroczynski, J
   Biswas, J
   Yao, J
   Yin, JW
   Bewersdorf, J
   Ries, J
   Bardales, J
   Roberti, J
   Zaret, K
   Chung, K
   Lam, K
   Qi, LS
   Schmitt, L
   Barinov, L
   Tu, LC
   Yang, LL
   Tian, L
   Cai, L
   Ellisman, M
   Mackey, M
   Haberl, M
   Huisman, M
   Clark, M
   Levo, M
   Levine, M
   Mir, M
   Walther, N
   Oedegaard, O
   Guo, P
   Zheng, QS
   Cheng, RH
   Ghosh, R
   Ramachandra, R
   Coleman, R
   Singer, R
   Liu, RW
   Walden, R
   Phan, S
   Ramachandra, S
   Coleman, R
   Singer, R
   Liu, RW
   Walden, R
   Phan, S
   Quanming, S
   Ganguly, S
   Alexander, S
   Peltier, S
   Fukaya, T
   Deerinck, T
   Gregor, T
   Fitzgerald, T
   Moerner, W
   Darzacq, X
   Zhang, YD
   Li, YM
   Takei, Y
   Izumiya, Y
   Lin, Y
   Frankenstein, Z
   Ren, B
   Kling, C
   Rivera, C
   Zheng, HZ
   Rivera, KZ
   Hebert, L
   Rivas-Astroza, M
   Wu, QY
   Calandrelli, R
   Subramaniam, S
   Zhong, S
   Chien, S
   Leshyk, V
   Chen, WZ
   Cao, XY
   Yan, ZM
   Balashov, A
   Schroeder, A
   Goloborodko, A
   Alver, BH
   Vitzthum, C
   Nam, C
   Li, DF
   Purushotham, D
   Pehrsson, EC
   Yue, F
   Lekschas, F
   Pfister, H
   Strobelt, H
   Brandao, H
   Jang, HS
   Luber, J
   Hwang, J
   Walsh, J
   Johnson, J
   Nubler, J
   Kirli, K
   Mirny, L
   Falk, M
   Imakaev, M
   Choudhary, MN
   Abdennur, N
   Gehlenborg, N
   Kerpedjiev, P
   Park, P
   Kharchenko, PV
   Sears, RL
   Lee, S
   Wang, S
   Yang, T
   Hu, TXM
   Wang, T
   Hou, Y
AF Dekker, Job
   Belmont, Andrew S.
   Guttman, Mitchell
   Leshyk, Victor O.
   Lis, John T.
   Lomvardas, Stavros
   Mirny, Leonid A.
   O'Shea, Clodagh C.
   Park, Peter J.
   Ren, Bing
   Politz, Joan C. Ritland
   Shendure, Jay
   Zhong, Sheng
   van den Berg, Aafke
   Heckert, Alec Basil
   Bertero, Alessandro
   Bortnick, Alex
   Kukalev, Alexander
   Moore, Amanda
   Pombo, Ana
   Hansen, Anders Sejr
   Chiariello, Andrea Maria
   Sali, Andrej
   Belmont, Andrew
   Stephens, Andrew
   Nand, Ankita
   Valton, Anne-Laure
   Goloborodko, Anton
   He, Arthur
   van Steensel, Bas
   Webb, Ben
   Roscoe, Benjamin
   Li, Bin
   Ren, Bing
   Chait, Brian
   Blau, C. Anthony
   Annunziatella, Carlo
   Ware, Carol
   Wei, Chia Lin
   Leemans, Christ
   Disteche, Christine
   Jarjour, Christine
   Thieme, Christoph
   Murry, Chuck
   Barcia, Claudia Trevilla
   Trapnell, Cole
   Murre, Cornelis
   Peric-Hupkes, Daan
   Simon, Dan
   Bartlett, Daniel
   Gao, Daniel
   Plewczynski, Dariusz
   Gilbert, David
   Gorkin, David
   McSwiggen, David
   Lin, Dejun
   Aghamirzaie, Delasa
   Banigan, Ed
   Finn, Elizabeth
   Sontheimer, Erik
   Cadete, Filipe Tavares
   Alber, Frank
   Mast, Fred
   Filippova, Gala
   Yardimci, Galip Gurkan
   Fudenberg, Geoffrey
   Loof, Gesa
   Bonora, Giancarlo
   Pegoraro, Gianluca
   Caglio, Giulia
   Polles, Guido
   Ozadam, Hakan
   Shin, Hanjun
   Pliner, Hannah
   Reinecke, Hans
   Li, Haochen
   Tjong, Harianto
   Fang, He
   Marie-Nelly, Herve
   Belaghzal, Houda
   Brandao, Hugo
   Zhao, Huimin
   Cisse, Ibrahim
   Jung, Inkyung
   Tasan, Ipek
   Juric, Ivan
   Andrews, J. Owen
   Schreiber, Jacob
   Spille, Jan-Hendrik
   Zimmerman, Jared
   Shendure, Jay
   Dixon, Jesse
   Ma, Jian
   Xu, Jiang
   Sima, Jiao
   Dekker, Job
   Gibcus, Johan
   Nuebler, Johannes
   Aitchison, John
   Marko, John
   Lam, Jonathan
   Mendieta, Jorge A. Bardales
   Rivera Mulia, Juan Carlos
   Cayford, Justin
   Cook, Kate
   Mitzelfelt, Katie
   Parsi, Krishna Mohan
   Klein, Kyle
   Brueckner, Laura
   Mirny, Leonid
   Zhang, Liguo
   Pabon, Lil
   Chen, Lin
   Carpp, Lindsay
   Yang, Liyan
   Pei, Long
   Sander, Maike
   Imakaev, Maksim
   Nicodemi, Mario
   Schueler, Markus
   Falk, Martin
   Denholtz, Matt
   Libbrecht, Maxwell
   Bolukbasi, Mehmet Fatih
   Zhen, Meizhen
   Yu, Miao
   Rout, Michael
   Hu, Ming
   Mir, Mustafa
   Armani, Nadia
   Hua, Nan
   Kubo, Naoki
   Abdennur, Nezar
   Krietenstein, Nils
   Khanna, Nimish
   Dudko, Olga
   Rando, Oliver
   Luo, Oscar
   Chaturvedi, Pankaj
   Blainey, Paul
   Fields, Paul
   Wang, Ping
   Li, Qingjiao
   Casellas, Rafael
   Gudla, Reddy
   Maeh, Rene
   Kempfer, Rieke
   Beagrie, Robert
   Biggs, Ronald
   Fang, Rongxing
   Qiu, Ruolan
   Jude Genga, Ryan Michael
   Srivatsan, Sanjay
   Kumar, Sanjeev
   Wolfe, Scot
   Shaffer, Scott
   Kim, Seungsoo
   Shachar, Sigal
   Bianco, Simona
   Jain, Surbhi
   Sasaki, Takayo
   Isoda, Takeshi
   Misteli, Tom
   van Schaik, Tom
   Liu, Tristin
   Hsieh, Tsung-han
   Ramani, Vijay
   Agarwal, Vikram
   Dileep, Vishnu
   Chandra, Vivek
   Winick-Ng, Warren
   Li, Wenyuan
   Noble, William
   Darzacq, Xavier
   Zhou, Xianghong Jasmine
   Deng, Xinxian
   Xiong, Xiong
   Yang, Xiulan
   Yang, Yang
   Zhang, Yang
   Kou, Yi
   Zhou, Yi
   Ruan, Yijun
   Chen, Yu
   Wang, Yuchuan
   Qiu, Yunjiang
   Duan, ZhiJun
   Tang, Zhonghui
   Ozer, Abdullah
   Cote, Allison
   Tanay, Amos
   Chow, Amy
   Omer, Arina D.
   Hwang, Astra
   Dudley, Carmel
   Bartman, Caroline
   Danko, Charles
   Varnai, Csilla
   Aiden, Erez Lieberman
   Blobel, Gerd
   Lin, Hening
   Phillips-Cremins, Jennifer
   Lis, John
   Wang, Juan
   Ray, Judhajeet
   Dunagin, Margaret
   Arrastia, Mary
   Lai, Mason
   Curtis, Mathew
   Kushner, Max
   Pham, Melanie
   Wang, Miao
   Yang, Min
   Guttman, Mitchell
   Durand, Neva C.
   Ollikainen, Noah
   Munn, Paul
   Fraser, Peter
   Ismagilov, Rustem
   Hsu, Sarah
   Bhardwaj, Saurabh
   Quinodoz, Sofia
   Nagano, Takashi
   Amarante, Tauanne
   Zipfel, Warren
   Baran, Yael
   Lubling, Yaniv
   Wang, Zhong
   Palla, Ali
   Muimbey-Wahula, Alice
   Vertii, Anastassiia
   Moradian, Annie
   Larabell, Carolyn
   Brangwynne, Cliff
   Lindsay, Cory
   Sanders, David
   Scalzo, David
   Cannavò, Enrico
   McDermott, Gerry
   Ozadam, Hakan
   Ma, Hanhui
   Moresco, James
   Ritland, Joan
   Dekker, Job
   Rinn, John
   Yates, John
   Zhu, Julie (Lihua)
   Roth, Katharine
   Gerace, Larry
   Tait, Leah
   Brown, Lewis
   Zhu, Lian
   Kordon, Magda
   Groudine, Mark
   Le Gros, Mark
   Escamilla, Martin
   Sweredoski, Michael
   Guttman, Mitchell
   Kaufman, Paul
   Maas, Phil
   Barutcu, Rasim
   Amin, Rupesh
   Baboo, Sabyasachi
   Debartolome, Salvador Martinez
   Hess, Sonja
   Lomvardas, Stavros
   Pederson, Thoru
   Szempruch, Tony
   Walkup, Ward
   Sun, Xiaoming
   Shin, Yongdae
   Senecal, Adrien
   Hansen, Anders
   Barentine, Andrew
   Spakowitz, Andrew
   Gustavsson, Anna-Karin
   Tangara, Astou
   Rieger, Bernd
   Nijmeijer, Bianca
   Lim, Bomyi
   English, Brian
   Barton, Carl
   Kenworthy, Charles
   Carroll, Christopher
   O'Shea, Clodagh
   Boassa, Daniela
   Baddeley, David
   Grunwald, David
   Birney, Ewan
   Chuang, Frank
   Castillon, Guillaume
   Wang, Haifeng
   Grabmayr, Heinrich
   Chen, Hongtao
   Ou, Horng
   Ellenberg, Jan
   Liphardt, Jan
   Soroczynski, Jan
   Biswas, Jeetayu
   Yao, Jie
   Yin, Jingwen
   Bewersdorf, Joerg
   Ries, Jonas
   Bardales, Jorge
   Roberti, Julia
   Zaret, Kenneth
   Chung, Kenny
   Lam, Kit
   Qi, Lei S.
   Schmitt, Leslie
   Barinov, Lev
   Tu, Li-Chun
   Yang, Li-Ling
   Tian, Lin
   Cai, Long
   Ellisman, Mark
   Mackey, Mason
   Haberl, Matthias
   Huisman, Maximillian
   Clark, Michael
   Levo, Michal
   Levine, Mike
   Mir, Mustafa
   Walther, Nike
   Oedegaard, Oeyvind
   Guo, Peng
   Zheng, Qinsi
   Cheng, R. Holland
   Ghosh, Rajarshi
   Ramachandra, Ranjan
   Coleman, Robert
   Singer, Robert
   Liu, Ruiwu
   Walden, Ryan
   Phan, Sebastien
   Ramachandra, Shi
   Coleman, Robert
   Singer, Robert
   Liu, Ruiwu
   Walden, Ryan
   Phan, Sebastien
   Quanming, Shi
   Ganguly, Sourav
   Alexander, Stephanie
   Peltier, Steven
   Fukaya, Takashi
   Deerinck, Thomas
   Gregor, Thomas
   Fitzgerald, Tomas
   Moerner, William
   Darzacq, Xavier
   Zhang, Yandong
   Li, Yiming
   Takei, Yodai
   Izumiya, Yoshihiro
   Lin, Yu
   Frankenstein, Ziv
   Ren, Bing
   Kling, Carol
   Rivera, Catherine
   Zheng, Haizi
   Rivera, Kathia Zaleta
   Hebert, Lucie
   Rivas-Astroza, Marcelo
   Wu, Qiuyang
   Calandrelli, Riccardo
   Subramaniam, Shankar
   Zhong, Sheng
   Chien, Shu
   Leshyk, Victor
   Chen, Weizhong
   Cao, Xiaoyi
   Yan, Zhangming
   Balashov, Alexander
   Schroeder, Andy
   Goloborodko, Anton
   Alver, Burak Han
   Vitzthum, Carl
   Nam, Chris (Kee-Myoung)
   Li, Daofeng
   Purushotham, Deepak
   Pehrsson, Erica C.
   Yue, Feng
   Lekschas, Fritz
   Pfister, Hanspeter
   Strobelt, Hendrik
   Brandao, Hugo
   Jang, Hyo Sik
   Luber, Jacob
   Hwang, Jeewon (Grace)
   Walsh, Jennifer
   Johnson, Jeremy
   Nubler, Johannes
   Kirli, Koray
   Mirny, Leonid
   Falk, Martin
   Imakaev, Maxim
   Choudhary, Mayank N. K.
   Abdennur, Nezar
   Gehlenborg, Nils
   Kerpedjiev, Peter
   Park, Peter
   Kharchenko, Peter V.
   Sears, Renee L.
   Lee, Soo
   Wang, Su
   Yang, Tao
   Hu, Tim Xiaoming
   Wang, Ting
   Hou, Yiran
TI The 4D nucleome project
SO NATURE
LA English
DT Article
ID hi-c reveals; human genome; chromosome conformation; in-vivo; localization microscopy; spatial-organization; electron-microscopy; chromatin domains; gene-expression; high-resolution
AB The 4D Nucleome Network aims to develop and apply approaches to map the structure and dynamics of the human and mouse genomes in space and time with the goal of gaining deeper mechanistic insights into how the nucleus is organized and functions. The project will develop and benchmark experimental and computational approaches for measuring genome conformation and nuclear organization, and investigate how these contribute to gene regulation and other genome functions. Validated experimental technologies will be combined with biophysical approaches to generate quantitative models of spatial genome organization in different biological states, both in cell populations and in single cells.
C1 [Dekker, Job] Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Program Syst Biol,Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA.
   [Belmont, Andrew S.] Univ Illinois, Dept Cell & Dev Biol, Urbana, IL 61801 USA.
   [Guttman, Mitchell] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
   [Leshyk, Victor O.; Zhong, Sheng] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA.
   [Lis, John T.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA.
   [Lomvardas, Stavros] Columbia Univ, Dept Biochem & Mol Biophys, Mortimer B Zuckerman Mind Brain & Behav Inst, 630 W 168th St, New York, NY 10027 USA.
   [Mirny, Leonid A.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Mirny, Leonid A.] MIT, Dept Phys, Cambridge, MA 02139 USA.
   [O'Shea, Clodagh C.] Salk Inst Biol Studies, Mol & Cell Biol Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA.
   [Park, Peter J.] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA.
   [Ren, Bing] Univ Calif San Diego, Inst Genom Med, Dept Cellular & Mol Med, Ludwig Inst Canc Res,Moores Canc Ctr, La Jolla, CA 92093 USA.
   [Politz, Joan C. Ritland] Fred Hutchinson Canc Res Ctr, Basic Sci, 1100 Fairview Ave North, Seattle, WA 98109 USA.
   [Shendure, Jay] Univ Washington, Howard Hughes Med Inst, Dept Genome Sci, Seattle, WA 98109 USA.
C3 Howard Hughes Medical Institute; University of Massachusetts System; University of Massachusetts Worcester; University of Illinois System; University of Illinois Urbana-Champaign; California Institute of Technology; University of California System; University of California San Diego; Cornell University; Columbia University; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Salk Institute; Harvard University; Harvard Medical School; Ludwig Institute for Cancer Research; University of California System; University of California San Diego; Fred Hutchinson Cancer Center; University of Washington; University of Washington Seattle; Howard Hughes Medical Institute
RP Dekker, J (corresponding author), Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Program Syst Biol,Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA.
EM job.dekker@umassmed.edu
FU NHLBI NIH HHS [U01 HL129958] Funding Source: Medline; NIDA NIH HHS [U01 DA040582] Funding Source: Medline; NIDCD NIH HHS [R01 DC013560] Funding Source: Medline; NIDDK NIH HHS [U54 DK107965, U54 DK107980] Funding Source: Medline; NIGMS NIH HHS [P50 GM085764] Funding Source: Medline
NR 101
TC 497
Z9 577
U1 7
U2 236
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 14
PY 2017
VL 549
IS 7671
BP 219
EP 226
DI 10.1038/nature23884
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG7AE
UT WOS:000410555900035
PM 28905911
DA 2026-03-09
ER

PT J
AU Enoto, T
   Wada, Y
   Furuta, Y
   Nakazawa, K
   Yuasa, T
   Okuda, K
   Makishima, K
   Sato, M
   Sato, Y
   Nakano, T
   Umemoto, D
   Tsuchiya, H
AF Enoto, Teruaki
   Wada, Yuuki
   Furuta, Yoshihiro
   Nakazawa, Kazuhiro
   Yuasa, Takayuki
   Okuda, Kazufumi
   Makishima, Kazuo
   Sato, Mitsuteru
   Sato, Yousuke
   Nakano, Toshio
   Umemoto, Daigo
   Tsuchiya, Harufumi
TI Photonuclear reactions triggered by lightning discharge
SO NATURE
LA English
DT Article
ID gamma-ray flashes; neutron generation; winter thunderstorms; ground-level; mechanism; bursts; events; air
AB Lightning and thunderclouds are natural particle accelerators(1). Avalanches of relativistic runaway electrons, which develop in electric fields within thunderclouds(2,3), emit bremsstrahlung gamma-rays. These gamma-rays have been detected by ground-based observatories(4-9), by airborne detectors(10) and as terrestrial gamma-ray flashes from space(10-14). The energy of the gamma-rays is sufficiently high that they can trigger atmospheric photonuclear reactions(10,15-19) that produce neutrons and eventually positrons via beta(+) decay of the unstable radioactive isotopes, most notably N-13, which is generated via N-14 + gamma -> N-13 + n, where gamma denotes a photon and n a neutron. However, this reaction has hitherto not been observed conclusively, despite increasing observational evidence of neutrons(7,20,21) and positrons(10,22) that are presumably derived from such reactions. Here we report ground-based observations of neutron and positron signals after lightning. During a thunderstorm on 6 February 2017 in Japan, a gamma-ray flash with a duration of less than one millisecond was detected at our monitoring sites 0.5-1.7 kilometres away from the lightning. The subsequent gamma-ray afterglow subsided quickly, with an exponential decay constant of 40-60 milliseconds, and was followed by prolonged line emission at about 0.511 megaelectronvolts, which lasted for a minute. The observed decay time-scale and spectral cutoff at about 10 megaelectronvolts of the gamma-ray afterglow are well explained by de-excitation gamma-rays from nuclei excited by neutron capture. The centre energy of the prolonged line emission corresponds to electron-positron annihilation, providing conclusive evidence of positrons being produced after the lightning.
C1 [Enoto, Teruaki] Kyoto Univ, Hakubi Ctr Adv Res, Kyoto 6068302, Japan.
   [Enoto, Teruaki] Kyoto Univ, Dept Astron, Kyoto 6068302, Japan.
   [Wada, Yuuki; Furuta, Yoshihiro; Nakazawa, Kazuhiro; Okuda, Kazufumi] Univ Tokyo, Grad Sch Sci, Dept Phys, Tokyo 1130033, Japan.
   [Wada, Yuuki; Nakano, Toshio] RIKEN Nishina Ctr, High Energy Astrophys Lab, Wako, Saitama 3510198, Japan.
   [Nakazawa, Kazuhiro] Univ Tokyo, Res Ctr Early Universe, Tokyo 1130033, Japan.
   [Yuasa, Takayuki] 55 Devonshire Rd, Singapore 239855, Singapore.
   [Makishima, Kazuo] RIKEN, MAXI Team, Wako, Saitama 3510198, Japan.
   [Sato, Mitsuteru] Hokkaido Univ, Grad Sch Sci, Sapporo, Hokkaido 0600808, Japan.
   [Sato, Yousuke] Nagoya Univ, Grad Sch Engn, Dept Appl Energy, Nagoya, Aichi 4648603, Japan.
   [Umemoto, Daigo] RIKEN, Adv Inst Computat Sci, Kobe, Hyogo 6500047, Japan.
   [Tsuchiya, Harufumi] Japan Atom Energy Agcy, Nucl Sci & Engn Ctr, Ibaraki 3191195, Japan.
C3 Kyoto University; Kyoto University; University of Tokyo; RIKEN; University of Tokyo; RIKEN; Hokkaido University; Nagoya University; RIKEN; Japan Atomic Energy Agency
RP Enoto, T (corresponding author), Kyoto Univ, Hakubi Ctr Adv Res, Kyoto 6068302, Japan.; Enoto, T (corresponding author), Kyoto Univ, Dept Astron, Kyoto 6068302, Japan.
EM teruaki.enoto@gmail.com
FU JSPS/MEXT KAKENHI [15K05115, 15H03653, 16H06006]; SPIRITS project of Kyoto University; Hakubi project of Kyoto University; joint research programme of the Institute for Cosmic Ray Research (ICRR), The University of Tokyo; Grants-in-Aid for Scientific Research [15H03653, 15K05115, 16H06006, 16H04055] Funding Source: KAKEN
NR 43
TC 142
Z9 161
U1 1
U2 68
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 23
PY 2017
VL 551
IS 7681
BP 481
EP +
DI 10.1038/nature24630
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FN5JO
UT WOS:000416043700040
PM 29168803
DA 2026-03-09
ER

PT J
AU Becker, LA
   Huang, B
   Bieri, G
   Ma, R
   Knowles, DA
   Jafar-Nejad, P
   Messing, J
   Kim, HJ
   Soriano, A
   Auburger, G
   Pulst, SM
   Taylor, JP
   Rigo, F
   Gitler, AD
AF Becker, Lindsay A.
   Huang, Brenda
   Bieri, Gregor
   Ma, Rosanna
   Knowles, David A.
   Jafar-Nejad, Paymaan
   Messing, James
   Kim, Hong Joo
   Soriano, Armand
   Auburger, Georg
   Pulst, Stefan M.
   Taylor, J. Paul
   Rigo, Frank
   Gitler, Aaron D.
TI Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice
SO NATURE
LA English
DT Article
ID amyotrophic-lateral-sclerosis; antisense oligonucleotide; stress granules; als; rna; degeneration; expansions; features; disease; models
AB Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that is characterized by motor neuron loss and that leads to paralysis and death 2-5 years after disease onset(1). Nearly all patients with ALS have aggregates of the RNA-binding protein TDP-43 in their brains and spinal cords(2), and rare mutations in the gene encoding TDP-43 can cause ALS3. There are no effective TDP-43-directed therapies for ALS or related TDP-43 proteinopathies, such as frontotemporal dementia. Antisense oligonucleotides (ASOs) and RNA-interference approaches are emerging as attractive therapeutic strategies in neurological diseases(4). Indeed, treatment of a rat model of inherited ALS (caused by a mutation in Sod1) with ASOs against Sod1 has been shown to substantially slow disease progression(5). However, as SOD1 mutations account for only around 2-5% of ALS cases, additional therapeutic strategies are needed. Silencing TDP-43 itself is probably not appropriate, given its critical cellular functions(1,6). Here we present a promising alternative therapeutic strategy for ALS that involves targeting ataxin-2. A decrease in ataxin-2 suppresses TDP-43 toxicity in yeast and flies(7), and intermediate-length polyglutamine expansions in the ataxin-2 gene increase risk of ALS(7,8). We used two independent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model of TDP-43 proteinopathy(9). First, we crossed ataxin-2 knockout mice with TDP-43 (also known as TARDBP) transgenic mice. The decrease in ataxin-2 reduced aggregation of TDP-43, markedly increased survival and improved motor function. Second, in a more therapeutically applicable approach, we administered ASOs targeting ataxin-2 to the central nervous system of TDP-43 transgenic mice. This single treatment markedly extended survival. Because TDP-43 aggregation is a component of nearly all cases of ALS6, targeting ataxin-2 could represent a broadly effective therapeutic strategy.
C1 [Becker, Lindsay A.; Huang, Brenda; Bieri, Gregor; Ma, Rosanna; Knowles, David A.; Gitler, Aaron D.] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA.
   [Becker, Lindsay A.; Bieri, Gregor] Stanford Univ, Sch Med, Stanford Neurosci Grad Program, Stanford, CA 94305 USA.
   [Knowles, David A.] Stanford Univ, Sch Med, Dept Radiol, Stanford, CA 94305 USA.
   [Jafar-Nejad, Paymaan; Soriano, Armand; Rigo, Frank] Ionis Pharmaceut, Carlsbad, CA 92010 USA.
   [Messing, James; Kim, Hong Joo; Taylor, J. Paul] St Jude Childrens Res Hosp, Dept Cell & Mol Biol, Memphis, TN 38105 USA.
   [Auburger, Georg; Pulst, Stefan M.] Goethe Univ, Dept Neurol, Expt Neurol, D-60590 Frankfurt, Germany.
   Univ Utah, Dept Neurol, Salt Lake City, UT 84112 USA.
   [Taylor, J. Paul] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
C3 Stanford University; Stanford University; Stanford University; Ionis Pharmaceuticals, Inc.; St Jude Children's Research Hospital; Goethe University Frankfurt; Utah System of Higher Education; University of Utah; Howard Hughes Medical Institute
RP Gitler, AD (corresponding author), Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA.
EM agitler@stanford.edu
FU NIH [R01NS065317, R01NS09386501, R01NS073660, R35NS097263, R35NS097974, R21NS081182, R37NS033123, NS069375]; HHMI; National Science Foundation Graduate Research Fellowship; Robert Packard Center for ALS Research at Johns Hopkins; Target ALS; Glenn Foundation; DFG [AU96/13-1]; National Institute of Mental Health; National Institute on Aging; National Institute of General Medical Sciences [T32MH020016] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [R35NS097974, R35NS097263] Funding Source: NIH RePORTER; National Institute on Aging [T32AG047126] Funding Source: NIH RePORTER
NR 35
TC 436
Z9 536
U1 6
U2 168
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 20
PY 2017
VL 544
IS 7650
BP 367
EP +
DI 10.1038/nature22038
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ES4SG
UT WOS:000399524400040
PM 28405022
DA 2026-03-09
ER

PT J
AU Andreeva, L
   Hiller, B
   Kostrewa, D
   Lässig, C
   Mann, CCD
   Drexler, DJ
   Maiser, A
   Gaidt, M
   Leonhardt, H
   Hornung, V
   Hopfner, KP
AF Andreeva, Liudmila
   Hiller, Bjoern
   Kostrewa, Dirk
   Laessig, Charlotte
   Mann, Carina C. de Oliveira
   Drexler, David Jan
   Maiser, Andreas
   Gaidt, Moritz
   Leonhardt, Heinrich
   Hornung, Veit
   Hopfner, Karl-Peter
TI cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders
SO NATURE
LA English
DT Article
ID cyclic gmp-amp; mycobacterium-tuberculosis; mitochondrial-dna; immune-responses; i interferons; sting pathway; cell-lines; synthase; transcription; expression
AB Cytosolic DNA arising from intracellular pathogens triggers a powerful innate immune response(1,2). It is sensed by cyclic GMP-AMP synthase (cGAS), which elicits the production of type I interferons by generating the second messenger 2' 3'-cyclic-GMP-AMP (cGAMP)(3-5). Endogenous nuclear or mitochondrial DNA can also be sensed by cGAS under certain conditions, resulting in sterile inflammation. The cGAS dimer binds two DNA ligands shorter than 20 base pairs side-by-side(6-9), but 20-base-pair DNA fails to activate cGAS in vivo and is a poor activator in vitro. Here we show that cGAS is activated in a strongly DNA length-dependent manner both in vitro and in human cells. We also show that cGAS dimers form ladder-like networks with DNA, leading to cooperative sensing of DNA length: assembly of the pioneering cGAS dimer between two DNA molecules is ineffective; but, once formed, it prearranges the flanking DNA to promote binding of subsequent cGAS dimers. Remarkably, bacterial and mitochondrial nucleoid proteins HU and mitochondrial transcription factor A (TFAM), as well as high-mobility group box 1 protein (HMGB1), can strongly stimulate long DNA sensing by cGAS. U-turns and bends in DNA induced by these proteins pre-structure DNA to nucleate cGAS dimers. Our results suggest a nucleation-cooperativity-based mechanism for sensitive detection of mitochondrial DNA(10) and pathogen genomes(11), and identify HMGB/TFAM proteins as DNA-structuring host factors. They provide an explanation for the peculiar cGAS dimer structure and suggest that cGAS preferentially binds incomplete nucleoid-like structures or bent DNA.
C1 [Andreeva, Liudmila; Hiller, Bjoern; Kostrewa, Dirk; Laessig, Charlotte; Mann, Carina C. de Oliveira; Drexler, David Jan; Gaidt, Moritz; Hornung, Veit; Hopfner, Karl-Peter] Ludwig Maximilians Univ Munchen, Dept Biochem, D-81377 Munich, Germany.
   [Andreeva, Liudmila; Hiller, Bjoern; Kostrewa, Dirk; Laessig, Charlotte; Mann, Carina C. de Oliveira; Drexler, David Jan; Gaidt, Moritz; Hornung, Veit; Hopfner, Karl-Peter] Ludwig Maximilians Univ Munchen, Gene Ctr, D-81377 Munich, Germany.
   [Maiser, Andreas; Leonhardt, Heinrich] Ludwig Maximilians Univ Munchen, Dept Biol, D-82152 Planegg Martinsried, Germany.
   [Leonhardt, Heinrich; Hornung, Veit; Hopfner, Karl-Peter] Ctr Integrated Prot Sci Munich, D-81377 Munich, Germany.
   [Mann, Carina C. de Oliveira] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA.
C3 University of Munich; University of Munich; University of Munich; University of Munich; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute
RP Hopfner, KP (corresponding author), Ludwig Maximilians Univ Munchen, Dept Biochem, D-81377 Munich, Germany.; Hopfner, KP (corresponding author), Ludwig Maximilians Univ Munchen, Gene Ctr, D-81377 Munich, Germany.; Hopfner, KP (corresponding author), Ctr Integrated Prot Sci Munich, D-81377 Munich, Germany.
EM hopfner@genzentrum.lmu.de
FU German Research Foundation [HO2489/8-1, RTG1721]; Center for Integrated Protein Sciences; BioSysNet (Bavarian Ministry of Education)
NR 45
TC 419
Z9 483
U1 7
U2 134
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 21
PY 2017
VL 549
IS 7672
BP 394
EP +
DI 10.1038/nature23890
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FH7PB
UT WOS:000411381300037
PM 28902841
DA 2026-03-09
ER

PT J
AU Dey, P
   Baddour, J
   Muller, F
   Wu, CC
   Wang, HM
   Liao, WT
   Lan, ZD
   Chen, A
   Gutschner, T
   Kang, Y
   Fleming, J
   Satani, N
   Zhao, D
   Chreja, AA
   Yang, LF
   Lee, J
   Chang, E
   Genovese, G
   Viale, A
   Ying, HQ
   Draetta, G
   Maitra, A
   Wang, YA
   Nagrath, D
   DePinho, RA
AF Dey, Prasenjit
   Baddour, Joelle
   Muller, Florian
   Wu, Chia Chin
   Wang, Huamin
   Liao, Wen-Ting
   Lan, Zangdao
   Chen, Alina
   Gutschner, Tony
   Kang, Yaan
   Fleming, Jason
   Satani, Nikunj
   Zhao, Di
   Chreja, Abhinav A.
   Yang, Lifeng
   Lee, Jiyoon
   Chang, Edward
   Genovese, Giannicola
   Viale, Andrea
   Ying, Haoqiang
   Draetta, Giulio
   Maitra, Anirban
   Wang, Y. Alan
   Nagrath, Deepak
   DePinho, Ronald A.
TI Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer
SO NATURE
LA English
DT Article
ID activated protein-kinase; amino-acid-metabolism; srebp activity; adenocarcinoma; glutamine; pathways; targets; biology; growth; gene
AB The genome of pancreatic ductal adenocarcinoma (PDAC) frequently contains deletions of tumour suppressor gene loci, most notably SMAD4, which is homozygously deleted in nearly one-third of cases(1). As loss of neighbouring housekeeping genes can confer collateral lethality, we sought to determine whether loss of the metabolic gene malic enzyme 2 (ME2) in the SMAD4 locus would create cancer-specific metabolic vulnerability upon targeting of its paralogous isoform ME3. The mitochondrial malic enzymes (ME2 and ME3) are oxidative decarboxylases that catalyse the conversion of malate to pyruvate and are essential for NADPH regeneration and reactive oxygen species homeostasis(2,3). Here we show that ME3 depletion selectively kills ME2-null PDAC cells in a manner consistent with an essential function for ME3 in ME2-null cancer cells. Mechanistically, integrated metabolomic and molecular investigation of cells deficient in mitochondrial malic enzymes revealed diminished NADPH production and consequent high levels of reactive oxygen species. These changes activate AMP activated protein kinase (AMPK), which in turn directly suppresses sterol regulatory element-binding protein 1 (SREBP1)-directed transcription of its direct targets including the BCAT2 branched-chain amino acid transaminase 2) gene. BCAT2 catalyses the transfer of the amino group from branched-chain amino acids to a-ketoglutarate (alpha-KG)(4) thereby regenerating glutamate, which functions in part to support de novo nucleotide synthesis. Thus, mitochondrial malic enzyme deficiency, which results in impaired NADPH production, provides a prime 'collateral lethality' therapeutic strategy for the treatment of a substantial fraction of patients diagnosed with this intractable disease.
C1 [Dey, Prasenjit; Liao, Wen-Ting; Lan, Zangdao; Chen, Alina; Wang, Y. Alan; DePinho, Ronald A.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA.
   [Dey, Prasenjit; Wu, Chia Chin; Wang, Y. Alan] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA.
   [Baddour, Joelle; Gutschner, Tony; Satani, Nikunj; Nagrath, Deepak] Rice Univ, Dept Chem & Biomol Engn, Dept Bioengn, 6100 Main St, Houston, TX 77005 USA.
   [Lan, Zangdao; Fleming, Jason; Yang, Lifeng] Univ Texas MD Anderson Canc Ctr, Dept Canc Syst Imaging, Houston, TX 77030 USA.
   [Muller, Florian; Gutschner, Tony; Chreja, Abhinav A.; Genovese, Giannicola] Univ Texas MD Anderson Canc Ctr, Div Pathol Lab Med, Dept Pathol, Houston, TX 77030 USA.
   [Wu, Chia Chin; Gutschner, Tony; Satani, Nikunj] Univ Texas MD Anderson Canc Ctr, Div Surg, Dept Surg Oncol, Houston, TX 77030 USA.
   [Wang, Huamin; Kang, Yaan; Chreja, Abhinav A.; Draetta, Giulio] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA.
   [Wu, Chia Chin; Gutschner, Tony; Zhao, Di; Lee, Jiyoon] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA.
   [Wu, Chia Chin; Gutschner, Tony; Chreja, Abhinav A.; Chang, Edward] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA.
   [Wang, Huamin; Kang, Yaan; Zhao, Di] Univ Texas MD Anderson Canc Ctr, Ahmed Bin Zayed Nahyan Ctr Pancreat Canc Res, Houston, TX 77030 USA.
C3 University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; Rice University; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center
RP Wang, YA; DePinho, RA (corresponding author), Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA.; Wang, YA (corresponding author), Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA.; Nagrath, D (corresponding author), Rice Univ, Dept Chem & Biomol Engn, Dept Bioengn, 6100 Main St, Houston, TX 77005 USA.
EM yalanwang@mdanderson.org; deepak.nagrath@rice.edu; rdepinho@mdanderson.org
FU NCI [P01 CA117969]; UT Star award; CPRIT grant [RP140612]; DOD Postdoctoral research fellowship [W81XWH-14-1-0429]; MD Anderson Bridge Fund; St. Louis Ovarian Cancer Awareness Research Grant; Odyssey Fellowships at MD Anderson; NIH [P30 CA16672]; National Cancer Institute [P01CA117969, P30CA016672] Funding Source: NIH RePORTER
NR 36
TC 213
Z9 247
U1 0
U2 81
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 2
PY 2017
VL 542
IS 7639
BP 119
EP +
DI 10.1038/nature21052
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6MY
UT WOS:000396119300043
PM 28099419
DA 2026-03-09
ER

PT J
AU Turner, KM
   Deshpande, V
   Beyter, D
   Koga, T
   Rusert, J
   Lee, C
   Li, B
   Arden, K
   Ren, B
   Nathanson, DA
   Kornblum, HI
   Taylor, MD
   Kaushal, S
   Cavenee, WK
   Wechsler-Reya, R
   Furnari, FB
   Vandenberg, SR
   Rao, PN
   Wahl, GM
   Bafna, V
   Mischel, PS
AF Turner, Kristen M.
   Deshpande, Viraj
   Beyter, Doruk
   Koga, Tomoyuki
   Rusert, Jessica
   Lee, Catherine
   Li, Bin
   Arden, Karen
   Ren, Bing
   Nathanson, David A.
   Kornblum, Harley I.
   Taylor, Michael D.
   Kaushal, Sharmeela
   Cavenee, Webster K.
   Wechsler-Reya, Robert
   Furnari, Frank B.
   Vandenberg, Scott R.
   Rao, P. Nagesh
   Wahl, Geoffrey M.
   Bafna, Vineet
   Mischel, Paul S.
TI Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity
SO NATURE
LA English
DT Article
ID targeted therapy; clonal evolution; cancer; resistance; mutations
AB Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood(1-4). We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis. Here we show that ecDNA was found in nearly half of human cancers; its frequency varied by tumour type, but it was almost never found in normal cells. Driver oncogenes were amplified most commonly in ecDNA, thereby increasing transcript level. Mathematical modelling predicted that ecDNA amplification would increase oncogene copy number and intratumoural heterogeneity more effectively than chromosomal amplification. We validated these predictions by quantitative analyses of cancer samples. The results presented here suggest that ecDNA contributes to accelerated evolution in cancer.
C1 [Turner, Kristen M.; Koga, Tomoyuki; Li, Bin; Arden, Karen; Ren, Bing; Cavenee, Webster K.; Furnari, Frank B.; Mischel, Paul S.] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA.
   [Deshpande, Viraj; Bafna, Vineet] Univ Calif San Diego, Dept Comp Sci & Engn, La Jolla, CA 92093 USA.
   [Rusert, Jessica; Wechsler-Reya, Robert] Sanford Burnham Prebys Med Discovery Inst, NCI Designated Canc Ctr, Tumor Initiat & Maintenance Program, La Jolla, CA 92037 USA.
   [Nathanson, David A.; Kornblum, Harley I.] David Geffen UCLA Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA.
   [Kornblum, Harley I.] David Geffen UCLA Sch Med, Neuropsychiat Inst, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA.
   [Kornblum, Harley I.] David Geffen UCLA Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA.
   [Taylor, Michael D.; Mischel, Paul S.] Hosp Sick Children, Arthur & Labatt Brain Tumour Res Ctr, Toronto, ON M5G 1X8, Canada.
   [Kaushal, Sharmeela] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA.
   [Vandenberg, Scott R.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA.
   [Rao, P. Nagesh] David Geffen UCLA Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA.
   [Wahl, Geoffrey M.] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA.
   [Mischel, Paul S.] Univ Calif San Diego, Dept Pathol, San Diego, CA 92093 USA.
C3 Ludwig Institute for Cancer Research; University of California System; University of California San Diego; University of California System; University of California San Diego; Sanford Burnham Prebys Medical Discovery Institute; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of Toronto; Hospital for Sick Children (SickKids); University of California System; University of California San Diego; University of California System; University of California San Francisco; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; Salk Institute; University of California System; University of California San Diego
RP Bafna, V (corresponding author), Univ Calif San Diego, Dept Comp Sci & Engn, La Jolla, CA 92093 USA.
EM vbafna@cs.ucsd.edu
FU Ludwig Institute for Cancer Research; Defeat GBM Program of the National Brain Tumor Society; Ben and Catherine Ivy Foundation; Susan G. Komen Foundation [SAC110036]; Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]; Breast Cancer Research Foundation (BCRF); CureSearch for Children's Cancer; California Institute for Regenerative Medicine; NIH [NS73831, GM114362, NS80939, CA014195, CA159859, CA151819, T32CA121938]; NSF [NSF-IIS-1318386, NSF-DBI-1458557]; National Cancer Institute [T32CA121938, P30CA014195, R01CA159859] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM114362] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [R01NS080939] Funding Source: NIH RePORTER; Direct For Computer & Info Scie & Enginr; Div Of Information & Intelligent Systems [1318386] Funding Source: National Science Foundation; Div Of Biological Infrastructure; Direct For Biological Sciences [1458557] Funding Source: National Science Foundation
NR 36
TC 571
Z9 664
U1 4
U2 205
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 2
PY 2017
VL 543
IS 7643
BP 122
EP +
DI 10.1038/nature21356
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0AA
UT WOS:000395671500045
PM 28178237
DA 2026-03-09
ER

PT J
AU Janda, CY
   Dang, LT
   You, CJ
   Chang, JL
   de Lau, W
   Zhong, ZDA
   Yan, KS
   Marecic, O
   Siepe, D
   Li, XN
   Moody, JD
   Williams, BO
   Clevers, H
   Piehler, J
   Baker, D
   Kuo, CJ
   Garcia, KC
AF Janda, Claudia Y.
   Dang, Luke T.
   You, Changjiang
   Chang, Junlei
   de Lau, Wim
   Zhong, Zhendong A.
   Yan, Kelley S.
   Marecic, Owen
   Siepe, Dirk
   Li, Xingnan
   Moody, James D.
   Williams, Bart O.
   Clevers, Hans
   Piehler, Jacob
   Baker, David
   Kuo, Calvin J.
   Garcia, K. Christopher
TI Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling
SO NATURE
LA English
DT Article
ID in-vitro expansion; stem-cells; structural basis; protein; dynamics; reveals; growth; activation; affinity; pathway
AB Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing beta-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues(1). The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors(2-4). As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD-LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic beta-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.
C1 [Janda, Claudia Y.; Siepe, Dirk; Garcia, K. Christopher] Stanford Univ, Howard Hughes Med Inst, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
   [Janda, Claudia Y.; Siepe, Dirk; Garcia, K. Christopher] Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA.
   [Dang, Luke T.; Moody, James D.; Kuo, Calvin J.] Univ Washington, Howard Hughes Med Inst, Dept Biochem, Seattle, WA 98195 USA.
   [Dang, Luke T.; Moody, James D.; Kuo, Calvin J.] Univ Washington, Inst Prot Design, Seattle, WA 98195 USA.
   [You, Changjiang; Piehler, Jacob] Univ Osnabruck, Dept Biol, Div Biophys, D-49076 Osnabruck, Germany.
   [Chang, Junlei; Yan, Kelley S.; Li, Xingnan; Kuo, Calvin J.] Stanford Univ, Dept Med, Div Hematol, Sch Med, Stanford, CA 94305 USA.
   [de Lau, Wim; Clevers, Hans] Royal Netherlands Acad Arts & Sci, Hubrecht Inst, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands.
   [de Lau, Wim; Clevers, Hans] Univ Med Ctr Utrecht, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands.
   [Zhong, Zhendong A.; Williams, Bart O.] Van Andel Res Inst, Program Skeletal Dis & Tumor Microenvironm, 333 Bostwick NE, Grand Rapids, MI 49503 USA.
   [Zhong, Zhendong A.; Williams, Bart O.] Van Andel Res Inst, Ctr Canc & Cell Biol, 333 Bostwick NE, Grand Rapids, MI 49503 USA.
   [Marecic, Owen] Stanford Univ, Sch Med, Hagey Lab Pediat Regenerat Med, Stanford, CA 94305 USA.
   [Marecic, Owen] Stanford Univ, Sch Med, Dept Surg, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA.
C3 Stanford University; Howard Hughes Medical Institute; Stanford University; University of Washington; University of Washington Seattle; Howard Hughes Medical Institute; University of Washington; University of Washington Seattle; University Osnabruck; Stanford University; Royal Netherlands Academy of Arts & Sciences; Hubrecht Institute (KNAW); Utrecht University; Utrecht University Medical Center; Van Andel Institute; Van Andel Research Institute; Van Andel Institute; Van Andel Research Institute; Stanford University; Stanford University
RP Garcia, KC (corresponding author), Stanford Univ, Howard Hughes Med Inst, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.; Garcia, KC (corresponding author), Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA.
EM kcgarcia@stanford.edu
FU National Institutes of Health (NIH) [R01 GM097015, K08DK096048, U01 DK085527, U19 AI116484, U01 CA176299]; DFG [SFB 944]; Bu,rroughs Wellcome Fund CAMS; Stinehart/Reed Foundation; Ludwig Foundation; Howard Hughes Medical Institute; European Union [668294]; NWO translational Adult Stem Cell Research grant [40-41400-98-1108]; National Cancer Institute [U01CA217851] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [U19AI116484] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [U01DK085527] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007266] Funding Source: NIH RePORTER
NR 70
TC 293
Z9 354
U1 0
U2 108
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 11
PY 2017
VL 545
IS 7653
BP 234
EP +
DI 10.1038/nature22306
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EU3XG
UT WOS:000400963800036
PM 28467818
DA 2026-03-09
ER

PT J
AU Sorrentino, V
   Omani, MR
   Ouchiroud, LM
   Beck, JS
   Zhang, HB
   D'Amico, D
   Moullan, N
   Potenza, F
   Schmid, AW
   Rietsch, S
   Counts, SE
   Auwerx, J
AF Sorrentino, Vincenzo
   Omani, Mario R.
   Ouchiroud, Laurent M.
   Beck, John S.
   Zhang, Hongbo
   D'Amico, Davide
   Moullan, Norman
   Potenza, Francesca
   Schmid, Adrien W.
   Rietsch, Solene
   Counts, Scott E.
   Auwerx, Johan
TI Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity
SO NATURE
LA English
DT Article
ID unfolded protein response; alzheimers-disease; life-span; gene-expression; stress-response; models; mitophagy; upr; overexpression; tetracyclines
AB Alzheimer's disease is a common and devastating disease characterized by aggregation of the amyloid-beta peptide. However, we know relatively little about the underlying molecular mechanisms or how to treat patients with Alzheimer's disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-beta proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-beta proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer's disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-beta proteotoxic diseases, such as Alzheimer's disease.
C1 [Sorrentino, Vincenzo; Omani, Mario R.; Ouchiroud, Laurent M.; Zhang, Hongbo; D'Amico, Davide; Moullan, Norman; Potenza, Francesca; Rietsch, Solene; Auwerx, Johan] Ecole Polytech Fed Lausanne, Lab Integrat & Syst Physiol, Inst Bioengn, CH-1015 Lausanne, Switzerland.
   [Beck, John S.; Counts, Scott E.] Michigan State Univ, Dept Translat Sci & Mol Med, Dept Family Med, Grand Rapids, MI 49503 USA.
   [Schmid, Adrien W.] Ecole Polytech Fed Lausanne, Prote Core Facil, CH-1015 Lausanne, Switzerland.
C3 Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Michigan State University; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne
RP Auwerx, J (corresponding author), Ecole Polytech Fed Lausanne, Lab Integrat & Syst Physiol, Inst Bioengn, CH-1015 Lausanne, Switzerland.
EM admin.auwerx@epfl.ch
FU NIH Office of Research Infrastructure Programs [P40 OD010440]; 'EPFL Fellows' program - Marie Sklodowska-Curie, Horizon 2020 Grant [665667]; Associazione Italiana per la Ricerca sul Cancro (AIRC); NIH [P01AG014449, R21AG053581, P30 AG053760, R01AG043930]; EPFL; Systems X [SySX.ch2013/153]; Velux Stiftung [1019]; Jebsen Foundation; Swiss National Science Foundation [31003A140780]; National Institute of General Medical Sciences; NIH Office of the Director [P40OD010440] Funding Source: NIH RePORTER; National Institute on Aging [P01AG014449] Funding Source: NIH RePORTER
NR 53
TC 529
Z9 590
U1 3
U2 210
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 14
PY 2017
VL 552
IS 7684
BP 187
EP +
DI 10.1038/nature25143
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ0FK
UT WOS:000418029500034
PM 29211722
DA 2026-03-09
ER

PT J
AU Hillenbrand, CD
   Smith, JA
   Hodell, DA
   Greaves, M
   Poole, CR
   Kender, S
   Williams, M
   Andersen, TJ
   Jernas, PE
   Elderfield, H
   Klages, JP
   Roberts, SJ
   Gohl, K
   Larter, RD
   Kuhn, G
AF Hillenbrand, Claus-Dieter
   Smith, James A.
   Hodell, David A.
   Greaves, Mervyn
   Poole, Christopher R.
   Kender, Sev
   Williams, Mark
   Andersen, Thorbjorn Joest
   Jernas, Patrycja E.
   Elderfield, Henry
   Klages, Johann P.
   Roberts, Stephen J.
   Gohl, Karsten
   Larter, Robert D.
   Kuhn, Gerhard
TI West Antarctic Ice Sheet retreat driven by Holocene warm water incursions
SO NATURE
LA English
DT Article
ID amundsen sea embayment; pine island glacier; benthic foraminiferal b/ca; grounding-line retreat; southern-ocean; weddell sea; planktonic-foraminifera; continental-margin; atlantic sector; shelf history
AB Glaciological and oceanographic observations coupled with numerical models show that warm Circumpolar Deep Water (CDW) incursions onto the West Antarctic continental shelf cause melting of the undersides of floating ice shelves. Because these ice shelves buttress glaciers feeding into them, their ocean-induced thinning is driving Antarctic ice-sheet retreat today. Here we present a multi-proxy data based reconstruction of variability in CDW inflow to the Amundsen Sea sector, the most vulnerable part of the West Antarctic Ice Sheet, during the Holocene epoch (from 11.7 thousand years ago to the present). The chemical compositions of foraminifer shells and benthic foraminifer assemblages in marine sediments indicate that enhanced CDW upwelling, controlled by the latitudinal position of the Southern Hemisphere westerly winds, forced deglaciation of this sector from at least 10,400 years ago until 7,500 years ago-when an ice-shelf collapse may have caused rapid ice-sheet thinning further upstream-and since the 1940s. These results increase confidence in the predictive capability of current ice-sheet models.
C1 [Hillenbrand, Claus-Dieter; Smith, James A.; Roberts, Stephen J.; Larter, Robert D.] British Antarctic Survey, High Cross,Madingley Rd, Cambridge CB3 0ET, England.
   [Hodell, David A.; Greaves, Mervyn; Elderfield, Henry] Univ Cambridge, Dept Earth Sci, Downing St, Cambridge CB2 3EQ, England.
   [Poole, Christopher R.; Williams, Mark] Univ Leicester, Dept Geol, Leicester LE1 7RH, Leics, England.
   [Poole, Christopher R.] UCL, Dept Earth Sci, London WC1E 6BT, England.
   [Kender, Sev] Univ Exeter, Camborne Sch Mines, Penryn TR10 9FE, Cornwall, England.
   [Kender, Sev] British Geol Survey, Nottingham NG12 5GG, England.
   [Andersen, Thorbjorn Joest] Univ Copenhagen, Dept Geosci & Nat Resource Management, Ctr Permafrost CENPERM, DK-1350 Copenhagen K, Denmark.
   [Jernas, Patrycja E.] Arctic Univ Norway, Univ Tromso, Dept Geosci, N-9037 Tromso, Norway.
   [Klages, Johann P.; Gohl, Karsten; Kuhn, Gerhard] Alfred Wegener Inst, Dept Geosci, Helmholtz Zentrum Polar & Meeresforsch, Alten Hafen 26, D-27568 Bremerhaven, Germany.
C3 UK Research & Innovation (UKRI); Natural Environment Research Council (NERC); NERC British Antarctic Survey; University of Cambridge; University of Leicester; University of London; University College London; University of Exeter; UK Research & Innovation (UKRI); Natural Environment Research Council (NERC); NERC British Geological Survey; University of Copenhagen; UiT The Arctic University of Tromso; Helmholtz Association; Alfred Wegener Institute, Helmholtz Centre for Polar & Marine Research
RP Hillenbrand, CD (corresponding author), British Antarctic Survey, High Cross,Madingley Rd, Cambridge CB3 0ET, England.
EM hilc@bas.ac.uk
FU Natural Environment Research Council (NERC); NERC [NE/M013081/1]; Helmholtz Association; European Research Council (ERC) [2010-NEWLOG ADG-267931 HE]; NERC [bas0100030, NE/M013081/1, nigl010001, NE/J006513/1] Funding Source: UKRI; Natural Environment Research Council [NE/M013081/1, bas0100030, nigl010001] Funding Source: researchfish
NR 97
TC 117
Z9 136
U1 2
U2 91
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 6
PY 2017
VL 547
IS 7661
BP 43
EP +
DI 10.1038/nature22995
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EZ6PM
UT WOS:000404839900028
PM 28682333
DA 2026-03-09
ER

PT J
AU Xu, GY
   Uan, MY
   Ai, CR
   Liu, LJ
   Zhuang, E
   Karapetyan, S
   Wang, S
   Dong, XN
AF Xu, Guoyong
   Uan, Meng Y.
   Ai, Chaoren
   Liu, Lijing
   Zhuang, Edward
   Karapetyan, Sargis
   Wang, Shiping
   Dong, Xinnian
TI uORF-mediated translation allows engineered plant disease resistance without fitness costs
SO NATURE
LA English
DT Article
ID molecular-patterns; immune-system; rice; arabidopsis; defense; gene; transformation; expression; protein; dissection
AB Controlling plant disease has been a struggle for humankind since the advent of agriculture. Studies of plant immune mechanisms have led to strategies of engineering resistant crops through ectopic transcription of plants' own defence genes, such as the master immune regulatory gene NPR1 (ref. 1). However, enhanced resistance obtained through such strategies is often associated with substantial penalties to fitness(2), making the resulting products undesirable for agricultural applications. To remedy this problem, we sought more stringent mechanisms of expressing defence proteins. On the basis of our latest finding that translation of key immune regulators, such as TBF1 (ref. 3), is rapidly and transiently induced upon pathogen challenge (see accompanying paper(4)), we developed a 'TBF1-cassette' consisting of not only the immune-inducible promoter but also two pathogen-responsive upstream open reading frames (uORFs(TBF1)) of the TBF1 gene. Here we demonstrate that inclusion of uORFs(TBF1)-mediated translational control over the production of snc1-1 (an autoactivated immune receptor) in Arabidopsis thaliana and AtNPR1 in rice enables us to engineer broad-spectrum disease resistance without compromising plant fitness in the laboratory or in the field. This broadly applicable strategy may lead to decreased pesticide use and reduce the selective pressure for resistant pathogens.
C1 [Xu, Guoyong; Liu, Lijing; Zhuang, Edward; Karapetyan, Sargis; Dong, Xinnian] Duke Univ, Dept Biol, Howard Hughes Med Inst, Gordon & Betty Moore Fdn, Durham, NC 27708 USA.
   [Uan, Meng Y.; Ai, Chaoren; Wang, Shiping] Huazhong Agr Univ, Natl Ctr Plant Gene Res Wuhan, Natl Key Lab Crop Genet Improvement, Wuhan 430070, Peoples R China.
C3 Duke University; Howard Hughes Medical Institute; Huazhong Agricultural University
RP Dong, XN (corresponding author), Duke Univ, Dept Biol, Howard Hughes Med Inst, Gordon & Betty Moore Fdn, Durham, NC 27708 USA.
EM xdong@duke.edu
FU National Institutes of Health [5R01 GM069594-11]; Howard Hughes Medical Institute; Gordon and Betty Moore Foundation [GBMF3032]; National Natural Science Foundation of China [31371926]; National Key Research and Development Program of China [2016YFD0100903]; Gordon and Betty Moore Foundation (GBMF) [GBMF3032] Funding Source: Gordon and Betty Moore Foundation (GBMF); National Institute of General Medical Sciences [R35GM118036] Funding Source: NIH RePORTER
CR Benedetti M, 2015, P NATL ACAD SCI USA, V112, P5533, DOI 10.1073/pnas.1504154112
   Boller T, 2009, ANNU REV PLANT BIOL, V60, P379, DOI 10.1146/annurev.arplant.57.032905.105346
   Bouwmeester K, 2014, PLANT BIOTECHNOL J, V12, P10, DOI 10.1111/pbi.12111
   Calvo SE, 2009, P NATL ACAD SCI USA, V106, P7507, DOI 10.1073/pnas.0810916106
   Chern Maw-Sheng, 2001, PLANT JOURNAL, V27, P101, DOI 10.1046/j.1365-313x.2001.01070.x
   Clough SJ, 1998, PLANT J, V16, P735, DOI 10.1046/j.1365-313x.1998.00343.x
   Dangl JL, 2013, SCIENCE, V341, P746, DOI 10.1126/science.1236011
   Fitzgerald HA, 2004, MOL PLANT MICROBE IN, V17, P140, DOI 10.1094/MPMI.2004.17.2.140
   Fu ZQ, 2013, ANNU REV PLANT BIOL, V64, P839, DOI 10.1146/annurev-arplant-042811-105606
   Gurr SJ, 2005, TRENDS BIOTECHNOL, V23, P275, DOI 10.1016/j.tibtech.2005.04.007
   Gurr SJ, 2005, TRENDS BIOTECHNOL, V23, P283, DOI 10.1016/j.tibtech.2005.04.009
   Huot B, 2014, MOL PLANT, V7, P1267, DOI 10.1093/mp/ssu049
   Johnson K C M, 2012, COLD SPRING HARB SYMP QUANT BIOL, V77, P259, DOI 10.1101/sqb.2013.77.014738
   Jones JDG, 2006, NATURE, V444, P323, DOI 10.1038/nature05286
   Kang HX, 2016, MOL PLANT PATHOL, V17, P959, DOI 10.1111/mpp.12340
   Kim SH, 2016, SCIENCE, V351, P684, DOI 10.1126/science.aad3436
   Lacombe S, 2010, NAT BIOTECHNOL, V28, P365, DOI 10.1038/nbt.1613
   Lawless C, 2009, BMC GENOMICS, V10, P0, DOI 10.1186/1471-2164-10-7
   Li X, 2001, MOL PLANT MICROBE IN, V14, P1131, DOI 10.1094/MPMI.2001.14.10.1131
   Li YQ, 2007, MOL PLANT MICROBE IN, V20, P1449, DOI 10.1094/MPMI-20-11-1449
   Lin YJ, 2005, PLANT CELL REP, V23, P540, DOI 10.1007/s00299-004-0843-6
   Molla KA, 2016, PLANT SCI, V250, P105, DOI 10.1016/j.plantsci.2016.06.005
   Nakagawa T, 2007, J BIOSCI BIOENG, V104, P34, DOI 10.1263/jbb.104.34
   Pajerowska-Mukhtar KM, 2012, CURR BIOL, V22, P103, DOI 10.1016/j.cub.2011.12.015
   Quilis J, 2008, MOL PLANT MICROBE IN, V21, P1215, DOI 10.1094/MPMI-21-9-1215
   Rahmani F, 2009, PLANT PHYSIOL, V150, P1356, DOI 10.1104/pp.109.136036
   Schwessinger B, 2015, PLOS PATHOG, V11, P0, DOI 10.1371/journal.ppat.1004809
   Xu G, 2017, NATURE, V0, P0
   Xu GY, 2012, PLANT J, V72, P57, DOI 10.1111/j.1365-313X.2012.05053.x
   Xu GY, 2010, NEW PHYTOL, V187, P240, DOI 10.1111/j.1469-8137.2010.03253.x
   Yi H, 2007, PLANT CELL, V19, P2929, DOI 10.1105/tpc.107.051821
   Yuan M, 2016, ELIFE, V5, P0, DOI 10.7554/eLife.19605
   Yuan YX, 2007, PLANT BIOTECHNOL J, V5, P313, DOI 10.1111/j.1467-7652.2007.00243.x
NR 33
TC 302
Z9 354
U1 17
U2 300
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 25
PY 2017
VL 545
IS 7655
BP 491
EP +
DI 10.1038/nature22372
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV6TH
UT WOS:000401906500054
PM 28514448
DA 2026-03-09
ER

PT J
AU Bononi, A
   Giorgi, C
   Patergnani, S
   Larson, D
   Verbruggen, K
   Tanji, M
   Pellegrini, L
   Signorato, V
   Olivetto, F
   Pastorino, S
   Nasu, M
   Napolitano, A
   Gaudino, G
   Morris, P
   Sakamoto, G
   Ferris, LK
   Danese, A
   Raimondi, A
   Tacchetti, C
   Kuchay, S
   Pass, HI
   Affar, E
   Yang, HN
   Pinton, P
   Carbone, M
AF Bononi, Angela
   Giorgi, Carlotta
   Patergnani, Simone
   Larson, David
   Verbruggen, Kaitlyn
   Tanji, Mika
   Pellegrini, Laura
   Signorato, Valentina
   Olivetto, Federica
   Pastorino, Sandra
   Nasu, Masaki
   Napolitano, Andrea
   Gaudino, Giovanni
   Morris, Paul
   Sakamoto, Greg
   Ferris, Laura K.
   Danese, Alberto
   Raimondi, Andrea
   Tacchetti, Carlo
   Kuchay, Shafi
   Pass, Harvey I.
   Affar, El Bachir
   Yang, Haining
   Pinton, Paolo
   Carbone, Michele
TI BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation
SO NATURE
LA English
DT Article
ID human mesothelial cells; strand break repair; tumor-suppressor; malignant mesothelioma; endoplasmic-reticulum; germline mutations; asbestos; cancer; predisposes; apoptosis
AB BRCA1-associated protein 1 (BAP1) is a potent tumour suppressor gene that modulates environmental carcinogenesis(1-3). All carriers of inherited heterozygous germline BAP1-inactivating mutations (BAP1(+/-)) developed one and often several BAP1(-/-) malignancies in their lifetime(4), mostly malignant mesothelioma, uveal melanoma(2,5), and so on(6-10). Moreover, BAP1-acquired biallelic mutations are frequent in human cancers(8,11-14). BAP1 tumour suppressor activity has been attributed to its nuclear localization, where it helps to maintain genome integrity(15-17). The possible activity of BAP1 in the cytoplasm is unknown. Cells with reduced levels of BAP1 exhibit chromosomal abnormalities and decreased DNA repair by homologous recombination(18), indicating that BAP1 dosage is critical. Cells with extensive DNA damage should die and not grow into malignancies. Here we discover that BAP1 localizes at the endoplasmic reticulum. Here, it binds, deubiquitylates, and stabilizes type 3 inositol-1,4,5-trisphosphate receptor (IP3R3), modulating calcium (Ca2+) release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1(+/-) carriers cause reduction both of IP3R3 levels and of Ca2+ flux, preventing BAP1(+/-) cells that accumulate DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survive genotoxic stress, resulting in a higher rate of cellular transformation. We propose that the high incidence of cancers in BAP1(+/-) carriers results from the combined reduced nuclear and cytoplasmic activities of BAP1. Our data provide a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction in human carcinogenesis.
C1 [Bononi, Angela; Larson, David; Verbruggen, Kaitlyn; Tanji, Mika; Pellegrini, Laura; Signorato, Valentina; Olivetto, Federica; Pastorino, Sandra; Nasu, Masaki; Napolitano, Andrea; Gaudino, Giovanni; Morris, Paul; Sakamoto, Greg; Yang, Haining; Carbone, Michele] Univ Hawaii, Canc Ctr, Honolulu, HI 96813 USA.
   [Giorgi, Carlotta; Patergnani, Simone; Signorato, Valentina; Olivetto, Federica; Danese, Alberto; Pinton, Paolo] Univ Ferrara, Dept Morphol Surg & Expt Med, I-44121 Ferrara, Italy.
   [Ferris, Laura K.] Univ Pittsburgh, Med Ctr, Dept Dermatol, Pittsburgh, PA 15213 USA.
   [Raimondi, Andrea; Tacchetti, Carlo] San Raffaele Sci Inst Milano, Expt Imaging Ctr, I-20132 Milan, Italy.
   [Tacchetti, Carlo] Univ Genoa, Dept Expt Med, I-16132 Genoa, Italy.
   [Kuchay, Shafi; Pass, Harvey I.] NYU, Canc Ctr, New York, NY 10016 USA.
   [Affar, El Bachir] Univ Montreal, Maisonneuve Rosemont Hosp, Res Ctr, Dept Med, Montreal, PQ H1T 2M4, Canada.
C3 University of Hawaii System; Cancer Research Center of Hawaii; University of Ferrara; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Genoa; New York University; Universite de Montreal
RP Yang, HN; Carbone, M (corresponding author), Univ Hawaii, Canc Ctr, Honolulu, HI 96813 USA.; Pinton, P (corresponding author), Univ Ferrara, Dept Morphol Surg & Expt Med, I-44121 Ferrara, Italy.
EM HYang@cc.hawaii.edu; paolo.pinton@unife.it; MCarbone@cc.hawaii.edu
FU National Cancer Institute (NCI) [R01 CA198138, R01 CA160715]; DOD [CA120355]; University of Hawai'i Foundation; Honeywell International; Riviera United 4-a Cure; Italian Association for Cancer Research (AIRC) [IG-18624, MFAG13521]; Italian Ministry of Health; National Cancer Institute [P30CA071789] Funding Source: NIH RePORTER
NR 41
TC 331
Z9 364
U1 4
U2 129
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 22
PY 2017
VL 546
IS 7659
BP 549
EP +
DI 10.1038/nature22798
PG 30
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY2QK
UT WOS:000403814100042
PM 28614305
DA 2026-03-09
ER

PT J
AU Acheson, JF
   Bailey, LJ
   Brunold, TC
   Fox, BG
AF Acheson, Justin F.
   Bailey, Lucas J.
   Brunold, Thomas C.
   Fox, Brian G.
TI In-crystal reaction cycle of a toluene-bound diiron hydroxylase
SO NATURE
LA English
DT Article
ID reduced methane monooxygenase; aromatic hydroxylation; deoxyhypusine hydroxylase; dioxygen activation; intermediate; mechanism; complex; 4-monooxygenase; desaturase; oxidation
AB Electrophilic aromatic substitution is one of the most important and recognizable classes of organic chemical transformation. Enzymes create the strong electrophiles that are needed for these highly energetic reactions by using O-2, electrons, and metals or other cofactors. Although the nature of the oxidants that carry out electrophilic aromatic substitution has been deduced from many approaches, it has been difficult to determine their structures. Here we show the structure of a diiron hydroxylase intermediate formed during a reaction with toluene. Density functional theory geometry optimizations of an active site model reveal that the intermediate is an arylperoxo Fe2+/Fe3+ species with delocalized aryl radical character. The structure suggests that a carboxylate ligand of the diiron centre may trigger homolytic cleavage of the O-O bond by transferring a proton from a metal-bound water. Our work provides the spatial and electronic constraints needed to propose a comprehensive mechanism for diiron enzyme arene hydroxylation that accounts for many prior experimental results.
C1 [Acheson, Justin F.; Bailey, Lucas J.; Fox, Brian G.] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA.
   [Brunold, Thomas C.] Univ Wisconsin, Dept Chem, Madison, WI 53706 USA.
C3 University of Wisconsin System; University of Wisconsin Madison; University of Wisconsin System; University of Wisconsin Madison
RP Fox, BG (corresponding author), Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA.
EM bgfox@biochem.wisc.edu
FU National Science Foundation [MCB-0843239]; US Department of Energy, Office of Science [W-31-109-ENG-38]; Wisconsin Distinguished Graduate Fellowship
NR 49
TC 43
Z9 50
U1 2
U2 81
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 13
PY 2017
VL 544
IS 7649
BP 191
EP +
DI 10.1038/nature21681
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ER6EK
UT WOS:000398897900029
PM 28346937
DA 2026-03-09
ER

PT J
AU Zhang, YL
   Kim, MS
   Jia, BS
   Yan, JQ
   Zuniga-Hertz, JP
   Han, C
   Cai, DS
AF Zhang, Yalin
   Kim, Min Soo
   Jia, Baosen
   Yan, Jingqi
   Zuniga-Hertz, Juan Pablo
   Han, Cheng
   Cai, Dongsheng
TI Hypothalamic stem cells control ageing speed partly through exosomal miRNAs
SO NATURE
LA English
DT Article
ID extends life-span; beta/nf-kappa-b; subventricular zone; microrna regulation; adult hippocampus; ikk-beta; neurogenesis; mice; obesity; differentiation
AB It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs.
C1 [Zhang, Yalin; Kim, Min Soo; Jia, Baosen; Yan, Jingqi; Zuniga-Hertz, Juan Pablo; Han, Cheng; Cai, Dongsheng] Albert Einstein Coll Med, Inst Aging, Diabet Res Ctr, Dept Mol Pharmacol, Bronx, NY 10461 USA.
C3 Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University
RP Cai, DS (corresponding author), Albert Einstein Coll Med, Inst Aging, Diabet Res Ctr, Dept Mol Pharmacol, Bronx, NY 10461 USA.
EM dongsheng.cai@einstein.yu.edu
FU NIH [R01 DK078750, AG031774, HL113180, DK099136]; National Institute on Aging [R01AG031774] Funding Source: NIH RePORTER
NR 41
TC 445
Z9 518
U1 7
U2 165
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 3
PY 2017
VL 548
IS 7665
BP 52
EP +
DI 10.1038/nature23282
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FC4SU
UT WOS:000406831700034
PM 28746310
DA 2026-03-09
ER

PT J
AU Zhang, J
   Ma, JF
   Liu, DS
   Qin, S
   Sun, S
   Zhao, JD
   Sui, SF
AF Zhang, Jun
   Ma, Jianfei
   Liu, Desheng
   Qin, Song
   Sun, Shan
   Zhao, Jindong
   Sui, Sen-Fang
TI Structure of phycobilisome from the red alga Griffithsia pacifica
SO NATURE
LA English
DT Article
ID terminal energy acceptor; light-harvesting pigment; bilin attachment sites; allophycocyanin b; crystal-structure; c-phycocyanin; cyanobacteria; refinement; angstrom; model
AB Life on Earth depends on photosynthesis for its conversion of solar energy to chemical energy. Photosynthetic organisms have developed a variety of light-harvesting systems to capture sunlight. The largest light-harvesting complex is the phycobilisome (PBS), the main light-harvesting antenna in cyanobacteria and red algae. It is composed of phycobiliproteins and linker proteins but the assembly mechanisms and energy transfer pathways of the PBS are not well understood. Here we report the structure of a 16.8-megadalton PBS from a red alga at 3.5 angstrom resolution obtained by single-particle cryo-electron microscopy. We modelled 862 protein subunits, including 4 linkers in the core, 16 rod-core linkers and 52 rod linkers, and located a total of 2,048 chromophores. This structure reveals the mechanisms underlying specific interactions between linkers and phycobiliproteins, and the formation of linker skeletons. These results provide a firm structural basis for our understanding of complex assembly and the mechanisms of energy transfer within the PBS.
C1 [Zhang, Jun; Ma, Jianfei; Liu, Desheng; Sun, Shan; Sui, Sen-Fang] Tsinghua Univ, State Key Lab Membrane Biol, Beijing Adv Innovat Ctr Struct Biol, Sch Life Sci, Beijing 100084, Peoples R China.
   [Qin, Song] Chinese Acad Sci, Yantai Inst Coast Zone Res, Yantai 264003, Peoples R China.
   [Zhao, Jindong] Peking Univ, Coll Life Sci, State Key Lab Prot & Plant Genet Engn, Beijing 100871, Peoples R China.
   [Zhao, Jindong] Chinese Acad Sci, Inst Hydrobiol, Key Lab Phycol CAS, Wuhan 430072, Hubei, Peoples R China.
   [Zhang, Jun] MRC Lab Mol Biol, Cambridge CB2 0QH, England.
C3 Tsinghua University; Chinese Academy of Sciences; Yantai Institute of Coastal Zone Research, CAS; Peking University; Chinese Academy of Sciences; Institute of Hydrobiology, CAS; MRC Laboratory Molecular Biology
RP Sun, S; Sui, SF (corresponding author), Tsinghua Univ, State Key Lab Membrane Biol, Beijing Adv Innovat Ctr Struct Biol, Sch Life Sci, Beijing 100084, Peoples R China.
EM shansun@mail.tsinghua.edu.cn; suisf@mail.tsinghua.edu.cn
FU National Basic Research Program [2016YFA0501101, 2017YFA0504600, 2015CB150100]; National Natural Science Foundation of China [31230016, 31370717, 31670745, 31670746, 31400632]; CAS fund [QYZDY-SSW-SMC004]
NR 59
TC 191
Z9 224
U1 3
U2 200
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 2
PY 2017
VL 551
IS 7678
BP 57
EP +
DI 10.1038/nature24278
PG 29
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FL4SY
UT WOS:000414222900043
PM 29045394
DA 2026-03-09
ER

PT J
AU Grewe, BF
   Gründemann, J
   Kitch, LJ
   Lecoq, JA
   Parker, JG
   Marshall, JD
   Larkin, MC
   Jercog, PE
   Grenier, F
   Li, JZ
   Lüthi, A
   Schnitzer, MJ
AF Grewe, Benjamin F.
   Grundemann, Jan
   Kitch, Lacey J.
   Lecoq, Jerome A.
   Parker, Jones G.
   Marshall, Jesse D.
   Larkin, Margaret C.
   Jercog, Pablo E.
   Grenier, Francois
   Li, Jin Zhong
   Luthi, Andreas
   Schnitzer, Mark J.
TI Neural ensemble dynamics underlying a long-term associative memory
SO NATURE
LA English
DT Article
ID lateral amygdala; primate amygdala; fear memory; hippocampus; responses; stimuli; neurons; competition; plasticity; circuits
AB The brain's ability to associate different stimuli is vital for long-term memory, but how neural ensembles encode associative memories is unknown. Here we studied how cell ensembles in the basal and lateral amygdala encode associations between conditioned and unconditioned stimuli (CS and US, respectively). Using a miniature fluorescence microscope, we tracked the Ca2+ dynamics of ensembles of amygdalar neurons during fear learning and extinction over 6 days in behaving mice. Fear conditioning induced both up-and down-regulation of individual cells' CS-evoked responses. This bi-directional plasticity mainly occurred after conditioning, and reshaped the neural ensemble representation of the CS to become more similar to the US representation. During extinction training with repetitive CS presentations, the CS representation became more distinctive without reverting to its original form. Throughout the experiments, the strength of the ensemble-encoded CS-US association predicted the level of behavioural conditioning in each mouse. These findings support a supervised learning model in which activation of the US representation guides the transformation of the CS representation.
C1 [Grewe, Benjamin F.; Kitch, Lacey J.; Lecoq, Jerome A.; Marshall, Jesse D.; Larkin, Margaret C.; Jercog, Pablo E.; Li, Jin Zhong; Schnitzer, Mark J.] Stanford Univ, James H Clark Ctr Biomed Engn & Sci, Stanford, CA 94305 USA.
   [Grewe, Benjamin F.; Kitch, Lacey J.; Lecoq, Jerome A.; Marshall, Jesse D.; Jercog, Pablo E.; Schnitzer, Mark J.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Grewe, Benjamin F.; Kitch, Lacey J.; Lecoq, Jerome A.; Parker, Jones G.; Marshall, Jesse D.; Larkin, Margaret C.; Jercog, Pablo E.; Li, Jin Zhong; Schnitzer, Mark J.] Stanford Univ, CNC Program, Stanford, CA 94305 USA.
   [Grundemann, Jan; Grenier, Francois; Luthi, Andreas] Friedrich Miescher Inst Biomed Res, Basel, Switzerland.
   [Parker, Jones G.] Pfizer Neurosci Res, Cambridge, MA USA.
   [Luthi, Andreas] Univ Basel, Basel, Switzerland.
   [Grenier, Francois] Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan.
C3 Stanford University; Stanford University; Howard Hughes Medical Institute; Stanford University; Friedrich Miescher Institute for Biomedical Research; Pfizer; Pfizer USA; University of Basel; University of Tsukuba
RP Schnitzer, MJ (corresponding author), Stanford Univ, James H Clark Ctr Biomed Engn & Sci, Stanford, CA 94305 USA.; Schnitzer, MJ (corresponding author), Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.; Schnitzer, MJ (corresponding author), Stanford Univ, CNC Program, Stanford, CA 94305 USA.
EM mschnitz@stanford.edu
FU Swiss National Science Foundation; Ambizione; US National Science Foundation; Stanford University; Simons Foundation; Helen Hay Whitney Foundation; Novartis Research Foundation; ERC; HHMI; DARPA
NR 49
TC 239
Z9 302
U1 1
U2 102
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 30
PY 2017
VL 543
IS 7647
BP 670
EP +
DI 10.1038/nature21682
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EP8IS
UT WOS:000397619700046
PM 28329757
DA 2026-03-09
ER

PT J
AU Zhang, HT
   Han, GW
   Batyuk, A
   Shchenko, AI
   White, KL
   Patel, N
   Sadybekov, A
   Zamlynny, B
   Rudd, MT
   Hollenstein, K
   Tolstikova, A
   White, TA
   Hunter, MS
   Weierstall, U
   Liu, W
   Babaoglu, K
   Moore, EL
   Katz, RD
   Shipman, JM
   Garcia-Calvo, M
   Sharma, S
   Sheth, P
   Soisson, SM
   Stevens, RC
   Katritch, V
   Herezov, VC
AF Zhang, Haitao
   Han, Gye Won
   Batyuk, Alexander
   Shchenko, Andrii I.
   White, Kate L.
   Patel, Nilkanth
   Sadybekov, Anastasiia
   Zamlynny, Beata
   Rudd, Michael T.
   Hollenstein, Kaspar
   Tolstikova, Alexandra
   White, Thomas A.
   Hunter, Mark S.
   Weierstall, Uwe
   Liu, Wei
   Babaoglu, Kerim
   Moore, Eric L.
   Katz, Ryan D.
   Shipman, Jennifer M.
   Garcia-Calvo, Margarita
   Sharma, Sujata
   Sheth, Payal
   Soisson, Stephen M.
   Stevens, Raymond C.
   Katritch, Vsevolod
   Herezov, Vadim C.
TI Structural basis for selectivity and diversity in angiotensin II receptors
SO NATURE
LA English
DT Article
ID lipidic cubic phase; factor-kappa-b; at(2) receptor; functional selectivity; international union; crystal-structure; at(1); binding; antagonists; activation
AB The angiotensin II receptors AT(1)R and AT(2)R serve as key components of the renin-angiotensin-aldosterone system. AT(1)R has a central role in the regulation of blood pressure, but the function of AT(2)R is unclear and it has a variety of reported effects. To identify the mechanisms that underlie the differences in function and ligand selectivity between these receptors, here we report crystal structures of human AT(2)R bound to an AT(2)R-selective ligand and to an AT(1)R/AT(2)R dual ligand, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position, stabilizing the active-like state, but at the same time preventing the recruitment of G proteins or beta-arrestins, in agreement with the lack of signalling responses in standard cellular assays. Structure-activity relationship, docking and mutagenesis studies revealed the crucial interactions for ligand binding and selectivity. Our results thus provide insights into the structural basis of the distinct functions of the angiotensin receptors, and may guide the design of new selective ligands.
C1 [Zhang, Haitao; Han, Gye Won; Shchenko, Andrii I.; White, Kate L.; Sadybekov, Anastasiia; Stevens, Raymond C.; Katritch, Vsevolod; Herezov, Vadim C.] Univ Southern Calif, Dept Chem, Bridge Inst, Los Angeles, CA 90089 USA.
   [Zhang, Haitao] Zhejiang Univ, Inst Pharmacol & Toxicol, Coll Pharmaceut Sci, 866 Yuhangtang Rd, Hangzhou 310058, Zhejiang, Peoples R China.
   [Batyuk, Alexander; Hunter, Mark S.] SLAC Natl Accelerator Lab, Linac Coherent Light Source, 2575 Sand Hill Rd, Menlo Pk, CA 94025 USA.
   [White, Kate L.; Patel, Nilkanth; Stevens, Raymond C.; Katritch, Vsevolod] Univ Southern Calif, Bridge Inst, Dept Biol Sci, Los Angeles, CA 90089 USA.
   [Zamlynny, Beata; Garcia-Calvo, Margarita; Sheth, Payal] Merck & Co Inc, MRL, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA.
   [Rudd, Michael T.; Hollenstein, Kaspar; Babaoglu, Kerim; Moore, Eric L.; Soisson, Stephen M.] Merck & Co Inc, MRL, 770 Sumneytown Pike, West Point, PA 19486 USA.
   [Tolstikova, Alexandra; White, Thomas A.] Deutsch Elektronen Synchrotron DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany.
   [Tolstikova, Alexandra] Univ Hamburg, Dept Phys, Luruper Chaussee 149, D-22761 Hamburg, Germany.
   [Weierstall, Uwe] Arizona State Univ, Dept Phys, Tempe, AZ 85287 USA.
   [Liu, Wei] Arizona State Univ, Biodesign Inst, Sch Mol Sci, Tempe, AZ 85287 USA.
   [Liu, Wei] Arizona State Univ, Biodesign Inst, Biodesign Ctr Appl Struct Discovery, Tempe, AZ 85287 USA.
   [Katz, Ryan D.; Shipman, Jennifer M.; Sharma, Sujata] Merck & Co Inc, MRL, 503 Louise Lane, N Wales, PA 19454 USA.
C3 University of Southern California; Zhejiang University; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; University of Southern California; Merck & Company; Merck & Company USA; Merck & Company; Merck & Company USA; Helmholtz Association; Deutsches Elektronen-Synchrotron (DESY); University of Hamburg; Arizona State University; Arizona State University-Tempe; Arizona State University; Arizona State University-Tempe; Arizona State University; Arizona State University-Tempe; Merck & Company; Merck & Company USA
RP Katritch, V; Herezov, VC (corresponding author), Univ Southern Calif, Dept Chem, Bridge Inst, Los Angeles, CA 90089 USA.; Katritch, V (corresponding author), Univ Southern Calif, Bridge Inst, Dept Biol Sci, Los Angeles, CA 90089 USA.
EM katritch@usc.edu; cherezov@usc.edu
FU National Institutes of Health (NIH) [R01 GM108635, U54 GM094618]; National Science Foundation (NSF) [1231306]; Helmholtz Association; 'X-probe' - European Union [637295]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]; GM/CA CAT and IMCA-CAT of the Advanced Photon Source, Argonne National Laboratory; NIH [P41GM103393]
NR 66
TC 172
Z9 191
U1 0
U2 114
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 20
PY 2017
VL 544
IS 7650
BP 327
EP +
DI 10.1038/nature22035
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ES4SG
UT WOS:000399524400032
PM 28379944
DA 2026-03-09
ER

PT J
AU Donnelly, C
   Guizar-Sicairos, M
   Scagnoli, V
   Gliga, S
   Holler, M
   Raabe, J
   Heyderman, LJ
AF Donnelly, Claire
   Guizar-Sicairos, Manuel
   Scagnoli, Valerio
   Gliga, Sebastian
   Holler, Mirko
   Raabe, Jorg
   Heyderman, Laura J.
TI Three-dimensional magnetization structures revealed with X-ray vector nanotomography
SO NATURE
LA English
DT Article
ID computed-tomography; phase tomography; pilatus
AB In soft ferromagnetic materials, the smoothly varying magnetization leads to the formation of fundamental patterns such as domains, vortices and domain walls(1). These have been studied extensively in thin films of thicknesses up to around 200 nanometres, in which the magnetization is accessible with current transmission imaging methods that make use of electrons or soft X-rays. In thicker samples, however, in which the magnetization structure varies throughout the thickness and is intrinsically three dimensional, determining the complex magnetic structure directly still represents a challenge(1,3). We have developed hard-X-ray vector nanotomography with which to determine the three-dimensional magnetic configuration at the nanoscale within micrometre-sized samples. We imaged the structure of the magnetization within a soft magnetic pillar of diameter 5 micrometres with a spatial resolution of 100 nanometres and, within the bulk, observed a complex magnetic configuration that consists of vortices and antivortices that form cross-tie walls and vortex walls along intersecting planes. At the intersections of these structures, magnetic singularities-Bloch points-occur. These were predicted more than fifty years ago(4) but have so far not been directly observed. Here we image the three-dimensional magnetic structure in the vicinity of the Bloch points, which until now has been accessible only through micromagnetic simulations, and identify two possible magnetization configurations: a circulating magnetization structure(5) and a twisted state that appears to correspond to an 'anti-Bloch point'. Our imaging method enables the nanoscale study of topological magnetic structures(6) in systems with sizes of the order of tens of micrometres. Knowledge of internal nanomagnetic textures is critical for understanding macroscopic magnetic properties and for designing bulk magnets for technological applications(7).
C1 [Donnelly, Claire; Scagnoli, Valerio; Heyderman, Laura J.] ETH, Dept Mat, Lab Mesoscop Syst, CH-8093 Zurich, Switzerland.
   [Donnelly, Claire; Guizar-Sicairos, Manuel; Scagnoli, Valerio; Holler, Mirko; Raabe, Jorg; Heyderman, Laura J.] Paul Scherrer Inst, CH-5232 Villigen, Switzerland.
   [Gliga, Sebastian] Univ Glasgow, Sch Phys & Astron, SUPA, Glasgow G12 8QQ, Lanark, Scotland.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich; Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute; University of Glasgow
RP Donnelly, C (corresponding author), ETH, Dept Mat, Lab Mesoscop Syst, CH-8093 Zurich, Switzerland.; Donnelly, C; Guizar-Sicairos, M (corresponding author), Paul Scherrer Inst, CH-5232 Villigen, Switzerland.; Gliga, S (corresponding author), Univ Glasgow, Sch Phys & Astron, SUPA, Glasgow G12 8QQ, Lanark, Scotland.
EM claire.donnelly@psi.ch; manuel.guizar-sicairos@psi.ch; sebastian.gliga@glasgow.ac.uk
FU European Union [708674]; Marie Curie Actions (MSCA) [708674] Funding Source: Marie Curie Actions (MSCA)
NR 50
TC 252
Z9 281
U1 1
U2 143
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 20
PY 2017
VL 547
IS 7663
BP 328
EP +
DI 10.1038/nature23006
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB0OR
UT WOS:000405844900029
PM 28726832
DA 2026-03-09
ER

PT J
AU Genova, D
   Kolzenburg, S
   Wiesmaier, S
   Dallanave, E
   Neuville, DR
   Hess, KU
   Dingwell, DB
AF Di Genova, D.
   Kolzenburg, S.
   Wiesmaier, S.
   Dallanave, E.
   Neuville, D. R.
   Hess, K. U.
   Dingwell, D. B.
TI A compositional tipping point governing the mobilization and eruption style of rhyolitic magma
SO NATURE
LA English
DT Article
ID puyehue-cordon caulle; yellowstone caldera; melt inclusions; large-volume; explosive volcanism; silicate-glasses; member rhyolites; high-temperature; chaiten volcano; aeolian islands
AB The most viscous volcanic melts and the largest explosive eruptions(1) on our planet consist of calcalkaline rhyolites(2,3). These eruptions have the potential to influence global climate(4). The eruptive products are commonly very crystal-poor and highly degassed, yet the magma is mostly stored as crystal mushes containing small amounts of interstitial melt with elevated water content(5). It is unclear how magma mushes are mobilized to create large batches of eruptible crystal-free magma. Further, rhyolitic eruptions(6-8) can switch repeatedly between effusive and explosive eruption styles and this transition is difficult to attribute to the rheological effects of water content or crystallinity(9,10). Here we measure the viscosity of a series of melts spanning the compositional range of the Yellowstone volcanic system and find that in a narrow compositional zone, melt viscosity increases by up to two orders of magnitude. These viscosity variations are not predicted by current viscosity models(11,12) and result from melt structure reorganization, as confirmed by Raman spectroscopy. We identify a critical compositional tipping point, independently documented in the global geochemical record of rhyolites, at which rhyolitic melts fluidize or stiffen and that clearly separates effusive from explosive deposits worldwide. This correlation between melt structure, viscosity and eruptive behaviour holds despite the variable water content and other parameters, such as temperature, that are inherent in natural eruptions. Thermodynamic modelling demonstrates how the observed subtle compositional changes that result in fluidization or stiffening of the melt can be induced by crystal growth from the melt or variation in oxygen fugacity. However, the rheological effects of water and crystal content alone cannot explain the correlation between composition and eruptive style. We conclude that the composition of calcalkaline rhyolites is decisive in determining the mobilization and eruption dynamics of Earth's largest volcanic systems, resulting in a better understanding of how the melt structure controls volcanic processes.
C1 [Di Genova, D.] Univ Bristol, Sch Earth Sci, Wills Mem Bldg,Queens Rd, Bristol BS8 1RJ, Avon, England.
   [Di Genova, D.; Kolzenburg, S.; Wiesmaier, S.; Dallanave, E.; Hess, K. U.; Dingwell, D. B.] Ludwig Maximilians Univ Munchen, Dept Earth & Environm Sci, Theresienstr 41-3, D-80333 Munich, Germany.
   [Neuville, D. R.] Univ Paris Diderot, Paris Sorbonne Cite, CNRS IPGP UMR 7154, Geomat, Paris, France.
C3 University of Bristol; University of Munich; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Universite Paris Cite
RP Genova, D (corresponding author), Univ Bristol, Sch Earth Sci, Wills Mem Bldg,Queens Rd, Bristol BS8 1RJ, Avon, England.; Genova, D (corresponding author), Ludwig Maximilians Univ Munchen, Dept Earth & Environm Sci, Theresienstr 41-3, D-80333 Munich, Germany.
EM danilo.digenova@bristol.ac.uk
FU European Research Council [247076]; DFG [ED 1757/1-1]
NR 124
TC 92
Z9 96
U1 2
U2 67
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 14
PY 2017
VL 552
IS 7684
BP 235
EP +
DI 10.1038/nature24488
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ0FK
UT WOS:000418029500043
PM 29239352
DA 2026-03-09
ER

PT J
AU Burgos-Barragan, G
   Wit, N
   Meiser, J
   Dingler, FA
   Pietzke, M
   Mulderrig, L
   Pontel, LB
   Rosado, IV
   Brewer, TF
   Cordell, RL
   Monks, PS
   Chang, CJ
   Vazquez, A
   Patel, KJ
AF Burgos-Barragan, Guillermo
   Wit, Niek
   Meiser, Johannes
   Dingler, Felix A.
   Pietzke, Matthias
   Mulderrig, Lee
   Pontel, Lucas B.
   Rosado, Ivan V.
   Brewer, Thomas F.
   Cordell, Rebecca L.
   Monks, Paul S.
   Chang, Christopher J.
   Vazquez, Alexei
   Patel, Ketan J.
TI Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism
SO NATURE
LA English
DT Article
ID folic-acid; living cells; human liver; dna-damage; folate; mitochondrial; dehydrogenase; compartmentalization; purification; catabolism
AB The folate-driven one-carbon (1C) cycle is a fundamental metabolic hub in cells that enables the synthesis of nucleotides and amino acids and epigenetic modifications. This cycle might also release formaldehyde, a potent protein and DNA crosslinking agent that organisms produce in substantial quantities. Here we show that supplementation with tetrahydrofolate, the essential cofactor of this cycle, and other oxidation-prone folate derivatives kills human, mouse and chicken cells that cannot detoxify formaldehyde or that lack DNA crosslink repair. Notably, formaldehyde is generated from oxidative decomposition of the folate backbone. Furthermore, we find that formaldehyde detoxification in human cells generates formate, and thereby promotes nucleotide synthesis. This supply of 1C units is sufficient to sustain the growth of cells that are unable to use serine, which is the predominant source of 1C units. These findings identify an unexpected source of formaldehyde and, more generally, indicate that the detoxification of this ubiquitous endogenous genotoxin creates a benign 1C unit that can sustain essential metabolism.
C1 [Burgos-Barragan, Guillermo; Wit, Niek; Dingler, Felix A.; Mulderrig, Lee; Pontel, Lucas B.; Patel, Ketan J.] MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England.
   [Meiser, Johannes; Pietzke, Matthias; Vazquez, Alexei] Canc Res UK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland.
   [Rosado, Ivan V.] Univ Seville, CSIC, Hosp Univ Virgen del Rocio, Inst Biomed Sevilla IBiS, Seville 41013, Spain.
   [Brewer, Thomas F.; Chang, Christopher J.] Univ Calif Berkeley, Dept Chem, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
   [Brewer, Thomas F.; Chang, Christopher J.] Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA.
   [Cordell, Rebecca L.; Monks, Paul S.] Univ Leicester, Dept Chem, Leicester LE1 7RH, Leics, England.
   [Patel, Ketan J.] Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 2QQ, England.
C3 MRC Laboratory Molecular Biology; Beatson Institute; Consejo Superior de Investigaciones Cientificas (CSIC); University of Sevilla; CSIC-JA-USE - Instituto de Biomedicina de Sevilla (IBIS); Virgen del Rocio University Hospital; University of California System; University of California Berkeley; University of California System; University of California Berkeley; Howard Hughes Medical Institute; University of Leicester; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; University of Cambridge
RP Patel, KJ (corresponding author), MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England.; Patel, KJ (corresponding author), Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 2QQ, England.
EM kjp@mrc-lmb.cam.ac.uk
FU CRUK Cambridge Cancer Centre studentship; Wellcome Trust; Children With Cancer; CRUK; European Union (FEDER) [BFU2013-42918-P, AES15/01409 (CP12/03273)]; NIH [GM 79465, ES004705]; Chemical Biology Training Grant from the NIH [T32 GM066698]; MRC; EPSRC; CRUK [C596/A21140, C596/A18076]; DFG Fellowship [ME 4636/2-1]; Medical Research Council;  [RYC-2015-18670]; Cancer Research UK [23273] Funding Source: researchfish; Cancer Research UK; Versus Arthritis [21140] Funding Source: researchfish; Medical Research Council [MC_U105178811] Funding Source: researchfish; Wellcome Trust [106202/Z/14/Z] Funding Source: researchfish; MRC [MC_U105178811] Funding Source: UKRI; Wellcome Trust [106202/Z/14/Z] Funding Source: Wellcome Trust; National Institute of Environmental Health Sciences [P42ES004705, R01ES028096] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM079465, T32GM066698] Funding Source: NIH RePORTER
NR 36
TC 277
Z9 305
U1 2
U2 127
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 31
PY 2017
VL 548
IS 7669
BP 549
EP +
DI 10.1038/nature23481
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FF2BO
UT WOS:000408703100030
PM 28813411
DA 2026-03-09
ER

PT J
AU Mall, M
   Kareta, MS
   Chanda, S
   Ahlenius, H
   Perotti, N
   Zhou, B
   Grieder, SD
   Ge, XC
   Drake, S
   Ang, CE
   Walker, BM
   Vierbuchen, T
   Fuentes, DR
   Brennecke, P
   Nitta, KR
   Jolma, A
   Steinmetz, LM
   Taipale, J
   Südhof, TC
   Wernig, M
AF Mall, Moritz
   Kareta, Michael S.
   Chanda, Soham
   Ahlenius, Henrik
   Perotti, Nicholas
   Zhou, Bo
   Grieder, Sarah D.
   Ge, Xuecai
   Drake, Sienna
   Ang, Cheen Euong
   Walker, Brandon M.
   Vierbuchen, Thomas
   Fuentes, Daniel R.
   Brennecke, Philip
   Nitta, Kazuhiro R.
   Jolma, Arttu
   Steinmetz, Lars M.
   Taipale, Jussi
   Sudhof, Thomas C.
   Wernig, Marius
TI Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates
SO NATURE
LA English
DT Article
ID finger transcription factors; lateral inhibition; nervous-system; expression; family; genes; differentiation; binding; cells; fibroblasts
AB Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs(1,2). In reprogramming, the same factors are often used to reprogram many different donor cell types3. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors(4,5), it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific transcription factor Myt1-like (Myt1l)(6) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knockdown of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar 'many-but-one' lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.
C1 [Mall, Moritz; Kareta, Michael S.; Chanda, Soham; Perotti, Nicholas; Zhou, Bo; Grieder, Sarah D.; Ang, Cheen Euong; Walker, Brandon M.; Vierbuchen, Thomas; Fuentes, Daniel R.; Wernig, Marius] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA.
   [Mall, Moritz; Kareta, Michael S.; Chanda, Soham; Perotti, Nicholas; Zhou, Bo; Grieder, Sarah D.; Ang, Cheen Euong; Walker, Brandon M.; Vierbuchen, Thomas; Fuentes, Daniel R.; Wernig, Marius] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA.
   [Chanda, Soham; Zhou, Bo; Sudhof, Thomas C.] Stanford Univ, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
   [Chanda, Soham; Zhou, Bo; Sudhof, Thomas C.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Ahlenius, Henrik; Drake, Sienna] Lund Univ, Div Neurol, Dept Clin Sci, S-22184 Lund, Sweden.
   [Ahlenius, Henrik; Drake, Sienna] Lund Univ, Lund Stem Cell Ctr, S-22184 Lund, Sweden.
   [Ge, Xuecai] Stanford Univ, Dept Dev Biol, Stanford, CA 94305 USA.
   [Brennecke, Philip] Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
   [Nitta, Kazuhiro R.; Jolma, Arttu; Taipale, Jussi] Karolinska Inst, Dept Med Biochem & Biophys, Div Funct Genom & Syst Biol, S-17177 Stockholm, Sweden.
   [Steinmetz, Lars M.] EMBL, Genome Biol Unit, D-69117 Heidelberg, Germany.
   [Taipale, Jussi] Univ Helsinki, Genome Scale Biol, Helsinki 00014, Finland.
   [Kareta, Michael S.] Genet & Genom Grp, Sanford Res, Sioux Falls, SD 57104 USA.
   [Ge, Xuecai] Univ Calif Merced, Mol & Cellular Biol, Merced, CA 95343 USA.
   [Vierbuchen, Thomas] Harvard Med Sch, Dept Neurobiol, Boston, MA 02115 USA.
   [Brennecke, Philip] Leibniz Inst Mol Pharmacol, D-13125 Berlin, Germany.
   [Nitta, Kazuhiro R.] RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa 2300045, Japan.
C3 Stanford University; Stanford University; Stanford University; Stanford University; Howard Hughes Medical Institute; Lund University; Lund University; Stanford University; Stanford University; Karolinska Institutet; European Molecular Biology Laboratory (EMBL); University of Helsinki; Sanford Health; University of California System; University of California Merced; Harvard University; Harvard Medical School; Leibniz Association; Leibniz Forschungsinstitut furr Molekulare Pharmakologie (FMP); RIKEN
RP Wernig, M (corresponding author), Stanford Univ, Dept Pathol, Stanford, CA 94305 USA.
EM wernig@stanford.edu
FU German Research Foundation; NCI [T32 CA09151]; DHHS; Spectrum Child Health Research Institute; Swedish Research Council; Swedish Government Initiative for Strategic Research Areas (StemTherapy); National Institutes of Health; California Institute for Regenerative Medicine
NR 53
TC 170
Z9 214
U1 1
U2 40
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 13
PY 2017
VL 544
IS 7649
BP 245
EP +
DI 10.1038/nature21722
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ER6EK
UT WOS:000398897900040
PM 28379941
DA 2026-03-09
ER

PT J
AU Pfisterer, JHK
   Liang, YC
   Schneider, O
   Bandarenka, AS
AF Pfisterer, Jonas H. K.
   Liang, Yunchang
   Schneider, Oliver
   Bandarenka, Aliaksandr S.
TI Direct instrumental identification of catalytically active surface sites
SO NATURE
LA English
DT Article
ID oxygen reduction reaction; scanning-tunneling-microscopy; hydrogen evolution reaction; single-crystal electrodes; high-index planes; platinum; reactivity; electrocatalysis; deposition; catalysis
AB The activity of heterogeneous catalysts-which are involved in some 80 per cent of processes in the chemical and energy industries-is determined by the electronic structure of specific surface sites that offer optimal binding of reaction intermediates. Directly identifying and monitoring these sites during a reaction should therefore provide insight that might aid the targeted development of heterogeneous catalysts and electrocatalysts (those that participate in electrochemical reactions) for practical applications. The invention of the scanning tunnelling microscope (STM)(1,2) and the electrochemical STM3,4 promised to deliver such imaging capabilities, and both have indeed contributed greatly to our atomistic understanding of heterogeneous catalysis(5-8). But although the STM has been used to probe and initiate surface reactions(9,10), and has even enabled local measurements of reactivity in some systems(11-13), it is not generally thought to be suited to the direct identification of catalytically active surface sites under reaction conditions. Here we demonstrate, however, that common STMs can readily map the catalytic activity of surfaces with high spatial resolution: we show that by monitoring relative changes in the tunnelling current noise, active sites can be distinguished in an almost quantitative fashion according to their ability to catalyse the hydrogen-evolution reaction or the oxygen-reduction reaction. These data allow us to evaluate directly the importance and relative contribution to overall catalyst activity of different defects and sites at the boundaries between two materials. With its ability to deliver such information and its ready applicability to different systems, we anticipate that our method will aid the rational design of heterogeneous catalysts.
C1 [Pfisterer, Jonas H. K.; Liang, Yunchang; Bandarenka, Aliaksandr S.] Tech Univ Munich, Phys Energy Convers & Storage, Phys Dept, James Franck Str 1, D-85748 Garching, Germany.
   [Liang, Yunchang; Schneider, Oliver] Tech Univ Munich, Inst Informat 6, Schleissheimerstr 90a, D-85748 Garching, Germany.
   [Liang, Yunchang; Bandarenka, Aliaksandr S.] NIM, Schellingstr 4, D-80799 Munich, Germany.
   [Bandarenka, Aliaksandr S.] TUM, Catalysis Res Ctr, Ernst Otto Fischer Str 1, D-85748 Garching, Germany.
C3 Technical University of Munich; Technical University of Munich; Technical University of Munich
RP Bandarenka, AS (corresponding author), Tech Univ Munich, Phys Energy Convers & Storage, Phys Dept, James Franck Str 1, D-85748 Garching, Germany.; Bandarenka, AS (corresponding author), NIM, Schellingstr 4, D-80799 Munich, Germany.; Bandarenka, AS (corresponding author), TUM, Catalysis Res Ctr, Ernst Otto Fischer Str 1, D-85748 Garching, Germany.
EM bandarenka@ph.tum.de
FU Deutsche Forschungsgemeinschaft (DFG) [BA 5795/3-1]; cluster of excellence Nanosystems Initiative Munich (NIM); Toyota Motor Europe
NR 38
TC 231
Z9 253
U1 8
U2 492
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 7
PY 2017
VL 549
IS 7670
BP 74
EP +
DI 10.1038/nature23661
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG0DH
UT WOS:000409388700035
PM 28880284
DA 2026-03-09
ER

PT J
AU Kumar, S
   Strachan, JP
   Williams, RST
AF Kumar, Suhas
   Strachan, John Paul
   Williams, R. S. Tanley
TI Chaotic dynamics in nanoscale NbO2 Mott memristors for analogue computing
SO NATURE
LA English
DT Article
ID recurrent neural-networks; computation; order; edge
AB At present, machine learning systems use simplified neuron models that lack the rich nonlinear phenomena observed in biological systems, which display spatio-temporal cooperative dynamics. There is evidence that neurons operate in a regime called the edge of chaos(1) that may be central to complexity, learning efficiency, adaptability and analogue (non-Boolean) computation in brains(2-7). Neural networks have exhibited enhanced computational complexity when operated at the edge of chaos(2), and networks of chaotic elements have been proposed for solving combinatorial or global optimization problems(8). Thus, a source of controllable chaotic behaviour that can be incorporated into a neural-inspired circuit may be an essential component of future computational systems. Such chaotic elements have been simulated using elaborate transistor circuits that simulate known equations of chaos(9-12), but an experimental realization of chaotic dynamics from a single scalable electronic device has been lacking(5,6,13). Here we describe niobium dioxide (NbO2) Mott memristors each less than 100 nanometres across that exhibit both a nonlinear-transport-driven current-controlled negative differential resistance and a Mott-transition-driven temperature-controlled negative differential resistance. Mott materials have a temperature-dependent metal-insulator transition that acts as an electronic switch, which introduces a history-dependent resistance into the device. We incorporate these memristors into a relaxation oscillator(14) and observe a tunable range of periodic and chaotic self-oscillations(15). We show that the nonlinear current transport coupled with thermal fluctuations at the nanoscale generates chaotic oscillations. Such memristors could be useful in certain types of neural-inspired computation by introducing a pseudo-random signal that prevents global synchronization and could also assist in finding a global minimum during a constrained search. We specifically demonstrate that incorporating such memristors into the hardware of a Hopfield computing network can greatly improve the efficiency and accuracy of converging to a solution for computationally difficult problems.
C1 [Kumar, Suhas; Strachan, John Paul; Williams, R. S. Tanley] Hewlett Packard Labs, 1501 Page Mill Rd, Palo Alto, CA 94304 USA.
C3 Hewlett-Packard
RP Kumar, S; Williams, RST (corresponding author), Hewlett Packard Labs, 1501 Page Mill Rd, Palo Alto, CA 94304 USA.
EM suhas.kumar@hpe.com; stan.williams@hpe.com
FU Office of the Director of National Intelligence (ODNI), Intelligence Advanced Research Projects Activity (IARPA) [2017-17013000002]
NR 29
TC 519
Z9 575
U1 13
U2 383
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 17
PY 2017
VL 548
IS 7667
BP 318
EP 321
DI 10.1038/nature23307
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD8AU
UT WOS:000407748400029
PM 28792931
DA 2026-03-09
ER

PT J
AU Park, E
   Ampbell, EBC
   MacKinnon, R
AF Park, Eunyong
   Ampbell, Ernest B. C.
   MacKinnon, Roderick
TI Structure of a CLC chloride ion channel by cryo-electron microscopy
SO NATURE
LA English
DT Article
ID /h+ exchange transporter; torpedo electroplax; binding-site; k channels; antiporter; kidney; selectivity; proteins; barttin; conservation
AB CLC proteins transport chloride (Cl-) ions across cellular membranes to regulate muscle excitability, electrolyte movement across epithelia, and acidification of intracellular organelles. Some CLC proteins are channels that conduct Cl- ions passively, whereas others are secondary active transporters that exchange two Cl- ions for one H+. The structural basis underlying these distinctive transport mechanisms is puzzling because CLC channels and transporters are expected to share the same architecture on the basis of sequence homology. Here we determined the structure of a bovine CLC channel (CLC-K) using cryo-electron microscopy. A conserved loop in the Cl- transport pathway shows a structure markedly different from that of CLC transporters. Consequently, the cytosolic constriction for Cl- passage is widened in CLC-K such that the kinetic barrier previously postulated for Cl-/H+ transporter function would be reduced. Thus, reduction of a kinetic barrier in CLC channels enables fast flow of Cl- down its electrochemical gradient.
C1 [Park, Eunyong; Ampbell, Ernest B. C.; MacKinnon, Roderick] Rockefeller Univ, Lab Mol Neurobiol & Biophys, 1230 York Ave, New York, NY 10065 USA.
   [Park, Eunyong; Ampbell, Ernest B. C.; MacKinnon, Roderick] Rockefeller Univ, Howard Hughes Med Inst, 1230 York Ave, New York, NY 10065 USA.
C3 Rockefeller University; Rockefeller University; Howard Hughes Medical Institute
RP MacKinnon, R (corresponding author), Rockefeller Univ, Lab Mol Neurobiol & Biophys, 1230 York Ave, New York, NY 10065 USA.; MacKinnon, R (corresponding author), Rockefeller Univ, Howard Hughes Med Inst, 1230 York Ave, New York, NY 10065 USA.
EM mackinn@rockefeller.edu
FU Jane Coffin Childs Memorial Fund fellowship [61-1513]
NR 48
TC 119
Z9 142
U1 1
U2 75
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 26
PY 2017
VL 541
IS 7638
BP 500
EP 505
DI 10.1038/nature20812
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6LX
UT WOS:000396116600044
PM 28002411
DA 2026-03-09
ER

PT J
AU Mauer, J
   Luo, XB
   Blanjoie, A
   Jiao, XF
   Grozhik, AV
   Patil, DP
   Linder, B
   Pickering, BF
   Vasseur, JJ
   Chen, QY
   Gross, SS
   Elemento, O
   Debart, F
   Kiledjian, M
   Jaffrey, SR
AF Mauer, Jan
   Luo, Xiaobing
   Blanjoie, Alexandre
   Jiao, Xinfu
   Grozhik, Anya V.
   Patil, Deepak P.
   Linder, Bastian
   Pickering, Brian F.
   Vasseur, Jean-Jacques
   Chen, Qiuying
   Gross, Steven S.
   Elemento, Olivier
   Debart, Francoise
   Kiledjian, Megerditch
   Jaffrey, Samie R.
TI Reversible methylation of m6Am in the 5′ cap controls mRNA stability
SO NATURE
LA English
DT Article
ID cell; protein; argonaute; seq; n-6-methyladenosine; demethylase; methylome; database; alkbh5; clip
AB Internal bases in mRNA can be subjected to modifications that influence the fate of mRNA in cells. One of the most prevalent modified bases is found at the 5' end of mRNA, at the first encoded nucleotide adjacent to the 7-methylguanosine cap. Here we show that this nucleotide, N-6,2'-O-dimethyladenosine (m(6)A(m)), is a reversible modification that influences cellular mRNA fate. Using a transcriptome-wide map of m(6)A(m) we find that m(6)A(m)-initiated transcripts are markedly more stable than mRNAs that begin with other nucleotides. We show that the enhanced stability of m(6)A(m)-initiated transcripts is due to resistance to the mRNA-decapping enzyme DCP2. Moreover, we find that m(6)A(m) is selectively demethylated by fat mass and obesity-associated protein (FTO). FTO preferentially demethylates m(6)A(m) rather than N-6-methyladenosine (m(6)A), and reduces the stability of m(6)A(m) mRNAs. Together, these findings show that the methylation status of m(6)A(m) in the 5' cap is a dynamic and reversible epitranscriptomic modification that determines mRNA stability.
C1 [Mauer, Jan; Grozhik, Anya V.; Patil, Deepak P.; Linder, Bastian; Pickering, Brian F.; Chen, Qiuying; Gross, Steven S.; Jaffrey, Samie R.] Cornell Univ, Weill Cornell Med, Dept Pharmacol, New York, NY 10065 USA.
   [Luo, Xiaobing; Jiao, Xinfu; Kiledjian, Megerditch] Rutgers State Univ, Dept Cell Biol & Neurosci, Piscataway, NJ 08854 USA.
   [Blanjoie, Alexandre; Vasseur, Jean-Jacques; Debart, Francoise] Univ Montpellier ENSCM, IBMM UMR 5247, CNRS, Dept Chem, F-34095 Montpellier 05, France.
   [Elemento, Olivier] Cornell Univ, Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.
   [Elemento, Olivier] Cornell Univ, Weill Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USA.
C3 Cornell University; Weill Cornell Medicine; Rutgers University System; Rutgers University New Brunswick; Universite de Montpellier; Centre National de la Recherche Scientifique (CNRS); Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine
RP Jaffrey, SR (corresponding author), Cornell Univ, Weill Cornell Med, Dept Pharmacol, New York, NY 10065 USA.
EM srj2003@med.cornell.edu
FU NIH [R01DA037755, P01HD67244, R37HL87062, T32HD060600]; Clinical and Translational Science Center Fellowship [T32CA062948, R01GM067005]; French Centre National de la Recherche Scientifique; DFG; Eunice Kennedy Shriver National Institute of Child Health and Human Development [T32HD060600] Funding Source: NIH RePORTER; National Cancer Institute [T32CA062948, R01CA186702] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM067005] Funding Source: NIH RePORTER
NR 60
TC 876
Z9 1051
U1 4
U2 265
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 19
PY 2017
VL 541
IS 7637
BP 371
EP +
DI 10.1038/nature21022
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6QP
UT WOS:000396128800037
PM 28002401
DA 2026-03-09
ER

PT J
AU Liu, K
   Kim, J
   Kim, DW
   Zhang, YS
   Bao, H
   Denaxa, M
   Lim, SA
   Kim, E
   Liu, C
   Wickersham, IR
   Pachinis, V
   Hattar, S
   Song, J
   Brown, SP
   Blackshaw, S
AF Liu, Kai
   Kim, Juhyun
   Kim, Dong Won
   Zhang, Yi Stephanie
   Bao, Hechen
   Denaxa, Myrto
   Lim, Szu-Aun
   Kim, Eileen
   Liu, Chang
   Wickersham, Ian R.
   Pachinis, Vassilis
   Hattar, Samer
   Song, Juan
   Brown, Solange P.
   Blackshaw, Seth
TI Lhx6-positive GABA-releasing neurons of the zona incerta promote sleep
SO NATURE
LA English
DT Article
ID gabaergic neurons; gene-expression; mouse-brain; cortex; orexin; mice; specification; subtypes; system; atlas
AB Multiple populations of wake-promoting neurons have been characterized in mammals, but few sleep-promoting neurons have been identified(1). Wake-promoting cell types include hypocretin and GABA (gamma-aminobutyric-acid)-releasing neurons of the lateral hypothalamus, which promote the transition to wakefulness from non-rapid eye movement (NREM) and rapid eye movement (REM) sleep(2,3). Here we show that a subset of GABAergic neurons in the mouse ventral zona incerta, which express the LIM homeodomain factor Lhx6 and are activated by sleep pressure, both directly inhibit wake-active hypocretin and GABAergic cells in the lateral hypothalamus and receive inputs from multiple sleep-wake-regulating neurons. Conditional deletion of Lhx6 from the developing diencephalon leads to decreases in both NREM and REM sleep. Furthermore, selective activation and inhibition of Lhx6-positive neurons in the ventral zona incerta bidirectionally regulate sleep time in adult mice, in part through hypocretin-dependent mechanisms. These studies identify a GABAergic subpopulation of neurons in the ventral zona incerta that promote sleep.
C1 [Liu, Kai; Kim, Juhyun; Kim, Dong Won; Zhang, Yi Stephanie; Liu, Chang; Brown, Solange P.; Blackshaw, Seth] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21218 USA.
   [Bao, Hechen; Lim, Szu-Aun; Song, Juan] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC USA.
   [Denaxa, Myrto; Pachinis, Vassilis] Francis Crick Inst, London, England.
   [Kim, Eileen] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA.
   [Wickersham, Ian R.] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Hattar, Samer] NIMH, Bethesda, MD 20892 USA.
C3 Johns Hopkins University; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; Francis Crick Institute; Johns Hopkins University; Massachusetts Institute of Technology (MIT); National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH)
RP Blackshaw, S (corresponding author), Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21218 USA.
EM sblack@jhmi.edu
FU Johns Hopkins Discovery Fund award; Klingenstein-Simons Foundation Fellowship in the Neurosciences; The Francis Crick Institute [10128] Funding Source: researchfish; National Institute of Mental Health [ZIAMH002964] Funding Source: NIH RePORTER
NR 42
TC 172
Z9 198
U1 1
U2 29
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 31
PY 2017
VL 548
IS 7669
BP 582
EP +
DI 10.1038/nature23663
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FF2BO
UT WOS:000408703100038
PM 28847002
DA 2026-03-09
ER

PT J
AU Aguado, LC
   Schmid, S
   May, J
   Sabin, LR
   Panis, M
   Blanco-Melo, D
   Shim, JV
   Sachs, D
   Cherry, S
   Simon, AE
   Levraud, JP
   Tenoever, BR
AF Aguado, Lauren C.
   Schmid, Sonja
   May, Jared
   Sabin, Leah R.
   Panis, Maryline
   Blanco-Melo, Daniel
   Shim, Jaehee V.
   Sachs, David
   Cherry, Sara
   Simon, Anne E.
   Levraud, Jean-Pierre
   tenOever, Benjamin R.
TI RNase III nucleases from diverse kingdoms serve as antiviral effectors
SO NATURE
LA English
DT Article
ID mammalian-cells; virus genome; evolution; replication; drosha; microprocessor; localization; attenuation; inhibition; expression
AB In contrast to the DNA-based viruses in prokaryotes, the emergence of eukaryotes provided the necessary compartmentalization and membranous environment for RNA viruses to flourish, creating the need for an RNA-targeting antiviral system(1,2). Present day eukaryotes employ at least two main defence strategies that emerged as a result of this viral shift, namely antiviral RNA interference and the interferon system(2). Here we demonstrate that Drosha and related RNase III ribonucleases from all three domains of life also elicit a unique RNA-targeting antiviral activity. Systemic evolution of ligands by exponential enrichment of this class of proteins illustrates the recognition of unbranched RNA stem loops. Biochemical analyses reveal that, in this context, Drosha functions as an antiviral clamp, conferring steric hindrance on the RNA-dependent RNA polymerases of diverse positive-stranded RNA viruses. We present evidence for cytoplasmic translocation of RNase III nucleases in response to virus in diverse eukaryotes including plants, arthropods, fish, and mammals. These data implicate RNase III recognition of viral RNA as an antiviral defence that is independent of, and possibly predates, other known eukaryotic antiviral systems.
C1 [Aguado, Lauren C.; Schmid, Sonja; Panis, Maryline; Blanco-Melo, Daniel; tenOever, Benjamin R.] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA.
   [May, Jared; Simon, Anne E.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA.
   [Sabin, Leah R.; Cherry, Sara] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA.
   [Shim, Jaehee V.] Icahn Sch Med Mt Sinai, Sch Med, Dept Pharm & Therapeut, New York, NY 10029 USA.
   [Sachs, David] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA.
   [Levraud, Jean-Pierre] CNRS, Inst Pasteur, Macrophages & Dev Immunite, UMR3738, 25-28 Rue Dr Roux, F-75724 Paris 15, France.
C3 Icahn School of Medicine at Mount Sinai; University System of Maryland; University of Maryland College Park; University of Pennsylvania; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Centre National de la Recherche Scientifique (CNRS)
RP Tenoever, BR (corresponding author), Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA.
EM Benjamin.tenOever@mssm.edu
FU Burroughs Wellcome Fund; National Institute of Allergy and Infectious Diseases (NIAID) [R01A1074951]; DIM Malinf, Conseil Regional d'Ile-de-France; American Heart Association [15PRE24930012]; National Science Foundation [MCB-1411836]; NIAID [R21AI117882, R01AI110575]; National Institute of General Medicine [F32 GM119235]; American Heart Association (AHA) [15PRE24930012] Funding Source: American Heart Association (AHA)
NR 39
TC 48
Z9 55
U1 3
U2 26
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 6
PY 2017
VL 547
IS 7661
BP 114
EP +
DI 10.1038/nature22990
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EZ6PM
UT WOS:000404839900041
PM 28658212
DA 2026-03-09
ER

PT J
AU Jiang, JA
   Doi, M
   Maeda, K
   Shigeyama, T
   Nomoto, K
   Yasuda, N
   Jha, SW
   Tanaka, M
   Morokuma, T
   Tominaga, N
   Ivezic, Z
   Ruiz-Lapuente, P
   Stritzinger, MD
   Mazzali, PA
   Ashall, C
   Mould, J
   Baade, D
   Suzuki, N
   Connolly, AJ
   Patat, F
   Wang, LF
   Yoachim, P
   Jones, D
   Furusawa, H
   Miyazaki, S
AF Jiang, Ji-an
   Doi, Mamoru
   Maeda, Keiichi
   Shigeyama, Toshikazu
   Nomoto, Ken'ichi
   Yasuda, Naoki
   Jha, Saurabh W.
   Tanaka, Masaomi
   Morokuma, Tomoki
   Tominaga, Nozomu
   Ivezic, Zeljko
   Ruiz-Lapuente, Pilar
   Stritzinger, Maximilian D.
   Mazzali, Paolo A.
   Ashall, Christopher
   Mould, Jeremy
   Baade, Dietrich
   Suzuki, Nao
   Connolly, Andrew J.
   Patat, Ferdinando
   Wang, Lifan
   Yoachim, Peter
   Jones, David
   Furusawa, Hisanori
   Miyazaki, Satoshi
TI A hybrid type Ia supernova with an early flash triggered by helium-shell detonation
SO NATURE
LA English
DT Article
ID double-degenerate scenario; light curves; sn 2011fe; spectra; models; progenitors; photometry; explosion; emission; binary
AB Type Ia supernovae arise from the thermonuclear explosion of white-dwarf stars that have cores of carbon and oxygen(1,2). The uniformity of their light curves makes these supernovae powerful cosmological distance indicators(3,4), but there have long been debates about exactly how their explosion is triggered and what kind of companion stars are involved(2,5,6). For example, the recent detection of the early ultraviolet pulse of a peculiar, subluminous type Ia supernova has been claimed as evidence for an interaction between a red-giant or a main-sequence companion and ejecta from a whited-warf explosion(7,8). Here we report observations of a prominent but red optical flash that appears about half a day after the explosion of a type Ia supernova. This supernova shows hybrid features of different supernova subclasses, namely a light curve that is typical of normal-brightness supernovae, but with strong titanium absorption, which is commonly seen in the spectra of subluminous ones. We argue that this early flash does not occur through previously suggested mechanisms such as the companion-ejecta interaction(8-10). Instead, our simulations show that it could occur through detonation of a thin helium shell either on a near-Chandrasekhar- mass white dwarf, or on a sub-Chandrasekhar-mass white dwarf merging with a less-massive white dwarf. Our finding provides evidence that one branch of previously proposed explosion models-the helium-ignition branch- does exist in nature, and that such a model may account for the explosions of white dwarfs in a mass range wider than previously supposed(11-14).
C1 [Jiang, Ji-an; Doi, Mamoru; Morokuma, Tomoki] Univ Tokyo, Grad Sch Sci, Inst Astron, 2-21-1 Osawa, Mitaka, Tokyo 1810015, Japan.
   [Jiang, Ji-an] Univ Tokyo, Grad Sch Sci, Dept Astron, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
   [Doi, Mamoru; Maeda, Keiichi; Nomoto, Ken'ichi; Yasuda, Naoki; Tanaka, Masaomi; Morokuma, Tomoki; Tominaga, Nozomu; Suzuki, Nao] Univ Tokyo, Kavli Inst Phys & Math Univ WPI, 5-1-5 Kashiwanoha, Kashiwa, Chiba 2778583, Japan.
   [Doi, Mamoru; Shigeyama, Toshikazu] Univ Tokyo, Grad Sch Sci, Res Ctr Early Universe, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
   [Maeda, Keiichi] Kyoto Univ, Dept Astron, Sakyo Ku, Kitashirakawa Oiwake Cho, Kyoto 6068502, Japan.
   [Jha, Saurabh W.] Rutgers State Univ, Dept Phys & Astron, 136 Frelinghuysen Rd, Piscataway, NJ 08854 USA.
   [Tanaka, Masaomi; Furusawa, Hisanori; Miyazaki, Satoshi] Natl Astron Observ Japan, 2-21-1 Osawa, Mitaka, Tokyo 1818588, Japan.
   [Tominaga, Nozomu] Konan Univ, Dept Phys, Fac Sci & Engn, 8-9-1 Okamoto, Kobe, Hyogo 6588501, Japan.
   [Ivezic, Zeljko; Connolly, Andrew J.; Yoachim, Peter] Univ Washington, Dept Astron, Box 351580, Seattle, WA 98195 USA.
   [Ruiz-Lapuente, Pilar] CSIC, Inst Fis Fundamental, Calle Serrano 121, E-28006 Madrid, Spain.
   [Ruiz-Lapuente, Pilar] Inst Ciencies Cosmos UB IEEC, Calle Marti & Franques 1, E-08028 Barcelona, Spain.
   [Stritzinger, Maximilian D.] Aarhus Univ, Dept Phys & Astron, Ny Munkegade 120, DK-8000 Aarhus C, Denmark.
   [Mazzali, Paolo A.; Ashall, Christopher] Liverpool John Moores Univ, Astrophys Res Inst, IC2 Liverpool Sci Pk,146 Brownlow Hill, Liverpool L3 5RF, Merseyside, England.
   [Mazzali, Paolo A.] Max Planck Inst Astrophys, Karl Schwarzschild Str 1, D-85748 Garching, Germany.
   [Mould, Jeremy] Swinburne Univ Technol, Ctr Astrophys & Supercomp, Hawthorn, Vic 3122, Australia.
   [Baade, Dietrich; Patat, Ferdinando] European Org Astron Res Southern Hemisphere ESO, Karl Schwarzschild Str 2, D-85748 Garching, Germany.
   [Wang, Lifan] Texas A&M Univ, Dept Phys & Astron, George P & Cynthia Woods Mitchell Inst Fundamenta, 4242 TAMU, College Stn, TX 77843 USA.
   [Wang, Lifan] Chinese Acad Sci, Purple Mt Observ, Nanjing 210008, Jiangsu, Peoples R China.
   [Jones, David] Inst Astrofis Canarias, E-38205 Tenerife, Spain.
   [Jones, David] Univ La Laguna, Dept Astrofis, E-38206 Tenerife, Spain.
   [Miyazaki, Satoshi] SOKENDAI, Mitaka, Tokyo 1818588, Japan.
C3 University of Tokyo; University of Tokyo; University of Tokyo; University of Tokyo; Kyoto University; Rutgers University System; Rutgers University New Brunswick; National Institutes of Natural Sciences (NINS) - Japan; National Astronomical Observatory of Japan (NAOJ); Konan University; University of Washington; University of Washington Seattle; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Fisica Fundamental (IFF); Institut d'Estudis Espacials de Catalunya (IEEC); Aarhus University; Liverpool John Moores University; Max Planck Society; Swinburne University of Technology; Texas A&M University System; Texas A&M University College Station; Chinese Academy of Sciences; Nanjing Institute of Astronomical Optics & Technology, NAOC, CAS; Purple Mountain Observatory, CAS; Instituto de Astrofisica de Canarias; Universidad de la Laguna; Graduate University for Advanced Studies - Japan
RP Jiang, JA (corresponding author), Univ Tokyo, Grad Sch Sci, Inst Astron, 2-21-1 Osawa, Mitaka, Tokyo 1810015, Japan.; Jiang, JA (corresponding author), Univ Tokyo, Grad Sch Sci, Dept Astron, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
EM yuzhoujiang@ioa.s.u-tokyo.ac.jp
FU Grants-in-Aid for Scientific Research [15H05440, 16H06341, 17H06363, 17H02864, 17H06357, 15H02075, 16H01087, 26287029, 16K05287] Funding Source: KAKEN; STFC [ST/F007159/1, ST/P006892/1, ST/P002218/1, ST/L00061X/1, ST/J001465/1, ST/M003035/1] Funding Source: UKRI; Science and Technology Facilities Council [ST/J001465/1, ST/F007159/1, ST/M000966/1, ST/L00061X/1, ST/P006892/1, ST/M003035/1, ST/P002218/1] Funding Source: researchfish; Villum Fonden [00013261] Funding Source: researchfish
NR 65
TC 120
Z9 134
U1 2
U2 16
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 5
PY 2017
VL 550
IS 7674
BP 80
EP +
DI 10.1038/nature23908
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI7XU
UT WOS:000412214100048
PM 28980637
DA 2026-03-09
ER

PT J
AU Wu, G
   Chan, KC
   Zhu, LL
   Sun, LG
   Lu, J
AF Wu, Ge
   Chan, Ka-Cheung
   Zhu, Linli
   Sun, Ligang
   Lu, Jian
TI Dual-phase nanostructuring as a route to high-strength magnesium alloys
SO NATURE
LA English
DT Article
ID mechanical-behavior; ultrahigh strength; size-reduction; cu; ductility; state; glasses; maximum; liquid; energy
AB It is not easy to fabricate materials that exhibit their theoretical 'ideal' strength. Most methods of producing stronger materials are based on controlling defects to impede the motion of dislocations, but such methods have their limitations. For example, industrial single-phase nanocrystalline alloys(1,2) and single-phase metallic glasses(3) can be very strong, but they typically soften at relatively low strains (less than two per cent) because of, respectively, the reverse Hall-Petch effect(4) and shear-band formation. Here we describe an approach that combines the strengthening benefits of nanocrystallinity with those of amorphization to produce a dualphase material that exhibits near-ideal strength at room temperature and without sample size effects. Our magnesium-alloy system consists of nanocrystalline cores embedded in amorphous glassy shells, and the strength of the resulting dual-phase material is a near-ideal 3.3 gigapascals-making this the strongest magnesiumalloy thin film yet achieved. We propose a mechanism, supported by constitutive modelling, in which the crystalline phase (consisting of almost-dislocation-free grains of around six nanometres in diameter) blocks the propagation of localized shear bands when under strain; moreover, within any shear bands that do appear, embedded crystalline grains divide and rotate, contributing to hardening and countering the softening effect of the shear band.
C1 [Wu, Ge; Chan, Ka-Cheung; Zhu, Linli; Sun, Ligang; Lu, Jian] City Univ Hong Kong, Dept Mech & Biomed Engn, Kowloon, Hong Kong, Peoples R China.
   [Zhu, Linli] Zhejiang Univ, Dept Engn Mech, Hangzhou 310027, Zhejiang, Peoples R China.
   [Zhu, Linli] Zhejiang Univ, Key Lab Soft Machines & Smart Devices Zhejiang Pr, Hangzhou 310027, Zhejiang, Peoples R China.
   [Lu, Jian] City Univ Hong Kong, Shenzhen Res Inst, Ctr Adv Struct Mat, 8 Yuexing 1st Rd,Shenzhen Hi Tech Ind Pk, Shenzhen, Peoples R China.
C3 City University of Hong Kong; Zhejiang University; Zhejiang University; City University of Hong Kong; Shenzhen Research Institute, City University of Hong Kong
RP Lu, J (corresponding author), City Univ Hong Kong, Dept Mech & Biomed Engn, Kowloon, Hong Kong, Peoples R China.; Lu, J (corresponding author), City Univ Hong Kong, Shenzhen Res Inst, Ctr Adv Struct Mat, 8 Yuexing 1st Rd,Shenzhen Hi Tech Ind Pk, Shenzhen, Peoples R China.
EM jianlu@cityu.edu.hk
FU National Natural Science Foundation of China (NSFC) [51590892]; Hong Kong Collaborative Research Fund (CRF) Scheme [C4028-14G, CityU9/CRF/13G]
NR 43
TC 592
Z9 643
U1 30
U2 1151
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 4
PY 2017
VL 545
IS 7652
BP 80
EP +
DI 10.1038/nature21691
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET7MK
UT WOS:000400480400034
PM 28379942
DA 2026-03-09
ER

PT J
AU Ali, SH
   Giurco, D
   Arndt, N
   Nickless, E
   Brown, G
   Demetriades, A
   Durrheim, R
   Enriquez, MA
   Kinnaird, J
   Littleboy, A
   Meinert, LD
   Oberhänsli, R
   Salem, J
   Schodde, R
   Schneider, G
   Vidal, O
   Yakovleva, N
AF Ali, Saleem H.
   Giurco, Damien
   Arndt, Nicholas
   Nickless, Edmund
   Brown, Graham
   Demetriades, Alecos
   Durrheim, Ray
   Enriquez, Maria Amelia
   Kinnaird, Judith
   Littleboy, Anna
   Meinert, Lawrence D.
   Oberhansli, Roland
   Salem, Janet
   Schodde, Richard
   Schneider, Gabi
   Vidal, Olivier
   Yakovleva, Natalia
TI Mineral supply for sustainable development requires resource governance
SO NATURE
LA English
DT Article
ID metals; criticality; challenges; society; demand; risk
AB Successful delivery of the United Nations sustainable development goals and implementation of the Paris Agreement requires technologies that utilize a wide range of minerals in vast quantities. Metal recycling and technological change will contribute to sustaining supply, but mining must continue and grow for the foreseeable future to ensure that such minerals remain available to industry. New links are needed between existing institutional frameworks to oversee responsible sourcing of minerals, trajectories for mineral exploration, environmental practices, and consumer awareness of the effects of consumption. Here we present, through analysis of a comprehensive set of data and demand forecasts, an interdisciplinary perspective on how best to ensure ecologically viable continuity of global mineral supply over the coming decades.
C1 [Ali, Saleem H.] Univ Delaware, Coll Earth Ocean & Environm, Newark, DE 19716 USA.
   [Ali, Saleem H.] Univ Queensland, Sustainable Minerals Inst, Brisbane, Qld, Australia.
   [Ali, Saleem H.] Univ Vermont, Gund Inst Ecol Econ, Burlington, VT 05405 USA.
   [Giurco, Damien] Univ Technol Sydney, Inst Sustainable Futures, Sydney, NSW, Australia.
   [Arndt, Nicholas; Vidal, Olivier] Univ Grenoble Alpes, Inst Sci Terre, Grenoble, France.
   [Nickless, Edmund] Geol Soc London, London, England.
   [Brown, Graham] Graham Brown Consulting, Buckland, Bucks, England.
   [Demetriades, Alecos] IUGS IAGC Commiss Global Geochem Baselines & Euro, Athens, Greece.
   [Durrheim, Ray; Kinnaird, Judith] Univ Witwatersrand, Johannesburg, South Africa.
   [Enriquez, Maria Amelia] Univ Para, Belem, Para, Brazil.
   [Littleboy, Anna] CSIRO, Brisbane, Qld, Australia.
   [Meinert, Lawrence D.] US Geol Survey, 959 Natl Ctr, Reston, VA 22092 USA.
   [Oberhansli, Roland] Potsdam Univ, Potsdam, Germany.
   [Oberhansli, Roland] Int Union Geol Sci, Potsdam, Germany.
   [Salem, Janet] UN, Environm Programme, Bangkok, Thailand.
   [Schodde, Richard] MinEx Consulting, Melbourne, Vic, Australia.
   [Schodde, Richard] Univ Western Australia, Ctr Explorat Targeting, Perth, WA, Australia.
   [Schneider, Gabi] Namibian Uranium Inst, Swakopmund, Namibia.
   [Yakovleva, Natalia] Newcastle Univ, London Campus, London, England.
C3 University of Delaware; University of Queensland; University of Vermont; University of Technology Sydney; Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Centre National de la Recherche Scientifique (CNRS); Institut de Recherche pour le Developpement (IRD); Universite Gustave-Eiffel; Universite Savoie Mont Blanc; University of Witwatersrand; Commonwealth Scientific & Industrial Research Organisation (CSIRO); United States Department of the Interior; United States Geological Survey; University of Potsdam; United Nations Environment Programme; University of Western Australia; Newcastle University - UK
RP Ali, SH (corresponding author), Univ Delaware, Coll Earth Ocean & Environm, Newark, DE 19716 USA.; Ali, SH (corresponding author), Univ Queensland, Sustainable Minerals Inst, Brisbane, Qld, Australia.; Ali, SH (corresponding author), Univ Vermont, Gund Inst Ecol Econ, Burlington, VT 05405 USA.
EM saleem@alum.mit.edu
FU UNESCO; IUGS; ICSU
NR 50
TC 548
Z9 643
U1 20
U2 397
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 16
PY 2017
VL 543
IS 7645
BP 367
EP 372
DI 10.1038/nature21359
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN9RN
UT WOS:000396337400040
PM 28300094
DA 2026-03-09
ER

PT J
AU Kingslake, J
   Ely, JC
   Das, I
   Bell, RE
AF Kingslake, Jonathan
   Ely, Jeremy C.
   Das, Indrani
   Bell, Robin E.
TI Widespread movement of meltwater onto and across Antarctic ice shelves
SO NATURE
LA English
DT Article
ID surface mass-balance; dronning maud land; supraglacial lakes; sheet; drainage; melt; evolution; peninsula; collapse; areas
AB Surface meltwater drains across ice sheets, forming melt ponds that can trigger ice-shelf collapse(1,2), acceleration of grounded ice flow and increased sea-level rise(3-5). Numerical models of the Antarctic Ice Sheet that incorporate meltwater's impact on ice shelves, but ignore the movement of water across the ice surface, predict a metre of global sea-level rise this century(5) in response to atmospheric warming(6). To understand the impact of water moving across the ice surface a broad quantification of surface meltwater and its drainage is needed. Yet, despite extensive research in Greenland(7-10) and observations of individual drainage systems in Antarctica(10-17), we have little understanding of Antarctic-wide surface hydrology or how it will evolve. Here we show widespread drainage of meltwater across the surface of the ice sheet through surface streams and ponds (hereafter 'surface drainage') as far south as 85 degrees S and as high as 1,300 metres above sea level. Our findings are based on satellite imagery from 1973 onwards and aerial photography from 1947 onwards. Surface drainage has persisted for decades, transporting water up to 120 kilometres from grounded ice onto and across ice shelves, feeding vast melt ponds up to 80 kilometres long. Large-scale surface drainage could deliver water to areas of ice shelves vulnerable to collapse, as melt rates increase this century. While Antarctic surface melt ponds are relatively well documented on some ice shelves, we have discovered that ponds often form part of widespread, large-scale surface drainage systems. In a warming climate, enhanced surface drainage could accelerate future ice-mass loss from Antarctic, potentially via positive feedbacks between the extent of exposed rock, melting and thinning of the ice sheet.
C1 [Kingslake, Jonathan; Das, Indrani; Bell, Robin E.] Columbia Univ, Lamont Doherty Earth Observ, Palisades, NY 10964 USA.
   [Ely, Jeremy C.] Univ Sheffield, Dept Geog, Sheffield, S Yorkshire, England.
C3 Columbia University; University of Sheffield
RP Kingslake, J (corresponding author), Columbia Univ, Lamont Doherty Earth Observ, Palisades, NY 10964 USA.
EM j.kingslake@columbia.edu
FU NASA [NNX14AH79G]; NSF [GG008566, 1443534]; Old York Foundation; Office of Polar Programs (OPP); Directorate For Geosciences [1443534] Funding Source: National Science Foundation; NASA [NNX14AH79G, 683635] Funding Source: Federal RePORTER
NR 34
TC 182
Z9 211
U1 1
U2 105
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 20
PY 2017
VL 544
IS 7650
BP 349
EP +
DI 10.1038/nature22049
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ES4SG
UT WOS:000399524400036
PM 28425995
DA 2026-03-09
ER

PT J
AU Simeonov, DR
   Gowen, BG
   Boontanrart, M
   Roth, TL
   Gagnon, JD
   Mumbach, MR
   Satpathy, AT
   Lee, YJ
   Bray, NL
   Chan, AY
   Lituiev, DS
   Nguyen, ML
   Gate, RE
   Subramaniam, M
   Li, ZM
   Woo, JM
   Mitros, T
   Ray, GJ
   Curie, GL
   Naddaf, N
   Chu, JS
   Ma, H
   Boyer, E
   Van Gool, F
   Huang, HL
   Liu, RZ
   Tobin, VR
   Schumann, K
   Daly, MJ
   Farh, KK
   Ansel, KM
   Ye, CJ
   Greenleaf, WJ
   Anderson, MS
   Bluestone, JA
   Chang, HY
   Corn, JE
   Marson, A
AF Simeonov, Dimitre R.
   Gowen, Benjamin G.
   Boontanrart, Mandy
   Roth, Theodore L.
   Gagnon, John D.
   Mumbach, Maxwell R.
   Satpathy, Ansuman T.
   Lee, Youjin
   Bray, Nicolas L.
   Chan, Alice Y.
   Lituiev, Dmytro S.
   Nguyen, Michelle L.
   Gate, Rachel E.
   Subramaniam, Meena
   Li, Zhongmei
   Woo, Jonathan M.
   Mitros, Therese
   Ray, Graham J.
   Curie, Gemma L.
   Naddaf, Nicki
   Chu, Julia S.
   Ma, Hong
   Boyer, Eric
   Van Gool, Frederic
   Huang, Hailiang
   Liu, Ruize
   Tobin, Victoria R.
   Schumann, Kathrin
   Daly, Mark J.
   Farh, Kyle K.
   Ansel, K. Mark
   Ye, Chun J.
   Greenleaf, William J.
   Anderson, Mark S.
   Bluestone, Jeffrey A.
   Chang, Howard Y.
   Corn, Jacob E.
   Marson, Alexander
TI Discovery of stimulation-responsive immune enhancers with CRISPR activation
SO NATURE
LA English
DT Article
ID interleukin-2; gene; expression; autoimmune; antibody; loci
AB The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular cues(1-3). Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption(4-6), but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus-responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa)(7) to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA. We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (T(H)17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs.
C1 [Simeonov, Dimitre R.; Roth, Theodore L.; Gagnon, John D.] Univ Calif San Francisco, Biomed Sci Grad Program, San Francisco, CA 94143 USA.
   [Simeonov, Dimitre R.; Roth, Theodore L.; Gagnon, John D.; Lee, Youjin; Nguyen, Michelle L.; Li, Zhongmei; Woo, Jonathan M.; Tobin, Victoria R.; Schumann, Kathrin; Ansel, K. Mark; Marson, Alexander] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA.
   [Simeonov, Dimitre R.; Roth, Theodore L.; Lee, Youjin; Chan, Alice Y.; Nguyen, Michelle L.; Li, Zhongmei; Woo, Jonathan M.; Boyer, Eric; Van Gool, Frederic; Tobin, Victoria R.; Schumann, Kathrin; Anderson, Mark S.; Bluestone, Jeffrey A.; Marson, Alexander] Univ Calif San Francisco, Diabet Ctr, San Francisco, CA 94143 USA.
   [Simeonov, Dimitre R.; Gowen, Benjamin G.; Boontanrart, Mandy; Roth, Theodore L.; Lee, Youjin; Bray, Nicolas L.; Nguyen, Michelle L.; Li, Zhongmei; Woo, Jonathan M.; Mitros, Therese; Ray, Graham J.; Curie, Gemma L.; Naddaf, Nicki; Chu, Julia S.; Ma, Hong; Boyer, Eric; Tobin, Victoria R.; Schumann, Kathrin; Corn, Jacob E.; Marson, Alexander] Univ Calif Berkeley, Innovat Genom Inst, Berkeley, CA 94720 USA.
   [Gowen, Benjamin G.; Boontanrart, Mandy; Bray, Nicolas L.; Mitros, Therese; Ray, Graham J.; Curie, Gemma L.; Naddaf, Nicki; Chu, Julia S.; Ma, Hong; Corn, Jacob E.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
   [Gagnon, John D.; Ansel, K. Mark] Univ Calif San Francisco, Sandler Asthma Basic Res Ctr, San Francisco, CA 94143 USA.
   [Mumbach, Maxwell R.; Satpathy, Ansuman T.; Chang, Howard Y.] Stanford Univ, Sch Med, Ctr Personal Dynam Regulomes, Stanford, CA 94305 USA.
   [Mumbach, Maxwell R.; Chang, Howard Y.] Stanford Univ, Sch Med, Program Epithelial Biol, Stanford, CA 94305 USA.
   [Mumbach, Maxwell R.; Satpathy, Ansuman T.; Greenleaf, William J.] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA.
   [Chan, Alice Y.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA.
   [Lituiev, Dmytro S.; Gate, Rachel E.; Subramaniam, Meena; Ye, Chun J.] Univ Calif San Francisco, IHG, Dept Bioengn & Therapeut Sci, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.
   [Gate, Rachel E.; Subramaniam, Meena] Univ Calif San Francisco, Biol & Med Informat Grad Program, San Francisco, CA 94158 USA.
   [Huang, Hailiang; Liu, Ruize; Daly, Mark J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Huang, Hailiang; Liu, Ruize; Daly, Mark J.] Harvard Med Sch, Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
   [Farh, Kyle K.] Illumina Inc, 5200 Illumina Way, San Diego, CA 92122 USA.
   [Greenleaf, William J.] Stanford Univ, Dept Appl Phys, Stanford, CA 94025 USA.
   [Greenleaf, William J.; Marson, Alexander] Chan Zuckerberg Biohub, San Francisco, CA 94158 USA.
   [Anderson, Mark S.; Marson, Alexander] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.
   [Marson, Alexander] Univ Calif San Francisco, UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.
C3 University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of California System; University of California San Francisco; Stanford University; Stanford University; Stanford University; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; Illumina; Stanford University; Chan Zuckerberg Initiative (CZI); University of California System; University of California San Francisco; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center
RP Marson, A (corresponding author), Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA.; Marson, A (corresponding author), Univ Calif San Francisco, Diabet Ctr, San Francisco, CA 94143 USA.; Corn, JE; Marson, A (corresponding author), Univ Calif Berkeley, Innovat Genom Inst, Berkeley, CA 94720 USA.; Corn, JE (corresponding author), Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.; Marson, A (corresponding author), Chan Zuckerberg Biohub, San Francisco, CA 94158 USA.; Marson, A (corresponding author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.; Marson, A (corresponding author), Univ Calif San Francisco, UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.
EM jcorn@berkeley.edu; alexander.marson@ucsf.edu
FU NIH [DP3DK111914-01, R01HG0081410-01, R01HL109102, P50-HG007735]; Scleroderma Research Foundation; UCSF Sandler Fellowship; National Multiple Sclerosis Society grant [CA 1074-A-21]; Marcus Program in Precision Medicine Innovation; Career Award for Medical Scientists from the Burroughs Wellcome Fund; Li Ka Shing Foundation; IGI-AstraZeneca Postdoctoral Fellowship; DFG Postdoctoral Fellowship; NIH S10 Instrumentation Grants [S10RR029668, S10RR027303]; Diabetes Research Center [NIH P30 DK063720]; National Heart Lung and Blood Institute [R01HL109102] Funding Source: NIH RePORTER; National Human Genome Research Institute [T32HG000044, R01HG008140] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [T32AI007334] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK043351, T32DK007418] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007232, T32GM067547] Funding Source: NIH RePORTER
NR 38
TC 212
Z9 289
U1 2
U2 69
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 7
PY 2017
VL 549
IS 7670
BP 111
EP +
DI 10.1038/nature23875
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG0DH
UT WOS:000409388700043
PM 28854172
DA 2026-03-09
ER

PT J
AU Betts, MG
   Wolf, C
   Ripple, WJ
   Phalan, B
   Millers, KA
   Duarte, A
   Butchart, SHM
   Levi, T
AF Betts, Matthew G.
   Wolf, Christopher
   Ripple, William J.
   Phalan, Ben
   Millers, Kimberley A.
   Duarte, Adam
   Butchart, Stuart H. M.
   Levi, Taal
TI Global forest loss disproportionately erodes biodiversity in intact landscapes
SO NATURE
LA English
DT Article
ID tropical forests; extinction risk; human footprint; habitat loss; worlds; fragmentation; richness; hotspots; impact
AB Global biodiversity loss is a critical environmental crisis, yet the lack of spatial data on biodiversity threats has hindered conservation strategies(1). Theory predicts that abrupt biodiversity declines are most likely to occur when habitat availability is reduced to very low levels in the landscape (10-30%)(2-4). Alternatively, recent evidence indicates that biodiversity is best conserved by minimizing human intrusion into intact and relatively unfragmented landscapes(5). Here we use recently available forest loss data(6) to test deforestation effects on International Union for Conservation of Nature Red List categories of extinction risk for 19,432 vertebrate species worldwide. As expected, deforestation substantially increased the odds of a species being listed as threatened, undergoing recent upgrading to a higher threat category and exhibiting declining populations. More importantly, we show that these risks were disproportionately high in relatively intact landscapes; even minimal deforestation has had severe consequences for vertebrate biodiversity. We found little support for the alternative hypothesis that forest loss is most detrimental in already fragmented landscapes. Spatial analysis revealed high-risk hot spots in Borneo, the central Amazon and the Congo Basin. In these regions, our model predicts that 121-219 species will become threatened under current rates of forest loss over the next 30 years. Given that only 17.9% of these high-risk areas are formally protected and only 8.9% have strict protection, new large-scale conservation efforts to protect intact forests(7,8) are necessary to slow deforestation rates and to avert a new wave of global extinctions.
C1 [Betts, Matthew G.; Wolf, Christopher; Ripple, William J.; Phalan, Ben; Levi, Taal] Oregon State Univ, Dept Forest Ecosyst & Soc, Forest Biodivers Res Network, Corvallis, OR 97331 USA.
   [Betts, Matthew G.; Wolf, Christopher; Ripple, William J.] Oregon State Univ, Dept Forest Ecosyst & Soc, Global Troph Cascades Program, Corvallis, OR 97331 USA.
   [Phalan, Ben; Butchart, Stuart H. M.] Univ Cambridge, Dept Zool, Downing St, Cambridge CB2 3EJ, England.
   [Millers, Kimberley A.; Levi, Taal] Oregon State Univ, Dept Fisheries & Wildlife, Corvallis, OR 97331 USA.
   [Duarte, Adam] Oregon State Univ, Dept Fisheries & Wildlife, Oregon Cooperat Fish & Wildlife Res Unit, Corvallis, OR 97331 USA.
   [Butchart, Stuart H. M.] BirdLife Int, David Attenborough Bldg,Pembroke St, Cambridge CB2 3QZ, England.
C3 Oregon State University; Oregon State University; University of Cambridge; Oregon State University; Oregon State University; BirdLife International
RP Betts, MG; Wolf, C (corresponding author), Oregon State Univ, Dept Forest Ecosyst & Soc, Forest Biodivers Res Network, Corvallis, OR 97331 USA.; Betts, MG; Wolf, C (corresponding author), Oregon State Univ, Dept Forest Ecosyst & Soc, Global Troph Cascades Program, Corvallis, OR 97331 USA.
EM matt.betts@oregonstate.edu; wolfch@science.oregonstate.edu
FU National Science Foundation [NSF-DEB-1457837]; College of Forestry IWFL Professorship in Forest Biodiversity Research
NR 64
TC 452
Z9 514
U1 20
U2 532
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 27
PY 2017
VL 547
IS 7664
BP 441
EP +
DI 10.1038/nature23285
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB7ZK
UT WOS:000406358300033
PM 28723892
DA 2026-03-09
ER

PT J
AU Medhaug, I
   Stolpe, MB
   Fischer, EM
   Knutti, R
AF Medhaug, Iselin
   Stolpe, Martin B.
   Fischer, Erich M.
   Knutti, Reto
TI Reconciling controversies about the 'global warming hiatus'
SO NATURE
LA English
DT Article
ID sea-surface temperature; ocean heat uptake; meridional overturning circulation; atlantic multidecadal oscillation; stratospheric water-vapor; earths energy imbalance; north-atlantic; climate-change; natural variability; thermohaline circulation
AB Between about 1998 and 2012, a time that coincided with political negotiations for preventing climate change, the surface of Earth seemed hardly to warm. This phenomenon, often termed the 'global warming hiatus', caused doubt in the public mind about how well anthropogenic climate change and natural variability are understood. Here we show that apparently contradictory conclusions stem from different definitions of 'hiatus' and from different datasets. A combination of changes in forcing, uptake of heat by the oceans, natural variability and incomplete observational coverage reconciles models and data. Combined with stronger recent warming trends in newer datasets, we are now more confident than ever that human influence is dominant in long-term warming.
C1 [Medhaug, Iselin; Stolpe, Martin B.; Fischer, Erich M.; Knutti, Reto] Swiss Fed Inst Technol, Inst Atmospher & Climate Sci, CH-8092 Zurich, Switzerland.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Medhaug, I (corresponding author), Swiss Fed Inst Technol, Inst Atmospher & Climate Sci, CH-8092 Zurich, Switzerland.
EM Iselin.medhaug@env.ethz.ch
CR Abraham JP, 2013, REV GEOPHYS, V51, P450, DOI 10.1002/rog.20022
   Allan RP, 2014, GEOPHYS RES LETT, V41, P5588, DOI 10.1002/2014GL060962
   Amaya DJ, 2015, J GEOPHYS RES-OCEANS, V120, P6782, DOI 10.1002/2015JC010906
   Andersson SM, 2015, NAT COMMUN, V6, P0, DOI 10.1038/ncomms8692
   Unknown -, 2009, J GEOPHYS RES ATMOS, V0, P0, DOI DOI 10.1029/2008JD011470
   Unknown -, 2013, B AM METEOROL SOC, V0, P0
   Unknown -, 1900, DOI 10.1002/2014E0040002, V0, P0
   Armour KC, 2016, NAT CLIM CHANGE, V6, P896, DOI 10.1038/nclimate3079
   Armour KC, 2013, J CLIMATE, V26, P4518, DOI 10.1175/JCLI-D-12-00544.1
   Bala G, 2013, CURR SCI INDIA, V105, P1031
   Balmaseda MA, 2013, GEOPHYS RES LETT, V40, P1754, DOI 10.1002/grl.50382
   Barcikowska MJ, 2017, J CLIMATE, V30, P721, DOI 10.1175/JCLI-D-16-0443.1
   Baumberger C, 2017, WILEY INTERDISCIP RE, V0, P0
   Bindoff NL, 2007, CLIMATE CHANGE 2007: THE PHYSICAL SCIENCE BASIS. CONTRIBUTION OF WORKING GROUP I TO THE FOURTH ASSESSMENT REPORT OF THE INTERGOVERNMENTAL PANEL ON CLIMATE CHANGE, V0, P0
   Bjerknes J, 1964, ADV GEOPHYS, V10, P1, DOI 10.1016/S0065-2687(08)60005-9
   Booth BBB, 2012, NATURE, V484, P228, DOI 10.1038/nature10946
   Boykoff MT, 2014, NAT CLIM CHANGE, V4, P156, DOI 10.1038/nclimate2156
   BROECKER WS, 1985, NATURE, V315, P21, DOI 10.1038/315021a0
   Brohan P, 2006, J GEOPHYS RES-ATMOS, V111, P0, DOI 10.1029/2005JD006548
   Brown PT, 2015, SCI REP-UK, V5, P0, DOI 10.1038/srep09957
   Brühl C, 2015, J GEOPHYS RES-ATMOS, V120, P2103, DOI 10.1002/2014JD022430
   Buckley MW, 2016, REV GEOPHYS, V54, P5, DOI 10.1002/2015RG000493
   Cahill N, 2015, ENVIRON RES LETT, V10, P0, DOI 10.1088/1748-9326/10/8/084002
   Carter B, 2006, TELEGRAPH, V0, P0
   Cazenave A, 2009, GLOBAL PLANET CHANGE, V65, P83, DOI 10.1016/j.gloplacha.2008.10.004
   Charney J, 1979, CARBON DIOXIDE AND CLIMATE, V0, P0
   Chen XY, 2014, SCIENCE, V345, P897, DOI 10.1126/science.1254937
   Cheng LJ, 2016, OCEAN SCI, V12, P925, DOI 10.5194/os-12-925-2016
   Chikamoto Y, 2016, GEOPHYS RES LETT, V43, P7143, DOI 10.1002/2016GL069544
   Church JA, 2011, GEOPHYS RES LETT, V38, P0, DOI 10.1029/2011GL048794
   Cohen JL, 2012, GEOPHYS RES LETT, V39, P0, DOI 10.1029/2011GL050582
   Cowtan K, 2015, GEOPHYS RES LETT, V42, P6526, DOI 10.1002/2015GL064888
   Cowtan K, 2014, Q J ROY METEOR SOC, V140, P1935, DOI 10.1002/qj.2297
   Dai AG, 2015, NAT CLIM CHANGE, V5, P555, DOI 10.1038/nclimate2605
   de Boisséson E, 2014, GEOPHYS RES LETT, V41, P4398, DOI 10.1002/2014GL060257
   De Saedeleer B, 2016, SCI REP-UK, V6, P0, DOI 10.1038/srep19881
   Delworth TL, 2015, J CLIMATE, V28, P3834, DOI 10.1175/JCLI-D-14-00616.1
   Delworth TL, 2000, CLIM DYNAM, V16, P661, DOI 10.1007/s003820000075
   Desbruyères DG, 2014, GEOPHYS RES LETT, V41, P7971, DOI 10.1002/2014GL061844
   Deser C, 2012, NAT CLIM CHANGE, V2, P775, DOI 10.1038/NCLIMATE1562
   Deser C, 2010, ANNU REV MAR SCI, V2, P115, DOI 10.1146/annurev-marine-120408-151453
   Dessler AE, 2013, P NATL ACAD SCI USA, V110, P18087, DOI 10.1073/pnas.1310344110
   Dessler AE, 2011, GEOPHYS RES LETT, V38, P0, DOI 10.1029/2011GL049236
   Dieng HB, 2015, OCEAN SCI, V11, P789, DOI 10.5194/os-11-789-2015
   Dieng HB, 2015, SURV GEOPHYS, V36, P209, DOI 10.1007/s10712-015-9314-6
   Domingues CM, 2008, NATURE, V453, P1090, DOI 10.1038/nature07080
   Dong L, 2014, J GEOPHYS RES-ATMOS, V119, P11272, DOI 10.1002/2013JD021395
   Douville H, 2015, GEOPHYS RES LETT, V42, P880, DOI 10.1002/2014GL062775
   Drijfhout SS, 2014, GEOPHYS RES LETT, V41, P7868, DOI 10.1002/2014GL061456
   Durack PJ, 2014, NAT CLIM CHANGE, V4, P999, DOI 10.1038/NCLIMATE2389
   Easterling DR, 2009, GEOPHYS RES LETT, V36, P0, DOI 10.1029/2009GL037810
   Enfield DB, 2001, GEOPHYS RES LETT, V28, P2077, DOI 10.1029/2000GL012745
   England MH, 2015, NAT CLIM CHANGE, V5, P394, DOI 10.1038/nclimate2575
   England MH, 2014, NAT CLIM CHANGE, V4, P222, DOI 10.1038/nclimate2106
   Fasullo JT, 2008, J CLIMATE, V21, P2297, DOI 10.1175/2007JCLI1935.1
   Fischer EM, 2016, NAT CLIM CHANGE, V6, P986, DOI 10.1038/NCLIMATE3110
   Flato G, 2013, CONTRIBUTION OF WORKING GROUP I TO THE FIFTH ASSESSMENT REPORT OF THE INTERGOVERNMENTAL PANEL ON CLIMATE CHANGE, V0, PP741, DOI 10.1017/CB09781107415324.020
   FOSTER G, 2015, VARIATIONS, V13, P6
   Foster G, 2011, ENVIRON RES LETT, V6, P0, DOI 10.1088/1748-9326/6/4/044022
   Frankcombe LM, 2015, J CLIMATE, V28, P8184, DOI 10.1175/JCLI-D-15-0069.1
   Fyfe JC, 2013, GEOPHYS RES LETT, V40, P584, DOI 10.1002/grl.50156
   Fyfe JC, 2016, NAT CLIM CHANGE, V6, P224, DOI 10.1038/nclimate2938
   Fyfe JC, 2013, NAT CLIM CHANGE, V3, P767, DOI 10.1038/nclimate1972
   Garfinkel CI, 2017, GEOPHYS RES LETT, V44, P374, DOI 10.1002/2016GL072035
   Gettelman A, 2015, CLIM DYNAM, V45, P2165, DOI 10.1007/s00382-014-2464-2
   Gilford DM, 2016, J CLIMATE, V29, P595, DOI 10.1175/JCLI-D-15-0167.1
   Gillett NP, 2012, GEOPHYS RES LETT, V39, P0, DOI 10.1029/2011GL050226
   Gleckler PJ, 2016, NAT CLIM CHANGE, V6, P394, DOI 10.1038/nclimate2915
   Gray ST, 2004, GEOPHYS RES LETT, V31, P0, DOI 10.1029/2004GL019932
   Gregory JM, 2015, PHILOS T R SOC A, V373, P0, DOI 10.1098/rsta.2014.0417
   Guemas V, 2013, NAT CLIM CHANGE, V3, P649, DOI 10.1038/nclimate1863
   Han WQ, 2014, CLIM DYNAM, V43, P1357, DOI 10.1007/s00382-013-1951-1
   Hansen J, 2010, REV GEOPHYS, V48, P0, DOI 10.1029/2010RG000345
   Hansen J, 2005, SCIENCE, V308, P1431, DOI 10.1126/science.1110252
   Hansen J, 2011, ATMOS CHEM PHYS, V11, P13421, DOI 10.5194/acp-11-13421-2011
   Hansen J, 2006, P NATL ACAD SCI USA, V103, P14288, DOI 10.1073/pnas.0606291103
   Hartmann DL, 2014, CLIMATE CHANGE 2013: THE PHYSICAL SCIENCE BASIS, V0, P159
   Hathaway DH, 2015, LIVING REV SOL PHYS, V12, P0, DOI 10.1007/lrsp-2015-4
   Hawkins E, 2014, NAT CLIM CHANGE, V4, P154, DOI 10.1038/nclimate2150
   Hawkins E, 2009, B AM METEOROL SOC, V90, P1095, DOI 10.1175/2009BAMS2607.1
   Haywood JM, 2014, ATMOS SCI LETT, V15, P92, DOI 10.1002/asl2.471
   Henley BJ, 2015, CLIM DYNAM, V45, P3077, DOI 10.1007/s00382-015-2525-1
   Hofmann D, 2009, GEOPHYS RES LETT, V36, P0, DOI 10.1029/2009GL039008
   Huang B, 2016, J CLIMATE, V29, P3119, DOI 10.1175/JCLI-D-15-0430.1
   Huang BY, 2015, J CLIMATE, V28, P911, DOI 10.1175/JCLI-D-14-00006.1
   Huber M, 2014, NAT GEOSCI, V7, P651, DOI 10.1038/ngeo2228
   Hunt BG, 2011, CLIM DYNAM, V36, P509, DOI 10.1007/s00382-010-0799-x
   Ishii M, 2009, J OCEANOGR, V65, P287, DOI 10.1007/s10872-009-0027-7
   Johansson DJA, 2015, NAT CLIM CHANGE, V5, P449, DOI 10.1038/nclimate2573
   Karl TR, 2015, SCIENCE, V348, P1469, DOI 10.1126/science.aaa5632
   Katsman CA, 2011, GEOPHYS RES LETT, V38, P0
   Kaufmann RK, 2011, P NATL ACAD SCI USA, V108, P11790, DOI 10.1073/pnas.1102467108
   Keenlyside NS, 2008, NATURE, V453, P84, DOI 10.1038/nature06921
   KELLOGG WW, 1993, CLIMATIC CHANGE, V25, P85, DOI 10.1007/BF01094085
   Kennedy JJ, 2011, J. GEOPHYS. RES, V116, PD14104, DOI 10.1029/2010JD015220
   Kent EC, 2017, B AM METEOROL SOC, V98, P1601, DOI 10.1175/BAMS-D-15-00251.1
   Kent EC, 2013, J GEOPHYS RES-ATMOS, V118, P1281, DOI 10.1002/jgrd.50152
   Kent EC, 2010, WIRES CLIM CHANGE, V1, P718, DOI 10.1002/wcc.55
   Kerr RA, 2009, SCIENCE, V326, P28
   Knight JR, 2005, GEOPHYS RES LETT, V32, P0, DOI 10.1029/2005GL024233
   Knight JR, 2009, BULL. AM. METEOROL. SOC., V90, PS22, DOI 10.1175/BAMS-90-8-STATE0FTHECLIMATE
   Knudsen MF, 2014, NAT COMMUN, V5, P0, DOI 10.1038/ncomms4323
   Knutson TR, 2016, NAT COMMUN, V7, P0, DOI 10.1038/ncomms13676
   Knutti R, 2000, J CLIMATE, V13, P1997, DOI 10.1175/1520-0442(2000)013<1997:IOTTCO>2.0.CO;2
   Knutti R, 2008, NAT GEOSCI, V1, P735, DOI 10.1038/ngeo337
   Knutti R, 2016, NAT GEOSCI, V9, P13, DOI 10.1038/NGEO2595
   Knutti R, 2015, PHILOS T R SOC A, V373, P0, DOI 10.1098/rsta.2015.0146
   Kociuba G, 2015, J CLIMATE, V28, P20, DOI 10.1175/JCLI-D-13-00752.1
   Kosaka Y, 2013, NATURE, V501, P403, DOI 10.1038/nature12534
   Kucharski F, 2011, GEOPHYS RES LETT, V38, P0, DOI 10.1029/2010GL046248
   Kucharski F, 2016, CLIM DYNAM, V46, P2337, DOI 10.1007/s00382-015-2705-z
   Kühn T, 2014, GEOPHYS RES LETT, V41, P4711, DOI 10.1002/2014GL060349
   Kummer JR, 2014, GEOPHYS RES LETT, V41, P3565, DOI 10.1002/2014GL060046
   Laepple T, 2014, GEOPHYS RES LETT, V41, P2528, DOI 10.1002/2014GL059345
   Lean JL, 2009, GEOPHYS RES LETT, V36, P0, DOI 10.1029/2009GL038932
   Lee SK, 2015, NAT GEOSCI, V8, P445, DOI 10.1038/NGEO2438
   Lee T, 2008, GEOPHYS RES LETT, V35, P0, DOI 10.1029/2007GL032419
   Levitus S, 2012, GEOPHYS RES LETT, V39, P0, DOI 10.1029/2012GL051106
   Levitus S, 2009, GEOPHYS RES LETT, V36, P0, DOI 10.1029/2008GL037155
   Lewandowsky S, 2016, B AM METEOROL SOC, V97, P723, DOI 10.1175/BAMS-D-14-00106.1
   Lewandowsky S, 2015, SCI REP-UK, V5, P0, DOI 10.1038/srep16784
   Lewandowsky S, 2015, GLOBAL ENVIRON CHANG, V33, P1, DOI 10.1016/j.gloenvcha.2015.02.013
   Lewis N, 2015, CLIM DYNAM, V45, P1009, DOI 10.1007/s00382-014-2342-y
   Li C, 2015, GEOPHYS RES LETT, V42, P8131, DOI 10.1002/2015GL065327
   Li JP, 2013, GEOPHYS RES LETT, V40, P5497, DOI 10.1002/2013GL057877
   Li XC, 2016, NAT CLIM CHANGE, V6, P275, DOI 10.1038/nclimate2840
   Liang XF, 2016, J CLIMATE, V29, P3647, DOI 10.1175/JCLI-D-15-0626.1
   Lin M, 2016, J CLIMATE, V29, P8673, DOI 10.1175/JCLI-D-16-0123.1
   Liu W, 2016, NAT COMMUN, V7, P0, DOI 10.1038/ncomms10926
   Llovel W, 2014, NAT CLIM CHANGE, V4, P1031, DOI 10.1038/NCLIMATE2387
   Lockwood M, 2008, P ROY SOC A-MATH PHY, V464, P1387, DOI 10.1098/rspa.2007.0348
   Lockwood M, 2010, P ROY SOC A-MATH PHY, V466, P303, DOI 10.1098/rspa.2009.0519
   Loeb NG, 2012, NAT GEOSCI, V5, P110, DOI 10.1038/ngeo1375
   Loeb NG, 2009, J CLIMATE, V22, P748, DOI 10.1175/2008JCLI2637.1
   Luo JJ, 2012, P NATL ACAD SCI USA, V109, P18701, DOI 10.1073/pnas.1210239109
   Lyman JM, 2010, NATURE, V465, P334, DOI 10.1038/nature09043
   Maher N, 2014, GEOPHYS RES LETT, V41, P5978, DOI 10.1002/2014GL060527
   Mann ME, 1998, NATURE, V392, P779, DOI 10.1038/33859
   MANN ME, 1994, J GEOPHYS RES-ATMOS, V99, P25819, DOI 10.1029/94JD02396
   Mann ME, 2014, GEOPHYS RES LETT, V41, P3211, DOI 10.1002/2014GL059233
   Mantua NJ, 1997, B AM METEOROL SOC, V78, P1069, DOI 10.1175/1520-0477(1997)078<1069:APICOW>2.0.CO;2
   Marotzke J, 2015, NATURE, V517, P565, DOI 10.1038/nature14117
   Marshall J, 2001, INT J CLIMATOL, V21, P1863, DOI 10.1002/joc.693
   Marvel K, 2016, NAT CLIM CHANGE, V6, P386, DOI 10.1038/NCLIMATE2888
   McCarthy GD, 2015, NATURE, V521, P508, DOI 10.1038/nature14491
   McGregor S, 2014, NAT CLIM CHANGE, V4, P888, DOI 10.1038/NCLIMATE2330
   Medhaug I, 2011, OCEAN SCI, V7, P389, DOI 10.5194/os-7-389-2011
   Medhaug I, 2016, CLIM DYNAM, V46, P3899, DOI 10.1007/s00382-015-2811-y
   Meehl GA, 2016, NAT CLIM CHANGE, V6, P1005, DOI 10.1038/NCLIMATE3107
   Meehl GA, 2014, NAT CLIM CHANGE, V4, P898, DOI 10.1038/NCLIMATE2357
   Meehl GA, 2014, B AM METEOROL SOC, V95, P243, DOI 10.1175/BAMS-D-12-00241.1
   Meehl GA, 2013, J CLIMATE, V26, P7298, DOI 10.1175/JCLI-D-12-00548.1
   Meehl GA, 2012, GEOPHYS RES LETT, V39, P0, DOI 10.1029/2012GL053423
   Meehl GA, 2011, NAT CLIM CHANGE, V1, P360, DOI 10.1038/NCLIMATE1229
   Middlemas EA, 2016, J CLIMATE, V29, P6245, DOI 10.1175/JCLI-D-15-0609.1
   Morice CP, 2012, J GEOPHYS RES-ATMOS, V117, P0, DOI 10.1029/2011JD017187
   Myhre G, 2013, CONTRIBUTION OF WORKING GROUP I TO THE FIFTH ASSESSMENT REPORT OF THE INTERGOVERNMENTAL PANEL ON CLIMATE CHANGE EDS, V0, PP659, DOI 10.1017/CBO9781107415324.018
   Myhre G, 2017, ATMOS CHEM PHYS, V17, P2709, DOI 10.5194/acp-17-2709-2017
   Newman M, 2016, J CLIMATE, V29, P4399, DOI 10.1175/JCLI-D-15-0508.1
   Nieves V, 2015, SCIENCE, V349, P532, DOI 10.1126/science.aaa4521
   Otterå OH, 2010, NAT GEOSCI, V3, P688, DOI 10.1038/NGEO955
   Otto A, 2013, NAT GEOSCI, V6, P415, DOI 10.1038/ngeo1836
   Outten S, 2015, J GEOPHYS RES-ATMOS, V120, P8575, DOI 10.1002/2015JD023859
   Palmer MD, 2014, ENVIRON RES LETT, V9, P0, DOI 10.1088/1748-9326/9/3/034016
   Palmer MD, 2011, GEOPHYS RES LETT, V38, P0, DOI 10.1029/2011GL047835
   Parker DE, 2010, WIRES CLIM CHANGE, V1, P123, DOI 10.1002/wcc.21
   Peterson TC, 1998, INT J CLIMATOL, V18, P1493, DOI 10.1002/(SICI)1097-0088(19981115)18:13<1493::AID-JOC329>3.0.CO;2-T
   Peyser CE, 2016, GEOPHYS RES LETT, V43, P8662, DOI 10.1002/2016GL069401
   Purkey SG, 2010, J CLIMATE, V23, P6336, DOI 10.1175/2010JCLI3682.1
   Rajaratnam B, 2015, CLIMATIC CHANGE, V133, P129, DOI 10.1007/s10584-015-1495-y
   Regayre LA, 2014, GEOPHYS RES LETT, V41, P9040, DOI 10.1002/2014GL062029
   Rhein M, 2013, CLIMATE CHANGE 2013, V0, P0
   Richardson M, 2016, NAT CLIM CHANGE, V6, P931, DOI 10.1038/nclimate3066
   Richter I, 2008, J GEOPHYS RES-ATMOS, V113, P0, DOI 10.1029/2008JD010561
   Ridley DA, 2014, GEOPHYS RES LETT, V41, P7763, DOI 10.1002/2014GL061541
   Risbey JS, 2014, NAT CLIM CHANGE, V4, P835, DOI 10.1038/nclimate2310
   Roberts CD, 2015, NAT CLIM CHANGE, V5, P337, DOI 10.1038/nclimate2531
   Robeson SM, 2014, GEOPHYS RES LETT, V41, P9065, DOI 10.1002/2014GL062323
   Robson J, 2016, NAT GEOSCI, V9, P513, DOI 10.1038/NGEO2727
   Roemmich D, 2015, NAT CLIM CHANGE, V5, P240, DOI 10.1038/nclimate2513
   Rohde R, 2013, GEOINFOR. GEOSTAT., V1, P0, DOI 10.4172/2327-4581.1000101
   Rose BEJ, 2014, GEOPHYS RES LETT, V41, P1071, DOI 10.1002/2013GL058955
   Rossby C-G, 1959, THE ATMOSPHERE AND THE SEA IN MOTION, V0, P9
   Saenger C, 2009, NAT GEOSCI, V2, P492, DOI 10.1038/ngeo552
   Saenko OA, 2016, CLIM DYNAM, V47, P2193, DOI 10.1007/s00382-015-2958-6
   Saffioti C, 2015, GEOPHYS RES LETT, V42, P2385, DOI 10.1002/2015GL063091
   Santer BD, 2011, J GEOPHYS RES-ATMOS, V116, P0, DOI 10.1029/2011JD016263
   Santer BD, 2015, GEOPHYS RES LETT, V42, P500, DOI 10.1002/2014GL062366
   Santer BD, 2014, NAT GEOSCI, V7, P185, DOI 10.1038/NGEO2098
   Schmidt GA, 2014, NAT GEOSCI, V7, P158, DOI 10.1038/ngeo2105
   Schurer AP, 2015, GEOPHYS RES LETT, V42, P5974, DOI 10.1002/2015GL064458
   Sévellec F, 2016, GEOPHYS RES LETT, V43, P8169, DOI 10.1002/2016GL068950
   Shindell DT, 2014, NAT CLIM CHANGE, V4, P274, DOI 10.1038/nclimate2136
   Simmons AJ, 2017, Q J ROY METEOR SOC, V143, P101, DOI 10.1002/qj.2949
   Smith DM, 2007, SCIENCE, V317, P796, DOI 10.1126/science.1139540
   Smith DM, 2016, NAT CLIM CHANGE, V6, P936, DOI 10.1038/nclimate3058
   Solomon S, 2011, SCIENCE, V333, P866, DOI 10.1126/science.1206027
   Solomon S, 2010, SCIENCE, V327, P1219, DOI 10.1126/science.1182488
   Steinman BA, 2015, SCIENCE, V347, P988, DOI 10.1126/science.1257856
   Storelvmo T, 2016, NAT GEOSCI, V9, P286, DOI 10.1038/NGEO2670
   Stott P, 2013, ENVIRON RES LETT, V8, P0, DOI 10.1088/1748-9326/8/1/014024
   Stouffer RJ, 2000, J CLIMATE, V13, P513, DOI 10.1175/1520-0442(2000)013<0513:ACOSAT>2.0.CO;2
   Sutton RT, 2005, SCIENCE, V309, P115, DOI 10.1126/science.1109496
   Tandon NF, 2015, J CLIMATE, V28, P6309, DOI 10.1175/JCLI-D-14-00664.1
   Thoma M, 2015, GEOPHYS RES LETT, V42, P6454, DOI 10.1002/2015GL064833
   Thompson DWJ, 2008, NATURE, V453, P646, DOI 10.1038/nature06982
   Thorne P, 2015, J GEOPHYS RES-ATMOS, V120, P8597, DOI 10.1002/2014JD022805
   Trenberth KE, 2004, Q J ROY METEOR SOC, V130, P2677, DOI 10.1256/qj.04.83
   Trenberth KE, 2002, J GEOPHYS RES-ATMOS, V107, P0, DOI 10.1029/2000JD000298
   Trenberth KE, 2016, J CLIMATE, V29, P7495, DOI 10.1175/JCLI-D-16-0339.1
   Trenberth KE, 2014, NAT CLIM CHANGE, V4, P911, DOI 10.1038/NCLIMATE2341
   Trenberth KE, 2014, J CLIMATE, V27, P3129, DOI 10.1175/JCLI-D-13-00294.1
   Trenberth KE, 2013, EARTHS FUTURE, V1, P19, DOI 10.1002/2013EF000165
   Trenberth KE, 2010, SCIENCE, V328, P316, DOI 10.1126/science.1187272
   Vernier JP, 2011, GEOPHYS RES LETT, V38, P0, DOI 10.1029/2011GL047563
   von Schuckmann K, 2016, NAT CLIM CHANGE, V6, P138, DOI 10.1038/NCLIMATE2876
   von Schuckmann K, 2011, OCEAN SCI, V7, P783, DOI 10.5194/os-7-783-2011
   Wang Y, 2017, CLIM DYNAM, V48, P2671, DOI 10.1007/s00382-016-3231-3
   Watanabe M, 2014, NAT CLIM CHANGE, V4, P893, DOI 10.1038/NCLIMATE2355
   Watanabe M, 2013, GEOPHYS RES LETT, V40, P3175, DOI 10.1002/grl.50541
   WATTS RG, 1991, CLIMATIC CHANGE, V18, PR3, DOI 10.1007/BF00142966
   WATTS RG, 1993, CLIMATIC CHANGE, V25, P89, DOI 10.1007/BF01094086
   Whitehouse D, 2013, MET OFFICE SAYS WARM, V0, P0
   WIGLEY TML, 1990, NATURE, V344, P324, DOI 10.1038/344324a0
   Wijffels S, 2016, NAT CLIM CHANGE, V6, P116, DOI 10.1038/nclimate2924
   Winton M, 2010, J CLIMATE, V23, P2333, DOI 10.1175/2009JCLI3139.1
   Xie SP, 2016, NAT GEOSCI, V9, P29, DOI 10.1038/NGEO2581
   Yan XH, 2016, EARTHS FUTURE, V4, P472, DOI 10.1002/2016EF000417
   Yao SL, 2016, THEOR APPL CLIMATOL, V123, P349, DOI 10.1007/s00704-014-1358-x
   Ying L, 2015, GEOPHYS RES LETT, V42, P6471
   Zhang LP, 2013, J GEOPHYS RES-OCEANS, V118, P5772, DOI 10.1002/jgrc.20390
   Zhang R, 2013, J ATMOS SCI, V70, P1135, DOI 10.1175/JAS-D-12-0331.1
   Zhou C, 2016, NAT GEOSCI, V9, P871, DOI 10.1038/NGEO2828
   Zhou CL, 2016, SCI REP-UK, V6, P0, DOI 10.1038/srep31789
NR 234
TC 369
Z9 423
U1 7
U2 482
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 4
PY 2017
VL 545
IS 7652
BP 41
EP +
DI 10.1038/nature22315
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET7MK
UT WOS:000400480400027
PM 28470193
DA 2026-03-09
ER

PT J
AU Praetorius, F
   Kick, B
   Behler, KL
   Honemann, MN
   Weuster-Botz, D
   Dietz, H
AF Praetorius, Florian
   Kick, Benjamin
   Behler, Karl L.
   Honemann, Maximilian N.
   Weuster-Botz, Dirk
   Dietz, Hendrik
TI Biotechnological mass production of DNA origami
SO NATURE
LA English
DT Article
ID single-stranded-dna; nanoscale shapes; drug-resistance; folding dna; nanostructures; mechanisms; patterns; complex
AB DNA nanotechnology, in particular DNA origami, enables the bottom-up self-assembly of micrometre-scale, three-dimensional structures with nanometre-precise features(1-12). These structures are customizable in that they can be site-specifically functionalized(13) or constructed to exhibit machine-like(14,15) or logic-gating behaviour(16). Their use has been limited to applications that require only small amounts of material (of the order of micrograms), owing to the limitations of current production methods. But many proposed applications, for example as therapeutic agents or in complex materials(3,16-22), could be realized if more material could be used. In DNA origami, a nanostructure is assembled from a very long single-stranded scaffold molecule held in place by many short single-stranded staple oligonucleotides. Only the bacteriophage-derived scaffold molecules are amenable to scalable and efficient mass production(23); the shorter staple strands are obtained through costly solid-phase synthesis(24) or enzymatic processes(25). Here we show that single strands of DNA of virtually arbitrary length and with virtually arbitrary sequences can be produced in a scalable and cost-efficient manner by using bacteriophages to generate single-stranded precursor DNA that contains target strand sequences interleaved with self-excising 'cassettes', with each cassette comprising two Zn2+-dependent DNA-cleaving DNA enzymes. We produce all of the necessary single strands of DNA for several DNA origami using shaker-flask cultures, and demonstrate end-to-end production of macroscopic amounts of a DNA origami nanorod in a litre-scale stirred-tank bioreactor. Our method is compatible with existing DNA origami design frameworks and retains the modularity and addressability of DNA origami objects that are necessary for implementing custom modifications using functional groups. With all of the production and purification steps amenable to scaling, we expect that our method will expand the scope of DNA nanotechnology in many areas of science and technology.
C1 [Praetorius, Florian; Kick, Benjamin; Honemann, Maximilian N.; Dietz, Hendrik] Techn Univ Munich, Dept Phys, Coulombwall 4a, D-85748 Garching, Germany.
   [Praetorius, Florian; Kick, Benjamin; Honemann, Maximilian N.; Dietz, Hendrik] Techn Univ Munich, Inst Adv Study, Coulombwall 4a, D-85748 Garching, Germany.
   [Kick, Benjamin; Behler, Karl L.; Weuster-Botz, Dirk] Tech Univ Munich, Inst Biochem Engn, Boltzmannstr 15, D-85748 Garching, Germany.
C3 Technical University of Munich; Technical University of Munich; Technical University of Munich
RP Dietz, H (corresponding author), Techn Univ Munich, Dept Phys, Coulombwall 4a, D-85748 Garching, Germany.; Dietz, H (corresponding author), Techn Univ Munich, Inst Adv Study, Coulombwall 4a, D-85748 Garching, Germany.
EM dietz@tum.de
FU European Research Council starting grant [256270]; Deutsche Forschungsgemeinschaft within TUM IGSSE (Biomat 05 PSN); Gottfried-Wilhelm-Leibniz Program; Excellence Cluster CIPSM (Center for Integrated Protein Science Munich); ERASynBio project 'BioOrigami' - Bundesministerium fur Bildung und Forschung grant [031 A 458];  [SFB863]; European Research Council (ERC) [256270] Funding Source: European Research Council (ERC)
NR 41
TC 416
Z9 504
U1 14
U2 476
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 7
PY 2017
VL 552
IS 7683
BP 84
EP +
DI 10.1038/nature24650
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FP4BA
UT WOS:000417560500047
PM 29219963
DA 2026-03-09
ER

PT J
AU Patel, SJ
   Sanjana, NE
   Kishton, RJ
   Eidizadeh, A
   Vodnala, SK
   Cam, M
   Gartner, JJ
   Jia, L
   Steinberg, SM
   Yamamoto, TN
   Merchant, AS
   Mehta, GU
   Chichura, A
   Shalem, O
   Tran, E
   Eil, R
   Sukumar, M
   Guijarro, EP
   Day, CP
   Robbins, P
   Feldman, S
   Merlino, G
   Zhang, F
   Restifo, NP
AF Patel, Shashank J.
   Sanjana, Neville E.
   Kishton, Rigel J.
   Eidizadeh, Arash
   Vodnala, Suman K.
   Cam, Maggie
   Gartner, Jared J.
   Jia, Li
   Steinberg, Seth M.
   Yamamoto, Tori N.
   Merchant, Anand S.
   Mehta, Gautam U.
   Chichura, Anna
   Shalem, Ophir
   Tran, Eric
   Eil, Robert
   Sukumar, Madhusudhanan
   Guijarro, Eva Perez
   Day, Chi-Ping
   Robbins, Paul
   Feldman, Steve
   Merlino, Glenn
   Zhang, Feng
   Restifo, Nicholas P.
TI Identification of essential genes for cancer immunotherapy
SO NATURE
LA English
DT Article
ID differential gene; ctla-4 blockade; pd-1 blockade; interferons; mutations; alignment; screens; pathway; cells
AB Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies. Here we perturbed genes in human melanoma cells to mimic loss-of-function mutations involved in resistance to these therapies, by using a genome-scale CRISPR-Cas9 library that consisted of around 123,000 single-guide RNAs, and profiled genes whose loss in tumour cells impaired the effector function of CD8(+) T cells. The genes that were most enriched in the screen have key roles in antigen presentation and interferon-gamma signalling, and correlate with cytolytic activity in patient tumours from The Cancer Genome Atlas. Among the genes validated using different cancer cell lines and antigens, we identified multiple loss-of-function mutations in APLNR, encoding the apelin receptor, in patient tumours that were refractory to immunotherapy. We show that APLNR interacts with JAK1, modulating interferon-gamma responses in tumours, and that its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in mouse models. Our results link the loss of essential genes for the effector function of CD8(+) T cells with the resistance or non-responsiveness of cancer to immunotherapies.
C1 [Patel, Shashank J.; Kishton, Rigel J.; Eidizadeh, Arash; Vodnala, Suman K.; Cam, Maggie; Gartner, Jared J.; Jia, Li; Steinberg, Seth M.; Yamamoto, Tori N.; Merchant, Anand S.; Mehta, Gautam U.; Chichura, Anna; Tran, Eric; Eil, Robert; Sukumar, Madhusudhanan; Guijarro, Eva Perez; Day, Chi-Ping; Robbins, Paul; Feldman, Steve; Merlino, Glenn; Restifo, Nicholas P.] NCI, NIH, Bethesda, MD 20892 USA.
   [Patel, Shashank J.] Georgetown Univ, Sch Med, NIH Georgetown Univ Grad Partnership Program, Washington, DC 20057 USA.
   [Sanjana, Neville E.] New York Genome Ctr, New York, NY 10013 USA.
   [Sanjana, Neville E.] NYU, Dept Biol, 550 1St Ave, New York, NY 10012 USA.
   [Yamamoto, Tori N.] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA.
   [Shalem, Ophir] Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA.
   [Shalem, Ophir] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA.
   [Zhang, Feng] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Zhang, Feng] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Restifo, Nicholas P.] NIH, Ctr Cell Based Therapy, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Georgetown University; New York University; University of Pennsylvania; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Massachusetts Institute of Technology (MIT); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
RP Patel, SJ; Restifo, NP (corresponding author), NCI, NIH, Bethesda, MD 20892 USA.; Patel, SJ (corresponding author), Georgetown Univ, Sch Med, NIH Georgetown Univ Grad Partnership Program, Washington, DC 20057 USA.; Sanjana, NE (corresponding author), New York Genome Ctr, New York, NY 10013 USA.; Sanjana, NE (corresponding author), NYU, Dept Biol, 550 1St Ave, New York, NY 10012 USA.; Restifo, NP (corresponding author), NIH, Ctr Cell Based Therapy, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA.
EM patelsj@mail.nih.gov; nsanjana@nygenome.org; restifon@mail.nih.gov
FU Intramural Research Program of the NCI; Cancer Moonshot program for the Center for Cell-based Therapy at the NCI, NIH; Milstein Family Foundation; NIH through NHGRI [R00-HG008171]; Sidney Kimmel Scholar Award; National Cancer Institute [ZIABC011167] Funding Source: NIH RePORTER
CR Bolger AM, 2014, BIOINFORMATICS, V30, P2114, DOI 10.1093/bioinformatics/btu170
   Cerami E, 2012, CANCER DISCOV, V2, P401, DOI 10.1158/2159-8290.CD-12-0095
   Chan TA, 2015, NEW ENGL J MED, V373, P1984, DOI 10.1056/NEJMc1508163
   Chen SD, 2015, CELL, V160, P1246, DOI 10.1016/j.cell.2015.02.038
   Dunn GP, 2006, NAT REV IMMUNOL, V6, P836, DOI 10.1038/nri1961
   Gao JJ, 2013, SCI SIGNAL, V6, P0, DOI 10.1126/scisignal.2004088
   Hart T, 2015, CELL, V163, P0, DOI 10.1016/j.cell.2015.11.015
   Hugo W, 2016, CELL, V165, P35, DOI 10.1016/j.cell.2016.02.065
   Indraccolo S, 2007, J IMMUNOL, V178, P1122, DOI 10.4049/jimmunol.178.2.1122
   Johnson LA, 2006, J IMMUNOL, V177, P6548, DOI 10.4049/jimmunol.177.9.6548
   Kammertoens T, 2017, NATURE, V545, P98, DOI 10.1038/nature22311
   Kan ZY, 2010, NATURE, V466, P869, DOI 10.1038/nature09208
   Kidoya H, 2012, ONCOGENE, V31, P3254, DOI 10.1038/onc.2011.489
   Kim D, 2013, GENOME BIOL, V14, P0, DOI 10.1186/gb-2013-14-4-r36
   Klijn C, 2015, NAT BIOTECHNOL, V33, P306, DOI 10.1038/nbt.3080
   Kvistborg P, 2014, SCI TRANSL MED, V6, P0, DOI 10.1126/scitranslmed.3008918
   Langmead B, 2012, NAT METHODS, V9, P357, DOI 10.1038/NMETH.1923
   Langmead B, 2009, GENOME BIOL, V10, P0, DOI 10.1186/gb-2009-10-3-r25
   Lawrence MS, 2013, NATURE, V499, P214, DOI 10.1038/nature12213
   Luo B, 2008, P NATL ACAD SCI USA, V105, P20380, DOI 10.1073/pnas.0810485105
   MARRERO MB, 1995, NATURE, V375, P247, DOI 10.1038/375247a0
   Martins M, 2011, EMBNET. JOURNAL, V17, P10, DOI 10.14806/EJ.17.1.200
   Nathanson T, 2017, CANCER IMMUNOL RES, V5, P84, DOI 10.1158/2326-6066.CIR-16-0019
   Noonan FP, 2012, NAT COMMUN, V3, P0, DOI 10.1038/ncomms1893
   OCarroll AM, 2013, J ENDOCRINOL, V219, PR13, DOI 10.1530/JOE-13-0227
   Overwijk WW, 2003, J EXP MED, V198, P569, DOI 10.1084/jem.20030590
   Restifo NP, 1996, J NATL CANCER I, V88, P100, DOI 10.1093/jnci/88.2.100
   Rizvi NA, 2015, SCIENCE, V348, P124, DOI 10.1126/science.aaa1348
   Robbins PF, 2008, J IMMUNOL, V180, P6116, DOI 10.4049/jimmunol.180.9.6116
   Robbins PF, 2015, CLIN CANCER RES, V21, P1019, DOI 10.1158/1078-0432.CCR-14-2708
   Robbins PF, 2013, NAT MED, V19, P747, DOI 10.1038/nm.3161
   Rooney MS, 2015, CELL, V160, P48, DOI 10.1016/j.cell.2014.12.033
   Sanda C, 2006, J INTERF CYTOK RES, V26, P462, DOI 10.1089/jir.2006.26.462
   Sanjana NE, 2014, NAT METHODS, V11, P783, DOI 10.1038/nmeth.3047
   Shalem O, 2014, SCIENCE, V343, P84, DOI 10.1126/science.1247005
   Spiotto MT, 2004, NAT MED, V10, P294, DOI 10.1038/nm999
   Stark C, 2006, NUCLEIC ACIDS RES, V34, PD535, DOI 10.1093/nar/gkj109
   Tran E, 2015, SCIENCE, V350, P1387, DOI 10.1126/science.aad1253
   Trapnell C, 2012, NAT PROTOC, V7, P562, DOI 10.1038/nprot.2012.016
   Van Allen EM, 2015, SCIENCE, V350, P207, DOI 10.1126/science.aad0095
   Viemann D, 2006, J LEUKOCYTE BIOL, V80, P174, DOI 10.1189/jlb.0905530
   Wan YW, 2016, BIOINFORMATICS, V32, P952, DOI 10.1093/bioinformatics/btv677
   Wang LX, 2013, PLOS ONE, V8, P0, DOI 10.1371/journal.pone.0062924
   Wang T, 2015, SCIENCE, V350, P1096, DOI 10.1126/science.aac7041
   Wang T, 2014, SCIENCE, V343, P80, DOI 10.1126/science.1246981
   Wrangle J, 2013, ONCOTARGET, V4, P2067, DOI 10.18632/oncotarget.1542
   Zaretsky JM, 2016, NEW ENGL J MED, V375, P819, DOI 10.1056/NEJMoa1604958
NR 49
TC 678
Z9 819
U1 8
U2 299
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 31
PY 2017
VL 548
IS 7669
BP 537
EP +
DI 10.1038/nature23477
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FF2BO
UT WOS:000408703100028
PM 28783722
DA 2026-03-09
ER

PT J
AU Moor, K
   Diard, M
   Sellin, ME
   Felmy, B
   Wotzka, SY
   Toska, A
   Bakkeren, E
   Arnoldini, M
   Bansept, F
   Dal Co, A
   Völler, T
   Minola, A
   Fernandez-Rodriguez, B
   Agatic, G
   Barbieri, S
   Piccoli, L
   Casiraghi, C
   Corti, D
   Lanzavecchia, A
   Regoes, RR
   Loverdo, C
   Stocker, R
   Brumley, DR
   Hardt, WD
   Slack, E
AF Moor, Kathrin
   Diard, Mederic
   Sellin, Mikael E.
   Felmy, Boas
   Wotzka, Sandra Y.
   Toska, Albulena
   Bakkeren, Erik
   Arnoldini, Markus
   Bansept, Florence
   Dal Co, Alma
   Voller, Tom
   Minola, Andrea
   Fernandez-Rodriguez, Blanca
   Agatic, Gloria
   Barbieri, Sonia
   Piccoli, Luca
   Casiraghi, Costanza
   Corti, Davide
   Lanzavecchia, Antonio
   Regoes, Roland R.
   Loverdo, Claude
   Stocker, Roman
   Brumley, Douglas R.
   Hardt, Wolf-Dietrich
   Slack, Emma
TI High-avidity IgA protects the intestine by enchaining growing bacteria
SO NATURE
LA English
DT Article
ID enterica serovar typhimurium; monoclonal iga; salmonella-typhimurium; epithelial-cells; o-antigen; b-cells; microbiota; colitis; invasion; model
AB Vaccine-induced high-avidity IgA can protect against bacterial enteropathogens by directly neutralizing virulence factors or by poorly defined mechanisms that physically impede bacterial interactions with the gut tissues ('immune exclusion')(1-3). IgA-mediated cross-linking clumps bacteria in the gut lumen and is critical for protection against infection by non-typhoidal Salmonella enterica subspecies enterica serovar Typhimurium (S. Typhimurium). However, classical agglutination, which was thought to drive this process, is efficient only at high pathogen densities (>= 10(8) non-motile bacteria per gram). In typical infections, much lower densities(4,5) (10(0)-10(7) colony-forming units per gram) of rapidly dividing bacteria are present in the gut lumen. Here we show that a different physical process drives formation of clumps in vivo: IgA-mediated cross-linking enchains daughter cells, preventing their separation after division, and clumping is therefore dependent on growth. Enchained growth is effective at all realistic pathogen densities, and accelerates pathogen clearance from the gut lumen. Furthermore, IgA enchains plasmid-donor and -recipient clones into separate clumps, impeding conjugative plasmid transfer in vivo. Enchained growth is therefore a mechanism by which IgA can disarm and clear potentially invasive species from the intestinal lumen without requiring high pathogen densities, inflammation or bacterial killing. Furthermore, our results reveal an untapped potential for oral vaccines in combating the spread of antimicrobial resistance.
C1 [Moor, Kathrin; Diard, Mederic; Sellin, Mikael E.; Felmy, Boas; Wotzka, Sandra Y.; Toska, Albulena; Bakkeren, Erik; Arnoldini, Markus; Voller, Tom; Lanzavecchia, Antonio; Hardt, Wolf-Dietrich; Slack, Emma] ETH, Inst Microbiol, CH-8093 Zurich, Switzerland.
   [Sellin, Mikael E.] Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab, S-75124 Uppsala, Sweden.
   [Bansept, Florence; Loverdo, Claude] CNRS UPMC, Lab Jean Perrin, UMR 8237, F-75005 Paris, France.
   [Dal Co, Alma] ETH, Dept Environm Syst Sci, Zurich, Switzerland.
   [Dal Co, Alma] Swiss Fed Inst Aquat Sci & Technol, Eawag, Dept Environm Microbiol, Dubendorf, Switzerland.
   [Minola, Andrea; Agatic, Gloria; Corti, Davide] Humabs BioMed SA, CH-6500 Bellinzona, Switzerland.
   [Fernandez-Rodriguez, Blanca; Barbieri, Sonia; Piccoli, Luca; Casiraghi, Costanza; Lanzavecchia, Antonio] Univ Svizzera Italiana, Inst Res Biomed, CH-6500 Bellinzona, Switzerland.
   [Regoes, Roland R.] ETH, Inst Integrat Biol, CH-8092 Zurich, Switzerland.
   [Stocker, Roman; Brumley, Douglas R.] ETH, Dept Civil Environm & Geomat Engn, Inst Environm Engn, CH-8093 Zurich, Switzerland.
   [Brumley, Douglas R.] Univ Melbourne, Sch Math & Stat, Parkville, Vic 3010, Australia.
   [Moor, Kathrin] Univ Zurich, Ctr Dent Med, Zurich, Switzerland.
   [Casiraghi, Costanza] Univ Bologna, Dept Expt Diagnost & Specialty Med, Bologna, Italy.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich; Uppsala University; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Physics (INP); Sorbonne Universite; Swiss Federal Institutes of Technology Domain; ETH Zurich; Swiss Federal Institutes of Technology Domain; Swiss Federal Institute of Aquatic Science & Technology (EAWAG); Universita della Svizzera Italiana; Swiss Federal Institutes of Technology Domain; ETH Zurich; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Melbourne; University of Zurich; University of Bologna
RP Hardt, WD; Slack, E (corresponding author), ETH, Inst Microbiol, CH-8093 Zurich, Switzerland.; Brumley, DR (corresponding author), ETH, Dept Civil Environm & Geomat Engn, Inst Environm Engn, CH-8093 Zurich, Switzerland.; Brumley, DR (corresponding author), Univ Melbourne, Sch Math & Stat, Parkville, Vic 3010, Australia.
EM d.brumley@unimelb.edu.au; wolf-dietrich.hardt@micro.biol.ethz.ch; emma.slack@micro.biol.ethz.ch
FU Swiss National Science Foundation (SNF) [PMPDP3_158364, PZ00P3_136742]; SNF [310030_53074, Sinergia CRSII_154414/1]; ETH Zurich [ETH-33 12-2]; Novartis Freenovation Programme; Human Frontier Science Program Cross-Disciplinary Fellowship; ETH; Gordon and Betty Moore Foundation Marine Microbial Initiative Award [GBMF 3783]; Swiss National Science Foundation [31003A_149769]; Deutsche Forschungsgemeinschaft [VO 2273/1-1]; Swedish Research Council [2012-262, 2015-00635]; Swedish Research Council [2015-00635] Funding Source: Swedish Research Council; Swiss National Science Foundation (SNF) [31003A_149769, PMPDP3_158364] Funding Source: Swiss National Science Foundation (SNF)
NR 54
TC 322
Z9 382
U1 3
U2 124
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 27
PY 2017
VL 544
IS 7651
BP 498
EP +
DI 10.1038/nature22058
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET1TN
UT WOS:000400051900047
PM 28405025
DA 2026-03-09
ER

PT J
AU Le, C
   Liang, YF
   Evans, RW
   Li, XM
   MacMillan, DWC
AF Le, Chip
   Liang, Yufan
   Evans, Ryan W.
   Li, Ximing
   MacMillan, David W. C.
TI Selective sp3 C-H alkylation via polarity-match-based cross-coupling
SO NATURE
LA English
DT Article
ID late-stage functionalization; photoredox catalysis; aryl halides; organic-chemistry; bonds; alpha; c(sp(3))-h; secondary; complex; carbon
AB The functionalization of carbon-hydrogen (C-H) bonds is one of the most attractive strategies for molecular construction in organic chemistry. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in organic molecules and its availability for functionalization at almost any stage in a synthetic sequence1. Although many C-H functionalization reactions involve C(sp(3))-C(sp(2)) coupling, there is a growing demand for C-H alkylation reactions, wherein sp(3) C-H bonds are replaced with sp(3) C-alkyl groups. Here we describe a polarity-match-based selective sp(3) C-H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodology simultaneously uses three catalytic cycles to achieve hydridic C-H bond abstraction (enabled by polarity matching), alkyl halide oxidative addition, and reductive elimination to enable alkyl-alkyl fragment coupling. The sp(3) C-H alkylation is highly selective for the alpha-C-H of amines, ethers and sulphides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry.
C1 [Le, Chip; Liang, Yufan; Evans, Ryan W.; Li, Ximing; MacMillan, David W. C.] Princeton Univ, Merck Ctr Catalysis, Princeton, NJ 08544 USA.
C3 Princeton University
RP MacMillan, DWC (corresponding author), Princeton Univ, Merck Ctr Catalysis, Princeton, NJ 08544 USA.
EM dmacmill@princeton.edu
FU NIH National Institute of General Medical Sciences [R01 GM078201-05]
CR Ackermann L, 2010, CHEM COMMUN, V46, P4866, DOI 10.1039/c0cc00778a
   Ackermann L, 2009, ANGEW CHEM INT EDIT, V48, P6045, DOI 10.1002/anie.200902458
   ADAMS J, 1989, TETRAHEDRON LETT, V30, P1749, DOI 10.1016/S0040-4039(00)99570-4
   Aihara Y, 2013, J AM CHEM SOC, V135, P5308, DOI 10.1021/ja401344e
   Cernak T, 2016, CHEM SOC REV, V45, P546, DOI 10.1039/c5cs00628g
   Chen X, 2009, ANGEW CHEM INT EDIT, V48, P5094, DOI 10.1002/anie.200806273
   Cheung MS, 2015, CHEM-EUR J, V21, P7480, DOI 10.1002/chem.201500110
   Colby DA, 2012, ACCOUNTS CHEM RES, V45, P814, DOI 10.1021/ar200190g
   Davies HML, 2003, J AM CHEM SOC, V125, P6462, DOI 10.1021/ja0290072
   Davies HML, 2016, J ORG CHEM, V81, P343, DOI 10.1021/acs.joc.5b02818
   DiRocco DA, 2014, ANGEW CHEM INT EDIT, V53, P4802, DOI 10.1002/anie.201402023
   Doyle MP, 2010, CHEM REV, V110, P704, DOI 10.1021/cr900239n
   Durandetti M, 1996, NEW J CHEM, V20, P659
   Gutierrez O, 2015, J AM CHEM SOC, V137, P4896, DOI 10.1021/ja513079r
   Ilies L, 2014, J AM CHEM SOC, V136, P13126, DOI 10.1021/ja5066015
   Jeffrey JL, 2015, SCIENCE, V349, P1532, DOI 10.1126/science.aac8555
   Kärkäs MD, 2016, CHEM REV, V116, P9683, DOI 10.1021/acs.chemrev.5b00760
   Lowry MS, 2005, CHEM MATER, V17, P5712, DOI 10.1021/cm051312+
   Lyons TW, 2010, CHEM REV, V110, P1147, DOI 10.1021/cr900184e
   Prier CK, 2013, CHEM REV, V113, P5322, DOI 10.1021/cr300503r
   Roberts BP, 1999, CHEM SOC REV, V28, P25, DOI 10.1039/a804291h
   Schönherr H, 2013, ANGEW CHEM INT EDIT, V52, P12256, DOI 10.1002/anie.201303207
   Shabashov D, 2010, J AM CHEM SOC, V132, P3965, DOI 10.1021/ja910900p
   Shaw MH, 2016, J ORG CHEM, V81, P6898, DOI 10.1021/acs.joc.6b01449
   Shaw MH, 2016, SCIENCE, V352, P1304, DOI 10.1126/science.aaf6635
   Zhang SY, 2013, J AM CHEM SOC, V135, P12135, DOI 10.1021/ja406484v
   Zhang XH, 2016, J AM CHEM SOC, V138, P13862, DOI 10.1021/jacs.6b09533
   Zhang YH, 2009, ANGEW CHEM INT EDIT, V48, P6097, DOI 10.1002/anie.200902262
   Zhu RY, 2014, J AM CHEM SOC, V136, P13194, DOI 10.1021/ja508165a
   Zuo ZW, 2014, SCIENCE, V345, P437, DOI 10.1126/science.1255525
NR 30
TC 481
Z9 550
U1 13
U2 480
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 6
PY 2017
VL 547
IS 7661
BP 79
EP 83
DI 10.1038/nature22813
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EZ6PM
UT WOS:000404839900034
PM 28636596
DA 2026-03-09
ER

PT J
AU Edwards, JT
   Merchant, RR
   McClymont, KS
   Knouse, KW
   Qin, T
   Malins, LR
   Vokits, B
   Shaw, SA
   Bao, DH
   Wei, FL
   Zhou, T
   Eastgate, MD
   Baran, PS
AF Edwards, Jacob T.
   Merchant, Rohan R.
   McClymont, Kyle S.
   Knouse, Kyle W.
   Qin, Tian
   Malins, Lara R.
   Vokits, Benjamin
   Shaw, Scott A.
   Bao, Deng-Hui
   Wei, Fu-Liang
   Zhou, Ting
   Eastgate, Martin D.
   Baran, Phil S.
TI Decarboxylative alkenylation
SO NATURE
LA English
DT Article
ID novo asymmetric-synthesis; redox-active esters; enantioselective synthesis; alkyl; analogs; catalysis; halides
AB Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, has an essential role in the manipulation of organic matter(1). Despite its importance, olefin synthesis still relies largely on chemistry introduced more than three decades ago, with metathesis(2) being the most recent addition. Here we describe a simple method of accessing olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids. The activating principles used in amide-bond synthesis can therefore be used, with nickel-or iron-based catalysis, to extract carbon dioxide from a carboxylic acid and economically replace it with an organozinc-derived olefin on a molar scale. We prepare more than 60 olefins across a range of substrate classes, and the ability to simplify retrosynthetic analysis is exemplified with the preparation of 16 different natural products across 10 different families.
C1 [Edwards, Jacob T.; Merchant, Rohan R.; McClymont, Kyle S.; Knouse, Kyle W.; Qin, Tian; Malins, Lara R.; Baran, Phil S.] Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA.
   [Vokits, Benjamin; Shaw, Scott A.] Bristol Myers Squibb, Discovery Chem, 350 Carter Rd, Hopewell, NJ 08540 USA.
   [Bao, Deng-Hui; Wei, Fu-Liang; Zhou, Ting] Tianjin Econ Technol Dev Zone, Asymchem Life Sci Tianjin, Tianjin 300457, Peoples R China.
   [Eastgate, Martin D.] Bristol Myers Squibb, Chem Dev, One Squibb Dr, New Brunswick, NJ 08903 USA.
C3 Scripps Research Institute; Bristol-Myers Squibb; Bristol-Myers Squibb
RP Baran, PS (corresponding author), Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA.
EM pbaran@scripps.edu
FU Bristol-Myers Squibb; NIH/NIGMS [GM118176]; Department of Defense (DoD); NIH [F32GM117816]; National Institute of General Medical Sciences [R35GM118176] Funding Source: NIH RePORTER
NR 54
TC 298
Z9 341
U1 7
U2 414
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 11
PY 2017
VL 545
IS 7653
BP 213
EP +
DI 10.1038/nature22307
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EU3XG
UT WOS:000400963800032
PM 28424520
DA 2026-03-09
ER

PT J
AU Thomou, T
   Mori, MA
   Dreyfuss, JM
   Konishi, M
   Sakaguchi, M
   Wolfrum, C
   Rao, TN
   Winnay, JN
   Garcia-Martin, R
   Grinspoon, SK
   Gorden, P
   Kahn, CR
AF Thomou, Thomas
   Mori, Marcelo A.
   Dreyfuss, Jonathan M.
   Konishi, Masahiro
   Sakaguchi, Masaji
   Wolfrum, Christian
   Rao, Tata Nageswara
   Winnay, Jonathon N.
   Garcia-Martin, Ruben
   Grinspoon, Steven K.
   Gorden, Phillip
   Kahn, C. Ronald
TI Adipose-derived circulating miRNAs regulate gene expression in other tissues
SO NATURE
LA English
DT Article
ID extracellular vesicles; microrna biogenesis; membrane-vesicles; exosm; rna; proteins; cells; dysregulation; adipogenesis; metabolism
AB Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue-brown especially-into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3'UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine.
C1 [Thomou, Thomas; Konishi, Masahiro; Sakaguchi, Masaji; Rao, Tata Nageswara; Winnay, Jonathon N.; Garcia-Martin, Ruben; Kahn, C. Ronald] Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA.
   [Thomou, Thomas; Dreyfuss, Jonathan M.; Konishi, Masahiro; Sakaguchi, Masaji; Rao, Tata Nageswara; Winnay, Jonathon N.; Garcia-Martin, Ruben; Grinspoon, Steven K.; Kahn, C. Ronald] Harvard Med Sch, Boston, MA 02115 USA.
   [Mori, Marcelo A.] Univ Estadual Campinas, Dept Biochem & Tissue Biol, Campinas, SP, Brazil.
   [Dreyfuss, Jonathan M.] Joslin Diabet Ctr, Bioinformat Core, Boston, MA 02215 USA.
   [Dreyfuss, Jonathan M.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA.
   [Wolfrum, Christian] ETHZ, Dept Hlth Sci & Metab, Zurich, Switzerland.
   [Rao, Tata Nageswara] Univ Basel Hosp, Dept Biomed, Expt Hematol, Basel, Switzerland.
   [Grinspoon, Steven K.] Massachusetts Gen Hosp, MGH Program Nutr Metab, Boston, MA 02114 USA.
   [Gorden, Phillip] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA.
C3 Harvard University; Harvard University Medical Affiliates; Joslin Diabetes Center, Inc.; Harvard University; Harvard Medical School; Universidade Estadual de Campinas; Harvard University; Harvard University Medical Affiliates; Joslin Diabetes Center, Inc.; Boston University; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Basel; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
RP Kahn, CR (corresponding author), Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA.; Kahn, CR (corresponding author), Harvard Med Sch, Boston, MA 02115 USA.
EM c.ronald.kahn@joslin.harvard.edu
FU NIH [R01 DK082659, R01 DK033201, P30 DK040561]; Mary K. Iacocca Professorship; Joslin Diabetes Center DRC [P30DK036836]; FAPESP [2010/52557-0, 2015/01316-7]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [15/01316-7] Funding Source: FAPESP; Formas [2015-01316] Funding Source: Formas; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK040561, R01DK082659, R01DK031036, T32DK007260, P30DK036836] Funding Source: NIH RePORTER
NR 50
TC 1234
Z9 1364
U1 3
U2 433
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 23
PY 2017
VL 542
IS 7642
BP 450
EP +
DI 10.1038/nature21365
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1RG
UT WOS:000395094100030
PM 28199304
DA 2026-03-09
ER

PT J
AU Brown, S
   Pineda, CM
   Xin, TC
   Boucher, J
   Suozzi, KC
   Park, S
   Matte-Martone, C
   Gonzalez, DG
   Rytlewski, J
   Beronja, S
   Greco, V
AF Brown, Samara
   Pineda, Cristiana M.
   Xin, Tianchi
   Boucher, Jonathan
   Suozzi, Kathleen C.
   Park, Sangbum
   Matte-Martone, Catherine
   Gonzalez, David G.
   Rytlewski, Julie
   Beronja, Slobodan
   Greco, Valentina
TI Correction of aberrant growth preserves tissue homeostasis
SO NATURE
LA English
DT Article
ID hair-follicle; beta-catenin; stem-cell; mutations; activation; mice; expression; niche
AB Cells in healthy tissues acquire mutations with surprising frequency. Many of these mutations are associated with abnormal cellular behaviours such as differentiation defects and hyperproliferation, yet fail to produce macroscopically detectable phenotypes(1-3). It is currently unclear how the tissue remains phenotypically normal, despite the presence of these mutant cells. Here we use intravital imaging to track the fate of mouse skin epithelium burdened with varying numbers of activated Wnt/beta-catenin stem cells. We show that all resulting growths that deform the skin tissue architecture regress, irrespective of their size. Wild-type cells are required for the active elimination of mutant cells from the tissue, while utilizing both endogenous and ectopic cellular behaviours to dismantle the aberrant structures. After regression, the remaining structures are either completely eliminated or converted into functional skin appendages in a niche-dependent manner. Furthermore, tissue aberrancies generated from oncogenic Hras, and even mutationin-dependent deformations to the tissue, can also be corrected, indicating that this tolerance phenomenon reflects a conserved principle in the skin. This study reveals an unanticipated plasticity of the adult skin epithelium when faced with mutational and non-mutational insult, and elucidates the dynamic cellular behaviours used for its return to a homeostatic state.
C1 [Brown, Samara; Pineda, Cristiana M.; Xin, Tianchi; Boucher, Jonathan; Suozzi, Kathleen C.; Park, Sangbum; Matte-Martone, Catherine; Gonzalez, David G.; Greco, Valentina] Yale Sch Med, Dept Genet, New Haven, CT 06510 USA.
   [Rytlewski, Julie; Beronja, Slobodan] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA.
   [Greco, Valentina] Yale Sch Med, Yale Stem Cell Ctr, New Haven, CT 06510 USA.
   [Greco, Valentina] Yale Sch Med, Yale Canc Ctr, New Haven, CT 06510 USA.
   [Greco, Valentina] Yale Sch Med, Dept Dermatol, New Haven, CT 06510 USA.
   [Greco, Valentina] Yale Sch Med, Dept Cell Biol, New Haven, CT 06510 USA.
C3 Yale University; Fred Hutchinson Cancer Center; Yale University; Yale University; Yale New Haven Hospital; Yale University; Yale University
RP Greco, V (corresponding author), Yale Sch Med, Dept Genet, New Haven, CT 06510 USA.; Beronja, S (corresponding author), Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA.; Greco, V (corresponding author), Yale Sch Med, Yale Stem Cell Ctr, New Haven, CT 06510 USA.; Greco, V (corresponding author), Yale Sch Med, Yale Canc Ctr, New Haven, CT 06510 USA.; Greco, V (corresponding author), Yale Sch Med, Dept Dermatol, New Haven, CT 06510 USA.; Greco, V (corresponding author), Yale Sch Med, Dept Cell Biol, New Haven, CT 06510 USA.
EM beronja@fredhutch.org; Valentina.Greco@yale.edu
FU New York Stem Cell Foundation; Edward Mallinckrodt, Jr. Foundation; Howard Hughes Medical Institute Scholar award; National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institutes of Health (NIH) [5R01AR063663-04, 1R01AR067755-01A1]; NIH Predoctoral Program in Cellular and Molecular Biology [NIH T32GM007223]; Human Genetics Training Grant [NIH T32HD001749]; National Cancer Institute of the NIH [F31CA206419]; James Hudson Brown - Alexander Brown Coxe Postdoctoral Fellowship; CT Stem Cell Grant [14-SCA-YALE-05]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [T32HD007149] Funding Source: NIH RePORTER; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR063663] Funding Source: NIH RePORTER
NR 35
TC 124
Z9 143
U1 1
U2 32
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 17
PY 2017
VL 548
IS 7667
BP 334
EP +
DI 10.1038/nature23304
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD8AU
UT WOS:000407748400033
PM 28783732
DA 2026-03-09
ER

PT J
AU Zhang, CX
   Chen, YS
   Sun, BF
   Wang, L
   Yang, Y
   Ma, DY
   Lv, JH
   Heng, J
   Ding, YY
   Xue, YY
   Lu, XY
   Xiao, W
   Yang, YG
   Liu, F
AF Zhang, Chunxia
   Chen, Yusheng
   Sun, Baofa
   Wang, Lu
   Yang, Ying
   Ma, Dongyuan
   Lv, Junhua
   Heng, Jian
   Ding, Yanyan
   Xue, Yuanyuan
   Lu, Xinyan
   Xiao, Wen
   Yang, Yun-Gui
   Liu, Feng
TI m6A modulates haematopoietic stem and progenitor cell specification
SO NATURE
LA English
DT Article
ID rna-methylation; aortic endothelium; hits-clip; reveals; micrornas; emergence
AB N-6-methyladenosine (m(6)A) has been identified as the most abundant modification on eukaryote messenger RNA (mRNA)(1). Although the rapid development of high-throughput sequencing technologies has enabled insight into the biological functions of m(6)A modification(2-13), the function of m(6)A during vertebrate embryogenesis remains poorly understood. Here we show that m(6)A determines cell fate during the endothelial-to-haematopoietic transition (EHT) to specify the earliest haematopoietic stem/progenitor cells (HSPCs) during zebrafish embryogenesis. m(6)A-specific methylated RNA immunoprecipitation combined with high-throughput sequencing (MeRIP-seq) and m(6)A individual-nucleotide-resolution cross-linking and immunoprecipitation with sequencing (miCLIP-seq) analyses reveal conserved features on zebrafish m(6)A methylome and preferential distribution of m(6)A peaks near the stop codon with a consensus RRACH motif. In mettl3-deficient embryos, levels of m(6)A are significantly decreased and emergence of HSPCs is blocked. Mechanistically, we identify that the delayed YTHDF2-mediated mRNA decay of the arterial endothelial genes notch1a and rhoca contributes to this deleterious effect. The continuous activation of Notch signalling in arterial endothelial cells of mettl3-deficient embryos blocks EHT, thereby repressing the generation of the earliest HSPCs. Furthermore, knockdown of Mettl3 in mice confers a similar phenotype. Collectively, our findings demonstrate the critical function of m(6)A modification in the fate determination of HSPCs during vertebrate embryogenesis.
C1 [Zhang, Chunxia; Wang, Lu; Ma, Dongyuan; Lv, Junhua; Heng, Jian; Ding, Yanyan; Xue, Yuanyuan; Lu, Xinyan; Liu, Feng] Chinese Acad Sci, Inst Zool, State Key Lab Membrane Biol, Beijing 100101, Peoples R China.
   [Zhang, Chunxia; Chen, Yusheng; Lv, Junhua; Heng, Jian; Ding, Yanyan; Xue, Yuanyuan; Lu, Xinyan; Yang, Yun-Gui; Liu, Feng] Univ Chinese Acad Sci, Beijing 100049, Peoples R China.
   [Chen, Yusheng; Sun, Baofa; Yang, Ying; Xiao, Wen; Yang, Yun-Gui] Chinese Acad Sci, CAS Key Lab Genom & Precis Med, Collaborat Innovat Ctr Genet & Dev,Beijing Inst G, CAS Ctr Excellence Mol Cell Sci,Coll Future Techn, Beijing 100101, Peoples R China.
C3 Chinese Academy of Sciences; Institute of Zoology, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences
RP Liu, F (corresponding author), Chinese Acad Sci, Inst Zool, State Key Lab Membrane Biol, Beijing 100101, Peoples R China.; Yang, YG; Liu, F (corresponding author), Univ Chinese Acad Sci, Beijing 100049, Peoples R China.; Yang, YG (corresponding author), Chinese Acad Sci, CAS Key Lab Genom & Precis Med, Collaborat Innovat Ctr Genet & Dev,Beijing Inst G, CAS Ctr Excellence Mol Cell Sci,Coll Future Techn, Beijing 100101, Peoples R China.
EM ygyang@big.ac.cn; liuf@ioz.ac.cn
FU National Natural Science Foundation of China [31425016, 81530004, 31625016]; Ministry of Science and Technology of China [2016YFA0100500, 2016YFC0900300]; Strategic Priority Research Program of the Chinese Academy of Sciences, China [XDA01010110, QYZDY-SSW-SMC027, XDB14030300]
NR 52
TC 478
Z9 557
U1 10
U2 203
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 14
PY 2017
VL 549
IS 7671
BP 273
EP +
DI 10.1038/nature23883
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG7AE
UT WOS:000410555900046
PM 28869969
DA 2026-03-09
ER

PT J
AU Luksza, M
   Riaz, N
   Makarov, V
   Balachandran, VP
   Hellmann, MD
   Solovyov, A
   Rizvi, NA
   Merghoub, T
   Levine, AJ
   Chan, TA
   Wolchok, JD
   Greenbaum, BD
AF Luksza, Marta
   Riaz, Nadeem
   Makarov, Vladimir
   Balachandran, Vinod P.
   Hellmann, Matthew D.
   Solovyov, Alexander
   Rizvi, Naiyer A.
   Merghoub, Taha
   Levine, Arnold J.
   Chan, Timothy A.
   Wolchok, Jedd D.
   Greenbaum, Benjamin D.
TI A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy
SO NATURE
LA English
DT Article
ID cell lung-cancer; pd-1 blockade; ctla-4 blockade; clinical-response; repertoires; melanoma; therapy; sensitivity; resistance; landscape
AB Checkpoint blockade immunotherapies enable the host immune system to recognize and destroy tumour cells(1). Their clinical activity has been correlated with activated T-cell recognition of neoantigens, which are tumour-specific, mutated peptides presented on the surface of cancer cells(2,3). Here we present a fitness model for tumours based on immune interactions of neoantigens that predicts response to immunotherapy. Two main factors determine neoantigen fitness: the likelihood of neoantigen presentation by the major histocompatibility complex (MHC) and subsequent recognition by T cells. We estimate these components using the relative MHC binding affinity of each neoantigen to its wild type and a nonlinear dependence on sequence similarity of neoantigens to known antigens. To describe the evolution of a heterogeneous tumour, we evaluate its fitness as a weighted effect of dominant neoantigens in the subclones of the tumour. Our model predicts survival in anti-CTLA-4-treated patients with melanoma(4,5) and anti-PD-1-treated patients with lung cancer(6). Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumours and rapidly evolving pathogens(7-9).
C1 [Luksza, Marta; Levine, Arnold J.] Inst Adv Study, Simons Ctr Syst Biol, Olden Lane, Princeton, NJ 08540 USA.
   [Riaz, Nadeem; Chan, Timothy A.] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA.
   [Riaz, Nadeem; Makarov, Vladimir; Chan, Timothy A.] Mem Sloan Kettering Canc Ctr, Immunogen & Precis Oncol Platform, 1275 York Ave, New York, NY 10021 USA.
   [Makarov, Vladimir; Chan, Timothy A.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA.
   [Balachandran, Vinod P.] Mem Sloan Kettering Canc Ctr, Dept Surg, 1275 York Ave, New York, NY 10021 USA.
   [Balachandran, Vinod P.] Mem Sloan Kettering Canc Ctr, David M Rubenstein Ctr Pancreat Canc Res, 1275 York Ave, New York, NY 10021 USA.
   [Balachandran, Vinod P.; Hellmann, Matthew D.; Merghoub, Taha; Chan, Timothy A.; Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Parker Inst Canc Immunotherapy, 1275 York Ave, New York, NY 10021 USA.
   [Hellmann, Matthew D.; Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA.
   [Hellmann, Matthew D.] Cornell Univ, Weill Cornell Med Coll, Dept Med, New York, NY 10021 USA.
   [Solovyov, Alexander; Greenbaum, Benjamin D.] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA.
   [Solovyov, Alexander; Greenbaum, Benjamin D.] Icahn Sch Med Mt Sinai, Dept Med Hematol & Med Oncol, New York, NY 10029 USA.
   [Solovyov, Alexander; Greenbaum, Benjamin D.] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA.
   [Solovyov, Alexander; Greenbaum, Benjamin D.] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA.
   [Rizvi, Naiyer A.] Columbia Univ, Med Ctr, Dept Med, New York, NY USA.
   [Merghoub, Taha; Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Ludwig Collaborat & Swim Amer Lab, 1275 York Ave, New York, NY 10021 USA.
   [Merghoub, Taha; Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Dept Med, Melanoma & Immunotherapeut Serv, 1275 York Ave, New York, NY 10021 USA.
C3 Institute for Advanced Study - USA; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Columbia University; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center
RP Wolchok, JD (corresponding author), Mem Sloan Kettering Canc Ctr, Parker Inst Canc Immunotherapy, 1275 York Ave, New York, NY 10021 USA.; Wolchok, JD (corresponding author), Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA.; Greenbaum, BD (corresponding author), Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA.; Greenbaum, BD (corresponding author), Icahn Sch Med Mt Sinai, Dept Med Hematol & Med Oncol, New York, NY 10029 USA.; Greenbaum, BD (corresponding author), Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA.; Greenbaum, BD (corresponding author), Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA.; Wolchok, JD (corresponding author), Mem Sloan Kettering Canc Ctr, Ludwig Collaborat & Swim Amer Lab, 1275 York Ave, New York, NY 10021 USA.; Wolchok, JD (corresponding author), Mem Sloan Kettering Canc Ctr, Dept Med, Melanoma & Immunotherapeut Serv, 1275 York Ave, New York, NY 10021 USA.
EM mluksza@ias.edu; benjamin.greenbaum@mssm.edu
FU Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant [SU2C-AACR-DT17-15]; Stand Up To Cancer-National Science Foundation-Lustgarten Foundation Convergence Dream Team Grant; Phillip A. Sharp Innovation in Collaboration Award from Stand Up To Cancer; Janssen Research & Development LLC; STARR Cancer Consortium; Pershing Square Sohn Cancer Research Alliance; NIH [R01 CA205426]; V Foundation; Lustgarten Foundation; National Science Foundation (NSF) [1545935]; Swim Across America; Ludwig Institute for Cancer Research; Parker Institute for Cancer Immunotherapy; NCI K12 Paul Calabresi Career Development Award for Clinical Oncology [K12CA184746-01A1]; MSKCC Core Grant [P30 CA008748]; Direct For Mathematical & Physical Scien; Division Of Physics [1545935] Funding Source: National Science Foundation; National Cancer Institute [R01CA205426, K12CA184746, P01CA087497, P30CA008748] Funding Source: NIH RePORTER
NR 40
TC 491
Z9 572
U1 3
U2 118
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 23
PY 2017
VL 551
IS 7681
BP 517
EP +
DI 10.1038/nature24473
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FN5JO
UT WOS:000416043700048
PM 29132144
DA 2026-03-09
ER

PT J
AU Abbott, BP
   Abbott, R
   Abbott, TD
   Acernese, F
   Ackley, K
   Adams, C
   Adams, T
   Addesso, P
   Adhikari, RX
   Adya, VB
   Affeldt, C
   Afrough, M
   Agarwal, B
   Agathos, M
   Agatsuma, K
   Aggarwal, N
   Aguiar, OD
   Aiello, L
   Ain, A
   Ajith, P
   Allen, B
   Allen, G
   Allocca, A
   Altin, PA
   Amato, A
   Ananyeva, A
   Anderson, SB
   Anderson, WG
   Angelova, SV
   Antier, S
   Appert, S
   Arai, K
   Araya, MC
   Areeda, JS
   Arnaud, N
   Arun, KG
   Ascenzi, S
   Ashton, G
   Ast, M
   Aston, SM
   Astone, P
   Atallah, DV
   Aufmuth, P
   Aulbert, C
   AultO'Neal, K
   Austin, C
   Avila-Alvarez, A
   Babak, S
   Bacon, P
   Bader, MKM
   Bae, S
   Baker, PT
   Baldaccini, F
   Ballardin, G
   Ballmer, SW
   Banagiri, S
   Barayoga, JC
   Barclay, SE
   Barish, BC
   Barker, D
   Barkett, K
   Barone, F
   Barr, B
   Barsotti, L
   Barsuglia, M
   Barta, D
   Bartlett, J
   Bartos, I
   Bassiri, R
   Basti, N
   Batch, JC
   Bawaj, M
   Bayley, JC
   Bazzan, M
   Bécsy, B
   Beer, C
   Bejger, M
   Belahcene, I
   Bell, AS
   Berger, BK
   Bergmann, G
   Bero, JJ
   Berry, CPL
   Bersanetti, D
   Bertolini, A
   Betzwieser, J
   Bhagwat, S
   Bhandare, R
   Bilenko, IA
   Billingsley, G
   Billman, CR
   Birch, J
   Birney, R
   Birnholtz, O
   Biscans, S
   Biscoveanu, S
   Bisht, A
   Bitossi, M
   Biwer, C
   Bizouard, A
   Blackburn, JK
   Blackman, J
   Blair, CD
   Blair, DG
   Blair, RM
   Bloemen, S
   Bock, O
   Bode, N
   Boer, M
   Bogaert, G
   Bohe, A
   Bondu, F
   Bonilla, E
   Bonnand, R
   Boom, BA
   Bork, R
   Boschi, V
   Bose, S
   Bossie, K
   Bouffanais, Y
   Bozzi, A
   Bradaschia, C
   Brady, PR
   Branchesi, M
   Brau, JE
   Briant, T
   Brillet, A
   Brinkmann, M
   Brisson, V
   Brockill, R
   Broida, JE
   Brooks, NF
   Brown, DA
   Brown, DD
   Brunett, S
   Buchanan, CC
   Buikema, A
   Bulik, H
   Bulten, HJ
   Buonanno, A
   Buskulic, D
   Buy, C
   Byer, RL
   Cabero, M
   Cadonati, L
   Cagnoli, G
   Cahillane, C
   Bustillo, JC
   Callister, TA
   Calloni, E
   Camp, JB
   Canepa, M
   Canizares, P
   Cannon, KC
   Cao, H
   Cao, J
   Capano, CD
   Capocasa, E
   Carbognani, F
   Caride, S
   Carney, MF
   Diaz, JC
   Casentini, C
   Caudill, S
   Cavaglià, M
   Cavalier, F
   Cavalieri, R
   Cella, G
   Cepeda, CB
   Cerdá-Durán, P
   Cerretani, G
   Cesarini, E
   Chamberlin, SJ
   Chan, M
   Chao, S
   Charlton, P
   Chase, E
   Chassande-Mottin, E
   Chatterjee, D
   Chatziioannou, K
   Cheeseboro, BD
   Chen, HY
   Chen, X
   Chen, Y
   Cheng, HP
   Chia, H
   Chincarini, N
   Chiummo, A
   Chmiel, T
   Cho, HS
   Cho, M
   Chow, JH
   Christensen, N
   Chu, Q
   Chua, AJK
   Chua, S
   Chung, AKW
   Chung, S
   Ciani, G
   Ciolfi, R
   Cirelli, CE
   Cirone, N
   Clara, F
   Clark, JA
   Clearwater, P
   Cleva, F
   Cocchieri, C
   Coccia, E
   Cohadon, PF
   Cohen, D
   Colla, A
   Collette, CG
   Cominsky, LR
   Constancio, M
   Conti, L
   Cooper, SJ
   Corban, P
   Corbitt, TR
   Cordero-Carrión, I
   Corley, KR
   Cornish, N
   Corsi, A
   Cortese, S
   Costa, CA
   Coughlin, MW
   Coughlin, SB
   Coulon, JP
   Countryman, ST
   Couvares, P
   Covas, PB
   Cowan, EE
   Coward, DM
   Cowart, MJ
   Coyne, DC
   Coyne, R
   Creighton, JDE
   Creighton, TD
   Cripe, J
   Crowder, SG
   Cullen, TJ
   Cumming, A
   Cunningham, L
   Cuoco, E
   Dal Canton, T
   Dálya, G
   Danilishin, SL
   D'Antonio, S
   Danzmann, K
   Dasgupta, A
   Costa, CFDS
   Datrier, LEH
   Dattilo, V
   Dave, I
   Davier, M
   Davis, EJ
   Daw, EJ
   Day, B
   De, S
   DeBra, D
   Degallaix, J
   De Laurentis, M
   Deléglise, S
   Del Pozzo, W
   Demos, N
   Denker, T
   Dent, T
   De Pietri, R
   Dergachev, V
   De Rosa, R
   DeRosa, RT
   De Rossi, C
   DeSalvo, R
   de Verona, O
   Devenson, J
   Dhurancihar, S
   Díaz, MC
   Di Fiore, L
   Di Giovanni, M
   Di Girolamo, T
   Di Lieto, A
   Di Pace, S
   Di Palma, I
   Di Renzo, F
   Doctor, Z
   Dolique, V
   Donovan, F
   Dooley, KL
   Doravari, S
   Dorrington, I
   Douglas, R
   Alvarez, MD
   Downes, TP
   Drago, M
   Dreissigacker, C
   Driggers, JC
   Du, Z
   Ducrot, M
   Dupej, P
   Dwyer, SE
   Edo, TB
   Edwards, MC
   Effler, N
   Eggenstein, HB
   Ehrens, P
   Eichholz, J
   Eikenberry, SS
   Eisenstein, RA
   Essick, RC
   Estevez, D
   Etienne, ZB
   Etzel, T
   Evans, M
   Evans, TM
   Factourovich, M
   Fafone, V
   Fair, H
   Fairhurst, S
   Fan, X
   Farinon, S
   Farr, B
   Farr, WM
   Fauchon-Jones, EJ
   Favata, M
   Fays, M
   Fee, C
   Fehrmann, H
   Feicht, J
   Fejer, MM
   Fernandez-Galiana, A
   Ferrante, I
   Ferreira, EC
   Ferrini, F
   Fidecaro, F
   Finstad, D
   Fiori, I
   Fiorucci, D
   Fishbach, M
   Fisher, RP
   Fitz-Axen, M
   Flaminio, R
   Fletcher, M
   Fong, H
   Font, JA
   Forsyth, PWF
   Forsyth, SS
   Fournier, JD
   Frasca, S
   Frasconi, E
   Frei, Z
   Freise, A
   Frey, R
   Frey, V
   Fries, EM
   Fritschel, P
   Frolov, VV
   Fulda, P
   Fyffe, M
   Gabbard, H
   Gadre, BU
   Gaebel, SM
   Gair, JR
   Gammaitoni, L
   Ganija, MR
   Gaonkar, SG
   Garcia-Quiros, C
   Garufi, F
   Gateley, B
   Gaudio, S
   Gaur, G
   Gayathril, V
   Gehrels, N
   Gemme, G
   Genin, E
   Gennai, A
   George, D
   George, J
   Gergely, L
   Germain, V
   Ghonge, S
   Ghosh, A
   Ghosh, A
   Ghosh, S
   Giaime, JA
   Giardina, KD
   Giazotto, A
   Gill, K
   Glover, L
   Goetz, E
   Goetz, R
   Gomes, S
   Goncharov, B
   González, G
   Castro, JMG
   Gopakumar, A
   Gorodetsky, ML
   Gossan, SE
   Gosselin, M
   Gouaty, R
   Grado, A
   Graef, C
   Granata, M
   Grant, A
   Gras, S
   Gray, C
   Greco, G
   Green, AC
   Gretarsson, EM
   Groot, P
   Grote, H
   Grunewald, S
   Gruning, P
   Guidi, GM
   Guo, X
   Gupta, A
   Gupta, MK
   Gushwa, KE
   Gustafson, EK
   Gustafson, R
   Halim, O
   Hall, BR
   Hall, ED
   Hamilton, EZ
   Hammond, G
   Haney, M
   Hanke, MM
   Hanks, J
   Hanna, C
   Hannam, MD
   Hannuksela, OA
   Hanson, J
   Hardwick, I
   Harms, J
   Harry, GM
   Harry, IW
   Hart, MJ
   Hester, CJ
   Haughian, K
   Healy, J
   Heidmann, N
   Heintze, MC
   Heitmann, H
   Hello, P
   Hemming, G
   Hendry, M
   Heng, IS
   Hennig, J
   Heptonstall, AW
   Heurs, M
   Hild, S
   Hinderer, T
   Hoak, D
   Hofman, D
   Holt, K
   Holz, DE
   Hopkins, P
   Horst, C
   Hough, J
   Houston, EA
   Howell, EJ
   Hreibi, A
   Hu, YM
   Huerta, EA
   Huet, D
   Hughey, B
   Husa, S
   Huttner, SH
   Huynh-Dinh, T
   Indik, N
   Inta, R
   Intini, G
   Isa, HN
   Isac, JM
   Isi, M
   Iyer, BR
   Izumi, K
   Jacqmin, T
   Jani, K
   Jaranowski, P
   Jawahar, S
   Jiménez-Forteza, F
   Johnson, WW
   Jones, DI
   Jones, R
   Jonker, RJG
   Ju, L
   Junker, J
   Kalaghatgi, CV
   Kalogera, V
   Kamai, B
   Kandhasamy, S
   Kang, G
   Kanner, JB
   Kapadia, SJ
   Karki, S
   Karvinen, KS
   Kasprzack, M
   Katolik, M
   Katsavounidis, E
   Katzman, W
   Kaufer, S
   Kawabe, K
   Kéfélian, E
   Keitel, D
   Kemball, AJ
   Kennedy, R
   Kent, C
   Key, JS
   Khalili, FY
   Khan, I
   Khan, S
   Khan, Z
   Khazanov, EA
   Kijbunchoo, N
   Kim, C
   Kim, JC
   Kim, K
   Kim, W
   Kim, WS
   Kim, YM
   Kimbrell, SJ
   King, EJ
   King, PJ
   Kinley-Hanlon, M
   Kirchhoff, R
   Kissel, JS
   Kleybolte, L
   Klimenko, S
   Knowles, TD
   Koch, P
   Koehlenbeck, SM
   Koley, S
   Kondrashov, V
   Kontos, A
   Korobko, M
   Korth, WZ
   Kowalska, I
   Kozak, DB
   Krämer, C
   Kringel, V
   Krishnan, B
   Królak, A
   Kuehn, G
   Kumar, P
   Kumar, R
   Kumar, S
   Kuo, L
   Kutynia, A
   Kwang, S
   Lackey, BD
   Lai, KH
   Landry, M
   Lang, RN
   Lange, J
   Lantz, B
   Lanza, RK
   Lartaux-Vollard, N
   Lasky, PD
   Laxen, M
   Lazzarini, A
   Lazzaro, C
   Leaci, P
   Leavey, S
   Lee, CH
   Lee, HK
   Lee, HM
   Lee, HW
   Lee, K
   Lehmann, J
   Lenon, A
   Leonardi, M
   Leroy, N
   Letendre, N
   Levin, Y
   Li, TGF
   Linker, SD
   Littenberg, TB
   Liu, J
   Liu, X
   Lo, RKL
   Lockerbie, NN
   London, LT
   Lord, JE
   Lorenzini, M
   Loriette, V
   Lormand, M
   Losurdo, G
   Lough, JD
   Lousto, CO
   Lovelace, G
   Lüock, H
   Lumaca, D
   Lundgren, AP
   Lynch, R
   Ma, Y
   Macas, R
   Macfoy, S
   Machenschalk, B
   Maclnnis, M
   Macleod, DM
   Hernandez, IM
   Magaña-Sandoval, F
   Zertuche, LM
   Magee, RM
   Majorana, E
   Maksimovic, I
   Man, N
   Mandic, V
   Mangano, V
   Mansell, GL
   Manske, M
   Mantovani, M
   Marchesoni, F
   Marion, F
   Márka, S
   Márka, Z
   Markakis, C
   Markosyan, AS
   Markowitz, A
   Maros, E
   Marquina, A
   Martelli, F
   Martellini, L
   Martin, IW
   Martin, RM
   Martynov, DV
   Mason, K
   Massera, E
   Masserot, A
   Massinger, TJ
   Masso-Reid, M
   Mastrogiovanni, S
   Matas, A
   Matichard, F
   Matone, L
   Mavalvala, N
   Mazumder, N
   McCarthy, R
   McClelland, DE
   McCormick, S
   McCuller, L
   McGuire, SC
   McIntyre, G
   McIver, J
   McManus, DJ
   McNeill, L
   Mcrae, T
   McWilliams, ST
   Meacher, D
   Meadors, GD
   Mehmet, M
   Meidam, J
   Mejuto-Villa, E
   Melatos, A
   Mendell, G
   Mercer, RA
   Merilh, EL
   Merzougui, M
   Meshkov, S
   Messenger, C
   Messick, C
   Metzdorff, R
   Meyers, PM
   Miao, H
   Michel, C
   Middleton, H
   Mikhailov, EE
   Milano, L
   Miller, AL
   Miller, BB
   Miller, J
   Millhouse, M
   Milovich-Goff, MC
   Minazzoli, O
   Minenkov, Y
   Ming, J
   Mishra, C
   Mitra, S
   Mitrofanov, VR
   Mitselmakher, G
   Mittleman, R
   Moffa, D
   Moggi, N
   Mogushi, K
   Mohan, M
   Mohapatra, SRP
   Montani, M
   Moore, CJ
   Moraru, D
   Moreno, G
   Morriss, SR
   Mours, B
   Mow-Lowry, CM
   Mueller, G
   Muir, AW
   Mukherjee, A
   Mukherjee, D
   Mukherjee, S
   Mukund, N
   Mullavey, A
   Munch, J
   Muñiz, EA
   Muratore, M
   Murray, PG
   Napier, K
   Nardecchia, I
   Naticchioni, L
   Nayak, RK
   Neilson, J
   Nelemans, G
   Nelson, TJN
   Nery, M
   Neunzert, A
   Nevin, L
   Newport, JM
   Newton, G
   Ng, KKY
   Nguyen, TT
   Nichols, D
   Nielsen, AB
   Nissanke, S
   Nitz, A
   Noack, A
   Nocera, F
   Nolting, D
   North, C
   Nuttall, LK
   Oberling, J
   O'Dea, GD
   Ogin, GH
   Oh, JJ
   Oh, SH
   Ohme, F
   Okada, MA
   Oliver, M
   Oppermann, P
   Oram, RJ
   O'Reilly, B
   Ormiston, R
   Ortega, LF
   O'Shaughnessy, R
   Ossokine, S
   Ottaway, DJ
   Overmier, H
   Owen, BJ
   Pace, AE
   Page, J
   Page, MA
   Pai, A
   Pai, SA
   Palamos, JR
   Palashov, O
   Palomba, C
   Pal-Singh, A
   Pan, H
   Pan, HW
   Pang, B
   Pang, PTH
   Pankow, C
   Pannarale, F
   Pant, BC
   Paoletti, F
   Paoli, A
   Papa, MA
   Parida, A
   Parker, W
   Pascucci, D
   Pasqualetti, A
   Passaquieti, R
   Passuello, D
   Patil, M
   Patricelli, B
   Pearlstone, BL
   Pedraza, M
   Pedurand, R
   Pekowsky, L
   Pele, A
   Penn, S
   Perez, CJ
   Perreca, A
   Perri, LM
   Pfeiffer, HP
   Phelps, M
   Piccinni, OJ
   Pichot, M
   Piergiovanni, F
   Pierro, V
   Pillant, G
   Pinard, L
   Pinto, IM
   Pirello, M
   Pitkin, M
   Poe, M
   Poggiani, R
   Popolizio, P
   Porter, EK
   Post, A
   Powell, J
   Prasad, J
   Pratt, JWW
   Pratten, G
   Predoi, V
   Prestegard, T
   Prijatelj, M
   Principe, M
   Privitera, S
   Prodi, GA
   Prokhorov, LG
   Puncken, O
   Punturo, M
   Puppo, P
   Pürrer, M
   Qi, H
   Quetschke, V
   Quintero, EA
   Quitzow-James, R
   Raab, FJ
   Rabeling, DS
   Radkins, H
   Raffai, P
   Raja, S
   Rajan, C
   Rajbhandari, B
   Rakhmanov, M
   Ramirez, KE
   Ramos-Buades, A
   Rapagnani, P
   Raymond, V
   Razzano, M
   Read, J
   Regimbau, T
   Rei, L
   Reid, S
   Reitze, DH
   Ren, W
   Reyes, SD
   Ricci, F
   Ricker, PM
   Rieger, S
   Riles, K
   Rizzo, M
   Robertson, NA
   Robie, R
   Robinet, F
   Rocchi, A
   Rolland, L
   Rollins, JG
   Roma, VJ
   Romano, JD
   Romano, R
   Romel, CL
   Romie, JH
   Rosinska, D
   Ross, MP
   Rowan, S
   Rüdiger, A
   Ruggi, P
   Rutins, G
   Ryan, K
   Sachdev, S
   Sadecki, I
   Sadeghian, L
   Sakellariadou, M
   Salconi, L
   Saleem, M
   Salemi, F
   Samajdar, A
   Sammut, L
   Sampson, LM
   Sanchez, EJ
   Sanchez, LE
   Sanchis-Gual, N
   Sandberg, V
   Sanders, JR
   Sassolas, B
   Sathyaprakash, BS
   Saulson, PR
   Sauter, O
   Savage, RL
   Sawadsky, A
   Schale, P
   Scheel, M
   Schauer, J
   Schmidt, J
   Schmidt, P
   Schnabel, R
   Schofield, RMS
   Schönbeck, A
   Schreiber, E
   Schuette, D
   Schulte, BW
   Schutz, BF
   Schwalbe, SG
   Scott, J
   Scott, SM
   Seidel, E
   Sellers, D
   Sengupta, AS
   Sentenac, D
   Sequino, V
   Sergeev, A
   Shaddock, DA
   Shaffer, TJ
   Shah, AA
   Shahriar, MS
   Shaner, MB
   Shao, L
   Shapiro, B
   Shawhan, P
   Shepard, A
   Shoemaker, DH
   Shoemaker, DM
   Siellez, K
   Siemens, X
   Sieniawska, M
   Sigg, D
   Silva, AD
   Singer, LP
   Singh, A
   Singhal, A
   Sintes, AM
   Slagmolen, BJJ
   Smith, B
   Smith, JR
   Smith, RJE
   Somala, S
   Son, EJ
   Sonnenberg, JN
   Sorazu, B
   Sorrentino, F
   Souradeep, T
   Spencer, AP
   Srivastava, AK
   Staats, K
   Staley, A
   Steer, D
   Steinke, M
   Steinlechner, J
   Steinlechner, S
   Steinmeyer, D
   Stevenson, SP
   Stone, R
   Stops, DJ
   Strain, KA
   Stratta, G
   Strigin, SE
   Strunk, A
   Sturani, R
   Stuver, AL
   Summerscales, TZ
   Sun, L
   Sunil, S
   Suresh, J
   Sutton, PJ
   Swinkels, BL
   Szczepanczyk, MJ
   Tacca, M
   Tait, SC
   Talbot, C
   Talukder, D
   Tanner, DB
   Tápai, M
   Taracchini, A
   Tasson, JD
   Taylor, JA
   Taylor, R
   Tewari, SV
   Theeg, T
   Thies, F
   Thomas, EG
   Thomas, M
   Thomas, P
   Thorne, KA
   Thrane, E
   Tiwari, S
   Tiwari, V
   Tokmakov, KV
   Toland, K
   Tonelli, M
   Tornasi, Z
   Torres-Forné, N
   Torrie, CI
   Töyrä, D
   Travasso, F
   Traylor, G
   Trinastic, J
   Tringali, MC
   Trozzon, L
   Tsang, KW
   Tse, M
   Tso, R
   Tsukada, L
   Tsuna, D
   Tuyenbayev, D
   Ueno, K
   Ugolini, D
   Unnikrishnan, CS
   Urban, AL
   Usman, SA
   Vahlbruch, H
   Vajente, G
   Valdese, G
   van Bakel, N
   van Beuzekom, M
   van den Brand, JFJ
   Van den Broeck, C
   Vander-Hyde, DC
   van der Schaaf, L
   van Heijningen, JV
   van Veggel, AA
   Vardaro, M
   Varma, V
   Vass, S
   Vasúth, M
   Vecchio, A
   Vedovato, G
   Veitch, J
   Veitch, PJ
   Venkateswara, K
   Venugopalan, G
   Verkindt, D
   Vetrano, F
   Viceré, A
   Viets, AD
   Vinciguerra, S
   Vine, DJ
   Vinet, JY
   Vitale, S
   Vo, T
   Vocca, H
   Vorvick, C
   Vyatchanin, SP
   Wade, AR
   Wade, LE
   Wade, M
   Walet, R
   Walker, M
   Wallace, L
   Walsh, S
   Wang, G
   Wang, H
   Wang, JZ
   Wang, WH
   Wang, YF
   Ward, RL
   Warner, J
   Was, M
   Watchi, J
   Weaver, B
   Wei, LW
   Weinert, M
   Weinstein, AJ
   Weiss, R
   Wen, L
   Wessel, EK
   Wessels, P
   Westerweck, J
   Westphal, T
   Wette, K
   Whelan, JT
   Whitcomb, SE
   Whiting, BF
   Whittle, C
   Wilken, D
   Williams, D
   Williams, RD
   Williamson, AR
   Willis, JL
   Willke, B
   Wimmer, MH
   Winkler, W
   Wipfl, CC
   Wittel, H
   Woan, G
   Woehler, J
   Wofford, J
   Wong, KWK
   Worden, J
   Wright, JL
   Wu, DS
   Wysocki, DM
   Xiao, S
   Yamamoto, H
   Yancey, CC
   Yang, L
   Yap, MJ
   Yazback, M
   Yu, H
   Yu, HC
   Yvert, M
   Zadrozny, A
   Zanolin, M
   Zelenova, T
   Zendri, JP
   Zevin, M
   Zhang, L
   Zhang, M
   Zhang, T
   Zhang, YH
   Zhao, C
   Zhou, M
   Zhou, Z
   Zhu, SJ
   Zhu, XJ
   Zimmerman, AB
   Zucker, ME
   Zweizig, J
   Foley, RJ
   Coulter, DA
   Drout, MR
   Kasen, D
   Kilpatrick, CD
   Madore, BF
   Murguia-Berthier, A
   Pan, YC
   Piro, AL
   Prochaska, JX
   Ramirez-Ruiz, E
   Rest, A
   Rojas-Bravo, C
   Shappee, BJ
   Siebert, MR
   Simon, JD
   Ulloas, N
   Annis, J
   Soares-Santos, M
   Brout, D
   Scolnic, D
   Diehl, HT
   Frieman, J
   Berger, E
   Alexander, KD
   Allam, S
   Balbinot, E
   Blanchard, P
   Butler, RE
   Chornock, R
   Cook, ER
   Cowpertwaite, P
   Drlica-Wagner, A
   Drout, MR
   Durret, F
   Eftekhari, T
   Finley, DA
   Fong, W
   Fryer, CL
   García-Bellido, J
   Gill, MSS
   Gruendl, RA
   Hanna, C
   Hartley, W
   Herner, K
   Huterer, D
   Kasen, D
   Kessler, R
   Li, TS
   Lin, H
   Lopes, PAA
   Lourenço, ACC
   Margutti, R
   Marriner, J
   Marshall, JL
   Matheson, T
   Medina, GE
   Metzger, BD
   Muñoz, RR
   Muir, J
   Nicholl, M
   Nugent, P
   Palmese, A
   Paz-Chinchón, F
   Quataert, E
   Sako, M
   Sauseda, M
   Schlegel, DJ
   Secco, LF
   Smith, N
   Sobreira, F
   Stebbins, A
   Villar, VA
   Vivas, AK
   Wester, W
   Williams, PKG
   Yanny, B
   Zenteno, A
   Abbott, TMC
   Abdalla, FB
   Bechtol, K
   Benoit-Lévy, A
   Bertin, E
   Bridle, SL
   Brooks, D
   Buckley-Geer, E
   Burke, DL
   Rosell, AC
   Kind, MC
   Carretero, J
   Castander, FJ
   Cunha, CE
   D'Andrea, CB
   da Costa, LN
   Davis, C
   DePoy, DL
   Desai, S
   Dietrich, JP
   Estrada, J
   Fernandez, E
   Flaugher, B
   Fosalba, P
   Gaztanaga, E
   Gerdes, DW
   Giannantonio, T
   Goldstein, DA
   Gruen, D
   Gutierrez, G
   Hartley, WG
   Honscheid, K
   Jain, B
   James, DJ
   Jeltema, T
   Johnson, MWG
   Kent, S
   Krause, E
   Kron, R
   Kuehn, K
   Kuhlmann, S
   Kuropatkin, N
   Lahav, O
   Lima, M
   Maia, MAG
   March, M
   Miller, CJ
   Miquel, R
   Neilsen, E
   Nord, B
   Ogando, RLC
   Plazas, AN
   Romer, AK
   Roodman, A
   Rykoff, ES
   Sanchez, E
   Scarpine, V
   Schubnell, M
   Sevilla-Noarbe, I
   Smith, M
   Smith', RC
   Suchyta, E
   Tarle, G
   Thomas, D
   Thomas, RC
   Troxel, MA
   Tucker, DL
   Vikram, V
   Walker, AR
   Weller, J
   Zhang, Y
   Haislip, JB
   Kouprinov, VV
   Reichart, DE
   Tartaglia, L
   Sand, DJ
   Valenti, S
   Yang, S
   Arcavi, I
   Hosseinzadeh, G
   Howell, DA
   McCully, C
   Poznanski, D
   Vasylyev, S
   Tanvir, NR
   Levan, NJ
   Hjorth, J
   Cano, Z
   Copperwheat, C
   de Ugarte-Postigo, A
   Evans, PA
   Fynbo, JPU
   González-Fernández, C
   Greiner, J
   Irwin, M
   Lyman, J
   Mandel, I
   McMahon, R
   Milvang-Jensen, B
   O'Brien, P
   Osborne, JP
   Perley, DA
   Pian, E
   Palazzi, E
   Rol, E
   Rosetti, S
   Rosswog, S
   Rowlinson, A
   Schulze, S
   Steeghs, DTH
   Thöne, CC
   Ulaczyk, K
   Watson, D
   Wiersema, K
   Lipunov, VM
   Gorbovskoy, E
   Kornilov, VG
   Tyurina, N
   Balanutsa, P
   Vlasenko, D
   Gorbunov, I
   Podesta, R
   Levato, H
   Saffe, C
   Buckley, DAH
   Budnev, NM
   Gress, O
   Yurkov, V
   Rebolo, R
   Serra-Ricart, M
AF Abbott, B. P.
   Abbott, R.
   Abbott, T. D.
   Acernese, F.
   Ackley, K.
   Adams, C.
   Adams, T.
   Addesso, P.
   Adhikari, R. X.
   Adya, V. B.
   Affeldt, C.
   Afrough, M.
   Agarwal, B.
   Agathos, M.
   Agatsuma, K.
   Aggarwal, N.
   Aguiar, O. D.
   Aiello, L.
   Ain, A.
   Ajith, P.
   Allen, B.
   Allen, G.
   Allocca, A.
   Altin, P. A.
   Amato, A.
   Ananyeva, A.
   Anderson, S. B.
   Anderson, W. G.
   Angelova, S. V.
   Antier, S.
   Appert, S.
   Arai, K.
   Araya, M. C.
   Areeda, J. S.
   Arnaud, N.
   Arun, K. G.
   Ascenzi, S.
   Ashton, G.
   Ast, M.
   Aston, S. M.
   Astone, P.
   Atallah, D. V.
   Aufmuth, P.
   Aulbert, C.
   AultO'Neal, K.
   Austin, C.
   Avila-Alvarez, A.
   Babak, S.
   Bacon, P.
   Bader, M. K. M.
   Bae, S.
   Baker, P. T.
   Baldaccini, F.
   Ballardin, G.
   Ballmer, S. W.
   Banagiri, S.
   Barayoga, J. C.
   Barclay, S. E.
   Barish, B. C.
   Barker, D.
   Barkett, K.
   Barone, F.
   Barr, B.
   Barsotti, L.
   Barsuglia, M.
   Barta, D.
   Bartlett, J.
   Bartos, I.
   Bassiri, R.
   Basti, N.
   Batch, J. C.
   Bawaj, M.
   Bayley, J. C.
   Bazzan, M.
   Becsy, B.
   Beer, C.
   Bejger, M.
   Belahcene, I.
   Bell, A. S.
   Berger, B. K.
   Bergmann, G.
   Bero, J. J.
   Berry, C. P. L.
   Bersanetti, D.
   Bertolini, A.
   Betzwieser, J.
   Bhagwat, S.
   Bhandare, R.
   Bilenko, I. A.
   Billingsley, G.
   Billman, C. R.
   Birch, J.
   Birney, R.
   Birnholtz, O.
   Biscans, S.
   Biscoveanu, S.
   Bisht, A.
   Bitossi, M.
   Biwer, C.
   Bizouard, A.
   Blackburn, J. K.
   Blackman, J.
   Blair, C. D.
   Blair, D. G.
   Blair, R. M.
   Bloemen, S.
   Bock, O.
   Bode, N.
   Boer, M.
   Bogaert, G.
   Bohe, A.
   Bondu, F.
   Bonilla, E.
   Bonnand, R.
   Boom, B. A.
   Bork, R.
   Boschi, V.
   Bose, S.
   Bossie, K.
   Bouffanais, Y.
   Bozzi, A.
   Bradaschia, C.
   Brady, P. R.
   Branchesi, M.
   Brau, J. E.
   Briant, T.
   Brillet, A.
   Brinkmann, M.
   Brisson, V.
   Brockill, R.
   Broida, J. E.
   Brooks, N. F.
   Brown, D. A.
   Brown, D. D.
   Brunett, S.
   Buchanan, C. C.
   Buikema, A.
   Bulik, H.
   Bulten, H. J.
   Buonanno, A.
   Buskulic, D.
   Buy, C.
   Byer, R. L.
   Cabero, M.
   Cadonati, L.
   Cagnoli, G.
   Cahillane, C.
   Bustillo, J. Calderon
   Callister, T. A.
   Calloni, E.
   Camp, J. B.
   Canepa, M.
   Canizares, P.
   Cannon, K. C.
   Cao, H.
   Cao, J.
   Capano, C. D.
   Capocasa, E.
   Carbognani, F.
   Caride, S.
   Carney, M. F.
   Diaz, J. Casanueva
   Casentini, C.
   Caudill, S.
   Cavaglia, M.
   Cavalier, F.
   Cavalieri, R.
   Cella, G.
   Cepeda, C. B.
   Cerda-Duran, P.
   Cerretani, G.
   Cesarini, E.
   Chamberlin, S. J.
   Chan, M.
   Chao, S.
   Charlton, P.
   Chase, E.
   Chassande-Mottin, E.
   Chatterjee, D.
   Chatziioannou, K.
   Cheeseboro, B. D.
   Chen, H. Y.
   Chen, X.
   Chen, Y.
   Cheng, H. -P.
   Chia, H.
   Chincarini, N.
   Chiummo, A.
   Chmiel, T.
   Cho, H. S.
   Cho, M.
   Chow, J. H.
   Christensen, N.
   Chu, Q.
   Chua, A. J. K.
   Chua, S.
   Chung, A. K. W.
   Chung, S.
   Ciani, G.
   Ciolfi, R.
   Cirelli, C. E.
   Cirone, N.
   Clara, F.
   Clark, J. A.
   Clearwater, P.
   Cleva, F.
   Cocchieri, C.
   Coccia, E.
   Cohadon, P. -F.
   Cohen, D.
   Colla, A.
   Collette, C. G.
   Cominsky, L. R.
   Constancio, M., Jr.
   Conti, L.
   Cooper, S. J.
   Corban, P.
   Corbitt, T. R.
   Cordero-Carrion, I.
   Corley, K. R.
   Cornish, N.
   Corsi, A.
   Cortese, S.
   Costa, C. A.
   Coughlin, M. W.
   Coughlin, S. B.
   Coulon, J. -P.
   Countryman, S. T.
   Couvares, P.
   Covas, P. B.
   Cowan, E. E.
   Coward, D. M.
   Cowart, M. J.
   Coyne, D. C.
   Coyne, R.
   Creighton, J. D. E.
   Creighton, T. D.
   Cripe, J.
   Crowder, S. G.
   Cullen, T. J.
   Cumming, A.
   Cunningham, L.
   Cuoco, E.
   Dal Canton, T.
   Dalya, G.
   Danilishin, S. L.
   D'Antonio, S.
   Danzmann, K.
   Dasgupta, A.
   Costa, C. F. Da Silva
   Datrier, L. E. H.
   Dattilo, V.
   Dave, I.
   Davier, M.
   Davis, E. J.
   Daw, E. J.
   Day, B.
   De, S.
   DeBra, D.
   Degallaix, J.
   De laurentis, M.
   Deleglise, S.
   Del Pozzo, W.
   Demos, N.
   Denker, T.
   Dent, T.
   De Pietri, R.
   Dergachev, V.
   De Rosa, R.
   DeRosa, R. T.
   De Rossi, C.
   DeSalvo, R.
   de Verona, O.
   Devenson, J.
   Dhurancihar, S.
   Diaz, M. C.
   Di Fiore, L.
   Di Giovanni, M.
   Di Girolamo, T.
   Di Lieto, A.
   Di Pace, S.
   Di Palma, I.
   Di Renzo, F.
   Doctor, Z.
   Dolique, V.
   Donovan, F.
   Dooley, K. L.
   Doravari, S.
   Dorrington, I.
   Douglas, R.
   Alvarez, M. Dovale
   Downes, T. P.
   Drago, M.
   Dreissigacker, C.
   Driggers, J. C.
   Du, Z.
   Ducrot, M.
   Dupej, P.
   Dwyer, S. E.
   Edo, T. B.
   Edwards, M. C.
   Effler, N.
   Eggenstein, H. -B.
   Ehrens, P.
   Eichholz, J.
   Eikenberry, S. S.
   Eisenstein, R. A.
   Essick, R. C.
   Estevez, D.
   Etienne, Z. B.
   Etzel, T.
   Evans, M.
   Evans, T. M.
   Factourovich, M.
   Fafone, V.
   Fair, H.
   Fairhurst, S.
   Fan, X.
   Farinon, S.
   Farr, B.
   Farr, W. M.
   Fauchon-Jones, E. J.
   Favata, M.
   Fays, M.
   Fee, C.
   Fehrmann, H.
   Feicht, J.
   Fejer, M. M.
   Fernandez-Galiana, A.
   Ferrante, I.
   Ferreira, E. C.
   Ferrini, F.
   Fidecaro, F.
   Finstad, D.
   Fiori, I.
   Fiorucci, D.
   Fishbach, M.
   Fisher, R. P.
   Fitz-Axen, M.
   Flaminio, R.
   Fletcher, M.
   Fong, H.
   Font, J. A.
   Forsyth, P. W. F.
   Forsyth, S. S.
   Fournier, J. -D.
   Frasca, S.
   Frasconi, E.
   Frei, Z.
   Freise, A.
   Frey, R.
   Frey, V.
   Fries, E. M.
   Fritschel, P.
   Frolov, V. V.
   Fulda, P.
   Fyffe, M.
   Gabbard, H.
   Gadre, B. U.
   Gaebel, S. M.
   Gair, J. R.
   Gammaitoni, L.
   Ganija, M. R.
   Gaonkar, S. G.
   Garcia-Quiros, C.
   Garufi, F.
   Gateley, B.
   Gaudio, S.
   Gaur, G.
   Gayathril, V.
   Gehrels, N.
   Gemme, G.
   Genin, E.
   Gennai, A.
   George, D.
   George, J.
   Gergely, L.
   Germain, V.
   Ghonge, S.
   Ghosh, Abhirup
   Ghosh, Archisman
   Ghosh, S.
   Giaime, J. A.
   Giardina, K. D.
   Giazotto, A.
   Gill, K.
   Glover, L.
   Goetz, E.
   Goetz, R.
   Gomes, S.
   Goncharov, B.
   Gonzalez, G.
   Castro, J. M. Gonzalez
   Gopakumar, A.
   Gorodetsky, M. L.
   Gossan, S. E.
   Gosselin, M.
   Gouaty, R.
   Grado, A.
   Graef, C.
   Granata, M.
   Grant, A.
   Gras, S.
   Gray, C.
   Greco, G.
   Green, A. C.
   Gretarsson, E. M.
   Groot, P.
   Grote, H.
   Grunewald, S.
   Gruning, P.
   Guidi, G. M.
   Guo, X.
   Gupta, A.
   Gupta, M. K.
   Gushwa, K. E.
   Gustafson, E. K.
   Gustafson, R.
   Halim, O.
   Hall, B. R.
   Hall, E. D.
   Hamilton, E. Z.
   Hammond, G.
   Haney, M.
   Hanke, M. M.
   Hanks, J.
   Hanna, C.
   Hannam, M. D.
   Hannuksela, O. A.
   Hanson, J.
   Hardwick, I.
   Harms, J.
   Harry, G. M.
   Harry, I. W.
   Hart, M. J.
   Hester, C. -J.
   Haughian, K.
   Healy, J.
   Heidmann, N.
   Heintze, M. C.
   Heitmann, H.
   Hello, P.
   Hemming, G.
   Hendry, M.
   Heng, I. S.
   Hennig, J.
   Heptonstall, A. W.
   Heurs, M.
   Hild, S.
   Hinderer, T.
   Hoak, D.
   Hofman, D.
   Holt, K.
   Holz, D. E.
   Hopkins, P.
   Horst, C.
   Hough, J.
   Houston, E. A.
   Howell, E. J.
   Hreibi, A.
   Hu, Y. M.
   Huerta, E. A.
   Huet, D.
   Hughey, B.
   Husa, S.
   Huttner, S. H.
   Huynh-Dinh, T.
   Indik, N.
   Inta, R.
   Intini, G.
   Isa, H. N.
   Isac, J. -M.
   Isi, M.
   Iyer, B. R.
   Izumi, K.
   Jacqmin, T.
   Jani, K.
   Jaranowski, P.
   Jawahar, S.
   Jimenez-Forteza, F.
   Johnson, W. W.
   Jones, D. I.
   Jones, R.
   Jonker, R. J. G.
   Ju, L.
   Junker, J.
   Kalaghatgi, C. V.
   Kalogera, V.
   Kamai, B.
   Kandhasamy, S.
   Kang, G.
   Kanner, J. B.
   Kapadia, S. J.
   Karki, S.
   Karvinen, K. S.
   Kasprzack, M.
   Katolik, M.
   Katsavounidis, E.
   Katzman, W.
   Kaufer, S.
   Kawabe, K.
   Kefelian, E.
   Keitel, D.
   Kemball, A. J.
   Kennedy, R.
   Kent, C.
   Key, J. S.
   Khalili, F. Y.
   Khan, I.
   Khan, S.
   Khan, Z.
   Khazanov, E. A.
   Kijbunchoo, N.
   Kim, Chunglee
   Kim, J. C.
   Kim, K.
   Kim, W.
   Kim, W. S.
   Kim, Y. -M.
   Kimbrell, S. J.
   King, E. J.
   King, P. J.
   Kinley-Hanlon, M.
   Kirchhoff, R.
   Kissel, J. S.
   Kleybolte, L.
   Klimenko, S.
   Knowles, T. D.
   Koch, P.
   Koehlenbeck, S. M.
   Koley, S.
   Kondrashov, V.
   Kontos, A.
   Korobko, M.
   Korth, W. Z.
   Kowalska, I.
   Kozak, D. B.
   Kraemer, C.
   Kringel, V.
   Krishnan, B.
   Krolak, A.
   Kuehn, G.
   Kumar, P.
   Kumar, R.
   Kumar, S.
   Kuo, L.
   Kutynia, A.
   Kwang, S.
   Lackey, B. D.
   Lai, K. H.
   Landry, M.
   Lang, R. N.
   Lange, J.
   Lantz, B.
   Lanza, R. K.
   Lartaux-Vollard, N.
   Lasky, P. D.
   Laxen, M.
   Lazzarini, A.
   Lazzaro, C.
   Leaci, P.
   Leavey, S.
   Lee, C. H.
   Lee, H. K.
   Lee, H. M.
   Lee, H. W.
   Lee, K.
   Lehmann, J.
   Lenon, A.
   Leonardi, M.
   Leroy, N.
   Letendre, N.
   Levin, Y.
   Li, T. G. F.
   Linker, S. D.
   Littenberg, T. B.
   Liu, J.
   Liu, X.
   Lo, R. K. L.
   Lockerbie, N. N.
   London, L. T.
   Lord, J. E.
   Lorenzini, M.
   Loriette, V.
   Lormand, M.
   Losurdo, G.
   Lough, J. D.
   Lousto, C. O.
   Lovelace, G.
   Lueock, H.
   Lumaca, D.
   Lundgren, A. P.
   Lynch, R.
   Ma, Y.
   Macas, R.
   Macfoy, S.
   Machenschalk, B.
   Maclnnis, M.
   Macleod, D. M.
   Hernandez, I. Magana
   Magana-Sandoval, F.
   Zertuche, L. Magana
   Magee, R. M.
   Majorana, E.
   Maksimovic, I.
   Man, N.
   Mandic, V.
   Mangano, V.
   Mansell, G. L.
   Manske, M.
   Mantovani, M.
   Marchesoni, F.
   Marion, F.
   Marka, S.
   Marka, Z.
   Markakis, C.
   Markosyan, A. S.
   Markowitz, A.
   Maros, E.
   Marquina, A.
   Martelli, F.
   Martellini, L.
   Martin, I. W.
   Martin, R. M.
   Martynov, D. V.
   Mason, K.
   Massera, E.
   Masserot, A.
   Massinger, T. J.
   Masso-Reid, M.
   Mastrogiovanni, S.
   Matas, A.
   Matichard, F.
   Matone, L.
   Mavalvala, N.
   Mazumder, N.
   McCarthy, R.
   McClelland, D. E.
   McCormick, S.
   McCuller, L.
   McGuire, S. C.
   McIntyre, G.
   McIver, J.
   McManus, D. J.
   McNeill, L.
   McRae, T.
   McWilliams, S. T.
   Meacher, D.
   Meadors, G. D.
   Mehmet, M.
   Meidam, J.
   Mejuto-Villa, E.
   Melatos, A.
   Mendell, G.
   Mercer, R. A.
   Merilh, E. L.
   Merzougui, M.
   Meshkov, S.
   Messenger, C.
   Messick, C.
   Metzdorff, R.
   Meyers, P. M.
   Miao, H.
   Michel, C.
   Middleton, H.
   Mikhailov, E. E.
   Milano, L.
   Miller, A. L.
   Miller, B. B.
   Miller, J.
   Millhouse, M.
   Milovich-Goff, M. C.
   Minazzoli, O.
   Minenkov, Y.
   Ming, J.
   Mishra, C.
   Mitra, S.
   Mitrofanov, V. R.
   Mitselmakher, G.
   Mittleman, R.
   Moffa, D.
   Moggi, N.
   Mogushi, K.
   Mohan, M.
   Mohapatra, S. R. P.
   Montani, M.
   Moore, C. J.
   Moraru, D.
   Moreno, G.
   Morriss, S. R.
   Mours, B.
   Mow-Lowry, C. M.
   Mueller, G.
   Muir, A. W.
   Mukherjee, Arunava
   Mukherjee, D.
   Mukherjee, S.
   Mukund, N.
   Mullavey, A.
   Munch, J.
   Muniz, E. A.
   Muratore, M.
   Murray, P. G.
   Napier, K.
   Nardecchia, I.
   Naticchioni, L.
   Nayak, R. K.
   Neilson, J.
   Nelemans, G.
   Nelson, T. J. N.
   Nery, M.
   Neunzert, A.
   Nevin, L.
   Newport, J. M.
   Newton, G.
   Ng, K. K. Y.
   Nguyen, T. T.
   Nichols, D.
   Nielsen, A. B.
   Nissanke, S.
   Nitz, A.
   Noack, A.
   Nocera, F.
   Nolting, D.
   North, C.
   Nuttall, L. K.
   Oberling, J.
   O'Dea, G. D.
   Ogin, G. H.
   Oh, J. J.
   Oh, S. H.
   Ohme, F.
   Okada, M. A.
   Oliver, M.
   Oppermann, P.
   Oram, Richard J.
   O'Reilly, B.
   Ormiston, R.
   Ortega, L. F.
   O'Shaughnessy, R.
   Ossokine, S.
   Ottaway, D. J.
   Overmier, H.
   Owen, B. J.
   Pace, A. E.
   Page, J.
   Page, M. A.
   Pai, A.
   Pai, S. A.
   Palamos, J. R.
   Palashov, O.
   Palomba, C.
   Pal-Singh, A.
   Pan, Howard
   Pan, Huang-Wei
   Pang, B.
   Pang, P. T. H.
   Pankow, C.
   Pannarale, F.
   Pant, B. C.
   Paoletti, F.
   Paoli, A.
   Papa, M. A.
   Parida, A.
   Parker, W.
   Pascucci, D.
   Pasqualetti, A.
   Passaquieti, R.
   Passuello, D.
   Patil, M.
   Patricelli, B.
   Pearlstone, B. L.
   Pedraza, M.
   Pedurand, R.
   Pekowsky, L.
   Pele, A.
   Penn, S.
   Perez, C. J.
   Perreca, A.
   Perri, L. M.
   Pfeiffer, H. P.
   Phelps, M.
   Piccinni, O. J.
   Pichot, M.
   Piergiovanni, F.
   Pierro, V.
   Pillant, G.
   Pinard, L.
   Pinto, I. M.
   Pirello, M.
   Pitkin, M.
   Poe, M.
   Poggiani, R.
   Popolizio, P.
   Porter, E. K.
   Post, A.
   Powell, J.
   Prasad, J.
   Pratt, J. W. W.
   Pratten, G.
   Predoi, V.
   Prestegard, T.
   Prijatelj, M.
   Principe, M.
   Privitera, S.
   Prodi, G. A.
   Prokhorov, L. G.
   Puncken, O.
   Punturo, M.
   Puppo, P.
   Puerrer, M.
   Qi, H.
   Quetschke, V.
   Quintero, E. A.
   Quitzow-James, R.
   Raab, F. J.
   Rabeling, D. S.
   Radkins, H.
   Raffai, P.
   Raja, S.
   Rajan, C.
   Rajbhandari, B.
   Rakhmanov, M.
   Ramirez, K. E.
   Ramos-Buades, A.
   Rapagnani, P.
   Raymond, V.
   Razzano, M.
   Read, J.
   Regimbau, T.
   Rei, L.
   Reid, S.
   Reitze, D. H.
   Ren, W.
   Reyes, S. D.
   Ricci, F.
   Ricker, P. M.
   Rieger, S.
   Riles, K.
   Rizzo, M.
   Robertson, N. A.
   Robie, R.
   Robinet, F.
   Rocchi, A.
   Rolland, L.
   Rollins, J. G.
   Roma, V. J.
   Romano, J. D.
   Romano, R.
   Romel, C. L.
   Romie, J. H.
   Rosinska, D.
   Ross, M. P.
   Rowan, S.
   Ruediger, A.
   Ruggi, P.
   Rutins, G.
   Ryan, K.
   Sachdev, S.
   Sadecki, I.
   Sadeghian, L.
   Sakellariadou, M.
   Salconi, L.
   Saleem, M.
   Salemi, F.
   Samajdar, A.
   Sammut, L.
   Sampson, L. M.
   Sanchez, E. J.
   Sanchez, L. E.
   Sanchis-Gual, N.
   Sandberg, V.
   Sanders, J. R.
   Sassolas, B.
   Sathyaprakash, B. S.
   Saulson, P. R.
   Sauter, O.
   Savage, R. L.
   Sawadsky, A.
   Schale, P.
   Scheel, M.
   Schauer, J.
   Schmidt, J.
   Schmidt, P.
   Schnabel, R.
   Schofield, R. M. S.
   Schoenbeck, A.
   Schreiber, E.
   Schuette, D.
   Schulte, B. W.
   Schutz, B. F.
   Schwalbe, S. G.
   Scott, J.
   Scott, S. M.
   Seidel, E.
   Sellers, D.
   Sengupta, A. S.
   Sentenac, D.
   Sequino, V.
   Sergeev, A.
   Shaddock, D. A.
   Shaffer, T. J.
   Shah, A. A.
   Shahriar, M. S.
   Shaner, M. B.
   Shao, L.
   Shapiro, B.
   Shawhan, P.
   Shepard, A.
   Shoemaker, D. H.
   Shoemaker, D. M.
   Siellez, K.
   Siemens, X.
   Sieniawska, M.
   Sigg, D.
   Silva, A. D.
   Singer, L. P.
   Singh, A.
   Singhal, A.
   Sintes, A. M.
   Slagmolen, B. J. J.
   Smith, B.
   Smith, J. R.
   Smith, R. J. E.
   Somala, S.
   Son, E. J.
   Sonnenberg, J. N.
   Sorazu, B.
   Sorrentino, F.
   Souradeep, T.
   Spencer, A. P.
   Srivastava, A. K.
   Staats, K.
   Staley, A.
   Steer, D.
   Steinke, M.
   Steinlechner, J.
   Steinlechner, S.
   Steinmeyer, D.
   Stevenson, S. P.
   Stone, R.
   Stops, D. J.
   Strain, K. A.
   Stratta, G.
   Strigin, S. E.
   Strunk, A.
   Sturani, R.
   Stuver, A. L.
   Summerscales, T. Z.
   Sun, L.
   Sunil, S.
   Suresh, J.
   Sutton, P. J.
   Swinkels, B. L.
   Szczepanczyk, M. J.
   Tacca, M.
   Tait, S. C.
   Talbot, C.
   Talukder, D.
   Tanner, D. B.
   Tapai, M.
   Taracchini, A.
   Tasson, J. D.
   Taylor, J. A.
   Taylor, R.
   Tewari, S. V.
   Theeg, T.
   Thies, F.
   Thomas, E. G.
   Thomas, M.
   Thomas, P.
   Thorne, K. A.
   Thrane, E.
   Tiwari, S.
   Tiwari, V.
   Tokmakov, K. V.
   Toland, K.
   Tonelli, M.
   Tornasi, Z.
   Torres-Forne, N.
   Torrie, C. I.
   Toyra, D.
   Travasso, F.
   Traylor, G.
   Trinastic, J.
   Tringali, M. C.
   Trozzon, L.
   Tsang, K. W.
   Tse, M.
   Tso, R.
   Tsukada, L.
   Tsuna, D.
   Tuyenbayev, D.
   Ueno, K.
   Ugolini, D.
   Unnikrishnan, C. S.
   Urban, A. L.
   Usman, S. A.
   Vahlbruch, H.
   Vajente, G.
   Valdese, G.
   van Bakel, N.
   van Beuzekom, M.
   van den Brand, J. F. J.
   Van den Broeck, C.
   Vander-Hyde, D. C.
   van der Schaaf, L.
   van Heijningen, J. V.
   van Veggel, A. A.
   Vardaro, M.
   Varma, V.
   Vass, S.
   Vasuth, M.
   Vecchio, A.
   Vedovato, G.
   Veitch, J.
   Veitch, P. J.
   Venkateswara, K.
   Venugopalan, G.
   Verkindt, D.
   Vetrano, F.
   Vicere, A.
   Viets, A. D.
   Vinciguerra, S.
   Vine, D. J.
   Vinet, J. -Y.
   Vitale, S.
   Vo, T.
   Vocca, H.
   Vorvick, C.
   Vyatchanin, S. P.
   Wade, A. R.
   Wade, L. E.
   Wade, M.
   Walet, R.
   Walker, M.
   Wallace, L.
   Walsh, S.
   Wang, G.
   Wang, H.
   Wang, J. Z.
   Wang, W. H.
   Wang, Y. F.
   Ward, R. L.
   Warner, J.
   Was, M.
   Watchi, J.
   Weaver, B.
   Wei, L. -W.
   Weinert, M.
   Weinstein, A. J.
   Weiss, R.
   Wen, L.
   Wessel, E. K.
   Wessels, P.
   Westerweck, J.
   Westphal, T.
   Wette, K.
   Whelan, J. T.
   Whitcomb, S. E.
   Whiting, B. F.
   Whittle, C.
   Wilken, D.
   Williams, D.
   Williams, R. D.
   Williamson, A. R.
   Willis, J. L.
   Willke, B.
   Wimmer, M. H.
   Winkler, W.
   Wipfl, C. C.
   Wittel, H.
   Woan, G.
   Woehler, J.
   Wofford, J.
   Wong, K. W. K.
   Worden, J.
   Wright, J. L.
   Wu, D. S.
   Wysocki, D. M.
   Xiao, S.
   Yamamoto, H.
   Yancey, C. C.
   Yang, L.
   Yap, M. J.
   Yazback, M.
   Yu, Hang
   Yu, Haocun
   Yvert, M.
   Zadrozny, A.
   Zanolin, M.
   Zelenova, T.
   Zendri, J. -P
   Zevin, M.
   Zhang, L.
   Zhang, M.
   Zhang, T.
   Zhang, Y. -H.
   Zhao, C.
   Zhou, M.
   Zhou, Z.
   Zhu, S. J.
   Zhu, X. J.
   Zimmerman, A. B.
   Zucker, M. E.
   Zweizig, J.
   Foley, R. J.
   Coulter, D. A.
   Drout, M. R.
   Kasen, D.
   Kilpatrick, C. D.
   Madore, B. F.
   Murguia-Berthier, A.
   Pan, Y. -C.
   Piro, A. L.
   Prochaska, J. X.
   Ramirez-Ruiz, E.
   Rest, A.
   Rojas-Bravo, C.
   Shappee, B. J.
   Siebert, M. R.
   Simon, J. D.
   Ulloas, N.
   Annis, J.
   Soares-Santos, M.
   Brout, D.
   Scolnic, D.
   Diehl, H. T.
   Frieman, J.
   Berger, E.
   Alexander, K. D.
   Allam, S.
   Balbinot, E.
   Blanchard, P.
   Butler, R. E.
   Chornock, R.
   Cook, E. R.
   Cowpertwaite, P.
   Drlica-Wagner, A.
   Drout, M. R.
   Durret, F.
   Eftekhari, T.
   Finley, D. A.
   Fong, W.
   Fryer, C. L.
   Garcia-Bellido, J.
   Gill, M. S. S.
   Gruendl, R. A.
   Hanna, C.
   Hartley, W.
   Herner, K.
   Huterer, D.
   Kasen, D.
   Kessler, R.
   Li, T. S.
   Lin, H.
   Lopes, P. A. A.
   Lourenco, A. C. C.
   Margutti, R.
   Marriner, J.
   Marshall, J. L.
   Matheson, T.
   Medina, G. E.
   Metzger, B. D.
   Munoz, R. R.
   Muir, J.
   Nicholl, M.
   Nugent, P.
   Palmese, A.
   Paz-Chinchon, F.
   Quataert, E.
   Sako, M.
   Sauseda, M.
   Schlegel, D. J.
   Secco, L. F.
   Smith, N.
   Sobreira, F.
   Stebbins, A.
   Villar, V. A.
   Vivas, A. K.
   Wester, W.
   Williams, P. K. G.
   Yanny, B.
   Zenteno, A.
   Abbott, T. M. C.
   Abdalla, F. B.
   Bechtol, K.
   Benoit-Levy, A.
   Bertin, E.
   Bridle, S. L.
   Brooks, D.
   Buckley-Geer, E.
   Burke, D. L.
   Rosell, A. Carnero
   Kind, M. Carrasco
   Carretero, J.
   Castander, F. J.
   Cunha, C. E.
   D'Andrea, C. B.
   da Costa, L. N.
   Davis, C.
   DePoy, D. L.
   Desai, S.
   Dietrich, J. P.
   Estrada, J.
   Fernandez, E.
   Flaugher, B.
   Fosalba, P.
   Gaztanaga, E.
   Gerdes, D. W.
   Giannantonio, T.
   Goldstein, D. A.
   Gruen, D.
   Gutierrez, G.
   Hartley, W. G.
   Honscheid, K.
   Jain, B.
   James, D. J.
   Jeltema, T.
   Johnson, M. W. G.
   Kent, S.
   Krause, E.
   Kron, R.
   Kuehn, K.
   Kuhlmann, S.
   Kuropatkin, N.
   Lahav, O.
   Lima, M.
   Maia, M. A. G.
   March, M.
   Miller, C. J.
   Miquel, R.
   Neilsen, E.
   Nord, B.
   Ogando, R. L. C.
   Plazas, A. N.
   Romer, A. K.
   Roodman, A.
   Rykoff, E. S.
   Sanchez, E.
   Scarpine, V.
   Schubnell, M.
   Sevilla-Noarbe, I.
   Smith, M.
   Smith', R. C.
   Suchyta, E.
   Tarle, G.
   Thomas, D.
   Thomas, R. C.
   Troxel, M. A.
   Tucker, D. L.
   Vikram, V.
   Walker, A. R.
   Weller, J.
   Zhang, Y.
   Haislip, J. B.
   Kouprinov, V. V.
   Reichart, D. E.
   Tartaglia, L.
   Sand, D. J.
   Valenti, S.
   Yang, S.
   Arcavi, Iair
   Hosseinzadeh, Griffin
   Howell, D. Andrew
   McCully, Curtis
   Poznanski, Dovi
   Vasylyev, Sergiy
   Tanvir, N. R.
   Levan, N. J.
   Hjorth, J.
   Cano, Z.
   Copperwheat, C.
   de Ugarte-Postigo, A.
   Evans, P. A.
   Fynbo, J. P. U.
   Gonzalez-Fernandez, C.
   Greiner, J.
   Irwin, M.
   Lyman, J.
   Mandel, I.
   McMahon, R.
   Milvang-Jensen, B.
   O'Brien, P.
   Osborne, J. P.
   Perley, D. A.
   Pian, E.
   Palazzi, E.
   Rol, E.
   Rosetti, S.
   Rosswog, S.
   Rowlinson, A.
   Schulze, S.
   Steeghs, D. T. H.
   Thone, C. C.
   Ulaczyk, K.
   Watson, D.
   Wiersema, K.
   Lipunov, V. M.
   Gorbovskoy, E.
   Kornilov, V. G.
   Tyurina, N.
   Balanutsa, P.
   Vlasenko, D.
   Gorbunov, I.
   Podesta, R.
   Levato, H.
   Saffe, C.
   Buckley, D. A. H.
   Budnev, N. M.
   Gress, O.
   Yurkov, V.
   Rebolo, R.
   Serra-Ricart, M.
TI A gravitational-wave standard siren measurement of the Hubble constant
SO NATURE
LA English
DT Article
ID telescope key project; gamma-ray bursts; galaxy; density
AB On 17 August 2017, the Advanced LIGO(1) and Virgo(2) detectors observed the gravitational-wave event GW170817-a strong signal from the merger of a binary neutron-star system(3). Less than two seconds after the merger, a gamma-ray burst (GRB 170817A) was detected within a region of the sky consistent with the LIGO-Virgo-derived location of the gravitational-wave source(4-6). This sky region was subsequently observed by optical astronomy facilities(7), resulting in the identification(8-13) of an optical transient signal within about ten arcseconds of the galaxy NGC 4993. This detection of GW170817 in both gravitational waves and electromagnetic waves represents the first 'multi-messenger' astronomical observation. Such observations enable GW170817 to be used as a 'standard siren'(14-18) (meaning that the absolute distance to the source can be determined directly from the gravitational-wave measurements) to measure the Hubble constant. This quantity represents the local expansion rate of the Universe, sets the overall scale of the Universe and is of fundamental importance to cosmology. Here we report a measurement of the Hubble constant that combines the distance to the source inferred purely from the gravitational-wave signal with the recession velocity inferred from measurements of the redshift using the electromagnetic data. In contrast to previous measurements, ours does not require the use of a cosmic 'distance ladder'(19): the gravitational-wave analysis can be used to estimate the luminosity distance out to cosmological scales directly, without the use of intermediate astronomical distance measurements. We determine the Hubble constant to be about 70 kilometres per second per megaparsec. This value is consistent with existing measurements(20,21), while being completely independent of them. Additional standard siren measurements from future gravitational-wave sources will enable the Hubble constant to be constrained to high precision.
C1 [Abbott, B. P.; Abbott, R.; Adhikari, R. X.; Ananyeva, A.; Anderson, S. B.; Appert, S.; Arai, K.; Araya, M. C.; Barayoga, J. C.; Barish, B. C.; Berger, B. K.; Bertolini, A.; Billingsley, G.; Blackburn, J. K.; Bork, R.; Brooks, N. F.; Brunett, S.; Cahillane, C.; Callister, T. A.; Cepeda, C. B.; Coughlin, M. W.; Couvares, P.; Coyne, D. C.; Ehrens, P.; Eichholz, J.; Etzel, T.; Feicht, J.; Fries, E. M.; Gossan, S. E.; Gushwa, K. E.; Gustafson, E. K.; Heptonstall, A. W.; Isi, M.; Kamai, B.; Kanner, J. B.; Kondrashov, V.; Korth, W. Z.; Kozak, D. B.; Lazzarini, A.; Markowitz, A.; Maros, E.; Massinger, T. J.; McIntyre, G.; Meshkov, S.; Nevin, L.; Pedraza, M.; Quintero, E. A.; Rollins, J. G.; Sachdev, S.; Sanchez, E. J.; Sanchez, L. E.; Taylor, R.; Torrie, C. I.; Tso, R.; Urban, A. L.; Vajente, G.; Vass, S.; Venugopalan, G.; Wade, A. R.; Wallace, L.; Weinstein, A. J.; Whitcomb, S. E.; Williams, R. D.; Wipfl, C. C.; Xiao, S.; Yamamoto, H.; Zhang, L.; Zweizig, J.] CALTECH, LIGO, Pasadena, CA 91125 USA.
   [Abbott, T. D.; Austin, C.; Buchanan, C. C.; Corbitt, T. R.; Cripe, J.; Cullen, T. J.; Gonzalez, G.; Hardwick, I.; Johnson, W. W.; Kasprzack, M.; Valdese, G.] Louisiana State Univ, Baton Rouge, LA 70303 USA.
   [Acernese, F.; Barone, F.; Romano, R.] Univ Salerno, I-34084 Salerno, Italy.
   [Acernese, F.; Addesso, P.; Barone, F.; Blair, R. M.; Calloni, E.; De laurentis, M.; De Rosa, R.; Di Fiore, L.; Di Girolamo, T.; Garufi, F.; Grado, A.; Mejuto-Villa, E.; Milano, L.; Pierro, V.; Pinto, I. M.; Principe, M.; Romano, R.] INFN, Sez Napoli, Complesso Univ Monte St Angelo, I-80126 Naples, Italy.
   [Ackley, K.; Bartos, I.; Billman, C. R.; Cheng, H. -P.; Chia, H.; Ciani, G.; Costa, C. F. Da Silva; Eikenberry, S. S.; Fulda, P.; Goetz, R.; Klimenko, S.; Miller, A. L.; Mitselmakher, G.; Mueller, G.; Ortega, L. F.; Reitze, D. H.; Tanner, D. B.; Trinastic, J.; Whiting, B. F.; Yazback, M.] Univ Florida, Gainesville, FL 32611 USA.
   [Ackley, K.; Biscoveanu, S.; Goncharov, B.; Lasky, P. D.; Levin, Y.; McNeill, L.; Sammut, L.; Smith, R. J. E.; Talbot, C.; Thrane, E.; Whittle, C.; Zhu, X. J.] Monash Univ, Sch Phys & Astron, OzGrav, Clayton, Vic 3800, Australia.
   [Adams, C.; Aston, S. M.; Betzwieser, J.; Birch, J.; Bossie, K.; Corban, P.; Cowart, M. J.; DeRosa, R. T.; Effler, N.; Evans, T. M.; Fyffe, M.; Giaime, J. A.; Giardina, K. D.; Hanson, J.; Heintze, M. C.; Holt, K.; Huynh-Dinh, T.; Kandhasamy, S.; Laxen, M.; Lormand, M.; McCormick, S.; Mullavey, A.; Nelson, T. J. N.; Nolting, D.; Oram, Richard J.; O'Reilly, B.; Overmier, H.; Pele, A.; Romie, J. H.; Sellers, D.; Smith, B.; Stuver, A. L.; Thomas, M.; Thorne, K. A.; Traylor, G.] LIGO Livingston Observ, Livingston, LA 70754 USA.
   [Adams, T.; Bonnand, R.; Buskulic, D.; Ducrot, M.; Estevez, D.; Germain, V.; Gouaty, R.; Letendre, N.; Marion, F.; Masserot, A.; Mours, B.; Rolland, L.; Verkindt, D.; Was, M.; Yvert, M.] Univ Savoie Mt Blanc, LAPP, CNRS IN2P3, F-74941 Annecy, France.
   [Addesso, P.; Mejuto-Villa, E.; Pierro, V.; Pinto, I. M.; Principe, M.] Univ Sannio Benevento, I-82100 Benevento, Italy.
   [Adya, V. B.; Affeldt, C.; Allen, B.; Ashton, G.; Aulbert, C.; Beer, C.; Bergmann, G.; Birnholtz, O.; Bock, O.; Bode, N.; Brinkmann, M.; Cabero, M.; Capano, C. D.; Danilishin, S. L.; Danzmann, K.; Denker, T.; Dent, T.; de Verona, O.; Doravari, S.; Drago, M.; Dreissigacker, C.; Eggenstein, H. -B.; Fehrmann, H.; Grote, H.; Hanke, M. M.; Heurs, M.; Hu, Y. M.; Indik, N.; Junker, J.; Karvinen, K. S.; Khan, S.; Kirchhoff, R.; Koch, P.; Koehlenbeck, S. M.; Kraemer, C.; Kringel, V.; Krishnan, B.; Kuehn, G.; Lehmann, J.; Lough, J. D.; Lueock, H.; Lundgren, A. P.; Machenschalk, B.; Meadors, G. D.; Mehmet, M.; Mukherjee, Arunava; Nery, M.; Nielsen, A. B.; Nitz, A.; Noack, A.; Ohme, F.; Oppermann, P.; Papa, M. A.; Post, A.; Prijatelj, M.; Puncken, O.; Rieger, S.; Ruediger, A.; Salemi, F.; Schmidt, J.; Schreiber, E.; Schuette, D.; Schulte, B. W.; Schutz, B. F.; Singh, A.; Steinke, M.; Steinmeyer, D.; Theeg, T.; Thies, F.; Walsh, S.; Wei, L. -W.; Weinert, M.; Wessels, P.; Westerweck, J.; Westphal, T.; Wilken, D.; Willke, B.; Wimmer, M. H.; Winkler, W.; Wittel, H.; Woehler, J.; Wu, D. S.; Zhu, S. J.] Albert Einstein Inst, Max Planck Inst Gravitat Phys, D-30167 Hannover, Germany.
   [Afrough, M.; Cavaglia, M.; Cocchieri, C.; Dooley, K. L.; Mogushi, K.] Univ Mississippi, University, MS 38677 USA.
   [Agarwal, B.; Allen, G.; George, D.; Huerta, E. A.; Katolik, M.; Kemball, A. J.; Markakis, C.; Ren, W.; Ricker, P. M.; Seidel, E.; Wessel, E. K.] Univ Illinois, NCSA, Urbana, IL 61301 USA.
   [Agathos, M.; Chua, A. J. K.; Moore, C. J.] Univ Cambridge, Cambridge CB2 1TN, England.
   [Agatsuma, K.; Bader, M. K. M.; Boom, B. A.; Bulten, H. J.; Caudill, S.; Ghosh, Archisman; Ghosh, S.; Jonker, R. J. G.; Koley, S.; Meidam, J.; Nelemans, G.; Nissanke, S.; Tacca, M.; Tsang, K. W.; van Bakel, N.; van Beuzekom, M.; van den Brand, J. F. J.; Van den Broeck, C.; van der Schaaf, L.; van Heijningen, J. V.; Walet, R.] Nikhef, Sci Pk, NL-1098 XG Amsterdam, Netherlands.
   [Aggarwal, N.; Barsotti, L.; Biscans, S.; Buikema, A.; Demos, N.; Donovan, F.; Eisenstein, R. A.; Essick, R. C.; Evans, M.; Fernandez-Galiana, A.; Fritschel, P.; Gras, S.; Hall, E. D.; Katsavounidis, E.; Kontos, A.; Lanza, R. K.; Lynch, R.; Maclnnis, M.; Martynov, D. V.; Mason, K.; Matichard, F.; Mavalvala, N.; McCuller, L.; Miller, J.; Mittleman, R.; Mohapatra, S. R. P.; Shoemaker, D. H.; Tse, M.; Vitale, S.; Weiss, R.; Yu, Hang; Yu, Haocun; Zucker, M. E.] MIT, LIGO, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Aguiar, O. D.; Constancio, M., Jr.; Costa, C. A.; Ferreira, E. C.; Okada, M. A.; Silva, A. D.] Inst Nacl Pesquisas Espaciais, BR-12227010 Sao Jose Dos Campos, SP, Brazil.
   [Aiello, L.; Branchesi, M.; Coccia, E.; De laurentis, M.; Fafone, V.; Halim, O.; Harms, J.; Khan, I.; Lorenzini, M.; Sequino, V.; Tiwari, S.; Wang, G.] GSSI, I-67100 Laquila, Italy.
   [Aiello, L.; Branchesi, M.; Coccia, E.; Halim, O.; Harms, J.; Lorenzini, M.] INFN, Lab Nazl Gran Sasso, I-67100 Laquila, Italy.
   [Ain, A.; Bose, S.; Dhurancihar, S.; Gadre, B. U.; Gaonkar, S. G.; Mitra, S.; Mukund, N.; Parida, A.; Prasad, J.; Souradeep, T.; Suresh, J.] Interunivers Ctr Astron & Astrophys, Pune 411007, Maharashtra, India.
   [Ajith, P.; Ghosh, Abhirup; Ghosh, Archisman; Iyer, B. R.; Kumar, S.] Tata Inst Fundamental Res, Int Ctr Theoret Sci, Bengaluru 560039, India.
   [Allen, B.; Anderson, W. G.; Brady, P. R.; Brockill, R.; Caudill, S.; Chatterjee, D.; Creighton, J. D. E.; Downes, T. P.; Ghosh, S.; Horst, C.; Kapadia, S. J.; Kwang, S.; Liu, X.; Hernandez, I. Magana; Manske, M.; McIver, J.; Mercer, R. A.; Mukherjee, D.; Papa, M. A.; Poe, M.; Prestegard, T.; Qi, H.; Sadeghian, L.; Shepard, A.; Siemens, X.; Sonnenberg, J. N.; Ueno, K.; Viets, A. D.; Walsh, S.] Univ Wisconsin Milwaukee, Milwaukee, WI 53201 USA.
   [Allen, B.; Aufmuth, P.; Bisht, A.; Danilishin, S. L.; Danzmann, K.; Heurs, M.; Kaufer, S.; Lueock, H.; Schuette, D.; Singh, A.; Vahlbruch, H.; Wei, L. -W.; Willke, B.; Wittel, H.] Leibniz Univ Hannover, D-30167 Hannover, Germany.
   [Allocca, A.; Basti, N.; Cerretani, G.; Del Pozzo, W.; Di Lieto, A.; Di Renzo, F.; Ferrante, I.; Fidecaro, F.; Castro, J. M. Gonzalez; Passaquieti, R.; Poggiani, R.; Razzano, M.; Tonelli, M.] Univ Pisa, I-56127 Pisa, Italy.
   [Allocca, A.; Basti, N.; Bitossi, M.; Boschi, V.; Bradaschia, C.; Cella, G.; Cerretani, G.; Del Pozzo, W.; Di Lieto, A.; Di Renzo, F.; Ferrante, I.; Fidecaro, F.; Frasconi, E.; Gennai, A.; Giazotto, A.; Castro, J. M. Gonzalez; Losurdo, G.; Moggi, N.; Paoletti, F.; Passaquieti, R.; Passuello, D.; Patricelli, B.; Poggiani, R.; Razzano, M.; Tonelli, M.; Trozzon, L.] INFN, Sez Pisa, I-56127 Pisa, Italy.
   [Altin, P. A.; Chow, J. H.; Forsyth, P. W. F.; Kijbunchoo, N.; Mansell, G. L.; Manske, M.; McClelland, D. E.; McManus, D. J.; McRae, T.; Nguyen, T. T.; Rabeling, D. S.; Scott, S. M.; Shaddock, D. A.; Slagmolen, B. J. J.; Ward, R. L.; Wette, K.; Yap, M. J.] Australian Natl Univ, OzGrav, Canberra, ACT 0200, Australia.
   [Amato, A.; Cagnoli, G.; Degallaix, J.; De Rossi, C.; Dolique, V.; Flaminio, R.; Granata, M.; Hofman, D.; Michel, C.; Pedurand, R.; Pinard, L.; Sassolas, B.] CNRS IN2P3, LMA, F-69622 Villeurbanne, France.
   [Angelova, S. V.; Devenson, J.; Macfoy, S.; Rutins, G.; Vine, D. J.; Matheson, T.] Univ West Scotland, SUPA, Paisley PA1 2BE, Renfrew, Scotland.
   [Antier, S.; Arnaud, N.; Belahcene, I.; Bizouard, A.; Brisson, V.; Diaz, J. Casanueva; Cavalier, F.; Cohen, D.; Davier, M.; Frey, V.; Gruning, P.; Hello, P.; Huet, D.; Lartaux-Vollard, N.; Leroy, N.; Robinet, F.] Univ Paris Sud, Univ Paris Saclay, CNRS IN2P3, LAL, F-91393 Orsay, France.
   [Areeda, J. S.; Avila-Alvarez, A.; Cullen, T. J.; Lovelace, G.; Read, J.; Smith, J. R.; Walker, M.] Calif State Univ Fullerton, Fullerton, CA 92831 USA.
   [Arnaud, N.; Ballardin, G.; Bitossi, M.; Boschi, V.; Bozzi, A.; Carbognani, F.; Cavalieri, R.; Chiummo, A.; Cortese, S.; Cuoco, E.; Dattilo, V.; De Rossi, C.; Ferrini, F.; Fiori, I.; Genin, E.; Gosselin, M.; Hemming, G.; Hoak, D.; Mantovani, M.; Mohan, M.; Nocera, F.; Paoli, A.; Pasqualetti, A.; Pillant, G.; Popolizio, P.; Ruggi, P.; Salconi, L.; Sentenac, D.; Swinkels, B. L.; Travasso, F.; Zelenova, T.] EGO, I-56021 Cascina, Italy.
   [Arun, K. G.] Chennai Math Inst, Chennai 603103, Tamil Nadu, India.
   [Ascenzi, S.; Casentini, C.; Fafone, V.; Lumaca, D.; Nardecchia, I.; Sequino, V.] Univ Roma Tor Vergata, I-00133 Rome, Italy.
   [Ascenzi, S.; Casentini, C.; Cesarini, E.; D'Antonio, S.; Fafone, V.; Khan, I.; Lumaca, D.; Minenkov, Y.; Nardecchia, I.; Rocchi, A.; Sequino, V.] INFN, Sez Roma Tor Vergata, I-00133 Rome, Italy.
   [Ast, M.; Kleybolte, L.; Korobko, M.; Pal-Singh, A.; Sawadsky, A.; Schnabel, R.; Schoenbeck, A.; Steinlechner, J.; Steinlechner, S.; Smith, N.] Univ Hamburg, D-22761 Hamburg, Germany.
   [Astone, P.; Colla, A.; Di Pace, S.; Di Palma, I.; Frasca, S.; Intini, G.; Leaci, P.; Majorana, E.; Mastrogiovanni, S.; Miller, A. L.; Naticchioni, L.; Palomba, C.; Piccinni, O. J.; Puppo, P.; Rapagnani, P.; Ricci, F.; Singhal, A.] INFN, Sez Roma, I-00185 Rome, Italy.
   [Atallah, D. V.; Dorrington, I.; Fairhurst, S.; Fauchon-Jones, E. J.; Fays, M.; Gomes, S.; Hamilton, E. Z.; Hannam, M. D.; Hopkins, P.; Kalaghatgi, C. V.; Kent, C.; London, L. T.; Macas, R.; Macleod, D. M.; Muir, A. W.; North, C.; Nuttall, L. K.; Pannarale, F.; Predoi, V.; Sathyaprakash, B. S.; Schutz, B. F.; Sutton, P. J.; Tiwari, V.; Usman, S. A.] Cardiff Univ, Cardiff CF24 3AA, S Glam, Wales.
   [AultO'Neal, K.; Gaudio, S.; Gill, K.; Gretarsson, E. M.; Hughey, B.; Muratore, M.; Pratt, J. W. W.; Schwalbe, S. G.; Staats, K.; Szczepanczyk, M. J.; Zanolin, M.] Embry Riddle Aeronaut Univ, Prescott, AZ 86301 USA.
   [Babak, S.; Bohe, A.; Buonanno, A.; Dergachev, V.; Eggenstein, H. -B.; Grunewald, S.; Harry, I. W.; Lackey, B. D.; Meadors, G. D.; Ming, J.; Ossokine, S.; Papa, M. A.; Pfeiffer, H. P.; Privitera, S.; Puerrer, M.; Raymond, V.; Shao, L.; Singh, A.; Taracchini, A.; Walsh, S.; Zhu, S. J.] Albert Einstein Inst, Max Planck Inst Gravitat Phys, D-14476 Potsdam, Germany.
   [Bacon, P.; Barsuglia, M.; Bouffanais, Y.; Buy, C.; Capocasa, E.; Chassande-Mottin, E.; Fiorucci, D.; Porter, E. K.; Steer, D.] Univ Paris Diderot, AstroParticule & Cosmol, CNRS IN2P3, CEA Irfu,Observ Paris,Sorbonne Paris Cite, F-75205 Paris, France.
   [Bae, S.; Kang, G.] Korea Inst Sci & Technol Informat, Daejeon 34141, South Korea.
   [Baker, P. T.; Cheeseboro, B. D.; Etienne, Z. B.; Knowles, T. D.; Lenon, A.; McWilliams, S. T.] West Virginia Univ, Morgantown, WV 26506 USA.
   [Baldaccini, F.; Gammaitoni, L.; Vocca, H.] Univ Perugia, I-06123 Perugia, Italy.
   [Baldaccini, F.; Bawaj, M.; Marchesoni, F.; Punturo, M.; Travasso, F.; Vocca, H.] INFN, Sez Perugia, I-06123 Perugia, Italy.
   [Ballmer, S. W.; Bhagwat, S.; Biwer, C.; Brown, D. A.; Davis, E. J.; De, S.; Fair, H.; Finstad, D.; Fisher, R. P.; Lord, J. E.; Magana-Sandoval, F.; Zertuche, L. Magana; Muniz, E. A.; Pekowsky, L.; Reyes, S. D.; Sanders, J. R.; Saulson, P. R.; Vander-Hyde, D. C.; Vo, T.] Syracuse Univ, Syracuse, NY 13244 USA.
   [Fitz-Axen, M.; Hendry, M.; Matas, A.; Meyers, P. M.; Ormiston, R.] Univ Minnesota, Minneapolis, MN 55455 USA.
   [Barclay, S. E.; Barr, B.; Bayley, J. C.; Bell, A. S.; Bersanetti, D.; Chan, M.; Cumming, A.; Cunningham, L.; Datrier, L. E. H.; Douglas, R.; Dupej, P.; Fletcher, M.; Gabbard, H.; Graef, C.; Grant, A.; Hammond, G.; Hart, M. J.; Haughian, K.; Heng, I. S.; Hennig, J.; Hild, S.; Hough, J.; Houston, E. A.; Huttner, S. H.; Isa, H. N.; Jones, R.; Keitel, D.; Leavey, S.; Lee, K.; Mangano, V.; Martin, I. W.; Masso-Reid, M.; Messenger, C.; Murray, P. G.; Newton, G.; Pascucci, D.; Pearlstone, B. L.; Phelps, M.; Pitkin, M.; Powell, J.; Robertson, N. A.; Robie, R.; Rowan, S.; Scott, J.; Sorazu, B.; Spencer, A. P.; Steinlechner, J.; Strain, K. A.; Tait, S. C.; Toland, K.; Tornasi, Z.; van Veggel, A. A.; Veitch, J.; Williams, D.; Woan, G.; Wright, J. L.; Zhang, T.] Univ Glasgow, SUPA, Glasgow G12 3QQ, Lanark, Scotland.
   LIGO Hanford Observ, Richland, WA 99352 USA.
   [Barkett, K.; Blackman, J.; Chen, Y.; Ma, Y.; Pang, B.; Scheel, M.; Varma, V.] CALTECH, CaRT, Pasadena, CA 91125 USA.
   [Barta, D.; Vasuth, M.] RMKI, Wigner RCP, Konkoly Thege Miklos Ut 29-33, H-1121 Budapest, Hungary.
   [Bartos, I.; Corley, K. R.; Countryman, S. T.; Di Girolamo, T.; Factourovich, M.; Marka, S.; Marka, Z.; Matone, L.; Staley, A.] Columbia Univ, New York, NY 10027 USA.
   [Bassiri, R.; Bonilla, E.; Byer, R. L.; Cirelli, C. E.; DeBra, D.; Fejer, M. M.; Lantz, B.; Markosyan, A. S.; Shapiro, B.] Stanford Univ, Stanford, CA 94305 USA.
   [Bawaj, M.; Marchesoni, F.] Univ Camerino, Dipartimento Fis, I-62032 Camerino, Italy.
   [Bazzan, M.; Ciani, G.; Vardaro, M.] Univ Padua, Dipartimento Fis & Astron, I-35131 Padua, Italy.
   [Bazzan, M.; Ciani, G.; Conti, L.; Lazzaro, C.; Vardaro, M.; Vedovato, G.; Zendri, J. -P] INFN, Sez Padova, I-35131 Padua, Italy.
   [Becsy, B.; Dalya, G.; Frei, Z.; Raffai, P.] Eotvos Lorand Univ, Inst Phys, Pazmany Peter Setany 1-A, H-1117 Budapest, Hungary.
   [Bejger, M.; Rosinska, D.; Sieniawska, M.; James, D. J.] Polish Acad Sci, Nicolaus Copernicus Astron Ctr, PL-00716 Warsaw, Poland.
   [Bero, J. J.; Healy, J.; Lange, J.; Lousto, C. O.; O'Shaughnessy, R.; Rizzo, M.; Whelan, J. T.; Wofford, J.; Wysocki, D. M.; Zhang, Y. -H.] Rochester Inst Technol, Rochester, NV 14623 USA.
   [Berry, C. P. L.; Cooper, S. J.; Del Pozzo, W.; Alvarez, M. Dovale; Farr, W. M.; Freise, A.; Gaebel, S. M.; Green, A. C.; Miao, H.; Middleton, H.; Mow-Lowry, C. M.; Stevenson, S. P.; Stops, D. J.; Thomas, E. G.; Toyra, D.; Vecchio, A.; Vinciguerra, S.; Wang, H.] Univ Birmingham, Birmingham B15 2TT, W Midlands, England.
   [Canepa, M.; Chincarini, N.; Cirone, N.; Farinon, S.; Gemme, G.; Rei, L.; Sorrentino, F.] INFN, Sez Genova, I-16146 Genoa, Italy.
   [Bhandare, R.; Dave, I.; George, J.; Pai, S. A.; Pant, B. C.; Raja, S.; Rajan, C.] RRCAT, Indore 452013, MP, India.
   [Bilenko, I. A.; Gorodetsky, M. L.; Khalili, F. Y.; Mitrofanov, V. R.; Prokhorov, L. G.; Strigin, S. E.; Vyatchanin, S. P.] Lomonosov Moscow State Univ, Fac Phys, Moscow 119991, Russia.
   [Birney, R.; Jawahar, S.; Lockerbie, N. N.; Reid, S.; Tokmakov, K. V.] Univ Strathclyde, SUPA, Glasgow G1 1XQ, Lanark, Scotland.
   [Biscoveanu, S.; Chamberlin, S. J.; Gupta, A.; Hanna, C.; Magee, R. M.; Meacher, D.; Messick, C.; Pace, A. E.; Sathyaprakash, B. S.; Wang, J. Z.] Penn State Univ, University Pk, PA 16802 USA.
   [Blair, C. D.; Blair, D. G.; Chen, X.; Chu, Q.; Chung, S.; Coward, D. M.; Howell, E. J.; Ju, L.; Liu, J.; Page, M. A.; Wen, L.; Zhao, C.] Univ Western Australia, OzGrav, Crawley, WA 6009, Australia.
   [Bloemen, S.; Canizares, P.; Ghosh, S.; Groot, P.; Hinderer, T.; Nelemans, G.; Nichols, D.; Nissanke, S.; Schmidt, P.; Williamson, A. R.] Radboud Univ Nijmegen, Dept Astrophys, IMAPP, POB 9010, NL-6500 GL Nijmegen, Netherlands.
   [Boer, M.; Bogaert, G.; Brillet, A.; Christensen, N.; Cleva, F.; Coulon, J. -P.; Fournier, J. -D.; Heitmann, H.; Hreibi, A.; Kefelian, E.; Man, N.; Martellini, L.; Merzougui, M.; Minazzoli, O.; Pichot, M.; Regimbau, T.; Vinet, J. -Y.] CNRS, Observ Cote Azur, CS 34229, Artemis Univ Cote Azur, F-06304 Nice, France.
   [Bondu, F.] Univ Rennes 1, CNRS, Inst FOTON, Rennes, France.
   [Bose, S.; Hall, B. R.; Mazumder, N.] Washington State Univ, Pullman, WA 99164 USA.
   [Brau, J. E.; Frey, R.; Karki, S.; Palamos, J. R.; Quitzow-James, R.; Roma, V. J.; Schale, P.; Schofield, R. M. S.; Talukder, D.] Univ Oregon, Eugene, OR 97403 USA.
   [Briant, T.; Chua, S.; Cohadon, P. -F.; Deleglise, S.; Heidmann, N.; Isac, J. -M.; Jacqmin, T.; Metzdorff, R.] ENS PSL Res Univ, Coll France, UPMC Sorbonne Univ, Lab Kastler Brossel,CNRS, F-75005 Paris, France.
   [Broida, J. E.; Christensen, N.; Coughlin, M. W.; Edwards, M. C.; Tasson, J. D.] Carleton Coll, Northfield, MN 55057 USA.
   [Brown, D. D.; Cao, H.; Ganija, M. R.; Kim, W.; King, E. J.; Munch, J.; Ottaway, D. J.; Veitch, P. J.] Univ Adelaide, OzGrav, Adelaide, SA 5005, Australia.
   [Bulik, H.; Kowalska, I.] Warsaw Univ, Astron Observ, PL-00478 Warsaw, Poland.
   [Bulten, H. J.; van den Brand, J. F. J.] Vrije Univ Amsterdam, NL-1081 HV Amsterdam, Netherlands.
   [Buonanno, A.; Cho, M.; Shawhan, P.; Yancey, C. C.] Univ Maryland, College Pk, MD 20742 USA.
   [Cadonati, L.; Bustillo, J. Calderon; Clark, J. A.; Cowan, E. E.; Day, B.; Forsyth, S. S.; Ghonge, S.; Jani, K.; Kimbrell, S. J.; Napier, K.; Shoemaker, D. M.; Siellez, K.] Georgia Inst Technol, Ctr Relativist Astrophys, Atlanta, GA 30332 USA.
   [Cagnoli, G.] Univ Claude Bernard Lyon 1, F-69622 Villeurbanne, France.
   [Calloni, E.; De Rosa, R.; Di Girolamo, T.; Garufi, F.; Milano, L.] Univ Napoli Federico II, Complesso Univ Monte St Angelo, I-80126 Naples, Italy.
   [Camp, J. B.; Dal Canton, T.; Gehrels, N.; Singer, L. P.] NASA, Goddard Space Flight Ctr, Greenbelt, MD 20771 USA.
   [Canepa, M.; Cirone, N.] Univ Genoa, Dipartimento Fis, I-16146 Genoa, Italy.
   [Cannon, K. C.; Tsukada, L.; Tsuna, D.] Univ Tokyo, RESCEU, Tokyo 1130033, Japan.
   [Cao, J.; Du, Z.; Fan, X.; Guo, X.] Tsinghua Univ, Beijing 100084, Peoples R China.
   [Caride, S.; Corsi, A.; Coyne, R.; Inta, R.; Owen, B. J.; Rajbhandari, B.] Texas Tech Univ, Lubbock, TX 79409 USA.
   [Cannon, K. C.; Tsukada, L.; Tsuna, D.] Kenyon Coll, Gambier, OH 43022 USA.
   [Cerda-Duran, P.; Font, J. A.; Sanchis-Gual, N.; Torres-Forne, N.] Univ Valencia, Dept Astron & Astrofis, E-46100 Burjassot, Spain.
   [Cesarini, E.] Museo Stor Fis & Ctr Studi Ric Enrico Fermi, I-00184 Rome, Italy.
   [Chao, S.; Kuo, L.; Pan, Howard; Pan, Huang-Wei] Natl Tsing Hua Univ, Hsinchu 30013, Taiwan.
   [Charlton, P.] Charles Sturt Univ, Wagga Wagga, NSW 2678, Australia.
   [Chase, E.; Coughlin, S. B.; Kalogera, V.; Miller, B. B.; Pankow, C.; Perri, L. M.; Sampson, L. M.; Schauer, J.; Shahriar, M. S.; Zevin, M.; Zhou, M.; Zhou, Z.] Northwestern Univ, CIERA, Evanston, IL 60208 USA.
   [Chatziioannou, K.; Fong, H.; Hester, C. -J.; Kumar, P.; Pfeiffer, H. P.; Zimmerman, A. B.] Univ Toronto, Canadian Inst Theoret Astrophys, Toronto, ON M5S 3H8, Canada.
   [Cho, H. S.; Kim, Y. -M.; Lee, C. H.] Pusan Natl Univ, Busan 46241, South Korea.
   [Chung, A. K. W.; Hannuksela, O. A.; Kim, K.; Lai, K. H.; Li, T. G. F.; Lo, R. K. L.; Ng, K. K. Y.; Pang, P. T. H.; Wang, Y. F.; Wong, K. W. K.] Chinese Univ Hong Kong, Shatin, Hong Kong, Peoples R China.
   [Ciolfi, R.] INAF, Osservatorio Astron Padova, I-35122 Padua, Italy.
   [Ciolfi, R.; Di Giovanni, M.; Leonardi, M.; Perreca, A.; Prodi, G. A.; Tiwari, S.; Tringali, M. C.] INFN, Trento Inst Fundamental Phys & Applicat, I-38123 Povo, Italy.
   [Clearwater, P.; Melatos, A.; Sun, L.] Univ Melbourne, OzGrav, Parkville, Vic 3010, Australia.
   [Colla, A.; Di Pace, S.; Di Palma, I.; Frasca, S.; Intini, G.; Leaci, P.; Miller, A. L.; Naticchioni, L.; Piccinni, O. J.; Rapagnani, P.; Ricci, F.] Univ Roma Sapienza, I-00185 Rome, Italy.
   [Collette, C. G.; Watchi, J.] Univ Libre Bruxelles, B-1050 Brussels, Belgium.
   [Cominsky, L. R.] Sonoma State Univ, Rohnert Pk, CA 94928 USA.
   [Cordero-Carrion, I.; Marquina, A.] Univ Valencia, Dept Matemat, E-46100 Burjassot, Spain.
   [Cornish, N.; Millhouse, M.] Montana State Univ, Bozeman, MT 59717 USA.
   [Covas, P. B.; Garcia-Quiros, C.; Husa, S.; Jimenez-Forteza, F.; Oliver, M.; Pratten, G.; Ramos-Buades, A.; Sintes, A. M.] Univ Illes Balears, IAC3 IEEC, E-07122 Palma de Mallorca, Spain.
   [Creighton, T. D.; Diaz, M. C.; Morriss, S. R.; Mukherjee, S.; Quetschke, V.; Rakhmanov, M.; Ramirez, K. E.; Romano, J. D.; Stone, R.; Tuyenbayev, D.; Wang, W. H.] Univ Texas Rio Grande Valley, Brownsville, TX 78520 USA.
   [Crowder, S. G.] Bellevue Coll, Bellevue, WA 98007 USA.
   [Daw, E. J.; Edo, T. B.; Kennedy, R.; Massera, E.] Inst Plasma Res, Bhat 382423, Gandhinagar, India.
   [Daw, E. J.; Edo, T. B.; Kennedy, R.; Massera, E.] Univ Sheffield, Sheffield S10 2TN, S Yorkshire, England.
   [De Pietri, R.] Univ Parma, Dipartimento Sci Matemat Fis & Informat, I-43124 Parma, Italy.
   [De Pietri, R.] INFN, Sez Milano Bicocca, Grp Coll Parma, I-43124 Parma, Italy.
   [DeSalvo, R.; Glover, L.; Linker, S. D.; Milovich-Goff, M. C.; Neilson, J.; O'Dea, G. D.; Shaner, M. B.] Calif State Univ Los Angeles, 5151 State Univ Dr, Los Angeles, CA 90032 USA.
   [Favata, M.; Martin, R. M.] Montclair State Univ, Montclair, NJ 07043 USA.
   [Flaminio, R.] Natl Astron Observ Japan, 2-21-1 Osawa, Mitaka, Tokyo 1313588, Japan.
   [Font, J. A.] Univ Valencia, Observ Astron, E-46980 Paterna, Spain.
   [Gair, J. R.] Univ Edinburgh, Sch Math, Edinburgh EH9 3FD, Midlothian, Scotland.
   [Gaur, G.] Univ & Inst Adv Res, Koba Inst Area, Gandhinagar 382007, Gujarat, India.
   [Gayathril, V.; Pai, A.; Saleem, M.] IISER TVM, CET Campus, Trivandrum 695016, Kerala, India.
   [Gergely, L.; Tapai, M.] Univ Szeged, Dom Ter 9, H-6720 Szeged, Hungary.
   [Goetz, E.; Gustafson, R.; Neunzert, A.; Riles, K.; Sauter, O.] Univ Michigan, Ann Arbor, MI 48109 USA.
   [Gopakumar, A.; Unnikrishnan, C. S.] Tata Inst Fundamental Res, Mumbai 400005, Maharashtra, India.
   [Grado, A.] INAF, Osservatorio Astron Capodimonte, I-80131 Naples, Italy.
   [Greco, G.; Guidi, G. M.; Martelli, F.; Montani, M.; Piergiovanni, F.; Stratta, G.; Vetrano, F.; Vicere, A.] Univ Urbino, I-61029 Urbino, Italy.
   [Greco, G.; Guidi, G. M.; Martelli, F.; Montani, M.; Piergiovanni, F.; Stratta, G.; Vetrano, F.; Vicere, A.; Wang, G.] INFN, Sez Firenze, I-50019 Sesto Fiorentino, Italy.
   [Haney, M.] Univ Zurich, Phys Inst, Winterthurerstr 190, CH-8057 Zurich, Switzerland.
   [Harry, G. M.; Kinley-Hanlon, M.; Newport, J. M.] Amer Univ, Washington, DC 20016 USA.
   [Jaranowski, P.] Univ Bialystok, PL-15424 Bialystok, Poland.
   [Jones, D. I.] Univ Southampton, Southampton SO17 1BJ, Hants, England.
   [Key, J. S.] Univ Washington, 18115 Campus Way NE, Bothell, WA 98011 USA.
   [Haney, M.] Univ Bialystok, PL-15424 Bialystok, Poland.
   [Harry, G. M.; Kinley-Hanlon, M.; Newport, J. M.] Amer Univ, Washington, DC 20016 USA.
   [Khazanov, E. A.; Palashov, O.; Sergeev, A.] Inst Appl Phys, Novgorod 34055, Russia.
   [Kim, Chunglee] Korea Astron & Space Sci Inst, Daejeon 34055, South Korea.
   [Kim, Chunglee] Korea Astron & Space Sci Inst, South Gyeongsang 34055, South Korea.
   [Kim, J. C.; Lee, H. W.] Inje Univ Gimhae, South Gyeongsang 50834, South Korea.
   [Kim, W. S.; Oh, J. J.; Oh, S. H.; Son, E. J.] Natl Inst Math Sci, Daejeon 34047, South Korea.
   [Krolak, A.; Kutynia, A.; Zadrozny, A.] NCBJ, PL-05400 Otwock, Poland.
   [Krolak, A.; Patil, M.] Polish Acad Sci, Inst Math, PL-00656 Warsaw, Poland.
   [Lang, R. N.] Hillsdale Coll, Hillsdale, MI 49242 USA.
   [Lee, H. K.] Hanyang Univ, Seoul 04763, South Korea.
   [Lee, H. M.] Seoul Natl Univ, Seoul 08826, South Korea.
   [Littenberg, T. B.; Page, J.; Shah, A. A.; Taylor, J. A.] NASA, Marshall Space Flight Ctr, Huntsville, AL 35811 USA.
   [Loriette, V.; Maksimovic, I.] CNRS, ESPCI, F-75005 Paris, France.
   [McGuire, S. C.] Southern Univ, Baton Rouge, LA 70813 USA.
   [McGuire, S. C.] A&M Coll, Baton Rouge, LA 70813 USA.
   [Mikhailov, E. E.; Zhang, M.] Coll William & Mary, Williamsburg, VA 23187 USA.
   [Minazzoli, O.] Ctr Sci Monaco, 8 Quai Antoine Ler, MC-98000 Monaco, Monaco.
   [Mishra, C.] Indian Inst Technol Madras, Chennai 600036, Tamil Nadu, India.
   [Nayak, R. K.; Samajdar, A.] IISER Kolkata, Mohanpur 741252, W Bengal, India.
   [Ogin, G. H.] Whitman Coll, 345 Boyer Ave, Walla Walla, WA 99362 USA.
   [Pai, A.] Indian Inst Technol, Mumbai 400076, Maharashtra, India.
   [Patricelli, B.] Scuola Normale Super Pisa, Piazza Cavalieri 7, I-56126 Pisa, Italy.
   [Pedurand, R.] Univ Lyon, F-69361 Lyon, France.
   [Penn, S.; Tewari, S. V.] Hobart & William Smith Colleges, Geneva, NY 14456 USA.
   [Powell, J.; Stevenson, S. P.] Swinburne Univ Technol, OzGrav, Hawthorn, Vic 3122, Australia.
   [Rosinska, D.] Univ Zielona Gora, Janusz Gil Inst Astron, PL-65265 Zielona Gora, Poland.
   [Ross, M. P.; Venkateswara, K.] Univ Washington, Seattle, WA 98195 USA.
   [Sakellariadou, M.] Univ London, Kings Coll London, London WC2R 2LS, England.
   [Somala, S.] Indian Inst Technol, Ahmadabad 382424, Gujarat, India.
   [Somala, S.] Indian Inst Technol Hyderabad, Khandi, Telangana, India.
   [Sturani, R.] Univ Fed Rio Grande do Norte, Int Inst Phys, BR-59078970 Natal, RN, Brazil.
   [Summerscales, T. Z.] Andrews Univ, Berrien Springs, MI 49104 USA.
   Univ Siena, I-53100 Siena, Italy.
   [Ugolini, D.] Trinity Univ, San Antonio, TX 78212 USA.
   [Willis, J. L.] Abilene Christian Univ, Abilene, TX 79699 USA.
   [Yang, L.] Colorado State Univ, Ft Collins, CO 80523 USA.
   [Foley, R. J.; Coulter, D. A.; Kilpatrick, C. D.; Murguia-Berthier, A.; Pan, Y. -C.; Prochaska, J. X.; Ramirez-Ruiz, E.; Rojas-Bravo, C.; Siebert, M. R.] Univ Calif Santa Cruz, Dept Astron & Astrophys, Santa Cruz, CA 95064 USA.
   [Drout, M. R.; Madore, B. F.; Piro, A. L.; Shappee, B. J.; Simon, J. D.] Observ Carnegie Inst Sci, 813 Santa Barbara St, Pasadena, CA 91101 USA.
   [Kasen, D.] Lawrence Berkeley Natl Lab Berkeley, Div Nucl Sci, Berkeley, CA 94720 USA.
   [Kasen, D.] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Kasen, D.] Univ Calif Berkeley, Dept Astron, Berkeley, CA 94720 USA.
   [Ramirez-Ruiz, E.] Univ Copenhagen, Niels Bohr Inst, Dark Cosmol Ctr, Blegdamsvej 17, DK-2100 Copenhagen, Denmark.
   [Rest, A.] Space Telescope Sci Inst, 3700 San Martin Dr, Baltimore, MD 21218 USA.
   [Shappee, B. J.] Univ Hawaii, Inst Astron, 2680 Woodlawn Dr, Honolulu, HI 96822 USA.
   [Ulloas, N.] Univ La Serena, Dept Fis & Astron, La Serena, Chile.
   [Annis, J.; Soares-Santos, M.; Diehl, H. T.; Frieman, J.; Allam, S.; Butler, R. E.; Drlica-Wagner, A.; Finley, D. A.; Herner, K.; Li, T. S.; Lin, H.; Marriner, J.; Stebbins, A.; Yanny, B.; Buckley-Geer, E.; Estrada, J.; Flaugher, B.; Gutierrez, G.; Kent, S.; Kron, R.; Kuropatkin, N.; Neilsen, E.; Nord, B.; Tucker, D. L.] Fermilab Natl Accelerator Lab, POB 500, Batavia, IL 60510 USA.
   [Soares-Santos, M.] Brandeis Univ, Dept Phys, Waltham, MA 02254 USA.
   [Brout, D.; Sako, M.; Secco, L. F.; D'Andrea, C. B.; Jain, B.; March, M.] Univ Penn, Dept Phys & Astron, Philadelphia, PA 19104 USA.
   [Scolnic, D.; Frieman, J.; Kessler, R.; Kent, S.; Kron, R.] Univ Chicago, Kavli Inst Cosmol Phys, Chicago, IL 60637 USA.
   [Berger, E.; Alexander, K. D.; Cowpertwaite, P.; Nicholl, M.] Harvard Smithsonian Ctr Astrophys, 60 Garden St, Cambridge, MA 02133 USA.
   [Balbinot, E.] Univ Surrey, Dept Phys, Guildford GU2 7XH, Surrey, England.
   [Balbinot, E.] Harvard Smithsonian Ctr Astrophys, Cambridge, MA 02138 USA.
   [Butler, R. E.] Indiana Univ, Dept Astron, 727 East Third St, Bloomington, IN 47405 USA.
   [Chornock, R.] Ohio Univ, Astrophys Inst, Dept Phys & Astron, 2518 Clippinger Lab, Athens, OH 45701 USA.
   [Cook, E. R.; Marshall, J. L.; Sauseda, M.; DePoy, D. L.] Texas A&M Univ, George P & Cynthia Woods Mitchell Inst Fundamen, College Stn, TX 77843 USA.
   [Cook, E. R.; Marshall, J. L.; Sauseda, M.; DePoy, D. L.] Texas A&M Univ, Dept Phys & Astron, College Stn, TX 77843 USA.
   [Cook, E. R.; Bechtol, K.] LSST, 933 North Cherry Ave, Tucson, AZ 85721 USA.
   [Durret, F.] Observ Carnegie Inst Sci, 813 Santa Barbara St, Pasaclena, CA 91101 USA.
   [Fong, W.] CNRS, UMR7095, Inst Astrophys Paris, 98 Bis Bd Arago, F-75014 Paris, France.
   [Fong, W.] UPMC, 98 Bis Bd Arago, F-75014 Paris, France.
   [Fryer, C. L.] Northwestern Univ, CIERA, Evanston, IL 60208 USA.
   [Fryer, C. L.] Northwestern Univ, Dept Phys & Astron, Evanston, IL 60208 USA.
   [Gill, M. S. S.; Burke, D. L.; Gruen, D.; Roodman, A.; Rykoff, E. S.] Los Alamos Natl Lab, Ctr Theoret Astrophys, Los Alamos, NM 87544 USA.
   [Gruendl, R. A.; Kind, M. Carrasco] Univ Autonoma Madrid, CSIC, Inst Fis Teor, E-28049 Madrid, Spain.
   [Gruendl, R. A.; Hanna, C.; Paz-Chinchon, F.; Kind, M. Carrasco; Johnson, M. W. G.] SLAC Natl Accelerator Lab, Menlo Pk, CA 94025 USA.
   [Hanna, C.] Univ Illinois, Dept Astron, 1002 West Green St, Urbana, IL 61801 USA.
   [Hartley, W.; Palmese, A.; Abdalla, F. B.; Benoit-Levy, A.; Brooks, D.; Hartley, W. G.; Lahav, O.] Natl Ctr Supercomp Applicat, Urbana, IL 61801 USA.
   [Hartley, W.; Hartley, W. G.] Penn State Univ, Dept Phys & Astron & Astrophys, University Pk, PA 16802 USA.
   [Kasen, D.] UCL, Dept Phys & Astron, Gower St, London WC1E 6BT, England.
   [Kasen, D.] Swiss Fed Inst Technol, Dept Phys, Wolfgang Pauli Str 16, CH-8093 Zurich, Switzerland.
   [Lopes, P. A. A.; Lourenco, A. C. C.] Univ Michigan, Dept Phys, Ann Arbor, MI 48109 USA.
   [Margutti, R.] Univ Calif Berkeley, Dept Phys & Astron, Berkeley, CA 94720 USA.
   [Margutti, R.] Univ Calif Berkeley, Theoret Astrophys Ctr, Berkeley, CA 94720 USA.
   [Matheson, T.] Univ Fed Rio de Janeiro, Observ Valongo, Ladeira Pedro Antonio 43, BR-20080090 Rio De Janeiro, RJ, Brazil.
   [Medina, G. E.; Munoz, R. R.] Northwestern Univ, CIERA, Evanston, IL 60208 USA.
   [Medina, G. E.; Munoz, R. R.] Northwestern Univ, Dept Phys & Astron, Evanston, IL 60208 USA.
   [Metzger, B. D.] Natl Opt Astron Observ, 950 North Cherry Ave, Tucson, AZ 35719 USA.
   [Muir, J.] Univ Chile, Dept Astron, Camino Observ 1515, Santiago, Chile.
   [Nugent, P.; Goldstein, D. A.; Thomas, R. C.] Columbia Univ, Dept Phys, New York, NY 10027 USA.
   [Nugent, P.; Goldstein, D. A.; Thomas, R. C.] Columbia Univ, Columbia Astrophys Lab, New York, NY 10027 USA.
   [Quataert, E.] Univ Michigan, Dept Phys, 450 Church St, Ann Arbor, MI 48109 USA.
   [Schlegel, D. J.] Lawrence Berkeley Natl Lab, 1 Cyclotron Rd, Berkeley, CA 94720 USA.
   [Smith, N.] Univ Calif Berkeley, Dept Astron & Theoret Astrophys Ctr, Berkeley, CA 94720 USA.
   [Sobreira, F.] Lawrence Berkeley Natl Lab, Div Phys, Berkeley, CA 94720 USA.
   [Sobreira, F.; Rosell, A. Carnero; da Costa, L. N.; Lima, M.; Maia, M. A. G.; Ogando, R. L. C.] Univ Arizona, 933 North Cherry Ave, Tucson, AZ 85721 USA.
   [Vivas, A. K.; Zenteno, A.; Abbott, T. M. C.; Smith', R. C.; Walker, A. R.] Univ Estadual Campinas, Inst Fis Gleb Wataghin, BR-13083859 Campinas, SP, Brazil.
   [Abdalla, F. B.] Lab Interinst & Astron, Rua Gal Jos6 Cristino 77, BR-20921400 Rio De Janeiro, RJ, Brazil.
   [Benoit-Levy, A.; Bertin, E.] Natl Opt Astron Observ, Cerro Tololo Interamer Observ, Casilla 603, La Serena, Chile.
   [Benoit-Levy, A.; Bertin, E.] Rhodes Univ, Dept Phys & Elect, POB 94, ZA-6140 Grahamstown, South Africa.
   [Bridle, S. L.] Inst Astrophys Paris, CNRS, UMR 7095, F-75014 Paris, France.
   [Burke, D. L.; Cunha, C. E.; Davis, C.; Gruen, D.; Krause, E.; Roodman, A.; Rykoff, E. S.] UPMC Univ Paris 06, Sorbonne Univ, UMR 7095, Inst Astrophys Paris, F-750I4 Paris, France.
   [Rosell, A. Carnero; da Costa, L. N.; Maia, M. A. G.; Ogando, R. L. C.] Univ Manchester, Jodrell Bank Ctr Astrophys, Sch Phys & Astron, Oxford Rd, Manchester M13 9PL, Lancs, England.
   [Carretero, J.; Fernandez, E.; Miquel, R.] Stanford Univ, Kavli Inst Particle Astrophys & Cosmol, POB 2450, Stanford, CA 94305 USA.
   [Castander, F. J.; Fosalba, P.; Gaztanaga, E.] Observ Nacl, Rua Gen Jose Cristino 77, BR-20921400 Rio De Janeiro, RJ, Brazil.
   [Desai, S.] Barcelona Inst Sci & Technol, IFAE, Campus UAB, Bellaterra 03193, Spain.
   [Dietrich, J. P.; Weller, J.] IEEC CSIC, Inst Space Sci, Campus UAB,Carrer Can Magrans, Barcelona 08193, Spain.
   [Dietrich, J. P.] IIT Hyderabad, Dept Phys, Kandi 502285, Telangana, India.
   [Gerdes, D. W.; Miller, C. J.] Excellence Cluster Univ, Boltzmannstr 2, D-85748 Garching, Germany.
   [Giannantonio, T.] Ludwig Maximilians Univ Munchen, Fac Phys, Scheinerstr 1, D-81679 Munich, Germany.
   Univ Michigan, Dept Astron, Ann Arbor, MI 48109 USA.
   [Giannantonio, T.; Weller, J.] Univ Cambridge, Inst Astron, Madingley Rd, Cambridge CB3 0HA, England.
   [Rosell, A. Carnero; da Costa, L. N.; Maia, M. A. G.; Ogando, R. L. C.] Univ Cambridge, Kavli Inst Cosmol, Madingley Rd, Cambridge CB3 0HA, England.
   [Honscheid, K.; Troxel, M. A.] Ludwig Maximilians Univ Munchen, Univ Sternwarte, Fak Phys, Scheinerstr 1, D-81679 Munich, Germany.
   [Honscheid, K.; Troxel, M. A.] Univ Calif Berkeley, Dept Astron, 501 Campbell Hall, Berkeley, CA USA.
   [James, D. J.] Ohio State Univ, Ctr Cosmol & Astroparticle Phys, Columbus, OH 43210 USA.
   [Jeltema, T.] Ohio State Univ, Dept Phys, Columbus, OH 43210 USA.
   [Kuehn, K.] Univ Washington, Astron Dept, Box 351580, Seattle, WA 98195 USA.
   [Kuhlmann, S.; Vikram, V.] Santa Cruz Inst Particle Phys, Santa Cruz, CA 95064 USA.
   [Lima, M.] Australian Astron Observ, N Ryde, NSW 2113, Australia.
   [Miquel, R.] Argonne Natl Lab, 9700 S Cass Ave, Lemont, IL 60439 USA.
   [Plazas, A. N.] Univ Sao Paulo, Inst Fis, Dept Fis Matemat, CP 66318, BR-05314970 Sao Paulo, SP, Brazil.
   [Romer, A. K.] Inst Catalana Recerca & Studis Avancats, E-08010 Barcelona, Spain.
   [Sanchez, E.; Sevilla-Noarbe, I.] CALTECH, Jet Prop Lab, 4800 Oak Grove Dr, Pasadena, CA 91109 USA.
   [Smith, M.] Univ Sussex, Dept Phys & Astron, Pevensey Bldg, Brighton BN1 9QH, E Sussex, England.
   [Suchyta, E.] CIEMAT, Madrid, Spain.
   [Bizouard, A.] Univ Southampton, Sch Phys & Astron, Southampton SO17 1BJ, Hants, England.
   [Weller, J.] Oak Ridge Natl Lab, Comp Sci & Math Div, Oak Ridge, TN 37831 USA.
   [Talukder, D.] Univ Portsmouth, Inst Cosmol & Gravitat, Portsmouth PO1 3FX, Hants, England.
   [Isac, J. -M.] Max Planck Inst Extraterr Phys, Giessenbachstr, D-85748 Garching, Germany.
   [Haislip, J. B.; Kouprinov, V. V.; Reichart, D. E.] Univ North Carolina Chapel Hill, Dept Phys & Astron, Chapel Hill, NC 27599 USA.
   [Tartaglia, L.; Sand, D. J.] Univ Arizona, Dept Astron & Steward Observ, 933 North Cherry Ave, Tucson, AZ 85719 USA.
   [Tartaglia, L.; Valenti, S.; Yang, S.] Univ Calif Davis, Dept Phys, 1 Shields Ave, Davis, CA 95616 USA.
   [Yang, S.] Univ Padua, Dept Phys & Astron, Via 8 Febbraio, I-35122 Padua, Italy.
   [Yang, S.] INAF, Osservatorio Astron Padova, Vicolo Osservatorio 5, I-35122 Padua, Italy.
   [Arcavi, Iair; Hosseinzadeh, Griffin; Howell, D. Andrew; McCully, Curtis; Vasylyev, Sergiy] Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA.
   [Arcavi, Iair; Hosseinzadeh, Griffin; Howell, D. Andrew; McCully, Curtis; Vasylyev, Sergiy] Las Cumbres Observ, 6740 Cortona Dr,Suite 102, Goleta, CA 93117 USA.
   [Poznanski, Dovi] Tel Aviv Univ, Sch Phys & Astron, IL-69973 Tel Aviv, Israel.
   [Tanvir, N. R.; Evans, P. A.; O'Brien, P.; Osborne, J. P.; Rosetti, S.; Wiersema, K.] Univ Leicester, Dept Phys & Astron, Univ Rd, Leicester LEI 7RH, Leics, England.
   [Levan, N. J.; Lyman, J.; Steeghs, D. T. H.; Ulaczyk, K.; Wiersema, K.] Univ Warwick, Dept Phys, Coventry CV4 7AL, W Midlands, England.
   [Hjorth, J.; Fynbo, J. P. U.; Milvang-Jensen, B.; Watson, D.] Univ Copenhagen, Niels Bohr Inst, DARK, Julian Maries Vej 30, DK-2100 Copenhagen O, Denmark.
   [Cano, Z.; de Ugarte-Postigo, A.; Thone, C. C.] Inst Astrofis Andalucia IAA CSIC, Granada 13008, Spain.
   [Copperwheat, C.; Perley, D. A.] Liverpool John Moores Univ, Astrophys Res Inst, IC2, Liverpool Sci Pk,146 Brownlow Hill, Liverpool L3 5RF, Merseyside, England.
   [Gonzalez-Fernandez, C.; Irwin, M.; McMahon, R.] Univ Cambridge, Inst Astron, Madingley Rd, Cambridge CB3 OHA, England.
   [Greiner, J.] Max Planck Inst Extraterr Phys, Giessenbachstr 1, D-85740 Garching, Germany.
   [Mandel, I.] Univ Birmingham, Birmingham Inst Gravitat Wave Astron, Birmingham B15 2TT, W Midlands, England.
   [Mandel, I.] Univ Birmingham, Sch Phys & Astron, Birmingham B15 2TT, W Midlands, England.
   [Pian, E.; Palazzi, E.] INAF, Inst Space Astrophys & Cosm Phys, Via Gobetti 101, I-40129 Bologna, Italy.
   [Rol, E.] Monash Univ, Sch Phys & Astron, Clayton, Vic 3800, Australia.
   [Rol, E.] Monash Univ, Monash Ctr Astrophys, Clayton, Vic 3800, Australia.
   [Rosswog, S.] Stockholm Univ, Alballova, Oskar Klein Ctr, Dept Astron, SE-10691 Stockholm, Sweden.
   [Rowlinson, A.] Univ Amsterdam, Anton Pannekoek Inst, Sci Pk 904, NL-1098 XH Amsterdam, Netherlands.
   [Schulze, S.] Netherlands Inst Radio Astron, ASTRON, Postbus 2, NL-7990 AA Dwingeloo, Netherlands.
   [Schulze, S.] Weizmann Inst Sci, Dept Particle Phys & Astrophys, IL-76100 Rehovot, Israel.
   [Lipunov, V. M.; Kornilov, V. G.; Vlasenko, D.] Moscow MV Lomonosov State Univ, Dept Phys, Leninskie Gory,GSP-1, Moscow 119991, Russia.
   [Lipunov, V. M.; Gorbovskoy, E.; Kornilov, V. G.; Tyurina, N.; Balanutsa, P.; Vlasenko, D.; Gorbunov, I.; Gress, O.] Moscow MV Lomonosov State Univ, Sternberg Astron Inst, Univ Sky 13, Moscow 119234, Russia.
   [Podesta, R.] Natl Univ San Juan, OAFA, San Juan, Argentina.
   [Levato, H.; Saffe, C.] ICATE, San Juan, Argentina.
   [Buckley, D. A. H.] South African Astrophys Observ, POB 9, ZA-7935 Cape Town, South Africa.
   [Budnev, N. M.; Gress, O.] Irkutsk State Univ, Inst Appl Phys, 20 Gagarin Blvd, Irkutsk 664003, Russia.
   [Yurkov, V.] Blagoveschensk State Pedag Univ, Lenin St 104, Blagoveshchensk 675000, Russia.
   [Rebolo, R.; Serra-Ricart, M.] Inst Astrofacuteis, Canarias Via Lactea, E-38205 San Cristobal la Laguna, Spain.
C3 California Institute of Technology; Louisiana State University System; Louisiana State University; University of Salerno; Istituto Nazionale di Fisica Nucleare (INFN); State University System of Florida; University of Florida; Monash University; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Universite Savoie Mont Blanc; University of Sannio; Max Planck Society; University of Mississippi; University of Illinois System; University of Illinois Urbana-Champaign; University of Cambridge; FOM National Institute for Subatomic Physics; Massachusetts Institute of Technology (MIT); Instituto Nacional de Pesquisas Espaciais (INPE); Gran Sasso Science Institute (GSSI); Istituto Nazionale di Fisica Nucleare (INFN); Gran Sasso Science Institute (GSSI); Inter-University Centre for Astronomy & Astrophysics; Tata Institute of Fundamental Research (TIFR); International Centre for Theoretical Sciences, Bengaluru; University of Wisconsin System; University of Wisconsin Milwaukee; Leibniz University Hannover; University of Pisa; Istituto Nazionale di Fisica Nucleare (INFN); Australian National University; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); University of West Scotland; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Universite Paris Saclay; California State University System; California State University Fullerton; Chennai Mathematical Institute; University of Rome Tor Vergata; Istituto Nazionale di Fisica Nucleare (INFN); University of Hamburg; Istituto Nazionale di Fisica Nucleare (INFN); Cardiff University; Embry-Riddle Aeronautical University; Max Planck Society; Universite PSL; Observatoire de Paris; CEA; Centre National de la Recherche Scientifique (CNRS); Universite Paris Cite; CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Universite Paris Saclay; Korea Institute of Science & Technology Information (KISTI); West Virginia University; University of Perugia; Istituto Nazionale di Fisica Nucleare (INFN); Syracuse University; University of Minnesota System; University of Minnesota Twin Cities; University of Glasgow; California Institute of Technology; HUN-REN; HUN-REN Wigner Research Centre for Physics; Institute for Particle & Nuclear Physics - HAS; Columbia University; Stanford University; University of Camerino; University of Padua; Istituto Nazionale di Fisica Nucleare (INFN); Eotvos Lorand University; Polish Academy of Sciences; Nicolaus Copernicus Astronomical Center of the Polish Academy of Sciences; Rochester Institute of Technology; University of Birmingham; Istituto Nazionale di Fisica Nucleare (INFN); Raja Ramanna Centre for Advanced Technology; Lomonosov Moscow State University; University of Strathclyde; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; University of Western Australia; Radboud University Nijmegen; Centre National de la Recherche Scientifique (CNRS); Universite Cote d'Azur; Observatoire de la Cote d'Azur; Centre National de la Recherche Scientifique (CNRS); Universite de Rennes; Washington State University; University of Oregon; Universite PSL; College de France; Ecole Normale Superieure (ENS); Centre National de la Recherche Scientifique (CNRS); Sorbonne Universite; Carleton College; Adelaide University; University of Adelaide; University of Warsaw; Vrije Universiteit Amsterdam; University System of Maryland; University of Maryland College Park; University System of Georgia; Georgia Institute of Technology; Universite Lyon 1; University of Naples Federico II; National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center; University of Genoa; University of Tokyo; Tsinghua University; Texas Tech University System; Texas Tech University; University System of Ohio; Kenyon College; University of Valencia; National Tsing Hua University; Charles Sturt University; Northwestern University; University of Toronto; Pusan National University; Chinese University of Hong Kong; Istituto Nazionale Astrofisica (INAF); University of Padua; Istituto Nazionale di Fisica Nucleare (INFN); University of Melbourne; Sapienza University Rome; Universite Libre de Bruxelles; California State University System; Sonoma State University; University of Valencia; Montana State University System; Montana State University Bozeman; Universitat de les Illes Balears; University of Texas System; University of Texas Rio Grande Valley; Institute for Plasma Research (IPR); University of Sheffield; University of Parma; Istituto Nazionale di Fisica Nucleare (INFN); California State University System; California State University Los Angeles; Montclair State University; National Institutes of Natural Sciences (NINS) - Japan; National Astronomical Observatory of Japan (NAOJ); University of Valencia; University of Edinburgh; Indian Institute of Science Education & Research (IISER) - Thiruvananthapuram; Szeged University; University of Michigan System; University of Michigan; Tata Institute of Fundamental Research (TIFR); Tata Institute of Fundamental Research (TIFR), Mumbai; Istituto Nazionale Astrofisica (INAF); University of Urbino; Istituto Nazionale di Fisica Nucleare (INFN); University of Zurich; American University; University of Bialystok; University of Southampton; University of Washington; University of Washington Bothell; University of Bialystok; American University; Institute of Applied Physics of the Russian Academy of Sciences; Korea Astronomy & Space Science Institute (KASI); Korea Astronomy & Space Science Institute (KASI); Inje University; National Institute for Mathematical Sciences (NIMS), Republic of Korea; National Centre for Nuclear Research; Polish Academy of Sciences; Institute of Mathematics of the Polish Academy of Sciences; Hillsdale College; Hanyang University; Seoul National University (SNU); National Aeronautics & Space Administration (NASA); Universite PSL; Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI); Centre National de la Recherche Scientifique (CNRS); Southern University System; Southern University & A&M College; Louisiana State University System; Louisiana State University; William & Mary; Indian Institute of Technology System (IIT System); Indian Institute of Technology (IIT) - Madras; Indian Institute of Science Education & Research (IISER) - Kolkata; Whitman College; Indian Institute of Technology System (IIT System); Indian Institute of Technology (IIT) - Bombay; Scuola Normale Superiore di Pisa; Hobart & William Smith Colleges; Swinburne University of Technology; University of Zielona Gora; University of Washington; University of Washington Seattle; University of London; King's College London; Indian Institute of Technology System (IIT System); Indian Institute of Technology (IIT) - Gandhinagar; Indian Institute of Technology System (IIT System); Indian Institute of Technology (IIT) - Hyderabad; Universidade Federal do Rio Grande do Norte; Andrews University; University of Siena; Trinity University; Abilene Christian University; Colorado State University System; Colorado State University Fort Collins; University of California System; University of California Santa Cruz; Carnegie Institution for Science; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of Copenhagen; Niels Bohr Institute; Space Telescope Science Institute; University of Hawaii System; Universidad de La Serena; United States Department of Energy (DOE); University of Chicago; Fermi National Accelerator Laboratory; Brandeis University; University of Pennsylvania; University of Chicago; Smithsonian Astrophysical Observatory; Smithsonian Institution; Harvard University; University of Surrey; Harvard University; Smithsonian Astrophysical Observatory; Smithsonian Institution; Indiana University System; Indiana University Bloomington; University System of Ohio; Ohio University; Texas A&M University System; Texas A&M University College Station; Texas A&M University System; Texas A&M University College Station; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Sorbonne Universite; Northwestern University; Northwestern University; United States Department of Energy (DOE); Los Alamos National Laboratory; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - UAM - Institut de Fisica Teorica (IFT); Autonomous University of Madrid; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; University of Illinois System; University of Illinois Urbana-Champaign; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; University of London; University College London; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Michigan System; University of Michigan; University of California System; University of California Berkeley; University of California System; University of California Berkeley; Universidade Federal do Rio de Janeiro; Northwestern University; Northwestern University; National Optical Astronomy Observatory; Universidad de Chile; Columbia University; Columbia University; University of Michigan System; University of Michigan; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; University of California System; University of California Berkeley; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; University of Arizona; Universidade Estadual de Campinas; Laboratorio Interinstitucional de e-Astronomia (LINEA); National Optical Astronomy Observatory; Cerro Tololo Inter-American Observatory; Rhodes University; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Sorbonne Universite; University of Manchester; Jodrell Bank Centre for Astrophysics; Stanford University; Barcelona Institute of Science & Technology; Institute for High Energy Physics (IFAE); Autonomous University of Barcelona; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Ciencias del Espacio (ICE); Institut d'Estudis Espacials de Catalunya (IEEC); Autonomous University of Barcelona; Indian Institute of Technology System (IIT System); Indian Institute of Technology (IIT) - Hyderabad; University of Munich; University of Michigan System; University of Michigan; University of Cambridge; University of Cambridge; University of Munich; University of California System; University of California Berkeley; University System of Ohio; Ohio State University; University System of Ohio; Ohio State University; University of Washington; University of Washington Seattle; United States Department of Energy (DOE); Argonne National Laboratory; Universidade de Sao Paulo; ICREA; California Institute of Technology; National Aeronautics & Space Administration (NASA); NASA Jet Propulsion Laboratory (JPL); University of Sussex; Centro de Investigaciones Energeticas, Medioambientales Tecnologicas; University of Southampton; United States Department of Energy (DOE); Oak Ridge National Laboratory; University of Portsmouth; Max Planck Society; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of Arizona; University of California System; University of California Davis; University of Padua; Istituto Nazionale Astrofisica (INAF); University of Padua; University of California System; University of California Santa Barbara; Tel Aviv University; University of Leicester; University of Warwick; University of Copenhagen; Niels Bohr Institute; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Astrofisica de Andalucia (IAA); Liverpool John Moores University; University of Cambridge; Max Planck Society; University of Birmingham; University of Birmingham; Istituto Nazionale Astrofisica (INAF); Monash University; Monash University; Stockholm University; Oskar Klein Centre; University of Amsterdam; Weizmann Institute of Science; Lomonosov Moscow State University; Lomonosov Moscow State University; Universidad Nacional de San Juan; Institute of Applied Physics of the Russian Academy of Sciences; Irkutsk State University
RP Abbott, BP (corresponding author), CALTECH, LIGO, Pasadena, CA 91125 USA.
FU United States National Science Foundation (NSF); Science and Technology Facilities Council (STFC) of the United Kingdom; Max-Planck-Society (MPS); State of Niedersachsen/Germany; Australian Research Council; Netherlands Organisation for Scientific Research; EGO consortium; Council of Scientific and Industrial Research of India; Department of Science and Technology, India; Science and Engineering Research Board (SERB), India; Ministry of Human Resource Development, India; Spanish Agencia Estatal de Investigation; Vicepresidencia i Conselleria d'Innovacio, Recerca i Turisme; Conselleria d'Educacia i Universitet del Govern de les Illes Balears; Conselleria d'Educacia, Investigacio, Culture i Esport de la Generalitat Valenciana; National Science Centre of Poland; Swiss National Science Foundation (SNSF); Russian Foundation for Basic Research; Russian Science Foundation; European Commission; European Regional Development Funds (ERDF); Royal Society; Scottish Funding Council; Scottish Universities Physics Alliance; Hungarian Scientific Research Fund (OTKA); Lyon Institute of Origins (LIO); National Research, Development and Innovation Office Hungary (NKFI); National Research Foundation of Korea, Industry Canada; Province of Ontario through the Ministry of Economic Development and Innovation; Natural Science and Engineering Research Council Canada; Canadian Institute for Advanced Research; Brazilian Ministry of Science, Technology, Innovations, and Communications; International Center for Theoretical Physics South American Institute for Fundamental Research (ICTP-SAIFR); Research Grants Council of Hong Kong; National Natural Science Foundation of China (NSFC); Leverhulme Trust; Research Corporation; Ministry of Science and Technology (MOST), Taiwan; Kavli Foundation; NSF; STFC; MPS; INFN; CNRS; Danish National Research Foundation; Niels Bohr International Academy; DARK Cosmology Centre; NSF [AST-1518052, AST-1411763, AST-1714498, AST -1138766, AST-1536171, AST-1517649, AST-1313484]; Gordon AMP; Betty Moore Foundation; Heising-Simons Foundation; UCSC Giving Day grant; Alfred P. Sloan Foundation; David and Lucile Packard Foundation; Niels Bohr Professorship from the DNRF; UCMEXUS-CONACYT Doctoral Fellowship; NASA through Hubble Fellowship - Space Telescope Science Institute [HST-HF-51348.001, HST-HF-51373.001]; NASA [NAS5-26555, NNX15AE50G, NNX16AC22G]; DOE (USA); NSF (USA); MEC/MICINN/MINECO (Spain); STFC (UK); HEFCE (UK); NCSA (UIUC); KICP (U. Chicago); CCAPP (Ohio State); MIFPA (Texas AM); CNPQ (Brazil); FAPERJ (Brazil); FINEP (Brazil); DFG (Germany); Argonne Lab; UC Santa Cruz; University of Cambridge; Dark Energy Survey; CIEMAT-Madrid; University of Chicago; University College London; DES-Brazil Consortium; University of Edinburgh; ETH Zurich; Fermilab; University of Illinois; ICE (IEEC-CSIC); IFAE Barcelona; Lawrence Berkeley Lab; LMU Munchen; associated Excellence Cluster Universe; University of Michigan; NOAO; University of Nottingham; Ohio State University; University of Pennsylvania; University of Portsmouth; SLAC National Lab; Stanford University; University of Sussex; Texas AM University; OzDES Membership Consortium; MINECO [AYA2015-71825, ESP2015-88861, FPA2015-68048]; Centro de Excelencia [SEV-2012-0234, SEV-2016-0597, MDM-2015-0509]; ERC under the European Union's Seventh Framework Programme [ERC 240672, 291329, 306478]; Australian Research Council Centre of Excellence for All-sky Astrophysics (CAASTRO) [CE110001020]; US Department of Energy, Office of Science, Office of High Energy Physics [DE-AC02-07CH11359]; NASA through the Einstein Fellowship Program [PF6-170148]; Israel Science Foundation [541/17]; Russian Science Foundation [16-12-00085] Funding Source: Russian Science Foundation; STFC [ST/L006529/1, ST/M003574/1, ST/M005844/1, ST/N000080/1, ST/L000954/1, ST/M006735/1, ST/N000064/1, 1653071, ST/N005422/1, ST/P000258/1, ST/I006269/1, ST/N000072/1, ST/I000887/1, ST/N000633/1, ST/I006285/1, 1653089, ST/L003465/1, Gravitational Waves, ST/K005014/1, ST/H001972/1, 1654298, ST/N005406/2, ST/N005406/1, ST/P000525/1, ST/J000019/1, ST/J000345/1, ST/N005716/1, ST/J00166X/1, PP/F001096/1, 1802888, ST/I000976/1, ST/L000733/1, ST/K005014/2, ST/M000931/1, ST/P000495/1, PPA/G/S/2002/00652, ST/N00003X/1, PP/F00110X/1, ST/M004090/2, ST/L000946/1, ST/N005481/1, ST/L000911/1, ST/G504284/1, ST/L000962/1, ST/N001087/1, ST/N000757/1, 2142081, 1802894, ST/J000302/1, ST/N000668/1, ST/K000845/1, ST/M001334/1, ST/N005430/1, ST/L00061X/1, ST/M004090/1, ST/L000652/1, ST/J000361/1, ST/H002006/1, ST/P000649/1, ST/F500972/1, ST/J001465/1, ST/H001581/1, 1785610, ST/I001085/1, ST/I006242/1, ST/I001026/1, ST/H008438/1] Funding Source: UKRI; Science and Technology Facilities Council [ST/J00166X/1, ST/N000668/1, ST/N000927/1, ST/N00003X/1, PPA/G/S/2002/00652, ST/H008438/1, ST/I006285/1, ST/I006242/1, ST/N000072/1, ST/M001334/1, 1802894, ST/L000911/1, ST/N005430/1, ST/N000064/1, ST/L000946/1, 1093560, ST/N005481/1, ST/N000080/1, ST/H001972/1, ST/H002006/1, ST/N005406/1, ST/M000966/1, ST/J000019/1 Gravitational Waves, ST/L000652/1, 1653071, ST/P000649/1, ST/J000302/1 Gravitational Waves, ST/F500972/1, PP/F001096/1, ST/P000258/1, Gravitational Waves, ST/I006269/1, ST/L000954/1, ST/I001026/1, ST/J001465/1, ST/P000525/1, ST/M000931/1, ST/H001581/1, ST/N005716/1, ST/L003465/1, ST/M006735/1, ST/L006529/1, ST/N005422/1, ST/J000345/1, ST/K005014/1, ST/J000361/1, ST/L00061X/1, ST/N000757/1, ST/N000633/1, ST/J000019/1, ST/I001085/1, ST/J000302/1, ST/I001026/1 Gravitational Waves, ST/I000887/1, ST/L000733/1, ST/M003574/1, ST/L000962/1, ST/M004090/1, ST/L000962/1 Gravitational Waves, ST/I000976/1, ST/L000342/1 Gravitational Waves, ST/M005844/1, ST/I006285/1 Gravitational Waves, ST/I006269/1 Gravitational Waves, PP/F00110X/1, 1096295, ST/N005406/2, ST/N001087/1, 1654298, ST/L000911/1 Gravitational Waves, ST/P000495/1, ST/K005014/2, ST/J000345/1 Gravitational Waves, ST/M004090/2, ST/G504284/1, ST/K000845/1, 1785610] Funding Source: researchfish; Direct For Mathematical & Physical Scien [1720756] Funding Source: National Science Foundation; Direct For Mathematical & Physical Scien; Division Of Astronomical Sciences [1517030, 1455090] Funding Source: National Science Foundation; Division Of Astronomical Sciences [1720756] Funding Source: National Science Foundation; Division Of Human Resource Development; Direct For Education and Human Resources [1242090] Funding Source: National Science Foundation; Division Of Physics; Direct For Mathematical & Physical Scien [1104371, 1607709] Funding Source: National Science Foundation; Division Of Physics; Direct For Mathematical & Physical Scien [1125897, 1607585, 1607336, 1404139, 1607520] Funding Source: National Science Foundation; Office of Advanced Cyberinfrastructure (OAC); Direct For Computer & Info Scie & Enginr [1541396] Funding Source: National Science Foundation; Office Of The Director; Office of Integrative Activities [1458952] Funding Source: National Science Foundation; Ministry of Science & ICT (MSIT), Republic of Korea [K-17-L01-C05] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS); Grants-in-Aid for Scientific Research [15H02082] Funding Source: KAKEN
NR 50
TC 737
Z9 821
U1 12
U2 44
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 2
PY 2017
VL 551
IS 7678
BP 85
EP +
DI 10.1038/nature24471
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FL4SY
UT WOS:000414222900049
PM 29094696
DA 2026-03-09
ER

PT J
AU Arnoult, N
   Correia, A
   Ma, J
   Merlo, A
   Garcia-Gomez, S
   Maric, M
   Tognetti, M
   Benner, CW
   Boulton, SJ
   Saghatelian, A
   Karlseder, J
AF Arnoult, Nausica
   Correia, Adriana
   Ma, Jiao
   Merlo, Anna
   Garcia-Gomez, Sara
   Maric, Marija
   Tognetti, Marco
   Benner, Christopher W.
   Boulton, Simon J.
   Saghatelian, Alan
   Karlseder, Jan
TI Regulation of DNA repair pathway choice in S and G2 phases by the NHEJ inhibitor CYREN
SO NATURE
LA English
DT Article
ID strand break repair; homologous recombination; end-protection; damage signal; telomeres; trf2; atm; identification; mechanism; resection
AB Classical non-homologous end joining(1) (cNHEJ) and homologous recombination(2) compete for the repair of double-stranded DNA breaks during the cell cycle. Homologous recombination is inhibited during the G1 phase of the cell cycle, but both pathways are active in the S and G2 phases. However, it is unclear why cNHEJ does not always outcompete homologous recombination during the S and G2 phases. Here we show that CYREN (cell cycle regulator of NHEJ) is a cell-cycle-specific inhibitor of cNHEJ. Suppression of CYREN allows cNHEJ to occur at telomeres and intrachromosomal breaks during the S and G2 phases, and cells lacking CYREN accumulate chromosomal aberrations upon damage induction, specifically outside the G1 phase. CYREN acts by binding to the Ku70/80 heterodimer and preferentially inhibits cNHEJ at breaks with overhangs by protecting them. We therefore propose that CYREN is a direct cell-cycle-dependent inhibitor of cNHEJ that promotes error-free repair by homologous recombination during cell cycle phases when sister chromatids are present.
C1 [Arnoult, Nausica; Correia, Adriana; Ma, Jiao; Merlo, Anna; Tognetti, Marco; Saghatelian, Alan; Karlseder, Jan] Salk Inst Biol Studies, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA.
   [Garcia-Gomez, Sara; Maric, Marija; Boulton, Simon J.] Francis Crick Inst, Dsb Repair Metab Lab, 1 Midland Rd, London NW1 1AT, England.
   [Benner, Christopher W.] Univ Calif San Diego, Dept Med, 9500 Gilman Dr, La Jolla, CA 92093 USA.
   [Tognetti, Marco] Swiss Fed Inst Technol, Inst Biochem, Otto Stern Weg 3, CH-8093 Zurich, Switzerland.
C3 Salk Institute; Francis Crick Institute; University of California System; University of California San Diego; Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Karlseder, J (corresponding author), Salk Inst Biol Studies, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA.
EM karlseder@salk.edu
FU Human Frontiers Science Program [LT000284/2013]; Paul F. Glenn Center for Biology of Aging Research; Larry Hillblom Foundation; Wellcome Trust; Francis Crick Institute (Cancer Research UK); UK Medical Research Council [FC0010048]; Wellcome Trust [FC0010048]; NIH [R01 GM102491, R01GM087476, R01CA174942]; NCI Cancer Center [P30 (CA014195)]; Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]; Dr. Frederick Paulsen Chair/Ferring Pharmaceuticals; Salk Institute Cancer Center [P30CA014195]; Fritz B. Burns Foundation; Emerald Foundation; Donald and Darlene Shiley Chair; Highland Street Foundation; Wellcome Trust [104558/Z/14/Z] Funding Source: Wellcome Trust; Cancer Research UK [11581] Funding Source: researchfish; Cancer Research UK; The Francis Crick Institute [10048] Funding Source: researchfish; Wellcome Trust [104558/Z/14/Z] Funding Source: researchfish; National Cancer Institute [P30CA014195] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM102491] Funding Source: NIH RePORTER
NR 38
TC 212
Z9 273
U1 1
U2 47
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 28
PY 2017
VL 549
IS 7673
BP 548
EP +
DI 10.1038/nature24023
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI4GT
UT WOS:000411930000056
PM 28959974
DA 2026-03-09
ER

PT J
AU Natterer, FD
   Yang, K
   Paul, W
   Willke, P
   Choi, TY
   Greber, T
   Heinrich, AJ
   Lutz, CP
AF Natterer, Fabian D.
   Yang, Kai
   Paul, William
   Willke, Philip
   Choi, Taeyoung
   Greber, Thomas
   Heinrich, Andreas J.
   Lutz, Christopher P.
TI Reading and writing single-atom magnets
SO NATURE
LA English
DT Article
ID molecule magnets; anisotropy; scale
AB The single-atom bit represents the ultimate limit of the classical approach to high-density magnetic storage media. So far, the smallest individually addressable bistable magnetic bits have consisted of 3-12 atoms(1-3). Long magnetic relaxation times have been demonstrated for single lanthanide atoms in molecular magnets(4-12), for lanthanides diluted in bulk crystals(13), and recently for ensembles of holmium (Ho) atoms supported on magnesium oxide (MgO)(14). These experiments suggest a path towards data storage at the atomic limit, but the way in which individual magnetic centres are accessed remains unclear. Here we demonstrate the reading and writing of the magnetism of individual Ho atoms on MgO, and show that they independently retain their magnetic information over many hours. We read the Ho states using tunnel magnetoresistance(15,16) and write the states with current pulses using a scanning tunnelling microscope. The magnetic origin of the long-lived states is confirmed by single-atom electron spin resonance(17) on a nearby iron sensor atom, which also shows that Ho has a large out-of-plane moment of 10.1 +/- 0.1 Bohr magnetons on this surface. To demonstrate independent reading and writing, we built an atomic-scale structure with two Ho bits, to which we write the four possible states and which we read out both magnetoresistively and remotely by electron spin resonance. The high magnetic stability combined with electrical reading and writing shows that single-atom magnetic memory is indeed possible.
C1 [Natterer, Fabian D.; Yang, Kai; Paul, William; Willke, Philip; Choi, Taeyoung; Greber, Thomas; Lutz, Christopher P.] IBM Almaden Res Ctr, San Jose, CA 95120 USA.
   [Natterer, Fabian D.] Ecole Polytech Fed Lausanne, Inst Phys, CH-1015 Lausanne, Switzerland.
   [Yang, Kai] Univ Chinese Acad Sci, Sch Phys Sci, Beijing 100049, Peoples R China.
   [Yang, Kai] Univ Chinese Acad Sci, Key Lab Vacuum Phys, Beijing 100049, Peoples R China.
   [Willke, Philip] Univ Gottingen, Phys Inst 4, Friedrich Hund Pl 1, D-37077 Gottingen, Germany.
   [Greber, Thomas] Univ Zurich, Inst Phys, Winterthurerstr 190, CH-8057 Zurich, Switzerland.
   [Heinrich, Andreas J.] Ctr Quantum Nanosci, Inst Basic Sci, Seoul, South Korea.
   [Heinrich, Andreas J.] Ewha Womans Univ, Dept Phys, Seoul, South Korea.
C3 International Business Machines (IBM); IBM USA; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; University of Gottingen; University of Zurich; Institute for Basic Science - Korea (IBS); Ewha Womans University
RP Natterer, FD; Lutz, CP (corresponding author), IBM Almaden Res Ctr, San Jose, CA 95120 USA.; Natterer, FD (corresponding author), Ecole Polytech Fed Lausanne, Inst Phys, CH-1015 Lausanne, Switzerland.; Heinrich, AJ (corresponding author), Ctr Quantum Nanosci, Inst Basic Sci, Seoul, South Korea.; Heinrich, AJ (corresponding author), Ewha Womans Univ, Dept Phys, Seoul, South Korea.
EM fabian.natterer@epfl.ch; heinrich@ewha.ac.kr; cplutz@us.ibm.com
FU Office of Naval Research; Swiss National Science Foundation [P300P2_158468, PZ00P2_167965]; National Natural Science Foundation of China [61471337]; Natural Sciences and Engineering Research Council of Canada; German academic exchange service; Swiss National Science Foundation (SNF) [PZ00P2_167965, P300P2_158468] Funding Source: Swiss National Science Foundation (SNF)
NR 33
TC 363
Z9 410
U1 10
U2 534
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 9
PY 2017
VL 543
IS 7644
BP 226
EP +
DI 10.1038/nature21371
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0GQ
UT WOS:000395688700035
PM 28277519
DA 2026-03-09
ER

PT J
AU Gulick, SPS
   Shevenell, AE
   Montelli, A
   Fernandez, R
   Smith, C
   Warny, S
   Bohaty, SM
   Sjunneskog, C
   Leventer, A
   Frederick, B
   Blankenship, DD
AF Gulick, Sean P. S.
   Shevenell, Amelia E.
   Montelli, Aleksandr
   Fernandez, Rodrigo
   Smith, Catherine
   Warny, Sophie
   Bohaty, Steven M.
   Sjunneskog, Charlotte
   Leventer, Amy
   Frederick, Bruce
   Blankenship, Donald D.
TI Initiation and long-term instability of the East Antarctic Ice Sheet
SO NATURE
LA English
DT Article
ID tunnel valleys; late eocene; meltwater features; totten glacier; north-sea; glaciation; evolution; morphology; middle; ocean
AB Antarctica's continental-scale ice sheets have evolved over the past 50 million years(1-4). However, the dearth of ice-proximal geological records(5-8) limits our understanding of past East Antarctic Ice Sheet (EAIS) behaviour and thus our ability to evaluate its response to ongoing environmental change. The EAIS is marine-terminating and grounded below sea level within the Aurora subglacial basin, indicating that this catchment, which drains ice to the Sabrina Coast, may be sensitive to climate perturbations(9-11). Here we show, using marine geological and geophysical data from the continental shelf seaward of the Aurora subglacial basin, that marine-terminating glaciers existed at the Sabrina Coast by the early to middle Eocene epoch. This finding implies the existence of substantial ice volume in the Aurora subglacial basin before continental-scale ice sheets were established about 34 million years ago(1-4). Subsequently, ice advanced across and retreated from the Sabrina Coast continental shelf at least 11 times during the Oligocene and Miocene epochs. Tunnel valleys(12) associated with half of these glaciations indicate that a surface-meltwater-rich sub-polar glacial system existed under climate conditions similar to those anticipated with continued anthropogenic warming(10,11). Cooling since the late Miocene(13) resulted in an expanded polar EAIS and a limited glacial response to Pliocene warmth in the Aurora subglacial basin catchment(14-16). Geological records from the Sabrina Coast shelf indicate that, in addition to ocean temperature, atmospheric temperature and surface-derived meltwater influenced East Antarctic ice mass balance under warmer-than-present climate conditions. Our results imply a dynamic EAIS response with continued anthropogenic warming and suggest that the EAIS contribution to future global sea-level projections(10,11,15,17) may be under-estimated.
C1 [Gulick, Sean P. S.; Montelli, Aleksandr; Fernandez, Rodrigo; Frederick, Bruce; Blankenship, Donald D.] Univ Texas Austin, Inst Geophys, Jackson Sch Geosci, Austin, TX 78758 USA.
   [Shevenell, Amelia E.; Smith, Catherine] Univ S Florida, Coll Marine Sci, St Petersburg, FL 33701 USA.
   [Warny, Sophie] Louisiana State Univ, Dept Geol & Geophys, Baton Rouge, LA 70803 USA.
   [Warny, Sophie] Louisiana State Univ, Museum Nat Sci, Baton Rouge, LA 70803 USA.
   [Bohaty, Steven M.] Univ Southampton, Sch Ocean & Earth Sci, Southampton SO14 3ZH, Hants, England.
   [Sjunneskog, Charlotte] Florida State Univ, Antarctic Marine Geol Res Facil, Tallahassee, FL 32306 USA.
   [Leventer, Amy] Colgate Univ, Geol Dept, Hamilton, NY 13346 USA.
   [Montelli, Aleksandr] Univ Cambridge, Scott Polar Res Inst, Cambridge CB2 1ER, England.
   [Sjunneskog, Charlotte] Texas A&M Univ, Int Ocean Discovery Program, 1000 Discovery Dr, College Stn, TX 77845 USA.
   [Frederick, Bruce] Univ Kansas, Dept Geol, Lawrence, KS 66045 USA.
C3 University of Texas System; University of Texas Austin; State University System of Florida; University of South Florida; Louisiana State University System; Louisiana State University; Louisiana State University System; Louisiana State University; NERC National Oceanography Centre; University of Southampton; State University System of Florida; Florida State University; Colgate University; University of Cambridge; Texas A&M University System; Texas A&M University College Station; University of Kansas
RP Gulick, SPS (corresponding author), Univ Texas Austin, Inst Geophys, Jackson Sch Geosci, Austin, TX 78758 USA.
EM sean@ig.utexas.edu
FU National Science Foundation [NSF PLR-1143836, PLR-1143837, PLR-1143843, PLR-1430550, PLR-1048343]; GSA graduate student research grant; UTIG [3137]; Natural Environment Research Council [NE/L007452/1] Funding Source: researchfish; NERC [NE/L007452/1] Funding Source: UKRI; Directorate For Geosciences; Office of Polar Programs (OPP) [1048343] Funding Source: National Science Foundation
NR 64
TC 108
Z9 127
U1 2
U2 120
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 14
PY 2017
VL 552
IS 7684
BP 225
EP +
DI 10.1038/nature25026
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ0FK
UT WOS:000418029500041
PM 29239353
DA 2026-03-09
ER

PT J
AU Nishi, M
   Kuwayama, Y
   Tsuchiya, J
   Tsuchiya, T
AF Nishi, Masayuki
   Kuwayama, Yasuhiro
   Tsuchiya, Jun
   Tsuchiya, Taku
TI The pyrite-type high-pressure form of FeOOH
SO NATURE
LA English
DT Article
ID equation-of-state; core-mantle boundary; iron-water reaction; x-ray-diffraction; velocity zones; delta-alooh; phase; transition; stability; transport
AB Water transported into Earth's interior by subduction strongly influences dynamics such as volcanism and plate tectonics(1-3). Several recent studies have reported hydrous minerals to be stable at pressure and temperature conditions representative of Earth's deep interior, implying that surface water may be transported as far as the core-mantle boundary(4-8). However, the hydrous mineral goethite, alpha-FeOOH, was recently reported(9) to decompose under the conditions of the middle region of the lower mantle to form FeO2 and release H-2, suggesting the upward migration of hydrogen and large fluctuations in the oxygen distribution within the Earth system. Here we report the stability of FeOOH phases at the pressure and temperature conditions of the deep lower mantle, based on first-principles calculations and in situ X-ray diffraction experiments. In contrast to previous work suggesting the dehydrogenation of FeOOH into FeO2 in the middle of the lower mantle(9), we report the formation of a new FeOOH phase with the pyrite-type framework of FeO6 octahedra, which is much denser than the surrounding mantle and is stable at the conditions of the base of the mantle. Pyrite-type FeOOH may stabilize as a solid solution with other hydrous minerals in deeply subducted slabs, and could form in subducted banded iron formations. Deep-seated pyrite-type FeOOH eventually dissociates into Fe2O3 and releases H2O when subducted slabs are heated at the base of the mantle. This process may cause the incorporation of hydrogen into the outer core by the formation of iron hydride, FeHx, in the reducing environment of the core-mantle boundary.
C1 [Nishi, Masayuki; Kuwayama, Yasuhiro; Tsuchiya, Jun; Tsuchiya, Taku] Ehime Univ, Geodynam Res Ctr, 2-5 Bunkyo Cho, Matsuyama, Ehime 7908577, Japan.
   [Nishi, Masayuki; Tsuchiya, Jun; Tsuchiya, Taku] Tokyo Inst Technol, Earth Life Sci Inst, Meguro Ku, 2-2-1 IE 1 Ookayama, Tokyo 1528550, Japan.
   [Kuwayama, Yasuhiro] Univ Tokyo, Sch Sci, Dept Earth & Planetary Sci, Bunkyo Ku, Hongo 7-3-1, Tokyo 1130033, Japan.
C3 Ehime University; Institute of Science Tokyo; Tokyo Institute of Technology; University of Tokyo
RP Nishi, M; Tsuchiya, J (corresponding author), Ehime Univ, Geodynam Res Ctr, 2-5 Bunkyo Cho, Matsuyama, Ehime 7908577, Japan.; Nishi, M; Tsuchiya, J (corresponding author), Tokyo Inst Technol, Earth Life Sci Inst, Meguro Ku, 2-2-1 IE 1 Ookayama, Tokyo 1528550, Japan.
EM nishi@sci.ehime-u.ac.jp; junt@ehime-u.ac.jp
FU MEXT/JSPS KAKENHI [JP15H05469, JP25220712, JP15H05829, JP16H06285, JP26800274, JP26400516, JP26287137, JP15H05834]; MEXT; RIKEN Advanced Institute for Computational Science through the HPCI System Research project [hp160251/hp170220]; Grants-in-Aid for Scientific Research [15H05834, 15H05829, 15H05826, 15K21712, 15H05469] Funding Source: KAKEN
NR 48
TC 143
Z9 163
U1 6
U2 184
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 13
PY 2017
VL 547
IS 7662
BP 205
EP +
DI 10.1038/nature22823
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FA3AX
UT WOS:000405314500036
PM 28678774
DA 2026-03-09
ER

PT J
AU Hall, MR
   Kocot, KM
   Baughman, KW
   Fernandez-Valverde, SL
   Gauthier, MEA
   Hatleberg, WL
   Krishnan, A
   McDougall, C
   Motti, CA
   Shoguchi, E
   Wang, TF
   Xiang, XY
   Zhao, M
   Bose, U
   Shinzato, C
   Hisata, K
   Fujie, M
   Kanda, M
   Cummins, SF
   Satoh, N
   Degnan, SM
   Degnan, BM
AF Hall, Michael R.
   Kocot, Kevin M.
   Baughman, Kenneth W.
   Fernandez-Valverde, Selene L.
   Gauthier, Marie E. A.
   Hatleberg, William L. .
   Krishnan, Arunkumar
   McDougall, Carmel
   Motti, Cherie A.
   Shoguchi, Eiichi
   Wang, Tianfang
   Xiang, Xueyan
   Zhao, Min
   Bose, Utpal
   Shinzato, Chuya
   Hisata, Kanako
   Fujie, Manabu
   Kanda, Miyuki
   Cummins, Scott F.
   Satoh, Noriyuki
   Degnan, Sandie M.
   Degnan, Bernard M.
TI The crown-of-thorns starfish genome as a guide for biocontrol of this coral reef pest
SO NATURE
LA English
DT Article
ID hidden markov model; acanthaster-planci; phylogenomic resolution; transmembrane topology; read alignment; receptor genes; identification; hemichordate; echinoderm; evolution
AB The crown-of-thorns starfish (COTS, the Acanthaster planci species group) is a highly fecund predator of reef-building corals throughout the Indo-Pacific region(1). COTS population outbreaks cause substantial loss of coral cover, diminishing the integrity and resilience of reef ecosystems(2-6). Here we sequenced genomes of COTS from the Great Barrier Reef, Australia and Okinawa, Japan to identify gene products that underlie species-specific communication and could potentially be used in biocontrol strategies. We focused on water-borne chemical plumes released from aggregating COTS, which make the normally sedentary starfish become highly active. Peptide sequences detected in these plumes by mass spectrometry are encoded in the COTS genome and expressed in external tissues. The exoproteome released by aggregating COTS consists largely of signalling factors and hydrolytic enzymes, and includes an expanded and rapidly evolving set of starfish-specific ependymin-related proteins. These secreted proteins may be detected by members of a large family of olfactory-receptor-like G-protein-coupled receptors that are expressed externally, sometimes in a sex-specific manner. This study provides insights into COTS-specific communication that may guide the generation of peptide mimetics for use on reefs with COTS outbreaks.
C1 [Hall, Michael R.; Motti, Cherie A.; Bose, Utpal] Australian Inst Marine Sci, Cape Ferguson, PMB 3, Townsville, Qld 4810, Australia.
   [Kocot, Kevin M.; Fernandez-Valverde, Selene L.; Gauthier, Marie E. A.; Hatleberg, William L. .; Krishnan, Arunkumar; McDougall, Carmel; Xiang, Xueyan; Zhao, Min; Degnan, Sandie M.; Degnan, Bernard M.] Univ Queensland, Sch Biol Sci, Ctr Marine Sci, Brisbane, Qld 4072, Australia.
   [Baughman, Kenneth W.; Shoguchi, Eiichi; Shinzato, Chuya; Hisata, Kanako; Satoh, Noriyuki] Grad Univ, Inst Sci & Technol, Marine Genom Unit, Onna, Okinawa 9040495, Japan.
   [Wang, Tianfang; Zhao, Min; Bose, Utpal; Cummins, Scott F.] Univ Sunshine Coast, Genecol Res Ctr, Maroochydore, Qld 4558, Australia.
   [Fujie, Manabu; Kanda, Miyuki] Grad Univ, Okinawa Inst Sci & Technol, DNA Sequencing Sect, Onna, Okinawa 9040495, Japan.
   [Kocot, Kevin M.] Univ Alabama, Dept Biol Sci, Tuscaloosa, AL 35487 USA.
   [Kocot, Kevin M.] Univ Alabama, Alabama Museum Nat Hist, Tuscaloosa, AL 35487 USA.
   [Fernandez-Valverde, Selene L.] Ctr Invest & Estud Avanzados IPN Irapuato, CONACYT, Lab Nacl Genom Biodiversidad, Guanajuato, Mexico.
C3 Australian Institute of Marine Science; University of Queensland; University of the Sunshine Coast; Okinawa Institute of Science & Technology Graduate University; University of Alabama System; University of Alabama Tuscaloosa; University of Alabama System; University of Alabama Tuscaloosa; Consejo Nacional de Ciencia y Tecnologia (CONACyT)
RP Degnan, BM (corresponding author), Univ Queensland, Sch Biol Sci, Ctr Marine Sci, Brisbane, Qld 4072, Australia.
EM b.degnan@uq.edu.au
FU Australian Research Council; Australian Government Department of Environment Reef Rescue Program; OIST for Marine Genomics Unit; NSF International Postdoctoral Research Fellowship
NR 78
TC 147
Z9 168
U1 4
U2 144
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 13
PY 2017
VL 544
IS 7649
BP 231
EP +
DI 10.1038/nature22033
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ER6EK
UT WOS:000398897900037
PM 28379940
DA 2026-03-09
ER

PT J
AU Schwarzer, W
   Abdennur, N
   Goloborodko, A
   Pekowska, A
   Fudenberg, G
   Loe-Mie, Y
   Fonseca, NA
   Huber, W
   Haering, CH
   Mirny, L
   Spitz, F
AF Schwarzer, Wibke
   Abdennur, Nezar
   Goloborodko, Anton
   Pekowska, Aleksandra
   Fudenberg, Geoffrey
   Loe-Mie, Yann
   Fonseca, Nuno A.
   Huber, Wolfgang
   Haering, Christian H.
   Mirny, Leonid
   Spitz, Francois
TI Two independent modes of chromatin organization revealed by cohesin removal
SO NATURE
LA English
DT Article
ID topological domains; gene-expression; cre recombinase; ctcf binding; human genome; principles; reorganization; architecture; dynamics; maps
AB Imaging and chromosome conformation capture studies have revealed several layers of chromosome organization, including segregation into megabase-sized active and inactive compartments, and partitioning into sub-megabase domains (TADs). It remains unclear, however, how these layers of organization form, interact with one another and influence genome function. Here we show that deletion of the cohesin-loading factor Nipbl in mouse liver leads to a marked reorganization of chromosomal folding. TADs and associated Hi-C peaks vanish globally, even in the absence of transcriptional changes. By contrast, compartmental segregation is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the three-dimensional organization of the genome results from the interplay of two independent mechanisms: cohesin-independent segregation of the genome into fine-scale compartments, defined by chromatin state; and cohesin-dependent formation of TADs, possibly by loop extrusion, which helps to guide distant enhancers to their target genes.
C1 [Schwarzer, Wibke; Spitz, Francois] European Mol Biol Lab, Dev Biol Unit, D-69117 Heidelberg, Germany.
   [Abdennur, Nezar] MIT, Computat & Syst Biol Program, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Goloborodko, Anton; Mirny, Leonid] MIT, Dept Phys, Cambridge, MA 02139 USA.
   [Pekowska, Aleksandra; Huber, Wolfgang; Spitz, Francois] European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany.
   [Fudenberg, Geoffrey; Mirny, Leonid] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Loe-Mie, Yann; Spitz, Francois] Inst Pasteur, Epi Genom Anim Dev Unit, Dev & Stem Cell Biol Dept, F-75015 Paris, France.
   [Loe-Mie, Yann; Spitz, Francois] CNRS, UMR3738, 25 Rue Dr Roux, F-75015 Paris, France.
   [Fonseca, Nuno A.] Wellcome Trust Genome Campus, European Bioinformat Inst, European Mol Biol Lab, Hinxton, Cambridgeshire, England.
   [Haering, Christian H.] European Mol Biol Lab, Cell Biol & Biophys Unit, D-69117 Heidelberg, Germany.
C3 European Molecular Biology Laboratory (EMBL); Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); European Molecular Biology Laboratory (EMBL); Massachusetts Institute of Technology (MIT); Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute; Wellcome Trust Sanger Institute; European Molecular Biology Laboratory (EMBL)
RP Spitz, F (corresponding author), European Mol Biol Lab, Dev Biol Unit, D-69117 Heidelberg, Germany.; Mirny, L (corresponding author), MIT, Dept Phys, Cambridge, MA 02139 USA.; Spitz, F (corresponding author), European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany.; Mirny, L (corresponding author), MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Spitz, F (corresponding author), Inst Pasteur, Epi Genom Anim Dev Unit, Dev & Stem Cell Biol Dept, F-75015 Paris, France.; Spitz, F (corresponding author), CNRS, UMR3738, 25 Rue Dr Roux, F-75015 Paris, France.
EM leonid@mit.edu; francois.spitz@pasteur.fr
FU EMBL Interdisciplinary Postdoc (EIPOD) Fellowship under Marie Curie Actions COFUND; NIH [R01 GM114190, U54 DK107980]; NSF [1504942]; MIT-France MISTI Fund; EMBL; Pasteur Institute; Deutsche Forschungsgesellschaft (DFG) [SP 1331/3-1]; European Commission's Seventh Framework Programme through the Collaborative Research Project RADIANT [305626]; Direct For Mathematical & Physical Scien; Division Of Physics [1504942] Funding Source: National Science Foundation; National Institute of General Medical Sciences [R01GM114190] Funding Source: NIH RePORTER
NR 69
TC 849
Z9 1016
U1 1
U2 130
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 2
PY 2017
VL 551
IS 7678
BP 51
EP +
DI 10.1038/nature24281
PG 28
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FL4SY
UT WOS:000414222900042
PM 29094699
DA 2026-03-09
ER

PT J
AU Ma, CY
   Kurita, D
   Li, NN
   Chen, Y
   Himeno, H
   Gao, N
AF Ma, Chengying
   Kurita, Daisuke
   Li, Ningning
   Chen, Yan
   Himeno, Hyouta
   Gao, Ning
TI Mechanistic insights into the alternative translation termination by ArfA and RF2
SO NATURE
LA English
DT Article
ID peptidyl-transfer-rna; ribosome-rescue; escherichia-coli; stalled ribosm; nonstop translation; crystal-structure; structural basis; messenger-rna; release; tmrna
AB During cellular translation of messenger RNAs by ribosomes, the translation apparatus sometimes pauses or stalls at the elongation and termination steps(1-6). With the exception of programmed stalling, which is usually used by cells for regulatory purposes(5,7,8), ribosomes stalled on mRNAs need to be terminated and recycled to maintain adequate translation capacity(9). Much ribosome stalling originates in aberrant mRNAs that lack a stop codon. Transcriptional errors, misprocessing of primary transcripts, and undesired mRNA cleavage all contribute to the formation of nonstop mRNAs. Ribosomes stalled at the 3' end of non-stop mRNAs do not undergo normal termination owing to the lack of specific stop-codon recognition by canonical peptide release factors at the A-site decoding centre. In bacteria, the transfer-messenger RNA (tmRNA)-SmpB-mediated trans-translation rescue system reroutes stalled ribosomes to the normal elongation cycle and translation termination(3,4,10-12). Two additional rescue systems, ArfA-RF2 (refs 13-16) and ArfB (formerly known as YaeJ)(17,18), are also present in many bacterial species, but their mechanisms are not fully understood. Here, using cryo-electron microscopy, we characterize the structure of the Escherichia coli 70S ribosome bound with ArfA, the release factor RF2, a short non-stop mRNA and a cognate P-site tRNA. The C-terminal loop of ArfA occupies the mRNA entry channel on the 30S subunit, whereas its N terminus is sandwiched between the decoding centre and the switch loop of RF2, leading to marked conformational changes in both the decoding centre and RF2. Despite the distinct conformation of RF2, its conserved catalytic GGQ motif is precisely positioned next to the CCA-end of the P-site tRNA. These data illustrate a stop-codon surrogate mechanism for ArfA in facilitating the termination of non-stop ribosomal complexes by RF2.
C1 [Ma, Chengying; Chen, Yan; Gao, Ning] Tsinghua Univ, Sch Life Sci, Beijing Adv Innovat Ctr Struct Biol, Minist Educ,Key Lab Prot Sci, Beijing 100084, Peoples R China.
   [Kurita, Daisuke; Himeno, Hyouta] Hirosaki Univ, Fac Agr & Life Sci, Dept Biochem & Mol Biol, Hirosaki, Aomori 0368561, Japan.
   [Li, Ningning] Peking Univ, Sch Life Sci, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China.
C3 Tsinghua University; Hirosaki University; Peking University
RP Gao, N (corresponding author), Tsinghua Univ, Sch Life Sci, Beijing Adv Innovat Ctr Struct Biol, Minist Educ,Key Lab Prot Sci, Beijing 100084, Peoples R China.; Himeno, H (corresponding author), Hirosaki Univ, Fac Agr & Life Sci, Dept Biochem & Mol Biol, Hirosaki, Aomori 0368561, Japan.
EM himeno@hirosaki-u.ac.jp; ninggao@tsinghua.edu.cn
FU National Natural Science Foundation of China [31422016, 31470722, 31630087]; Ministry of Science and Technology of China [2016YFA0500700, 2013CB910404]; Japan Society for the Promotion of Science [16K18684]; Peking-Tsinghua Center for Life Sciences; Grants-in-Aid for Scientific Research [16K18684] Funding Source: KAKEN
NR 47
TC 36
Z9 100
U1 0
U2 31
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 26
PY 2017
VL 541
IS 7638
BP 550
EP 553
DI 10.1038/nature20822
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6LX
UT WOS:000396116600055
PM 27906160
DA 2026-03-09
ER

PT J
AU Elling, U
   Wimmer, RA
   Leibbrandt, A
   Urkard, TB
   Michlits, G
   Leopoldi, A
   Micheler, T
   Abdeen, D
   Zhuk, S
   Aspalter, IM
   Handl, C
   Liebergesell, J
   Hubmann, M
   Husa, AM
   Kinzer, M
   Schuller, N
   Wetzel, E
   van de Loo, N
   Martinez, JAZ
   Estoppey, D
   Riedl, R
   Yang, FT
   Fu, BY
   Dechat, T
   Ivics, Z
   Agu, CA
   Bell, O
   Blaas, D
   Gerhardt, H
   Hoepfner, D
   Stark, A
   Penninger, JM
AF Elling, Ulrich
   Wimmer, Reiner A.
   Leibbrandt, Andreas
   Urkard, Thomas B.
   Michlits, Georg
   Leopoldi, Alexandra
   Micheler, Thomas
   Abdeen, Dana
   Zhuk, Sergei
   Aspalter, Irene M.
   Handl, Cornelia
   Liebergesell, Julia
   Hubmann, Maria
   Husa, Anna-Maria
   Kinzer, Manuela
   Schuller, Nicole
   Wetzel, Ellen
   van de Loo, Nina
   Zepeda Martinez, Jorge Arturo
   Estoppey, David
   Riedl, Ralph
   Yang, Fengtang
   Fu, Beiyuan
   Dechat, Thomas
   Ivics, Zoltan
   Agu, Chukwuma A.
   Bell, Oliver
   Blaas, Dieter
   Gerhardt, Holger
   Hoepfner, Dominic
   Stark, Alexander
   Penninger, Josef M.
TI A reversible haploid mouse embryonic stem cell biobank resource for functional genomics
SO NATURE
LA English
DT Article
ID density-lipoprotein receptor; preimplantation development; mammalian-cells; essential genes; rnai screens; angiogenesis; identification; heterogeneity; mutagenesis; transposon
AB The ability to directly uncover the contributions of genes to a given phenotype is fundamental for biology research. However, ostensibly homogeneous cell populations exhibit large clonal variance(1,2) that can confound analyses and undermine reproducibility(3). Here we used genome-saturated mutagenesis to create a biobank of over 100,000 individual haploid mouse embryonic stem (mES) cell lines targeting 16,970 genes with genetically barcoded, conditional and reversible mutations. This Haplobank is, to our knowledge, the largest resource of hemi/homozygous mutant mES cells to date and is available to all researchers. Reversible mutagenesis overcomes clonal variance by permitting functional annotation of the genome directly in sister cells. We use the Haplobank in reverse genetic screens to investigate the temporal resolution of essential genes in mES cells, and to identify novel genes that control sprouting angiogenesis and lineage specification of blood vessels. Furthermore, a genome-wide forward screen with Haplobank identified PLA2G16 as a host factor that is required for cytotoxicity by rhinoviruses, which cause the common cold. Therefore, clones from the Haplobank combined with the use of reversible technologies enable high-throughput, reproducible, functional annotation of the genome.
C1 [Elling, Ulrich; Wimmer, Reiner A.; Leibbrandt, Andreas; Urkard, Thomas B.; Michlits, Georg; Leopoldi, Alexandra; Abdeen, Dana; Zhuk, Sergei; Handl, Cornelia; Liebergesell, Julia; Hubmann, Maria; Husa, Anna-Maria; Kinzer, Manuela; Schuller, Nicole; Wetzel, Ellen; van de Loo, Nina; Zepeda Martinez, Jorge Arturo; Agu, Chukwuma A.; Bell, Oliver; Penninger, Josef M.] Austrian Acad Sci IMBA, Inst Mol Biotechnol, Vienna Bioctr VBC, Dr Bohr Gasse 3, Vienna, Austria.
   [Micheler, Thomas] Vienna Bioctr VBC, Vienna Bioctr Core Facil, Dr Bohr Gasse 3, Vienna, Austria.
   [Aspalter, Irene M.] UCL, MRC Lab Mol Cell Biol, London, England.
   [Aspalter, Irene M.] UCL, Inst Phys Living Syst, London, England.
   [Estoppey, David; Riedl, Ralph; Hoepfner, Dominic] Novartis Inst BioMed Res, Basel, Switzerland.
   [Yang, Fengtang; Fu, Beiyuan] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.
   [Dechat, Thomas; Blaas, Dieter] Med Univ Vienna, Max F Perutz Labs, Dr Bohr Gasse 9, Vienna, Austria.
   [Ivics, Zoltan] Paul Ehrlich Inst, Paul Ehrlich Str 51-59, D-63225 Langen, Germany.
   [Gerhardt, Holger] Helmholtz Assoc, Max Delbruck Ctr Mol Med, Berlin, Germany.
   [Gerhardt, Holger] German Ctr Cardiovasc Res, Berlin, Germany.
   [Gerhardt, Holger] Berlin Inst Hlth, Berlin, Germany.
   [Stark, Alexander] Vienna Bioctr VBC, Res Inst Mol Pathol IMP, Dr Bohr Gasse 7, A-1030 Vienna, Austria.
C3 Vienna Biocenter (VBC); Institute of Molecular Biotechnology (IMBA); Austrian Academy of Sciences; Vienna Biocenter (VBC); University of London; University College London; MRC Laboratory Molecular Biology; University of London; University College London; Novartis; Wellcome Trust Sanger Institute; Vienna Biocenter (VBC); Max F. Perutz Laboratories (MFPL); Medical University of Vienna; Paul Ehrlich Institute; Helmholtz Association; Max Delbruck Center for Molecular Medicine; German Centre for Cardiovascular Research; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Vienna Biocenter (VBC); Research Institute of Molecular Pathology (IMP)
RP Elling, U; Penninger, JM (corresponding author), Austrian Acad Sci IMBA, Inst Mol Biotechnol, Vienna Bioctr VBC, Dr Bohr Gasse 3, Vienna, Austria.
EM Ulrich.elling@imba.oeaw.ac.at; josef.penninger@imba.oeaw.ac.at
FU Austrian National Bank (OeNB), an Advanced ERC grant; Era of Hope/National Coalition against Breast Cancer/DoD; ERC; Boehringer Ingelheim; FFG;  [FWF P23308-B13]; Austrian Science Fund (FWF) [P27444, P23308] Funding Source: Austrian Science Fund (FWF); Austrian Science Fund (FWF) [P 27444, P 23308] Funding Source: researchfish
NR 49
TC 61
Z9 67
U1 0
U2 23
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 5
PY 2017
VL 550
IS 7674
BP 114
EP +
DI 10.1038/nature24027
PG 27
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI7XU
UT WOS:000412214100056
PM 28953874
DA 2026-03-09
ER

PT J
AU Kits, KD
   Sedlacek, CJ
   Lebedeva, EV
   Han, P
   Bulaev, A
   Pjevac, P
   Daebeler, A
   Romano, S
   Albertsen, M
   Stein, LY
   Daims, H
   Wagner, M
AF Kits, K. Dimitri
   Sedlacek, Christopher J.
   Lebedeva, Elena V.
   Han, Ping
   Bulaev, Alexandr
   Pjevac, Petra
   Daebeler, Anne
   Romano, Stefano
   Albertsen, Mads
   Stein, Lisa Y.
   Daims, Holger
   Wagner, Michael
TI Kinetic analysis of a complete nitrifier reveals an oligotrophic lifestyle
SO NATURE
LA English
DT Article
ID ammonia-oxidizing archaeon; oxidation-kinetics; nitrite oxidation; nitrososphaera-viennensis; complete nitrification; nitrosomonas-europaea; bacteria; water; soil; community
AB Nitrification, the oxidation of ammonia (NH3) via nitrite (NO2-) to nitrate (NO3-), is a key process of the biogeochemical nitrogen cycle. For decades, ammonia and nitrite oxidation were thought to be separately catalysed by ammonia-oxidizing bacteria (AOB) and archaea (AOA), and by nitrite-oxidizing bacteria (NOB). The recent discovery of complete ammonia oxidizers (comammox) in the NOB genus Nitrospira(1,2), which alone convert ammonia to nitrate, raised questions about the ecological niches in which comammox Nitrospira successfully compete with canonical nitrifiers. Here we isolate a pure culture of a comammox bacterium, Nitrospira inopinata, and show that it is adapted to slow growth in oligotrophic and dynamic habitats on the basis of a high affinity for ammonia, low maximum rate of ammonia oxidation, high growth yield compared to canonical nitrifiers, and genomic potential for alternative metabolisms. The nitrification kinetics of four AOA from soil and hot springs were determined for comparison. Their surprisingly poor substrate affinities and lower growth yields reveal that, in contrast to earlier assumptions, AOA are not necessarily the most competitive ammonia oxidizers present in strongly oligotrophic environments and that N. inopinata has the highest substrate affinity of all analysed ammonia oxidizer isolates except the marine AOA Nitrosopumilus maritimus SCM1 (ref. 3). These results suggest a role for comammox organisms in nitrification under oligotrophic and dynamic conditions.
C1 [Kits, K. Dimitri; Sedlacek, Christopher J.; Han, Ping; Pjevac, Petra; Daebeler, Anne; Romano, Stefano; Daims, Holger; Wagner, Michael] Univ Vienna, Div Microbial Ecol, Dept Microbiol & Ecosyst Sci, Res Network Chem Meets Microbiol, Althanstr 14, A-1090 Vienna, Austria.
   [Lebedeva, Elena V.; Bulaev, Alexandr] Russian Acad Sci, Biotechnol Res Ctr, Winogradsky Inst Microbiol, Leninsky Ave 33,Bld 2, Moscow 119071, Russia.
   [Albertsen, Mads] Aalborg Univ, Dept Chem & Biosci, Ctr Microbial Communities, Fredrik Bajers Vej 7H, DK-9220 Aalborg, Denmark.
   [Stein, Lisa Y.] Univ Alberta, Dept Biol Sci, CW405 Biol Sci Bldg, Edmonton, AB T6G 2E9, Canada.
C3 University of Vienna; Russian Academy of Sciences; Research Center of Biotechnology RAS; Aalborg University; University of Alberta
RP Daims, H (corresponding author), Univ Vienna, Div Microbial Ecol, Dept Microbiol & Ecosyst Sci, Res Network Chem Meets Microbiol, Althanstr 14, A-1090 Vienna, Austria.
EM daims@microbial-ecology.net
FU European Research Council Advanced Grant project [NITRICARE 294343]; Austrian Science Fund (FWF) [P27319-B21]; FWF [P25231-B21]; Natural Sciences and Engineering Research Council of Canada [RGPIN-2014-03745]; VILLUM FONDEN [15510]; Austrian Science Fund (FWF) [P27319] Funding Source: Austrian Science Fund (FWF); Villum Fonden [00015510] Funding Source: researchfish
NR 55
TC 677
Z9 793
U1 47
U2 1224
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 14
PY 2017
VL 549
IS 7671
BP 269
EP +
DI 10.1038/nature23679
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG7AE
UT WOS:000410555900045
PM 28847001
DA 2026-03-09
ER

PT J
AU Liu, XY
   Ahn, S
   Kahsai, AW
   Meng, KC
   Latorraca, NR
   Pani, B
   Venkatakrishnan, AJ
   Masoudi, A
   Weis, WI
   Dror, RO
   Chen, X
   Lefkowitz, RJ
   Kobilka, BK
AF Liu, Xiangyu
   Ahn, Seungkirl
   Kahsai, Alem W.
   Meng, Kai-Cheng
   Latorraca, Naomi R.
   Pani, Biswaranjan
   Venkatakrishnan, A. J.
   Masoudi, Ali
   Weis, William I.
   Dror, Ron O.
   Chen, Xin
   Lefkowitz, Robert J.
   Kobilka, Brian K.
TI Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure
SO NATURE
LA English
DT Article
ID general force-field; molecular-dynamics; validation; automation; activation; proteins; insights
AB G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects. The majority of GPCR crystal structures published to date were obtained with receptors bound to orthosteric antagonists, and only a few structures bound to allosteric ligands have been reported. Compound 15 (Cmpd-15) is an allosteric modulator of the beta(2) adrenergic receptor (beta(2)AR) that was recently isolated from a DNA-encoded small-molecule library(1). Orthosteric beta-adrenergic receptor antagonists, known as beta-blockers, are amongst the most prescribed drugs in the world and Cmpd-15 is the first allosteric beta-blocker. Cmpd-15 exhibits negative cooperativity with agonists and positive cooperativity with inverse agonists. Here we present the structure of the beta(2)AR bound to a polyethylene glycol-carboxylic acid derivative (Cmpd-15PA) of this modulator. Cmpd-15PA binds to a pocket formed primarily by the cytoplasmic ends of transmembrane segments 1, 2, 6 and 7 as well as intracellular loop 1 and helix 8. A comparison of this structure with inactive-and active-state structures of the beta(2)AR reveals the mechanism by which Cmpd-15 modulates agonist binding affinity and signalling.
C1 [Liu, Xiangyu; Kobilka, Brian K.] Tsinghua Univ, Sch Med, Beijing Adv Innovat Ctr Struct Biol, Beijing 100084, Peoples R China.
   [Ahn, Seungkirl; Kahsai, Alem W.; Pani, Biswaranjan; Masoudi, Ali; Lefkowitz, Robert J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA.
   [Meng, Kai-Cheng; Chen, Xin] Changzhou Univ, Sch Pharmaceut Engn & Life Sci, Dept Med Chem, Changzhou 213164, Jiangsu, Peoples R China.
   [Latorraca, Naomi R.; Venkatakrishnan, A. J.; Dror, Ron O.] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA.
   [Latorraca, Naomi R.; Venkatakrishnan, A. J.; Dror, Ron O.] Stanford Univ, Inst Computat & Math Engn, Stanford, CA 94305 USA.
   [Venkatakrishnan, A. J.; Kobilka, Brian K.] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, 279 Campus Dr, Stanford, CA 94305 USA.
   [Weis, William I.] Stanford Univ, Sch Med, Dept Struct Biol, Stanford, CA 94305 USA.
   [Lefkowitz, Robert J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA.
   [Lefkowitz, Robert J.] Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC 27710 USA.
C3 Tsinghua University; Duke University; Changzhou University; Stanford University; Stanford University; Stanford University; Stanford University; Duke University; Howard Hughes Medical Institute; Duke University
RP Kobilka, BK (corresponding author), Tsinghua Univ, Sch Med, Beijing Adv Innovat Ctr Struct Biol, Beijing 100084, Peoples R China.; Lefkowitz, RJ (corresponding author), Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA.; Kobilka, BK (corresponding author), Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, 279 Campus Dr, Stanford, CA 94305 USA.; Lefkowitz, RJ (corresponding author), Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA.; Lefkowitz, RJ (corresponding author), Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC 27710 USA.
EM lefko001@receptor-biol.duke.edu; kobilka@stanford.edu
FU National Institute of Health [NS028471, GM106990, HL16037, T32HL007101]; Amgen-China Postdoc fellowship; Mathers Foundation; National Heart Lung and Blood Institute [R01HL016037] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [R01NS028471] Funding Source: NIH RePORTER
NR 40
TC 158
Z9 185
U1 3
U2 80
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 24
PY 2017
VL 548
IS 7668
BP 480
EP +
DI 10.1038/nature23652
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FE5VI
UT WOS:000408279000044
PM 28813418
DA 2026-03-09
ER

PT J
AU Kategaya, L
   Di Lello, P
   Rougé, L
   Pastor, R
   Clark, KR
   Drummond, J
   Kleinheinz, T
   Lin, E
   Upton, JP
   Prakash, S
   Heideker, J
   McCleland, M
   Ritorto, MS
   Alessi, DR
   Trost, M
   Bainbridge, TW
   Kwok, MCM
   Ma, TP
   Stiffler, Z
   Brasher, B
   Tang, YY
   Jaishankar, P
   Hearn, BR
   Renslo, AR
   Arkin, MR
   Cohen, F
   Yu, KB
   Peale, F
   Gnad, F
   Chang, MT
   Klijn, C
   Blackwood, E
   Martin, SE
   Forrest, WF
   Ernst, JA
   Ndubaku, C
   Wang, XJ
   Beresini, MH
   Tsui, V
   Schwerdtfeger, C
   Blake, RA
   Murray, J
   Maurer, T
   Wertz, IE
AF Kategaya, Lorna
   Di Lello, Paola
   Rouge, Lionel
   Pastor, Richard
   Clark, Kevin R.
   Drummond, Jason
   Kleinheinz, Tracy
   Lin, Eva
   Upton, John-Paul
   Prakash, Sumit
   Heideker, Johanna
   McCleland, Mark
   Ritorto, Maria Stella
   Alessi, Dario R.
   Trost, Matthias
   Bainbridge, Travis W.
   Kwok, Michael C. M.
   Ma, Taylur P.
   Stiffler, Zachary
   Brasher, Bradley
   Tang, Yinyan
   Jaishankar, Priyadarshini
   Hearn, Brian R.
   Renslo, Adam R.
   Arkin, Michelle R.
   Cohen, Frederick
   Yu, Kebing
   Peale, Frank
   Gnad, Florian
   Chang, Matthew T.
   Klijn, Christiaan
   Blackwood, Elizabeth
   Martin, Scott E.
   Forrest, William F.
   Ernst, James A.
   Ndubaku, Chudi
   Wang, Xiaojing
   Beresini, Maureen H.
   Tsui, Vickie
   Schwerdtfeger, Carsten
   Blake, Robert A.
   Murray, Jeremy
   Maurer, Till
   Wertz, Ingrid E.
TI USP7 small-molecule inhibitors interfere with ubiquitin binding
SO NATURE
LA English
DT Article
ID deubiquitinating enzyme; linked ubiquitin
AB The ubiquitin system regulates essential cellular processes in eukaryotes. Ubiquitin is ligated to substrate proteins as monomers or chains and the topology of ubiquitin modifications regulates substrate interactions with specific proteins. Thus ubiquitination directs a variety of substrate fates including proteasomal degradation(1). Deubiquitinase enzymes cleave ubiquitin from substrates and are implicated in disease(2); for example, ubiquitin-specific protease-7 (USP7) regulates stability of the p53 tumour suppressor and other proteins critical for tumour cell survival(3). However, developing selective deubiquitinase inhibitors has been challenging(4) and no co-crystal structures have been solved with small-molecule inhibitors. Here, using nuclear magnetic resonance-based screening and structure-based design, we describe the development of selective USP7 inhibitors GNE-6640 and GNE-6776. These compounds induce tumour cell death and enhance cytotoxicity with chemotherapeutic agents and targeted compounds, including PIM kinase inhibitors. Structural studies reveal that GNE-6640 and GNE-6776 non-covalently target USP7 12 angstrom distant from the catalytic cysteine. The compounds attenuate ubiquitin binding and thus inhibit USP7 deubiquitinase activity. GNE-6640 and GNE-6776 interact with acidic residues that mediate hydrogen-bond interactions with the ubiquitin Lys48 side chain5, suggesting that USP7 preferentially interacts with and cleaves ubiquitin moieties that have free Lys48 side chains. We investigated this idea by engineering di-ubiquitin chains containing differential proximal and distal isotopic labels and measuring USP7 binding by nuclear magnetic resonance. This preferential binding protracted the depolymerization kinetics of Lys48-linked ubiquitin chains relative to Lys63-linked chains. In summary, engineering compounds that inhibit USP7 activity by attenuating ubiquitin binding suggests opportunities for developing other deubiquitinase inhibitors and may be a strategy more broadly applicable to inhibiting proteins that require ubiquitin binding for full functional activity.
C1 [Kategaya, Lorna; Lin, Eva; Upton, John-Paul; Prakash, Sumit; Heideker, Johanna; McCleland, Mark; Martin, Scott E.; Wertz, Ingrid E.] Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA.
   [Kategaya, Lorna; Upton, John-Paul; Prakash, Sumit; Heideker, Johanna; McCleland, Mark; Wertz, Ingrid E.] Genentech Inc, Dept Early Discovery Biochem, San Francisco, CA 94080 USA.
   [Di Lello, Paola; Rouge, Lionel; Murray, Jeremy; Maurer, Till] Genentech Inc, Dept Struct Biol, San Francisco, CA 94080 USA.
   [Pastor, Richard; Cohen, Frederick; Ndubaku, Chudi; Wang, Xiaojing; Tsui, Vickie] Genentech Inc, Dept Discovery Chem, San Francisco, CA 94080 USA.
   [Clark, Kevin R.; Drummond, Jason; Kleinheinz, Tracy; Beresini, Maureen H.; Blake, Robert A.] Genentech Inc, Dept Biochem & Cellular Pharmacol, San Francisco, CA 94080 USA.
   [Ritorto, Maria Stella; Alessi, Dario R.] Univ Dundee, Sch Life Sci, MRC Prot Phosphorylat & Ubiquitylat Unit, Dundee DD1 5EH, Scotland.
   [Trost, Matthias] Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE2 1HH, Tyne & Wear, England.
   [Bainbridge, Travis W.; Kwok, Michael C. M.; Ernst, James A.] Genentech Inc, Dept Prot Chem, San Francisco, CA 94080 USA.
   [Ma, Taylur P.; Yu, Kebing] Genentech Inc, Dept Microchem Prote & Lipid, San Francisco, CA 94080 USA.
   [Stiffler, Zachary; Brasher, Bradley; Schwerdtfeger, Carsten] Boston Biochem, 840 Mem Dr, Cambridge, MA 02139 USA.
   [Tang, Yinyan; Jaishankar, Priyadarshini; Hearn, Brian R.; Renslo, Adam R.; Arkin, Michelle R.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA.
   [Tang, Yinyan; Jaishankar, Priyadarshini; Hearn, Brian R.; Renslo, Adam R.; Arkin, Michelle R.] Univ Calif San Francisco, Small Mol Discovery Ctr, San Francisco, CA 94143 USA.
   [Peale, Frank] Genentech Inc, Dept Res Pathol, San Francisco, CA 94080 USA.
   [Gnad, Florian; Chang, Matthew T.; Klijn, Christiaan; Forrest, William F.] Genentech Inc, Dept Bioinformat & Computat Biol, San Francisco, CA 94080 USA.
   [Blackwood, Elizabeth] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA.
C3 Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Roche Holding USA; Genentech; University of Dundee; Newcastle University - UK; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Genentech; Roche Holding USA; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech
RP Wertz, IE (corresponding author), Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA.; Wertz, IE (corresponding author), Genentech Inc, Dept Early Discovery Biochem, San Francisco, CA 94080 USA.; Maurer, T (corresponding author), Genentech Inc, Dept Struct Biol, San Francisco, CA 94080 USA.
EM maurer.till@gene.com; ingrid@gene.com
FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]; DOE Office of Biological and Environmental Research; National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]; Medical Research Council [MC_UP_A500_1020, MC_UU_12016/5, MC_UU_12016/2] Funding Source: researchfish; MRC [MC_UU_12016/2, MC_UP_A500_1020, MC_UU_12016/5] Funding Source: UKRI
NR 30
TC 277
Z9 323
U1 6
U2 145
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 26
PY 2017
VL 550
IS 7677
BP 534
EP +
DI 10.1038/nature24006
PG 30
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK7OW
UT WOS:000413697800046
PM 29045385
DA 2026-03-09
ER

PT J
AU Giles, S
   Xu, GH
   Near, TJ
   Friedman, M
AF Giles, Sam
   Xu, Guang-Hui
   Near, Thomas J.
   Friedman, Matt
TI Early members of 'living fossil' lineage imply later origin of modern ray-finned fishes
SO NATURE
LA English
DT Article
ID actinopterygii; interrelationships; diversification; scanilepiform; polypterus; phylogeny; inference; scale; china
AB Modern ray-finned fishes (Actinopterygii) comprise half of extant vertebrate species and are widely thought to have originated before or near the end of the Middle Devonian epoch (around 385 million years ago)(1-4). Polypterids (bichirs and ropefish) represent the earliest-diverging lineage of living actinopterygians, with almost all Palaeozoic taxa interpreted as more closely related to other extant actinopterygians than to polypterids(5-10). By contrast, the earliest material assigned to the polypterid lineage is mid-Cretaceous in age (around 100 million years old)(11), implying a quarter-of-a-billion-year palaeontological gap. Here we show that scanilepiforms, a widely distributed radiation from the Triassic period (around 252-201 million years ago), are stem polypterids. Importantly, these fossils break the long polypterid branch and expose many supposedly primitive features of extant polypterids as reversals. This shifts numerous Palaeozoic ray-fins to the actinopterygian stem, reducing the minimum age for the crown lineage by roughly 45 million years. Recalibration of molecular clocks to exclude phylogenetically reassigned Palaeozoic taxa results in estimates that the actinopterygian crown lineage is about 20-40 million years younger than was indicated by previous molecular analyses(1-4). These new dates are broadly consistent with our revised palaeontological timescale and coincident with an interval of conspicuous morphological and taxonomic diversification among ray-fins centred on the Devonian-Carboniferous boundary(12-14). A shifting timescale, combined with ambiguity in the relationships of late Palaeozoic actinopterygians, highlights this part of the fossil record as a major frontier in understanding the evolutionary assembly of modern vertebrate diversity.
C1 [Giles, Sam; Friedman, Matt] Univ Oxford, Dept Earth Sci, South Parks Rd, Oxford OX1 3AN, England.
   [Xu, Guang-Hui] Chinese Acad Sci, Inst Vertebrate Paleontol & Paleoanthropol, Key Lab Vertebrate Evolut & Human Origins, Beijing 100044, Peoples R China.
   [Near, Thomas J.] Yale Univ, Dept Ecol & Evolutionary Biol, 165 Prospect St, New Haven, CT 06520 USA.
   [Near, Thomas J.] Yale Univ, Peabody Museum Nat Hist, 165 Prospect St, New Haven, CT 06520 USA.
   [Friedman, Matt] Univ Michigan, Museum Paleontol, 1109 Geddes Ave, Ann Arbor, MI 48109 USA.
   [Friedman, Matt] Univ Michigan, Dept Earth & Environm Sci, 1109 Geddes Ave, Ann Arbor, MI 48109 USA.
C3 University of Oxford; Chinese Academy of Sciences; Institute of Vertebrate Paleontology & Paleoanthropology, CAS; Yale University; Yale University; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan
RP Giles, S (corresponding author), Univ Oxford, Dept Earth Sci, South Parks Rd, Oxford OX1 3AN, England.
EM sam.giles@earth.ox.ac.uk
FU Junior Research Fellowship from Christ Church, Oxford; L'Oreal-UNESCO For Women in Science Fellowship; National Natural Science Foundation of China [41672001]; National Science Foundation [ANT-134166]; Bingham Oceanographic Fund from the Peabody Museum of Natural History, Yale University; Philip Leverhulme Prize [PLP-2012-130]; Leverhulme Trust Project Grant [RPG-2012-65A]
NR 43
TC 90
Z9 100
U1 0
U2 46
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 14
PY 2017
VL 549
IS 7671
BP 265
EP +
DI 10.1038/nature23654
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG7AE
UT WOS:000410555900044
PM 28854173
DA 2026-03-09
ER

PT J
AU Glenwright, AJ
   Pothula, KR
   Bhamidimarri, SP
   Chorev, DS
   Baslé, A
   Firbank, SJ
   Zheng, HJ
   Robinson, CV
   Winterhalter, M
   Kleinekathöfer, U
   Bolam, DN
   van den Berg, B
AF Glenwright, Amy J.
   Pothula, Karunakar R.
   Bhamidimarri, Satya P.
   Chorev, Dror S.
   Basle, Arnaud
   Firbank, Susan J.
   Zheng, Hongjun
   Robinson, Carol V.
   Winterhalter, Mathias
   Kleinekathoefer, Ulrich
   Bolam, David N.
   van den Berg, Bert
TI Structural basis for nutrient acquisition by dominant members of the human gut microbiota
SO NATURE
LA English
DT Article
ID outer-membrane proteins; tonb; software; complex; starch; recognition; validation; metabolism; catabolism
AB The human large intestine is populated by a high density of microorganisms, collectively termed the colonic microbiota(1), which has an important role in human health and nutrition(2). The survival of microbiota members from the dominant Gram-negative phylum Bacteroidetes depends on their ability to degrade dietary glycans that cannot be metabolized by the host(3). The genes encoding proteins involved in the degradation of specific glycans are organized into co-regulated polysaccharide utilization loci(4-8), with the archetypal locus sus (for starch utilisation system) encoding seven proteins, SusA-SusG(8-10). Glycan degradation mainly occurs intracellularly and depends on the import of oligosaccharides by an outer membrane protein complex composed of an extracellular SusD-like lipoprotein and an integral membrane SusC-like TonB-dependent transporter(4-7,11-13). The presence of the partner SusD-like lipoprotein is the major feature that distinguishes SusC-like proteins from previously characterized TonB-dependent transporters. Many sequenced gut Bacteroides spp. encode over 100 SusCD pairs, of which the majority have unknown functions and substrate specificities(3,8,14,15). The mechanism by which extracellular substrate binding by SusD proteins is coupled to outer membrane passage through their cognate SusC transporter is unknown. Here we present X-ray crystal structures of two functionally distinct SusCD complexes purified from Bacteroides thetaiotaomicron and derive a general model for substrate translocation. The SusC transporters form homodimers, with each beta-barrel protomer tightly capped by SusD. Ligands are bound at the SusC-SusD interface in a large solvent-excluded cavity. Molecular dynamics simulations and single-channel electrophysiology reveal a 'pedal bin' mechanism, in which SusD moves away from SusC in a hinge-like fashion in the absence of ligand to expose the substrate-binding site to the extracellular milieu. These data provide mechanistic insights into outer membrane nutrient import by members of the microbiota, an area of major importance for understanding human-microbiota symbiosis.
C1 [Glenwright, Amy J.; Basle, Arnaud; Firbank, Susan J.; Zheng, Hongjun; Bolam, David N.; van den Berg, Bert] Newcastle Univ, Sch Med, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
   [Pothula, Karunakar R.; Kleinekathoefer, Ulrich] Jacobs Univ Bremen, Dept Phys & Earth Sci, D-28759 Bremen, Germany.
   [Bhamidimarri, Satya P.; Winterhalter, Mathias] Jacobs Univ Bremen, Dept Life Sci & Chem, D-28759 Bremen, Germany.
   [Chorev, Dror S.; Robinson, Carol V.] Univ Oxford, Phys & Theoret Chem Lab, South Parks Rd, Oxford OX1 3QZ, England.
C3 Newcastle University - UK; Constructor University; Constructor University; University of Oxford
RP van den Berg, B (corresponding author), Newcastle Univ, Sch Med, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
EM bert.van-den-berg@ncl.ac.uk
FU Barbour Foundation; EU FP7-PEOPLE-ITN Translocation network [607694]; Innovative Medicines Initiatives Joint Undertaking [115525]; European Union
NR 51
TC 174
Z9 217
U1 5
U2 205
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 19
PY 2017
VL 541
IS 7637
BP 407
EP +
DI 10.1038/nature20828
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6QP
UT WOS:000396128800045
PM 28077872
DA 2026-03-09
ER

PT J
AU Sok, D
   Le, KM
   Vadnais, ML
   Saye-Francisco, KL
   Jardine, JG
   Torres, JL
   Berndsen, ZT
   Kong, L
   Tanfield, RS
   Ruiz, J
   Ramos, A
   Liang, CH
   Chen, PL
   Criscitiello, MF
   Mwangi, W
   Wilson, IA
   Ward, AB
   Smider, VV
   Burton, DR
AF Sok, Devin
   Le, Khoa M.
   Vadnais, Melissa L.
   Saye-Francisco, Karen L.
   Jardine, Joseph G.
   Torres, Jonathan L.
   Berndsen, Zachary T.
   Kong, Leopold
   Tanfield, Robyn S.
   Ruiz, Jennifer
   Ramos, Alejandra
   Liang, Chi-Hui
   Chen, Patricia L.
   Criscitiello, Michael F.
   Mwangi, Waithaka
   Wilson, Ian A.
   Ward, Andrew B.
   Smider, Vaughn V.
   Burton, Dennis R.
TI Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows
SO NATURE
LA English
DT Article
ID v-h family; long cdr3s; envelope; potent; generation; target; region
AB No immunogen to date has reliably elicited broadly neutralizing antibodies to HIV in humans or animal models. Advances in the design of immunogens that antigenically mimic the HIV envelope glycoprotein (Env), such as the soluble cleaved trimer BG505 SOSIP1, have improved the elicitation of potent isolate-specific antibody responses in rabbits(2) and macaques(3), but so far failed to induce broadly neutralizing antibodies. One possible reason for this failure is that the relevant antibody repertoires are poorly suited to target the conserved epitope regions on Env, which are somewhat occluded relative to the exposed variable epitopes. Here, to test this hypothesis, we immunized four cows with BG505 SOSIP. The antibody repertoire of cows contains long third heavy chain complementary determining regions (HCDR3) with an ultralong subset that can reach more than 70 amino acids in length(4-9). Remarkably, BG505 SOSIP immunization resulted in rapid elicitation of broad and potent serum antibody responses in all four cows. Longitudinal serum analysis for one cow showed the development of neutralization breadth (20%, n = 117 crossclade isolates) in 42 days and 96% breadth (n = 117) at 381 days. A monoclonal antibody isolated from this cow harboured an ultralong HCDR3 of 60 amino acids and neutralized 72% of crossclade isolates (n = 117) with a potent median IC50 of 0.028 mu g ml(-1). Breadth was elicited with a single trimer immunogen and did not require additional envelope diversity. Immunization of cows may provide an avenue to rapidly generate antibody prophylactics and therapeutics to address disease agents that have evolved to avoid human antibody responses.
C1 [Sok, Devin; Le, Khoa M.; Saye-Francisco, Karen L.; Jardine, Joseph G.; Ruiz, Jennifer; Ramos, Alejandra; Liang, Chi-Hui; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbiol, La Jolla, CA 92037 USA.
   [Sok, Devin; Le, Khoa M.; Saye-Francisco, Karen L.; Jardine, Joseph G.; Ruiz, Jennifer; Ramos, Alejandra; Liang, Chi-Hui; Wilson, Ian A.; Ward, Andrew B.; Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA.
   [Sok, Devin; Le, Khoa M.; Saye-Francisco, Karen L.; Jardine, Joseph G.; Ruiz, Jennifer; Ramos, Alejandra; Liang, Chi-Hui; Wilson, Ian A.; Ward, Andrew B.; Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Disc, La Jolla, CA 92037 USA.
   [Sok, Devin; Le, Khoa M.; Ruiz, Jennifer; Ramos, Alejandra] Int AIDS Vaccine Initiat, Beijing 100044, Peoples R China.
   [Vadnais, Melissa L.; Smider, Vaughn V.] Scripps Res Inst, Dept Mol Med, La Jolla, CA 92037 USA.
   [Torres, Jonathan L.; Berndsen, Zachary T.; Kong, Leopold; Tanfield, Robyn S.; Wilson, Ian A.; Ward, Andrew B.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA.
   [Chen, Patricia L.; Criscitiello, Michael F.] Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Pathobiol, College Stn, TX 77843 USA.
   [Mwangi, Waithaka] Kansas State Univ, Coll Vet Med, Dept Diagnost Med Pathobiol, Manhattan, KS 66506 USA.
   [Burton, Dennis R.] Ragon Inst MGH MIT & Harvard, Boston, MA 02129 USA.
C3 Scripps Research Institute; International AIDS Vaccine Initiative; Scripps Research Institute; Scripps Research Institute; International AIDS Vaccine Initiative; Scripps Research Institute; Scripps Research Institute; Texas A&M University System; Texas A&M University College Station; Kansas State University; Harvard University; Massachusetts Institute of Technology (MIT); Ragon Institute
RP Burton, DR (corresponding author), Scripps Res Inst, Dept Immunol & Microbiol, La Jolla, CA 92037 USA.; Burton, DR (corresponding author), Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA.; Burton, DR (corresponding author), Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Disc, La Jolla, CA 92037 USA.; Smider, VV (corresponding author), Scripps Res Inst, Dept Mol Med, La Jolla, CA 92037 USA.; Burton, DR (corresponding author), Ragon Inst MGH MIT & Harvard, Boston, MA 02129 USA.
EM vvsmider@scripps.edu; burton@scripps.edu
FU International AIDS Vaccine Initiative Neutralizing Antibody Consortium through Collaboration for AIDS Vaccine Discovery grant [OPP1084519]; NIH [R21 AI120791, R01 GM105826]; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery Grant [UM1AI100663]; IOS [1257829]; USDA-NIFA grant [CSREES 2008-35204]; James and Jessie Minor Chair in Immunology; IAVI; Bill AMP; Melinda Gates Foundation; Ministry of Foreign Affairs of Denmark; Irish Aid; Ministry of Finance of Japan; World Bank; Ministry of Foreign Affairs of the Netherlands; Norwegian Agency for Development Cooperation (NORAD); United Kingdom Department for International Development (DFID); United States Agency for International Development (USAID); National Institute of General Medical Sciences [R01GM105826] Funding Source: NIH RePORTER
NR 36
TC 134
Z9 168
U1 0
U2 52
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 3
PY 2017
VL 548
IS 7665
BP 108
EP +
DI 10.1038/nature23301
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FC4SU
UT WOS:000406831700046
PM 28726771
DA 2026-03-09
ER

PT J
AU Sahin, U
   Derhovanessian, E
   Miller, M
   Kloke, BP
   Simon, P
   Löwer, M
   Bukur, V
   Tadmor, AD
   Luxemburger, U
   Schrörs, B
   Omokoko, T
   Vormehr, M
   Albrecht, C
   Paruzynski, A
   Kuhn, AN
   Buck, J
   Heesch, S
   Katharina, H
   Müller, F
   Ortseifer, I
   Vogler, I
   Godehardt, E
   Attig, S
   Rae, R
   Breitkreuz, A
   Tolliver, C
   Suchan, M
   Martic, G
   Hohberger, A
   Sorn, P
   Diekmann, J
   Ciesla, J
   Waksmann, O
   Bürck, AK
   Witt, M
   Zillgen, M
   Rothermel, A
   Kasemann, B
   Langer, D
   Bolte, S
   Diken, M
   Kreiter, S
   Nemecek, R
   Gebhardt, C
   Grabbe, S
   Höller, C
   Utikal, J
   Huber, C
   Loquai, C
   Türeci, Ö
AF Sahin, Ugur
   Derhovanessian, Evelyna
   Miller, Matthias
   Kloke, Bjoern-Philipp
   Simon, Petra
   Loewer, Martin
   Bukur, Valesca
   Tadmor, Arbel D.
   Luxemburger, Ulrich
   Schroers, Barbara
   Omokoko, Tana
   Vormehr, Mathias
   Albrecht, Christian
   Paruzynski, Anna
   Kuhn, Andreas N.
   Buck, Janina
   Heesch, Sandra
   Katharina, H.
   Mueller, Felicitas
   Ortseifer, Inga
   Vogler, Isabel
   Godehardt, Eva
   Attig, Sebastian
   Rae, Richard
   Breitkreuz, Andrea
   Tolliver, Claudia
   Suchan, Martin
   Martic, Goran
   Hohberger, Alexander
   Sorn, Patrick
   Diekmann, Jan
   Ciesla, Janko
   Waksmann, Olga
   Burck, Alexandra-Kemmer
   Witt, Meike
   Zillgen, Martina
   Rothermel, Andree
   Kasemann, Barbara
   Langer, David
   Bolte, Stefanie
   Diken, Mustafa
   Kreiter, Sebastian
   Nemecek, Romina
   Gebhardt, Christoffer
   Grabbe, Stephan
   Holler, Christoph
   Utikal, Jochen
   Huber, Christoph
   Loquai, Carmen
   Tuereci, Oezlem
TI Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer
SO NATURE
LA English
DT Article
ID pd-1 blockade; mass-spectrometry; ctla-4 blockade; t-cells; mutations; alignment; reveals; sensitivity; efficiency; stability
AB T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome vaccines and implemented an RNA-based poly-neoepitope approach to mobilize immunity against a spectrum of cancer mutations(1,2). Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of beta 2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.
C1 [Sahin, Ugur; Derhovanessian, Evelyna; Miller, Matthias; Kloke, Bjoern-Philipp; Simon, Petra; Bukur, Valesca; Luxemburger, Ulrich; Omokoko, Tana; Vormehr, Mathias; Paruzynski, Anna; Kuhn, Andreas N.; Buck, Janina; Heesch, Sandra; Katharina, H.; Mueller, Felicitas; Ortseifer, Inga; Vogler, Isabel; Godehardt, Eva; Breitkreuz, Andrea; Tolliver, Claudia; Diekmann, Jan; Burck, Alexandra-Kemmer; Witt, Meike; Zillgen, Martina; Langer, David; Bolte, Stefanie; Diken, Mustafa; Kreiter, Sebastian; Huber, Christoph] Biopharmaceut New Technol BioNTech Corp, Goldgrube 12, D-55131 Mainz, Germany.
   [Sahin, Ugur; Loewer, Martin; Bukur, Valesca; Tadmor, Arbel D.; Schroers, Barbara; Albrecht, Christian; Attig, Sebastian; Rae, Richard; Suchan, Martin; Martic, Goran; Sorn, Patrick; Rothermel, Andree; Kasemann, Barbara; Diken, Mustafa; Kreiter, Sebastian; Huber, Christoph] Johannes Gutenberg Univ gGmbH, Univ Med Ctr, TRON Translat Oncol, Freiligrathstr 12, D-55131 Mainz, Germany.
   [Sahin, Ugur; Vormehr, Mathias; Attig, Sebastian; Hohberger, Alexander; Grabbe, Stephan; Huber, Christoph; Loquai, Carmen] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Langenbeckstr 1, D-55131 Mainz, Germany.
   [Ciesla, Janko; Waksmann, Olga] EUFETS GmbH, Vollmersbachstr 66, D-55743 Idar Oberstein, Germany.
   [Nemecek, Romina; Holler, Christoph] Med Univ Vienna, Spitalgasse 23, A-1090 Vienna, Austria.
   [Gebhardt, Christoffer; Utikal, Jochen] German Canc Res Ctr, Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
   [Gebhardt, Christoffer; Utikal, Jochen] Heidelberg Univ, Univ Med Ctr Mannheim, Theodor Kutzer Ufer 1-3, D-68135 Mannheim, Germany.
   [Tuereci, Oezlem] CI3 Cluster Individualized Immunointervent eV, Holderlinstr 8, D-55131 Mainz, Germany.
C3 BioNTech SE; Johannes Gutenberg University of Mainz; Johannes Gutenberg University of Mainz; Medical University of Vienna; Helmholtz Association; German Cancer Research Center (DKFZ); Ruprecht Karls University Heidelberg
RP Sahin, U (corresponding author), Biopharmaceut New Technol BioNTech Corp, Goldgrube 12, D-55131 Mainz, Germany.; Sahin, U (corresponding author), Johannes Gutenberg Univ gGmbH, Univ Med Ctr, TRON Translat Oncol, Freiligrathstr 12, D-55131 Mainz, Germany.; Sahin, U (corresponding author), Johannes Gutenberg Univ Mainz, Univ Med Ctr, Langenbeckstr 1, D-55131 Mainz, Germany.
EM sahin@uni-mainz.de
FU CI3 cluster program of the Federal Ministry of Education and Research (BMBF)
NR 42
TC 1905
Z9 2268
U1 16
U2 563
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 13
PY 2017
VL 547
IS 7662
BP 222
EP +
DI 10.1038/nature23003
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FA3AX
UT WOS:000405314500040
PM 28678784
DA 2026-03-09
ER

PT J
AU Schroeder, TBH
   Guha, A
   Lamoureux, A
   VanRenterghem, G
   Sept, D
   Shtein, M
   Yang, J
   Mayer, M
AF Schroeder, Thomas B. H.
   Guha, Anirvan
   Lamoureux, Aaron
   VanRenterghem, Gloria
   Sept, David
   Shtein, Max
   Yang, Jerry
   Mayer, Michael
TI An electric-eel-inspired soft power source from stacked hydrogels
SO NATURE
LA English
DT Article
ID electrophorus-electricus; electronics
AB Progress towards the integration of technology into living organisms requires electrical power sources that are biocompatible, mechanically flexible, and able to harness the chemical energy available inside biological systems. Conventional batteries were not designed with these criteria in mind. The electric organ of the knifefish Electrophorus electricus (commonly known as the electric eel) is, however, an example of an electrical power source that operates within biological constraints while featuring power characteristics that include peak potential differences of 600 volts and currents of 1 ampere(1,2). Here we introduce an electric-eel-inspired power concept that uses gradients of ions between miniature polyacrylamide hydrogel compartments bounded by a repeating sequence of cation-and anion-selective hydrogel membranes. The system uses a scalable stacking or folding geometry that generates 110 volts at open circuit or 27 milliwatts per square metre per gel cell upon simultaneous, self-registered mechanical contact activation of thousands of gel compartments in series while circumventing power dissipation before contact. Unlike typical batteries, these systems are soft, flexible, transparent, and potentially biocompatible. These characteristics suggest that artificial electric organs could be used to power next-generation implant materials such as pacemakers, implantable sensors, or prosthetic devices in hybrids of living and non-living systems(3-6).
C1 [Schroeder, Thomas B. H.] Univ Michigan, Dept Chem Engn, Ann Arbor, MI 48109 USA.
   [Schroeder, Thomas B. H.; Guha, Anirvan; Mayer, Michael] Univ Fribourg, Adolphe Merkle Inst, Fribourg, Switzerland.
   [Lamoureux, Aaron; VanRenterghem, Gloria; Shtein, Max] Univ Michigan, Dept Mat Sci & Engn, Ann Arbor, MI 48109 USA.
   [Sept, David; Mayer, Michael] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA.
   [Sept, David] Univ Michigan, Ctr Computat Med & Biol, Ann Arbor, MI 48109 USA.
   [Yang, Jerry] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA.
C3 University of Michigan System; University of Michigan; University of Fribourg; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of California System; University of California San Diego
RP Mayer, M (corresponding author), Univ Fribourg, Adolphe Merkle Inst, Fribourg, Switzerland.; Mayer, M (corresponding author), Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA.
EM michael.mayer@unifr.ch
FU Air Force Office of Scientific Research [FA9550-12-1-0435]; National Institute of General Medical Sciences of the National Institutes of Health [National Institute of General Medical Sciences of the National Institutes of Health under award T32GM008353]; Cellular Biotechnology Training Program; National Institute of General Medical Sciences [T32GM008353] Funding Source: NIH RePORTER
NR 33
TC 497
Z9 544
U1 47
U2 1111
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 14
PY 2017
VL 552
IS 7684
BP 214
EP +
DI 10.1038/nature24670
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ0FK
UT WOS:000418029500039
PM 29239354
DA 2026-03-09
ER

PT J
AU Kotz, F
   Arnold, K
   Bauer, W
   Schild, D
   Keller, N
   Sachsenheimer, K
   Nargang, TM
   Richter, C
   Helmer, D
   Rapp, BE
AF Kotz, Frederik
   Arnold, Karl
   Bauer, Werner
   Schild, Dieter
   Keller, Nico
   Sachsenheimer, Kai
   Nargang, Tobias M.
   Richter, Christiane
   Helmer, Dorothea
   Rapp, Bastian E.
TI Three-dimensional printing of transparent fused silica glass
SO NATURE
LA English
DT Article
AB Glass is one of the most important high-performance materials used for scientific research, in industry and in society, mainly owing to its unmatched optical transparency, outstanding mechanical, chemical and thermal resistance as well as its thermal and electrical insulating properties(1-3). However, glasses and especially high-purity glasses such as fused silica glass are notoriously difficult to shape, requiring high-temperature melting and casting processes for macroscopic objects or hazardous chemicals for microscopic features(3,4). These drawbacks have made glasses inaccessible to modern manufacturing technologies such as three-dimensional printing (3D printing). Using a casting nanocomposite(5), here we create transparent fused silica glass components using stereolithography 3D printers at resolutions of a few tens of micrometres. The process uses a photocurable silica nanocomposite that is 3D printed and converted to high-quality fused silica glass via heat treatment. The printed fused silica glass is non-porous, with the optical transparency of commercial fused silica glass, and has a smooth surface with a roughness of a few nanometres. By doping with metal salts, coloured glasses can be created. This work widens the choice of materials for 3D printing, enabling the creation of arbitrary macro-and microstructures in fused silica glass for many applications in both industry and academia.
C1 [Kotz, Frederik; Arnold, Karl; Keller, Nico; Sachsenheimer, Kai; Nargang, Tobias M.; Richter, Christiane; Helmer, Dorothea; Rapp, Bastian E.] KIT, IMT, Hermann von Helmholtz Pl 1, D-76344 Eggenstein Leopoldshafen, Germany.
   [Bauer, Werner] KIT, IAM, Hermann von Helmholtz Pl 1, D-76344 Eggenstein Leopoldshafen, Germany.
   [Schild, Dieter] KIT, Inst Nucl Waste Disposal INE, Hermann von Helmholtz Pl 1, D-76344 Eggenstein Leopoldshafen, Germany.
C3 Helmholtz Association; Karlsruhe Institute of Technology; Helmholtz Association; Karlsruhe Institute of Technology; Helmholtz Association; Karlsruhe Institute of Technology
RP Rapp, BE (corresponding author), KIT, IMT, Hermann von Helmholtz Pl 1, D-76344 Eggenstein Leopoldshafen, Germany.
EM Bastian.Rapp@kit.edu
FU German Federal Ministry of Education and Research (BMBF) [03X5527, 031A095C]; Karlsruhe Nano Micro Facility, a Helmholtz Research Infrastructure at KIT
NR 23
TC 694
Z9 811
U1 44
U2 1028
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 20
PY 2017
VL 544
IS 7650
BP 337
EP +
DI 10.1038/nature22061
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ES4SG
UT WOS:000399524400033
PM 28425999
DA 2026-03-09
ER

PT J
AU Li, JR
   Lee, J
   Huang, W
   Burchesky, S
   Shteynas, B
   Top, FC
   Jamison, AO
   Ketterle, W
AF Li, Jun-Ru
   Lee, Jeongwon
   Huang, Wujie
   Burchesky, Sean
   Shteynas, Boris
   Top, Furkan Cagri
   Jamison, Alan O.
   Ketterle, Wolfgang
TI A stripe phase with supersolid properties in spin-orbit-coupled Bose-Einstein condensates
SO NATURE
LA English
DT Article
ID gas
AB Supersolidity combines superfluid flow with long-range spatial periodicity of solids(1), two properties that are often mutually exclusive. The original discussion of quantum crystals(2) and supersolidity focused on solid He-4 and triggered extensive experimental efforts(3,4) that, instead of supersolidity, revealed exotic phenomena including quantum plasticity and mass supertransport(4). The concept of supersolidity was then generalized from quantum crystals to other superfluid systems that break continuous translational symmetry. Bose-Einstein condensates with spin-orbit coupling are predicted to possess a stripe phase(5-7) with supersolid properties(8,9). Despite several recent studies of the miscibility of the spin components of such a condensate(10-12), the presence of stripes has not been detected. Here we observe the predicted density modulation of this stripe phase using Bragg reflection (which provides evidence for spontaneous long-range order in one direction) while maintaining a sharp momentum distribution (the hallmark of superfluid Bose-Einstein condensates). Our work thus establishes a system with continuous symmetry-breaking properties, associated collective excitations and superfluid behaviour.
C1 [Li, Jun-Ru; Lee, Jeongwon; Huang, Wujie; Burchesky, Sean; Shteynas, Boris; Top, Furkan Cagri; Jamison, Alan O.; Ketterle, Wolfgang] MIT, Harvard Ctr Ultracold Atoms, Dept Phys, Cambridge, MA 02139 USA.
   [Li, Jun-Ru; Lee, Jeongwon; Huang, Wujie; Burchesky, Sean; Shteynas, Boris; Top, Furkan Cagri; Jamison, Alan O.; Ketterle, Wolfgang] MIT, Res Lab Eelct, Cambridge, MA 02139 USA.
C3 Harvard University; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT)
RP Li, JR (corresponding author), MIT, Harvard Ctr Ultracold Atoms, Dept Phys, Cambridge, MA 02139 USA.; Li, JR (corresponding author), MIT, Res Lab Eelct, Cambridge, MA 02139 USA.
EM junruli@mit.edu
FU NSF through the Center for Ultracold Atoms; ARO-MURI Non-equilibrium Many-body Dynamics [W911NF-14-1-0003]; AFOSR-MURI Quantum Phases of Matter [FA9550-14-1- 0035];  [1506369]; Division Of Physics; Direct For Mathematical & Physical Scien [1125846] Funding Source: National Science Foundation
NR 30
TC 506
Z9 565
U1 2
U2 139
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 2
PY 2017
VL 543
IS 7643
BP 91
EP +
DI 10.1038/nature21431
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0AA
UT WOS:000395671500038
PM 28252062
DA 2026-03-09
ER

PT J
AU Cheng, RKY
   Fiez-Vandal, C
   Schlenker, O
   Edman, K
   Aggeler, B
   Brown, DG
   Brown, GA
   Cooke, RM
   Dumelin, CE
   Doré, AS
   Geschwindner, S
   Grebner, C
   Hermansson, NO
   Jazayeri, A
   Johansson, P
   Leong, L
   Prihandoko, R
   Rappas, M
   Soutter, H
   Snijder, A
   Sundström, L
   Tehan, B
   Thornton, P
   Troast, D
   Wiggin, G
   Zhukov, A
   Marshall, FH
   Dekker, N
AF Cheng, Robert K. Y.
   Fiez-Vandal, Cedric
   Schlenker, Oliver
   Edman, Karl
   Aggeler, Birte
   Brown, Dean G.
   Brown, Giles A.
   Cooke, Robert M.
   Dumelin, Christoph E.
   Dore, Andrew S.
   Geschwindner, Stefan
   Grebner, Christoph
   Hermansson, Nils-Olov
   Jazayeri, Ali
   Johansson, Patrik
   Leong, Louis
   Prihandoko, Rudi
   Rappas, Mathieu
   Soutter, Holly
   Snijder, Arjan
   Sundstrom, Linda
   Tehan, Benjamin
   Thornton, Peter
   Troast, Dawn
   Wiggin, Giselle
   Zhukov, Andrei
   Marshall, Fiona H.
   Dekker, Niek
TI Structural insight into allosteric modulation of protease-activated receptor 2
SO NATURE
LA English
DT Article
ID crystal-structure; thrombin
AB Protease-activated receptors ( PARs) are a family of G-proteincoupled receptors ( GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation(1-3). PARs have been the subject of major pharmaceutical research efforts(3) but the discovery of small-molecule antagonists that effectively bind them has proved challenging. The only marketed drug targeting a PAR is vorapaxar(4), a selective antagonist of PAR1 used to prevent thrombosis. The structure of PAR1 in complex with vorapaxar has been reported previously(5). Despite sequence homology across the PAR isoforms, discovery of PAR2 antagonists has been less successful, although GB88 has been described as a weak antagonist6. Here we report crystal structures of PAR2 in complex with two distinct antagonists and a blocking antibody. The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. We also show that a blocking antibody antigen-binding fragment binds to the extracellular surface of PAR2, preventing access of the tethered ligand to the peptide-binding site. These structures provide a basis for the development of selective PAR2 antagonists for a range of therapeutic uses.
C1 [Cheng, Robert K. Y.; Fiez-Vandal, Cedric; Schlenker, Oliver; Brown, Giles A.; Cooke, Robert M.; Dore, Andrew S.; Jazayeri, Ali; Johansson, Patrik; Prihandoko, Rudi; Rappas, Mathieu; Tehan, Benjamin; Wiggin, Giselle; Zhukov, Andrei; Marshall, Fiona H.] Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England.
   [Edman, Karl; Geschwindner, Stefan; Hermansson, Nils-Olov; Johansson, Patrik; Snijder, Arjan; Sundstrom, Linda; Dekker, Niek] Astra Zeneca, Discovery Sci Innovat Med & Early Dev Biotech Uni, Pepparedsleden 1, S-43183 Molndal, Sweden.
   [Aggeler, Birte; Leong, Louis] Biotechne, 614 McKinley Pl NE, Minneapolis, MN 55413 USA.
   [Brown, Dean G.] AstraZeneca R&D, Discovery Sci Innovat Med & Early Dev Biotech Uni, 35 Gatehouse Dr, Waltham, MA 02451 USA.
   [Dumelin, Christoph E.; Soutter, Holly; Troast, Dawn] X Chem Inc, 100 Beaver St, Waltham, MA 02453 USA.
   [Grebner, Christoph] Astra Zeneca, Cardiovasc & Metab Dis Innovat Med & Early Dev Bi, Pepparedsleden 1, S-43183 Molndal, Sweden.
   [Thornton, Peter] Astra Zeneca, Neurosc Innovat Med & Early Dev Biotech Unit, Granta Pk, Cambridge CB21 6GH, England.
C3 Heptares Therapeutics Ltd.; AstraZeneca; AstraZeneca; AstraZeneca; AstraZeneca
RP Marshall, FH (corresponding author), Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England.
EM fiona.marshall@heptares.com
NR 28
TC 196
Z9 233
U1 2
U2 47
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 4
PY 2017
VL 545
IS 7652
BP 112
EP +
DI 10.1038/nature22309
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET7MK
UT WOS:000400480400041
PM 28445455
DA 2026-03-09
ER

PT J
AU Smith, ZD
   Shi, JT
   Gu, HC
   Donaghey, J
   Clement, K
   Cacchiarelli, D
   Gnirke, A
   Michor, F
   Meissner, A
AF Smith, Zachary D.
   Shi, Jiantao
   Gu, Hongcang
   Donaghey, Julie
   Clement, Kendell
   Cacchiarelli, Davide
   Gnirke, Andreas
   Michor, Franziska
   Meissner, Alexander
TI Epigenetic restriction of extraembryonic lineages mirrors the somatic transition to cancer
SO NATURE
LA English
DT Article
ID dna methylation maps; cpg islands; dnmt3a mutations; prc1 complex; stem-cells; genes; chromatin; trophectoderm; expression; hypermethylation
AB In mammals, the canonical somatic DNA methylation landscape is established upon specification of the embryo proper and subsequently disrupted within many cancer types(1-4). However, the underlying mechanisms that direct this genome-scale transformation remain elusive, with no clear model for its systematic acquisition or potential developmental utility(5,6). Here, we analysed global remethylation from the mouse preimplantation embryo into the early epiblast and extraembryonic ectoderm. We show that these two states acquire highly divergent genomic distributions with substantial disruption of bimodal, CpG density-dependent methylation in the placental progenitor(7,8). The extraembryonic epigenome includes specific de novo methylation at hundreds of embryonically protected CpG island promoters, particularly those that are associated with key developmental regulators and are orthologously methylated across most human cancer types(9). Our data suggest that the evolutionary innovation of extraembryonic tissues may have required co-option of DNA methylation-based suppression as an alternative to regulation by Polycomb-group proteins, which coordinate embryonic germ-layer formation in response to extraembryonic cues(10). Moreover, we establish that this decision is made deterministically, downstream of promiscuously used-and frequently oncogenic-signalling pathways, via a novel combination of epigenetic cofactors. Methylation of developmental gene promoters during tumorigenesis may therefore reflect the misappropriation of an innate trajectory and the spontaneous reacquisition of a latent, developmentally encoded epigenetic landscape.
C1 [Smith, Zachary D.; Gu, Hongcang; Donaghey, Julie; Clement, Kendell; Cacchiarelli, Davide; Gnirke, Andreas; Michor, Franziska; Meissner, Alexander] Broad Inst MIT & Harvard, Cambridge, MA USA.
   [Smith, Zachary D.; Donaghey, Julie; Clement, Kendell; Cacchiarelli, Davide; Michor, Franziska; Meissner, Alexander] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.
   [Smith, Zachary D.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA.
   [Shi, Jiantao; Michor, Franziska] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA.
   [Shi, Jiantao; Michor, Franziska] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA.
   [Clement, Kendell] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA.
   [Meissner, Alexander] Max Planck Inst Mol Genet, Dept Genome Regulat, D-14195 Berlin, Germany.
C3 Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard T.H. Chan School of Public Health; Harvard University; Max Planck Society
RP Michor, F; Meissner, A (corresponding author), Broad Inst MIT & Harvard, Cambridge, MA USA.; Michor, F; Meissner, A (corresponding author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.; Michor, F (corresponding author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA.; Michor, F (corresponding author), Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA.; Meissner, A (corresponding author), Max Planck Inst Mol Genet, Dept Genome Regulat, D-14195 Berlin, Germany.
EM michor@jimmy.harvard.edu; meissner@molgen.mpg.de
FU Dana-Farber Cancer Institute Physical Sciences-Oncology Center [NIH U54CA193461]; New York Stem Cell Foundation; Broad-ISF Partnership for Cell Circuit Research; Starr Foundation; NIH [1P50HG006193, P01GM099117, R01DA036898]; Max Planck Society; National Institute of General Medical Sciences [P01GM099117] Funding Source: NIH RePORTER
NR 67
TC 141
Z9 159
U1 4
U2 34
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 28
PY 2017
VL 549
IS 7673
BP 543
EP +
DI 10.1038/nature23891
PG 29
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI4GT
UT WOS:000411930000055
PM 28959968
DA 2026-03-09
ER

PT J
AU Tang, AT
   Hoi, JPC
   Kotzin, JJ
   Yang, YQ
   Hong, CC
   Hobson, N
   Girard, R
   Zeineddine, HA
   Lightle, R
   Moore, T
   Cao, Y
   Shenkar, R
   Chen, M
   Mericko, P
   Yang, JS
   Li, L
   Tanes, C
   Kobuley, D
   Vosa, U
   Whitehead, KJ
   Li, DY
   Franke, L
   Hart, B
   Schwaninger, M
   Henao-Mejia, J
   Morrison, L
   Kim, H
   Awad, IA
   Zheng, XJ
   Kahn, ML
AF Tang, Alan T.
   Hoi, Jaesung P. C.
   Kotzin, Jonathan J.
   Yang, Yiqing
   Hong, Courtney C.
   Hobson, Nicholas
   Girard, Romuald
   Zeineddine, Hussein A.
   Lightle, Rhonda
   Moore, Thomas
   Cao, Ying
   Shenkar, Robert
   Chen, Mei
   Mericko, Patricia
   Yang, Jisheng
   Li, Li
   Tanes, Ceylan
   Kobuley, Dmytro
   Vosa, Urmo
   Whitehead, Kevin J.
   Li, Dean Y.
   Franke, Lude
   Hart, Blaine
   Schwaninger, Markus
   Henao-Mejia, Jorge
   Morrison, Leslie
   Kim, Helen
   Awad, Issam A.
   Zheng, Xiangjian
   Kahn, Mark L.
TI Endothelial TLR4 and the microbiome drive cerebral cavernous malformations
SO NATURE
LA English
DT Article
ID lps; receptor; angiogenesis; bacteria; lipopolysaccharide; interface; stability; insights; genes; host
AB Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no effective medical therapies yet exist. CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3-KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. Here we identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by Gram-negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment.
C1 [Tang, Alan T.; Yang, Yiqing; Hong, Courtney C.; Chen, Mei; Mericko, Patricia; Yang, Jisheng; Li, Li; Kahn, Mark L.] Univ Penn, Dept Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA.
   [Tang, Alan T.; Yang, Yiqing; Hong, Courtney C.; Chen, Mei; Mericko, Patricia; Yang, Jisheng; Li, Li; Kahn, Mark L.] Univ Penn, Cardiovasc Inst, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA.
   [Hoi, Jaesung P. C.; Zheng, Xiangjian] Centenary Inst, Lab Cardiovasc Signaling, Sydney, NSW 2050, Australia.
   [Kotzin, Jonathan J.; Henao-Mejia, Jorge] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA.
   [Kotzin, Jonathan J.; Kobuley, Dmytro; Henao-Mejia, Jorge] Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA.
   [Hobson, Nicholas; Girard, Romuald; Zeineddine, Hussein A.; Lightle, Rhonda; Moore, Thomas; Cao, Ying; Shenkar, Robert; Awad, Issam A.] Univ Chicago, Dept Surg, Sch Med & Biol Sci, Neurovasc Surg Program, 5841 S Maryland Ave, Chicago, IL 60637 USA.
   [Tanes, Ceylan] Childrens Hosp Philadelphia, CHOP Microbiome Ctr, Philadelphia, PA 19104 USA.
   [Kobuley, Dmytro] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA.
   [Vosa, Urmo; Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
   [Whitehead, Kevin J.; Li, Dean Y.] Univ Utah, Div Cardiovasc Med, Salt Lake City, UT 84112 USA.
   [Whitehead, Kevin J.; Li, Dean Y.] Univ Utah, Program Mol Med, Salt Lake City, UT 84112 USA.
   [Hart, Blaine; Morrison, Leslie] Univ New Mexico, Dept Neurol & Pediat, Albuquerque, NM 87131 USA.
   [Schwaninger, Markus] Univ Lubeck, Inst Expt & Clin Pharmacol & Toxicol, D-23562 Lubeck, Germany.
   [Henao-Mejia, Jorge] Univ Penn, Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Div Transplant Immunol, Philadelphia, PA 19104 USA.
   [Kim, Helen] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, Ctr Cerebrovasc Res, San Francisco, CA 94143 USA.
   [Zheng, Xiangjian] Univ Sydney, Sydney Med Sch, Fac Med, Sydney, NSW 2050, Australia.
   [Zheng, Xiangjian] Tianjian Med Univ, Sch Basic Med Sci, Dept Pharmacol, Tianjin, Peoples R China.
C3 University of Pennsylvania; University of Pennsylvania; University of Sydney; Centenary Institute; University of Pennsylvania; University of Pennsylvania; University of Chicago; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; University of Groningen; Utah System of Higher Education; University of Utah; Utah System of Higher Education; University of Utah; University of New Mexico; University of Lubeck; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of California System; University of California San Francisco; University of Sydney; Tianjin Medical University
RP Kahn, ML (corresponding author), Univ Penn, Dept Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA.; Kahn, ML (corresponding author), Univ Penn, Cardiovasc Inst, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA.
EM markkahn@mail.med.upenn.edu
FU National Institute of Health [R01HL094326, P01NS092521, R01NS075168, T32HL07439, F30NS100252, T32DK007780]; DFG [SCHWD-416/5-2, U54NS065705]; Penn-CHOP Microbiome Pilot & Feasibility Award Grant; Australian NHMRC [161558]; National Center for Advancing Translational Sciences; National Institute of Neurological Disorders and Stroke [U54NS065705] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [T32HL007439] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK019525, T32DK007780] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM008076] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [P01NS092521, R01NS100949] Funding Source: NIH RePORTER
NR 65
TC 241
Z9 279
U1 0
U2 95
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 18
PY 2017
VL 545
IS 7654
BP 305
EP +
DI 10.1038/nature22075
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV0WF
UT WOS:000401466500054
PM 28489816
DA 2026-03-09
ER

PT J
AU Ashkenazi, A
   Bento, CF
   Ricketts, T
   Vicinanza, M
   Siddiqi, F
   Pavel, M
   Squitieri, F
   Hardenberg, MC
   Imarisio, S
   Menzies, FM
   Rubinsztein, DC
AF Ashkenazi, Avraham
   Bento, Carla F.
   Ricketts, Thomas
   Vicinanza, Mariella
   Siddiqi, Farah
   Pavel, Mariana
   Squitieri, Ferdinando
   Hardenberg, Maarten C.
   Imarisio, Sara
   Menzies, Fiona M.
   Rubinsztein, David C.
TI Polyglutamine tracts regulate beclin 1-dependent autophagy
SO NATURE
LA English
DT Article
ID machado-joseph-disease; mutant huntingtin; intranuclear inclusions; mouse models; protein; ataxin-3; lc3; aggregation; cells; pathogenesis
AB Nine neurodegenerative diseases are caused by expanded polyglutamine (polyQ) tracts in different proteins, such as huntingtin in Huntington's disease and ataxin 3 in spinocerebellar ataxia type 3 (SCA3)(1,2). Age at onset of disease decreases with increasing polyglutamine length in these proteins and the normal length also varies(3). PolyQ expansions drive pathogenesis in these diseases, as isolated polyQ tracts are toxic, and an N-terminal huntingtin fragment comprising exon 1, which occurs in vivo as a result of alternative splicing(4), causes toxicity. Although such mutant proteins are prone to aggregation(5), toxicity is also associated with soluble forms of the proteins(6). The function of the polyQ tracts in many normal cytoplasmic proteins is unclear. One such protein is the deubiquitinating enzyme ataxin 3 (refs 7, 8), which is widely expressed in the brain(9,10). Here we show that the polyQ domain enables wild-type ataxin 3 to interact with beclin 1, a key initiator of autophagy(11). This interaction allows the deubiquitinase activity of ataxin 3 to protect beclin 1 from proteasome-mediated degradation and thereby enables autophagy. Starvation-induced autophagy, which is regulated by beclin 1, was particularly inhibited in ataxin3- depleted human cell lines and mouse primary neurons, and in vivo in mice. This activity of ataxin 3 and its polyQ-mediated interaction with beclin 1 was competed for by other soluble proteins with polyQ tracts in a length-dependent fashion. This competition resulted in impairment of starvation-induced autophagy in cells expressing mutant huntingtin exon 1, and this impairment was recapitulated in the brains of a mouse model of Huntington's disease and in cells from patients. A similar phenomenon was also seen with other polyQ disease proteins, including mutant ataxin 3 itself. Our data thus describe a specific function for a wild-type polyQ tract that is abrogated by a competing longer polyQ mutation in a disease protein, and identify a deleterious function of such mutations distinct from their propensity to aggregate.
C1 [Ashkenazi, Avraham; Bento, Carla F.; Ricketts, Thomas; Vicinanza, Mariella; Siddiqi, Farah; Pavel, Mariana; Hardenberg, Maarten C.; Imarisio, Sara; Menzies, Fiona M.; Rubinsztein, David C.] Univ Cambridge, CIMR, Dept Med Genet, Cambridge, England.
   [Squitieri, Ferdinando] IRCCS Casa Sollievo Sofferenza, Huntington & Rare Dis Unit, San Giovanni Rotondo, Italy.
C3 University of Cambridge; IRCCS Casa Sollievo Della Sofferenza
RP Rubinsztein, DC (corresponding author), Univ Cambridge, CIMR, Dept Med Genet, Cambridge, England.
EM dcr1000@cam.ac.uk
FU Wellcome Trust [095317/Z/11/Z, 100140/Z/12/Z]; National Institute for Health Research Biomedical Research Centre at Addenbrooke's Hospital; Federation of European Biochemical Societies (FEBS); Addenbrooke's Charitable Trust; Wellcome Trust [100140/Z/12/Z] Funding Source: Wellcome Trust
NR 40
TC 281
Z9 327
U1 0
U2 98
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 4
PY 2017
VL 545
IS 7652
BP 108
EP +
DI 10.1038/nature22078
PG 25
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET7MK
UT WOS:000400480400040
PM 28445460
DA 2026-03-09
ER

PT J
AU Bohnert, KA
   Kenyon, C
AF Bohnert, K. Adam
   Kenyon, Cynthia
TI A lysosomal switch triggers proteostasis renewal in the immortal C. elegans germ lineage
SO NATURE
LA English
DT Article
ID oocyte meiotic maturation; caenorhabditis-elegans; paternal mitochondria; life-span; protein; cells; gene; degradation; expression; identification
AB Although individuals age and die with time, an animal species can continue indefinitely, because of its immortal germ-cell lineage(1). How the germline avoids transmitting damage from one generation to the next remains a fundamental question in biology. Here we identify a lysosomal switch that enhances germline proteostasis before fertilization. We find that Caenorhabditis elegans oocytes whose maturation is arrested by the absence of sperm(2) exhibit hallmarks of proteostasis collapse, including protein aggregation. Remarkably, sperm-secreted hormones re-establish oocyte proteostasis once fertilization becomes imminent. Key to this restoration is activation of the vacuolar H+-ATPase (V-ATPase), a proton pump that acidifies lysosomes(3). Sperm stimulate V-ATPase activity in oocytes by signalling the degradation of GLD-1, a translational repressor(4) that blocks V-ATPase synthesis. Activated lysosomes, in turn, promote a metabolic shift that mobilizes protein aggregates for degradation, and reset proteostasis by enveloping and clearing the aggregates. Lysosome acidification also occurs during Xenopus oocyte maturation; thus, a lysosomal switch that enhances oocyte proteostasis in anticipation of fertilization may be conserved in other species.
C1 [Bohnert, K. Adam; Kenyon, Cynthia] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA.
   [Bohnert, K. Adam; Kenyon, Cynthia] Calico Life Sci, San Francisco, CA 94080 USA.
C3 University of California System; University of California San Francisco
RP Kenyon, C (corresponding author), Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA.; Kenyon, C (corresponding author), Calico Life Sci, San Francisco, CA 94080 USA.
EM cynthia@calicolabs.com
FU NIH Office of Research Infrastructure Programs [P40 OD010440]; UCSF by the George and Judy Marcus Family Foundation; Life Extension Foundation; Chuan Lyu Foundation; NIH [R37/R01 AG11816]; National Institute of General Medical Sciences; NIH Office of the Director [P40OD010440] Funding Source: NIH RePORTER
NR 36
TC 124
Z9 155
U1 0
U2 57
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 30
PY 2017
VL 551
IS 7682
BP 629
EP +
DI 10.1038/nature24620
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FO1KW
UT WOS:000416520400043
PM 29168500
DA 2026-03-09
ER

PT J
AU Dargie, GC
   Lewis, SL
   Lawson, IT
   Mitchard, ETA
   Page, SE
   Bocko, YE
   Ifo, SA
AF Dargie, Greta C.
   Lewis, Simon L.
   Lawson, Ian T.
   Mitchard, Edward T. A.
   Page, Susan E.
   Bocko, Yannick E.
   Ifo, Suspense A.
TI Age, extent and carbon storage of the central Congo Basin peatland complex
SO NATURE
LA English
DT Article
ID aboveground biomass; vegetation; amazon
AB Peatlands are carbon-rich ecosystems that cover just three per cent of Earth's land surface(1), but store one-third of soil carbon(2). Peat soils are formed by the build-up of partially decomposed organic matter under waterlogged anoxic conditions. Most peat is found in cool climatic regions where unimpeded decomposition is slower, but deposits are also found under some tropical swamp forests(2,3). Here we present field measurements from one of the world's most extensive regions of swamp forest, the Cuvette Centrale depression in the central Congo Basin(4). We find extensive peat deposits beneath the swamp forest vegetation (peat defined as material with an organic matter content of at least 65 per cent to a depth of at least 0.3 metres). Radiocarbon dates indicate that peat began accumulating from about 10,600 years ago, coincident with the onset of more humid conditions in central Africa at the beginning of the Holocene(5). The peatlands occupy large interfluvial basins, and seem to be largely rain-fed and ombrotrophic-like (of low nutrient status) systems. Although the peat layer is relatively shallow (with a maximum depth of 5.9 metres and a median depth of 2.0 metres), by combining in situ and remotely sensed data, we estimate the area of peat to be approximately 145,500 square kilometres (95 per cent confidence interval of 131,900-156,400 square kilometres), making the Cuvette Centrale the most extensive peatland complex in the tropics. This area is more than five times the maximum possible area reported for the Congo Basin in a recent synthesis of pantropical peat extent(2). We estimate that the peatlands store approximately 30.6 petagrams (30.6 x 10(15) grams) of carbon belowground (95 per cent confidence interval of 6.3-46.8 petagrams of carbon)-a quantity that is similar to the above-ground carbon stocks of the tropical forests of the entire Congo Basin(6). Our result for the Cuvette Centrale increases the best estimate of global tropical peatland carbon stocks by 36 per cent, to 104.7 petagrams of carbon (minimum estimate of 69.6 petagrams of carbon; maximum estimate of 129.8 petagrams of carbon(2)). This stored carbon is vulnerable to land-use change and any future reduction in precipitation(7,8).
C1 [Dargie, Greta C.; Lewis, Simon L.] Univ Leeds, Sch Geog, Leeds LS2 9JT, W Yorkshire, England.
   [Dargie, Greta C.; Lewis, Simon L.] UCL, Dept Geog, London WC1E 6BT, England.
   [Lawson, Ian T.] Univ St Andrews, Dept Geog & Sustainable Dev, St Andrews KY16 9AL, Fife, Scotland.
   [Mitchard, Edward T. A.] Univ Edinburgh, Sch GeoSci, Edinburgh EH9 3FF, Midlothian, Scotland.
   [Page, Susan E.] Univ Leicester, Dept Geog, Leicester LE1 7RH, Leics, England.
   [Bocko, Yannick E.; Ifo, Suspense A.] Univ Marien Ngouabi, Fac Sci & Tech, Brazzaville, Rep Congo.
C3 University of Leeds; University of London; University College London; University of St Andrews; University of Edinburgh; University of Leicester
RP Dargie, GC (corresponding author), Univ Leeds, Sch Geog, Leeds LS2 9JT, W Yorkshire, England.; Dargie, GC (corresponding author), UCL, Dept Geog, London WC1E 6BT, England.
EM greta.dargie@btinternet.com
FU Natural Environment Research Council [NRCF010001, 1688.0313, 1797.0414]; Wildlife Conservation Society-Congo; Royal Society; Philip Leverhulme Prize; European Union (FP7, GEOCARBON); European Union (ERC T-FORCES); NERC [NRCF010001] Funding Source: UKRI; Natural Environment Research Council [smru10001, 1087746, NRCF010001] Funding Source: researchfish
NR 48
TC 451
Z9 524
U1 18
U2 399
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 2
PY 2017
VL 542
IS 7639
BP 86
EP +
DI 10.1038/nature21048
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6MY
UT WOS:000396119300036
PM 28077869
DA 2026-03-09
ER

PT J
AU Li, XL
   Selesnick, R
   Schiller, Q
   Zhang, K
   Zhao, H
   Baker, DN
   Temerin, MA
AF Li, Xinlin
   Selesnick, Richard
   Schiller, Quintin
   Zhang, Kun
   Zhao, Hong
   Baker, Daniel N.
   Temerin, Michael A.
TI Measurement of electrons from albedo neutron decay and neutron density in near-Earth space
SO NATURE
LA English
DT Article
ID radiation belt electrons; cosmic-ray albedo; diffusion; fields
AB The Galaxy is filled with cosmic-ray particles, mostly protons with kinetic energies greater than hundreds of megaelectronvolts. Around Earth, trapped energetic protons, electrons and other particles circulate at altitudes from about 500 to 40,000 kilometres in the Van Allen radiation belts. Soon after these radiation belts were discovered six decades ago, it was recognized that the main source of inner-belt protons (with kinetic energies of tens to hundreds of megaelectronvolts) is cosmic-ray albedo neutron decay (CRAND)(1). In this process, cosmic rays that reach the upper atmosphere interact with neutral atoms to produce albedo neutrons, which, being prone to beta-decay, are a possible source of geomagnetically trapped protons and electrons. These protons would retain most of the kinetic energy of the neutrons, while the electrons would have lower energies, mostly less than one megaelectronvolt. The viability of CRAND as an electron source has, however, been uncertain, because measurements have shown that the electron intensity in the inner Van Allen belt can vary greatly, while the neutron-decay rate should be almost constant(2,3). Here we report measurements of relativistic electrons near the inner edge of the inner radiation belt. We demonstrate that the main source of these electrons is indeed CRAND, and that this process also contributes to electrons in the inner belt elsewhere. Furthermore, measurement of the intensity of electrons generated by CRAND provides an experimental determination of the neutron density in near-Earth space-2 x 10(-9) per cubic centimetre-confirming theoretical estimates(4).
C1 [Li, Xinlin; Zhang, Kun; Zhao, Hong; Baker, Daniel N.] Univ Colorado, Lab Atmospher & Space Phys, Boulder, CO 80303 USA.
   [Li, Xinlin; Zhang, Kun] Univ Colorado, Ann & HJ Smead Dept Aerosp Engn Sci, Boulder, CO 80309 USA.
   [Selesnick, Richard] US Air Force, Res Lab, Space Vehicles Directorate, Kirtland AFB, NM 87117 USA.
   [Schiller, Quintin] NASA, Goddard Space Flight Ctr, Heliophys Lab, Greenbelt, MD 20771 USA.
   [Temerin, Michael A.] Univ Calif Berkeley, Space Sci Lab, Berkeley, CA 94720 USA.
C3 University of Colorado System; University of Colorado Boulder; University of Colorado System; University of Colorado Boulder; United States Department of Defense; United States Air Force; National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center; University of California System; University of California Berkeley
RP Li, XL (corresponding author), Univ Colorado, Lab Atmospher & Space Phys, Boulder, CO 80303 USA.; Li, XL (corresponding author), Univ Colorado, Ann & HJ Smead Dept Aerosp Engn Sci, Boulder, CO 80309 USA.
EM lix@lasp.colorado.edu
FU National Science Foundation (NSF) [AGS 1443749]; NASA/Radiation Belt Storm Probes (RBSP)-Energetic particle, Composition and Thermal plasma (ECT) through Johns Hopkins University (JHU)/Applied Physics Laboratory (APL) under prime NASA [967399, NAS5-01072]; Div Atmospheric & Geospace Sciences; Directorate For Geosciences [1443749] Funding Source: National Science Foundation
NR 21
TC 71
Z9 78
U1 1
U2 23
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 21
PY 2017
VL 552
IS 7685
BP 382
EP +
DI 10.1038/nature24642
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ7RI
UT WOS:000418559800054
PM 29236693
DA 2026-03-09
ER

PT J
AU Aguet, F
   Brown, AA
   Castel, SE
   Davis, JR
   He, Y
   Jo, B
   Mohammadi, P
   Park, Y
   Parsana, P
   Segre, AV
   Strober, BJ
   Zappala, Z
   Cummings, BB
   Gelfand, ET
   Hadley, K
   Huang, KH
   Lek, M
   Li, X
   Nedzel, JL
   Nguyen, DY
   Noble, MS
   Sullivan, TJ
   Tukiainen, T
   MacArthur, DG
   Getz, G
   Management, NP
   Addington, A
   Guan, P
   Koester, S
   Little, AR
   Lockhart, NC
   Moore, HM
   Rao, A
   Struewing, JP
   Volpi, S
   Collection, B
   Brigham, LE
   Hasz, R
   Hunter, M
   Johns, C
   Johnson, M
   Kopen, G
   Leinweber, WF
   Lonsdale, JT
   McDonald, A
   Mestichelli, B
   Myer, K
   Roe, B
   Salvatore, M
   Shad, S
   Thomas, JA
   Walters, G
   Washington, M
   Wheeler, J
   Bridge, J
   Foster, BA
   Gillard, BM
   Karasik, E
   Kumar, R
   Miklos, M
   Moser, MT
   Jewell, SD
   Montroy, RG
   Rohrer, DC
   Valley, D
   Mash, DC
   Davis, DA
   Sobin, L
   Barcus, ME
   Branton, PA
   Grp, EMW
   Abell, NS
   Balliu, B
   Delaneau, O
   Fresard, L
   Gamazon, ER
   Garrido-Martin, D
   Gewirtz, ADH
   Gliner, G
   Gloudemans, MJ
   Han, B
   He, AZ
   Hormozdiari, F
   Li, X
   Liu, B
   Kang, EY
   McDowell, IC
   Ongen, H
   Palowitch, JJ
   Peterson, CB
   Quon, G
   Ripke, S
   Saha, A
   Shabalin, AA
   Shimko, TC
   Sul, JH
   Teran, NA
   Tsang, EK
   Zhang, H
   Zhou, YH
   Bustamante, CD
   Cox, NJ
   Guigo, R
   Kellis, M
   McCarthy, MI
   Conrad, DF
   Eskin, E
   Li, G
   Nobel, AB
   Sabatti, C
   Stranger, BE
   Wen, X
   Wright, FA
   Ardlie, KG
   Dermitzakis, ET
   Lappalainen, T
   Battle, A
   Brown, CD
   Engelhardt, BE
   Montgomery, SB
   Aguet, F
   Ardlie, KG
   Cummings, BB
   Gelfand, ET
   Getz, G
   Hadley, K
   Handsaker, RE
   Huang, KH
   Kashin, S
   Karczewski, KJ
   Lek, M
   Li, X
   MacArthur, DG
   Nedzel, JL
   Nguyen, DT
   Noble, MS
   Segre, AV
   Trowbridge, CA
   Tukiainen, T
   Abell, NS
   Balliu, B
   Barshir, R
   Basha, O
   Battle, A
   Bogu, GK
   Brown, A
   Brown, CD
   Castel, SE
   Chen, LS
   Chiang, C
   Conrad, DF
   Cox, NJ
   Damani, FN
   Davis, JR
   Delaneau, O
   Dermitzakis, ET
   Engelhardt, BE
   Eskin, E
   Ferreira, PG
   Fresard, L
   Gamazon, ER
   Garrido-Martin, D
   Gewirtz, ADH
   Gliner, G
   Gloudemans, MJ
   Guigo, R
   Hall, IM
   Han, B
   He, Y
   Hormozdiari, F
   Howald, C
   Im, HK
   Jo, B
   Kang, EY
   Kim, Y
   Kim-Hellmuth, S
   Lappalainen, T
   Li, G
   Li, X
   Liu, B
   Mangul, S
   McCarthy, MI
   McDowell, IC
   Mohammadi, P
   Monlong, J
   Montgomery, SB
   Munoz-Aguirre, M
   Ndungu, AW
   Nicolae, DL
   Nobel, AB
   Oliva, M
   Ongen, H
   Palowitch, JJ
   Panousis, N
   Papasaikas, P
   Park, Y
   Parsana, P
   Payne, AJ
   Peterson, CB
   Quan, J
   Reverter, F
   Sabatti, C
   Saha, A
   Sammeth, M
   Scott, AJ
   Shabalin, AA
   Sodaei, R
   Stephens, M
   Stranger, BE
   Strober, BJ
   Sul, JH
   Tsang, EK
   Urbut, S
   De Bunt, MV
   Wang, G
   Wen, X
   Wright, FA
   Xi, HS
   Yeger-Lotem, E
   Zappala, Z
   Zaugg, JB
   Zhou, YH
   Akey, JM
   Bates, D
   Chan, J
   Chen, LS
   Claussnitzer, M
   Demanelis, K
   Diegel, M
   Doherty, JA
   Feinberg, AP
   Fernando, MS
   Halow, J
   Hansen, KD
   Haugen, E
   Hickey, PF
   Hou, L
   Jasmine, F
   Jian, R
   Jiang, L
   Johnson, A
   Kaul, R
   Kellis, M
   Kibriya, MG
   Lee, K
   Li, JB
   Li, Q
   Li, X
   Lin, J
   Lin, S
   Linder, S
   Linke, C
   Liu, Y
   Maurano, MT
   Molinie, B
   Montgomery, SB
   Nelson, J
   Neri, FJ
   Oliva, M
   Park, Y
   Pierce, BL
   Rinaldi, NJ
   Rizzardi, LF
   Sandstrom, R
   Skol, A
   Smith, KS
   Snyder, MP
   Stamatoyannopoulos, J
   Stranger, BE
   Tang, H
   Tsang, EK
   Wang, L
   Wang, M
   Van Wittenberghe, N
   Wu, F
   Zhang, R
   Fund, NC
   Nierras, CR
   Nci, N
   Branton, PA
   Carithers, LJ
   Guan, P
   Moore, HM
   Rao, A
   Vaught, JB
   Nhgri, N
   Gould, SE
   Lockart, NC
   Martin, C
   Struewing, JP
   Volpi, S
   Nimh, N
   Addington, AM
   Koester, SE
   Nida, N
   Little, AR
   Brigham, LE
   Hasz, R
   Hunter, M
   Johns, C
   Johnson, M
   Kopen, G
   Leinweber, WF
   Lonsdale, JT
   McDonald, A
   Mestichelli, B
   Myer, K
   Roe, B
   Salvatore, M
   Shad, S
   Thomas, JA
   Walters, G
   Washington, M
   Wheeler, J
   Bridge, J
   Foster, BA
   Gillard, BM
   Karasik, E
   Kumar, R
   Miklos, M
   Moser, MT
   Jewell, SD
   Montroy, RG
   Rohrer, DC
   Valley, DR
   Davis, DA
   Mash, DC
   Undale, AH
   Smith, AM
   Tabor, DE
   Roche, NV
   McLean, JA
   Vatanian, N
   Robinson, KL
   Sobin, L
   Barcus, ME
   Valentino, KM
   Qi, L
   Hunter, S
   Hariharan, P
   Singh, S
   Um, KS
   Matose, T
   Tomaszewski, MM
   Study, E
   Barker, LK
   Mosavel, M
   Siminoff, LA
   Traino, HM
   Flicek, P
   Juettemann, T
   Ruffier, M
   Sheppard, D
   Taylor, K
   Trevanion, SJ
   Zerbino, DR
   Craft, B
   Goldman, M
   Haeussler, M
   Kent, WJ
   Lee, CM
   Paten, B
   Rosenbloom, KR
   Vivian, J
   Zhu, J
AF Aguet, Francois
   Brown, Andrew A.
   Castel, Stephane E.
   Davis, Joe R.
   He, Yuan
   Jo, Brian
   Mohammadi, Pejman
   Park, Yoson
   Parsana, Princy
   Segre, Ayellet V.
   Strober, Benjamin J.
   Zappala, Zachary
   Cummings, Beryl B.
   Gelfand, Ellen T.
   Hadley, Kane
   Huang, Katherine H.
   Lek, Monkol
   Li, Xiao
   Nedzel, Jared L.
   Nguyen, Duyen Y.
   Noble, Michael S.
   Sullivan, Timothy J.
   Tukiainen, Taru
   MacArthur, Daniel G.
   Getz, Gad
   Management, Nih Program
   Addington, Anjene
   Guan, Ping
   Koester, Susan
   Little, A. Roger
   Lockhart, Nicole C.
   Moore, Helen M.
   Rao, Abhi
   Struewing, Jeffery P.
   Volpi, Simona
   Collection, Biospecimen
   Brigham, Lori E.
   Hasz, Richard
   Hunter, Marcus
   Johns, Christopher
   Johnson, Mark
   Kopen, Gene
   Leinweber, William F.
   Lonsdale, John T.
   McDonald, Alisa
   Mestichelli, Bernadette
   Myer, Kevin
   Roe, Bryan
   Salvatore, Michael
   Shad, Saboor
   Thomas, Jeffrey A.
   Walters, Gary
   Washington, Michael
   Wheeler, Joseph
   Bridge, Jason
   Foster, Barbara A.
   Gillard, Bryan M.
   Karasik, Ellen
   Kumar, Rachna
   Miklos, Mark
   Moser, Michael T.
   Jewell, Scott D.
   Montroy, Robert G.
   Rohrer, Daniel C.
   Valley, Dana
   Mash, Deborah C.
   Davis, David A.
   Sobin, Leslie
   Barcus, Mary E.
   Branton, Philip A.
   Grp, Eqtl Manuscript Working
   Abell, Nathan S.
   Balliu, Brunilda
   Delaneau, Olivier
   Fresard, Laure
   Gamazon, Eric R.
   Garrido-Martin, Diego
   Gewirtz, Ariel D. H.
   Gliner, Genna
   Gloudemans, Michael J.
   Han, Buhm
   He, Amy Z.
   Hormozdiari, Farhad
   Li, Xin
   Liu, Boxiang
   Kang, Eun Yong
   McDowell, Ian C.
   Ongen, Halit
   Palowitch, John J.
   Peterson, Christine B.
   Quon, Gerald
   Ripke, Stephan
   Saha, Ashis
   Shabalin, Andrey A.
   Shimko, Tyler C.
   Sul, Jae Hoon
   Teran, Nicole A.
   Tsang, Emily K.
   Zhang, Hailei
   Zhou, Yi-Hui
   Bustamante, Carlos D.
   Cox, Nancy J.
   Guigo, Roderic
   Kellis, Manolis
   McCarthy, Mark I.
   Conrad, Donald F.
   Eskin, Eleazar
   Li, Gen
   Nobel, Andrew B.
   Sabatti, Chiara
   Stranger, Barbara E.
   Wen, Xiaoquan
   Wright, Fred A.
   Ardlie, Kristin G.
   Dermitzakis, Emmanouil T.
   Lappalainen, Tuuli
   Battle, Alexis
   Brown, Christopher D.
   Engelhardt, Barbara E.
   Montgomery, Stephen B.
   Aguet, Francois
   Ardlie, Kristin G.
   Cummings, Beryl B.
   Gelfand, Ellen T.
   Getz, Gad
   Hadley, Kane
   Handsaker, Robert E.
   Huang, Katherine H.
   Kashin, Seva
   Karczewski, Konrad J.
   Lek, Monkol
   Li, Xiao
   MacArthur, Daniel G.
   Nedzel, Jared L.
   Nguyen, Duyen T.
   Noble, Michael S.
   Segre, Ayellet V.
   Trowbridge, Casandra A.
   Tukiainen, Taru
   Abell, Nathan S.
   Balliu, Brunilda
   Barshir, Ruth
   Basha, Omer
   Battle, Alexis
   Bogu, Gireesh K.
   Brown, Andrew
   Brown, Christopher D.
   Castel, Stephane E.
   Chen, Lin S.
   Chiang, Colby
   Conrad, Donald F.
   Cox, Nancy J.
   Damani, Farhan N.
   Davis, Joe R.
   Delaneau, Olivier
   Dermitzakis, Emmanouil T.
   Engelhardt, Barbara E.
   Eskin, Eleazar
   Ferreira, Pedro G.
   Fresard, Laure
   Gamazon, Eric R.
   Garrido-Martin, Diego
   Gewirtz, Ariel D. H.
   Gliner, Genna
   Gloudemans, Michael J.
   Guigo, Roderic
   Hall, Ira M.
   Han, Buhm
   He, Yuan
   Hormozdiari, Farhad
   Howald, Cedric
   Im, Hae Kyung
   Jo, Brian
   Kang, Eun Yong
   Kim, Yungil
   Kim-Hellmuth, Sarah
   Lappalainen, Tuuli
   Li, Gen
   Li, Xin
   Liu, Boxiang
   Mangul, Serghei
   McCarthy, Mark I.
   McDowell, Ian C.
   Mohammadi, Pejman
   Monlong, Jean
   Montgomery, Stephen B.
   Munoz-Aguirre, Manuel
   Ndungu, Anne W.
   Nicolae, Dan L.
   Nobel, Andrew B.
   Oliva, Meritxell
   Ongen, Halit
   Palowitch, John J.
   Panousis, Nikolaos
   Papasaikas, Panagiotis
   Park, Yoson
   Parsana, Princy
   Payne, Anthony J.
   Peterson, Christine B.
   Quan, Jie
   Reverter, Ferran
   Sabatti, Chiara
   Saha, Ashis
   Sammeth, Michael
   Scott, Alexandra J.
   Shabalin, Andrey A.
   Sodaei, Reza
   Stephens, Matthew
   Stranger, Barbara E.
   Strober, Benjamin J.
   Sul, Jae Hoon
   Tsang, Emily K.
   Urbut, Sarah
   De Bunt, Martijn Van
   Wang, Gao
   Wen, Xiaoquan
   Wright, Fred A.
   Xi, Hualin S.
   Yeger-Lotem, Esti
   Zappala, Zachary
   Zaugg, Judith B.
   Zhou, Yi-Hui
   Akey, Joshua M.
   Bates, Daniel
   Chan, Joanne
   Chen, Lin S.
   Claussnitzer, Melina
   Demanelis, Kathryn
   Diegel, Morgan
   Doherty, Jennifer A.
   Feinberg, Andrew P.
   Fernando, Marian S.
   Halow, Jessica
   Hansen, Kasper D.
   Haugen, Eric
   Hickey, Peter F.
   Hou, Lei
   Jasmine, Farzana
   Jian, Ruiqi
   Jiang, Lihua
   Johnson, Audra
   Kaul, Rajinder
   Kellis, Manolis
   Kibriya, Muhammad G.
   Lee, Kristen
   Li, Jin Billy
   Li, Qin
   Li, Xiao
   Lin, Jessica
   Lin, Shin
   Linder, Sandra
   Linke, Caroline
   Liu, Yaping
   Maurano, Matthew T.
   Molinie, Benoit
   Montgomery, Stephen B.
   Nelson, Jemma
   Neri, Fidencio J.
   Oliva, Meritxell
   Park, Yongjin
   Pierce, Brandon L.
   Rinaldi, Nicola J.
   Rizzardi, Lindsay F.
   Sandstrom, Richard
   Skol, Andrew
   Smith, Kevin S.
   Snyder, Michael P.
   Stamatoyannopoulos, John
   Stranger, Barbara E.
   Tang, Hua
   Tsang, Emily K.
   Wang, Li
   Wang, Meng
   Van Wittenberghe, Nicholas
   Wu, Fan
   Zhang, Rui
   Fund, Nih Common
   Nierras, Concepcion R.
   Nci, Nih
   Branton, Philip A.
   Carithers, Latarsha J.
   Guan, Ping
   Moore, Helen M.
   Rao, Abhi
   Vaught, Jimmie B.
   Nhgri, Nih
   Gould, Sarah E.
   Lockart, Nicole C.
   Martin, Casey
   Struewing, Jeffery P.
   Volpi, Simona
   Nimh, Nih
   Addington, Anjene M.
   Koester, Susan E.
   Nida, Nih
   Little, A. Roger
   Brigham, Lori E.
   Hasz, Richard
   Hunter, Marcus
   Johns, Christopher
   Johnson, Mark
   Kopen, Gene
   Leinweber, William F.
   Lonsdale, John T.
   McDonald, Alisa
   Mestichelli, Bernadette
   Myer, Kevin
   Roe, Brian
   Salvatore, Michael
   Shad, Saboor
   Thomas, Jeffrey A.
   Walters, Gary
   Washington, Michael
   Wheeler, Joseph
   Bridge, Jason
   Foster, Barbara A.
   Gillard, Bryan M.
   Karasik, Ellen
   Kumar, Rachna
   Miklos, Mark
   Moser, Michael T.
   Jewell, Scott D.
   Montroy, Robert G.
   Rohrer, Daniel C.
   Valley, Dana R.
   Davis, David A.
   Mash, Deborah C.
   Undale, Anita H.
   Smith, Anna M.
   Tabor, David E.
   Roche, Nancy V.
   McLean, Jeffrey A.
   Vatanian, Negin
   Robinson, Karna L.
   Sobin, Leslie
   Barcus, Mary E.
   Valentino, Kimberly M.
   Qi, Liqun
   Hunter, Steven
   Hariharan, Pushpa
   Singh, Shilpi
   Um, Ki Sung
   Matose, Takunda
   Tomaszewski, Maria M.
   Study, Elsi
   Barker, Laura K.
   Mosavel, Maghboeba
   Siminoff, Laura A.
   Traino, Heather M.
   Flicek, Paul
   Juettemann, Thomas
   Ruffier, Magali
   Sheppard, Dan
   Taylor, Kieron
   Trevanion, Stephen J.
   Zerbino, Daniel R.
   Craft, Brian
   Goldman, Mary
   Haeussler, Maximilian
   Kent, W. James
   Lee, Christopher M.
   Paten, Benedict
   Rosenbloom, Kate R.
   Vivian, John
   Zhu, Jingchun
TI Genetic effects on gene expression across human tissues
SO NATURE
LA English
DT Article
ID false discovery rate; transcription factor; trans-eqtls; genome; variants; identification; hypothyroidism; associations; thousands; power
AB Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.
C1 [Aguet, Francois; Segre, Ayellet V.; Cummings, Beryl B.; Gelfand, Ellen T.; Hadley, Kane; Huang, Katherine H.; Nedzel, Jared L.; Nguyen, Duyen Y.; MacArthur, Daniel G.; Getz, Gad] Harvard Univ, Broad Inst Massachusetts Inst Technol, Cambridge, MA 02142 USA.
   [Brown, Andrew A.; Delaneau, Olivier; Ongen, Halit; Dermitzakis, Emmanouil T.; Cummings, Beryl B.; Karczewski, Konrad J.; Lek, Monkol; MacArthur, Daniel G.; Tukiainen, Taru] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
   [Brown, Andrew A.; Delaneau, Olivier; Ongen, Halit; Dermitzakis, Emmanouil T.; Getz, Gad] Massachusetts Gen, Massachusetts Gen Hosp, Hosp Canc Ctr & Dept Pathol, Boston, MA 02114 USA.
   [Brown, Andrew A.; Delaneau, Olivier; Ongen, Halit; Dermitzakis, Emmanouil T.; Handsaker, Robert E.; Kashin, Seva] Harvard Med Sch, Dept Genet, Boston, MA 02114 USA.
   [Castel, Stephane E.; Mohammadi, Pejman; Lappalainen, Tuuli; Abell, Nathan S.; Davis, Joe R.; Fresard, Laure; Gloudemans, Michael J.; Liu, Boxiang; Montgomery, Stephen B.; Zappala, Zachary; Chan, Joanne; Jian, Ruiqi; Jiang, Lihua; Li, Jin Billy; Li, Qin; Li, Xiao; Lin, Jessica; Lin, Shin; Linder, Sandra; Smith, Kevin S.; Snyder, Michael P.; Tang, Hua; Wang, Meng; Zhang, Rui] Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
   [Castel, Stephane E.; Mohammadi, Pejman; Lappalainen, Tuuli; Abell, Nathan S.; Balliu, Brunilda; Davis, Joe R.; Fresard, Laure; Gloudemans, Michael J.; Li, Xin; Liu, Boxiang; Tsang, Emily K.; Zappala, Zachary; Linder, Sandra; Smith, Kevin S.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA.
   [Davis, Joe R.; Zappala, Zachary; Abell, Nathan S.; Shimko, Tyler C.; Teran, Nicole A.; Bustamante, Carlos D.; Montgomery, Stephen B.; Barshir, Ruth; Basha, Omer; Battle, Alexis; Yeger-Lotem, Esti] Ben Gurion Univ Negev, Dept Clin Biochem & Pharmacol, Fac Hlth Sci, Negev, IL-84105 Beer Sheva, Israel.
   [Davis, Joe R.; Zappala, Zachary; Abell, Nathan S.; Balliu, Brunilda; Fresard, Laure; Gloudemans, Michael J.; Li, Xin; Liu, Boxiang; Shimko, Tyler C.; Teran, Nicole A.; Tsang, Emily K.; Montgomery, Stephen B.; Damani, Farhan N.; Kim, Yungil; Parsana, Princy; Saha, Ashis] Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA.
   [He, Yuan; Strober, Benjamin J.; Bogu, Gireesh K.; Garrido-Martin, Diego; Guigo, Roderic; Monlong, Jean; Munoz-Aguirre, Manuel; Papasaikas, Panagiotis; Reverter, Ferran; Sodaei, Reza] Barcelona Inst Sci & Technol, Ctr Genom Regulat CRC, Barcelona 08003, Spain.
   [Jo, Brian; Gewirtz, Ariel D. H.; Bogu, Gireesh K.; Garrido-Martin, Diego; Guigo, Roderic; Monlong, Jean; Munoz-Aguirre, Manuel; Papasaikas, Panagiotis; Reverter, Ferran; Sodaei, Reza] Univ Pompeu Fabra UPF, Barcelona 08002, Spain.
   [Park, Yoson; Brown, Christopher D.; Brown, Andrew; Delaneau, Olivier; Dermitzakis, Emmanouil T.; Howald, Cedric; Ongen, Halit; Panousis, Nikolaos; Park, Yoson] Univ Geneva Med Sch, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland.
   [Parsana, Princy; He, Amy Z.; Saha, Ashis; Battle, Alexis; Brown, Andrew; Delaneau, Olivier; Dermitzakis, Emmanouil T.; Howald, Cedric; Ongen, Halit; Panousis, Nikolaos] Univ Geneva, Inst Genet & Genom Geneva iG3, CH-1211 Geneva, Switzerland.
   [Cummings, Beryl B.; Lek, Monkol; Tukiainen, Taru; MacArthur, Daniel G.; Ripke, Stephan; Brown, Andrew; Delaneau, Olivier; Dermitzakis, Emmanouil T.; Howald, Cedric; Ongen, Halit; Panousis, Nikolaos] Swiss Inst Bioinformat, CH-1211 Geneva, Switzerland.
   [Getz, Gad; Brown, Christopher D.] Univ Pennsylvania, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA.
   [Addington, Anjene; Koester, Susan; Castel, Stephane E.; Kim-Hellmuth, Sarah; Lappalainen, Tuuli; Mohammadi, Pejman] New York Genome Ctr, New York, NY 10013 USA.
   [Guan, Ping; Moore, Helen M.; Rao, Abhi; Branton, Philip A.; Castel, Stephane E.; Kim-Hellmuth, Sarah; Lappalainen, Tuuli; Mohammadi, Pejman] Columbia Univ rvlecl Ctr, Dept Syst Biol, New York, NY 10032 USA.
   [Little, A. Roger; Chen, Lin S.; Demanelis, Kathryn; Jasmine, Farzana; Kibriya, Muhammad G.; Pierce, Brandon L.] Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA.
   [Lockhart, Nicole C.; Chiang, Colby; Hall, Ira M.; Scott, Alexandra J.] Washington Univ Sch Med, McDonnell Genome Inst, St Louis, MO USA.
   [Struewing, Jeffery P.; Volpi, Simona; Conrad, Donald F.; Hall, Ira M.] Washington Univ Sch Med, Dept Genet, St Louis, MO 63108 USA.
   [Brigham, Lori E.; Conrad, Donald F.] Washington Univ Sch Med, Dept Pathol Immunol, St Louis, MO 63108 USA.
   [Hasz, Richard; Cox, Nancy J.; Gamazon, Eric R.] Vanderbilt Univ tvlecl Ctr, Dept tvleclicine, Divis Genet Med, Nashville, TN 37232 USA.
   [Hunter, Marcus; Myer, Kevin; Roe, Bryan; Engelhardt, Barbara E.] Princeton Univ, Dept Comp Sci, Ctr Stat & Machine Learning, Princeton, NJ 08540 USA.
   [Johns, Christopher; Wheeler, Joseph; Eskin, Eleazar; Hormozdiari, Farhad; Kang, Eun Yong] Univ Calif Los Angeles, Dept Comp Sci, Los Angeles, CA 90095 USA.
   [Johnson, Mark; Walters, Gary; Washington, Michael; Eskin, Eleazar] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA.
   [Kopen, Gene; Leinweber, William F.; Lonsdale, John T.; McDonald, Alisa; Mestichelli, Bernadette; Salvatore, Michael; Shad, Saboor; Thomas, Jeffrey A.; Ferreira, Pedro G.] Univ Porto, Inst Investigac Inovac Saucle i3S, P-4200135 Oporto, Portugal.
   [Bridge, Jason; Miklos, Mark; Ferreira, Pedro G.] Univ Porto, Inst Mol Pathol & Immunol IPATIMUP, P-4200625 Oporto, Portugal.
   [Foster, Barbara A.; Gillard, Bryan M.; Karasik, Ellen; Kumar, Rachna; Moser, Michael T.; Gamazon, Eric R.] Univ Amsterdam, Acad Mecl Ctr, Dept Clin Epidemiol, Biostatist & Bioinformat, NL-1105 AZ Amsterdam, Netherlands.
   [Jewell, Scott D.; Montroy, Robert G.; Rohrer, Daniel C.; Valley, Dana; Gamazon, Eric R.; Mangul, Serghei] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, NL-1105 AZ Amsterdam, Netherlands.
   [Mash, Deborah C.; Davis, David A.; Gewirtz, Ariel D. H.; Jo, Brian; Akey, Joshua M.] Princeton Univ, Lewis Sigler Inst, Princeton, NJ 08540 USA.
   [Sobin, Leslie; Barcus, Mary E.; Gliner, Genna] Princeton Univ, Dept Operat Res & Financial Engn, Princeton, NJ 08540 USA.
   [Gamazon, Eric R.; Cox, Nancy J.; Gloudemans, Michael J.] Stanford Univ, Biomed Informat Program, Stanford, CA 94305 USA.
   [Garrido-Martin, Diego; Guigo, Roderic; Guigo, Roderic] Inst Hosp Mar Investigac Med IMIM, Barcelona 08003, Spain.
   [Garrido-Martin, Diego; Guigo, Roderic; Hall, Ira M.] Washington Univ Sch Med, Dept Med, St Louis, MO 63108 USA.
   [Gliner, Genna; Han, Buhm] Univ Ulsan Coll Med, Dept Convergence Med, Asan Med Ctr, Seoul 138736, South Korea.
   [Gloudemans, Michael J.; Tsang, Emily K.; He, Yuan; Strober, Benjamin J.; Feinberg, Andrew P.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA.
   [Han, Buhm; Im, Hae Kyung; Nicolae, Dan L.; Oliva, Meritxell; Stranger, Barbara E.; Fernando, Marian S.; Linke, Caroline; Skol, Andrew; Wu, Fan] Univ Chicago, Sect Genet Med, Dept Med, Chicago, IL 60637 USA.
   [Hormozdiari, Farhad; Eskin, Eleazar; Li, Gen] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostatist, New York, NY 10032 USA.
   [Liu, Boxiang; Liu, Boxiang] Stanford Univ, Dept Biol, Stanford, CA 94305 USA.
   [Kang, Eun Yong; Eskin, Eleazar; McCarthy, Mark I.; Ndungu, Anne W.; Payne, Anthony J.; De Bunt, Martijn Van] Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.
   [McDowell, Ian C.; McCarthy, Mark I.; De Bunt, Martijn Van] Univ Oxford, Churchill Hosp, Ctr Diabet, Endocrinol & Metab, Oxford 033 7LE, England.
   [Palowitch, John J.; Nobel, Andrew B.; McCarthy, Mark I.] Oxford NIHR Biomed Res Ctr, Churchill Hosp, Oxford 0X3 7LJ, England.
   [Peterson, Christine B.; McDowell, Ian C.] Duke Univ, Computat Biol Bioinformat Grad Program, Durham, NC 27708 USA.
   [Quon, Gerald; Kellis, Manolis; Monlong, Jean] McGill Univ, Human Genet Dept, Montreal, PQ H3A 2T5, Canada.
   [Ripke, Stephan; Munoz-Aguirre, Manuel] Univ Politecn Cataluna, Dept Estadist Investigac Operat, Barcelona 08034, Spain.
   [Shabalin, Andrey A.; Nicolae, Dan L.; Stephens, Matthew] Univ Chicago, Dept Stat, Chicago, IL 60637 USA.
   [Sul, Jae Hoon; Nicolae, Dan L.; Stephens, Matthew; Urbut, Sarah; Wang, Gao] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA.
   [Zhou, Yi-Hui; Nobel, Andrew B.; Palowitch, John J.] Univ N Carolina, Dept Stat & Operat Res, Chapel Hill, NC 27599 USA.
   [Bustamante, Carlos D.; Sabatti, Chiara; Nobel, Andrew B.] Univ N Carolina, Dept Biostatist, Chapel Hill, NC 27599 USA.
   [McCarthy, Mark I.; Fernando, Marian S.; Linke, Caroline; Skol, Andrew; Wu, Fan] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA.
   [McCarthy, Mark I.; Peterson, Christine B.] Univ Texas MD Anderson Canc Ctr, Dept Biostatist, Houston, TX 77030 USA.
   [McCarthy, Mark I.; Quan, Jie; Xi, Hualin S.] Pfizer Inc, Computat Sci, Cambridge, MA 02139 USA.
   [Conrad, Donald F.; Reverter, Ferran] Univ Barcelona, E-08028 Barcelona, Spain.
   [Conrad, Donald F.; Sabatti, Chiara] Stanford Univ, Dept Biomed Data Sci, Stanford, CA 94305 USA.
   [Li, Gen; Sabatti, Chiara] Stanford Univ, Dept Stat, Stanford, CA 94305 USA.
   [Sabatti, Chiara; Sammeth, Michael] Fed Univ Rio Janeiro UFRJ, Inst Biophys Carlos Chagas Filho IBCCF, BR-21941902 Rio De Janeiro, Brazil.
   [Stranger, Barbara E.; Shabalin, Andrey A.] Univ Utah, Dept Psychiat, Salt Lake City, UT 84108 USA.
   [Wen, Xiaoquan; Skol, Andrew] Univ Chicago, Ctr Data Intens Sci, Chicago, IL 60637 USA.
   [Wright, Fred A.; Sul, Jae Hoon] Univ Calif Los Angeles, Dept Psychiat & Biobehavi Sci, Los Angeles, CA 90095 USA.
   [Engelhardt, Barbara E.; Wen, Xiaoquan] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.
   [Wright, Fred A.; Zhou, Yi-Hui] N Carolina State Univ, Bioinformat Res Ctr, Dept Stat & Biol Sci, Raleigh, NC 27695 USA.
   [Yeger-Lotem, Esti] Natl Inst Biotechnol Negev, IL-34105 Beer Sheva, Israel.
   [Zaugg, Judith B.] European Mol Biol Lab, D-69117 Heidelberg, Germany.
   [Akey, Joshua M.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ USA.
   [Bates, Daniel; Diegel, Morgan; Halow, Jessica; Haugen, Eric; Johnson, Audra; Kaul, Rajinder; Lee, Kristen; Nelson, Jemma; Neri, Fidencio J.; Sandstrom, Richard; Stamatoyannopoulos, John] Altius Inst Biomed Sci, Seattle, WA 98121 USA.
   [Claussnitzer, Melina] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA.
   [Claussnitzer, Melina] Univ Hohenheim, D-70599 Stuttgart, Germany.
   [Doherty, Jennifer A.] Univ Utah, Huntsman Canc Inst, Dept Populat Hlth Sci, Salt Lake City, UT 84112 USA.
   [Feinberg, Andrew P.; Hansen, Kasper D.; Rizzardi, Lindsay F.] Johns Hopkins Univ Sch Med, Ctr Epigenet, Baltimore, MD 21205 USA.
   [Feinberg, Andrew P.] Johns Hopkins Univ Sch Med, Dept Med, Baltimore, MD 21205 USA.
   [Feinberg, Andrew P.] Johns Hopkins Univ Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21205 USA.
   [Hansen, Kasper D.] McKusick Nathans Inst Genet Med, Johns Hopkins Sch Med, Baltimore, MD 21205 USA.
   [Hansen, Kasper D.; Hickey, Peter F.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA.
   [Hou, Lei; Kellis, Manolis; Liu, Yaping; Park, Yongjin; Rinaldi, Nicola J.] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA.
   [Lin, Jessica; Stamatoyannopoulos, John] Univ Washington, Dept Med, Seattle, WA 98195 USA.
   [Lin, Shin] Univ Washington, Div Cardiol, Seattle, WA 98195 USA.
   [Maurano, Matthew T.] New York Univ Langone Med Ctr, Inst Syst Genet, New York, NY 10016 USA.
   [Stamatoyannopoulos, John] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.
   [Nierras, Concepcion R.] Div Program Coordinat, Off Strateg Coordinat, Planning & Strateg Initiat, Rockville, MD 20852 USA.
   [Branton, Philip A.; Carithers, Latarsha J.; Guan, Ping; Moore, Helen M.; Rao, Abhi; Vaught, Jimmie B.] Natl Canc Inst, Div Canc Treatment & Diag, Biorepositories & Biospecimen Res Branch, Bethesda, MD 20892 USA.
   [Carithers, Latarsha J.] Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA.
   [Gould, Sarah E.; Lockart, Nicole C.; Martin, Casey; Struewing, Jeffery P.; Volpi, Simona] Natl Human Genome Res Inst, Divis Genom Med, Rockville, MD 20852 USA.
   [Addington, Anjene M.; Koester, Susan E.] Natl Inst Mental Hlth, Div Neuroscience & Basic Behav Sci, NIH, Bethesda, MD 20892 USA.
   [Little, A. Roger] Natl Inst Drug Abuse, Div Neuroscience & Behav, NIH, Bethesda, MD USA.
   [Brigham, Lori E.] Washington Reg Transplant Community, Falls Church, VA 22003 USA.
   [Hasz, Richard] Gift Life Donor Program, Philadelphia, PA 19103 USA.
   [Hunter, Marcus; Johnson, Mark; Myer, Kevin; Roe, Brian] LifeGift, Houston, TX 77055 USA.
   [Johns, Christopher; Wheeler, Joseph] Ctr Organ Recovery & Educ, Pittsburgh, PA 15238 USA.
   [Walters, Gary; Washington, Michael] LifeNet Hlth, Virginia Beach, VA 23453 USA.
   [Kopen, Gene; Leinweber, William F.; Lonsdale, John T.; McDonald, Alisa; Mestichelli, Bernadette; Salvatore, Michael; Shad, Saboor; Thomas, Jeffrey A.] Natl Dis Res Interchange, Philadelphia, PA 19103 USA.
   [Bridge, Jason; Miklos, Mark] Unyts, Buffalo, NY 14203 USA.
   [Foster, Barbara A.; Gillard, Bryan M.; Karasik, Ellen; Kumar, Rachna; Moser, Michael T.] Roswell Pk Canc Inst, Pharmacol & Therapeut, Buffalo, NY 14263 USA.
   [Jewell, Scott D.; Montroy, Robert G.; Rohrer, Daniel C.; Valley, Dana R.] Van Andel Res Inst, Grand Rapids, MI 49503 USA.
   [Davis, David A.; Mash, Deborah C.] Univ Miami, Miller Sch Med, Brain Endowment Bank, Miami, FL 33136 USA.
   [Undale, Anita H.] Natl Inst Allergy & Infect Dis, NIH, Rockville, MD 20852 USA.
   [Smith, Anna M.; Tabor, David E.; Roche, Nancy V.; McLean, Jeffrey A.; Vatanian, Negin; Robinson, Karna L.; Sobin, Leslie; Valentino, Kimberly M.; Qi, Liqun; Hunter, Steven; Hariharan, Pushpa; Singh, Shilpi; Um, Ki Sung; Matose, Takunda; Tomaszewski, Maria M.] Leidos Biomedical Res Inc, Clin Res Directorate, Biospecimen Res Grp, Rockville, MD 20852 USA.
   [Barcus, Mary E.] Leidos Biomed Res Inc, Frederick, MD 21701 USA.
   [Barker, Laura K.; Siminoff, Laura A.; Traino, Heather M.] Temple Univ, Philadelphia, PA 19122 USA.
   [Mosavel, Maghboeba] Virginia Commonwealth Univ, Sch Med, Dept Hlth Behav & Policy, Richmond, VA 23298 USA.
   European Bioinformat Inst, European Mol Biol Lab, Hinxton CB1O ISD, England.
   [Craft, Brian; Goldman, Mary; Haeussler, Maximilian; Kent, W. James; Lee, Christopher M.; Paten, Benedict; Rosenbloom, Kate R.; Vivian, John; Zhu, Jingchun] Univ Calif Santa Cruz, UCSC Genom Inst, Santa Cruz, CA 95064 USA.
C3 Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Stanford University; Stanford University; Ben-Gurion University of the Negev; Johns Hopkins University; Barcelona Institute of Science & Technology; Pompeu Fabra University; Centre de Regulacio Genomica (CRG); Pompeu Fabra University; University of Geneva; University of Geneva; Swiss Institute of Bioinformatics; University of Pennsylvania; University of Chicago; Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Princeton University; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; Universidade do Porto; i3S - Instituto de Investigacao e Inovacao em Saude, Universidade do Porto; Universidade do Porto; University of Amsterdam; University of Amsterdam; Academic Medical Center Amsterdam; Princeton University; Princeton University; Stanford University; Hospital del Mar Research Institute; Washington University (WUSTL); University of Ulsan; Asan Medical Center; Johns Hopkins University; University of Chicago; Columbia University; Stanford University; University of Oxford; Wellcome Centre for Human Genetics; University of Oxford; Duke University; McGill University; Universitat Politecnica de Catalunya; University of Chicago; University of Chicago; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of Chicago; University of Texas System; UTMD Anderson Cancer Center; Pfizer; Pfizer USA; University of Barcelona; Stanford University; Stanford University; Utah System of Higher Education; University of Utah; University of Chicago; University of California System; University of California Los Angeles; University of Michigan System; University of Michigan; North Carolina State University; European Molecular Biology Laboratory (EMBL); Princeton University; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard Medical School; University Hohenheim; Utah System of Higher Education; University of Utah; Huntsman Cancer Institute; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins Medicine; Johns Hopkins University; Massachusetts Institute of Technology (MIT); University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; New York University; University of Washington; University of Washington Seattle; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); NIH Division of Cancer Treatment & Diagnosis; National Institutes of Health (NIH) - USA; NIH National Institute of Dental & Craniofacial Research (NIDCR); National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI); National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH); National Institutes of Health (NIH) - USA; NIH National Institute on Drug Abuse (NIDA); Roswell Park Comprehensive Cancer Center; Van Andel Institute; Van Andel Research Institute; University of Miami; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; Pennsylvania Commonwealth System of Higher Education (PCSHE); Temple University; Virginia Commonwealth University; European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute; University of California System; University of California Santa Cruz
RP Brown, AA (corresponding author), Massachusetts Gen, Massachusetts Gen Hosp, Hosp Canc Ctr & Dept Pathol, Boston, MA 02114 USA.
EM ajbattle@cs.jhu.edu; chrbro@pennmedicine.upenn.edu; bee@princeton.edu; ajbattle@cs.jhu.edu; chrbro@pennmedicine.upenn.edu; bee@princeton.edu; smontgom@stanford.edu
FU Common Fund of the Office of the Director of the National Institutes of Health; National Cancer Institute (NCI); National Human Genome Research Institute (NHGRI); National Heart, Lung, and Blood Institute (NHLBI); National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH); National Institute of Neurological Disorders and Stroke (NINDS); Leidos Biomedical, Inc. (Leidos) [10XS170, 10XS171]; Leidos subcontract [10ST1035]; University of Miami [DA006227]; Lucille P. Markey Biomedical Research Stanford Graduate Fellowship; Stanford Genome Training Program (SGTP) [NIH/NHGRI T32HG000044]; National Science Foundation (NSF) GRFP [DGE-114747]; Stanford Center for Computational, Evolutionary, and Human Genomics (CEHG); "la Caixa"-Severo Ochoa pre-doctoral fellowship; NIH [U54DK105566, R01GM104371, T32GM007057, R01MH109905, R01HG008150, R01MH101814, R01MH101822, R00HG006265, U01 HG007900, R01MH101819, R01HG009125, R21HG007840, R01MH106842, UM1HG008901, HHSN2682010000029C, 2T32HG003284-11, R01MH101782, R01MH101810, R01MH101820, R01MH090937A]; Hewlett-Packard Stanford Graduate Fellowship; Natural Science and Engineering Council of Canada; National Science Foundation Graduate Research Fellowship [DGE-1656518]; Searle Scholars Program; NHGRI [U01HG007436, U01HG009080]; Sloan Faculty Fellowship;  [HHSN268201000029C]; National Human Genome Research Institute [T32HG000044, U41HG002371, T32HG003284] Funding Source: NIH RePORTER; National Institute of Mental Health [R01MH106842] Funding Source: NIH RePORTER; National Library of Medicine; National Institute of Allergy and Infectious Diseases [T15LM007033] Funding Source: NIH RePORTER; National Institute for Health Research [NF-SI-0611-10099] Funding Source: researchfish
NR 80
TC 2842
Z9 3298
U1 13
U2 310
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 12
PY 2017
VL 550
IS 7675
BP 204
EP +
DI 10.1038/nature24277
PG 37
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FJ5YG
UT WOS:000412829500039
PM 29022597
DA 2026-03-09
ER

PT J
AU Glanville, J
   Huang, H
   Nau, A
   Hatton, O
   Wagar, LE
   Rubelt, F
   Ji, XH
   Han, A
   Krams, SM
   Pettus, C
   Haas, N
   Arlehamn, CSL
   Sette, A
   Boyd, SD
   Scriba, TJ
   Martinez, OM
   Davis, MM
AF Glanville, Jacob
   Huang, Huang
   Nau, Allison
   Hatton, Olivia
   Wagar, Lisa E.
   Rubelt, Florian
   Ji, Xuhuai
   Han, Arnold
   Krams, Sheri M.
   Pettus, Christina
   Haas, Nikhil
   Arlehamn, Cecilia S. Lindestam
   Sette, Alessandro
   Boyd, Scott D.
   Scriba, Thomas J.
   Martinez, Olivia M.
   Davis, Mark M.
TI Identifying specificity groups in the T cell receptor repertoire
SO NATURE
LA English
DT Article
ID cd4(+); diversity; protein; naive
AB T cell receptor (TCR) sequences are very diverse, with many more possible sequence combinations than T cells in any one individual(1-4). Here we define the minimal requirements for TCR antigen specificity, through an analysis of TCR sequences using a panel of peptide and major histocompatibility complex (pMHC)-tetramer-sorted cells and structural data. From this analysis we developed an algorithm that we term GLIPH (grouping of lymphocyte interactions by paratope hotspots) to cluster TCRs with a high probability of sharing specificity owing to both conserved motifs and global similarity of complementarity-determining region 3 (CDR3) sequences. We show that GLIPH can reliably group TCRs of common specificity from different donors, and that conserved CDR3 motifs help to define the TCR clusters that are often contact points with the antigenic peptides. As an independent validation, we analysed 5,711 TCR beta chain sequences from reactive CD4 T cells from 22 individuals with latent Mycobacterium tuberculosis infection. We found 141 TCR specificity groups, including 16 distinct groups containing TCRs from multiple individuals. These TCR groups typically shared HLA alleles, allowing prediction of the likely HLA restriction, and a large number of M. tuberculosis T cell epitopes enabled us to identify pMHC ligands for all five of the groups tested. Mutagenesis and de novo TCR design confirmed that the GLIPH-identified motifs were critical and sufficient for shared-antigen recognition. Thus the GLIPH algorithm can analyse large numbers of TCR sequences and define TCR specificity groups shared by TCRs and individuals, which should greatly accelerate the analysis of T cell responses and expedite the identification of specific ligands.
C1 [Glanville, Jacob] Stanford Univ, Sch Med, Computat & Syst Immunol Program, Stanford, CA 94305 USA.
   [Glanville, Jacob; Huang, Huang; Nau, Allison; Wagar, Lisa E.; Rubelt, Florian; Ji, Xuhuai; Davis, Mark M.] Stanford Univ, Sch Med, Inst Immun Transplantat & Infect, Stanford, CA 94305 USA.
   [Huang, Huang; Wagar, Lisa E.; Davis, Mark M.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA.
   [Hatton, Olivia; Krams, Sheri M.; Martinez, Olivia M.] Stanford Univ, Sch Med, Dept Surg, Stanford, CA 94305 USA.
   [Ji, Xuhuai] Stanford Univ, Sch Med, Human Immune Monitoring Ctr, Stanford, CA 94305 USA.
   [Han, Arnold; Boyd, Scott D.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA.
   [Pettus, Christina; Haas, Nikhil] Univ San Francisco, PSM Biotechnol, Stanford, CA 94305 USA.
   [Arlehamn, Cecilia S. Lindestam; Sette, Alessandro] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA 92037 USA.
   [Boyd, Scott D.] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA.
   [Scriba, Thomas J.] Univ Cape Town, Inst Infect Dis & Mol Med, South African TB Vaccine Initiat, Cape Town, South Africa.
   [Scriba, Thomas J.] Univ Cape Town, Div Immunol, Dept Pathol, Cape Town, South Africa.
   [Davis, Mark M.] Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Hatton, Olivia] Colorado Coll, Dept Mol Biol, Colorado Springs, CO 80905 USA.
   [Han, Arnold] Columbia Univ, Dept Med & Microbiol & Immunol, New York, NY 10032 USA.
C3 Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; University of San Francisco; La Jolla Institute for Immunology; Stanford University; University of Cape Town; University of Cape Town; Howard Hughes Medical Institute; Stanford University; Colorado College; Columbia University
RP Davis, MM (corresponding author), Stanford Univ, Sch Med, Inst Immun Transplantat & Infect, Stanford, CA 94305 USA.; Davis, MM (corresponding author), Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA.; Davis, MM (corresponding author), Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA.
EM mmdavis@stanford.edu
FU Stanford Human Immune Monitoring Center; Bill and Melinda Gates Foundation; National Institutes of Health [2U19 AI057229]; Howard Hughes Medical Institute; NIH [S10RR025518-01]; National Institute of Allergy and Infectious Diseases [T32AI007290] Funding Source: NIH RePORTER
NR 23
TC 728
Z9 839
U1 2
U2 161
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 6
PY 2017
VL 547
IS 7661
BP 94
EP +
DI 10.1038/nature22976
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EZ6PM
UT WOS:000404839900037
PM 28636589
DA 2026-03-09
ER

PT J
AU Hua, T
   Vemuri, K
   Nikas, SP
   Laprairie, RB
   Wu, Y
   Qu, L
   Pu, M
   Korde, A
   Jiang, S
   Ho, JH
   Han, GW
   Ding, K
   Li, X
   Liu, H
   Hanson, MA
   Zhao, S
   Bohn, LM
   Makriyannis, A
   Stevens, RC
   Liu, ZJ
AF Hua, Tian
   Vemuri, Kiran
   Nikas, Spyros P.
   Laprairie, Robert B.
   Wu, Yiran
   Qu, Lu
   Pu, Mengchen
   Korde, Anisha
   Jiang, Shan
   Ho, Jo-Hao
   Han, Gye Won
   Ding, Kang
   Li, Xuanxuan
   Liu, Haiguang
   Hanson, Michael A.
   Zhao, Suwen
   Bohn, Laura M.
   Makriyannis, Alexandros
   Stevens, Raymond C.
   Liu, Zhi-Jie
TI RETRACTED: Crystal structures of agonist-bound human cannabinoid receptor CB1
SO NATURE
LA English
DT Article; Retracted Publication
ID membrane-proteins; accurate docking; glide; chemistry
AB The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonist Delta(9)-tetrahydrocannabinol (Delta(9)-THC)(1). Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 angstrom and 2.95 angstrom resolution, respectively. The two CB1-agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state(2), including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a 'twin toggle switch' of Phe200(3.36) and Trp356(6.48) (superscripts denote Ballesteros-Weinstein numbering(3)) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of Delta(9)-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.
C1 [Hua, Tian; Wu, Yiran; Qu, Lu; Pu, Mengchen; Ding, Kang; Zhao, Suwen; Stevens, Raymond C.; Liu, Zhi-Jie] ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China.
   [Hua, Tian; Qu, Lu; Liu, Zhi-Jie] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China.
   [Hua, Tian; Qu, Lu; Ding, Kang] Univ Chinese Acad Sci, Beijing 100049, Peoples R China.
   [Vemuri, Kiran; Nikas, Spyros P.; Korde, Anisha; Jiang, Shan; Makriyannis, Alexandros] Northeastern Univ, Dept Pharmaceut Sci, Ctr Drug Discovery, Boston, MA 02115 USA.
   [Vemuri, Kiran; Nikas, Spyros P.; Korde, Anisha; Jiang, Shan; Makriyannis, Alexandros] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA.
   [Laprairie, Robert B.; Ho, Jo-Hao; Bohn, Laura M.] Scripps Res Inst, Dept Mol Med, Jupiter, FL 33458 USA.
   [Laprairie, Robert B.; Ho, Jo-Hao; Bohn, Laura M.] Scripps Res Inst, Dept Neurosci, Jupiter, FL 33458 USA.
   [Han, Gye Won; Stevens, Raymond C.] Univ Southern Calif, Bridge Inst, Dept Biol Sci, Los Angeles, CA 90089 USA.
   [Han, Gye Won; Stevens, Raymond C.] Univ Southern Calif, Bridge Inst, Dept Chem, Los Angeles, CA 90089 USA.
   [Ding, Kang; Zhao, Suwen; Stevens, Raymond C.; Liu, Zhi-Jie] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China.
   [Li, Xuanxuan; Liu, Haiguang] Beijing Computat Sci Res Ctr, Complex Syst Div, Beijing 100193, Peoples R China.
   [Hanson, Michael A.] GPCR Consortium, San Marcos, CA 92078 USA.
C3 ShanghaiTech University; Chinese Academy of Sciences; Institute of Biophysics, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Northeastern University; Northeastern University; State University System of Florida; University of Florida; Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology; State University System of Florida; University of Florida; Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology; University of Southern California; University of Southern California; ShanghaiTech University; Chinese Academy of Engineering Physics; Beijing Computational Science Research Center (CSRC)
RP Zhao, S; Liu, ZJ (corresponding author), ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China.; Liu, ZJ (corresponding author), Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China.; Makriyannis, A (corresponding author), Northeastern Univ, Dept Pharmaceut Sci, Ctr Drug Discovery, Boston, MA 02115 USA.; Makriyannis, A (corresponding author), Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA.; Bohn, LM (corresponding author), Scripps Res Inst, Dept Mol Med, Jupiter, FL 33458 USA.; Bohn, LM (corresponding author), Scripps Res Inst, Dept Neurosci, Jupiter, FL 33458 USA.; Zhao, S; Liu, ZJ (corresponding author), ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China.
EM zhaosw@shanghaitech.edu.cn; lbohn@scripps.edu; a.makriyannis@northeastern.edu; liuzhj@shanghaitech.edu.cn
FU NSF of China [31330019]; MOST of China [2014CB910400, 2015CB910104]; NSF of Shanghai [16ZR1448500]; Key R&D Program of China [2016YCF0905902]; NIH [R01DA041435, P01DA009158, R37DA023142]; NSF; Shanghai Municipal Government; ShanghaiTech University; GPCR Consortium; National Institute on Drug Abuse [R01DA045020, P01DA009158] Funding Source: NIH RePORTER
NR 39
TC 394
Z9 445
U1 4
U2 217
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 27
PY 2017
VL 547
IS 7664
BP 468
EP +
DI 10.1038/nature23272
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB7ZK
UT WOS:000406358300039
PM 28678776
DA 2026-03-09
ER

PT J
AU Pinheiro, D
   Hannezo, E
   Herszterg, S
   Bosveld, F
   Gaugue, I
   Balakireva, M
   Wang, ZM
   Cristo, I
   Rigaud, SU
   Markova, O
   Bellaïche, Y
AF Pinheiro, Diana
   Hannezo, Edouard
   Herszterg, Sophie
   Bosveld, Floris
   Gaugue, Isabelle
   Balakireva, Maria
   Wang, Zhimin
   Cristo, Ines
   Rigaud, Stephane U.
   Markova, Olga
   Bellaiche, Yohanns
TI Transmission of cytokinesis forces via E-cadherin dilution and actomyosin flows
SO NATURE
LA English
DT Article
ID alpha-catenin; cell-division; actin cytoskeleton; adherens junctions; epithelial tissue; myosin-ii; drosophila; contractility; morphogenesis; polarity
AB During epithelial cytokinesis, the remodelling of adhesive cell-cell contacts between the dividing cell and its neighbours has profound implications for the integrity, arrangement and morphogenesis of proliferative tissues(1-7). In both vertebrates and invertebrates, this remodelling requires the activity of non-muscle myosin II (MyoII) in the interphasic cells neighbouring the dividing cell(1,3,5). However, the mechanisms that coordinate cytokinesis and MyoII activity in the neighbours are unknown. Here we show that in the Drosophila notum epithelium, each cell division is associated with a mechanosensing and transmission event that controls MyoII dynamics in neighbouring cells. We find that the ring pulling forces promote local junction elongation, which results in local E-cadherin dilution at the ingressing adherens junction. In turn, the reduction in E-cadherin concentration and the contractility of the neighbouring cells promote self-organized actomyosin flows, ultimately leading to accumulation of MyoII at the base of the ingressing junction. Although force transduction has been extensively studied in the context of adherens junction reinforcement to stabilize adhesive cell-cell contacts(8), we propose an alternative mechanosensing mechanism that coordinates actomyosin dynamics between epithelial cells and sustains the remodelling of the adherens junction in response to mechanical forces.
C1 [Pinheiro, Diana; Herszterg, Sophie; Bosveld, Floris; Gaugue, Isabelle; Balakireva, Maria; Wang, Zhimin; Cristo, Ines; Rigaud, Stephane U.; Markova, Olga; Bellaiche, Yohanns] PSL Res Univ, INSERM U934, CNRS UMR 3215, Inst Curie, F-75248 Paris 05, France.
   [Pinheiro, Diana; Herszterg, Sophie; Bosveld, Floris; Gaugue, Isabelle; Balakireva, Maria; Wang, Zhimin; Cristo, Ines; Rigaud, Stephane U.; Markova, Olga; Bellaiche, Yohanns] UPMC Univ Paris 06, Sorbonne Univ, CNRS, INSERM U934,UMR 3215, F-75005 Paris, France.
   [Pinheiro, Diana] Univ Porto, Abel Salazar Biomed Sci Inst, Grad Program Areas Basic & Appl Biol, Oporto, Portugal.
   [Hannezo, Edouard] Univ Cambridge, Cavendish Lab, Dept Phys, JJ Thomson Ave, Cambridge CB3 0HE, England.
   [Hannezo, Edouard] Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Tennis Court Rd, Cambridge CB2 1QN, England.
   [Herszterg, Sophie] Francis Crick Inst, 1 Brill Pl, London NW1 1BF, England.
C3 Universite PSL; UNICANCER; Institut Curie; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite PSL; UNICANCER; Institut Curie; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Sorbonne Universite; CNRS - National Institute for Biology (INSB); Universidade do Porto; University of Cambridge; University of Cambridge; Francis Crick Institute
RP Bellaïche, Y (corresponding author), PSL Res Univ, INSERM U934, CNRS UMR 3215, Inst Curie, F-75248 Paris 05, France.; Bellaïche, Y (corresponding author), UPMC Univ Paris 06, Sorbonne Univ, CNRS, INSERM U934,UMR 3215, F-75005 Paris, France.
EM yohanns.bellaiche@curie.fr
FU ANR-MaxForce; ERC (TiMoprh) [340784]; ARC [SL220130607097]; ANR-DEEP [11-LBX-0044, ANR-10-IDEX-0001-02]; PSL grants; FCT [SFRH/BD/51700/2011]; FRM [FDT20150531972]; Wellcome Trust [110326/Z/15/Z]; Trinity College; Bettencourt-Schueller Foundation; Fundação para a Ciência e a Tecnologia [SFRH/BD/51700/2011] Funding Source: FCT; Wellcome Trust [110326/Z/15/Z] Funding Source: Wellcome Trust; European Research Council (ERC) [340784] Funding Source: European Research Council (ERC)
NR 50
TC 103
Z9 111
U1 0
U2 34
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 4
PY 2017
VL 545
IS 7652
BP 103
EP +
DI 10.1038/nature22041
PG 26
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET7MK
UT WOS:000400480400039
PM 28296858
DA 2026-03-09
ER

PT J
AU Johnson, TE
   Brown, M
   Gardiner, NJ
   Kirkland, CL
   Smithies, RH
AF Johnson, Tim E.
   Brown, Michael
   Gardiner, Nicholas J.
   Kirkland, Christopher L.
   Smithies, R. Hugh
TI Earth's first stable continents did not form by subduction
SO NATURE
LA English
DT Article
ID mineral equilibria calculations; archean crust; system k2o-feo-mgo-al2o3-sio2-h2o-tio2-fe2o3; mantle; delamination; lithosphere; genesis; growth; amphibolite; australia
AB The geodynamic environment in which Earth's first continents formed and were stabilized remains controversial(1). Most exposed continental crust that can be dated back to the Archaean eon (4 billion to 2.5 billion years ago) comprises tonalite-trondhjemite-granodiorite rocks (TTGs) that were formed through partial melting of hydrated low-magnesium basaltic rocks(2); notably, these TTGs have 'arc-like' signatures of trace elements and thus resemble the continental crust produced in modern subduction settings(3). In the East Pilbara Terrane, Western Australia, low-magnesium basalts of the Coucal Formation at the base of the Pilbara Supergroup have trace-element compositions that are consistent with these being source rocks for TTGs. These basalts may be the remnants of a thick (more than 35 kilometres thick), ancient (more than 3.5 billion years old) basaltic crust(4,5) that is predicted to have existed if Archaean mantle temperatures were much hotter than today's(6-8). Here, using phase equilibria modelling of the Coucal basalts, we confirm their suitability as TTG 'parents', and suggest that TTGs were produced by around 20 per cent to 30 per cent melting of the Coucal basalts along high geothermal gradients (of more than 700 degrees Celsius per gigapascal). We also analyse the trace-element composition of the Coucal basalts, and propose that these rocks were themselves derived from an earlier generation of high-magnesium basaltic rocks, suggesting that the arc-like signature in Archaean TTGs was inherited from an ancestral source lineage. This protracted, multistage process for the production and stabilization of the first continents-coupled with the high geothermal gradients-is incompatible with modern-style plate tectonics, and favours instead the formation of TTGs near the base of thick, plateau-like basaltic crust(9). Thus subduction was not required to produce TTGs in the early Archaean eon.
C1 [Johnson, Tim E.; Gardiner, Nicholas J.; Kirkland, Christopher L.] Curtin Univ, Dept Appl Geol, Inst Geosci Res TIGeR, Ctr Explorat Targeting Curtin Node,Australian Res, GPO Box U1987, Perth, WA 6845, Australia.
   [Brown, Michael] Univ Maryland, Dept Geol, Lab Crustal Petrol, College Pk, MD 20742 USA.
   [Smithies, R. Hugh] Geol Survey Western Australia, 100 Plain St, East Perth, WA 6004, Australia.
C3 Curtin University; University System of Maryland; University of Maryland College Park; Geological Survey of Western Australia
RP Johnson, TE (corresponding author), Curtin Univ, Dept Appl Geol, Inst Geosci Res TIGeR, Ctr Explorat Targeting Curtin Node,Australian Res, GPO Box U1987, Perth, WA 6845, Australia.
EM tim.johnson@curtin.edu.au
FU Institute of Geoscience Research (TIGeR) at Curtin University
NR 36
TC 366
Z9 401
U1 5
U2 181
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 9
PY 2017
VL 543
IS 7644
BP 239
EP +
DI 10.1038/nature21383
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0GQ
UT WOS:000395688700038
PM 28241147
DA 2026-03-09
ER

PT J
AU Peng, M
   Yin, N
   Li, MO
AF Peng, Min
   Yin, Na
   Li, Ming O.
TI SZT2 dictates GATOR control of mTORC1 signalling
SO NATURE
LA English
DT Article
ID rag gtpases; nutrient regulation; complex; pathway; torc1; activation; encephalopathy; metabolism; inhibitors; interact
AB Mechanistic target of rapamycin complex 1 (TORC1) integrates nutrient signals to control cell growth and organismal homeostasis across eukaryotes(1-4). The evolutionarily conserved GATOR complex regulates mTORC1 signalling through Rag GTPases, and GATOR1 displays GTPase activating protein (GAP) activity for RAGA and RAGB (RAGA/B) and GATOR2 has been proposed to be an inhibitor of GATOR1(5,6). Furthermore, the metazoan-specific SESN proteins function as guanine nucleotide dissociation inhibitors (GDIs) for RAGA/B, and interact with GATOR2 with unknown effects(7-9). Here we show that SZT2 (seizure threshold 2), a metazoan-specific protein mutated in epilepsy(10-13), recruits a fraction of mammalian GATOR1 and GATOR2 to form a SZT2-orchestrated GATOR (SOG) complex with an essential role in GATOR-and SESN-dependent nutrient sensing and mTORC1 regulation. The interaction of SZT2 with GATOR1 and GATOR2 was synergistic, and an intact SOG complex was required for its localization at the lysosome. SZT2 deficiency resulted in constitutive mTORC1 signalling in cells under nutrient-deprived conditions and neonatal lethality in mice, which was associated with failure to inactivate mTORC1 during fasting. Hyperactivation of mTORC1 in SZT2-deficient cells could be partially corrected by overexpression of the GATOR1 component DEPDC5, and by the lysosome-targeted GATOR2 component WDR59 or lysosome-targeted SESN2. These findings demonstrate that SZT2 has a central role in dictating GATOR-dependent nutrient sensing by promoting lysosomal localization of SOG, and reveal an unexpected function of lysosome-located GATOR2 in suppressing mTORC1 signalling through SESN recruitment.
C1 [Peng, Min; Yin, Na; Li, Ming O.] Mem Sloan Kettering Canc Ctr, Immunol Program, New York, NY 10065 USA.
C3 Memorial Sloan Kettering Cancer Center
RP Li, MO (corresponding author), Mem Sloan Kettering Canc Ctr, Immunol Program, New York, NY 10065 USA.
EM lim@mskcc.org
FU Leukemia & Lymphoma Society Scholar Award; Functional Genomics Initiative Grant from Memorial Sloan Kettering Cancer Center; Howard Hughes Medical Institute; Memorial Sloan Kettering Cancer Center Support Grant/Core Grant [P30 CA008748]; National Cancer Institute [P30CA008748] Funding Source: NIH RePORTER
NR 28
TC 154
Z9 189
U1 0
U2 39
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 16
PY 2017
VL 543
IS 7645
BP 433
EP +
DI 10.1038/nature21378
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN9RN
UT WOS:000396337400053
PM 28199315
DA 2026-03-09
ER

PT J
AU Mott, A
   Job, J
   Vlimant, JR
   Lidar, D
   Spiropulu, M
AF Mott, Alex
   Job, Joshua
   Vlimant, Jean-Roch
   Lidar, Daniel
   Spiropulu, Maria
TI Solving a Higgs optimization problem with quantum annealing for machine learning
SO NATURE
LA English
DT Article
AB The discovery of Higgs-boson decays in a background of standard-model processes was assisted by machine learning methods(1,2). The classifiers used to separate signals such as these from background are trained using highly unerring but not completely perfect simulations of the physical processes involved, often resulting in incorrect labelling of background processes or signals (label noise) and systematic errors. Here we use quantum(3-6) and classical(7,8) annealing (probabilistic techniques for approximating the global maximum or minimum of a given function) to solve a Higgs-signal-versus-background machine learning optimization problem, mapped to a problem of finding the ground state of a corresponding Ising spin model. We build a set of weak classifiers based on the kinematic observables of the Higgs decay photons, which we then use to construct a strong classifier. This strong classifier is highly resilient against overtraining and against errors in the correlations of the physical observables in the training data. We show that the resulting quantum and classical annealing-based classifier systems perform comparably to the state-of-the-art machine learning methods that are currently used in particle physics(9,10). However, in contrast to these methods, the annealing-based classifiers are simple functions of directly interpretable experimental parameters with clear physical meaning. The annealer-trained classifiers use the excited states in the vicinity of the ground state and demonstrate some advantage over traditional machine learning methods for small training datasets. Given the relative simplicity of the algorithm and its robustness to error, this technique may find application in other areas of experimental particle physics, such as real-time decision making in event-selection problems and classification in neutrino physics.
C1 [Mott, Alex; Vlimant, Jean-Roch; Spiropulu, Maria] CALTECH, Dept Phys, Pasadena, CA 91125 USA.
   [Job, Joshua; Lidar, Daniel] Univ Southern Calif, Dept Phys, Los Angeles, CA 90089 USA.
   [Job, Joshua; Lidar, Daniel] Univ Southern Calif, Ctr Quantum Informat Sci & Technol, Los Angeles, CA 90089 USA.
   [Lidar, Daniel] Univ Southern Calif, Dept Elect Engn, Los Angeles, CA 90089 USA.
   [Lidar, Daniel] Univ Southern Calif, Dept Chem, Los Angeles, CA 90089 USA.
   [Mott, Alex] DeepMind, London, England.
C3 California Institute of Technology; University of Southern California; University of Southern California; University of Southern California; University of Southern California; Alphabet Inc.; DeepMind
RP Spiropulu, M (corresponding author), CALTECH, Dept Phys, Pasadena, CA 91125 USA.
EM smaria@caltech.edu
FU United States Department of Energy, Office of High Energy Physics Research Technology Computational HEP; Fermi Research Alliance, LLC [DE-AC02-07CH11359]; ARO grant [W911NF-12-1-0523]; NSF [INSPIRE-1551064]; AT&T Foundry Innovation Centers through INQNET, a programme for accelerating quantum technologies; Division of Computing and Communication Foundations; Direct For Computer & Info Scie & Enginr [1551064] Funding Source: National Science Foundation
NR 29
TC 153
Z9 179
U1 1
U2 69
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 19
PY 2017
VL 550
IS 7676
BP 375
EP +
DI 10.1038/nature24047
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK1NF
UT WOS:000413247900056
PM 29052620
DA 2026-03-09
ER

PT J
AU Colangelo, G
   Ciurana, FM
   Bianchet, LC
   Sewell, RJ
   Mitchell, MW
AF Colangelo, Giorgio
   Ciurana, Ferran Martin
   Bianchet, Lorena C.
   Sewell, Robert J.
   Mitchell, Morgan W.
TI Simultaneous tracking of spin angle and amplitude beyond classical limits
SO NATURE
LA English
DT Article
ID quantum-nondemolition measurements; atomic magnetometer; sensitivity; entanglement; times
AB Measurement of spin precession is central to extreme sensing in physics(1,2), geophysics(3), chemistry(4), nanotechnology5 and neuroscience6, and underlies magnetic resonance spectroscopy(7). Because there is no spin-angle operator, any measurement of spin precession is necessarily indirect, for example, it may be inferred from spin projectors at different times. Such projectors do not commute, and so quantum measurement back-action-the random change in a quantum state due to measurement-necessarily enters the spin measurement record, introducing errors and limiting sensitivity. Here we show that this disturbance in the spin projector can be reduced below N-1/2-the classical limit for N spins-by directing the quantum measurement back-action almost entirely into an unmeasured spin component. This generates a planar squeezed state(8) that, because spins obey non-Heisenberg uncertainty relations(9,10), enables simultaneous precise knowledge of spin angle and spin amplitude. We use high-dynamic-range optical quantum non-demolition measurements(11-13) applied to a precessing magnetic spin ensemble to demonstrate spin tracking with steady-state angular sensitivity 2,9 decibels below the standard quantum limit, simultaneously with amplitude sensitivity 7.0 decibels below the Poissonian variance14. The standard quantum limit and Poissonian variance indicate the best possible sensitivity with independent particles. Our method surpasses these limits in non-commuting observables, enabling orders-of-magnitude improvements in sensitivity for state-of-the-art sensing(15-18) and spectroscopy(19,20).
C1 [Colangelo, Giorgio; Ciurana, Ferran Martin; Bianchet, Lorena C.; Sewell, Robert J.; Mitchell, Morgan W.] Barcelona Inst Sci & Technol, ICFO, Barcelona, Spain.
   [Mitchell, Morgan W.] Inst Catalana Rec Estudis Avancats, ICREA, Barcelona 08015, Spain.
C3 Barcelona Institute of Science & Technology; Universitat Politecnica de Catalunya; Institut de Ciencies Fotoniques (ICFO); ICREA
RP Colangelo, G; Mitchell, MW (corresponding author), Barcelona Inst Sci & Technol, ICFO, Barcelona, Spain.; Mitchell, MW (corresponding author), Inst Catalana Rec Estudis Avancats, ICREA, Barcelona 08015, Spain.
EM giorgio.colangelo@icfo.eu; morgan.mitchell@icfo.eu
FU MINECO/ FEDER; MINECO project MAQRO [FIS2015-68039-P]; MINECO project XPLICA [FIS2014-62181-EXP]; Severo Ochoa grant [SEV-2015-0522]; Catalan [2014-SGR-1295]; European Union Project QUIC [641122]; European Research Council project AQUMET [280169]; European Research Council project ERIDIAN [713682]; Fundacio Privada CELLEX; International Fellowship Programme 'La Caixa' - Severo Ochoa; 'La Caixa' Foundation; European Research Council (ERC) [713682] Funding Source: European Research Council (ERC); ICREA Funding Source: Custom
NR 48
TC 57
Z9 66
U1 1
U2 65
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 23
PY 2017
VL 543
IS 7646
BP 525
EP +
DI 10.1038/nature21434
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EO9OM
UT WOS:000397018000045
PM 28332519
DA 2026-03-09
ER

PT J
AU Morgan, M
   Much, C
   DiGiacomo, M
   Azzi, C
   Ivanova, I
   Vitsios, DM
   Pistolic, J
   Collier, P
   Moreira, PN
   Benes, V
   Enright, AJ
   O'Carroll, D
AF Morgan, Marcos
   Much, Christian
   DiGiacomo, Monica
   Azzi, Chiara
   Ivanova, Ivayla
   Vitsios, Dimitrios M.
   Pistolic, Jelena
   Collier, Paul
   Moreira, Pedro N.
   Benes, Vladimir
   Enright, Anton J.
   O'Carroll, Donal
TI mRNA 3′ uridylation and poly(A) tail length sculpt the mammalian maternal transcriptome
SO NATURE
LA English
DT Article
ID mouse oocytes; expression; maturation; microrna; recombinase; degradation; transition; triggers; reveals; growth
AB A fundamental principle in biology is that the program for early development is established during oogenesis in the form of the maternal transcriptome(1,2). How the maternal transcriptome acquires the appropriate content and dosage of transcripts is not fully understood. Here we show that 3' terminal uridylation of mRNA mediated by TUT4 and TUT7 sculpts the mouse maternal transcriptome by eliminating transcripts during oocyte growth. Uridylation mediated by TUT4 and TUT7 is essential for both oocyte maturation and fertility. In comparison to somatic cells, the oocyte transcriptome has a shorter poly(A) tail and a higher relative proportion of terminal oligo-uridylation. Deletion of TUT4 and TUT7 leads to the accumulation of a cohort of transcripts with a high frequency of very short poly(A) tails, and a loss of 3' oligouridylation. By contrast, deficiency of TUT4 and TUT7 does not alter gene expression in a variety of somatic cells. In summary, we show that poly(A) tail length and 3' terminal uridylation have essential and specific functions in shaping a functional maternal transcriptome.
C1 [Morgan, Marcos; Much, Christian; Ivanova, Ivayla; Moreira, Pedro N.; O'Carroll, Donal] Univ Edinburgh, Inst Stem Cell Res, Sch Biol Sci, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland.
   [Morgan, Marcos; Much, Christian; DiGiacomo, Monica; Azzi, Chiara; Ivanova, Ivayla; Moreira, Pedro N.; O'Carroll, Donal] EMBL, Mouse Biol Unit, I-00015 Monterotondo, Italy.
   [Vitsios, Dimitrios M.; Enright, Anton J.] EMBL, EBI, Wellcome Genome Campus, Cambridge CB10 1SD, England.
   [Pistolic, Jelena; Collier, Paul; Benes, Vladimir] EMBL, Genom Core Facil, D-69117 Heidelberg, Germany.
C3 University of Edinburgh; European Molecular Biology Laboratory (EMBL); European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute; European Molecular Biology Laboratory (EMBL)
RP O'Carroll, D (corresponding author), Univ Edinburgh, Inst Stem Cell Res, Sch Biol Sci, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland.; O'Carroll, D (corresponding author), EMBL, Mouse Biol Unit, I-00015 Monterotondo, Italy.
EM donal.ocarroll@ed.ac.uk
FU Wellcome Trust [106144]; Medical Research Council [MR/K017047/1] Funding Source: researchfish; MRC [MR/K017047/1] Funding Source: UKRI
NR 42
TC 141
Z9 167
U1 2
U2 41
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 17
PY 2017
VL 548
IS 7667
BP 347
EP +
DI 10.1038/nature23318
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD8AU
UT WOS:000407748400036
PM 28792939
DA 2026-03-09
ER

PT J
AU Hattori, A
   Tsunoda, M
   Konuma, T
   Kobayashi, M
   Nagy, T
   Glushka, J
   Tayyari, F
   Cskimming, DM
   Kannan, N
   Tojo, A
   Edison, AS
   Ito, T
AF Hattori, Ayuna
   Tsunoda, Makoto
   Konuma, Takaaki
   Kobayashi, Masayuki
   Nagy, Tamas
   Glushka, John
   Tayyari, Fariba
   Cskimming, Daniel M.
   Kannan, Natarajan
   Tojo, Arinobu
   Edison, Arthur S.
   Ito, Takahiro
TI Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia
SO NATURE
LA English
DT Article
ID hematopoietic stem-cells; amino-acid-metabolism; gene-expression; leucine sensor; murine model; rna; musashi; proliferation; survival; pathway
AB Reprogrammed cellular metabolism is a common characteristic observed in various cancers(1,2). However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukaemia (CML) in humans and in mouse models of CML. BCAT1 is upregulated during progression of CML and promotes BCAA production in leukaemia cells by aminating the branched-chain keto acids. Blocking BCAT1 gene expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML both in vitro and in vivo. Stable-isotope tracer experiments combined with nuclear magnetic resonance-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function through BCAA production in blast crisis CML cells. Importantly, BCAT1 expression not only is activated in human blast crisis CML and de novo acute myeloid leukaemia, but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for blast crisis CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukaemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2-BCAT1 axis drives cancer progression in myeloid leukaemia.
C1 [Hattori, Ayuna; Tayyari, Fariba; Cskimming, Daniel M.; Kannan, Natarajan; Edison, Arthur S.; Ito, Takahiro] Univ Georgia, Dept Biochem & Mol Biol, Franklin Coll Arts & Sci, Athens, GA 30602 USA.
   [Hattori, Ayuna; Kannan, Natarajan; Ito, Takahiro] Univ Georgia, Ctr Canc, Athens, GA 30602 USA.
   [Tsunoda, Makoto] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan.
   [Konuma, Takaaki; Kobayashi, Masayuki; Tojo, Arinobu] Univ Tokyo, Inst Med Sci, Dept Hematol & Oncol, Minato Ku, Tokyo 1088639, Japan.
   [Nagy, Tamas] Univ Georgia, Coll Vet Med, Dept Pathol, Athens, GA 30602 USA.
   [Glushka, John; Tayyari, Fariba; Edison, Arthur S.] Univ Georgia, Complex Carbohydrate Res Ctr, 220 Riverbend Rd, Athens, GA 30602 USA.
   [Cskimming, Daniel M.; Kannan, Natarajan; Edison, Arthur S.] Univ Georgia, Inst Bioinformat, Athens, GA 30602 USA.
   [Edison, Arthur S.] Univ Georgia, Dept Genet, Franklin Coll Arts & Sci, Athens, GA 30602 USA.
C3 University System of Georgia; University of Georgia; University System of Georgia; University of Georgia; University of Tokyo; University of Tokyo; University System of Georgia; University of Georgia; University System of Georgia; University of Georgia; University System of Georgia; University of Georgia; University System of Georgia; University of Georgia
RP Ito, T (corresponding author), Univ Georgia, Dept Biochem & Mol Biol, Franklin Coll Arts & Sci, Athens, GA 30602 USA.; Ito, T (corresponding author), Univ Georgia, Ctr Canc, Athens, GA 30602 USA.
EM ito@bmb.uga.edu
FU University of Georgia Research Foundation; Heather Wright Cancer Research Fund; Japan Society for the Promotion of Science Bilateral Open Partnership Joint Research Projects Program; Southeast Center for Integrated Metabolomics, National Institutes of Health [U24DK097209]; Georgia Research Alliance; Grants-in-Aid for Scientific Research [16J02129, 17K08234, 16K19570, 16H06277] Funding Source: KAKEN
NR 37
TC 325
Z9 372
U1 0
U2 88
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 25
PY 2017
VL 545
IS 7655
BP 500
EP +
DI 10.1038/nature22314
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV6TH
UT WOS:000401906500056
PM 28514443
DA 2026-03-09
ER

PT J
AU Birkenbach, AM
   Kaczan, DJ
   Smith, MD
AF Birkenbach, Anna M.
   Kaczan, David J.
   Smith, Martin D.
TI Catch shares slow the race to fish
SO NATURE
LA English
DT Article
ID fisheries management; efficiency costs; resource; quotas; risk
AB In fisheries, the tragedy of the commons manifests as a competitive race to fish that compresses fishing seasons, resulting in ecological damage, economic waste, and occupational hazards(1-8). Catch shares are hypothesized to halt the race by securing each individual's right to a portion of the total catch, but there is evidence for this from selected examples only(2,9). Here we systematically analyse natural experiments to test whether catch shares reduce racing in 39 US fisheries. We compare each fishery treated with catch shares to an individually matched control before and after the policy change. We estimate an average policy treatment effect in a pooled model and in a meta-analysis that combines separate estimates for each treatment-control pair. Consistent with the theory that market-based management ends the race to fish, we find strong evidence that catch shares extend fishing seasons. This evidence informs the current debate over expanding the use of market-based regulation to other fisheries.
C1 [Birkenbach, Anna M.; Kaczan, David J.; Smith, Martin D.] Duke Univ, Nicholas Sch Environm, Durham, NC 27708 USA.
   [Birkenbach, Anna M.; Kaczan, David J.] Duke Univ, Sanford Sch Publ Policy, Durham, NC 27708 USA.
   [Smith, Martin D.] Duke Univ, Dept Econ, Durham, NC 27708 USA.
C3 Duke University; Duke University; Duke University
RP Smith, MD (corresponding author), Duke Univ, Nicholas Sch Environm, Durham, NC 27708 USA.; Smith, MD (corresponding author), Duke Univ, Dept Econ, Durham, NC 27708 USA.
EM martin.smith@duke.edu
FU NOAA; NC Sea Grant; ECS Federal
NR 32
TC 146
Z9 164
U1 1
U2 77
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 13
PY 2017
VL 544
IS 7649
BP 223
EP +
DI 10.1038/nature21728
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ER6EK
UT WOS:000398897900035
PM 28379945
DA 2026-03-09
ER

PT J
AU Arcavi, I
   Howell, DA
   Kasen, D
   Bildsten, L
   Hosseinzadeh, G
   McCully, C
   Wong, ZC
   Katz, SR
   Gal-Yam, A
   Sollerman, J
   Taddia, F
   Leloudas, G
   Fremling, C
   Nugent, PE
   Horesh, A
   Mooley, K
   Rumsey, C
   Cenko, SBR
   Graham, ML
   Perley, DA
   Nakar, E
   Shaviv, NJ
   Bromberg, O
   Shen, KJ
   Ofek, EO
   Cao, Y
   Wang, XF
   Huang, F
   Rui, LM
   Zhang, TM
   Li, WX
   Li, ZT
   Zhang, JJ
   Valenti, S
   Guevel, D
   Shappee, B
   Kochanek, CS
   Holoien, TWS
   Filippenko, AV
   Fender, R
   Nyholm, A
   Yaron, O
   Kasliwal, MM
   Sullivan, M
   Lagorodnova, NB
   Walters, RS
   Lunnan, R
   Khazov, D
   Andreoni, I
   Laher, RR
   Konidaris, N
   Wozniak, P
   Bue, B
AF Arcavi, Iair
   Howell, D. Andrew
   Kasen, Daniel
   Bildsten, Lars
   Hosseinzadeh, Griffin
   McCully, Curtis
   Wong, Zheng Chuen
   Katz, Sarah Rebekah
   Gal-Yam, Avishay
   Sollerman, Jesper
   Taddia, Francesco
   Leloudas, Giorgos
   Fremling, Christoffer
   Nugent, Peter E.
   Horesh, Assaf
   Mooley, Kunal
   Rumsey, Clare
   Cenko, S. B. Radley
   Graham, Melissa L.
   Perley, Daniel A.
   Nakar, Ehud
   Shaviv, Nir J.
   Bromberg, Omer
   Shen, Ken J.
   Ofek, Eran O.
   Cao, Yi
   Wang, Xiaofeng
   Huang, Fang
   Rui, Liming
   Zhang, Tianmeng
   Li, Wenxiong
   Li, Zhitong
   Zhang, Jujia
   Valenti, Stefano
   Guevel, David
   Shappee, Benjamin
   Kochanek, Christopher S.
   Holoien, Thomas W. -S.
   Filippenko, Alexei V.
   Fender, Rob
   Nyholm, Anders
   Yaron, Ofer
   Kasliwal, Mansi M. .
   Sullivan, Mark
   Lagorodnova, Nadja B.
   Walters, Richard S.
   Lunnan, Ragnhild
   Khazov, Danny
   Andreoni, Igor
   Laher, Russ R.
   Konidaris, Nick
   Wozniak, Przemek
   Bue, Brian
TI Energetic eruptions leading to a peculiar hydrogen-rich explosion of a massive star
SO NATURE
LA English
DT Article
ID expanding photosphere method; pulsational pair-instability; ii supernovae; high-redshift; light curves; low-resolution; sky survey; telescope; galaxy; spectrograph
AB Every supernova so far observed has been considered to be the terminal explosion of a star. Moreover, all supernovae with absorption lines in their spectra show those lines decreasing in velocity over time, as the ejecta expand and thin, revealing slower-moving material that was previously hidden. In addition, every supernova that exhibits the absorption lines of hydrogen has one main light-curve peak, or a plateau in luminosity, lasting approximately 100 days before declining(1). Here we report observations of iPTF14hls, an event that has spectra identical to a hydrogen-rich core-collapse supernova, but characteristics that differ extensively from those of known supernovae. The light curve has at least five peaks and remains bright for more than 600 days; the absorption lines show little to no decrease in velocity; and the radius of the line-forming region is more than an order of magnitude bigger than the radius of the photosphere derived from the continuum emission. These characteristics are consistent with a shell of several tens of solar masses ejected by the progenitor star at supernova-level energies a few hundred days before a terminal explosion. Another possible eruption was recorded at the same position in 1954. Multiple energetic pre-supernova eruptions are expected to occur in stars of 95 to 130 solar masses, which experience the pulsational pair instability(2-5). That model, however, does not account for the continued presence of hydrogen, or the energetics observed here. Another mechanism for the violent ejection of mass in massive stars may be required.
C1 [Arcavi, Iair; Howell, D. Andrew; Hosseinzadeh, Griffin; McCully, Curtis; Wong, Zheng Chuen; Katz, Sarah Rebekah; Guevel, David] Las Cumbres Observ, Goleta, CA 93117 USA.
   [Arcavi, Iair; Bildsten, Lars] Univ Calif Santa Barbara, Kavli Inst Theoret Phys, Santa Barbara, CA 93106 USA.
   [Arcavi, Iair; Howell, D. Andrew; Bildsten, Lars; Hosseinzadeh, Griffin; McCully, Curtis; Wong, Zheng Chuen; Katz, Sarah Rebekah; Guevel, David] Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA.
   [Kasen, Daniel] Lawrence Berkeley Natl Lab, Nucl Sci Div, Berkeley, CA 94720 USA.
   [Kasen, Daniel] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Kasen, Daniel; Nugent, Peter E.; Graham, Melissa L.; Filippenko, Alexei V.] Univ Calif Berkeley, Dept Astron, Berkeley, CA 94720 USA.
   [Gal-Yam, Avishay; Leloudas, Giorgos; Horesh, Assaf; Ofek, Eran O.; Yaron, Ofer; Khazov, Danny] Weizmann Inst Sci, Dept Particle Phys & Astrophys, IL-76100 Rehovot, Israel.
   [Sollerman, Jesper; Taddia, Francesco; Fremling, Christoffer; Shen, Ken J.; Nyholm, Anders] Stockholm Univ, Dept Astron, Oskar Klein Ctr, SE-10691 Stockholm, Sweden.
   [Leloudas, Giorgos; Perley, Daniel A.] Univ Copenhagen, Niels Bohr Inst, Dark Cosmol Ctr, Juliane Maries Vej 30, DK-2100 Copenhagen, Denmark.
   [Nugent, Peter E.] Lawrence Berkeley Natl Lab, Computat Res Div, Berkeley, CA 94720 USA.
   [Horesh, Assaf; Shaviv, Nir J.] Hebrew Univ Jerusalem, Racah Inst Phys, IL-91904 Jerusalem, Israel.
   [Mooley, Kunal; Fender, Rob] Univ Oxford, Dept Phys Astrophys, Denys Wilkinson Bldg, Oxford OX1 3RH, England.
   [Rumsey, Clare] Cavendish Lab, Astrophys Grp, 19 JJ Thomson Ave, Cambridge CB3 0HE, England.
   [Cenko, S. B. Radley] NASA, Goddard Space Flight Ctr, Astrophys Sci Div, Code 661, Greenbelt, MD 20771 USA.
   [Cenko, S. B. Radley] Univ Maryland, Joint Space Sci Inst, College Pk, MD 20742 USA.
   [Graham, Melissa L.; Cao, Yi] Univ Washington, Dept Astron, Box 351580, Seattle, WA 98195 USA.
   [Perley, Daniel A.] Liverpool John Moores Univ, Astrophys Res Inst, IC2,Liverpool Sci Pk,146 Brownlow Hill, Liverpool L3 5RF, Merseyside, England.
   [Nakar, Ehud; Bromberg, Omer] Tel Aviv Univ, Raymond & Beverly Sackler Sch Phys & Astron, IL-69978 Tel Aviv, Israel.
   [Cao, Yi] Univ Washington, eScience Inst, Box 351570, Seattle, WA 98195 USA.
   [Wang, Xiaofeng; Huang, Fang; Rui, Liming; Li, Wenxiong; Li, Zhitong] Tsinghua Univ, Phys Dept, Beijing 100084, Peoples R China.
   [Wang, Xiaofeng; Huang, Fang; Rui, Liming; Li, Wenxiong; Li, Zhitong] Tsinghua Univ, Tsinghua Ctr Astrophys, Beijing 100084, Peoples R China.
   [Zhang, Tianmeng] Chinese Acad Sci, Natl Astron Observ China, Key Lab Opt Astron, Beijing 100012, Peoples R China.
   [Zhang, Tianmeng] Univ Chinese Acad Sci, Sch Astron & Space Sci, Beijing 101408, Peoples R China.
   [Zhang, Jujia] Chinese Acad Sci, Yunnan Observ, Kunming 650011, Yunnan, Peoples R China.
   [Zhang, Jujia] Chinese Acad Sci, Key Lab Struct & Evolut Celestial Objects, Kunming 650216, Yunnan, Peoples R China.
   [Valenti, Stefano] Univ Calif Davis, Dept Phys, 1 Shields Ave, Davis, CA 95616 USA.
   [Shappee, Benjamin; Konidaris, Nick] Carnegie Observ, 813 Santa Barbara St, Pasadena, CA 91101 USA.
   [Kochanek, Christopher S.; Holoien, Thomas W. -S.] Ohio State Univ, Dept Astron, 140 West 18th Ave, Columbus, OH 43210 USA.
   [Kochanek, Christopher S.; Holoien, Thomas W. -S.] Ohio State Univ, Ctr Cosmol & AstroParticle Phys CCAPP, 191 W Woodruff Ave, Columbus, OH 43210 USA.
   [Filippenko, Alexei V.] Univ Calif Berkeley, Miller Inst Basic Res Sci, Berkeley, CA 94720 USA.
   [Kasliwal, Mansi M. .; Lagorodnova, Nadja B.; Walters, Richard S.; Lunnan, Ragnhild] CALTECH, Cahill Ctr Astrophys, Pasadena, CA 91125 USA.
   [Sullivan, Mark] Univ Southampton, Dept Phys & Astron, Southampton SO17 1BJ, Hants, England.
   [Andreoni, Igor] Swinburne Univ Technol, Ctr Astrophys & Supercomp, POB 218, Melbourne, Vic 3122, Australia.
   [Andreoni, Igor] ARC Ctr Excellence All Sky Astrophys CAASTRO, Sydney, NSW, Australia.
   [Andreoni, Igor] Australian Astron Observ, POB 915, N Ryde, NSW 1670, Australia.
   [Laher, Russ R.] CALTECH, Spitzer Sci Ctr, MS 314-6, Pasadena, CA 91125 USA.
   [Wozniak, Przemek] Los Alamos Natl Lab, Space & Atmospher Sci Grp, Mail Stop D466, Los Alamos, NM 87545 USA.
   [Bue, Brian] CALTECH, Jet Prop Lab, Pasadena, CA 91109 USA.
C3 University of California System; University of California Santa Barbara; University of California System; University of California Santa Barbara; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; University of California System; University of California Berkeley; University of California System; University of California Berkeley; Weizmann Institute of Science; Stockholm University; Oskar Klein Centre; University of Copenhagen; Niels Bohr Institute; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; Hebrew University of Jerusalem; University of Oxford; University of Cambridge; National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center; University System of Maryland; University of Maryland College Park; University of Washington; University of Washington Seattle; Liverpool John Moores University; Tel Aviv University; University of Washington; University of Washington Seattle; Tsinghua University; Tsinghua University; Chinese Academy of Sciences; National Astronomical Observatory, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; Yunnan Astronomical Observatory, NAOC, CAS; Chinese Academy of Sciences; University of California System; University of California Davis; Carnegie Institution for Science; University System of Ohio; Ohio State University; University System of Ohio; Ohio State University; University of California System; University of California Berkeley; California Institute of Technology; University of Southampton; Swinburne University of Technology; University of Sydney; ARC Centre of Excellence for All-Sky Astrophysics; California Institute of Technology; United States Department of Energy (DOE); Los Alamos National Laboratory; National Aeronautics & Space Administration (NASA); NASA Jet Propulsion Laboratory (JPL); California Institute of Technology
RP Arcavi, I (corresponding author), Las Cumbres Observ, Goleta, CA 93117 USA.; Arcavi, I (corresponding author), Univ Calif Santa Barbara, Kavli Inst Theoret Phys, Santa Barbara, CA 93106 USA.; Arcavi, I (corresponding author), Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA.
EM arcavi@gmail.com
NR 81
TC 9
Z9 18
U1 1
U2 32
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 9
PY 2017
VL 551
IS 7679
BP 210
EP +
DI 10.1038/nature24030
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM1KF
UT WOS:000414734200043
PM 29120417
DA 2026-03-09
ER

PT J
AU Venkatesh, HS
   Tam, LT
   Woo, PJ
   Lennon, J
   Nagaraja, S
   Gillespie, SM
   Ni, J
   Duveau, DY
   Morris, PJ
   Zhao, JJ
   Thomas, CJ
   Monje, M
AF Venkatesh, Humsa S. .
   Tam, Lydia T. .
   Woo, Pamelyn J.
   Lennon, James
   Nagaraja, Surya
   Gillespie, Shawn M. .
   Ni, Jing
   Duveau, Damien Y.
   Morris, Patrick J.
   Zhao, Jean J.
   Thomas, Craig J.
   Monje, Michelle
TI Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma
SO NATURE
LA English
DT Article
ID oligodendrocyte precursor cells; self-renewal; phosphorylation; cleavage; mutation; autism; hippocampal; disintegrin; peptides; subtypes
AB High-grade gliomas (HGG) are a devastating group of cancers, and represent the leading cause of brain tumour-related death in both children and adults. Therapies aimed at mechanisms intrinsic to glioma cells have translated to only limited success; effective therapeutic strategies will need also to target elements of the tumour microenvironment that promote glioma progression. Neuronal activity promotes the growth of a range of molecularly and clinically distinct HGG types, including adult and paediatric glioblastoma (GBM), anaplastic oligodendroglioma, and diffuse intrinsic pontine glioma (DIPG)(1). An important mechanism that mediates this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic adhesion molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway(1). However, the necessity of NLGN3 for glioma growth, the proteolytic mechanism of NLGN3 secretion, and the further molecular consequences of NLGN3 secretion in glioma cells remain unknown. Here we show that HGG growth depends on microenvironmental NLGN3, identify signalling cascades downstream of NLGN3 binding in glioma, and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of paediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. NLGN3 stimulates several oncogenic pathways, such as early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes that include upregulation of several synapse-related genes in glioma cells. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent the release of NLGN3 into the tumour microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting NLGN3 secretion, which could prove transformative for HGG therapy.
C1 [Venkatesh, Humsa S. .; Tam, Lydia T. .; Woo, Pamelyn J.; Lennon, James; Nagaraja, Surya; Gillespie, Shawn M. .; Monje, Michelle] Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA.
   [Venkatesh, Humsa S. .; Gillespie, Shawn M. .] Stanford Univ, Sch Med, Canc Biol Grad Program, Stanford, CA 94305 USA.
   [Ni, Jing; Zhao, Jean J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA.
   [Ni, Jing; Zhao, Jean J.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA.
   [Duveau, Damien Y.; Morris, Patrick J.; Thomas, Craig J.] Natl Ctr Adv Translat Sci, Div Preclin Innovat, NIH, Bldg 10, Bethesda, MD 20892 USA.
   [Monje, Michelle] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA.
   [Monje, Michelle] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA.
   [Monje, Michelle] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS); Stanford University; Stanford University; Stanford University
RP Monje, M (corresponding author), Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA.; Monje, M (corresponding author), Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA.; Monje, M (corresponding author), Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA.; Monje, M (corresponding author), Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA.
EM mmonje@stanford.edu
FU National Institutes of Health [NINDS R01NS092597, NCI 1F31CA200273, P50 CA168504, P50 CA165962, R35 CA210057]; Department of Defense [W81XWH-151-0131]; McKenna Claire Foundation; Alex's Lemonade Stand Foundation; Cure Starts Now Foundation; Lyla Nsouli Foundation; Unravel Pediatric Cancer; California Institute for Regenerative Medicine [RN3-06510]; Childhood Brain Tumor Foundation; Matthew Larson Foundation; Joey Fabus Childhood Cancer Foundation; Wayland Villars DIPG Foundation; Declan Gloster Memorial Funds; N8 Foundation; Virginia and D.K. Ludwig Fund for Cancer Research; Child Health Research Institute at Stanford Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases; Breast Cancer Research Foundation; National Center for Advancing Translational Sciences; National Cancer Institute; V Foundation; DIPG; National Cancer Institute [R35CA210057, P30CA124435, P50CA168504, P50CA165962] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [R01NS092597] Funding Source: NIH RePORTER
NR 43
TC 425
Z9 487
U1 11
U2 134
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 28
PY 2017
VL 549
IS 7673
BP 533
EP +
DI 10.1038/nature24014
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI4GT
UT WOS:000411930000053
PM 28959975
DA 2026-03-09
ER

PT J
AU Taniguchi, R
   Inoue, A
   Sayama, M
   Uwamizu, A
   Yamashita, K
   Hirata, K
   Yoshida, M
   Tanaka, Y
   Kato, HE
   Nakada-Nakura, Y
   Otani, Y
   Nishizawa, T
   Doi, T
   Ohwada, T
   Ishitani, R
   Aoki, J
   Nureki, O
AF Taniguchi, Reiya
   Inoue, Asuka
   Sayama, Misa
   Uwamizu, Akiharu
   Yamashita, Keitaro
   Hirata, Kunio
   Yoshida, Masahito
   Tanaka, Yoshiki
   Kato, Hideaki E.
   Nakada-Nakura, Yoshiko
   Otani, Yuko
   Nishizawa, Tomohiro
   Doi, Takayuki
   Ohwada, Tomohiko
   Ishitani, Ryuichiro
   Aoki, Junken
   Nureki, Osamu
TI Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6
SO NATURE
LA English
DT Article
ID protein-coupled receptor; resolution crystal-structure; accurate docking; activation; assay; identification; family; glide; p2y5
AB Lysophosphatidic acid (LPA) is a bioactive lipid composed of a phosphate group, a glycerol backbone, and a single acyl chain that varies in length and saturation. LPA activates six class A G-proteincoupled receptors to provoke various cellular reactions(1). Because LPA signalling has been implicated in cancer(2) and fibrosis(3), the LPA receptors are regarded as promising drug targets. The six LPA receptors are subdivided into the endothelial differentiation gene (EDG) family (LPA(1)-LPA(3))(1) and the phylogenetically distant nonEDG family (LPA(4)-LPA(6))(4). The structure of LPA(1) has enhanced our understanding of the EDG family of LPA receptors(5). By contrast, the functional and pharmacological characteristics of the non-EDG family of LPA receptors have remained unknown, owing to the lack of structural information. Although the non-EDG LPA receptors share sequence similarity with the P2Y family of nucleotide receptors(4), the LPA recognition mechanism cannot be deduced from the P2Y(1) and P2Y(12) structures(6-8) because of the large differences in the chemical structures of their ligands. Here we determine the 3.2 angstrom crystal structure of LPA(6), the gene deletion of which is responsible for congenital hair loss(9,10), to clarify the ligand recognition mechanism of the non-EDG family of LPA receptors. Notably, the ligand-binding pocket of LPA(6) is laterally open towards the membrane, and the acyl chain of the lipid used for the crystallization is bound within this pocket, indicating the binding mode of the LPA acyl chain. Docking and mutagenesis analyses also indicated that the conserved positively charged residues within the central cavity recognize the phosphate head group of LPA by inducing an inward shift of transmembrane helices 6 and 7, suggesting that the receptor activation is triggered by this conformational rearrangement.
C1 [Taniguchi, Reiya; Kato, Hideaki E.; Nishizawa, Tomohiro; Ishitani, Ryuichiro; Nureki, Osamu] Univ Tokyo, Grad Sch Sci, Dept Biol Sci, Bunkyo Ku, Tokyo 1130032, Japan.
   [Taniguchi, Reiya; Kato, Hideaki E.; Nishizawa, Tomohiro; Ishitani, Ryuichiro; Nureki, Osamu] RIKEN, Global Res Cluster, Wako, Saitama 3510198, Japan.
   [Inoue, Asuka; Uwamizu, Akiharu; Aoki, Junken] Tohoku Univ, Grad Sch Pharmaceut Sci, Lab Mol & Cellular Biochem, Sendai, Miyagi 9808578, Japan.
   [Inoue, Asuka; Hirata, Kunio; Nishizawa, Tomohiro] Japan Sci & Technol Agcy JST, Precursory Res Embryon Sci & Technol PRESTO, Kawaguchi, Saitama 3320012, Japan.
   [Sayama, Misa; Otani, Yuko; Ohwada, Tomohiko] Univ Tokyo, Grad Sch Pharmaceut Sci, Lab Organ & Med Chem, Bunkyo Ku, Tokyo 1130033, Japan.
   [Yamashita, Keitaro; Hirata, Kunio] RIKEN SPring 8 Ctr, Mikazuki, Hyogo 6795148, Japan.
   [Yoshida, Masahito; Doi, Takayuki] Tohoku Univ, Grad Sch Pharmaceut Sci, Lab Heterocycl Chem, Sendai, Miyagi 9808578, Japan.
   [Tanaka, Yoshiki] Nara Inst Sci & Technol, Grad Sch Biol Sci, Dept Syst Biol, Ikoma, Nara 6300192, Japan.
   [Nakada-Nakura, Yoshiko] Kyoto Univ, Grad Sch Med, Dept Cell Biol, Sakyo Ku, Kyoto 6068501, Japan.
   [Aoki, Junken] Japan Agcy Med Res & Dev, Core Res Evolut Sci & Technol AMED CREST, Chiyoda Ku, Tokyo 1000004, Japan.
   [Kato, Hideaki E.] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
C3 University of Tokyo; RIKEN; Tohoku University; Japan Science & Technology Agency (JST); University of Tokyo; RIKEN; Tohoku University; Nara Institute of Science & Technology; Kyoto University; Stanford University
RP Nureki, O (corresponding author), Univ Tokyo, Grad Sch Sci, Dept Biol Sci, Bunkyo Ku, Tokyo 1130032, Japan.; Nureki, O (corresponding author), RIKEN, Global Res Cluster, Wako, Saitama 3510198, Japan.; Aoki, J (corresponding author), Tohoku Univ, Grad Sch Pharmaceut Sci, Lab Mol & Cellular Biochem, Sendai, Miyagi 9808578, Japan.; Aoki, J (corresponding author), Japan Agcy Med Res & Dev, Core Res Evolut Sci & Technol AMED CREST, Chiyoda Ku, Tokyo 1000004, Japan.
EM jaoki@m.tohoku.ac.jp; nureki@bs.s.u-tokyo.ac.jp
FU AMED-CREST; Platform for Drug Discovery, Informatics and Structural Life Science from AMED; MEXT [16H06294, 15H05897]; JSPS KAKENHI [16J07583, 15H06862, 17H05000, 16H06574]; JST, PRESTO [JPMJPR1331, JPMJPR14L9, JPMJPR14L8]; PRIME from AMED; AMED; Grants-in-Aid for Scientific Research [15H06862, 16K08157, 16J07583, 17H05000, 16H06574, 16J08059, 17H03640, 16H00822] Funding Source: KAKEN
NR 50
TC 102
Z9 114
U1 1
U2 53
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 17
PY 2017
VL 548
IS 7667
BP 356
EP +
DI 10.1038/nature23448
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD8AU
UT WOS:000407748400038
PM 28792932
DA 2026-03-09
ER

PT J
AU Liang, YL
   Khoshouei, M
   Radjainia, M
   Zhang, Y
   Glukhova, A
   Tarrasch, J
   Thal, DM
   Furness, SGB
   Christopoulos, G
   Coudrat, T
   Danev, R
   Baumeister, W
   Miller, LJ
   Christopoulos, A
   Kobilka, BK
   Wootten, D
   Skiniotis, G
   Sexton, PM
AF Liang, Yi-Lynn
   Khoshouei, Maryam
   Radjainia, Mazdak
   Zhang, Yan
   Glukhova, Alisa
   Tarrasch, Jeffrey
   Thal, David M.
   Furness, Sebastian G. B.
   Christopoulos, George
   Coudrat, Thomas
   Danev, Radostin
   Baumeister, Wolfgang
   Miller, Laurence J.
   Christopoulos, Arthur
   Kobilka, Brian K.
   Wootten, Denise
   Skiniotis, Georgios
   Sexton, Patrick M.
TI Phase-plate cryo-EM structure of a class B GPCR-G-protein complex
SO NATURE
LA English
DT Article
ID peptide-1 receptor; salmon-calcitonin; binding; activation; mechanism; pharmacology; consequences; specificity; modulation; microscopy
AB Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, such as osteoporosis, diabetes and obesity. Here we report the structure of a full-length class B receptor, the calcitonin receptor, in complex with peptide ligand and heterotrimeric G alpha(s)beta gamma protein determined by Volta phase-plate single-particle cryo-electron microscopy. The peptide agonist engages the receptor by binding to an extended hydrophobic pocket facilitated by the large outward movement of the extracellular ends of transmembrane helices 6 and 7. This conformation is accompanied by a 60 degrees kink in helix 6 and a large outward movement of the intracellular end of this helix, opening the bundle to accommodate interactions with the alpha 5-helix of G alpha(s). Also observed is an extended intracellular helix 8 that contributes to both receptor stability and functional G-protein coupling via an interaction with the G beta subunit. This structure provides a new framework for understanding G-protein-coupled receptor function.
C1 [Liang, Yi-Lynn; Glukhova, Alisa; Thal, David M.; Furness, Sebastian G. B.; Christopoulos, George; Coudrat, Thomas; Christopoulos, Arthur; Wootten, Denise; Sexton, Patrick M.] Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic 3052, Australia.
   [Liang, Yi-Lynn; Glukhova, Alisa; Thal, David M.; Furness, Sebastian G. B.; Christopoulos, George; Coudrat, Thomas; Christopoulos, Arthur; Wootten, Denise; Sexton, Patrick M.] Monash Univ, Monash Inst Pharmaceut Sci, Dept Pharmacol, Parkville, Vic 3052, Australia.
   [Khoshouei, Maryam; Danev, Radostin; Baumeister, Wolfgang] Max Planck Inst Biochem, Dept Mol Struct Biol, D-82152 Martinsried, Germany.
   [Radjainia, Mazdak] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia.
   [Zhang, Yan; Tarrasch, Jeffrey; Skiniotis, Georgios] Univ Michigan, Inst Life Sci, Sch Med, Ann Arbor, MI 48109 USA.
   [Zhang, Yan; Tarrasch, Jeffrey; Skiniotis, Georgios] Univ Michigan, Dept Biol Chem, Sch Med, Ann Arbor, MI 48109 USA.
   [Miller, Laurence J.] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Scottsdale, AZ 85259 USA.
   [Kobilka, Brian K.] Stanford Univ, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA.
   [Radjainia, Mazdak] FEI, NL-5651 GG Eindhoven, Netherlands.
C3 Monash University; Monash University; Max Planck Society; Monash University; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Mayo Clinic; Mayo Clinic Phoenix; Stanford University
RP Wootten, D; Sexton, PM (corresponding author), Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic 3052, Australia.; Wootten, D; Sexton, PM (corresponding author), Monash Univ, Monash Inst Pharmaceut Sci, Dept Pharmacol, Parkville, Vic 3052, Australia.; Skiniotis, G (corresponding author), Univ Michigan, Inst Life Sci, Sch Med, Ann Arbor, MI 48109 USA.; Skiniotis, G (corresponding author), Univ Michigan, Dept Biol Chem, Sch Med, Ann Arbor, MI 48109 USA.
EM denise.wootten@monash.edu; skinioti@umich.edu; patrick.sexton@monash.edu
FU National Health and Medical Research Council of Australia (NHMRC) [1055134, 1061044, 1120919]; NIH [DK090165, NS092695]; Melbourne Bioinformatics at the University of Melbourne [VR0024]; National Health and Medical Research Council (NHMRC) [1120919] Funding Source: National Health and Medical Research Council (NHMRC); National Institute of General Medical Sciences [R01GM083118] Funding Source: NIH RePORTER; National Health and Medical Research Council of Australia [1120919] Funding Source: NHMRC
NR 56
TC 391
Z9 466
U1 3
U2 224
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 1
PY 2017
VL 546
IS 7656
BP 118
EP +
DI 10.1038/nature22327
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW3CR
UT WOS:000402372800039
PM 28437792
DA 2026-03-09
ER

PT J
AU Geng, L
   Murray, LT
   Mickley, LJ
   Lin, P
   Fu, Q
   Schauer, AJ
   Alexander, B
AF Geng, Lei
   Murray, Lee T.
   Mickley, Loretta J.
   Lin, Pu
   Fu, Qiang
   Schauer, Andrew J.
   Alexander, Becky
TI Isotopic evidence of multiple controls on atmospheric oxidants over climate transitions
SO NATURE
LA English
DT Article
ID nitrate; troposphere; methane; greenland; chemistry; model; preindustrial; variability; circulation; delta-o-17
AB The abundance of tropospheric oxidants, such as ozone (O-3) and hydroxyl (OH) and peroxy radicals (HO2 + RO2), determines the lifetimes of reduced trace gases such as methane and the production of particulate matter important for climate and human health. The response of tropospheric oxidants to climate change is poorly constrained owing to large uncertainties in the degree to which processes that influence oxidants may change with climate(1) and owing to a lack of palaeo-records with which to constrain levels of atmospheric oxidants during past climate transitions(2). At present, it is thought that temperature-dependent emissions of tropospheric O-3 precursors and water vapour abundance determine the climate response of oxidants, resulting in lower tropospheric O-3 in cold climates while HOx (= OH + HO2 + RO2) remains relatively buffered(3). Here we report observations of oxygen-17 excess of nitrate (a proxy for the relative abundance of atmospheric O-3 and HOx) from a Greenland ice core over the most recent glacial-interglacial cycle and for two Dansgaard-Oeschger events. We find that tropospheric oxidants are sensitive to climate change with an increase in the O-3/HOx ratio in cold climates, the opposite of current expectations. We hypothesize that the observed increase in O-3/HOx in cold climates is driven by enhanced stratosphere-to-troposphere transport of O-3, and that reactive halogen chemistry is also enhanced in cold climates. Reactive halogens influence the oxidative capacity of the troposphere directly as oxidants themselves and indirectly(4) via their influence on O-3 and HOx. The strength of stratosphere-to-troposphere transport is largely controlled by the Brewer-Dobson circulation(5), which may be enhanced in colder climates owing to a stronger meridional gradient of sea surface temperatures(6), with implications for the response of tropospheric oxidants(7) and stratospheric thermal and mass balance(8). These two processes may represent important, yet relatively unexplored, climate feedback mechanisms during major climate transitions.
C1 [Geng, Lei; Fu, Qiang; Alexander, Becky] Univ Washington, Dept Atmospher Sci, Seattle, WA 98195 USA.
   [Geng, Lei] Univ Grenoble Alpes, Inst Geosci & Environm, F-38508 Grenoble, France.
   [Geng, Lei] Univ Sci & Technol China, Sch Earth & Space Sci, Hefei 230026, Anhui, Peoples R China.
   [Murray, Lee T.] Univ Rochester, Dept Earth & Environm Sci, Rochester, NY USA.
   [Mickley, Loretta J.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA.
   [Lin, Pu] Princeton Univ, Program Atmospher & Ocean Sci, Princeton, NJ 08544 USA.
   [Schauer, Andrew J.] Univ Washington, Dept Earth & Space Sci, Seattle, WA 98195 USA.
C3 University of Washington; University of Washington Seattle; Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Chinese Academy of Sciences; University of Science & Technology of China, CAS; University of Rochester; Harvard University; National Oceanic Atmospheric Admin (NOAA) - USA; Princeton University; University of Washington; University of Washington Seattle
RP Alexander, B (corresponding author), Univ Washington, Dept Atmospher Sci, Seattle, WA 98195 USA.
EM beckya@uw.edu
FU NSF [AGS 1103163, PLR 1106317, PLR 1244817, AGS 1102880]; NASA Postdoctoral Program Fellowship [NNH06CC03B]; NASA [NNX13AN49G]; National Oceanic and Atmospheric Administration, US Department of Commerce [NA14OAR4320106]
NR 39
TC 49
Z9 60
U1 6
U2 150
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 1
PY 2017
VL 546
IS 7656
BP 133
EP +
DI 10.1038/nature22340
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW3CR
UT WOS:000402372800042
PM 28514452
DA 2026-03-09
ER

PT J
AU Hirose, K
   Morard, G
   Sinmyo, R
   Umemoto, K
   Hernlund, J
   Helffrich, G
   Labrosse, S
AF Hirose, Kei
   Morard, Guillaume
   Sinmyo, Ryosuke
   Umemoto, Koichio
   Hernlund, John
   Helffrich, George
   Labrosse, Stephane
TI Crystallization of silicon dioxide and compositional evolution of the Earth's core
SO NATURE
LA English
DT Article
ID x-ray-diffraction; deep magma-ocean; liquid-iron; pressures implications; system; mantle; accretion; geodynamo; dynamo; ni
AB The Earth's core is about ten per cent less dense than pure iron (Fe), suggesting that it contains light elements as well as iron. Modelling of core formation at high pressure (around 40-60 gigapascals) and high temperature (about 3,500 kelvin) in a deep magma ocean(1-5) predicts that both silicon (Si) and oxygen (O) are among the impurities in the liquid outer core(6-9). However, only the binary systems Fe-Si and Fe-O have been studied in detail at high pressures, and little is known about the compositional evolution of the Fe-Si-O ternary alloy under core conditions. Here we performed melting experiments on liquid Fe-Si-O alloy at core pressures in a laser-heated diamond-anvil cell. Our results demonstrate that the liquidus field of silicon dioxide (SiO2) is unexpectedly wide at the iron-rich portion of the Fe-Si-O ternary, such that an initial Fe-Si-O core crystallizes SiO2 as it cools. If crystallization proceeds on top of the core, the buoyancy released should have been more than sufficient to power core convection and a dynamo, in spite of high thermal conductivity(10,11), from as early on as the Hadean eon(12). SiO2 saturation also sets limits on silicon and oxygen concentrations in the present-day outer core.
C1 [Hirose, Kei; Sinmyo, Ryosuke; Umemoto, Koichio; Hernlund, John; Helffrich, George] Tokyo Inst Technol, Earth Life Sci Inst, Meguro Ku, 2-12-1 Ookayama, Tokyo 1528550, Japan.
   [Morard, Guillaume] Univ Paris 06, Sorbonne Univ, CNRS,Inst Mineral Phys Mat & Cosmochim, Museum Natl Hist Natl,IRD,UMR 7590, 4 Pl Jussieu, F-75005 Paris, France.
   [Labrosse, Stephane] Univ Lyon 1, Ecole Normale Super Lyon, CNRS, UMR 5276 LGL TPE, F-69364 Lyon, France.
C3 Institute of Science Tokyo; Tokyo Institute of Technology; Museum National d'Histoire Naturelle (MNHN); Sorbonne Universite; Institut de Recherche pour le Developpement (IRD); Universite Paris Cite; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Physics (INP); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Universite Lyon 1; Ecole Normale Superieure de Lyon (ENS de LYON)
RP Hirose, K (corresponding author), Tokyo Inst Technol, Earth Life Sci Inst, Meguro Ku, 2-12-1 Ookayama, Tokyo 1528550, Japan.
EM kei@elsi.jp
FU Grants-in-Aid for Scientific Research [26400525, 16H01115, 15H05834, 15H05832, 17K05627, 16H06285, 16H06023] Funding Source: KAKEN
NR 48
TC 193
Z9 214
U1 2
U2 175
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 2
PY 2017
VL 543
IS 7643
BP 99
EP +
DI 10.1038/nature21367
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0AA
UT WOS:000395671500040
PM 28225759
DA 2026-03-09
ER

PT J
AU Starr, TN
   Picton, LK
   Hornton, JWT
AF Starr, Tyler N.
   Picton, Lora K.
   Hornton, Joseph W. T.
TI Alternative evolutionary histories in the sequence space of an ancient protein
SO NATURE
LA English
DT Article
ID glucocorticoid-receptor; crystal-structure; dna; yeast; epistasis; transformation; specificity; contingency; prediction; family
AB To understand why molecular evolution turned out as it did, we must characterize not only the path that evolution followed across the space of possible molecular sequences but also the many alternative trajectories that could have been taken but were not. A large-scale comparison of real and possible histories would establish whether the outcome of evolution represents an optimal state driven by natural selection or the contingent product of historical chance events(1); it would also reveal how the underlying distribution of functions across sequence space shaped historical evolution(2,3). Here we combine ancestral protein reconstruction(4) with deep mutational scanning(5-10) to characterize alternative histories in the sequence space around an ancient transcription factor, which evolved a novel biological function through well-characterized mechanisms(11,12). We find hundreds of alternative protein sequences that use diverse biochemical mechanisms to perform the derived function at least as well as the historical outcome. These alternatives all require prior permissive substitutions that do not enhance the derived function, but not all require the same permissive changes that occurred during history. We find that if evolution had begun from a different starting point within the network of sequences encoding the ancestral function, outcomes with different genetic and biochemical forms would probably have resulted; this contingency arises from the distribution of functional variants in sequence space and epistasis between residues. Our results illuminate the topology of the vast space of possibilities from which history sampled one path, highlighting how the outcome of evolution depends on a serial chain of compounding chance events.
C1 [Starr, Tyler N.] Univ Chicago, Dept Biochem & Mol Biol, 920 E 58Th St, Chicago, IL 60637 USA.
   [Picton, Lora K.; Hornton, Joseph W. T.] Univ Chicago, Dept Ecol & Evolut, 940 E 57Th St, Chicago, IL 60637 USA.
   [Hornton, Joseph W. T.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA.
C3 University of Chicago; University of Chicago; University of Chicago
RP Hornton, JWT (corresponding author), Univ Chicago, Dept Ecol & Evolut, 940 E 57Th St, Chicago, IL 60637 USA.; Hornton, JWT (corresponding author), Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA.
EM joet1@uchicago.edu
FU National Institutes of Health [R01GM104397, R01GM121931, T32-GM007183, UL1-TR000430]; National Science Foundation; National Institute of General Medical Sciences [T32GM007183] Funding Source: NIH RePORTER
NR 54
TC 138
Z9 182
U1 1
U2 52
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 21
PY 2017
VL 549
IS 7672
BP 409
EP +
DI 10.1038/nature23902
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FH7PB
UT WOS:000411381300040
PM 28902834
DA 2026-03-09
ER

PT J
AU Agarwal, J
   Jewitt, D
   Mutchler, M
   Weaver, H
   Larson, S
AF Agarwal, Jessica
   Jewitt, David
   Mutchler, Max
   Weaver, Harold
   Larson, Stephen
TI A binary main-belt comet
SO NATURE
LA English
DT Article
ID asteroid belt; population; satellites; collisions; dynamics; breakup; yorp
AB Asteroids are primitive Solar System bodies that evolve both collisionally and through disruptions arising from rapid rotation(1). These processes can lead to the formation of binary asteroids(2-4) and to the release of dust(5), both directly and, in some cases, through uncovering frozen volatiles. In a subset of the asteroids called main-belt comets, the sublimation of excavated volatiles causes transient comet-like activity(6-8). Torques exerted by sublimation measurably influence the spin rates of active comets(9) and might lead to the splitting of bilobate comet nuclei(10). The kilometre-sized main-belt asteroid 288P (300163) showed activity for several months around its perihelion 2011 (ref. 11), suspected to be sustained by the sublimation of water ice(12) and supported by rapid rotation(13), while at least one component rotates slowly with a period of 16 hours (ref. 14). The object 288P is part of a young family of at least 11 asteroids that formed from a precursor about 10 kilometres in diameter during a shattering collision 7.5 million years ago(15). Here we report that 288P is a binary main-belt comet. It is different from the known asteroid binaries in its combination of wide separation, near-equal component size, high eccentricity and comet-like activity. The observations also provide strong support for sublimation as the driver of activity in 288P and show that sublimation torques may play an important part in binary orbit evolution.
C1 [Agarwal, Jessica] Max Planck Inst Solar Syst Res, Justus von Liebig Weg 3, D-37077 Gottingen, Germany.
   [Jewitt, David] Univ Calif Los Angeles, Dept Earth Planetary & Space Sci, 595 Charles Young Dr East, Los Angeles, CA 90095 USA.
   [Jewitt, David] Univ Calif Los Angeles, Dept Phys & Astron, 430 Portola Plaza,Box 951547, Los Angeles, CA 90095 USA.
   [Mutchler, Max] Space Telescope Sci Inst, 3700 San Martin Dr, Baltimore, MD 21218 USA.
   [Weaver, Harold] Johns Hopkins Univ, Appl Phys Lab, 11100 Johns Hopkins Rd, Laurel, MD 20723 USA.
   [Larson, Stephen] Univ Arizona, Lunar & Planetary Lab, 1629 East Univ Blvd, Tucson, AZ 85721 USA.
C3 University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; Space Telescope Science Institute; Johns Hopkins University; Johns Hopkins University Applied Physics Laboratory; University of Arizona
RP Agarwal, J (corresponding author), Max Planck Inst Solar Syst Res, Justus von Liebig Weg 3, D-37077 Gottingen, Germany.
EM agarwal@mps.mpg.de
FU NASA [NAS 5-26555]
NR 36
TC 34
Z9 37
U1 0
U2 18
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 21
PY 2017
VL 549
IS 7672
BP 357
EP +
DI 10.1038/nature23892
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FH7PB
UT WOS:000411381300029
PM 28933430
DA 2026-03-09
ER

PT J
AU Tarnita, CE
   Bonachela, JA
   Sheffer, E
   Guyton, JA
   Coverdale, TC
   Long, RA
   Pringle, RM
AF Tarnita, Corina E.
   Bonachela, Juan A.
   Sheffer, Efrat
   Guyton, Jennifer A.
   Coverdale, Tyler C.
   Long, Ryan A.
   Pringle, Robert M.
TI A theoretical foundation for multi-scale regular vegetation patterns
SO NATURE
LA English
DT Article
ID termite macrotermes-michaelseni; heterotermes-aureus isoptera; desert subterranean termite; fairy circles; colony size; intraspecific competition; self-organization; rhinotermitidae; populations; ecosystems
AB Self-organized regular vegetation patterns are widespread(1) and thought to mediate ecosystem functions such as productivity and robustness(2-4), but the mechanisms underlying their origin and maintenance remain disputed. Particularly controversial are landscapes of overdispersed (evenly spaced) elements, such as North American Mima mounds, Brazilian murundus, South African heuweltjies, and, famously, Namibian fairy circles(5-13). Two competing hypotheses are currently debated. On the one hand, models of scale-dependent feedbacks, whereby plants facilitate neighbours while competing with distant individuals, can reproduce various regular patterns identified in satellite imagery(1,14,15). Owing to deep theoretical roots and apparent generality, scale-dependent feedbacks are widely viewed as a unifying and near-universal principle of regular-pattern formation(1,16,17) despite scant empirical evidence(18). On the other hand, many overdispersed vegetation patterns worldwide have been attributed to subterranean ecosystem engineers such as termites, ants, and rodents(3,4,7,19-22). Although potentially consistent with territorial competition(19-21,23,24), this interpretation has been challenged theoretically and empirically(11,17,24-26) and (unlike scale-dependent feedbacks) lacks a unifying dynamical theory, fuelling scepticism about its plausibility and generality(5,9-11,16-18,24-26). Here we provide a general theoretical foundation for self-organization of social-insect colonies, validated using data from four continents, which demonstrates that intraspecific competition between territorial animals can generate the large-scale hexagonal regularity of these patterns. However, this mechanism is not mutually exclusive with scale-dependent feedbacks. Using Namib Desert fairy circles as a case study, we present field data showing that these landscapes exhibit multi-scale patterning-previously undocumented in this system-that cannot be explained by either mechanism in isolation. These multi-scale patterns and other emergent properties, such as enhanced resistance to and recovery from drought, instead arise from dynamic interactions in our theoretical framework, which couples both mechanisms. The potentially global extent of animal-induced regularity in vegetation-which can modulate other patterning processes in functionally important ways-emphasizes the need to integrate multiple mechanisms of ecological self-organization(27).
C1 [Tarnita, Corina E.; Guyton, Jennifer A.; Coverdale, Tyler C.; Pringle, Robert M.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA.
   [Tarnita, Corina E.; Pringle, Robert M.] Mpala Res Ctr, POB 555, Nanyuki, Kenya.
   [Bonachela, Juan A.] Univ Strathclyde, Dept Math & Stat, Marine Populat Modelling Grp, Glasgow G1 1XH, Lanark, Scotland.
   [Sheffer, Efrat] Hebrew Univ Jerusalem, Fac Agr, Robert H Smith Inst Plant Sci & Genet Agr, IL-7610001 Rehovot, Israel.
   [Long, Ryan A.] Univ Idaho, Dept Fish & Wildlife Serv, Moscow, ID 83844 USA.
C3 Princeton University; University of Strathclyde; Hebrew University of Jerusalem; University of Idaho
RP Tarnita, CE (corresponding author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA.; Tarnita, CE (corresponding author), Mpala Res Ctr, POB 555, Nanyuki, Kenya.; Bonachela, JA (corresponding author), Univ Strathclyde, Dept Math & Stat, Marine Populat Modelling Grp, Glasgow G1 1XH, Lanark, Scotland.
EM ctarnita@princeton.edu; juan.bonachela@strath.ac.uk
FU US National Science Foundation [DEB-1355122]; Princeton Environmental Institute's Grand Challenges Program; Marine Alliance for Science and Technology for Scotland (MASTS) pooling initiative; Scottish Funding Council [HR09011]; DigitalGlobe Foundation; Division Of Environmental Biology; Direct For Biological Sciences [1355122] Funding Source: National Science Foundation
NR 60
TC 156
Z9 174
U1 6
U2 238
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 19
PY 2017
VL 541
IS 7637
BP 398
EP +
DI 10.1038/nature20801
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6QP
UT WOS:000396128800043
PM 28102267
DA 2026-03-09
ER

PT J
AU Garcia-Seisdedos, H
   Empereur-Mot, C
   Elad, N
   Levy, ED
AF Garcia-Seisdedos, Hector
   Empereur-Mot, Charly
   Elad, Nadav
   Levy, Emmanuel D.
TI Proteins evolve on the edge of supramolecular self-assembly
SO NATURE
LA English
DT Article
ID escherichia-coli reveals; de-novo design; crystal-structure; arginine decarboxylase; computational design; amyloid state; principles; image; evolutionary; inhibition
AB The self-association of proteins into symmetric complexes is ubiquitous in all kingdoms of life(1-6). Symmetric complexes possess unique geometric and functional properties, but their internal symmetry can pose a risk. In sickle-cell disease, the symmetry of haemoglobin exacerbates the effect of a mutation, triggering assembly into harmful fibrils(7). Here we examine the universality of this mechanism and its relation to protein structure geometry. We introduced point mutations solely designed to increase surface hydrophobicity among 12 distinct symmetric complexes from Escherichia coli. Notably, all responded by forming supramolecular assemblies in vitro, as well as in vivo upon heterologous expression in Saccharomyces cerevisiae. Remarkably, in four cases, micrometre-long fibrils formed in vivo in response to a single point mutation. Biophysical measurements and electron microscopy revealed that mutants self-assembled in their folded states and so were not amyloid-like. Structural examination of 73 mutants identified supramolecular assembly hot spots predictable by geometry. A subsequent structural analysis of 7,471 symmetric complexes showed that geometric hot spots were buffered chemically by hydrophilic residues, suggesting a mechanism preventing mis-assembly of these regions. Thus, point mutations can frequently trigger folded proteins to self-assemble into higher-order structures. This potential is counterbalanced by negative selection and can be exploited to design nanomaterials in living cells.
C1 [Garcia-Seisdedos, Hector; Empereur-Mot, Charly; Levy, Emmanuel D.] Weizmann Inst Sci, Dept Biol Struct, IL-7610001 Rehovot, Israel.
   [Elad, Nadav] Weizmann Inst Sci, Dept Chem Res Support, IL-7610001 Rehovot, Israel.
   [Empereur-Mot, Charly] Conservatoire Natl Arts & Metiers, F-75003 Paris, France.
C3 Weizmann Institute of Science; Weizmann Institute of Science; heSam Universite; Conservatoire National Arts & Metiers (CNAM)
RP Levy, ED (corresponding author), Weizmann Inst Sci, Dept Biol Struct, IL-7610001 Rehovot, Israel.
EM emmanuel.levy@weizmann.ac.il
FU Israel Science Foundation; I-CORE Program of the Planning and Budgeting Committee [1775/12, 2179/14]; Marie Curie Career Integration Grants Program [711715]; Human Frontier Science Program [CDA00077/2015]; Koshland Foundation; McDonald-Leapman Grant; Irving and Cherna Moskowitz Center for Nano and Bio-Nano Imaging
NR 72
TC 196
Z9 234
U1 2
U2 178
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 10
PY 2017
VL 548
IS 7666
BP 244
EP +
DI 10.1038/nature23320
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD1GB
UT WOS:000407284300050
PM 28783726
DA 2026-03-09
ER

PT J
AU Lan, XY
   Jörg, DJ
   Cavalli, FMG
   Richards, LM
   Nguyen, LV
   Vanner, RJ
   Guilhamon, P
   Lee, L
   Kushida, MM
   Pellacani, D
   Park, NI
   Coutinho, FJ
   Whetstone, H
   Selvadurai, HJ
   Che, C
   Luu, B
   Carles, A
   Moksa, M
   Rastegar, N
   Head, R
   Dolma, S
   Prinos, P
   Cusimano, MD
   Das, S
   Bernstein, M
   Arrowsmith, CH
   Mungall, AJ
   Moore, RA
   Ma, Y
   Gallo, M
   Lupien, M
   Pugh, TJ
   Taylor, MD
   Hirst, M
   Eaves, CJ
   Simons, BD
   Dirks, PB
AF Lan, Xiaoyang
   Jorg, David J.
   Cavalli, Florence M. G.
   Richards, Laura M.
   Nguyen, Long V.
   Vanner, Robert J.
   Guilhamon, Paul
   Lee, Lilian
   Kushida, Michelle M.
   Pellacani, Davide
   Park, Nicole I.
   Coutinho, Fiona J.
   Whetstone, Heather
   Selvadurai, Hayden J.
   Che, Clare
   Luu, Betty
   Carles, Annaick
   Moksa, Michelle
   Rastegar, Naghmeh
   Head, Renee
   Dolma, Sonam
   Prinos, Panagiotis
   Cusimano, Michael D.
   Das, Sunit
   Bernstein, Mark
   Arrowsmith, Cheryl H.
   Mungall, Andrew J.
   Moore, Richard A.
   Ma, Yussanne
   Gallo, Marco
   Lupien, Mathieu
   Pugh, Trevor J.
   Taylor, Michael D.
   Hirst, Martin
   Eaves, Connie J.
   Simons, Benjamin D.
   Dirks, Peter B.
TI Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy
SO NATURE
LA English
DT Article
ID clonal dynamics; read alignment; diverse growth; copy number; cancer; model; heterogeneity; identification; mutations; evolution
AB Human glioblastomas harbour a subpopulation of glioblastoma stem cells that drive tumorigenesis. However, the origin of intratumoural functional heterogeneity between glioblastoma cells remains poorly understood. Here we study the clonal evolution of barcoded glioblastoma cells in an unbiased way following serial xenotransplantation to define their individual fate behaviours. Independent of an evolving mutational signature, we show that the growth of glioblastoma clones in vivo is consistent with a remarkably neutral process involving a conserved proliferative hierarchy rooted in glioblastoma stem cells. In this model, slow-cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, which in turn generates non-proliferative cells. We also identify rare 'outlier' clones that deviate from these dynamics, and further show that chemotherapy facilitates the expansion of pre-existing drug-resistant glioblastoma stem cells. Finally, we show that functionally distinct glioblastoma stem cells can be separately targeted using epigenetic compounds, suggesting new avenues for glioblastoma-targeted therapy.
C1 [Lan, Xiaoyang; Cavalli, Florence M. G.; Vanner, Robert J.; Lee, Lilian; Kushida, Michelle M.; Park, Nicole I.; Coutinho, Fiona J.; Whetstone, Heather; Selvadurai, Hayden J.; Che, Clare; Luu, Betty; Rastegar, Naghmeh; Head, Renee; Dolma, Sonam; Taylor, Michael D.; Dirks, Peter B.] Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON M5G 0A4, Canada.
   [Lan, Xiaoyang; Cavalli, Florence M. G.; Vanner, Robert J.; Lee, Lilian; Kushida, Michelle M.; Park, Nicole I.; Coutinho, Fiona J.; Whetstone, Heather; Selvadurai, Hayden J.; Che, Clare; Luu, Betty; Rastegar, Naghmeh; Head, Renee; Dolma, Sonam; Taylor, Michael D.; Dirks, Peter B.] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON M5G 0A4, Canada.
   [Lan, Xiaoyang; Vanner, Robert J.; Park, Nicole I.; Coutinho, Fiona J.; Dirks, Peter B.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada.
   [Jorg, David J.; Simons, Benjamin D.] Cavendish Lab, Dept Phys, JJ Thomson Ave, Cambridge CB3 0HE, England.
   [Jorg, David J.; Simons, Benjamin D.] Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England.
   [Richards, Laura M.; Guilhamon, Paul; Lupien, Mathieu; Pugh, Trevor J.] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada.
   [Richards, Laura M.; Guilhamon, Paul; Prinos, Panagiotis; Arrowsmith, Cheryl H.; Lupien, Mathieu; Pugh, Trevor J.] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada.
   [Nguyen, Long V.; Pellacani, Davide; Eaves, Connie J.] BC Canc Agcy, Terry Fox Lab, 675 West 10th Ave, Vancouver, BC V5Z 1L3, Canada.
   [Guilhamon, Paul; Lupien, Mathieu] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada.
   [Pellacani, Davide; Eaves, Connie J.] Univ British Columbia, Dept Med Genet, Vancouver, BC V6T 2B5, Canada.
   [Carles, Annaick; Moksa, Michelle; Hirst, Martin] Univ British Columbia, Dept Microbiol & Immunol, Ctr High Throughput Biol, Vancouver, BC V6T 1Z4, Canada.
   [Dolma, Sonam; Taylor, Michael D.; Dirks, Peter B.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5G 0A4, Canada.
   [Prinos, Panagiotis; Arrowsmith, Cheryl H.] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada.
   [Cusimano, Michael D.; Das, Sunit] St Michaels Hosp, Div Neurosurg, Toronto, ON M5B 1W8, Canada.
   [Cusimano, Michael D.; Das, Sunit; Bernstein, Mark; Taylor, Michael D.; Dirks, Peter B.] Univ Toronto, Dept Surg, Div Neurosurg, Toronto, ON M5S 1A8, Canada.
   [Bernstein, Mark] Toronto Western Hosp, Div Neurosurg, Toronto, ON M5T 2S8, Canada.
   [Mungall, Andrew J.; Moore, Richard A.; Ma, Yussanne; Hirst, Martin] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, 675 West 10th Ave, Vancouver, BC V5Z 1L3, Canada.
   [Gallo, Marco] Univ Calgary, Arnie Charbonneau Canc Inst, Alberta Childrens Hosp Res Inst, Dept Physiol & Pharmacol, Calgary, AB T2N 4N1, Canada.
   [Gallo, Marco] Univ Calgary, Arnie Charbonneau Canc Inst, Alberta Childrens Hosp Res Inst, Dept Biochem, Calgary, AB T2N 4N1, Canada.
   [Gallo, Marco] Univ Calgary, Arnie Charbonneau Canc Inst, Alberta Childrens Hosp Res Inst, Dept Mol Biol, Calgary, AB T2N 4N1, Canada.
   [Taylor, Michael D.; Dirks, Peter B.] Hosp Sick Children, Div Neurosurg, Toronto, ON M5S 3E1, Canada.
   [Simons, Benjamin D.] Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge, England.
C3 University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; University of Cambridge; University of Cambridge; University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; University of Toronto; British Columbia Cancer Agency; University of Toronto; Ontario Institute for Cancer Research; University of British Columbia; University of British Columbia; University of Toronto; University of Toronto; Structural Genomics Consortium; University of Toronto; Saint Michaels Hospital Toronto; University of Toronto; University of Toronto; University Health Network Toronto; British Columbia Cancer Agency; University of Calgary; University of Calgary; University of Calgary; University of Toronto; Hospital for Sick Children (SickKids); University of Cambridge
RP Dirks, PB (corresponding author), Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON M5G 0A4, Canada.; Dirks, PB (corresponding author), Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON M5G 0A4, Canada.; Dirks, PB (corresponding author), Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada.; Simons, BD (corresponding author), Cavendish Lab, Dept Phys, JJ Thomson Ave, Cambridge CB3 0HE, England.; Simons, BD (corresponding author), Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England.; Dirks, PB (corresponding author), Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5G 0A4, Canada.; Dirks, PB (corresponding author), Univ Toronto, Dept Surg, Div Neurosurg, Toronto, ON M5S 1A8, Canada.; Dirks, PB (corresponding author), Hosp Sick Children, Div Neurosurg, Toronto, ON M5S 3E1, Canada.; Simons, BD (corresponding author), Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge, England.
EM bds10@cam.ac.uk; peter.dirks@sickkids.ca
FU Canadian Institutes of Health Research [142434]; Ontario Institute for Cancer Research through Government of Ontario; Stand Up To Cancer (SU2C) Canada; Terry Fox Research Institute; Canadian Cancer Society; Hospital for Sick Children Foundation; Jessica's Footprint Foundation; Hopeful Minds Foundation; Bresler family; B.R.A.I.N. Child; Wellcome Trust [098357/Z/12/Z]; Terry Fox Run; SU2C Canada Cancer Stem Cell Dream Team Research Funding by Government of Canada through Genome Canada [SU2C-AACR-DT-19-15]; Canadian Institutes of Health Research; American Association for Cancer Research International - Canada; AbbVie; Bayer; Boehringer Ingelheim; GSK; Genome Canada; Ontario Genomics Institute; Janssen; Lilly; Merck; Novartis; government of Ontario; Pfizer; Takeda; Wellcome Trust; Medical Research Council [MC_PC_12009] Funding Source: researchfish; Wellcome Trust [098357/Z/12/Z] Funding Source: researchfish
NR 63
TC 305
Z9 363
U1 0
U2 52
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 14
PY 2017
VL 549
IS 7671
BP 227
EP +
DI 10.1038/nature23666
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG7AE
UT WOS:000410555900036
PM 28854171
DA 2026-03-09
ER

PT J
AU Tsai, KL
   Yu, XD
   Gopalan, S
   Chao, TC
   Zhang, Y
   Florens, L
   Washburn, MP
   Murakami, K
   Conaway, RC
   Conaway, JW
   Asturias, FJ
AF Tsai, Kuang-Lei
   Yu, Xiaodi
   Gopalan, Sneha
   Chao, Ti-Chun
   Zhang, Ying
   Florens, Laurence
   Washburn, Michael P.
   Murakami, Kenji
   Conaway, Ronald C.
   Conaway, Joan W.
   Asturias, Francisco J.
TI Mediator structure and rearrangements required for holoenzyme formation
SO NATURE
LA English
DT Article
ID rna-polymerase-ii; subunit architecture; proteomic analysis; transcription; initiation; complex; yeast; identification; microscopy; visualization
AB The conserved Mediator co-activator complex has an essential role in the regulation of RNA polymerase II transcription in all eukaryotes. Understanding the structure and interactions of Mediator is crucial for determining how the complex influences transcription initiation and conveys regulatory information to the basal transcription machinery. Here we present a 4.4 angstrom resolution cryo-electron microscopy map of Schizosaccharomyces pombe Mediator in which conserved Mediator subunits are individually resolved. The essential Med14 subunit works as a central backbone that connects the Mediator head, middle and tail modules. Comparison with a 7.8 angstrom resolution cryo-electron microscopy map of a Mediator-RNA polymerase II holoenzyme reveals that changes in the structure of Med14 facilitate a large-scale Mediator rearrangement that is essential for holoenzyme formation. Our study suggests that access to different conformations and crosstalk between structural elements are essential for the Mediator regulation mechanism, and could explain the capacity of the complex to integrate multiple regulatory signals.
C1 [Tsai, Kuang-Lei; Yu, Xiaodi; Asturias, Francisco J.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA.
   [Gopalan, Sneha; Zhang, Ying; Florens, Laurence; Washburn, Michael P.; Conaway, Ronald C.; Conaway, Joan W.] Stowers Inst Med Res, Kansas City, MO USA.
   [Gopalan, Sneha; Zhang, Ying; Florens, Laurence; Washburn, Michael P.; Conaway, Ronald C.; Conaway, Joan W.] Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 USA.
   [Chao, Ti-Chun] Univ Calif San Diego, Sch Med, Inst Genom Med, La Jolla, CA 92093 USA.
   [Washburn, Michael P.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA.
   [Murakami, Kenji] Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA.
   [Conaway, Ronald C.; Conaway, Joan W.] Univ Kansas, Med Ctr, Dept Biochem & Mol Biol, Kansas City, KS USA.
   [Murakami, Kenji] Univ Penn, Dept Biochem & Biophys, Perelman Sch Med, Philadelphia, PA 19104 USA.
   [Asturias, Francisco J.] Univ Colorado, Sch Med, Dept Biochem & Mol Genet, Aurora, CO 80045 USA.
C3 Scripps Research Institute; Stowers Institute for Medical Research; University of California System; University of California San Diego; University of California System; University of California San Diego; University of Kansas; University of Kansas Medical Center; Stanford University; University of Kansas; University of Kansas Medical Center; University of Pennsylvania; University of Colorado System; University of Colorado Anschutz Medical Campus
RP Asturias, FJ (corresponding author), Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA.; Asturias, FJ (corresponding author), Univ Colorado, Sch Med, Dept Biochem & Mol Genet, Aurora, CO 80045 USA.
EM francisco.asturias@ucdenver.edu
FU US National Institutes of Health [R01 GM67167, R01 GM41628]; Helen Nelson Medical Research Fund at the Greater Kansas City Community Foundation; National Institute of General Medical Sciences [R01GM067167] Funding Source: NIH RePORTER
NR 60
TC 115
Z9 141
U1 7
U2 40
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 13
PY 2017
VL 544
IS 7649
BP 196
EP +
DI 10.1038/nature21393
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ER6EK
UT WOS:000398897900030
PM 28241144
DA 2026-03-09
ER

PT J
AU Kelliher, T
   Starr, D
   Richbourg, L
   Chintamanani, S
   Delzer, B
   Nuccio, ML
   Green, J
   Chen, ZY
   McCuiston, J
   Wang, WL
   Liebler, T
   Bullock, P
   Martin, B
AF Kelliher, Timothy
   Starr, Dakota
   Richbourg, Lee
   Chintamanani, Satya
   Delzer, Brent
   Nuccio, Michael L.
   Green, Julie
   Chen, Zhongying
   McCuiston, Jamie
   Wang, Wenling
   Liebler, Tara
   Bullock, Paul
   Martin, Barry
TI MATRILINEAL, a sperm-specific phospholipase, triggers maize haploid induction
SO NATURE
LA English
DT Article
ID pollen-tube growth; in-vivo induction; maternal haploids; fertilization; elimination; a(2)
AB Sexual reproduction in flowering plants involves double fertilization, the union of two sperm from pollen with two sex cells in the female embryo sac. Modern plant breeders increasingly seek to circumvent this process to produce doubled haploid individuals, which derive from the chromosome-doubled cells of the haploid gametophyte. Doubled haploid production fixes recombinant haploid genomes in inbred lines, shaving years off the breeding process(1). Costly, genotype-dependent tissue culture methods are used in many crops(2), while seed-based in vivo doubled haploid systems are rare in nature(3) and difficult to manage in breeding programmes(4). The multi-billion-dollar maize hybrid seed business, however, is supported by industrial doubled haploid pipelines using intraspecific crosses to in vivo haploid inducer males derived from Stock 6, first reported in 1959 (ref. 5), followed by colchicine treatment. Despite decades of use, the mode of action remains controversial(6-10). Here we establish, through fine mapping, genome sequencing, genetic complementation, and gene editing, that haploid induction in maize (Zea mays) is triggered by a frame-shift mutation in MATRILINEAL (MTL), a pollen-specific phospholipase, and that novel edits in MTL lead to a 6.7% haploid induction rate (the percentage of haploid progeny versus total progeny). Wildtype MTL protein localizes exclusively to sperm cytoplasm, and pollen RNA-sequence profiling identifies a suite of pollen-specific genes overexpressed during haploid induction, some of which may mediate the formation of haploid seed(11-15). These findings highlight the importance of male gamete cytoplasmic components to reproductive success and male genome transmittance. Given the conservation of MTL in the cereals, this discovery may enable development of in vivo haploid induction systems to accelerate breeding in crop plants.
C1 [Kelliher, Timothy; Starr, Dakota; Richbourg, Lee; Nuccio, Michael L.; Green, Julie; Chen, Zhongying; McCuiston, Jamie; Wang, Wenling; Liebler, Tara; Martin, Barry] Syngenta Crop Protect, Seeds Res, 9 Davis Dr, Res Triangle Pk, NC 27709 USA.
   [Chintamanani, Satya; Bullock, Paul] Syngenta Seeds, 2369 330th St, Slater, IA 50244 USA.
   [Delzer, Brent] Syngenta Seeds, 4133 East Cty Rd O, Janesville, WI 53546 USA.
   [Martin, Barry] CiBO Technol, 155 2nd St, Cambridge, MA 02141 USA.
C3 Syngenta; Syngenta; Syngenta
RP Kelliher, T (corresponding author), Syngenta Crop Protect, Seeds Res, 9 Davis Dr, Res Triangle Pk, NC 27709 USA.
EM tim.kelliher@syngenta.com
NR 37
TC 329
Z9 409
U1 22
U2 353
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 2
PY 2017
VL 542
IS 7639
BP 105
EP +
DI 10.1038/nature20827
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6MY
UT WOS:000396119300040
PM 28114299
DA 2026-03-09
ER

PT J
AU Sungkaworn, T
   Jobin, ML
   Burnecki, K
   Weron, A
   Lohse, MJ
   Calebiro, D
AF Sungkaworn, Titiwat
   Jobin, Marie-Lise
   Burnecki, Krzysztof
   Weron, Aleksander
   Lohse, Martin J.
   Calebiro, Davide
TI Single-molecule imaging reveals receptor-G protein interactions at cell surface hot spots
SO NATURE
LA English
DT Article
ID coupled-receptors; activation; determines; dynamics; tracking; organization; complexes; efficacy
AB G-protein-coupled receptors mediate the biological effects of many hormones and neurotransmitters and are important pharmacological targets(1). They transmit their signals to the cell interior by interacting with G proteins. However, it is unclear how receptors and G proteins meet, interact and couple. Here we analyse the concerted motion of G-protein-coupled receptors and G proteins on the plasma membrane and provide a quantitative model that reveals the key factors that underlie the high spatiotemporal complexity of their interactions. Using two-colour, single-molecule imaging we visualize interactions between individual receptors and G proteins at the surface of living cells. Under basal conditions, receptors and G proteins form activity-dependent complexes that last for around one second. Agonists specifically regulate the kinetics of receptor-G protein interactions, mainly by increasing their association rate. We find hot spots on the plasma membrane, at least partially defined by the cytoskeleton and clathrin-coated pits, in which receptors and G proteins are confined and preferentially couple. Imaging with the nanobody Nb37 suggests that signalling by G-protein-coupled receptors occurs preferentially at these hot spots. These findings shed new light on the dynamic interactions that control G-protein-coupled receptor signalling.
C1 [Sungkaworn, Titiwat; Jobin, Marie-Lise; Lohse, Martin J.; Calebiro, Davide] Univ Wurzburg, Inst Pharmacol & Toxicol, Versbacher Str 9, D-97078 Wurzburg, Germany.
   [Sungkaworn, Titiwat; Jobin, Marie-Lise; Lohse, Martin J.; Calebiro, Davide] Univ Wurzburg, Rudolf Virchow Ctr, Bioimaging Ctr, Versbacher Str 9, D-97078 Wurzburg, Germany.
   [Burnecki, Krzysztof; Weron, Aleksander] Wroclaw Univ Sci & Technol, Hugo Steinhaus Ctr, Fac Pure & Appl Math, Wyspianskiego 27, PL-50370 Wroclaw, Poland.
   [Lohse, Martin J.] Max Delbruck Ctr Mol Med, Robert Rossle Str 10, D-13125 Berlin, Germany.
   [Calebiro, Davide] Univ Birmingham, Inst Metab & Syst Res, Birmingham B15 2TT, W Midlands, England.
   [Calebiro, Davide] Univ Birmingham, Ctr Membrane Prot & Receptors COMPARE, Birmingham B15 2TT, W Midlands, England.
   [Calebiro, Davide] Univ Nottingham, Ctr Membrane Prot & Receptors COMPARE, Birmingham B15 2TT, W Midlands, England.
C3 University of Wurzburg; University of Wurzburg; Wroclaw University of Science & Technology; Helmholtz Association; Max Delbruck Center for Molecular Medicine; University of Birmingham; University of Birmingham; University of Nottingham
RP Calebiro, D (corresponding author), Univ Wurzburg, Inst Pharmacol & Toxicol, Versbacher Str 9, D-97078 Wurzburg, Germany.; Calebiro, D (corresponding author), Univ Wurzburg, Rudolf Virchow Ctr, Bioimaging Ctr, Versbacher Str 9, D-97078 Wurzburg, Germany.; Calebiro, D (corresponding author), Univ Birmingham, Inst Metab & Syst Res, Birmingham B15 2TT, W Midlands, England.; Calebiro, D (corresponding author), Univ Birmingham, Ctr Membrane Prot & Receptors COMPARE, Birmingham B15 2TT, W Midlands, England.; Calebiro, D (corresponding author), Univ Nottingham, Ctr Membrane Prot & Receptors COMPARE, Birmingham B15 2TT, W Midlands, England.
EM davide.calebiro@toxi.uni-wuerzburg.de
FU Deutsche Forschungsgemeinschaft [Sonderforschungsbereich/Transregio 166, CA 1014/1-1, FZT82]; IZKF Wurzburg [B-281]; European Research Council [232944-TOPAS]; Polish National Science Center [2012/06/A/ST1/00258]; Alexander-von-Humboldt/Bayer Foundation
NR 38
TC 263
Z9 286
U1 2
U2 129
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 26
PY 2017
VL 550
IS 7677
BP 543
EP +
DI 10.1038/nature24264
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK7OW
UT WOS:000413697800048
PM 29045395
DA 2026-03-09
ER

PT J
AU Staring, J
   von Castelmur, E
   Blomen, VA
   van den Hengel, LG
   Brockmann, M
   Baggen, J
   Thibaut, HJ
   Nieuwenhuis, J
   Janssen, H
   van Kuppeveld, FJM
   Perrakis, A
   Carette, JE
   Brummelkamp, TR
AF Staring, Jacqueline
   von Castelmur, Eleonore
   Blomen, Vincent A.
   van den Hengel, Lisa G.
   Brockmann, Markus
   Baggen, Jim
   Thibaut, Hendrik Jan
   Nieuwenhuis, Joppe
   Janssen, Hans
   van Kuppeveld, Frank J. M.
   Perrakis, Anastassis
   Carette, Jan E.
   Brummelkamp, Thijn R.
TI PLA2G16 represents a switch between entry and clearance of Picornaviridae
SO NATURE
LA English
DT Article
ID lassa virus entry; phospholipase a(2); mammalian-cells; enterovirus 71; 2a proteins; receptor; infection; autophagy; requires; screens
AB Picornaviruses are a leading cause of human and veterinary infections that result in various diseases, including polio and the common cold. As archetypical non-enveloped viruses, their biology has been extensively studied(1). Although a range of different cell-surface receptors are bound by different picornaviruses(2-7), it is unclear whether common host factors are needed for them to reach the cytoplasm. Using genome-wide haploid genetic screens, here we identify the lipid-modifying enzyme PLA2G16 (refs 8-11) as a picornavirus host factor that is required for a previously unknown event in the viral life cycle. We find that PLA2G16 functions early during infection, enabling virion-mediated genome delivery into the cytoplasm, but not in any virion-assigned step, such as cell binding, endosomal trafficking or pore formation. To resolve this paradox, we screened for suppressors of the Delta PLA2G16 phenotype and identified a mechanism previously implicated in the clearance of intracellular bacteria(12). The sensor of this mechanism, galectin-8 (encoded by LGALS8), detects permeated endosomes and marks them for autophagic degradation, whereas PLA2G16 facilitates viral genome translocation and prevents clearance. This study uncovers two competing processes triggered by virus entry: activation of a pore-activated clearance pathway and recruitment of a phospholipase to enable genome release.
C1 [Staring, Jacqueline; von Castelmur, Eleonore; Blomen, Vincent A.; van den Hengel, Lisa G.; Brockmann, Markus; Nieuwenhuis, Joppe; Janssen, Hans; Perrakis, Anastassis; Brummelkamp, Thijn R.] Netherlands Canc Inst, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands.
   [Baggen, Jim; Thibaut, Hendrik Jan; van Kuppeveld, Frank J. M.] Univ Utrecht, Fac Vet Med, Dept Infect Dis & Immunol, Div Virol, Yalelaan 1, NL-3584 CL Utrecht, Netherlands.
   [Carette, Jan E.] Stanford Univ, Sch Med, Dept Immunol & Microbiol, 299 Campus Dr, Stanford, CA 94305 USA.
   [Brummelkamp, Thijn R.] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria.
   [Brummelkamp, Thijn R.] CGC Nl, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands.
C3 Netherlands Cancer Institute; Utrecht University; Stanford University; Austrian Academy of Sciences; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
RP Brummelkamp, TR (corresponding author), Netherlands Canc Inst, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands.; Brummelkamp, TR (corresponding author), Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria.; Brummelkamp, TR (corresponding author), CGC Nl, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands.
EM t.brummelkamp@nki.nl
FU SNSF Fellowship [PA00P3_145411]; Cancer Genomics Center (CGC.nl); Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)-VIDI grant [91711316]; European Research Council (ERC) [ERC-2012-StG 309634]; NWO-VICI grant [91812628]; Swiss National Science Foundation (SNF) [PA00P3_145411] Funding Source: Swiss National Science Foundation (SNF)
NR 38
TC 164
Z9 182
U1 0
U2 42
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 19
PY 2017
VL 541
IS 7637
BP 412
EP +
DI 10.1038/nature21032
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6QP
UT WOS:000396128800046
PM 28077878
DA 2026-03-09
ER

PT J
AU Pollock, LJ
   Thuiller, W
   Jetz, W
AF Pollock, Laura J.
   Thuiller, Wilfried
   Jetz, Walter
TI Large conservation gains possible for global biodiversity facets
SO NATURE
LA English
DT Article
ID diversity-area relationships; phylogenetic diversity; species richness; functional diversity; extinction risk; selection; predictors; priority; endemism; hotspots
AB Different facets of biodiversity other than species numbers are increasingly appreciated as critical for maintaining the function of ecosystems and their services to humans(1,2). While new international policy and assessment processes such as the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) recognize the importance of an increasingly global, quantitative and comprehensive approach to biodiversity protection, most insights are still focused on a single facet of biodiversity-species(3). Here we broaden the focus and provide an evaluation of how much of the world's species, functional and phylogenetic diversity of birds and mammals is currently protected and the scope for improvement. We show that the large existing gaps in the coverage for each facet of diversity could be remedied by a slight expansion of protected areas: an additional 5% of the land has the potential to more than triple the protected range of species or phylogenetic or functional units. Further, the same areas are often priorities for multiple diversity facets and for both taxa. However, we find that the choice of conservation strategy has a fundamental effect on outcomes. It is more difficult (that is, requires more land) to maximize basic representation of the global biodiversity pool than to maximize local diversity. Overall, species and phylogenetic priorities are more similar to each other than they are to functional priorities, and priorities for the different bird biodiversity facets are more similar than those of mammals. Our work shows that large gains in biodiversity protection are possible, while also highlighting the need to explicitly link desired conservation objectives and biodiversity metrics. We provide a framework and quantitative tools to advance these goals for multi-faceted biodiversity conservation.
C1 [Pollock, Laura J.; Thuiller, Wilfried] Univ Grenoble Alpes, CNRS, LECA, Lab Ecol Alpine, F-38000 Grenoble, France.
   [Jetz, Walter] Yale Univ, Ecol & Evolutionary Biol, 165 Prospect St, New Haven, CT 06511 USA.
   [Jetz, Walter] Dept Life Sci, Imperial Coll London, Silwood Pk, Ascot SL5 7PY, Berks, England.
C3 Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Centre National de la Recherche Scientifique (CNRS); Universite Savoie Mont Blanc; Yale University; Imperial College London
RP Pollock, LJ (corresponding author), Univ Grenoble Alpes, CNRS, LECA, Lab Ecol Alpine, F-38000 Grenoble, France.
EM laura.pollock@univ-grenoble-alpes.fr
FU European Union [659422]; European Research Council [ERC-2011-StG-281422-TEEMBIO]; NSF [DEB 1441737, DBI 1262600, DEB 1558568]; NASA [NNX11AP72G]; Yale Center for Biodiversity and Global Change; Marie Curie Actions (MSCA) [659422] Funding Source: Marie Curie Actions (MSCA); Direct For Biological Sciences; Division Of Environmental Biology [1441737] Funding Source: National Science Foundation; Div Of Biological Infrastructure; Direct For Biological Sciences [1262600] Funding Source: National Science Foundation
NR 45
TC 229
Z9 254
U1 4
U2 179
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 1
PY 2017
VL 546
IS 7656
BP 141
EP +
DI 10.1038/nature22368
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW3CR
UT WOS:000402372800044
PM 28538726
DA 2026-03-09
ER

PT J
AU Stegen, G
   Pasmans, F
   Schmidt, BR
   Rouffaer, LO
   Van Praet, S
   Schaub, M
   Canessa, S
   Laudelout, A
   Kinet, T
   Adriaensen, C
   Haesebrouck, F
   Bert, W
   Bossuyt, F
   Martel, A
AF Stegen, Gwij
   Pasmans, Frank
   Schmidt, Benedikt R.
   Rouffaer, Lieze O.
   Van Praet, Sarah
   Schaub, Michael
   Canessa, Stefano
   Laudelout, Arnaud
   Kinet, Thierry
   Adriaensen, Connie
   Haesebrouck, Freddy
   Bert, Wim
   Bossuyt, Franky
   Martel, An
TI Drivers of salamander extirpation mediated by Batrachochytrium salamandrivorans
SO NATURE
LA English
DT Article
ID infection dynamics; amphibians; decline
AB The recent arrival of Batrachochytrium salamandrivorans in Europe was followed by rapid expansion of its geographical distribution and host range, confirming the unprecedented threat that this chytrid fungus poses to western Palaearctic amphibians(1,2). Mitigating this hazard requires a thorough understanding of the pathogen's disease ecology that is driving the extinction process. Here, we monitored infection, disease and host population dynamics in a Belgian fire salamander (Salamandra salamandra) population for two years immediately after the first signs of infection. We show that arrival of this chytrid is associated with rapid population collapse without any sign of recovery, largely due to lack of increased resistance in the surviving salamanders and a demographic shift that prevents compensation for mortality. The pathogen adopts a dual transmission strategy, with environmentally resistant non-motile spores in addition to the motile spores identified in its sister species B. dendrobatidis. The fungus retains its virulence not only in water and soil, but also in anurans and less susceptible urodelan species that function as infection reservoirs. The combined characteristics of the disease ecology suggest that further expansion of this fungus will behave as a ` perfect storm' that is able to rapidly extirpate highly susceptible salamander populations across Europe.
C1 [Stegen, Gwij; Pasmans, Frank; Rouffaer, Lieze O.; Van Praet, Sarah; Canessa, Stefano; Adriaensen, Connie; Haesebrouck, Freddy; Martel, An] Univ Ghent, Dept Pathol Bacteriol & Avian Dis, Fac Vet Med, Salisburylaan 133, B-9820 Merelbeke, Belgium.
   [Schmidt, Benedikt R.] Univ Zurich, Dept Evolutionary Biol & Environm Studies, Winterthurerstr 190, CH-8057 Zurich, Switzerland.
   [Schmidt, Benedikt R.] KARCH, Passage Maximilien de Meuron 6, CH-2000 Neuchatel, Switzerland.
   [Schaub, Michael] Swiss Ornithol Inst, Seerose 1, CH-6204 Sempach, Switzerland.
   [Laudelout, Arnaud; Kinet, Thierry] Mundo Namur, Natagora, Rue Nanon 98, B-5000 Namur, Belgium.
   [Bert, Wim] Univ Ghent, Dept Biol, Nematol Res Unit, KL Ledeganckstr 35, B-9000 Ghent, Belgium.
   [Bossuyt, Franky] Vrije Univ Brussel, Dept Biol, Amphibian Evolut Lab, Pl Laan 2, B-1050 Brussels, Belgium.
C3 Ghent University; University of Zurich; Swiss Ornithological Institute; Ghent University; Vrije Universiteit Brussel
RP Martel, A (corresponding author), Univ Ghent, Dept Pathol Bacteriol & Avian Dis, Fac Vet Med, Salisburylaan 133, B-9820 Merelbeke, Belgium.
EM An.Martel@ugent.be
FU Ghent University [GOA 01G02416, BOF01J030313]; Research Foundation Flanders (FWO) [G007016N, FWO16/PDO/019, FWO12/ASP/210]
NR 28
TC 218
Z9 266
U1 4
U2 166
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 20
PY 2017
VL 544
IS 7650
BP 353
EP +
DI 10.1038/nature22059
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ES4SG
UT WOS:000399524400037
PM 28425998
DA 2026-03-09
ER

PT J
AU Barbieri, I
   Tzelepis, K
   Pandolfini, L
   Shi, JW
   Millán-Zambrano, G
   Robson, SC
   Aspris, D
   Migliori, V
   Bannister, AJ
   Han, N
   De Braekeleer, E
   Ponstingl, H
   Hendrick, A
   Vakoc, CR
   Vassiliou, GS
   Kouzarides, T
AF Barbieri, Isaia
   Tzelepis, Konstantinos
   Pandolfini, Luca
   Shi, Junwei
   Millan-Zambrano, Gonzalo
   Robson, Samuel C.
   Aspris, Demetrios
   Migliori, Valentina
   Bannister, Andrew J.
   Han, Namshik
   De Braekeleer, Etienne
   Ponstingl, Hannes
   Hendrick, Alan
   Vakoc, Christopher R.
   Vassiliou, George S.
   Kouzarides, Tony
TI Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control
SO NATURE
LA English
DT Article
ID messenger-rna translation; transcription factors; n-6-methyladenosine; binding; methylation; inhibition; elements; targets; murine; atlas
AB N-6-methyladenosine (m(6)A) is an abundant internal RNA modification in both coding(1) and non-coding RNAs2,3 that is catalysed by the METTL3-METTL14 methyltransferase complex4. However, the specific role of these enzymes in cancer is still largely unknown. Here we define a pathway that is specific for METTL3 and is implicated in the maintenance of a leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia cells in two distinct genetic screens. Downregulation of METTL3 results in cell cycle arrest, differentiation of leukaemic cells and failure to establish leukaemia in immunodeficient mice. We show that METTL3, independently of METTL14, associates with chromatin and localizes to the transcriptional start sites of active genes. The vast majority of these genes have the CAATT-box binding protein CEBPZ present at the transcriptional start site(5), and this is required for recruitment of METTL3 to chromatin. Promoterbound METTL3 induces m(6)A modification within the coding region of the associated mRNA transcript, and enhances its translation by relieving ribosome stalling. We show that genes regulated by METTL3 in this way are necessary for acute myeloid leukaemia. Together, these data define METTL3 as a regulator of a chromatinbased pathway that is necessary for maintenance of the leukaemic state and identify this enzyme as a potential therapeutic target for acute myeloid leukaemia.
C1 [Barbieri, Isaia; Pandolfini, Luca; Millan-Zambrano, Gonzalo; Robson, Samuel C.; Migliori, Valentina; Bannister, Andrew J.; Han, Namshik; Kouzarides, Tony] Univ Cambridge, Gurdon Inst, Tennis Court Rd, Cambridge CB2 1QN, England.
   [Barbieri, Isaia; Pandolfini, Luca; Millan-Zambrano, Gonzalo; Robson, Samuel C.; Migliori, Valentina; Bannister, Andrew J.; Han, Namshik; Kouzarides, Tony] Univ Cambridge, Dept Pathol, Tennis Court Rd, Cambridge CB2 1QN, England.
   [Tzelepis, Konstantinos; Aspris, Demetrios; De Braekeleer, Etienne; Ponstingl, Hannes; Vassiliou, George S.] Wellcome Trust Sanger Inst, Haematol Canc Genet, Cambridge CB10 1SA, England.
   [Shi, Junwei; Vakoc, Christopher R.] Cold Spring Harbor Lab, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA.
   [Hendrick, Alan] Storm Therapeut Ltd, Moneta Bldg B280,Babraham Res Campus, Cambridge CB22 3AT, England.
   [Vassiliou, George S.] Univ Cambridge, Wellcome Trust MRC Cambridge Stem Cell Inst, Cambridge CB2 0XY, England.
   [Vassiliou, George S.] Cambridge Univ Hosp NHS Trust, Dept Haematol, Cambridge CB2 0QQ, England.
   [Shi, Junwei] Univ Penn, Perelman Sch Med, Abramson Family Canc Res Inst, Dept Canc Biol, 421 Curie Blvd, Philadelphia, PA 19104 USA.
   [Robson, Samuel C.] Univ Portsmouth, Sch Pharm & Biomed Sci, St Michaels Bldg,White Swan Rd, Portsmouth, Hants, England.
C3 University of Cambridge; University of Cambridge; Wellcome Trust Sanger Institute; Cold Spring Harbor Laboratory; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); Babraham Institute; University of Cambridge; University of Pennsylvania; University of Portsmouth
RP Kouzarides, T (corresponding author), Univ Cambridge, Gurdon Inst, Tennis Court Rd, Cambridge CB2 1QN, England.; Kouzarides, T (corresponding author), Univ Cambridge, Dept Pathol, Tennis Court Rd, Cambridge CB2 1QN, England.; Vassiliou, GS (corresponding author), Wellcome Trust Sanger Inst, Haematol Canc Genet, Cambridge CB10 1SA, England.; Vassiliou, GS (corresponding author), Univ Cambridge, Wellcome Trust MRC Cambridge Stem Cell Inst, Cambridge CB2 0XY, England.; Vassiliou, GS (corresponding author), Cambridge Univ Hosp NHS Trust, Dept Haematol, Cambridge CB2 0QQ, England.
EM gsv20@sanger.ac.uk; t.kouzarides@gurdon.cam.ac.uk
FU Cancer Research UK [RG17001, C6946/A14492]; ERC [268569]; Wellcome Trust [092096]; Kay Kendall Leukaemia Fund project grant [RG88664]; EMBO fellowship [ALTF907-2014]; Wellcome Trust Senior Fellowship in Clinical Science [WT095663MA]; Cancer Research UK Senior Cancer Research Fellowship [C22324/A23015]; Kay Kendall Leukemia Fund; Bloodwise; Sanger Institute [WT098051]; Northwell Health; Cancer Research UK [17001, 23015] Funding Source: researchfish; Cancer Research UK; The Francis Crick Institute [10827] Funding Source: researchfish; Medical Research Council [MC_PC_12009] Funding Source: researchfish; European Research Council (ERC) [268569] Funding Source: European Research Council (ERC)
NR 52
TC 916
Z9 1021
U1 6
U2 231
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 7
PY 2017
VL 552
IS 7683
BP 126
EP +
DI 10.1038/nature24678
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FP4BA
UT WOS:000417560500056
PM 29186125
DA 2026-03-09
ER

PT J
AU Kikuchi, T
   Morizane, A
   Doi, D
   Magotani, H
   Onoe, H
   Hayashi, T
   Mizuma, H
   Takara, S
   Takahashi, R
   Inoue, H
   Morita, S
   Yamamoto, M
   Okita, K
   Nakagawa, M
   Parmar, M
   Takahashi, J
AF Kikuchi, Tetsuhiro
   Morizane, Asuka
   Doi, Daisuke
   Magotani, Hiroaki
   Onoe, Hirotaka
   Hayashi, Takuya
   Mizuma, Hiroshi
   Takara, Sayuki
   Takahashi, Ryosuke
   Inoue, Haruhisa
   Morita, Satoshi
   Yamamoto, Michio
   Okita, Keisuke
   Nakagawa, Masato
   Parmar, Malin
   Takahashi, Jun
TI Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model
SO NATURE
LA English
DT Article
ID pluripotent stem-cells; neural progenitors; macaque monkey; brain images; human es; transplantation; expression; robust; blood; pet
AB Induced pluripotent stem cells (iPS cells) are a promising source for a cell-based therapy to treat Parkinson's disease (PD), in which midbrain dopaminergic neurons progressively degenerate(1,2). However, long-term analysis of human iPS cell-derived dopaminergic neurons in primate PD models has never been performed to our knowledge. Here we show that human iPS cell-derived dopaminergic progenitor cells survived and functioned as midbrain dopaminergic neurons in a primate model of PD (Macaca fascicularis) treated with the neurotoxin MPTP. Score-based and video-recording analyses revealed an increase in spontaneous movement of the monkeys after transplantation. Histological studies showed that the mature dopaminergic neurons extended dense neurites into the host striatum; this effect was consistent regardless of whether the cells were derived from patients with PD or from healthy individuals. Cells sorted by the floor plate marker CORIN did not form any tumours in the brains for at least two years. Finally, magnetic resonance imaging and positron emission tomography were used to monitor the survival, expansion and function of the grafted cells as well as the immune response in the host brain. Thus, this preclinical study using a primate model indicates that human iPS cell-derived dopaminergic progenitors are clinically applicable for the treatment of patients with PD.
C1 [Kikuchi, Tetsuhiro; Morizane, Asuka; Doi, Daisuke; Magotani, Hiroaki; Takahashi, Jun] Kyoto Univ, Dept Clin Applicat, Ctr IPS Cell Res & Applicat, Kyoto 6068507, Japan.
   [Onoe, Hirotaka; Hayashi, Takuya; Mizuma, Hiroshi; Takara, Sayuki] RIKEN Ctr Life Sci Technol, Div Biofunct Dynam Imaging, Kobe, Hyogo 6500047, Japan.
   [Takahashi, Ryosuke] Kyoto Univ, Dept Neurol, Grad Sch Med, Kyoto 6068507, Japan.
   [Inoue, Haruhisa] Kyoto Univ, Ctr IPS Cell Res & Applicat, Dept Cell Growth & Differentiat, Kyoto 6068507, Japan.
   [Morita, Satoshi; Yamamoto, Michio] Kyoto Univ, Dept Biomed Stat & Bioinformat, Grad Sch Med, Kyoto 6068507, Japan.
   [Okita, Keisuke; Nakagawa, Masato] Kyoto Univ, Dept Life Sci Frontiers, Ctr IPS Cell Res & Applicat, Kyoto 6068507, Japan.
   [Parmar, Malin] Lund Univ, Wallenberg Neurosci Ctr, S-22184 Lund, Sweden.
   [Parmar, Malin] Lund Univ, Lund Stem Cell Ctr, S-22184 Lund, Sweden.
   [Takahashi, Jun] Kyoto Univ, Grad Sch Med, Clin Neurosci, Dept Neurosurg, Kyoto 6068507, Japan.
C3 Kyoto University; RIKEN; Kyoto University; Kyoto University; Kyoto University; Kyoto University; Lund University; Lund University; Kyoto University
RP Takahashi, J (corresponding author), Kyoto Univ, Dept Clin Applicat, Ctr IPS Cell Res & Applicat, Kyoto 6068507, Japan.; Takahashi, J (corresponding author), Kyoto Univ, Grad Sch Med, Clin Neurosci, Dept Neurosurg, Kyoto 6068507, Japan.
EM jbtaka@cira.kyoto-u.ac.jp
FU Highway Project for Realization of Regenerative Medicine from the Ministry of Education, Culture, Sports, Science and Technology (MEXT); Network Program for Realization of Regenerative Medicine from the Japan Agency for Medical Research and Development (AMED); Program for Intractable Diseases Research using disease-specific iPS cells from AMED; Grants-in-Aid for Scientific Research [16H03300, 17H05698, 16H03306, 15H02502, 15H02540, 15K12779] Funding Source: KAKEN
NR 46
TC 512
Z9 624
U1 7
U2 352
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 31
PY 2017
VL 548
IS 7669
BP 592
EP +
DI 10.1038/nature23664
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FF2BO
UT WOS:000408703100040
PM 28858313
DA 2026-03-09
ER

PT J
AU Dang, SY
   Feng, SJ
   Tien, J
   Peters, CJ
   Bulkley, D
   Lolicato, M
   Zhao, JH
   Zuberbuhler, K
   Ye, WL
   Qi, LJ
   Chen, TX
   Craik, CS
   Jan, YN
   Minor, DL
   Cheng, YF
   Jan, LY
AF Dang, Shangyu
   Feng, Shengjie
   Tien, Jason
   Peters, Christian J.
   Bulkley, David
   Lolicato, Marco
   Zhao, Jianhua
   Zuberbuhler, Kathrin
   Ye, Wenlei
   Qi, Lijun
   Chen, Tingxu
   Craik, Charles S.
   Jan, Yuh Nung
   Minor, Daniel L., Jr.
   Cheng, Yifan
   Jan, Lily Yeh
TI Cryo-EM structures of the TMEM16A calcium-activated chloride channel
SO NATURE
LA English
DT Article
ID independent activation; electron-microscopy; membrane-proteins; visualization; validation; expression; pores; model
AB Calcium-activated chloride channels (CaCCs) encoded by TMEM16A(1-3) control neuronal signalling, smooth muscle contraction, airway and exocrine gland secretion, and rhythmic movements of the gastrointestinal system(4-7). To understand how CaCCs mediate and control anion permeation to fulfil these physiological functions, knowledge of the mammalian TMEM16A structure and identification of its pore-lining residues are essential. TMEM16A forms a dimer with two pores(8,9). Previous CaCC structural analyses have relied on homology modelling of a homologue (nhTMEM16) from the fungus Nectria haematococca that functions primarily as a lipid scramblase(10-12), as well as subnanometre-resolution electron cryo-microscopy(12). Here we present de novo atomic structures of the transmembrane domains of mouse TMEM16A in nanodiscs and in lauryl maltose neopentyl glycol as determined by single-particle electron cryo-microscopy. These structures reveal the ion permeation pore and represent different functional states. The structure in lauryl maltose neopentyl glycol has one Ca2+ ion resolved within each monomer with a constricted pore; this is likely to correspond to a closed state, because a CaCC with a single Ca2+ occupancy requires membrane depolarization in order to open (C.J.P.etal., manuscript submitted). The structure in nanodiscs has two Ca2+ ions per monomer and its pore is in a closed conformation; this probably reflects channel rundown, which is the gradual loss of channel activity that follows prolonged CaCC activation in 1 mM Ca2+. Our mutagenesis and electrophysiological studies, prompted by analyses of the structures, identified ten residues distributed along the pore that interact with permeant anions and affect anion selectivity, as well as seven porelining residues that cluster near pore constrictions and regulate channel gating. Together, these results clarify the basis of CaCC anion conduction.
C1 [Dang, Shangyu; Bulkley, David; Zhao, Jianhua; Jan, Yuh Nung; Minor, Daniel L., Jr.; Cheng, Yifan; Jan, Lily Yeh] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA.
   [Feng, Shengjie; Tien, Jason; Peters, Christian J.; Ye, Wenlei; Qi, Lijun; Chen, Tingxu; Jan, Yuh Nung; Jan, Lily Yeh] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA.
   [Lolicato, Marco; Minor, Daniel L., Jr.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA.
   [Zuberbuhler, Kathrin; Craik, Charles S.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA.
   [Jan, Yuh Nung; Cheng, Yifan; Jan, Lily Yeh] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA.
   [Minor, Daniel L., Jr.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA.
   [Minor, Daniel L., Jr.] Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA.
C3 University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Howard Hughes Medical Institute; University of California System; University of California San Francisco; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory
RP Cheng, YF; Jan, LY (corresponding author), Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA.; Jan, LY (corresponding author), Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA.; Cheng, YF; Jan, LY (corresponding author), Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA.
EM ycheng@ucsf.edu; Lily.Jan@ucsf.edu
FU NIH [R01GM098672, S100D0020054, R01NS069229, R35NS097227, R01HL080050, R01DC007664, P41CA196276, P50GM111126, K99DA041500]; American Heart Association; UCSF Breakthrough Biomedical Research; Human Frontier Science Program (HFSP) Postdoctoral Fellowship; Canadian Institute of Health Research; National Heart Lung and Blood Institute [R01HL080050] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [R35NS097227] Funding Source: NIH RePORTER; National Institute on Deafness and Other Communication Disorders [R01DC007664] Funding Source: NIH RePORTER
NR 52
TC 254
Z9 300
U1 0
U2 104
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 21
PY 2017
VL 552
IS 7685
BP 426
EP +
DI 10.1038/nature25024
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ7RI
UT WOS:000418559800063
PM 29236684
DA 2026-03-09
ER

PT J
AU Han, S
   Schroeder, EA
   Silva-García, CG
   Hebestreit, K
   Mair, WB
   Brunet, A
AF Han, Shuo
   Schroeder, Elizabeth A.
   Silva-Garica, Carlos G.
   Hebestreit, Katja
   Mair, William B.
   Brunet, Anne
TI Mono-unsaturated fatty acids link H3K4me3 modifiers to C. elegans lifespan
SO NATURE
LA English
DT Article
ID cardiovascular-disease; subunit; gene; rna; identification; desaturase; metabolism; mechanisms; expression; longevity
AB Chromatin and metabolic states both influence lifespan, but how they interact in lifespan regulation is largely unknown. The COMPASS chromatin complex, which trimethylates lysine 4 on histone H3 (H3K4me3), regulates lifespan in Caenorhabditis elegans. However, the mechanism by which H3K4me3 modifiers affect longevity, and whether this mechanism involves metabolic changes, remain unclear. Here we show that a deficiency in H3K4me3 methyltransferase, which extends lifespan, promotes fat accumulation in worms with a specific enrichment of mono-unsaturated fatty acids (MUFAs). This fat metabolism switch in H3K4me3 methyltransferase-deficient worms is mediated at least in part by the downregulation of germline targets, including S6 kinase, and by the activation of an intestinal transcriptional network that upregulates delta-9 fatty acid desaturases. Notably, the accumulation of MUFAs is necessary for the lifespan extension of H3K4me3 methyltransferase-deficient worms, and dietary MUFAs are sufficient to extend lifespan. Given the conservation of lipid metabolism, dietary or endogenous MUFAs could extend lifespan and healthspan in other species, including mammals.
C1 [Han, Shuo; Schroeder, Elizabeth A.; Hebestreit, Katja; Brunet, Anne] Stanford Univ, Dept Genet, 300 Pasteur Dr, Stanford, CA 94305 USA.
   [Han, Shuo] Stanford Univ, Grad Program Genet, 300 Pasteur Dr, Stanford, CA 94305 USA.
   [Silva-Garica, Carlos G.; Mair, William B.] Harvard TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA.
   [Brunet, Anne] Stanford Univ, Glenn Labs Biol Aging, Stanford, CA 94305 USA.
C3 Stanford University; Stanford Medicine; Stanford University; Stanford Medicine; Harvard University; Harvard T.H. Chan School of Public Health; Stanford University
RP Brunet, A (corresponding author), Stanford Univ, Dept Genet, 300 Pasteur Dr, Stanford, CA 94305 USA.; Brunet, A (corresponding author), Stanford Univ, Glenn Labs Biol Aging, Stanford, CA 94305 USA.
EM anne.brunet@stanford.edu
FU NIH [DP1AG044848, R01AG054201, R01AG044346, T32AG047126, F32AG051337]; Stanford Mass Spectrometry grant; NSF; Stanford Graduate Fellowship; National Institute on Aging [T32AG047126, R01AG044346] Funding Source: NIH RePORTER
NR 40
TC 243
Z9 281
U1 5
U2 133
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 13
PY 2017
VL 544
IS 7649
BP 185
EP +
DI 10.1038/nature21686
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ER6EK
UT WOS:000398897900028
PM 28379943
DA 2026-03-09
ER

PT J
AU Westaway, KE
   Louys, J
   Awe, RD
   Morwood, MJ
   Price, GJ
   Zhao, JX
   Aubert, M
   Joannes-Boyau, R
   Smith, TM
   Skinner, MM
   Compton, T
   Bailey, RM
   van den Bergh, GD
   de Vos, J
   Pike, AWG
   Stringer, C
   Saptomo, EW
   Rizal, Y
   Zaim, J
   Santoso, WD
   Trihascaryo, A
   Kinsley, L
   Sulistyanto, B
AF Westaway, K. E.
   Louys, J.
   Awe, R. Due
   Morwood, M. J.
   Price, G. J.
   Zhao, J. -X.
   Aubert, M.
   Joannes-Boyau, R.
   Smith, T. M.
   Skinner, M. M.
   Compton, T.
   Bailey, R. M.
   van den Bergh, G. D.
   de Vos, J.
   Pike, A. W. G. .
   Stringer, C.
   Saptomo, E. W.
   Rizal, Y.
   Zaim, J.
   Santoso, W. D.
   Trihascaryo, A.
   Kinsley, L.
   Sulistyanto, B.
TI An early modern human presence in Sumatra 73,000-63,000 years ago
SO NATURE
LA English
DT Article
ID regenerative-dose protocol; u-series; enamel thickness; tooth enamel; single-aliquot; homo-sapiens; lower molars; quartz; luminescence; indonesia
AB Genetic evidence for anatomically modern humans (AMH) out of Africa before 75 thousand years ago (ka)(1) and in island southeast Asia (ISEA) before 60 ka (93-61 ka)(2) predates accepted archaeological records of occupation in the region(3). Claims that AMH arrived in ISEA before 60 ka (ref. 4) have been supported only by equivocal(5) or non-skeletal evidence(6). AMH evidence from this period is rare and lacks robust chronologies owing to a lack of direct dating applications(7), poor preservation and/or excavation strategies(8) and questionable taxonomic identifications(9). Lida Ajer is a Sumatran Pleistocene cave with a rich rainforest fauna associated with fossil human teeth(7,10). The importance of the site is unclear owing to unsupported taxonomic identification of these fossils and uncertainties regarding the age of the deposit, therefore it is rarely considered in models of human dispersal. Here we reinvestigate Lida Ajer to identify the teeth confidently and establish a robust chronology using an integrated dating approach. Using enamel-dentine junction morphology, enamel thickness and comparative morphology, we show that the teeth are unequivocally AMH. Luminescence and uranium-series techniques applied to bone-bearing sediments and speleothems, and coupled uranium-series and electron spin resonance dating of mammalian teeth, place modern humans in Sumatra between 73 and 63 ka. This age is consistent with biostratigraphic estimations(7), palaeoclimate and sea-level reconstructions, and genetic evidence for a pre-60 ka arrival of AMH into ISEA(2). Lida Ajer represents, to our knowledge, the earliest evidence of rainforest occupation by AMH, and underscores the importance of reassessing the timing and environmental context of the dispersal of modern humans out of Africa.
C1 [Westaway, K. E.] Macquarie Univ, Dept Environm Sci, Fac Sci & Engn, Sydney, NSW 2109, Australia.
   [Louys, J.] Australian Natl Univ, Sch Culture Hist & Languages, ANU Coll Asia & Pacific, Canberra, ACT, Australia.
   [Awe, R. Due; Saptomo, E. W.; Sulistyanto, B.] Indonesian Ctr Archaeol, Jl Raya Condet Pejaten 4, Jakarta 12001, Indonesia.
   [Morwood, M. J.; van den Bergh, G. D.] Univ Wollongong, Sch Earth & Environm Sci, Ctr Archaeol Sci, Wollongong, NSW 2522, Australia.
   [Price, G. J.; Zhao, J. -X.] Univ Queensland, Sch Earth & Environm Sci, Brisbane, Qld 4072, Australia.
   [Aubert, M.] Griffith Univ, PERAHU, Gold Coast, Australia.
   [Joannes-Boyau, R.] Southern Cross Univ, Southern Cross GeoSci, Mil Rd, Lismore, NSW 2480, Australia.
   [Smith, T. M.] Griffith Univ, Australian Res Ctr Human Evolut, Environm Futures Res Inst, 170 Kessels Rd, Nathan, Qld 4111, Australia.
   [Smith, T. M.] Harvard Univ, Dept Human Evolutionary Biol, 11 Divinity Ave, Cambridge, MA 02138 USA.
   [Skinner, M. M.] Univ Kent, Sch Anthropol & Conservat, Canterbury CT2 7NR, Kent, England.
   [Skinner, M. M.] Max Planck Inst Evolutionary Anthropol, Dept Human Evolut, Deutsch Pl 6, D-04103 Leipzig, Germany.
   [Compton, T.] Nat Hist Museum, Dept Earth Sci, Cromwell Rd, London SW7 5BD, England.
   [Bailey, R. M.] Univ Oxford, Sch Geog & Environm, Oxford OX1 2JD, England.
   [de Vos, J.] Nat Biodivers Ctr, Dept Geol, Leiden, Netherlands.
   [Pike, A. W. G. .] Univ Southampton, Dept Archaeol, Highfield Rd, Southampton SO17 1BF, Hants, England.
   [Rizal, Y.; Zaim, J.; Santoso, W. D.; Trihascaryo, A.] Inst Teknologi Bandung, Geol Study Program, Java, Indonesia.
   [Trihascaryo, A.] Australian Natl Univ, Sch Earth Sci, Canberra, ACT, Australia.
C3 Macquarie University; Australian National University; University of Wollongong; University of Queensland; Griffith University; Southern Cross University; Griffith University; Harvard University; University of Kent; Max Planck Society; Natural History Museum London; University of Oxford; Naturalis Biodiversity Center; University of Southampton; Institute Technology of Bandung; Australian National University
RP Westaway, KE (corresponding author), Macquarie Univ, Dept Environm Sci, Fac Sci & Engn, Sydney, NSW 2109, Australia.
EM kira.westaway@mq.edu.au
FU Australian Research Council [DP1093049, DP140100919, DP120101752]; Leaky Foundation grant; Research School of Asia; Human Origins Research Fund; Calleva Foundation; Max Planck Society; Pacific Grant Development Support grant; Australian Research Council [DP1093049] Funding Source: Australian Research Council
NR 73
TC 195
Z9 219
U1 1
U2 96
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 17
PY 2017
VL 548
IS 7667
BP 322
EP +
DI 10.1038/nature23452
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD8AU
UT WOS:000407748400030
PM 28792933
DA 2026-03-09
ER

PT J
AU Richter, D
   Grün, R
   Joannes-Boyau, R
   Steele, TE
   Amani, F
   Rué, M
   Fernandes, P
   Raynal, JP
   Geraads, D
   Ben-Ncer, A
   Hublin, JJ
   McPherron, SP
AF Richter, Daniel
   Grun, Rainer
   Joannes-Boyau, Renaud
   Steele, Teresa E. .
   Amani, Fethi
   Rue, Mathieu
   Fernandes, Paul
   Raynal, Jean-Paul
   Geraads, Denis
   Ben-Ncer, Abdelouahed
   Hublin, Jean-Jacques
   McPherron, Shannon P.
TI The age of the hominin fossils from Jebel Irhoud, Morocco, and the origins of the Middle Stone Age
SO NATURE
LA English
DT Article
ID u-series disequilibrium; early homo-sapiens; burnt flints; paleolithic site; tooth enamel; esr/u-series; tabun cave; omo i; luminescence; israel
AB The timing and location of the emergence of our species and of associated behavioural changes are crucial for our understanding of human evolution. The earliest fossil attributed to a modern form of Homo sapiens comes from eastern Africa and is approximately 195 thousand years old(1,2), therefore the emergence of modern human biology is commonly placed at around 200 thousand years ago(3,4). The earliest Middle Stone Age assemblages come from eastern and southern Africa but date much earlier(5-7). Here we report the ages, determined by thermoluminescence dating, of fire-heated flint artefacts obtained from new excavations at the Middle Stone Age site of Jebel Irhoud, Morocco, which are directly associated with newly discovered remains of H. sapiens(8). A weighted average age places these Middle Stone Age artefacts and fossils at 315 +/- 34 thousand years ago. Support is obtained through the recalculated uranium series with electron spin resonance date of 286 +/- 32 thousand years ago for a tooth from the Irhoud 3 hominin mandible. These ages are also consistent with the faunal and microfaunal(9) assemblages and almost double the previous age estimates for the lower part of the deposits(10,11). The north African site of Jebel Irhoud contains one of the earliest directly dated Middle Stone Age assemblages, and its associated human remains are the oldest reported for H. sapiens. The emergence of our species and of the Middle Stone Age appear to be close in time, and these data suggest a larger scale, potentially pan-African, origin for both.
C1 [Richter, Daniel; Steele, Teresa E. .; Raynal, Jean-Paul; Geraads, Denis; Hublin, Jean-Jacques; McPherron, Shannon P.] Max Planck Inst Evolutionary Anthropol, Dept Human Evolut, Deutsch Pl 6, D-04103 Leipzig, Germany.
   [Richter, Daniel] Leuphana Univ Luneburg, Inst Ecol Subject Area Landscape Change, Scharnhorststr 1, D-21335 Luneburg, Germany.
   [Richter, Daniel] Freiberg Instruments GmbH, Delfterstr 6, D-09599 Freiberg, Germany.
   [Grun, Rainer; Joannes-Boyau, Renaud] Australian Natl Univ, Res Sch Earth Sci, Canberra, ACT 0200, Australia.
   [Grun, Rainer] Griffith Univ, Australian Res Ctr Human Evolut, Environm Futures Res Inst, Nathan, Qld 4111, Australia.
   [Joannes-Boyau, Renaud] Southern Cross Univ, Southern Cross GeoSci, Mil Rd, Lismore, NSW 2480, Australia.
   [Steele, Teresa E. .] Univ Calif Davis, Dept Anthropol, One Shields Ave, Davis, CA USA.
   [Amani, Fethi; Ben-Ncer, Abdelouahed] Minist Culture & Commun, Inst Natl Sci Archeol & Patrimoine, Angle Rues 5&7,BP 6828, Rabat, Morocco.
   [Rue, Mathieu; Fernandes, Paul] Paleotime, 6173 Rue Jean Seraphin Achard Picard, F-38250 Villard De Lans, France.
   [Rue, Mathieu] Univ Montpellier 3, MCC, CNRS, ASM,UMR 5140, Route Mende, F-34199 Montpellier 5, France.
   [Fernandes, Paul; Raynal, Jean-Paul] Univ Bordeaux, CNRS, UMR 5199, PACEA,MCC, Batiment B18,Allee Geoffroy St Hilaire,CS 500, F-33615 Pessac, France.
   [Geraads, Denis] Sorbonne Univ, UPMC, MNHN, CNRS,CR2P,UMR 7207, CP 38,8 Rue Buffon, F-75231 Paris 05, France.
   [Hublin, Jean-Jacques] Coll France, Chaire Int Paleoanthropol, Paris, France.
C3 Max Planck Society; Leuphana University Luneburg; Australian National University; Griffith University; Southern Cross University; University of California System; University of California Davis; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute for Humanities & Social Sciences (INSHS); Universite Paul-Valery; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Ecology & Environment (INEE); Universite de Bordeaux; Museum National d'Histoire Naturelle (MNHN); Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); Universite PSL; College de France
RP McPherron, SP (corresponding author), Max Planck Inst Evolutionary Anthropol, Dept Human Evolut, Deutsch Pl 6, D-04103 Leipzig, Germany.
EM mcpherron@eva.mpg.de
FU Moroccan Institut National des Sciences de l'Archeologie et du Patrimoine; Department of Human Evolution of the Max Planck Institute for Evolutionary Anthropology (MPI-EVA); Max Planck Society; ARC [DP0664144, DP140100919]
NR 65
TC 331
Z9 389
U1 1
U2 151
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 8
PY 2017
VL 546
IS 7657
BP 293
EP +
DI 10.1038/nature22335
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW9FY
UT WOS:000402823400038
PM 28593967
DA 2026-03-09
ER

PT J
AU Flock, T
   Hauser, AS
   Lund, N
   Gloriam, DE
   Balaji, S
   Babu, MM
AF Flock, Tilman
   Hauser, Alexander S.
   Lund, Nadia
   Gloriam, David E.
   Balaji, Santhanam
   Babu, M. Madan
TI Selectivity determinants of GPCR-G-protein binding
SO NATURE
LA English
DT Article
ID coupled receptors; iuphar/bps guide; repertoire; activation; system; conservation; pharmacology; profiles; networks; features
AB The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs allows the identification of these selectivity-determining residues. These findings lay the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins.
C1 [Flock, Tilman; Balaji, Santhanam; Babu, M. Madan] MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England.
   [Flock, Tilman] Fitzwilliam Coll, Cambridge CB3 0DG, England.
   [Hauser, Alexander S.; Lund, Nadia; Gloriam, David E.] Univ Copenhagen, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark.
C3 MRC Laboratory Molecular Biology; University of Cambridge; University of Copenhagen
RP Flock, T; Babu, MM (corresponding author), MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England.; Flock, T (corresponding author), Fitzwilliam Coll, Cambridge CB3 0DG, England.
EM tf284@cam.ac.uk; madanm@mrc-lmb.cam.ac.uk
FU Medical Research Council [MC_U105185859]; Boehringer Ingelheim Fond; European Research Council [DE-ORPHAN 639125]; Lundbeck Foundation [R163-2013-16327]; European Research Council; MRC [MC_U105185859] Funding Source: UKRI; Lundbeck Foundation [R163-2013-16327] Funding Source: researchfish; Medical Research Council [MC_U105185859] Funding Source: researchfish
NR 61
TC 297
Z9 361
U1 3
U2 118
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 18
PY 2017
VL 545
IS 7654
BP 317
EP +
DI 10.1038/nature22070
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV0WF
UT WOS:000401466500056
PM 28489817
DA 2026-03-09
ER

PT J
AU Lupi, L
   Hudait, A
   Peters, B
   Grünwald, M
   Mullen, RG
   Nguyen, AH
   Molinero, V
AF Lupi, Laura
   Hudait, Arpa
   Peters, Baron
   Grunwald, Michael
   Mullen, Ryan Gotchy
   Nguyen, Andrew H.
   Molinero, Valeria
TI Role of stacking disorder in ice nucleation
SO NATURE
LA English
DT Article
ID x-ray-diffraction; cubic ice; hexagonal ice; supercooled water; silica nanopores; heat-capacity; liquid water; glassy water; free-energy; i-c
AB The freezing of water affects the processes that determine Earth's climate. Therefore, accurate weather and climate forecasts hinge on good predictions of ice nucleation rates(1). Such rate predictions are based on extrapolations using classical nucleation theory(1,2), which assumes that the structure of nanometre-sized ice crystallites corresponds to that of hexagonal ice, the thermodynamically stable form of bulk ice. However, simulations with various water models find that ice nucleated and grown under atmospheric temperatures is at all sizes stacking-disordered, consisting of random sequences of cubic and hexagonal ice layers(3-8). This implies that stacking-disordered ice crystallites either are more stable than hexagonal ice crystallites or form because of non-equilibrium dynamical effects. Both scenarios challenge central tenets of classical nucleation theory. Here we use rare-event sampling(9-11) and free energy calculations(12) with the mW water model(13) to show that the entropy of mixing cubic and hexagonal layers makes stacking-disordered ice the stable phase for crystallites up to a size of at least 100,000 molecules. We find that stacking-disordered critical crystallites at 230 kelvin are about 14 kilojoules per mole of crystallite more stable than hexagonal crystallites, making their ice nucleation rates more than three orders of magnitude higher than predicted by classical nucleation theory. This effect on nucleation rates is temperature dependent, being the most pronounced at the warmest conditions, and should affect the modelling of cloud formation and ice particle numbers, which are very sensitive to the temperature dependence of ice nucleation rates(1). We conclude that classical nucleation theory needs to be corrected to include the dependence of the crystallization driving force on the size of the ice crystallite when interpreting and extrapolating ice nucleation rates from experimental laboratory conditions to the temperatures that occur in clouds.
C1 [Lupi, Laura; Hudait, Arpa; Grunwald, Michael; Nguyen, Andrew H.; Molinero, Valeria] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA.
   [Peters, Baron; Mullen, Ryan Gotchy] Univ Calif Santa Barbara, Dept Chem Engn, Santa Barbara, CA 93106 USA.
   [Peters, Baron; Mullen, Ryan Gotchy] Univ Calif Santa Barbara, Dept Chem & Biochem, Santa Barbara, CA 93106 USA.
C3 Utah System of Higher Education; University of Utah; University of California System; University of California Santa Barbara; University of California System; University of California Santa Barbara
RP Molinero, V (corresponding author), Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA.
EM valeria.molinero@utah.edu
FU National Science Foundation through Center of Chemical Innovation award "Center for Aerosol Impacts on Climate and the Environment" [CHE-1305427]; Environmental Chemical Sciences award [CHE-1309601]
NR 71
TC 225
Z9 256
U1 9
U2 229
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 9
PY 2017
VL 551
IS 7679
BP 218
EP +
DI 10.1038/nature24279
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM1KF
UT WOS:000414734200045
PM 29120424
DA 2026-03-09
ER

PT J
AU Tai, ME
   Lukin, A
   Rispoli, M
   Schittko, R
   Menke, T
   Borgnia, D
   Preiss, PM
   Grusdt, F
   Kaufman, AM
   Greiner, M
AF Tai, M. Eric
   Lukin, Alexander
   Rispoli, Matthew
   Schittko, Robert
   Menke, Tim
   Borgnia, Dan
   Preiss, Philipp M.
   Grusdt, Fabian
   Kaufman, Adam M.
   Greiner, Markus
TI Microscopy of the interacting Harper-Hofstadter model in the two-body limit
SO NATURE
LA English
DT Article
ID magnetic-fields; optical lattice; edge states; neutral atoms; quantum; fermions; regime; gas
AB The interplay between magnetic fields and interacting particles can lead to exotic phases of matter that exhibit topological order and high degrees of spatial entanglement(1). Although these phases were discovered in a solid-state setting(2,3), recent innovations in systems of ultracold neutral atoms-uncharged atoms that do not naturally experience a Lorentz force-allow the synthesis of artificial magnetic, or gauge, fields(4-10). This experimental platform holds promise for exploring exotic physics in fractional quantum Hall systems, owing to the microscopic control and precision that is achievable in cold-atom systems(11,12). However, so far these experiments have mostly explored the regime of weak interactions, which precludes access to correlated many-body states(4,13-17). Here, through microscopic atomic control and detection, we demonstrate the controlled incorporation of strong interactions into a two-body system with a chiral band structure. We observe and explain the way in which interparticle interactions induce chirality in the propagation dynamics of particles in a ladder-like, real-space lattice governed by the interacting Harper-Hofstadter model, which describes lattice-confined, coherently mobile particles in the presence of a magnetic field(18). We use a bottom-up strategy to prepare interacting chiral quantum states, thus circumventing the challenges of a top-down approach that begins with a many-body system, the size of which can hinder the preparation of controlled states. Our experimental platform combines all of the necessary components for investigating highly entangled topological states, and our observations provide a benchmark for future experiments in the fractional quantum Hall regime.
C1 [Tai, M. Eric; Lukin, Alexander; Rispoli, Matthew; Schittko, Robert; Menke, Tim; Borgnia, Dan; Preiss, Philipp M.; Grusdt, Fabian; Kaufman, Adam M.; Greiner, Markus] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.
   [Preiss, Philipp M.] Heidelberg Univ, Phys Inst, D-69120 Heidelberg, Germany.
C3 Harvard University; Ruprecht Karls University Heidelberg
RP Greiner, M (corresponding author), Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.
EM greiner@physics.harvard.edu
FU National Science Foundation; Gordon and Betty Moore Foundation's EPiQS Initiative; Air Force Office of Scientific Research MURI programme; Army Research Office MURI programme; NSF Graduate Research Fellowship Program; Direct For Mathematical & Physical Scien; Division Of Physics [1734006, 1506203] Funding Source: National Science Foundation
NR 29
TC 245
Z9 269
U1 3
U2 81
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 22
PY 2017
VL 546
IS 7659
BP 519
EP 523
DI 10.1038/nature22811
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY2QK
UT WOS:000403814100036
PM 28640260
DA 2026-03-09
ER

PT J
AU Moores, JE
   Smith, CL
   Toigo, AD
   Guzewich, SD
AF Moores, John E.
   Smith, Christina L.
   Toigo, Anthony D.
   Guzewich, Scott D.
TI Penitentes as the origin of the bladed terrain of Tartarus Dorsa on Pluto
SO NATURE
LA English
DT Article
ID convection; horizons; methane
AB Penitentes are snow and ice features formed by erosion that, on Earth, are characterized by bowl-shaped depressions several tens of centimetres across, whose edges grade into spires up to several metres tall(1-3). Penitentes have been suggested as an explanation for anomalous radar data on Europa(4), but until now no penitentes have been identified conclusively on planetary bodies other than Earth. Regular ridges with spacings of 3,000 to 5,000 metres and depths of about 500 metres with morphologies that resemble penitentes have been observed by the New Horizons spacecraft(5-8) in the Tartarus Dorsa region of Pluto (220 degrees-250 degrees E, 0 degrees-20 degrees N). Here we report simulations, based upon a recent model(3) representing conditions on Pluto(7,9), in which deepening penitentes reproduce both the tri-modal (north-south, east-west and northeast-southwest) orientation and the spacing of the ridges of this bladed terrain. At present, these penitentes deepen by approximately one centimetre per orbital cycle and grow only during periods of relatively high atmospheric pressure, suggesting a formation timescale of several tens of millions of years, consistent with crater ages. This timescale implies that the penitentes formed from initial topographic variations of no more than a few tens of metres, consistent with Pluto's youngest terrains.
C1 [Moores, John E.; Smith, Christina L.] York Univ, Ctr Res Earth & Space Sci, Dept Earth & Space Sci & Engn, 4700 Keele St, N York, ON M3J 1P3, Canada.
   [Toigo, Anthony D.] Johns Hopkins Univ, Appl Phys Lab, Baltimore, MD 21218 USA.
   [Guzewich, Scott D.] NASA, Goddard Space Flight Ctr, Greenbelt, MD USA.
C3 York University - Canada; Johns Hopkins University; Johns Hopkins University Applied Physics Laboratory; National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center
RP Moores, JE (corresponding author), York Univ, Ctr Res Earth & Space Sci, Dept Earth & Space Sci & Engn, 4700 Keele St, N York, ON M3J 1P3, Canada.
EM jmoores@yorku.ca
FU Natural Sciences and Engineering Research Council of Canada (NSERC) [436252-2013]; Integrating Atmospheric Chemistry and Physics from the Earth to Space (IACPES) Collaborative Research and Training Experience (CREATE) programme of NSERC
NR 27
TC 44
Z9 50
U1 0
U2 12
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 12
PY 2017
VL 541
IS 7636
BP 188
EP +
DI 10.1038/nature20779
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6PI
UT WOS:000396125500034
PM 28052055
DA 2026-03-09
ER

PT J
AU Stevens, TJ
   Lando, D
   Basu, S
   Atkinson, LP
   Cao, Y
   Lee, SF
   Leeb, M
   Wohlfahrt, KJ
   Boucher, W
   O'Shaughnessy-Kirwan, A
   Cramard, J
   Faure, AJ
   Ralser, M
   Blanco, E
   Morey, L
   Sansó, M
   Palayret, MGS
   Lehner, B
   Di Croce, L
   Wutz, A
   Hendrich, B
   Klenerman, D
   Laue, ED
AF Stevens, Tim J.
   Lando, David
   Basu, Srinjan
   Atkinson, Liam P.
   Cao, Yang
   Lee, Steven F.
   Leeb, Martin
   Wohlfahrt, Kai J.
   Boucher, Wayne
   O'Shaughnessy-Kirwan, Aoife
   Cramard, Julie
   Faure, Andre J.
   Ralser, Meryem
   Blanco, Enrique
   Morey, Lluis
   Sanso, Miriam
   Palayret, Matthieu G. S.
   Lehner, Ben
   Di Croce, Luciano
   Wutz, Anton
   Hendrich, Brian
   Klenerman, Dave
   Laue, Ernest D.
TI 3D structures of individual mammalian genomes studied by single-cell Hi-C
SO NATURE
LA English
DT Article
ID chromosome conformation capture; nuclear lamina interactions; embryonic stem-cells; spatial-organization; pluripotency factors; lineage commitment; chromatin domains; gene-expression; transcription; reveals
AB The folding of genomic DNA from the beads-on-a-string-like structure of nucleosomes into higher-order assemblies is crucially linked to nuclear processes. Here we calculate 3D structures of entire mammalian genomes using data from a new chromosome conformation capture procedure that allows us to first image and then process single cells. The technique enables genome folding to be examined at a scale of less than 100 kb, and chromosome structures to be validated. The structures of individual topological-associated domains and loops vary substantially from cell to cell. By contrast, A and B compartments, lamina-associated domains and active enhancers and promoters are organized in a consistent way on a genome-wide basis in every cell, suggesting that they could drive chromosome and genome folding. By studying genes regulated by pluripotency factor and nucleosome remodelling deacetylase (NuRD), we illustrate how the determination of single-cell genome structure provides a new approach for investigating biological processes.
C1 [Stevens, Tim J.; Lando, David; Basu, Srinjan; Atkinson, Liam P.; Cao, Yang; Wohlfahrt, Kai J.; Boucher, Wayne; O'Shaughnessy-Kirwan, Aoife; Hendrich, Brian; Laue, Ernest D.] Univ Cambridge, Dept Biochem, 80 Tennis Court Rd, Cambridge CB2 1GA, England.
   [Stevens, Tim J.] MRC, Mol Biol Lab, Francis Crick Ave,Cambridge Biomed Campus, Cambridge CB2 0QH, England.
   [Lee, Steven F.; Palayret, Matthieu G. S.; Klenerman, Dave] Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England.
   [Leeb, Martin; O'Shaughnessy-Kirwan, Aoife; Cramard, Julie; Ralser, Meryem; Wutz, Anton; Hendrich, Brian] Univ Cambridge, Wellcome Trust MRC Stem Cell Inst, Tennis Court Rd, Cambridge CB2 1QR, England.
   [Faure, Andre J.; Blanco, Enrique; Morey, Lluis; Sanso, Miriam; Lehner, Ben; Di Croce, Luciano] Ctr Genom Regulat CRG, EMBL CRG Syst Biol Unit, Barcelona 08003, Spain.
   [Lehner, Ben; Di Croce, Luciano] Univ Pompeu Fabra, Barcelona 08003, Spain.
   [Lehner, Ben; Di Croce, Luciano] ICREA, Barcelona 08010, Spain.
   [Leeb, Martin] Univ Vienna, Max F Perutz Labs, Vienna Bioctr, Dr Bohr Gasse 9-3, A-1030 Vienna, Austria.
   [Morey, Lluis] Univ Miami, Miller Sch Med, Dept Human Genet, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA.
   [Wutz, Anton] Swiss Fed Inst Technol, Inst Mol Hlth Sci, HPL E 12,Otto Stern Weg 7, Zurich, Switzerland.
C3 University of Cambridge; MRC Laboratory Molecular Biology; University of Cambridge; University of Cambridge; Barcelona Institute of Science & Technology; Pompeu Fabra University; Centre de Regulacio Genomica (CRG); Pompeu Fabra University; ICREA; Vienna Biocenter (VBC); Max F. Perutz Laboratories (MFPL); University of Vienna; University of Miami; Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Laue, ED (corresponding author), Univ Cambridge, Dept Biochem, 80 Tennis Court Rd, Cambridge CB2 1GA, England.
EM e.d.laue@bioc.cam.ac.uk
FU Wellcome Trust [082010/Z/07/Z]; EC FP7 4DCellFate project [277899]; MRC [MR/M010082/1]; Wellcome Trust [082010/Z/07/Z, 206291/Z/17/Z] Funding Source: Wellcome Trust; ICREA Funding Source: Custom; Medical Research Council [MR/M010082/1, MC_PC_12009, MR/P019471/1, MC_U105178783] Funding Source: researchfish; Wellcome Trust [206291/Z/17/Z] Funding Source: researchfish; MRC [MC_U105178783, MR/P019471/1, MR/M010082/1] Funding Source: UKRI
NR 40
TC 603
Z9 749
U1 4
U2 229
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 6
PY 2017
VL 544
IS 7648
BP 59
EP +
DI 10.1038/nature21429
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EQ8GQ
UT WOS:000398323300032
PM 28289288
DA 2026-03-09
ER

PT J
AU Anenberg, SC
   Miller, J
   Injares, RM
   Du, L
   Henze, DK
   Lacey, F
   Malley, CS
   Emberson, L
   Franco, V
   Klimont, Z
   Heyes, C
AF Anenberg, Susan C.
   Miller, Joshua
   Injares, Ray M.
   Du, Li
   Henze, Daven K.
   Lacey, Forrest
   Malley, Christopher S.
   Emberson, Lisa
   Franco, Vicente
   Klimont, Zbigniew
   Heyes, Chris
TI Impacts and mitigation of excess diesel-related NOx emissions in 11 major vehicle markets
SO NATURE
LA English
DT Article
ID fine particulate matter; term ozone exposure; future air-quality; global burden; passenger cars; co-benefits; mortality; climate; health; disease
AB Vehicle emissions contribute to fine particulate matter (PM2.5) and tropospheric ozone air pollution, affecting human health(1-5), crop yields(5,6) and climate(5,7) worldwide. On-road diesel vehicles produce approximately 20 per cent of global anthropogenic emissions of nitrogen oxides (NOx), which are key PM2.5 and ozone precursors(8,9). Regulated NOx emission limits in leading markets have been progressively tightened, but current diesel vehicles emit far more NOx under real-world operating conditions than during laboratory certification testing(10-20). Here we show that across 11 markets, representing approximately 80 per cent of global diesel vehicle sales, nearly one-third of on-road heavy-duty diesel vehicle emissions and over half of on-road light-duty diesel vehicle emissions are in excess of certification limits. These excess emissions (totalling 4.6 million tons) are associated with about 38,000 PM2.5- and ozone-related premature deaths globally in 2015, including about 10 per cent of all ozone-related premature deaths in the 28 European Union member states. Heavy-duty vehicles are the dominant contributor to excess diesel NOx emissions and associated health impacts in almost all regions. Adopting and enforcing next-generation standards (more stringent than Euro 6/VI) could nearly eliminate real-world diesel-related NOx emissions in these markets, avoiding approximately 174,000 global PM2.5- and ozone-related premature deaths in 2040. Most of these benefits can be achieved by implementing Euro VI standards where they have not yet been adopted for heavy-duty vehicles.
C1 [Anenberg, Susan C.] Environm Hlth Analyt LLC, Washington, DC 20015 USA.
   [Miller, Joshua; Injares, Ray M.; Du, Li; Franco, Vicente] Int Council Clean Transportat, Washington, DC 20005 USA.
   [Henze, Daven K.; Lacey, Forrest] Univ Colorado, Dept Mech Engn, Boulder, CO 80309 USA.
   [Malley, Christopher S.; Emberson, Lisa] Univ York, Stockholm Environm Inst, York, N Yorkshire, England.
   [Klimont, Zbigniew; Heyes, Chris] Int Inst Appl Syst Anal, Laxenburg, Austria.
   [Lacey, Forrest] Natl Ctr Atmospher Res, POB 3000, Boulder, CO 80307 USA.
   [Franco, Vicente] European Commiss, Directorate Gen Environm, Brussels, Belgium.
C3 University of Colorado System; University of Colorado Boulder; University of York - UK; International Institute for Applied Systems Analysis (IIASA); National Center Atmospheric Research (NCAR) - USA
RP Anenberg, SC (corresponding author), Environm Hlth Analyt LLC, Washington, DC 20015 USA.; Miller, J (corresponding author), Int Council Clean Transportat, Washington, DC 20005 USA.
EM susan.anenberg@envhealthanalytics.com; josh@theicct.org
FU Hewlett Foundation; ClimateWorks Foundation; European Climate Foundation; Energy Foundation China; NASA Health and Air Quality Applied System Team
NR 73
TC 579
Z9 660
U1 11
U2 569
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 25
PY 2017
VL 545
IS 7655
BP 467
EP +
DI 10.1038/nature22086
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV6TH
UT WOS:000401906500049
PM 28505629
DA 2026-03-09
ER

PT J
AU Frieda, KL
   Linton, JM
   Hormoz, S
   Choi, J
   Chow, KHK
   Singer, ZS
   Budde, MW
   Elowitz, MB
   Cai, L
AF Frieda, Kirsten L.
   Linton, James M.
   Hormoz, Sahand
   Choi, Joonhyuk
   Chow, Ke-Huan K.
   Singer, Zakary S.
   Budde, Mark W.
   Elowitz, Michael B.
   Cai, Long
TI Synthetic recording and in situ readout of lineage information in single cells
SO NATURE
LA English
DT Article
ID embryonic stem-cells; phylogenetic trees; rna; gene; heterogeneity; pluripotent; molecules; dynamics; systems; esrrb
AB Reconstructing the lineage relationships and dynamic event histories of individual cells within their native spatial context is a long-standing challenge in biology. Many biological processes of interest occur in optically opaque or physically inaccessible contexts, necessitating approaches other than direct imaging. Here we describe a synthetic system that enables cells to record lineage information and event histories in the genome in a format that can be subsequently read out of single cells in situ. This system, termed memory by engineered mutagenesis with optical in situ readout (MEMOIR), is based on a set of barcoded recording elements termed scratchpads. The state of a given scratchpad can be irreversibly altered by CRISPR/Cas9-based targeted mutagenesis, and later read out in single cells through multiplexed single-molecule RNA fluorescence hybridization (smFISH). Using MEMOIR as a proof of principle, we engineered mouse embryonic stem cells to contain multiple scratchpads and other recording components. In these cells, scratchpads were altered in a progressive and stochastic fashion as the cells proliferated. Analysis of the final states of scratchpads in single cells in situ enabled reconstruction of lineage information from cell colonies. Combining analysis of endogenous gene expression with lineage reconstruction in the same cells further allowed inference of the dynamic rates at which embryonic stem cells switch between two gene expression states. Finally, using simulations, we show how parallel MEMOIR systems operating in the same cell could enable recording and readout of dynamic cellular event histories. MEMOIR thus provides a versatile platform for information recording and in situ, single-cell readout across diverse biological systems.
C1 [Frieda, Kirsten L.; Linton, James M.; Hormoz, Sahand; Chow, Ke-Huan K.; Singer, Zakary S.; Budde, Mark W.; Elowitz, Michael B.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
   [Choi, Joonhyuk; Cai, Long] CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA.
   [Elowitz, Michael B.] CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA.
C3 California Institute of Technology; California Institute of Technology; Howard Hughes Medical Institute; California Institute of Technology
RP Elowitz, MB (corresponding author), CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.; Cai, L (corresponding author), CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA.; Elowitz, MB (corresponding author), CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA.
EM melowitz@caltech.edu; lcai@caltech.edu
FU Allen Distinguished Investigator Program, through The Paul G. Allen Frontiers Group; NIH [R01HD075605, K99GM118910]; Gordon and Betty Moore Foundation [GBMF2809]; Beckman Institute pilot program; Gordon and Betty Moore Foundation (GBMF) [GBMF2809] Funding Source: Gordon and Betty Moore Foundation (GBMF)
NR 42
TC 314
Z9 406
U1 4
U2 146
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 5
PY 2017
VL 541
IS 7635
BP 107
EP +
DI 10.1038/nature20777
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6NA
UT WOS:000396119500039
PM 27869821
DA 2026-03-09
ER

PT J
AU Bell, RE
   Chu, WN
   Kingslake, J
   Das, I
   Tedesco, M
   Tinto, KJ
   Zappa, CJ
   Frezzotti, M
   Boghosian, A
   Lee, WS
AF Bell, Robin E.
   Chu, Winnie
   Kingslake, Jonathan
   Das, Indrani
   Tedesco, Marco
   Tinto, Kirsty J.
   Zappa, Christopher J.
   Frezzotti, Massimo
   Boghosian, Alexandra
   Lee, Won Sang
TI Antarctic ice shelf potentially stabilized by export of meltwater in surface river
SO NATURE
LA English
DT Article
ID supraglacial lakes; water-flow; streams; field; zone
AB Meltwater stored in ponds(1) and crevasses can weaken and fracture ice shelves, triggering their rapid disintegration(2). This ice-shelf collapse results in an increased flux of ice from adjacent glaciers(3) and ice streams, thereby raising sea level globally(4). However, surface rivers forming on ice shelves could potentially export stored meltwater and prevent its destructive effects. Here we present evidence for persistent active drainage networks-interconnected streams, ponds and rivers-on the Nansen Ice Shelf in Antarctica that export a large fraction of the ice shelf's meltwater into the ocean. We find that active drainage has exported water off the ice surface through waterfalls and dolines for more than a century. The surface river terminates in a 130-metre-wide waterfall that can export the entire annual surface melt over the course of seven days. During warmer melt seasons, these drainage networks adapt to changing environmental conditions by remaining active for longer and exporting more water. Similar networks are present on the ice shelf in front of Petermann Glacier, Greenland, but other systems, such as on the Larsen C and Amery Ice Shelves, retain surface water at present. The underlying reasons for export versus retention remain unclear. Nonetheless our results suggest that, in a future warming climate, surface rivers could export melt off the large ice shelves surrounding Antarctica-contrary to present Antarctic ice-sheet models(1), which assume that meltwater is stored on the ice surface where it triggers ice-shelf disintegration.
C1 [Bell, Robin E.; Chu, Winnie; Kingslake, Jonathan; Das, Indrani; Tedesco, Marco; Tinto, Kirsty J.; Zappa, Christopher J.; Boghosian, Alexandra] Columbia Univ, Lamont Doherty Earth Observ, New York, NY 10964 USA.
   [Chu, Winnie; Kingslake, Jonathan; Boghosian, Alexandra] Columbia Univ, Dept Earth & Environm Sci, New York, NY 10964 USA.
   [Tedesco, Marco] NASA, Goddard Inst Space Studies, New York, NY 10021 USA.
   [Frezzotti, Massimo] Italian Natl Agcy New Technol Energy & Sustainabl, Anguillarese 301, I-00123 Rome, Italy.
   [Lee, Won Sang] Korea Polar Res Inst KOPRI, Incheon 21990, South Korea.
   [Lee, Won Sang] Korea Univ Sci & Technol, Daejeon 34113, South Korea.
C3 Columbia University; Columbia University; National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center; Goddard Institute for Space Studies; Italian National Agency New Technical Energy & Sustainable Economics Development; Italian National Agency New Technical Energy & Sustainable Economics Development; Korea Polar Research Institute (KOPRI); University of Science & Technology (UST)
RP Bell, RE (corresponding author), Columbia Univ, Lamont Doherty Earth Observ, New York, NY 10964 USA.
EM robinb@ldeo.columbia.edu
FU National Science Foundation [1443534, DGE-16-44869, 1341688]; NASA [IceBridge NNX16AJ65G, NNX14AH79G]; NASA Earth and Space Science fellowship [NNX15AN28H]; Old York Foundation; Korean Ministry of Oceans and Fisheries [PM16020]; Office of Polar Programs (OPP); Directorate For Geosciences [1443534, 1341688] Funding Source: National Science Foundation; NASA [683635, NNX14AH79G, NNX15AN28H, 798531] Funding Source: Federal RePORTER
NR 40
TC 135
Z9 164
U1 0
U2 102
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 20
PY 2017
VL 544
IS 7650
BP 344
EP +
DI 10.1038/nature22048
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ES4SG
UT WOS:000399524400035
PM 28426005
DA 2026-03-09
ER

PT J
AU Nguyen, TT
   Koh, MJ
   Mann, TJ
   Schrock, RR
   Hoveyda, AH
AF Nguyen, Thach T.
   Koh, Ming Joo
   Mann, Tyler J.
   Schrock, Richard R.
   Hoveyda, Amir H.
TI Synthesis of E- and Z-trisubstituted alkenes by catalytic cross-metathesis
SO NATURE
LA English
DT Article
ID olefin-metathesis; stereoselective-synthesis; alkylidene complexes; coupling reaction; allylic alcohols; wittig reaction; molybdenum; efficient; alkynes; carbometalation
AB Catalytic cross-metathesis is a central transformation in chemistry, yet corresponding methods for the stereoselective generation of acyclic trisubstituted alkenes in either the E or the Z isomeric forms are not known. The key problems are a lack of chemoselectivity-namely, the preponderance of side reactions involving only the less hindered starting alkene, resulting in homo-metathesis by-products-and the formation of short-lived methylidene complexes. By contrast, in catalytic cross-coupling, substrates are more distinct and homocoupling is less of a problem. Here we show that through cross-metathesis reactions involving E-or Z-trisubstituted alkenes, which are easily prepared from commercially available starting materials by cross-coupling reactions, many desirable and otherwise difficult-to-access linear E-or Z-trisubstituted alkenes can be synthesized efficiently and in exceptional stereoisomeric purity (up to 98 per cent E or 95 per cent Z). The utility of the strategy is demonstrated by the concise stereoselective syntheses of biologically active compounds, such as the antifungal indiacen B and the anti-inflammatory coibacin D.
C1 [Nguyen, Thach T.; Koh, Ming Joo; Mann, Tyler J.; Hoveyda, Amir H.] Boston Coll, Dept Chem, Merkert Chem Ctr, Chestnut Hill, MA 02467 USA.
   [Schrock, Richard R.] MIT, Dept Chem, Cambridge, MA 02139 USA.
C3 Boston College; Massachusetts Institute of Technology (MIT)
RP Hoveyda, AH (corresponding author), Boston Coll, Dept Chem, Merkert Chem Ctr, Chestnut Hill, MA 02467 USA.
EM amir.hoveyda@bc.edu
FU United States National Institutes of Health, Institute of General Medical Sciences [GM-59426, CHE-1362763]; Bristol Myers-Squibb Fellowship in Organic Chemistry; John LaMattina Graduate Fellowship
NR 51
TC 88
Z9 92
U1 5
U2 131
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 21
PY 2017
VL 552
IS 7685
BP 347
EP +
DI 10.1038/nature25002
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ7RI
UT WOS:000418559800048
PM 29293209
DA 2026-03-09
ER

PT J
AU Tikhomirov, G
   Petersen, P
   Qian, LL
AF Tikhomirov, Grigory
   Petersen, Philip
   Qian, Lulu
TI Fractal assembly of micrometre-scale DNA origami arrays with arbitrary patterns
SO NATURE
LA English
DT Article
ID nanostructures
AB Self-assembled DNA nanostructures(1) enable nanometre-precise patterning that can be used to create programmable molecular machines(2-6) and arrays of functional materials(7-9). DNA origami(10) is particularly versatile in this context because each DNA strand in the origami nanostructure occupies a unique position and can serve as a uniquely addressable pixel. However, the scale of such structures(11-14) has been limited to about 0.05 square micrometres, hindering applications that demand a larger layout(15) and integration with more conventional patterning methods. Hierarchical multistage assembly of simple sets of tiles(16,17) can in principle overcome this limitation, but so far has not been sufficiently robust to enable successful implementation of larger structures using DNA origami tiles. Here we show that by using simple local assembly rules(18) that are modified and applied recursively throughout a hierarchical, multistage assembly process, a small and constant set of unique DNA strands can be used to create DNA origami arrays of increasing size and with arbitrary patterns. We illustrate this method, which we term 'fractal assembly', by producing DNA origami arrays with sizes of up to 0.5 square micrometres and with up to 8,704 pixels, allowing us to render images such as the Mona Lisa and a rooster. We find that self-assembly of the tiles into arrays is unaffected by changes in surface patterns on the tiles, and that the yield of the fractal assembly process corresponds to about 0.95(m-1) for arrays containing m tiles. When used in conjunction with a software tool that we developed that converts an arbitrary pattern into DNA sequences and experimental protocols, our assembly method is readily accessible and will facilitate the construction of sophisticated materials and devices with sizes similar to that of a bacterium using DNA nanostructures.
C1 [Tikhomirov, Grigory; Qian, Lulu] CALTECH, Bioengn, Pasadena, CA 91125 USA.
   [Petersen, Philip] CALTECH, Biol, Pasadena, CA 91125 USA.
   [Qian, Lulu] CALTECH, Comp Sci, Pasadena, CA 91125 USA.
C3 California Institute of Technology; California Institute of Technology; California Institute of Technology
RP Qian, LL (corresponding author), CALTECH, Bioengn, Pasadena, CA 91125 USA.; Qian, LL (corresponding author), CALTECH, Comp Sci, Pasadena, CA 91125 USA.
EM luluqian@caltech.edu
FU BWF grant [1010684]; NIH/NRSA training grant [5 T32 GM07616]; Burroughs Wellcome Fund [1010684]; Faculty Early Career Development Award from NSF [1351081]
NR 30
TC 425
Z9 509
U1 14
U2 444
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 7
PY 2017
VL 552
IS 7683
BP 67
EP 71
DI 10.1038/nature24655
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FP4BA
UT WOS:000417560500044
PM 29219965
DA 2026-03-09
ER

PT J
AU Valm, AM
   Cohen, S
   Legant, WR
   Melunis, J
   Hershberg, U
   Wait, E
   Cohen, AR
   Davidson, MW
   Betzig, E
   Lippincott-Schwartz, J
AF Valm, Alex M.
   Cohen, Sarah
   Legant, Wesley R.
   Melunis, Justin
   Hershberg, Uri
   Wait, Eric
   Cohen, Andrew R.
   Davidson, Michael W.
   Betzig, Eric
   Lippincott-Schwartz, Jennifer
TI Applying systems-level spectral imaging and analysis to reveal the organelle interactome
SO NATURE
LA English
DT Article
ID contact sites; tracking; segmentation; trafficking; autophagy; dynamics
AB The organization of the eukaryotic cell into discrete membrane-bound organelles allows for the separation of incompatible biochemical processes, but the activities of these organelles must be coordinated. For example, lipid metabolism is distributed between the endoplasmic reticulum for lipid synthesis, lipid droplets for storage and transport, mitochondria and peroxisomes for beta-oxidation, and lysosomes for lipid hydrolysis and recycling(1-5). It is increasingly recognized that organelle contacts have a vital role in diverse cellular functions(5-8). However, the spatial and temporal organization of organelles within the cell remains poorly characterized, as fluorescence imaging approaches are limited in the number of different labels that can be distinguished in a single image(9). Here we present a systems-level analysis of the organelle interactome using a multispectral image acquisition method that overcomes the challenge of spectral overlap in the fluorescent protein palette. We used confocal and lattice light sheet(10) instrumentation and an imaging informatics pipeline of five steps to achieve mapping of organelle numbers, volumes, speeds, positions and dynamic inter-organelle contacts in live cells from a monkey fibroblast cell line. We describe the frequency and locality of two-, three-, four-and five-way interactions among six different membrane-bound organelles (endoplasmic reticulum, Golgi, lysosome, peroxisome, mitochondria and lipid droplet) and show how these relationships change over time. We demonstrate that each organelle has a characteristic distribution and dispersion pattern in three-dimensional space and that there is a reproducible pattern of contacts among the six organelles, that is affected by microtubule and cell nutrient status. These live-cell confocal and lattice light sheet spectral imaging approaches are applicable to any cell system expressing multiple fluorescent probes, whether in normal conditions or when cells are exposed to disturbances such as drugs, pathogens or stress. This methodology thus offers a powerful descriptive tool and can be used to develop hypotheses about cellular organization and dynamics.
C1 [Valm, Alex M.; Cohen, Sarah; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA.
   [Legant, Wesley R.; Betzig, Eric; Lippincott-Schwartz, Jennifer] Janelia Res Campus, Howard Hughes Med Inst, Ashburn, VA 20147 USA.
   [Melunis, Justin; Hershberg, Uri] Drexel Univ, Sch Biomed Engn Sci & Hlth Syst, Philadelphia, PA 19104 USA.
   [Hershberg, Uri] Drexel Univ, Dept Microbiol & Immunol, Coll Med, Philadelphia, PA 19104 USA.
   [Wait, Eric; Cohen, Andrew R.] Drexel Univ, Dept Elect & Comp Engn, Coll Engn, Philadelphia, PA 19104 USA.
   [Davidson, Michael W.] Florida State Univ, Natl High Magnet Field Lab, Tallahassee, FL 32313 USA.
   [Davidson, Michael W.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32313 USA.
C3 National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD); Howard Hughes Medical Institute; Drexel University; Drexel University; Drexel University; State University System of Florida; Florida State University; State University System of Florida; Florida State University
RP Lippincott-Schwartz, J (corresponding author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA.; Lippincott-Schwartz, J (corresponding author), Janelia Res Campus, Howard Hughes Med Inst, Ashburn, VA 20147 USA.
EM lippincottschwartzj@janelia.hhmi.org
FU Intramural Research Program of the National Institutes of Health; Howard Hughes Medical Institute; Postdoctoral Research Associate (PRAT) Fellowship from National Institute of General Medical Sciences; NIH from National Institute on Aging [R01AG041861]
CR Barbosa AD, 2015, CURR OPIN CELL BIOL, V35, P91, DOI 10.1016/j.ceb.2015.04.017
   Chen BC, 2014, SCIENCE, V346, P439, DOI 10.1126/science.1257998
   Cohen AR, 2009, IEEE T PATTERN ANAL, V31, P1386, DOI 10.1109/TPAMI.2008.162
   de Forges H, 2012, INT J BIOCHEM CELL B, V44, P266, DOI 10.1016/j.biocel.2011.11.009
   Dickinson ME, 2001, BIOTECHNIQUES, V31, P1272, DOI 10.2144/01316bt01
   Eisenberg-Bord M, 2016, DEV CELL, V39, P395, DOI 10.1016/j.devcel.2016.10.022
   Friedman JR, 2013, MOL BIOL CELL, V24, P1030, DOI 10.1091/mbc.E12-10-0733
   Friedman JR, 2011, SCIENCE, V334, P358, DOI 10.1126/science.1207385
   Friedman JR, 2010, J CELL BIOL, V190, P363, DOI 10.1083/jcb.200911024
   Garini Y, 2006, CYTOM PART A, V69A, P735, DOI 10.1002/cyto.a.20311
   Gatta AT, 2017, TRENDS CELL BIOL, V27, P214, DOI 10.1016/j.tcb.2016.08.010
   Gonzales RC, 2009, DIGITAL IMAGE PROCESSING USING MATLAB, V2nd, P0
   Herms A, 2015, NAT COMMUN, V6, P0, DOI 10.1038/ncomms8176
   Ikonen E, 2008, NAT REV MOL CELL BIO, V9, P125, DOI 10.1038/nrm2336
   Jahr W, 2015, NAT COMMUN, V6, P0, DOI 10.1038/ncomms8990
   Jaqaman K, 2008, NAT METHODS, V5, P695, DOI 10.1038/nmeth.1237
   Neher R, 2004, J MICROSC-OXFORD, V213, P46, DOI 10.1111/j.1365-2818.2004.01262.x
   OTSU N, 1979, IEEE T SYST MAN CYB, V9, P62, DOI 10.1109/TSMC.1979.4310076
   Phillips MJ, 2016, NAT REV MOL CELL BIO, V17, P69, DOI 10.1038/nrm.2015.8
   Rambold AS, 2015, DEV CELL, V32, P678, DOI 10.1016/j.devcel.2015.01.029
   Rodriguez EA, 2016, NAT METHODS, V13, P763, DOI 10.1038/NMETH.3935
   Rowland AA, 2014, CELL, V159, P1027, DOI 10.1016/j.cell.2014.10.023
   Schneider CA, 2012, NAT METHODS, V9, P671, DOI 10.1038/nmeth.2089
   Settembre C, 2013, NAT REV MOL CELL BIO, V14, P283, DOI 10.1038/nrm3565
   Shaner NC, 2005, NAT METHODS, V2, P905, DOI 10.1038/NMETH819
   Singh R, 2009, NATURE, V458, P1131, DOI 10.1038/nature07976
   Spence MT, 2010, THE MOLECULAR PROBES HANDBOOK: A GUIDE TO FLUORESCENT PROBES AND LABELING TECHNOLOGIES, V0, P0
   Tatsuta T, 2014, TRENDS CELL BIOL, V24, P44, DOI 10.1016/j.tcb.2013.07.011
   Tibshirani R, 2001, J ROY STAT SOC B, V63, P411, DOI 10.1111/1467-9868.00293
   Tsuriel S, 2015, NAT METHODS, V12, P547, DOI 10.1038/nmeth.3367
   Valm AM, 2016, PLOS ONE, V11, P0, DOI 10.1371/journal.pone.0158495
   Valm AM, 2011, P NATL ACAD SCI USA, V108, P4152, DOI 10.1073/pnas.1101134108
   Wait E, 2014, BMC BIOINFORMATICS, V15, P0, DOI 10.1186/1471-2105-15-328
   Wilfling F, 2014, ELIFE, V3, P0, DOI 10.7554/eLife.01607
   Winter M, 2016, BIOINFORMATICS, V32, P3530, DOI 10.1093/bioinformatics/btw406
NR 36
TC 844
Z9 988
U1 16
U2 677
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 1
PY 2017
VL 546
IS 7656
BP 162
EP +
DI 10.1038/nature22369
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW3CR
UT WOS:000402372800049
PM 28538724
DA 2026-03-09
ER

PT J
AU Zliobaite, I
   Fortelius, M
   Stenseth, NC
AF Zliobaite, Indre
   Fortelius, Mikael
   Stenseth, Nils C.
TI Reconciling taxon senescence with the Red Queen's hypothesis
SO NATURE
LA English
DT Article
ID predicting extinction; mass extinctions; mammals; occupancy; evolution; macroevolutionary; ecosystems; phylogeny; climate; models
AB In the fossil record, taxa exhibit a regular pattern of waxing and waning of occupancy, range or diversity between their origin and extinction. This pattern appears to contradict the law of constant extinction(1), which states that the probability of extinction in a given taxon is independent of that taxon's age. It is nevertheless well established for species, genera and higher taxa of terrestrial mammals(2-4), marine invertebrates(5-7), marine microorganisms(8), and recent Hawaiian clades of animals and plants(9). Here we show that the apparent contradiction between a stochastically constant extinction rate and the seemingly deterministic waxing and waning pattern of taxa disappears when we consider their peak of expansion rather than their final extinction. To a first approximation, we find that biotic drivers of evolution pertain mainly to the peak of taxon expansion, whereas abiotic drivers mainly apply to taxon extinction. The Red Queen's hypothesis(1), which emphasizes biotic interactions, was originally proposed as an explanation of the law of constant extinction. Much effort has since been devoted to determining how this hypothesis, emphasizing competition for resources, relates to the effects of environmental change. One proposed resolution is that biotic and abiotic processes operate at different scales(10). By focusing attention on taxon expansion rather than survival, we resolve an apparent contradiction between the seemingly deterministic waxing and waning patterns over time and the randomness of extinction that the Red Queen's hypothesis implies.
C1 [Zliobaite, Indre; Fortelius, Mikael] Univ Helsinki, Dept Geosci & Geog, POB 64, FI-00014 Helsinki, Finland.
   [Zliobaite, Indre; Fortelius, Mikael; Stenseth, Nils C.] Univ Oslo, Ctr Ecol & Evolutionary Synth CEES, Dept Biosci, POB 1066 Blindern, NO-0316 Oslo, Norway.
   [Zliobaite, Indre] Univ Helsinki, Dept Comp Sci, POB 64, FI-00014 Helsinki, Finland.
C3 University of Helsinki; University of Oslo; University of Helsinki
RP Zliobaite, I (corresponding author), Univ Helsinki, Dept Geosci & Geog, POB 64, FI-00014 Helsinki, Finland.; Zliobaite, I (corresponding author), Univ Oslo, Ctr Ecol & Evolutionary Synth CEES, Dept Biosci, POB 1066 Blindern, NO-0316 Oslo, Norway.; Zliobaite, I (corresponding author), Univ Helsinki, Dept Comp Sci, POB 64, FI-00014 Helsinki, Finland.
EM indre.zliobaite@heslinki.fi
FU Finnish Academy (ECHOES project); Alexander von Humboldt Foundation; Research Council of Norway via CEES
NR 42
TC 63
Z9 65
U1 1
U2 82
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 7
PY 2017
VL 552
IS 7683
BP 92
EP +
DI 10.1038/nature24656
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FP4BA
UT WOS:000417560500049
PM 29186124
DA 2026-03-09
ER

PT J
AU Rozel, AB
   Golabek, GJ
   Jain, C
   Tackley, PJ
   Gerya, T
AF Rozel, A. B.
   Golabek, G. J.
   Jain, C.
   Tackley, P. J.
   Gerya, T.
TI Continental crust formation on early Earth controlled by intrusive magmatism
SO NATURE
LA English
DT Article
ID mantle convection; plate-tectonics; corona formation; venus; subduction; rheology; origin; novae; plume; evolution
AB The global geodynamic regime of early Earth, which operated before the onset of plate tectonics, remains contentious. As geological and geochemical data suggest hotter Archean mantle temperature(1,2) and more intense juvenile magmatism than in the present-day Earth(3,4), two crust-mantle interaction modes differing in melt eruption efficiency have been proposed: the Io-like heat-pipe tectonics regime dominated by volcanism(5,6) and the "Plutonic squishy lid" tectonics regime governed by intrusive magmatism, which is thought to apply to the dynamics of Venus(7-9). Both tectonics regimes are capable of producing primordial tonalite-trondhjemite-granodiorite (TTG) continental crust(5,10) but lithospheric geotherms and crust production rates as well as proportions of various TTG compositions differ greatly(9,10), which implies that the heat-pipe and Plutonic squishy lid hypotheses can be tested using natural data(11). Here we investigate the creation of primordial TTG-like continental crust using self-consistent numerical models of global thermochemical convection associated with magmatic processes. We show that the volcanism-dominated heat-pipe tectonics model results in cold crustal geotherms and is not able to produce Earth-like primordial continental crust. In contrast, the Plutonic squishy lid tectonics regime dominated by intrusive magmatism results in hotter crustal geotherms and is capable of reproducing the observed proportions of various TTG rocks. Using a systematic parameter study, we show that the typical modern eruption efficiency of less than 40 per cent(12) leads to the production of the expected amounts of the three main primordial crustal compositions previously reported from field data(4,11) (low-, medium- and high-pressure TTG). Our study thus suggests that the pre-plate-tectonics Archean Earth operated globally in the Plutonic squishy lid regime rather than in an Io-like heat-pipe regime.
C1 [Rozel, A. B.; Jain, C.; Tackley, P. J.; Gerya, T.] Swiss Fed Inst Technol, Inst Geophys, CH-8092 Zurich, Switzerland.
   [Golabek, G. J.] Univ Bayreuth, Bayer Geoinst, D-95440 Bayreuth, Germany.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Bayreuth
RP Rozel, AB (corresponding author), Swiss Fed Inst Technol, Inst Geophys, CH-8092 Zurich, Switzerland.
EM antoine.rozel@erdw.ethz.ch
FU European Research Council under the European Union/ERC [320639]; SNF [200020_166063]; European Research Council (ERC) [320639] Funding Source: European Research Council (ERC); Swiss National Science Foundation (SNF) [200020_166063] Funding Source: Swiss National Science Foundation (SNF)
NR 63
TC 177
Z9 193
U1 3
U2 127
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 18
PY 2017
VL 545
IS 7654
BP 332
EP +
DI 10.1038/nature22042
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV0WF
UT WOS:000401466500059
PM 28482358
DA 2026-03-09
ER

PT J
AU Escamilla, CO
   Filonova, I
   Walker, AK
   Xuan, ZX
   Holehonnur, R
   Espinosa, F
   Liu, SN
   Thyme, SB
   López-García, IA
   Mendoza, DB
   Usui, N
   Ellegood, J
   Eisch, AJ
   Konopka, G
   Lerch, JP
   Schier, AF
   Speed, HE
   Powell, CM
AF Escamilla, Christine Ochoa
   Filonova, Irina
   Walker, Angela K.
   Xuan, Zhong X.
   Holehonnur, Roopashri
   Espinosa, Felipe
   Liu, Shunan
   Thyme, Summer B.
   Lopez-Garcia, Isabel A.
   Mendoza, Dorian B.
   Usui, Noriyoshi
   Ellegood, Jacob
   Eisch, Amelia J.
   Konopka, Genevieve
   Lerch, Jason P.
   Schier, Alexander F.
   Speed, Haley E.
   Powell, Craig M.
TI Kctd13 deletion reduces synaptic transmission via increased RhoA
SO NATURE
LA English
DT Article
ID small gtpases; mouse; 16p11.2; brain; protein; mri; rim1-alpha; behaviors; neurons; number
AB Copy-number variants of chromosome 16 region 16p11.2 are linked to neuropsychiatric disorders(1-6) and are among the most prevalent in autism spectrum disorders(1,2,7). Of many 16p11.2 genes, Kctd13 has been implicated as a major driver of neurodevelopmental phenotypes(8,9). The function of KCTD13 in the mammalian brain, however, remains unknown. Here we delete the Kctd13 gene in mice and demonstrate reduced synaptic transmission. Reduced synaptic transmission correlates with increased levels of Ras homolog gene family, member A (RhoA), a KCTD13/CUL3 ubiquitin ligase substrate, and is reversed by RhoA inhibition, suggesting increased RhoA as an important mechanism. In contrast to a previous knockdown study(8), deletion of Kctd13 or kctd13 does not increase brain size or neurogenesis in mice or zebrafish, respectively. These findings implicate Kctd13 in the regulation of neuronal function relevant to neuropsychiatric disorders and clarify the role of Kctd13 in neurogenesis and brain size. Our data also reveal a potential role for RhoA as a therapeutic target in disorders associated with KCTD13 deletion.
C1 [Escamilla, Christine Ochoa; Filonova, Irina; Walker, Angela K.; Xuan, Zhong X.; Holehonnur, Roopashri; Espinosa, Felipe; Liu, Shunan; Lopez-Garcia, Isabel A.; Mendoza, Dorian B.; Speed, Haley E.; Powell, Craig M.] Univ Texas Southwestern Med Ctr Dallas, Dept Neurol & Neurotherapeut, Dallas, TX 75390 USA.
   [Thyme, Summer B.; Schier, Alexander F.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA.
   [Usui, Noriyoshi; Konopka, Genevieve; Powell, Craig M.] Univ Texas Southwestern Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA.
   [Ellegood, Jacob; Lerch, Jason P.] Hosp Sick Children, Mouse Imaging Ctr MICe, Toronto, ON M5T 3H7, Canada.
   [Eisch, Amelia J.; Powell, Craig M.] Univ Texas Southwestern Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA.
   [Lerch, Jason P.] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1X8, Canada.
   [Schier, Alexander F.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA.
   [Schier, Alexander F.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Schier, Alexander F.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA.
   [Schier, Alexander F.] Harvard Univ, FAS Ctr Syst Biol, Cambridge, MA 02138 USA.
   [Filonova, Irina] Grad Univ, Okinawa Inst Sci & Technol, Fac Affairs Off, 1919-1 Tancha, Onna Son, Okinawa 9040495, Japan.
   [Usui, Noriyoshi] Univ Fukui, Res Ctr Child Mental Dev, Div Dev Mental Funct, Fukui 9101193, Japan.
   [Usui, Noriyoshi] Chiba Univ, United Grad Sch Child Dev, Hamamatsu Univ,Kanazawa Univ,Osaka Univ, Div Dev Higher Brain Funct,Sch Med, Osaka 5650871, Japan.
   [Usui, Noriyoshi] Univ Fukui, Osaka 5650871, Japan.
   [Eisch, Amelia J.] Univ Penn, Perelman Sch Med, Dept Neurosci, Philadelphia, PA 19104 USA.
   [Eisch, Amelia J.] Childrens Hosp Philadelphia, Dept Anesthesiol & Crit Care Med, Philadelphia, PA 19104 USA.
C3 University of Texas System; University of Texas Southwestern Medical Center; Harvard University; University of Texas System; University of Texas Southwestern Medical Center; University of Toronto; Hospital for Sick Children (SickKids); University of Texas System; University of Texas Southwestern Medical Center; University of Toronto; Harvard University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University; Okinawa Institute of Science & Technology Graduate University; University of Fukui; Chiba University; Hamamatsu University School of Medicine; University of Osaka; Kanazawa University; University of Fukui; University of Pennsylvania; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia
RP Powell, CM (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Neurol & Neurotherapeut, Dallas, TX 75390 USA.; Powell, CM (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA.; Powell, CM (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA.
EM craig.powell@utsouthwestern.edu
FU National Institutes of Health (NIH) [R01HD069560, R01HD069560-S1, 2K02DA023555, MH102603, K99MH110603, R01HL109525, U01HG004085]; Autism Speaks; Hartwell Foundation; Ed and Sue Rose Distinguished Professorship in Neurology; BRAINS for Autism; Autism Science Foundation; Canadian Institute for Health Research; Ontario Brain Institute; NASA [NNX15AE09G]; Uehara Foundation; Damon Runyon Cancer Research Foundation; Harvard Brain Institute Bipolar Seed Grant; CSD Consortium [U01HG004080]; H2020 - Industrial Leadership [803243] Funding Source: H2020 - Industrial Leadership; NASA [803243, NNX15AE09G] Funding Source: Federal RePORTER
NR 63
TC 110
Z9 138
U1 0
U2 30
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 9
PY 2017
VL 551
IS 7679
BP 227
EP +
DI 10.1038/nature24470
PG 25
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM1KF
UT WOS:000414734200047
PM 29088697
DA 2026-03-09
ER

PT J
AU Zhang, ZP
   Tanaka, K
   Yu, JQ
AF Zhang, Zhipeng
   Tanaka, Keita
   Yu, Jin-Quan
TI Remote site-selective C-H activation directed by a catalytic bifunctional template
SO NATURE
LA English
DT Article
ID bond activation; asymmetric catalysis; bimetallic catalysis; meta; complexes; alkenylation; substitution; alkylation; arylation; ligands
AB In chemical syntheses, the activation of carbon-hydrogen (C-H) bonds converts them directly into carbon-carbon or carbonheteroatom bonds without requiring any prior functionalization. C-H activation can thus substantially reduce the number of steps involved in a synthesis. A single specific C-H bond in a substrate can be activated by using a 'directing' (usually a functional) group to obtain the desired product selectively(1-5). The applicability of such a C-H activation reaction can be severely curtailed by the distance of the C-H bond in question from the directing group, and by the shape of the substrate, but several approaches have been developed to overcome these limitations(6-12). In one such approach, an understanding of the distal and geometric relationships between the functional groups and C-H bonds of a substrate has been exploited to achieve meta-selective C-H activation by using a covalently attached, U-shaped template(13-17). However, stoichiometric installation of this template has not been feasible in the absence of an appropriate functional group on which to attach it. Here we report the design of a catalytic, bifunctional nitrile template that binds a heterocyclic substrate via a reversible coordination instead of a covalent linkage. The two metal centres coordinated to this template have different roles: one reversibly anchors substrates near the catalyst, and the other cleaves remote C-H bonds. Using this strategy, we demonstrate remote, site-selective C-H olefination of heterocyclic substrates that do not have the necessary functional groups for covalently attaching templates.
C1 [Zhang, Zhipeng; Tanaka, Keita; Yu, Jin-Quan] Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA.
C3 Scripps Research Institute
RP Yu, JQ (corresponding author), Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA.
EM yu200@scripps.edu
FU Scripps Research Institute; United States National Institutes of Health (National Institute of General Medical Sciences) [1R01 GM102265]; Ito Foundation for International Education Exchange; National Institute of General Medical Sciences [R01GM102265] Funding Source: NIH RePORTER
NR 30
TC 240
Z9 270
U1 7
U2 322
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 23
PY 2017
VL 543
IS 7646
BP 538
EP 542
DI 10.1038/nature21418
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EO9OM
UT WOS:000397018000048
PM 28273068
DA 2026-03-09
ER

PT J
AU Michailidou, K
   Lindstrom, S
   Dennis, J
   Beesley, J
   Hui, S
   Kar, S
   Lemaçon, A
   Soucy, P
   Glubb, D
   Rostamianfar, A
   Bolla, MK
   Wang, Q
   Tyrer, J
   Dicks, E
   Lee, A
   Wang, ZM
   Allen, J
   Keeman, R
   Eilber, U
   French, JD
   Chen, XQ
   Fachal, L
   Mccue, K
   McCart, AE
   Reed, AEM
   Ghoussaini, M
   Carroll, JS
   Jiang, X
   Finucane, H
   Adams, M
   Adank, MA
   Ahsan, H
   Aittomaki, K
   Anton-Culver, H
   Antonenkova, NN
   Arndt, V
   Aronson, KJ
   Arun, B
   Auer, PL
   Bacot, F
   Barrdahl, M
   Baynes, C
   Beckmann, MW
   Behrens, S
   Benitez, J
   Bermisheva, M
   Bernstein, L
   Blomqvist, C
   Bogdanova, NV
   Bojesen, SE
   Bonanni, B
   Borresen-Dale, AL
   Brand, JS
   Brauch, H
   Brennan, P
   Brenner, H
   Brinton, L
   Broberg, P
   Brock, IW
   Broeks, A
   Brooks-Wilson, A
   Brucker, SY
   Brüning, T
   Burwinkel, B
   Butterbach, K
   Cai, QY
   Cai, H
   Caldés, T
   Canzian, F
   Carracedo, A
   Carter, BD
   Castelao, JE
   Chan, TL
   Cheng, TYD
   Chia, KS
   Choi, JY
   Christiansen, H
   Clarke, CL
   Collée, M
   Conroy, DM
   Cordina-Duverger, E
   Cornelissen, S
   Cox, DG
   Cox, A
   Cross, SS
   Cunningham, JM
   Czene, K
   Daly, MB
   Devilee, P
   Doheny, KF
   Dörk, T
   dos-Santos-Silva, I
   Dumont, M
   Durcan, L
   Dwek, M
   Eccles, DM
   Ekici, AB
   Eliassen, AH
   Ellberg, C
   Elvira, M
   Engel, C
   Eriksson, M
   Fasching, PA
   Figueroa, J
   Flesch-Janys, D
   Fletcher, O
   Flyger, H
   Fritschi, L
   Gaborieau, V
   Gabrielson, M
   Gago-Dominguez, M
   Gao, YT
   Gapstur, SM
   García-Sáenz, JA
   Gaudet, MM
   Georgoulias, V
   Giles, GG
   Glendon, G
   Goldberg, MS
   Goldgar, DE
   González-Neira, A
   Alnæs, GIG
   Grip, M
   Gronwald, J
   Grundy, A
   Guénel, P
   Haeberle, L
   Hahnen, E
   Haiman, CA
   Håkansson, N
   Hamann, U
   Hamel, N
   Hankinson, S
   Harrington, P
   Hart, SN
   Hartikainen, JM
   Hartman, M
   Hein, A
   Heyworth, J
   Hicks, B
   Hillemanns, P
   Ho, DN
   Hollestelle, A
   Hooning, MJ
   Hoover, RN
   Hopper, JL
   Hou, MF
   Hsiung, CN
   Huang, GMQ
   Humphreys, K
   Ishiguro, J
   Ito, H
   Iwasaki, M
   Iwata, H
   Jakubowska, A
   Janni, W
   John, EM
   Johnson, N
   Jones, K
   Jones, M
   Jukkola-Vuorinen, A
   Kaaks, R
   Kabisch, M
   Kaczmarek, K
   Kang, D
   Kasuga, Y
   Kerin, MJ
   Khan, S
   Khusnutdinova, E
   Kiiski, JI
   Kim, SW
   Knight, JA
   Kosma, VM
   Kristensen, VN
   Krüger, U
   Kwong, A
   Lambrechts, D
   Le Marchand, L
   Lee, E
   Lee, MH
   Lee, JW
   Lee, CN
   Lejbkowicz, F
   Li, JM
   Lilyquist, J
   Lindblom, A
   Lissowska, J
   Lo, WY
   Loibl, S
   Long, JR
   Lophatananon, A
   Lubinski, J
   Luccarini, C
   Lux, MP
   Ma, ESK
   MacInnis, RJ
   Maishman, T
   Makalic, E
   Malone, KE
   Kostovska, IM
   Mannermaa, A
   Manoukian, S
   Manson, JE
   Margolin, S
   Mariapun, S
   Martinez, ME
   Matsuo, K
   Mavroudis, D
   McKay, J
   McLean, C
   Meijers-Heijboer, H
   Meindl, A
   Menéndez, P
   Menon, U
   Meyer, J
   Miao, H
   Miller, N
   Taib, NAM
   Muir, K
   Mulligan, AM
   Mulot, C
   Neuhausen, SL
   Nevanlinna, H
   Neven, P
   Nielsen, SF
   Noh, DY
   Nordestgaard, BG
   Norman, A
   Olopade, OI
   Olson, JE
   Olsson, H
   Olswold, C
   Orr, N
   Pankratz, VS
   Park, SK
   Park-Simon, TW
   Lloyd, R
   Perez, JIA
   Peterlongo, P
   Peto, J
   Phillips, KA
   Pinchev, M
   Plaseska-Karanfilska, D
   Prentice, R
   Presneau, N
   Prokofyeva, D
   Pugh, E
   Pylkas, K
   Rack, B
   Radice, P
   Rahman, N
   Rennert, G
   Rennert, HS
   Rhenius, V
   Romero, A
   Romm, J
   Ruddy, KJ
   Rüdiger, T
   Rudolph, A
   Ruebner, M
   Rutgers, EJT
   Saloustros, E
   Sandler, DP
   Sangrajrang, S
   Sawyer, EJ
   Schmidt, DF
   Schmutzler, RK
   Schneeweiss, A
   Schoemaker, MJ
   Schumacher, F
   Schürmann, P
   Scott, RJ
   Scott, C
   Seal, S
   Seynaeve, C
   Shah, M
   Sharma, P
   Shen, CY
   Sheng, G
   Sherman, ME
   Shrubsole, MJ
   Shu, XO
   Smeets, A
   Sohn, C
   Southey, MC
   Spinelli, JJ
   Stegmaier, C
   Stewart-Brown, S
   Stone, J
   Stram, DO
   Surowy, H
   Swerdlow, A
   Tamimi, R
   Taylor, JA
   Tengström, M
   Teo, SH
   Terry, MB
   Tessier, DC
   Thanasitthichai, S
   Thöne, K
   Tollenaar, RAEM
   Tomlinson, I
   Tong, L
   Torres, D
   Truong, T
   Tseng, CC
   Tsugane, S
   Ulmer, HU
   Ursin, G
   Untch, M
   Vachon, C
   van Asperen, CJ
   Van Den Berg, D
   van den Ouweland, AMW
   van der Kolk, L
   van der Luijt, RB
   Vincent, D
   Vollenweider, J
   Waisfisz, Q
   Wang-Gohrke, S
   Weinberg, CR
   Wendt, C
   Whittemore, AS
   Wildiers, H
   Willett, W
   Winqvist, R
   Wolk, A
   Wu, AH
   Xia, L
   Yamaji, T
   Yang, XHR
   Yip, CH
   Yoo, KY
   Yu, JC
   Zheng, W
   Zheng, Y
   Zhu, B
   Ziogas, A
   Ziv, E
   Lakhani, SR
   Antoniou, AC
   Droit, A
   Andrulis, IL
   Amos, CI
   Couch, FJ
   Pharoah, PDP
   Chang-Claude, J
   Hall, P
   Hunter, DJ
   Milne, RL
   García-Closas, M
   Schmidt, MK
   Chanock, SJ
   Dunning, AM
   Edwards, SL
   Bader, GD
   Chenevix-Trench, G
   Simard, J
   Kraft, P
   Easton, DF
AF Michailidou, Kyriaki
   Lindstrom, Sara
   Dennis, Joe
   Beesley, Jonathan
   Hui, Shirley
   Kar, Siddhartha
   Lemacon, Audrey
   Soucy, Penny
   Glubb, Dylan
   Rostamianfar, Asha
   Bolla, Manjeet K.
   Wang, Qin
   Tyrer, Jonathan
   Dicks, Ed
   Lee, Andrew
   Wang, Zhaoming
   Allen, Jamie
   Keeman, Renske
   Eilber, Ursula
   French, Juliet D.
   Chen, Xiao Qing
   Fachal, Laura
   McCue, Karen
   McCart, Amy E.
   Reed, Amy E. McCart
   Ghoussaini, Maya
   Carroll, Jason S.
   Jiang, Xia
   Finucane, Hilary
   Adams, Marcia
   Adank, Muriel A.
   Ahsan, Habibul
   Aittomaki, Kristiina
   Anton-Culver, Hoda
   Antonenkova, Natalia N.
   Arndt, Volker
   Aronson, Kristan J.
   Arun, Banu
   Auer, Paul L.
   Bacot, Francois
   Barrdahl, Myrto
   Baynes, Caroline
   Beckmann, Matthias W.
   Behrens, Sabine
   Benitez, Javier
   Bermisheva, Marina
   Bernstein, Leslie
   Blomqvist, Carl
   Bogdanova, Natalia V.
   Bojesen, Stig E.
   Bonanni, Bernardo
   Borresen-Dale, Anne-Lise
   Brand, Judith S.
   Brauch, Hiltrud
   Brennan, Paul
   Brenner, Hermann
   Brinton, Louise
   Broberg, Per
   Brock, Ian W.
   Broeks, Annegien
   Brooks-Wilson, Angela
   Brucker, Sara Y.
   Bruening, Thomas
   Burwinkel, Barbara
   Butterbach, Katja
   Cai, Qiuyin
   Cai, Hui
   Caldes, Trinidad
   Canzian, Federico
   Carracedo, Angel
   Carter, Brian D.
   Castelao, Jose E.
   Chan, Tsun L.
   Cheng, Ting-Yuan David
   Chia, Kee Seng
   Choi, Ji-Yeob
   Christiansen, Hans
   Clarke, Christine L.
   Collee, Margriet
   Conroy, Don M.
   Cordina-Duverger, Emilie
   Cornelissen, Sten
   Cox, David G.
   Cox, Angela
   Cross, Simon S.
   Cunningham, Julie M.
   Czene, Kamila
   Daly, Mary B.
   Devilee, Peter
   Doheny, Kimberly F.
   Doerk, Thilo
   dos-Santos-Silva, Isabel
   Dumont, Martine
   Durcan, Lorraine
   Dwek, Miriam
   Eccles, Diana M.
   Ekici, Arif B.
   Eliassen, A. Heather
   Ellberg, Carolina
   Elvira, Mingajeva
   Engel, Christoph
   Eriksson, Mikael
   Fasching, Peter A.
   Figueroa, Jonine
   Flesch-Janys, Dieter
   Fletcher, Olivia
   Flyger, Henrik
   Fritschi, Lin
   Gaborieau, Valerie
   Gabrielson, Marike
   Gago-Dominguez, Manuela
   Gao, Yu-Tang
   Gapstur, Susan M.
   Garcia-Saenz, Jose A.
   Gaudet, Mia M.
   Georgoulias, Vassilios
   Giles, Graham G.
   Glendon, Gord
   Goldberg, Mark S.
   Goldgar, David E.
   Gonzalez-Neira, Anna
   Alnaes, Grethe I. Grenaker
   Grip, Mervi
   Gronwald, Jacek
   Grundy, Anne
   Guenel, Pascal
   Haeberle, Lothar
   Hahnen, Eric
   Haiman, Christopher A.
   Hakansson, Niclas
   Hamann, Ute
   Hamel, Nathalie
   Hankinson, Susan
   Harrington, Patricia
   Hart, Steven N.
   Hartikainen, Jaana M.
   Hartman, Mikael
   Hein, Alexander
   Heyworth, Jane
   Hicks, Belynda
   Hillemanns, Peter
   Ho, Dona N.
   Hollestelle, Antoinette
   Hooning, Maartje J.
   Hoover, Robert N.
   Hopper, John L.
   Hou, Ming-Feng
   Hsiung, Chia-Ni
   Huang, Guanmengqian
   Humphreys, Keith
   Ishiguro, Junko
   Ito, Hidemi
   Iwasaki, Motoki
   Iwata, Hiroji
   Jakubowska, Anna
   Janni, Wolfgang
   John, Esther M.
   Johnson, Nichola
   Jones, Kristine
   Jones, Michael
   Jukkola-Vuorinen, Arja
   Kaaks, Rudolf
   Kabisch, Maria
   Kaczmarek, Katarzyna
   Kang, Daehee
   Kasuga, Yoshio
   Kerin, Michael J.
   Khan, Sofia
   Khusnutdinova, Elza
   Kiiski, Johanna I.
   Kim, Sung-Won
   Knight, Julia A.
   Kosma, Veli-Matti
   Kristensen, Vessela N.
   Kruger, Ute
   Kwong, Ava
   Lambrechts, Diether
   Le Marchand, Loic
   Lee, Eunjung
   Lee, Min Hyuk
   Lee, Jong Won
   Lee, Chuen Neng
   Lejbkowicz, Flavio
   Li, Jingmei
   Lilyquist, Jenna
   Lindblom, Annika
   Lissowska, Jolanta
   Lo, Wing-Yee
   Loibl, Sibylle
   Long, Jirong
   Lophatananon, Artitaya
   Lubinski, Jan
   Luccarini, Craig
   Lux, Michael P.
   Ma, Edmond S. K.
   MacInnis, Robert J.
   Maishman, Tom
   Makalic, Enes
   Malone, Kathleen E.
   Kostovska, Ivana Maleva
   Mannermaa, Arto
   Manoukian, Siranoush
   Manson, Joann E.
   Margolin, Sara
   Mariapun, Shivaani
   Martinez, Maria Elena
   Matsuo, Keitaro
   Mavroudis, Dimitrios
   McKay, James
   McLean, Catriona
   Meijers-Heijboer, Hanne
   Meindl, Alfons
   Menendez, Primitiva
   Menon, Usha
   Meyer, Jeffery
   Miao, Hui
   Miller, Nicola
   Taib, Nur Aishah Mohd
   Muir, Kenneth
   Mulligan, Anna Marie
   Mulot, Claire
   Neuhausen, Susan L.
   Nevanlinna, Heli
   Neven, Patrick
   Nielsen, Sune F.
   Noh, Dong-Young
   Nordestgaard, Borge G.
   Norman, Aaron
   Olopade, Olufunmilayo I.
   Olson, Janet E.
   Olsson, Hakan
   Olswold, Curtis
   Orr, Nick
   Pankratz, V. Shane
   Park, Sue K.
   Park-Simon, Tjoung-Won
   Lloyd, Rachel
   Perez, Jose I. A.
   Peterlongo, Paolo
   Peto, Julian
   Phillips, Kelly-Anne
   Pinchev, Mila
   Plaseska-Karanfilska, Dijana
   Prentice, Ross
   Presneau, Nadege
   Prokofyeva, Darya
   Pugh, Elizabeth
   Pylkas, Katri
   Rack, Brigitte
   Radice, Paolo
   Rahman, Nazneen
   Rennert, Gadi
   Rennert, Hedy S.
   Rhenius, Valerie
   Romero, Atocha
   Romm, Jane
   Ruddy, Kathryn J.
   Ruediger, Thomas
   Rudolph, Anja
   Ruebner, Matthias
   Rutgers, Emiel J. T.
   Saloustros, Emmanouil
   Sandler, Dale P.
   Sangrajrang, Suleeporn
   Sawyer, Elinor J.
   Schmidt, Daniel F.
   Schmutzler, Rita K.
   Schneeweiss, Andreas
   Schoemaker, Minouk J.
   Schumacher, Fredrick
   Schuermann, Peter
   Scott, Rodney J.
   Scott, Christopher
   Seal, Sheila
   Seynaeve, Caroline
   Shah, Mitul
   Sharma, Priyanka
   Shen, Chen-Yang
   Sheng, Grace
   Sherman, Mark E.
   Shrubsole, Martha J.
   Shu, Xiao-Ou
   Smeets, Ann
   Sohn, Christof
   Southey, Melissa C.
   Spinelli, John J.
   Stegmaier, Christa
   Stewart-Brown, Sarah
   Stone, Jennifer
   Stram, Daniel O.
   Surowy, Harald
   Swerdlow, Anthony
   Tamimi, Rulla
   Taylor, Jack A.
   Tengstrom, Maria
   Teo, Soo H.
   Terry, Mary Beth
   Tessier, Daniel C.
   Thanasitthichai, Somchai
   Thoene, Kathrin
   Tollenaar, Rob A. E. M.
   Tomlinson, Ian
   Tong, Ling
   Torres, Diana
   Truong, Therese
   Tseng, Chiu-Chen
   Tsugane, Shoichiro
   Ulmer, Hans-Ulrich
   Ursin, Giske
   Untch, Michael
   Vachon, Celine
   van Asperen, Christi J.
   Van Den Berg, David
   van den Ouweland, Ans M. W.
   van der Kolk, Lizet
   van der Luijt, Rob B.
   Vincent, Daniel
   Vollenweider, Jason
   Waisfisz, Quinten
   Wang-Gohrke, Shan
   Weinberg, Clarice R.
   Wendt, Camilla
   Whittemore, Alice S.
   Wildiers, Hans
   Willett, Walter
   Winqvist, Robert
   Wolk, Alicja
   Wu, Anna H.
   Xia, Lucy
   Yamaji, Taiki
   Yang, Xiaohong R.
   Yip, Cheng Har
   Yoo, Keun-Young
   Yu, Jyh-Cherng
   Zheng, Wei
   Zheng, Ying
   Zhu, Bin
   Ziogas, Argyrios
   Ziv, Elad
   Lakhani, Sunil R.
   Antoniou, Antonis C.
   Droit, Arnaud
   Andrulis, Irene L.
   Amos, Christopher I.
   Couch, Fergus J.
   Pharoah, Paul D. P.
   Chang-Claude, Jenny
   Hall, Per
   Hunter, David J.
   Milne, Roger L.
   Garcia-Closas, Montserrat
   Schmidt, Marjanka K.
   Chanock, Stephen J.
   Dunning, Alison M.
   Edwards, Stacey L.
   Bader, Gary D.
   Chenevix-Trench, Georgia
   Simard, Jacques
   Kraft, Peter
   Easton, Douglas F.
TI Association analysis identifies 65 new breast cancer risk loci
SO NATURE
LA English
DT Article
ID genome-wide association; comprehensive molecular portraits; susceptibility loci; pathway analysis; protein; expression; mutations; architecture; annotation; enhancers
AB Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry(1). We identified 65 new loci that are associated with overall breast cancer risk at P < 5 x 10(-8). The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.
C1 [Michailidou, Kyriaki; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; Lee, Andrew; Allen, Jamie; Antoniou, Antonis C.; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England.
   [Michailidou, Kyriaki] Cyprus Inst Neurol & Genet, Dept Electron Microscopy Mol Pathol, Nicosia, Cyprus.
   [Lindstrom, Sara] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA.
   [Lindstrom, Sara; Jiang, Xia; Finucane, Hilary; Tamimi, Rulla; Hunter, David J.; Kraft, Peter] Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA.
   [Beesley, Jonathan; Glubb, Dylan; French, Juliet D.; Chen, Xiao Qing; McCue, Karen; Edwards, Stacey L.; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld, Australia.
   [Hui, Shirley; Rostamianfar, Asha; Bader, Gary D.] Univ Toronto, Donnelly Ctr, Toronto, ON, Canada.
   [Kar, Siddhartha; Tyrer, Jonathan; Dicks, Ed; Fachal, Laura; Ghoussaini, Maya; Baynes, Caroline; Conroy, Don M.; Harrington, Patricia; Ho, Dona N.; Luccarini, Craig; Rhenius, Valerie; Shah, Mitul; Pharoah, Paul D. P.; Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England.
   [Lemacon, Audrey; Soucy, Penny; Dumont, Martine; Droit, Arnaud; Simard, Jacques] Laval Univ, Genom Ctr, Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ, Canada.
   [Wang, Zhaoming] St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA.
   [Wang, Zhaoming; Hicks, Belynda; Jones, Kristine; Zhu, Bin] NCI, Canc Genom Res Lab CGR, Div Canc Epidemiol & Genet, Rockville, MD USA.
   [Keeman, Renske; Broeks, Annegien; Cornelissen, Sten; Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands.
   [Eilber, Ursula; Barrdahl, Myrto; Behrens, Sabine; Kaaks, Rudolf; Rudolph, Anja; Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany.
   [Reed, Amy E. McCart; Lakhani, Sunil R.] Univ Queensland, Ctr Clin Res, Brisbane, Qld, Australia.
   [Carroll, Jason S.] Univ Cambridge, Canc Res UK Cambridge Res Inst, Li Ka Shing Ctr, Cambridge, England.
   [Finucane, Hilary] MIT, Dept Math, Cambridge, MA 02139 USA.
   [Adams, Marcia; Doheny, Kimberly F.; Pugh, Elizabeth; Romm, Jane] Johns Hopkins Univ, Sch Med, Inst Med Genet, CIDR, Baltimore, MD USA.
   [Adank, Muriel A.; Meijers-Heijboer, Hanne; Waisfisz, Quinten] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands.
   [Ahsan, Habibul; Tong, Ling] Univ Chicago, Ctr Canc Epidemiol & Prevent, Chicago, IL 60637 USA.
   [Aittomaki, Kristiina] Univ Helsinki, Helsinki Univ Hosp, Dep Clin Genet, Helsinki, Finland.
   [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA.
   [Antonenkova, Natalia N.; Bogdanova, Natalia V.] NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, BELARUS.
   [Arndt, Volker; Brenner, Hermann; Butterbach, Katja] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
   [Aronson, Kristan J.] Queens Univ, Dept Publ Hlth Sci, Kingston, ON, Canada.
   [Aronson, Kristan J.] Queens Univ, Canc Res Inst, Kingston, ON, Canada.
   [Arun, Banu] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA.
   [Auer, Paul L.; Prentice, Ross] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA.
   [Auer, Paul L.] Univ Wisconsin Milwaukee, Zilber Sch Publ Hlth, Milwaukee, WI USA.
   [Bacot, Francois; Hamel, Nathalie; Tessier, Daniel C.; Vincent, Daniel] McGill Univ, Montreal, PQ, Canada.
   [Bacot, Francois; Hamel, Nathalie; Tessier, Daniel C.; Vincent, Daniel] Genome Quebec Innovat Ctr, Montreal, PQ, Canada.
   [Beckmann, Matthias W.; Fasching, Peter A.; Haeberle, Lothar; Hein, Alexander; Lux, Michael P.; Ruebner, Matthias] Friedrich Alexander Univ Erlangen Nuremberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynecol & Obstet, Erlangen, Germany.
   [Benitez, Javier; Gonzalez-Neira, Anna] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain.
   [Benitez, Javier] Ctr Invest Red Enfermedades Raras CIBERER, Valencia, Spain.
   [Bermisheva, Marina; Khusnutdinova, Elza] Russian Acad Sci, Ufa Sci Ctr, Inst Biochem & Genet, Ufa, Russia.
   [Bernstein, Leslie; Neuhausen, Susan L.] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA.
   [Blomqvist, Carl] Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland.
   [Bogdanova, Natalia V.; Christiansen, Hans] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany.
   [Bogdanova, Natalia V.; Doerk, Thilo; Hillemanns, Peter; Park-Simon, Tjoung-Won; Schuermann, Peter] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany.
   [Bojesen, Stig E.; Nielsen, Sune F.; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark.
   [Bojesen, Stig E.; Nielsen, Sune F.; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark.
   [Bojesen, Stig E.; Nordestgaard, Borge G.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.
   [Bonanni, Bernardo] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy.
   [Borresen-Dale, Anne-Lise; Alnaes, Grethe I. Grenaker; Kristensen, Vessela N.] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.
   [Brand, Judith S.; Czene, Kamila; Eriksson, Mikael; Gabrielson, Marike; Humphreys, Keith; Li, Jingmei; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
   [Brauch, Hiltrud; Lo, Wing-Yee] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany.
   [Brauch, Hiltrud; Lindblom, Annika] Univ Tubingen, Tubingen, Germany.
   [Brauch, Hiltrud; Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany.
   [Brennan, Paul; Gaborieau, Valerie; McKay, James] Int Agcy Res Canc, Lyon, France.
   [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.
   [Brenner, Hermann] Natl Ctr Tumor Dis NCT, Heidelberg, Germany.
   [Brinton, Louise; Figueroa, Jonine; Hoover, Robert N.; Yang, Xiaohong R.; Garcia-Closas, Montserrat; Chanock, Stephen J.] Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA.
   [Broberg, Per; Ellberg, Carolina; Kruger, Ute; Olsson, Hakan] Lund Univ, Dept Canc Epidemiol, Clin Sci, Lund, Sweden.
   [Brock, Ian W.; Cox, Angela] Univ Sheffield, Dept Oncol & Metab, Sheffield Inst Nucle Acids SInFoNiA, Sheffield, S Yorkshire, England.
   [Brooks-Wilson, Angela] BC Canc Agcy, Genome Sci Ctr, Vancouver, BC, Canada.
   [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC, Canada.
   [Brucker, Sara Y.] Univ Tubingen, Dept Gynecol & Obstet, Tubingen, Germany.
   [Bruening, Thomas] Ruhr Univ Bochum, German Social Accid Insurance Inst, Inst Prevent & Occupat Med, Bochum, Germany.
   [Burwinkel, Barbara; Schneeweiss, Andreas; Surowy, Harald] Heidelberg Univ, Dept Obstet & Gynaecol, Heidelberg, Germany.
   [Burwinkel, Barbara; Surowy, Harald] German Canc Res Ctr, Mol Epidemiol Grp C080, Heidelberg, Germany.
   [Cai, Qiuyin; Cai, Hui; Long, Jirong; Shrubsole, Martha J.; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr,Dept Med,Div Epidemiol, Nashville, TN 37212 USA.
   [Caldes, Trinidad; Garcia-Saenz, Jose A.; Romero, Atocha] IdISSC Ctr Invest Biomed Red, CIBERONC, Inst Invest Sanitaria San Carlos, Hosp Clin San Carlos,Med Oncol Dept, Madrid, Spain.
   [Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany.
   [Carracedo, Angel; Gago-Dominguez, Manuela] Complejo Hosp Univ Santiago, Inst Invest Sanitaria Santiago Compostela IDIS, Galician Fdn Genom Med, Genom Med Grp,SERGAS, Santiago De Compostela, Spain.
   [Carracedo, Angel] Univ Santiago Compostela, Ctr Invest Red Enfermedades Raras CIBERER, Santiago De Compostela, Spain.
   [Carracedo, Angel] Univ Santiago Compostela, Ctr Nacl Genotipado CEGEN PRB2, Santiago De Compostela, Spain.
   [Carter, Brian D.; Gapstur, Susan M.; Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA.
   [Castelao, Jose E.] Xerencia Xest Integrada Vigo SERGAS, Inst Investigac Biomed IBI, Oncol & Genet Unit, Orense Pontevedra Vigo, Vigo, Spain.
   [Chan, Tsun L.; Kwong, Ava; Ma, Edmond S. K.] Hong Kong Hereditary Breast Canc Family Registry, Happy Valley, Peoples R China.
   [Chan, Tsun L.; Ho, Dona N.; Ma, Edmond S. K.] Hong Kong Sanat & Hosp, Dept Pathol, Happy Valley, Peoples R China.
   [Cheng, Ting-Yuan David] Roswell Pk Canc Inst, Div Canc Prevent & Control, Buffalo, NY 14263 USA.
   [Chia, Kee Seng; Hartman, Mikael; Miao, Hui] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.
   [Choi, Ji-Yeob; Kang, Daehee; Park, Sue K.] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Seoul, South Korea.
   [Choi, Ji-Yeob; Kang, Daehee; Park, Sue K.] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea.
   [Clarke, Christine L.] Univ Sydney, Westmead Inst Med Res, Sydney, NSW, Australia.
   [Collee, Margriet; van den Ouweland, Ans M. W.] Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands.
   [Cordina-Duverger, Emilie; Guenel, Pascal; Truong, Therese] Univ Paris Saclay, Univ Paris Sud, Ctr Res Epidemiol & Populat Hlth CESP, Canc & Environm Grp,INSERM, Villejuif, France.
   [Cox, David G.] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.
   [Cox, David G.] Canc Res Ctr Lyon, INSERM U1052, Lyon, France.
   [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England.
   [Cunningham, Julie M.; Meyer, Jeffery; Vollenweider, Jason; Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA.
   [Daly, Mary B.] Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA.
   [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands.
   [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands.
   [dos-Santos-Silva, Isabel; Peto, Julian] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England.
   [Durcan, Lorraine; Maishman, Tom] Univ Southampton, Fac Med, Southampton Clin Trials Unit, Southampton, Hants, England.
   [Durcan, Lorraine; Eccles, Diana M.; Maishman, Tom] Univ Southampton, Fac Med, Cancer Sci Acad Unit, Southampton, Hants, England.
   [Dwek, Miriam; Presneau, Nadege] Univ Westminster, Fac Sci & Technol, Dept Biomed Sci, London, England.
   [Ekici, Arif B.] Friedrich Alexander Univ Erlangen Nuremberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Inst Human Genet, Erlangen, Germany.
   [Eliassen, A. Heather; Tamimi, Rulla] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA USA.
   [Eliassen, A. Heather; Manson, Joann E.; Tamimi, Rulla; Willett, Walter; Hunter, David J.; Kraft, Peter] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.
   [Ellberg, Carolina] Lund Univ, Dept Clin Sci, Oncol & Pathol, Lund, Sweden.
   [Elvira, Mingajeva; Khusnutdinova, Elza; Prokofyeva, Darya] Bashkir State Univ, Dept Genet & Fundamental Med, Ufa, Russia.
   [Engel, Christoph] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany.
   [Engel, Christoph] Univ Leipzig, Leipzig Res Ctr Civilizat Dis, LIFE, Leipzig, Germany.
   [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA.
   [Figueroa, Jonine] Univ Edinburgh, Med Sch, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland.
   [Flesch-Janys, Dieter] Univ Med Ctr Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany.
   [Flesch-Janys, Dieter; Thoene, Kathrin] Univ Med Ctr Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany.
   [Fletcher, Olivia; Johnson, Nichola; Orr, Nick] Inst Canc Res, Breast Canc Now Toby Robins Res Ctr, London, England.
   [Flyger, Henrik] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Breast Surg, Herlev, Denmark.
   [Fritschi, Lin] Curtin Univ, Sch Publ Hlth, Perth, WA, Australia.
   [Gago-Dominguez, Manuela; Martinez, Maria Elena] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA.
   [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China.
   [Georgoulias, Vassilios; Mavroudis, Dimitrios] Univ Hosp Herakl, Dept Med Oncol, Iraklion, Greece.
   [Giles, Graham G.; MacInnis, Robert J.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.
   [Giles, Graham G.; Hopper, John L.; MacInnis, Robert J.; Makalic, Enes; Phillips, Kelly-Anne; Schmidt, Daniel F.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia.
   [Glendon, Gord; Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Fred A Litwin Ctr Canc Genet, Toronto, ON, Canada.
   [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ, Canada.
   [Goldberg, Mark S.] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ, Canada.
   [Goldgar, David E.] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, Salt Lake City, UT USA.
   [Grip, Mervi] Univ Oulu, Oulu Univ Hosp, Dept Surg, Oulu, Finland.
   [Gronwald, Jacek; Jakubowska, Anna; Kaczmarek, Katarzyna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland.
   [Grundy, Anne] Univ Montreal, Ctr Rech, CHUM, Montreal, PQ, Canada.
   [Hahnen, Eric; Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany.
   [Hahnen, Eric; Schmutzler, Rita K.] Univ Hosp Cologne, CIO, Cologne, Germany.
   [Hahnen, Eric; Schmutzler, Rita K.] Univ Cologne, CMMC, Cologne, Germany.
   [Haiman, Christopher A.; Lee, Eunjung; Sheng, Grace; Stram, Daniel O.; Tseng, Chiu-Chen; Van Den Berg, David; Wu, Anna H.; Xia, Lucy] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA.
   [Hakansson, Niclas; Wolk, Alicja] Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
   [Hamann, Ute; Huang, Guanmengqian; Kabisch, Maria; Torres, Diana] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany.
   [Hankinson, Susan] Univ Massachusetts Amherst, Dept Biostat & Epidemiol, Amherst, MA USA.
   [Hart, Steven N.; Lilyquist, Jenna; Norman, Aaron; Olson, Janet E.; Olswold, Curtis; Scott, Christopher; Vachon, Celine] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA.
   [Hartikainen, Jaana M.; Kosma, Veli-Matti; Mannermaa, Arto; Tengstrom, Maria] Univ Eastern Finland, Translat Canc Res Area, Kuopio, Finland.
   [Hartikainen, Jaana M.; Kosma, Veli-Matti; Mannermaa, Arto] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland.
   [Hartikainen, Jaana M.; Kosma, Veli-Matti; Mannermaa, Arto] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio, Finland.
   [Hartman, Mikael; Lee, Chuen Neng] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore.
   [Heyworth, Jane] Univ Western Australia, Sch Populat Hlth, Perth, WA, Australia.
   [Hollestelle, Antoinette; Hooning, Maartje J.; Seynaeve, Caroline] Erasmus MC Canc Inst, Dept Med Oncol, Family Canc Clin, Rotterdam, Netherlands.
   [Hou, Ming-Feng] Kaohsiung Med Univ, Dept Surg, Div Breast Surg, Kaohsiung, Taiwan.
   [Hsiung, Chia-Ni] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan.
   [Ishiguro, Junko; Ito, Hidemi] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan.
   [Ishiguro, Junko; Ito, Hidemi; Matsuo, Keitaro] Nagoya Univ, Grad Sch Med, Dept Epidemiol, Nagoya, Aichi, Japan.
   [Iwasaki, Motoki; Yamaji, Taiki] Natl Canc Ctr, Ctr Publ Hlth Sci, Div Epidemiol, Tokyo, Japan.
   [Iwata, Hiroji] Aichi Canc Ctr Hosp, Dept Breast Oncol, Nagoya, Aichi, Japan.
   [Janni, Wolfgang] Univ Hosp Ulm, Dept Gynecol & Obstet, Ulm, Germany.
   [John, Esther M.] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA.
   [John, Esther M.; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA.
   [John, Esther M.; Whittemore, Alice S.] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA.
   [Jones, Michael; Schoemaker, Minouk J.; Swerdlow, Anthony] Inst Canc Res, Div Genet & Epidemiol, London, England.
   [Jukkola-Vuorinen, Arja] Univ Oulu, Oulu Univ Hosp, Dept Oncol, Oulu, Finland.
   [Kang, Daehee; Park, Sue K.] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea.
   [Kasuga, Yoshio] Nagano Matsushiro Gen Hosp, Dept Surg, Nagano, Japan.
   [Kerin, Michael J.; Miller, Nicola] Natl Univ Ireland, Sch Med, Galway, Ireland.
   [Khan, Sofia; Kiiski, Johanna I.; Nevanlinna, Heli] Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynaecol, Helsinki, Finland.
   [Kim, Sung-Won] Daerim St Marys Hosp, Dept Surg, Seoul, South Korea.
   [Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON, Canada.
   [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada.
   [Kristensen, Vessela N.] Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway.
   [Kristensen, Vessela N.] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway.
   [Kwong, Ava] Univ Hong Kong, Dept Surg, Pok Fu Lam, Peoples R China.
   [Kwong, Ava] Hong Kong Sanat & Hosp, Dept Surg, Happy Valley, Peoples R China.
   [Lambrechts, Diether] VIB, Vesalius Res Ctr, Leuven, Belgium.
   [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium.
   [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA.
   [Lee, Min Hyuk] Soonchunhyang Univ, Coll Med, Dept Surg, Seoul, South Korea.
   [Lee, Min Hyuk] Soonchunhyang Univ Hosp, Seoul, South Korea.
   [Lee, Jong Won] Univ Ulsan, Coll Med, Dept Surg, Seoul, South Korea.
   [Lee, Jong Won] Asan Med Ctr, Seoul, South Korea.
   [Lee, Chuen Neng] Natl Univ Hlth Syst, Dept Cardiac Thorac & Vasc Surg, Singapore, Singapore.
   [Lejbkowicz, Flavio; Pinchev, Mila; Rennert, Gadi; Rennert, Hedy S.] Carmel Hosp, Clalit Natl Canc Control Ctr, Haifa, Israel.
   [Lejbkowicz, Flavio; Pinchev, Mila; Rennert, Gadi; Rennert, Hedy S.] Technion Fac Med, Haifa, Israel.
   [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
   [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland.
   [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland.
   [Loibl, Sibylle] German Breast Grp GmbH, Neu Isenburg, Germany.
   [Lophatananon, Artitaya; Muir, Kenneth; Stewart-Brown, Sarah] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry, W Midlands, England.
   [Lophatananon, Artitaya; Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England.
   [Malone, Kathleen E.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
   [Kostovska, Ivana Maleva; Plaseska-Karanfilska, Dijana] Macedonian Acad Sci & Arts, Res Ctr Genet Engn & Biotechnol Georgi D Efremov, Skopje, Macedonia.
   [Manoukian, Siranoush] Fdn IRCCS, Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy.
   [Manson, Joann E.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA.
   [Margolin, Sara; Wendt, Camilla] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.
   [Mariapun, Shivaani; Teo, Soo H.] Canc Res Malaysia, Subang Jaya, Selangor, Malaysia.
   [Martinez, Maria Elena] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA.
   [Matsuo, Keitaro] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan.
   [McLean, Catriona] Alfred Hosp, Anat Pathol, Melbourne, Vic, Australia.
   [Meindl, Alfons] Tech Univ Munich, Div Gynaecol & Obstet, Munich, Germany.
   [Menendez, Primitiva] Hosp Monte Naranco, Serv Anat Patol, Oviedo, Spain.
   [Menon, Usha] UCL, Inst Womens Hlth, Dept Womens Canc, Gynaecol Canc Res Ctr, London, England.
   [Taib, Nur Aishah Mohd; Teo, Soo H.] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia.
   [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada.
   [Mulligan, Anna Marie] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada.
   [Mulot, Claire] Univ Paris 05, Univ Paris Sorbonne Cite, INSERM UMR S1147, Paris, France.
   [Neven, Patrick; Smeets, Ann; Wildiers, Hans] Univ Hosp Leuven, Leuven Canc Inst, Dept Oncol, Leuven Multidisciplinary Breast Ctr, Leuven, Belgium.
   [Noh, Dong-Young] Seoul Natl Univ, Coll Med, Dept Surg, Seoul, South Korea.
   [Olopade, Olufunmilayo I.] Univ Chicago, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA.
   [Pankratz, V. Shane] Univ New Mexico, Hlth Sci Ctr, Albuquerque, NM 87131 USA.
   [Lloyd, Rachel; Stone, Jennifer] Curtin Univ, Curtin UWA Ctr Genet Origins Hlth & Dis, Perth, WA, Australia.
   [Lloyd, Rachel; Stone, Jennifer] Univ Western Australia, Perth, WA, Australia.
   [Perez, Jose I. A.] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain.
   [Peterlongo, Paolo] FIRC Italian Fdn Canc Res, Inst Mol Oncol, IFOM, Milan, Italy.
   [Phillips, Kelly-Anne] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia.
   [Phillips, Kelly-Anne] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia.
   [Phillips, Kelly-Anne] Univ Melbourne, St Vincents Hosp, Dept Med, Fitzroy, Vic, Australia.
   [Pylkas, Katri; Winqvist, Robert] Univ Oulu, Bioctr Oulu, Canc & Translat Med Res Unit, Lab Canc Genet & Tumor Biol, Oulu, Finland.
   [Pylkas, Katri; Winqvist, Robert] Northern Finland Lab Ctr Oulu, Lab Canc Genet & Tumor Biol, Oulu, Finland.
   [Rack, Brigitte] Ludwig Maximilians Univ Munchen, Dept Gynecol & Obstet, Munich, Germany.
   [Radice, Paolo] Fdn IRCCS, Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy.
   [Rahman, Nazneen; Seal, Sheila] Inst Canc Res, Sect Canc Genet, London, England.
   [Romero, Atocha] Hosp Univ Puerta Hierro, Med Oncol Dept, Madrid, Spain.
   [Ruddy, Kathryn J.] Mayo Clin, Dept Oncol, Rochester, MN USA.
   [Ruediger, Thomas] Staedt Klinikum Karlsruhe, Inst Pathol, Karlsruhe, Germany.
   [Rutgers, Emiel J. T.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Surg, Amsterdam, Netherlands.
   [Saloustros, Emmanouil] Univ Hosp Herakl, Hereditary Canc Clin, Iraklion, Greece.
   [Sandler, Dale P.; Taylor, Jack A.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Res Triangle Pk, NC USA.
   [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand.
   [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Res Oncol, London, England.
   [Schneeweiss, Andreas; Sohn, Christof] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany.
   [Schumacher, Fredrick] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA.
   [Scott, Rodney J.] John Hunter Hosp, Div Mol Med, Pathol North, Newcastle, NSW, Australia.
   [Scott, Rodney J.] Univ Newcastle, Fac Hlth, Sch Biomed Sci & Pharm, Discipline Med Genet, Callaghan, NSW, Australia.
   [Sharma, Priyanka] Univ Kansas, Med Ctr, Dept Med, Kansas City, KS 66103 USA.
   [Shen, Chen-Yang] China Med Univ, Sch Publ Hlth, Taichung, Taiwan.
   [Shen, Chen-Yang] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan.
   [Sherman, Mark E.] Natl Canc Inst, Canc Prevent Div, Rockville, MD USA.
   [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia.
   [Spinelli, John J.] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada.
   [Spinelli, John J.] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada.
   [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany.
   [Stone, Jennifer] Univ Melbourne, Dept Obstet & Gynaecol, Melbourne, Vic, Australia.
   [Stone, Jennifer] Royal Womens Hosp, Melbourne, Vic, Australia.
   [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London, England.
   [Taylor, Jack A.] Natl Inst Environm Hlth Sci, Epigenet & Stem Cell Biol Lab, NIH, Res Triangle Pk, NC USA.
   [Tengstrom, Maria] Kuopio Univ Hosp, Canc Ctr, Kuopio, Finland.
   [Tengstrom, Maria] Univ Eastern Finland, Inst Clin Med, Oncol, Kuopio, Finland.
   [Terry, Mary Beth] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA.
   [Thanasitthichai, Somchai] Minist Publ Hlth, Natl Canc Inst, Nonthaburi, Thailand.
   [Tollenaar, Rob A. E. M.] Leiden Univ, Med Ctr, Dept Surg, Leiden, Netherlands.
   [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
   [Torres, Diana] Univ Oxford, Oxford NIHR Biomed Res Ctr, Oxford, England.
   [Tsugane, Shoichiro] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia.
   [Ulmer, Hans-Ulrich] Natl Canc Ctr, Ctr Publ Hlth Sci, Tokyo, Japan.
   [Ulmer, Hans-Ulrich] Frauenklin Stadtklin Baden Baden, Baden Baden, Germany.
   [Ursin, Giske] Canc Registry Norway, Oslo, Norway.
   [Ursin, Giske] Univ Oslo, Inst Basic Med Sci, Dept Nutr, Oslo, Norway.
   [Untch, Michael] Helios Clin Berlin Buch, Dept Gynecol & Obstet, Berlin, Germany.
   [van Asperen, Christi J.] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands.
   [van der Kolk, Lizet] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands.
   [van der Luijt, Rob B.] Univ Med Ctr Utrecht, Div Biomed Genet, Utrecht, Netherlands.
   [Wang-Gohrke, Shan] Univ Ulm, Dept Gynecol & Obstet, Ulm, Germany.
   [Weinberg, Clarice R.] Natl Inst Environm Hlth Sci, Biostat & Computat Biol Branch, NIH, Res Triangle Pk, NC USA.
   [Willett, Walter] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.
   [Yip, Cheng Har] Subang Jaya Med Ctr, Subang Jaya, Selangor, Malaysia.
   [Yoo, Keun-Young] Seoul Natl Univ, Coll Med, Seoul, South Korea.
   [Yoo, Keun-Young] Armed Forces Capital Hosp, Seongnam, South Korea.
   [Yu, Jyh-Cherng] Triserv Gen Hosp, Natl Def Med Ctr, Dept Surg, Taipei, Taiwan.
   [Zheng, Wei] Shanghai Municipal Ctr Dis Control & Prevent, Shanghai, Peoples R China.
   [Ziv, Elad] Univ Calif San Francisco, UCSF Helen Diller Family Comprehens Canc Ctr, Inst Human Genet, Dept Med, San Francisco, CA 94143 USA.
   [Lakhani, Sunil R.] Royal Brisbane & Womens Hosp, Pathol Queensland, Brisbane, Qld 4029, Australia.
   [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.
   [Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med, Dept Biomed Data Sci, Ctr Genom Med, Hanover, NH 03755 USA.
   [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany.
   [Hall, Per] Soder Sjukhuset, Dept Oncol, Stockholm, Sweden.
   [Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands.
C3 University of Cambridge; Cyprus Institute of Neurology & Genetics; University of Washington; University of Washington Seattle; Harvard University; Harvard T.H. Chan School of Public Health; QIMR Berghofer Medical Research Institute; University of Toronto; University of Cambridge; Laval University; Laval University Hospital; St Jude Children's Research Hospital; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); NIH National Cancer Institute- Division of Cancer Epidemiology & Genetics; Netherlands Cancer Institute; Helmholtz Association; German Cancer Research Center (DKFZ); University of Queensland; CRUK Cambridge Institute; University of Cambridge; Cancer Research UK; Massachusetts Institute of Technology (MIT); Johns Hopkins University; Vrije Universiteit Amsterdam; University of Chicago; University of Helsinki; Helsinki University Central Hospital; University of California System; University of California Irvine; Helmholtz Association; German Cancer Research Center (DKFZ); Queens University - Canada; Queens University - Canada; University of Texas System; UTMD Anderson Cancer Center; Fred Hutchinson Cancer Center; University of Wisconsin System; University of Wisconsin Milwaukee; McGill University; University of Erlangen Nuremberg; Centro Nacional de Investigaciones Oncologicas (CNIO); CIBER - Centro de Investigacion Biomedica en Red; CIBERER; Russian Academy of Sciences; Institute of Biochemistry & Genetics of Ufa Science Centre of the RAS; City of Hope; Beckman Research Institute of City of Hope; University of Helsinki; Helsinki University Central Hospital; Hannover Medical School; Hannover Medical School; University of Copenhagen; Copenhagen University Hospital; University of Copenhagen; Copenhagen University Hospital; University of Copenhagen; IRCCS European Institute of Oncology (IEO); University of Oslo; Karolinska Institutet; Eberhard Karls University of Tubingen; Eberhard Karls University Hospital; Eberhard Karls University of Tubingen; Helmholtz Association; German Cancer Research Center (DKFZ); World Health Organization; International Agency for Research on Cancer (IARC); Helmholtz Association; German Cancer Research Center (DKFZ); Helmholtz Association; German Cancer Research Center (DKFZ); Ruprecht Karls University Heidelberg; National Center for Tumor Diseases; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); NIH National Cancer Institute- Division of Cancer Epidemiology & Genetics; Lund University; University of Sheffield; British Columbia Cancer Agency; Simon Fraser University; Eberhard Karls University of Tubingen; Ruhr University Bochum; Ruprecht Karls University Heidelberg; Helmholtz Association; German Cancer Research Center (DKFZ); Vanderbilt University; Hospital Clinico San Carlos; CIBER - Centro de Investigacion Biomedica en Red; CIBERONC; Helmholtz Association; German Cancer Research Center (DKFZ); Universidade de Santiago de Compostela; Complexo Hospitalario Universitario de Santiago de Compostela; Universidade de Santiago de Compostela; CIBER - Centro de Investigacion Biomedica en Red; CIBERER; Universidade de Santiago de Compostela; American Cancer Society; Roswell Park Comprehensive Cancer Center; National University of Singapore; Seoul National University (SNU); Seoul National University (SNU); University of Sydney; Westmead Institute for Medical Research; Erasmus University Rotterdam; Erasmus MC; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Saclay; Imperial College London; Universite Lyon 1; Institut National de la Sante et de la Recherche Medicale (Inserm); UNICANCER; Centre Leon Berard; University of Sheffield; Mayo Clinic; Fox Chase Cancer Center; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; University of London; London School of Hygiene & Tropical Medicine; University of Southampton; University of Southampton; University of Westminster; University of Erlangen Nuremberg; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard T.H. Chan School of Public Health; Lund University; Ufa University of Science & Technology; Leipzig University; Leipzig University; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of Edinburgh; University of Hamburg; University Medical Center Hamburg-Eppendorf; University of Hamburg; University Medical Center Hamburg-Eppendorf; Royal Marsden NHS Foundation Trust; University of London; Institute of Cancer Research - UK; University of Copenhagen; Copenhagen University Hospital; Curtin University; University of California System; University of California San Diego; Shanghai Jiao Tong University; University Hospital of Heraklion; Cancer Council Victoria; University of Melbourne; University of Toronto; Sinai Health System Toronto; Lunenfeld Tanenbaum Research Institute; McGill University; Royal Victoria Hospital; McGill University; Utah System of Higher Education; University of Utah; Huntsman Cancer Institute; University of Oulu; Pomeranian Medical University; Universite de Montreal; University of Cologne; University of Cologne; University of Cologne; University of Southern California; Karolinska Institutet; Helmholtz Association; German Cancer Research Center (DKFZ); University of Massachusetts System; University of Massachusetts Amherst; Mayo Clinic; University of Eastern Finland; University of Eastern Finland; University of Eastern Finland; University of Eastern Finland Hospital; Kuopio University Hospital; National University of Singapore; University of Western Australia; Erasmus University Rotterdam; Erasmus MC; Erasmus MC Cancer Institute; Kaohsiung Medical University; Academia Sinica - Taiwan; Aichi Cancer Center; Nagoya University; National Cancer Center - Japan; Aichi Cancer Center; Ulm University; Cancer Prevention Institute of California; Stanford University; Stanford University; Stanford Cancer Institute; University of London; Institute of Cancer Research - UK; Royal Marsden NHS Foundation Trust; University of Oulu; Seoul National University (SNU); Ollscoil na Gaillimhe-University of Galway; University of Helsinki; Helsinki University Central Hospital; Catholic University of Korea; University of Toronto; Sinai Health System Toronto; Lunenfeld Tanenbaum Research Institute; University of Toronto; University of Oslo; University of Oslo; University of Hong Kong; Flanders Institute for Biotechnology (VIB); KU Leuven; Cancer Research Center of Hawaii; University of Hawaii System; Soonchunhyang University; Soonchunhyang University; Soonchunhyang University Hospital; University of Ulsan; University of Ulsan; Asan Medical Center; National University of Singapore; Clalit Health Services; Carmel Medical Center; Technion Israel Institute of Technology; Rappaport Faculty of Medicine; Karolinska Institutet; Maria Sklodowska-Curie National Research Institute of Oncology; Maria Sklodowska-Curie National Research Institute of Oncology; German Breast Group; University of Warwick; University of Manchester; Fred Hutchinson Cancer Center; Fondazione IRCCS Istituto Nazionale Tumori Milan; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; Karolinska Institutet; University of California System; University of California San Diego; Aichi Cancer Center; Florey Institute of Neuroscience & Mental Health; Howard Florey Institute Affiliates; Technical University of Munich; University of London; University College London; Universiti Malaya; University of Toronto; University of Toronto; University Health Network Toronto; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; KU Leuven; University Hospital Leuven; Seoul National University (SNU); University of Chicago; University of New Mexico; University of New Mexico's Health Sciences Center; Curtin University; University of Western Australia; IFOM - FIRC Institute of Molecular Oncology; Peter Maccallum Cancer Center; Peter Maccallum Cancer Center; University of Melbourne; University of Melbourne; St Vincent's Health; St Vincent's Hospital Melbourne; NSW Health; St Vincents Hospital Sydney; University of Oulu; University of Munich; Fondazione IRCCS Istituto Nazionale Tumori Milan; University of London; Institute of Cancer Research - UK; Royal Marsden NHS Foundation Trust; Hospital Puerta de Hierro-Majadahonda; Mayo Clinic; Municipal Hospital Karlsruhe; Netherlands Cancer Institute; University Hospital of Heraklion; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS); National Cancer Institute - Thailand; Guy's & St Thomas' NHS Foundation Trust; University of London; King's College London; Helmholtz Association; German Cancer Research Center (DKFZ); Ruprecht Karls University Heidelberg; National Center for Tumor Diseases; University System of Ohio; Case Western Reserve University; John Hunter Hospital; University of Newcastle; University of Kansas; University of Kansas Medical Center; China Medical University Taiwan; Academia Sinica - Taiwan; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); University of Melbourne; British Columbia Cancer Agency; University of British Columbia; University of Melbourne; The Royal Women's Hospital; Royal Marsden NHS Foundation Trust; University of London; Institute of Cancer Research - UK; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS); Kuopio University Hospital; University of Eastern Finland; University of Eastern Finland Hospital; University of Eastern Finland; Columbia University; Ministry of Public Health - Thailand; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; University of Oxford; Wellcome Centre for Human Genetics; University of Oxford; Pontificia Universidad Javeriana; National Cancer Center - Japan; University of Oslo; University of Oslo; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Netherlands Cancer Institute; Utrecht University; Utrecht University Medical Center; Ulm University; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS); Harvard University; Harvard T.H. Chan School of Public Health; Seoul National University (SNU); National Defense Medical University; Tri-Service General Hospital; Shanghai Center for Disease Control & Prevention; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; Royal Brisbane & Women's Hospital; University of Toronto; Dartmouth College; University of Hamburg; University Medical Center Hamburg-Eppendorf; Sodersjukhuset Hospital; Netherlands Cancer Institute
RP Easton, DF (corresponding author), Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England.; Easton, DF (corresponding author), Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England.
EM dfe20@medschl.cam.ac.uk
FU PERSPECTIVE project; Government of Canada through Genome Canada; Canadian Institutes of Health Research; Ministere de l'Economie, de la Science et de l'Innovation du Quebec' through Genome Quebec; Quebec Breast Cancer Foundation; NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative; Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH) [U19 CA148065, X01HG007492]; Cancer Research UK [C1287/A10118, C1287/A16563, C1287/A10710]; European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; European Union's Horizon 2020 Research and Innovation Programme [633784, 634935]; European Union [HEALTH-F2-2009-223175]; Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program; Ministry of Economic Development, Innovation and Export Trade of Quebec [PSR-SIIRI-701]; National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative [U19 CA 148065]; MRC [MC_PC_14105] Funding Source: UKRI; Cancer Foundation Finland sr [150147, 160099, 130168, 110135] Funding Source: researchfish; Cancer Research UK [20861, 15106, 10118, 16563, 20411, 19187, 16561] Funding Source: researchfish; Medical Research Council [MC_PC_14105] Funding Source: researchfish; National Institute for Health Research [03/DHCS/03/G121/51] Funding Source: researchfish; The Francis Crick Institute; Cancer Research UK [10124] Funding Source: researchfish; National Cancer Institute [P30CA023108, K24CA169004, ZIACP010126, P50CA116201, UM1CA186107, U01CA199277, U01CA194393, R35CA197449, P30CA068485] Funding Source: NIH RePORTER; National Institute of Environmental Health Sciences [ZIAES044005, ZIAES049032, ZIAES049033, ZIAES102245] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [P41GM103504] Funding Source: NIH RePORTER; National Institute of Mental Health [R01MH101244] Funding Source: NIH RePORTER; Grants-in-Aid for Scientific Research [16H06277] Funding Source: KAKEN
NR 76
TC 1053
Z9 1168
U1 7
U2 331
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 2
PY 2017
VL 551
IS 7678
BP 92
EP +
DI 10.1038/nature24284
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FL4SY
UT WOS:000414222900051
PM 29059683
DA 2026-03-09
ER

PT J
AU Huter, P
   Müller, C
   Beckert, B
   Arenz, S
   Berninghausen, O
   Beckmann, R
   Wilson, DN
AF Huter, Paul
   Mueller, Claudia
   Beckert, Bertrand
   Arenz, Stefan
   Berninghausen, Otto
   Beckmann, Roland
   Wilson, Daniel N.
TI Structural basis for ArfA-RF2-mediated translation termination on mRNAs lacking stop codons
SO NATURE
LA English
DT Article
ID ribosome-rescue factor; release factor rf2; escherichia-coli; stalled ribosm; peptide release; tmrna-smpb; arfa; mechanism; distinct; absence
AB In bacteria, ribosomes stalled on truncated mRNAs that lack a stop codon are rescued by the transfer-messenger RNA (tmRNA), alternative rescue factor A (ArfA) or ArfB systems(1). Although tmRNA-ribosome and ArfB-ribosome structures have been determined(2-7), how ArfA recognizes the presence of truncated mRNAs and recruits the canonical termination release factor RF2 to rescue the stalled ribosomes is unclear. Here we present a cryoelectron microscopy reconstruction of the Escherichia coli 70S ribosome stalled on a truncated mRNA in the presence of ArfA and RF2. The structure shows that the C terminus of ArfA binds within the mRNA entry channel on the small ribosomal subunit, and explains how ArfA distinguishes between ribosomes that bear truncated or full-length mRNAs. The N terminus of ArfA establishes several interactions with the decoding domain of RF2, and this finding illustrates how ArfA recruits RF2 to the stalled ribosome. Furthermore, ArfA is shown to stabilize a unique conformation of the switch loop of RF2, which mimics the canonical translation termination state by directing the catalytically important GGQ motif within domain 3 of RF2 towards the peptidyl-transferase centre of the ribosome. Thus, our structure reveals not only how ArfA recruits RF2 to the ribosome but also how it promotes an active conformation of RF2 to enable translation termination in the absence of a stop codon.
C1 [Huter, Paul; Mueller, Claudia; Beckert, Bertrand; Arenz, Stefan; Berninghausen, Otto; Beckmann, Roland; Wilson, Daniel N.] Ludwig Maximilians Univ Munchen, Gene Ctr Dept Biochem, Feodor Lynen Str 2, D-81377 Munich, Germany.
   [Huter, Paul; Mueller, Claudia; Beckert, Bertrand; Arenz, Stefan; Berninghausen, Otto; Beckmann, Roland; Wilson, Daniel N.] Ludwig Maximilians Univ Munchen, Ctr integrated Prot Sci Munich CiPSM, Feodor Lynen Str 2, D-81377 Munich, Germany.
   [Beckert, Bertrand; Wilson, Daniel N.] Univ Hamburg, Inst Biochem & Mol Biol, Martin Luther King Pl 6, D-20146 Hamburg, Germany.
C3 University of Munich; University of Munich; University of Hamburg
RP Wilson, DN (corresponding author), Ludwig Maximilians Univ Munchen, Gene Ctr Dept Biochem, Feodor Lynen Str 2, D-81377 Munich, Germany.; Wilson, DN (corresponding author), Ludwig Maximilians Univ Munchen, Ctr integrated Prot Sci Munich CiPSM, Feodor Lynen Str 2, D-81377 Munich, Germany.; Wilson, DN (corresponding author), Univ Hamburg, Inst Biochem & Mol Biol, Martin Luther King Pl 6, D-20146 Hamburg, Germany.
EM daniel.wilson@chemie.uni-hamburg.de
FU Deutsche Forschungsgemeinschaft [WI3285/4-1, SPP-1879, GRK 1721, FOR1805]
NR 25
TC 36
Z9 95
U1 1
U2 17
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 26
PY 2017
VL 541
IS 7638
BP 546
EP 549
DI 10.1038/nature20821
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6LX
UT WOS:000396116600054
PM 27906161
DA 2026-03-09
ER

PT J
AU Silver, D
   Schrittwieser, J
   Simonyan, K
   Antonoglou, I
   Huang, A
   Guez, A
   Hubert, T
   Baker, L
   Lai, M
   Bolton, A
   Chen, YT
   Lillicrap, T
   Hui, F
   Sifre, L
   van den Driessche, G
   Graepel, T
   Hassabis, D
AF Silver, David
   Schrittwieser, Julian
   Simonyan, Karen
   Antonoglou, Ioannis
   Huang, Aja
   Guez, Arthur
   Hubert, Thomas
   Baker, Lucas
   Lai, Matthew
   Bolton, Adrian
   Chen, Yutian
   Lillicrap, Timothy
   Hui, Fan
   Sifre, Laurent
   van den Driessche, George
   Graepel, Thore
   Hassabis, Demis
TI Mastering the game of Go without human knowledge
SO NATURE
LA English
DT Article
ID policy iteration; world
AB A long-standing goal of artificial intelligence is an algorithm that learns, tabula rasa, superhuman proficiency in challenging domains. Recently, AlphaGo became the first program to defeat a world champion in the game of Go. The tree search in AlphaGo evaluated positions and selected moves using deep neural networks. These neural networks were trained by supervised learning from human expert moves, and by reinforcement learning from self-play. Here we introduce an algorithm based solely on reinforcement learning, without human data, guidance or domain knowledge beyond game rules. AlphaGo becomes its own teacher: a neural network is trained to predict AlphaGo's own move selections and also the winner of AlphaGo's games. This neural network improves the strength of the tree search, resulting in higher quality move selection and stronger self-play in the next iteration. Starting tabula rasa, our new program AlphaGo Zero achieved superhuman performance, winning 100-0 against the previously published, champion-defeating AlphaGo.
C1 [Silver, David; Schrittwieser, Julian; Simonyan, Karen; Antonoglou, Ioannis; Huang, Aja; Guez, Arthur; Hubert, Thomas; Baker, Lucas; Lai, Matthew; Bolton, Adrian; Chen, Yutian; Lillicrap, Timothy; Hui, Fan; Sifre, Laurent; van den Driessche, George; Graepel, Thore; Hassabis, Demis] DeepMind, 5 New St Sq, London EC4A 3TW, England.
C3 Alphabet Inc.; DeepMind
RP Silver, D (corresponding author), DeepMind, 5 New St Sq, London EC4A 3TW, England.
EM davidsilver@google.com
NR 68
TC 6293
Z9 8075
U1 77
U2 2283
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 19
PY 2017
VL 550
IS 7676
BP 354
EP +
DI 10.1038/nature24270
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK1NF
UT WOS:000413247900053
PM 29052630
DA 2026-03-09
ER

PT J
AU Morikawa, Y
   Heallen, T
   Each, JL
   Xiao, Y
   Martin, JF
AF Morikawa, Yuka
   Heallen, Todd
   Each, John L.
   Xiao, Yang
   Martin, James F.
TI Dystrophin-glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation
SO NATURE
LA English
DT Article
ID duchenne muscular-dystrophy; adult heart regeneration; in-vivo; pressure-overload; mouse model; muscle; gene; mice
AB The regenerative capacity of the adult mammalian heart is limited, because of the reduced ability of cardiomyocytes to progress through mitosis(1). Endogenous cardiomyocytes have regenerative capacity at birth but this capacity is lost postnatally, with subsequent organ growth occurring through cardiomyocyte hypertrophy(2,3). The Hippo pathway, a conserved kinase cascade, inhibits cardiomyocyte proliferation in the developing heart to control heart size and prevents regeneration in the adult heart(4,5). The dystrophingly-coprotein complex (DGC), a multicomponent transmembrane complex linking the actin cytoskeleton to extracellular matrix, is essential for cardiomyocyte homeostasis. DGC deficiency in humans results in muscular dystrophy, including the lethal Duchenne muscular dystrophy. Here we show that the DGC component dystroglycan 1 (Dag1) directly binds to the Hippo pathway effector Yap to inhibit cardiomyocyte proliferation in mice. The Yap-Dag1 interaction was enhanced by Hippo-induced Yap phosphorylation, revealing a connection between Hippo pathway function and the DGC. After injury, Hippo-deficient postnatal mouse hearts maintained organ size control by repairing the defect with correct dimensions, whereas postnatal hearts deficient in both Hippo and the DGC showed cardiomyocyte overproliferation at the injury site. In the hearts of mature Mdx mice (which have a point mutation in Dmd)-a model of Duchenne muscular dystrophy-Hippo deficiency protected against overload-induced heart failure.
C1 [Morikawa, Yuka; Heallen, Todd; Xiao, Yang; Martin, James F.] Texas Heart Inst, Cardiomyocyte Renewal Lab, Houston, TX 77030 USA.
   [Each, John L.; Martin, James F.] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA.
   [Martin, James F.] Baylor Coll Med, Program Dev Biol, Houston, TX 77030 USA.
   [Martin, James F.] Baylor Coll Med, Houston, TX 77030 USA.
C3 Texas Heart Institute; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine
RP Martin, JF (corresponding author), Texas Heart Inst, Cardiomyocyte Renewal Lab, Houston, TX 77030 USA.; Martin, JF (corresponding author), Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA.; Martin, JF (corresponding author), Baylor Coll Med, Program Dev Biol, Houston, TX 77030 USA.; Martin, JF (corresponding author), Baylor Coll Med, Houston, TX 77030 USA.
EM jfmartin@bcm.edu
FU Intellectual and Developmental Disability Research Center grant from Eunice Kennedy Shriver National Institute of Child Health & Human Development [1U54 HD083092]; Mouse Phenotyping Core at Baylor College of Medicine; National Institutes of Health [U54 HG006348, DE 023177, HL 127717, HL 130804, HL 118761]; Vivian L. Smith Foundation; Transatlantic Network of Excellence Award LeDucq Foundation Transatlantic Networks of Excellence in Cardiovascular Research [14CVD01]; American Heart Association [16SDG26460001]; American Heart Association (AHA) [16SDG26460001] Funding Source: American Heart Association (AHA); National Heart Lung and Blood Institute [R01HL118761, R01HL127717] Funding Source: NIH RePORTER
NR 21
TC 233
Z9 284
U1 1
U2 59
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 13
PY 2017
VL 547
IS 7662
BP 227
EP +
DI 10.1038/nature22979
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FA3AX
UT WOS:000405314500041
PM 28581498
DA 2026-03-09
ER

PT J
AU Reuveni, S
   Ehrenberg, M
   Paulsson, J
AF Reuveni, Shlomi
   Ehrenberg, Mans
   Paulsson, Johan
TI Ribosomes are optimized for autocatalytic production
SO NATURE
LA English
DT Article
ID mitochondrial ribosome; protein-synthesis; cell-growth; bacterial; translation; reveals; origin; limits; laws; s1
AB Many fine-scale features of ribosomes have been explained in terms of function, revealing a molecular machine that is optimized for error-correction, speed and control. Here we demonstrate mathematically that many less well understood, larger-scale features of ribosomes-such as why a few ribosomal RNA molecules dominate the mass and why the ribosomal protein content is divided into 55-80 small, similarly sized segments-speed up their autocatalytic production.
C1 [Reuveni, Shlomi; Paulsson, Johan] Harvard Univ, Dept Syst Biol, HMS, 200 Longwood Ave, Boston, MA 02115 USA.
   [Ehrenberg, Mans] Uppsala Univ, Dept Cell & Mol Biol, Uppsala Biomed Ctr BMC, Husargatan 3, Uppsala, Sweden.
C3 Harvard University; Harvard Medical School; Uppsala University
RP Paulsson, J (corresponding author), Harvard Univ, Dept Syst Biol, HMS, 200 Longwood Ave, Boston, MA 02115 USA.
EM johan_paulsson@hms.harvard.edu
FU James S. McDonnell Foundation; NSF-DMS grant [PD127334]; NIH [R01GM095784]; HFSP grant [RGP0042]; Swedish Research Council; Wallenberg Foundation (RiboCORE); Division Of Mathematical Sciences; Direct For Mathematical & Physical Scien [1517372] Funding Source: National Science Foundation
NR 34
TC 50
Z9 64
U1 0
U2 57
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 20
PY 2017
VL 547
IS 7663
BP 293
EP +
DI 10.1038/nature22998
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB0OR
UT WOS:000405844900023
PM 28726822
DA 2026-03-09
ER

PT J
AU Mock, T
   Otillar, RP
   Strauss, J
   McMullan, M
   Paajanen, P
   Schmutz, J
   Salamov, A
   Sanges, R
   Toseland, A
   Ward, BJ
   Allen, AE
   Dupont, CL
   Frickenhaus, S
   Maumus, F
   Veluchamy, A
   Wu, TY
   Barry, KW
   Falciatore, A
   Ferrante, MI
   Fortunato, AE
   Glöckner, G
   Gruber, A
   Hipkin, R
   Janech, MG
   Kroth, PG
   Leese, F
   Lindquist, EA
   Lyon, BR
   Martin, J
   Mayer, C
   Parker, M
   Quesneville, H
   Raymond, JA
   Uhlig, C
   Valas, RE
   Valentin, KU
   Worden, AZ
   Armbrust, EV
   Clark, MD
   Bowler, C
   Green, BR
   Moulton, V
   van Oosterhout, C
   Grigoriev, IV
AF Mock, Thomas
   Otillar, Robert P.
   Strauss, Jan
   McMullan, Mark
   Paajanen, Pirita
   Schmutz, Jeremy
   Salamov, Asaf
   Sanges, Remo
   Toseland, Andrew
   Ward, Ben J.
   Allen, Andrew E.
   Dupont, Christopher L.
   Frickenhaus, Stephan
   Maumus, Florian
   Veluchamy, Alaguraj
   Wu, Taoyang
   Barry, Kerrie W.
   Falciatore, Angela
   Ferrante, Maria I.
   Fortunato, Antonio E.
   Gloeckner, Gernot
   Gruber, Ansgar
   Hipkin, Rachel
   Janech, Michael G.
   Kroth, Peter G.
   Leese, Florian
   Lindquist, Erika A.
   Lyon, Barbara R.
   Martin, Joel
   Mayer, Christoph
   Parker, Micaela
   Quesneville, Hadi
   Raymond, James A.
   Uhlig, Christiane
   Valas, Ruben E.
   Valentin, Klaus U.
   Worden, Alexandra Z.
   Armbrust, E. Virginia
   Clark, Matthew D.
   Bowler, Chris
   Green, Beverley R.
   Moulton, Vincent
   van Oosterhout, Cock
   Grigoriev, Igor V.
TI Evolutionary genomics of the cold-adapted diatom Fragilariopsis cylindrus
SO NATURE
LA English
DT Article
ID differential expression analysis; antarctic sea-ice; gene-expression; thalassiosira-pseudonana; maximum-likelihood; classification; proteins; database; identification; temperature
AB The Southern Ocean houses a diverse and productive community of organisms(1,2). Unicellular eukaryotic diatoms are the main primary producers in this environment, where photosynthesis is limited by low concentrations of dissolved iron and large seasonal fluctuations in light, temperature and the extent of sea ice(3-7). How diatoms have adapted to this extreme environment is largely unknown. Here we present insights into the genome evolution of a cold-adapted diatom from the Southern Ocean, Fragilariopsis cylindrus(8,9), based on a comparison with temperate diatoms. We find that approximately 24.7 per cent of the diploid F. cylindrus genome consists of genetic loci with alleles that are highly divergent (15.1 megabases of the total genome size of 61.1 megabases). These divergent alleles were differentially expressed across environmental conditions, including darkness, low iron, freezing, elevated temperature and increased CO2. Alleles with the largest ratio of non-synonymous to synonymous nucleotide substitutions also show the most pronounced condition-dependent expression, suggesting a correlation between diversifying selection and allelic differentiation. Divergent alleles may be involved in adaptation to environmental fluctuations in the Southern Ocean.
C1 [Mock, Thomas] Univ East Anglia, Sch Environm Sci, Res Pk, Norwich NR4 7TJ, Norfolk, England.
   [Otillar, Robert P.; Schmutz, Jeremy] Dept Energy Joint Genome Inst, 2800 Mitchell Dr, Walnut Creek, CA 94598 USA.
   [Paajanen, Pirita] Earlham Inst, Res Pk, Norwich NR4 7UH, Norfolk, England.
   [Schmutz, Jeremy] HudsonAlpha Inst Biotechnol, 601 Genome Way, Huntsville, AL 35801 USA.
   [Sanges, Remo] Univ East Anglia, Sch Comp Sci, Res Pk, Norwich NR4 7TJ, Norfolk, England.
   [Toseland, Andrew] J Craig Venter Inst, Microbial & Environm Genom, La Jolla, CA 92037 USA.
   [Allen, Andrew E.] Univ Calif San Diego, Scripps Inst Oceanog, Integrat Oceanog Div, La Jolla, CA 92037 USA.
   [Allen, Andrew E.] Hochschule Bremerhaven, Karlsburg 8, D-27568 Bremerhaven, Germany.
   [Frickenhaus, Stephan] Univ Paris Saclay, URGI, INRA, F-78026 Versailles, France.
   [Frickenhaus, Stephan] PSL Res Univ, CNRS UMR 8197, Inst Biol Ecole Normale Super IBENS, Ecole Normale Super, 46 Rue Ulm, F-75005 Paris, France.
   [Maumus, Florian] Sorbonne Univ, Inst Biol Paris Seine, CNRS, Lab Biol Computat & Quantitat UMR 7238, F-75006 Paris, France.
   [Falciatore, Angela] Integrat Marine Ecol, Staz Zool Anton Dohrn, Villa Comunale, I-80121 Naples, Italy.
   [Salamov, Asaf; Gloeckner, Gernot; Quesneville, Hadi; Valentin, Klaus U.; Green, Beverley R.] Univ Cologne, Fac Med, Inst Biochem, Joseph Stelzmann Str, D-5250931 Cologne, Germany.
   [McMullan, Mark; Gloeckner, Gernot] Inst Freshwater, Ecol & Inland Fisheries, IGB, Maggelseedamm 301, D-12587 Berlin, Germany.
   [McMullan, Mark; Dupont, Christopher L.; Frickenhaus, Stephan; Maumus, Florian] Univ Konstanz, Fachbereich Biol, D-78457 Constance, Germany.
   [Salamov, Asaf; Falciatore, Angela; Bowler, Chris] Med Univ South Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA.
   [Otillar, Robert P.; Dupont, Christopher L.] Univ Duisburg Essen, Fac Biol, Aquat Ecosyst Res Univ 5, D-45141 Essen, Germany.
   [Toseland, Andrew; Gloeckner, Gernot; Bowler, Chris] Med Univ South Carolina, Marine Biomed & Environm Sci Ctr, Charleston, SC 29412 USA.
   [Uhlig, Christiane; Grigoriev, Igor V.] Leibniz Inst Biodiversitat Tiere, Zoolog Forsch Museum Alexander Koenig, Adenauerallee 160, D-53113 Bonn, Germany.
   [Sanges, Remo; Barry, Kerrie W.; Lyon, Barbara R.] Univ Washington, Ctr Environm Genom, Sch Oceanog, Box 357940, Seattle, WA 98195 USA.
   [Sanges, Remo; Veluchamy, Alaguraj; Barry, Kerrie W.; Lyon, Barbara R.; Parker, Micaela; Uhlig, Christiane] Univ Nevada, Sch Life Sci, Las Vegas, NV 89154 USA.
   [Allen, Andrew E.; Fortunato, Antonio E.; Gruber, Ansgar] Monterey Bay Aquarium Res Inst, 7700 Sandholdt Rd, Moss Landing, CA 95039 USA.
   [Sanges, Remo; Frickenhaus, Stephan; Veluchamy, Alaguraj; Wu, Taoyang] Univ British Columbia, Univ Blvd, Dept Bot, Vancouver, BC V6T 1Z4, Canada.
   [Mock, Thomas; Schmutz, Jeremy; Frickenhaus, Stephan] Univ Calif Berkeley, Dept Plant & Microbial Biol, Berkeley, CA 94720 USA.
   [Strauss, Jan; Maumus, Florian; Barry, Kerrie W.] European Mol Biol Lab, German Elect Synchrotron DESY, Notkestr 85, Hamburg, Germany.
   [Paajanen, Pirita; Mayer, Christoph; Clark, Matthew D.] John Innes Ctr, Dept Cell & Dev Biol, Res Pk, Norwich NR4 7UH, Norfolk, England.
   [Otillar, Robert P.; Salamov, Asaf; Ward, Ben J.; Veluchamy, Alaguraj] King Abdullah Univ Sci & Technol, Biol & Environm Sci & Engn Div, Thuwal 239556900, Saudi Arabia.
   [Strauss, Jan; Schmutz, Jeremy; Salamov, Asaf; Lyon, Barbara R.] Bowdoin Coll, Ctr Coastal Studies, Brunswick, ME 04011 USA.
   [Otillar, Robert P.; McMullan, Mark; Uhlig, Christiane] Univ Rhode Isl, Grad Sch Oceanog, 215 South Ferry Rd, Narragansett, RI 02882 USA.
C3 University of East Anglia; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); Earlham Institute; HudsonAlpha Institute for Biotechnology; University of East Anglia; J. Craig Venter Institute; University of California System; University of California San Diego; Scripps Institution of Oceanography; Universite Paris Saclay; INRAE; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite PSL; Ecole Normale Superieure (ENS); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Sorbonne Universite; Stazione Zoologica Anton Dohrn; University of Cologne; Leibniz Association; Leibniz Institut fur Gewasserokologie und Binnenfischerei (IGB); University of Konstanz; Medical University of South Carolina; University of Duisburg Essen; Medical University of South Carolina; Zoologisches Forschungsmuseum Alexander Koenig (ZFMK); University of Washington; University of Washington Seattle; Nevada System of Higher Education (NSHE); University of Nevada Las Vegas; Monterey Bay Aquarium Research Institute; University of British Columbia; University of California System; University of California Berkeley; Helmholtz Association; Deutsches Elektronen-Synchrotron (DESY); European Molecular Biology Laboratory (EMBL); UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); John Innes Centre; King Abdullah University of Science & Technology; Bowdoin College; University of Rhode Island
RP Mock, T (corresponding author), Univ East Anglia, Sch Environm Sci, Res Pk, Norwich NR4 7TJ, Norfolk, England.
EM t.mock@uea.ac.uk
FU ERC; Office of Science of the U.S. Department of Energy [DE-AC02-05CH11231]; BBSRC [BB/J004669/1]; NERC [NE/I001751/1, NE/K004530/1]; MGF (NBAF) [197]; Royal Society [RG090774]; Earth & Life Systems Alliance in Norwich; Biotechnology and Biological Sciences Research Council [BBS/E/T/000PR6193, BBS/E/T/000PR5885, BBS/E/T/000PR9816, BBS/E/T/000PR9818, BBS/E/D/20310000] Funding Source: researchfish; Natural Environment Research Council [NBAF010003, NE/K004530/1, NE/I001751/1, NE/K013734/1] Funding Source: researchfish; BBSRC [BBS/E/T/000PR9816, BBS/E/T/000PR6193, BBS/E/T/000PR9818, BBS/E/T/000PR5885, BBS/E/D/20310000] Funding Source: UKRI; NERC [NE/K013734/1, NE/K004530/1, NBAF010003, NE/I001751/1] Funding Source: UKRI
NR 81
TC 264
Z9 296
U1 12
U2 208
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 26
PY 2017
VL 541
IS 7638
BP 536
EP 540
DI 10.1038/nature20803
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6LX
UT WOS:000396116600052
PM 28092920
DA 2026-03-09
ER

PT J
AU Liu, Y
   Liu, JY
   Du, SY
   Shan, C
   Nie, KX
   Zhang, R
   Li, XF
   Zhang, R
   Wang, T
   Qin, CF
   Wang, P
   Shi, PY
   Cheng, G
AF Liu, Yang
   Liu, Jianying
   Du, Senyan
   Shan, Chao
   Nie, Kaixiao
   Zhang, Rudian
   Li, Xiao-Feng
   Zhang, Renli
   Wang, Tao
   Qin, Cheng-Feng
   Wang, Penghua
   Shi, Pei-Yong
   Cheng, Gong
TI Evolutionary enhancement of Zika virus infectivity in Aedes aegypti mosquitoes
SO NATURE
LA English
DT Article
ID flavivirus ns1 protein; sera
AB Zika virus (ZIKV) remained obscure until the recent explosive outbreaks in French Polynesia (2013-2014) and South America (2015-2016)(1-3). Phylogenetic studies have shown that ZIKV has evolved into African and Asian lineages. The Asian lineage of ZIKV was responsible for the recent epidemics in the Americas(1,3). However, the underlying mechanisms through which ZIKV rapidly and explosively spread from Asia to the Americas are unclear. Non-structural protein 1 (NS1) facilitates flavivirus acquisition by mosquitoes from an infected mammalian host and subsequently enhances viral prevalence in mosquitoes(4). Here we show that NS1 antigenaemia determines ZIKV infectivity in its mosquito vector Aedes aegypti, which acquires ZIKV via a blood meal. Clinical isolates from the most recent outbreak in the Americas were much more infectious in mosquitoes than the FSS13025 strain, which was isolated in Cambodia in 2010. Further analyses showed that these epidemic strains have higher NS1 antigenaemia than the FSS13025 strain because of an alanine-to-valine amino acid substitution at residue 188 in NS1. ZIKV infectivity was enhanced by this amino acid substitution in the ZIKV FSS13025 strain in mosquitoes that acquired ZIKV from a viraemic C57BL/6 mouse deficient in type I and II interferon (IFN) receptors (AG6 mouse). Our results reveal that ZIKV evolved to acquire a spontaneous mutation in its NS1 protein, resulting in increased NS1 antigenaemia. Enhancement of NS1 antigenaemia in infected hosts promotes ZIKV infectivity and prevalence in mosquitoes, which could have facilitated transmission during recent ZIKV epidemics.
C1 [Liu, Yang; Liu, Jianying; Du, Senyan; Nie, Kaixiao; Zhang, Rudian; Cheng, Gong] Tsinghua Univ, Sch Med, Tsinghua Peking Ctr Life Sci, Beijing 100084, Peoples R China.
   [Liu, Yang; Zhang, Rudian] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China.
   [Liu, Yang; Liu, Jianying; Zhang, Renli; Wang, Tao; Cheng, Gong] Shenzhen Ctr Dis Control & Prevent, SZCDC SUSTech Joint Key Lab Trop Dis, Shenzhen 518055, Guangdong, Peoples R China.
   [Shan, Chao; Shi, Pei-Yong] Univ Texas Med Branch, Dept Biochem & Mol Biol, Dept Pharmacol & Toxicol, Galveston, TX 77555 USA.
   [Shan, Chao; Shi, Pei-Yong] Univ Texas Med Branch, Sealy Ctr Struct Biol & Mol Biophys, Galveston, TX 77555 USA.
   [Li, Xiao-Feng; Qin, Cheng-Feng] Beijing Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, Beijing 100071, Peoples R China.
   [Wang, Tao] Southern Univ Sci & Technol, Dept Biol, Shenzhen 518055, Guangdong, Peoples R China.
   [Wang, Penghua] New York Med Coll, Sch Med, Dept Microbiol & Immunol, Valhalla, NY 10595 USA.
C3 Tsinghua University; Tsinghua University; Shenzhen Center for Disease Control & Prevention (SZCDC); University of Texas System; University of Texas Medical Branch Galveston; University of Texas System; University of Texas Medical Branch Galveston; Beijing Institute of Microbiology & Epidemiology; Southern University of Science & Technology; New York Medical College
RP Cheng, G (corresponding author), Tsinghua Univ, Sch Med, Tsinghua Peking Ctr Life Sci, Beijing 100084, Peoples R China.; Cheng, G (corresponding author), Shenzhen Ctr Dis Control & Prevent, SZCDC SUSTech Joint Key Lab Trop Dis, Shenzhen 518055, Guangdong, Peoples R China.; Shi, PY (corresponding author), Univ Texas Med Branch, Dept Biochem & Mol Biol, Dept Pharmacol & Toxicol, Galveston, TX 77555 USA.; Shi, PY (corresponding author), Univ Texas Med Branch, Sealy Ctr Struct Biol & Mol Biophys, Galveston, TX 77555 USA.
EM peshi@utmb.edu; gongcheng@mail.tsinghua.edu.cn
FU National Key Research and Development Plan of China [2016YFD0500400, 2016ZX10004001-008, 2017ZX09101-005, 2016YFC1201000, 2016YFD0500300]; National Natural Science Foundation of China [81422028, 81571975, 81522025, 31300600]; National Key Basic Research Program of China [2013CB911500, SZSTI-JCYJ2016033111585 3521]; National Institutes of Health of the United States [R01AI087856, AI103807]; Shenzhen San-Ming Project; Academy of Medical Sciences; Newton Fund; University of Texas Medical Branch (UTMB); University of Texas STARs Award; National Institute of Allergy and Infectious Diseases [R01AI087856] Funding Source: NIH RePORTER; Academy of Medical Sciences (AMS) [AMS-NAF1-Cheng] Funding Source: researchfish
NR 30
TC 304
Z9 368
U1 0
U2 168
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 25
PY 2017
VL 545
IS 7655
BP 482
EP +
DI 10.1038/nature22365
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV6TH
UT WOS:000401906500052
PM 28514450
DA 2026-03-09
ER

PT J
AU Bomphrey, RJ
   Nakata, T
   Phillips, N
   Walker, SM
AF Bomphrey, Richard J.
   Nakata, Toshiyuki
   Phillips, Nathan
   Walker, Simon M.
TI Smart wing rotation and trailing-edge vortices enable high frequency mosquito flight
SO NATURE
LA English
DT Article
ID lift-generating mechanisms; hovering insect flight; quasi-steady model; dragonfly flight; flapping flight; aerodynamics; kinematics; flow
AB Mosquitoes exhibit unusual wing kinematics; their long, slender wings flap at remarkably high frequencies for their size (> 800 Hz) and with lower stroke amplitudes than any other insect group(1). This shifts weight support away from the translation-dominated, aerodynamic mechanisms used by most insects(2), as well as by helicopters and aeroplanes, towards poorly understood rotational mechanisms that occur when pitching at the end of each half-stroke. Here we report free-flight mosquito wing kinematics, solve the full Navier-Stokes equations using computational fluid dynamics with overset grids, and validate our results with in vivo flow measurements. We show that, although mosquitoes use familiar separated flow patterns, much of the aerodynamic force that supports their weight is generated in a manner unlike any previously described for a flying animal. There are three key features: leading-edge vortices (a well-known mechanism that appears to be almost ubiquitous in insect flight), trailing-edge vortices caused by a form of wake capture at stroke reversal, and rotational drag. The two new elements are largely independent of the wing velocity, instead relying on rapid changes in the pitch angle (wing rotation) at the end of each half-stroke, and they are therefore relatively immune to the shallow flapping amplitude. Moreover, these mechanisms are particularly well suited to high aspect ratio mosquito wings.
C1 [Bomphrey, Richard J.; Nakata, Toshiyuki; Phillips, Nathan] Univ London, Royal Vet Coll, Struct & Mot Lab, Hatfield AL9 7TA, Herts, England.
   [Nakata, Toshiyuki] Chiba Univ, Grad Sch Engn, Inage Ku, 1-33Yayoi Cho, Chiba 2638522, Japan.
   [Walker, Simon M.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England.
C3 University of London; University of London Royal Veterinary College; Chiba University; University of Oxford
RP Bomphrey, RJ (corresponding author), Univ London, Royal Vet Coll, Struct & Mot Lab, Hatfield AL9 7TA, Herts, England.
EM rbomphrey@rvc.ac.uk
FU EPSRC [EP/H004025/1, EP/M003698/1]; BBSRC [BB/J001244/1]; EPSRC Career Acceleration Fellowship; Royal Society University Research Fellowship; Autonomous Systems Underpinning Research (ASUR) programme under the Defence Science and Technology Laboratory (Dstl), UK Ministry of Defence; European Research Council (ERC) [204513]; Biotechnology and Biological Sciences Research Council [BB/J001244/2, BB/J001244/1] Funding Source: researchfish; Engineering and Physical Sciences Research Council [EP/H004025/1, EP/H004025/2, EP/M003698/1] Funding Source: researchfish; Grants-in-Aid for Scientific Research [24120007] Funding Source: KAKEN; BBSRC [BB/J001244/2, BB/J001244/1] Funding Source: UKRI; EPSRC [EP/M003698/1, EP/H004025/1, EP/H004025/2] Funding Source: UKRI; European Research Council (ERC) [204513] Funding Source: European Research Council (ERC)
NR 29
TC 232
Z9 256
U1 8
U2 258
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 6
PY 2017
VL 544
IS 7648
BP 92
EP +
DI 10.1038/nature21727
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EQ8GQ
UT WOS:000398323300039
PM 28355184
DA 2026-03-09
ER

PT J
AU Saleheen, D
   Natarajan, P
   Armean, IM
   Zhao, W
   Rasheed, A
   Khetarpal, SA
   Won, HH
   Karczewski, KJ
   O'Donnell-Luria, AH
   Samocha, KE
   Weisburd, B
   Gupta, N
   Zaidi, M
   Samuel, M
   Imran, A
   Abbas, S
   Majeed, F
   Ishaq, M
   Akhtar, S
   Trindade, K
   Mucksavage, M
   Qamar, N
   Zaman, KS
   Yaqoob, Z
   Saghir, T
   Rizvi, SNH
   Memon, A
   Mallick, NH
   Ishaq, M
   Rasheed, SZ
   Memon, FUR
   Mahmood, K
   Ahmed, N
   Do, R
   Krauss, RM
   MacArthur, DG
   Gabriel, S
   Lander, ES
   Daly, MJ
   Frossard, P
   Danesh, J
   Rader, DJ
   Kathiresan, S
AF Saleheen, Danish
   Natarajan, Pradeep
   Armean, Irina M.
   Zhao, Wei
   Rasheed, Asif
   Khetarpal, Sumeet A.
   Won, Hong-Hee
   Karczewski, Konrad J.
   O'Donnell-Luria, Anne H.
   Samocha, Kaitlin E.
   Weisburd, Benjamin
   Gupta, Namrata
   Zaidi, Mozzam
   Samuel, Maria
   Imran, Atif
   Abbas, Shahid
   Majeed, Faisal
   Ishaq, Madiha
   Akhtar, Saba
   Trindade, Kevin
   Mucksavage, Megan
   Qamar, Nadeem
   Zaman, Khan Shah
   Yaqoob, Zia
   Saghir, Tahir
   Rizvi, Syed Nadeem Hasan
   Memon, Anis
   Mallick, Nadeem Hayyat
   Ishaq, Mohammad
   Rasheed, Syed Zahed
   Memon, Fazal-ur-Rehman
   Mahmood, Khalid
   Ahmed, Naveeduddin
   Do, Ron
   Krauss, Ronald M.
   MacArthur, Daniel G.
   Gabriel, Stacey
   Lander, Eric S.
   Daly, Mark J.
   Frossard, Philippe
   Danesh, John
   Rader, Daniel J.
   Kathiresan, Sekar
TI Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity
SO NATURE
LA English
DT Article
ID genome-wide association; apolipoprotein c-iii; coronary-heart-disease; of-function mutations; dna-sequencing data; genetic-variation; apoc3; identification; population; framework
AB A major goal of biomedicine is to understand the function of every gene in the human genome(1). Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high(2). Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia(3). We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease(4,5); we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans.
C1 [Saleheen, Danish; Zhao, Wei] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA USA.
   [Saleheen, Danish; Rasheed, Asif; Zaidi, Mozzam; Samuel, Maria; Imran, Atif; Majeed, Faisal; Ishaq, Madiha; Akhtar, Saba; Frossard, Philippe] Ctr Non Communicable Dis, Karachi, Pakistan.
   [Natarajan, Pradeep] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.
   [Natarajan, Pradeep] Harvard Med Sch, Dept Med, Boston, MA USA.
   [Natarajan, Pradeep; Armean, Irina M.; Karczewski, Konrad J.; O'Donnell-Luria, Anne H.; Samocha, Kaitlin E.; Weisburd, Benjamin; MacArthur, Daniel G.; Kathiresan, Sekar] Harvard & MIT, Broad Inst, Cambridge, MA USA.
   [Armean, Irina M.; Karczewski, Konrad J.; O'Donnell-Luria, Anne H.; Samocha, Kaitlin E.; Weisburd, Benjamin; MacArthur, Daniel G.; Daly, Mark J.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
   [Karczewski, Konrad J.; O'Donnell-Luria, Anne H.; Samocha, Kaitlin E.; Weisburd, Benjamin; MacArthur, Daniel G.; Daly, Mark J.] Harvard Med Sch, Boston, MA USA.
   [Khetarpal, Sumeet A.; Trindade, Kevin; Mucksavage, Megan] Univ Penn, Perelman Sch Med, Inst Translat Med & Therapeut, Dept Genet, Philadelphia, PA 19104 USA.
   [Khetarpal, Sumeet A.; Trindade, Kevin; Mucksavage, Megan] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA.
   [Won, Hong-Hee] Sungkyunkwan Univ, Samsung Med Ctr, SAIHST, Seoul, South Korea.
   [O'Donnell-Luria, Anne H.] Boston Childrens Hosp, Div Genet & Gen, Boston, MA USA.
   [Abbas, Shahid] Faisalabad Inst Cardiol, Faisalabad, Pakistan.
   [Qamar, Nadeem; Zaman, Khan Shah; Yaqoob, Zia; Saghir, Tahir; Rizvi, Syed Nadeem Hasan; Memon, Anis] Natl Inst Cardiovasc Disorders, Karachi, Pakistan.
   [Mallick, Nadeem Hayyat] Punjab Inst Cardiol, Lahore, Pakistan.
   [Ishaq, Mohammad; Rasheed, Syed Zahed] Karachi Inst Heart Dis, Karachi, Pakistan.
   [Memon, Fazal-ur-Rehman] Red Crescent Inst Cardiol, Hyderabad, Andhra Pradesh, Pakistan.
   [Mahmood, Khalid] Civil Hosp, Karachi, Pakistan.
   [Ahmed, Naveeduddin] Liaquat Natl Hosp, Karachi, Pakistan.
   [Do, Ron] Icahn Sch Med, Dept Genet & Genom Sci, New York, NY USA.
   [Do, Ron] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA.
   [Krauss, Ronald M.] Childrens Hosp Oakland, Res Inst, Oakland, CA USA.
   [Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB2 1TN, England.
   [Danesh, John] Wellcome Trust Sanger Inst, Cambridge, England.
   [Rader, Daniel J.] Univ Penn, Dept Human Genet, Philadelphia, PA 19104 USA.
C3 University of Pennsylvania; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; University of Pennsylvania; University of Pennsylvania; Sungkyunkwan University (SKKU); Samsung Medical Center; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Dow University of Health Sciences; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Children's Hospital Oakland Research Institute; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Benioff Children's Hospital Oakland; University of Cambridge; Wellcome Trust Sanger Institute; University of Pennsylvania
RP Saleheen, D (corresponding author), Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA USA.; Saleheen, D (corresponding author), Ctr Non Communicable Dis, Karachi, Pakistan.
EM saleheen@mail.med.upenn.edu; sekar@broadinstitute.org
FU National Institutes of Health; Fogarty International; Wellcome Trust; British Heart Foundation; Pfizer; John S. LaDue Memorial Fellowship in Cardiology from Harvard Medical School; Samsung Medical Center, Korea [SMO116163]; Ofer and Shelly Nemirovsky MGH Research Scholar Award; National Institutes of Health [R01HL107816, R01GM104371]; Donovan Family Foundation; Fondation Leducq; NHGRI [5U54HG003067-11]; UK Medical Research Council; NIHR Cambridge Biomedical Research Centre; British Heart Foundation [RG/08/014/24067, CH/12/2/29428, RG/13/13/30194, RG/16/4/32218] Funding Source: researchfish; Medical Research Council [MR/P02811X/1, MR/P013880/1, MR/L003120/1] Funding Source: researchfish; National Institute for Health Research [NF-SI-0512-10165] Funding Source: researchfish; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK043351] Funding Source: NIH RePORTER; GCRF [MR/P02811X/1] Funding Source: UKRI; MRC [MR/L003120/1, MR/P013880/1] Funding Source: UKRI
NR 59
TC 253
Z9 276
U1 0
U2 60
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 13
PY 2017
VL 544
IS 7649
BP 235
EP +
DI 10.1038/nature22034
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ER6EK
UT WOS:000398897900038
PM 28406212
DA 2026-03-09
ER

PT J
AU Hoffmann, C
   Zimmermann, F
   Biek, R
   Kuehl, H
   Nowak, K
   Mundry, R
   Agbor, A
   Angedakin, S
   Arandjelovic, M
   Blankenburg, A
   Brazolla, G
   Corogenes, K
   Couacy-Hymann, E
   Deschner, T
   Dieguez, P
   Dierks, K
   Düx, A
   Dupke, S
   Eshuis, H
   Formenty, P
   Yuh, YGI
   Oedmakers, AG
   Ogarten, JFG
   Ranjon, ACG
   McGraw, S
   Runow, RG
   Hart, J
   Jones, S
   Junker, J
   Kiang, J
   Langergraber, K
   Lapuente, J
   Lee, K
   Leendertz, SA
   Léguillon, F
   Leinert, V
   Löhrich, T
   Marrocoli, S
   Mätz-Rensing, K
   Meier, A
   Merkel, K
   Metzger, S
   Murai, M
   Niedorf, S
   De Nys, H
   Achse, AS
   van Schijndel, J
   Thiesen, U
   Ton, E
   Wu, D
   Wieler, LH
   Boesch, C
   Klee, SR
   Wittig, RM
   Calvignac-Spencer, S
   Leendertz, FH
AF Hoffmann, Constanze
   Zimmermann, Fee
   Biek, Roman
   Kuehl, Hjalmar
   Nowak, Kathrin
   Mundry, Roger
   Agbor, Anthony
   Angedakin, Samuel
   Arandjelovic, Mimi
   Blankenburg, Anja
   Brazolla, Gregory
   Corogenes, Katherine
   Couacy-Hymann, Emmanuel
   Deschner, Tobias
   Dieguez, Paula
   Dierks, Karsten
   Duex, Ariane
   Dupke, Susann
   Eshuis, Henk
   Formenty, Pierre
   Yuh, Yisa G. Inath
   Oedmakers, Annemarie G.
   Ogarten, Jan F. G.
   Ranjon, Anne-Celine G.
   McGraw, Scott
   Runow, Roland G.
   Hart, John
   Jones, Sorrel
   Junker, Jessica
   Kiang, John
   Langergraber, Kevin
   Lapuente, Juan
   Lee, Kevin
   Leendertz, Siv Aina
   Leguillon, Floraine
   Leinert, Vera
   Loehrich, Therese
   Marrocoli, Sergio
   Maetz-Rensing, Kerstin
   Meier, Amelia
   Merkel, Kevin
   Metzger, Sonja
   Murai, Mizuki
   Niedorf, Svenja
   De Nys, Helene
   Achse, Andreas S.
   van Schijndel, Joost
   Thiesen, Ulla
   Ton, Els
   Wu, Doris
   Wieler, Lothar H.
   Boesch, Christophe
   Klee, Silke R.
   Wittig, Roman M.
   Calvignac-Spencer, Sebastien
   Leendertz, Fabian H.
TI Persistent anthrax as a major driver of wildlife mortality in a tropical rainforest
SO NATURE
LA English
DT Article
ID ancient dna extraction; bacillus-anthracis; outbreak; performance; framework
AB Anthrax is a globally important animal disease and zoonosis. Despite this, our current knowledge of anthrax ecology is largely limited to arid ecosystems, where outbreaks are most commonly reported(1-3). Here we show that the dynamics of an anthrax-causing agent, Bacillus cereus biovar anthracis, in a tropical rainforest have severe consequences for local wildlife communities. Using data and samples collected over three decades, we show that rainforest anthrax is a persistent and widespread cause of death for a broad range of mammalian hosts. We predict that this pathogen will accelerate the decline and possibly result in the extirpation of local chimpanzee (Pan troglodytes verus) populations. We present the epidemiology of a cryptic pathogen and show that its presence has important implications for conservation.
C1 [Hoffmann, Constanze; Zimmermann, Fee; Nowak, Kathrin; Blankenburg, Anja; Duex, Ariane; Ogarten, Jan F. G.; Leendertz, Siv Aina; Leguillon, Floraine; Loehrich, Therese; Merkel, Kevin; Metzger, Sonja; Niedorf, Svenja; De Nys, Helene; Achse, Andreas S.; Thiesen, Ulla; Wu, Doris; Calvignac-Spencer, Sebastien; Leendertz, Fabian H.] Robert Koch Inst, Epidemiol Highly Pathogen Microorganisms P3, Seestr 10-11, D-13353 Berlin, Germany.
   [Zimmermann, Fee; Dupke, Susann; Runow, Roland G.; Klee, Silke R.] Robert Koch Inst, ZBS Ctr Biol Threats & Special Pathogens, Highly Pathogen Microorganisms, Seestr 10-11, D-13353 Berlin, Germany.
   [Biek, Roman] Univ Glasgow, Inst Biodivers Anim Hlth & Comparat Med, Coll Med Vet & Life Sci, Boyd Orr Ctr Populat & Ecosyst Hlth, Glasgow G12 8QQ, Lanark, Scotland.
   [Kuehl, Hjalmar; Mundry, Roger; Agbor, Anthony; Angedakin, Samuel; Arandjelovic, Mimi; Brazolla, Gregory; Corogenes, Katherine; Deschner, Tobias; Dieguez, Paula; Dierks, Karsten; Eshuis, Henk; Yuh, Yisa G. Inath; Ogarten, Jan F. G.; Ranjon, Anne-Celine G.; Jones, Sorrel; Junker, Jessica; Lapuente, Juan; Lee, Kevin; Loehrich, Therese; Marrocoli, Sergio; Meier, Amelia; Murai, Mizuki; De Nys, Helene; van Schijndel, Joost; Wu, Doris; Boesch, Christophe; Wittig, Roman M.] Max Planck Inst Evolutionary Anthropol MPI EVAN, Deutsch Pl 6, D-04103 Leipzig, Germany.
   [Couacy-Hymann, Emmanuel] LANADA LCVB, Bingerville 206, Cote Ivoire.
   [Formenty, Pierre] WHO, CH-1211 Geneva 27, Switzerland.
   [Oedmakers, Annemarie G.; Ton, Els] Chimbo Fdn, Amstel 49, NL-1011 PW Amsterdam, Netherlands.
   [Ogarten, Jan F. G.] McGill Univ, Dept Biol, 855 Sherbrooke St, West Montreal, PQ H3A 2T7, Canada.
   [McGraw, Scott] Ohio State Univ, Dept Anthropol, 4034 Smith Lab,174 West 18th Ave, Columbus, OH 43210 USA.
   [Hart, John] Lukuru Fdn, 1235 Ave Poids Lourds Quartier Kingabois, Kinshasa, DEM REP CONGO.
   [Kiang, John] Limbe Wildlife Ctr, Limbe, Cameroon.
   [Langergraber, Kevin] Arizona State Univ, POB 872402, Tempe, AZ 85287 USA.
   [Leinert, Vera] Wild Chimpanzee Fdn WCF, Deutsch Pl 6, D-04103 Leipzig, Germany.
   [Maetz-Rensing, Kerstin] German Primate Ctr, Kellnerweg 4, D-37077 Gottingen, Germany.
   [Wieler, Lothar H.] Robert Koch Inst, Seestr 10-11, D-13353 Berlin, Germany.
C3 Robert Koch Institute; Robert Koch Institute; University of Glasgow; World Health Organization; University System of Ohio; Ohio State University; Arizona State University; Arizona State University-Tempe; Leibniz Association; Deutsches Primatenzentrum (DPZ); Robert Koch Institute
RP Leendertz, FH (corresponding author), Robert Koch Inst, Epidemiol Highly Pathogen Microorganisms P3, Seestr 10-11, D-13353 Berlin, Germany.
EM leendertzf@rki.de
FU German Research Council DFG [KL 2521/1-1]; Sonnenfeld-Stiftung; Max-Planck-Society; Krekeler Foundation
NR 60
TC 94
Z9 107
U1 3
U2 86
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 3
PY 2017
VL 548
IS 7665
BP 82
EP +
DI 10.1038/nature23309
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FC4SU
UT WOS:000406831700041
PM 28770842
DA 2026-03-09
ER

PT J
AU Gold, DA
   Caron, A
   Fournier, GP
   Summons, RE
AF Gold, David A.
   Caron, Abigail
   Fournier, Gregory P.
   Summons, Roger E.
TI Paleoproterozoic sterol biosynthesis and the rise of oxygen
SO NATURE
LA English
DT Article
ID hydrocarbon biomarkers; mixed models; evolution; bacteria; eukaryotes; proteins; fossils; origin; ocean; root
AB Natural products preserved in the geological record can function as 'molecular fossils', providing insight into organisms and physiologies that existed in the deep past. One important group of molecular fossils is the steroidal hydrocarbons (steranes), which are the diagenetic remains of sterol lipids. Complex sterols with modified side chains are unique to eukaryotes, although simpler sterols can also be synthesized by a few bacteria(1). Sterol biosynthesis is an oxygen-intensive process; thus, the presence of complex steranes in ancient rocks not only signals the presence of eukaryotes, but also aerobic metabolic processes(2). In 1999, steranes were reported in 2.7 billion year (Gyr)-old rocks from the Pilbara Craton in Australia(3), suggesting a long delay between photosynthetic oxygen production and its accumulation in the atmosphere (also known as the Great Oxidation Event) 2.45-2.32 Gyr ago(4). However, the recent reappraisal and rejection of these steranes as contaminants(5) pushes the oldest reported steranes forward to around 1.64 Gyr ago (ref. 6). Here we use a molecular clock approach to improve constraints on the evolution of sterol biosynthesis. We infer that stem eukaryotes shared functionally modern sterol biosynthesis genes with bacteria via horizontal gene transfer. Comparing multiple molecular clock analyses, we find that the maximum marginal probability for the divergence time of bacterial and eukaryal sterol biosynthesis genes is around 2.31 Gyr ago, concurrent with the most recent geochemical evidence for the Great Oxidation Event(7). Our results therefore indicate that simple sterol biosynthesis existed well before the diversification of living eukaryotes, substantially predating the oldest detected sterane biomarkers (approximately 1.64 Gyr ago(6)), and furthermore, that the evolutionary history of sterol biosynthesis is tied to the first widespread availability of molecular oxygen in the ocean-atmosphere system.
C1 [Gold, David A.; Caron, Abigail; Fournier, Gregory P.; Summons, Roger E.] MIT, Dept Earth Atmospher & Planetary Sci, Cambridge, MA 02139 USA.
   [Gold, David A.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
C3 Massachusetts Institute of Technology (MIT); California Institute of Technology
RP Summons, RE (corresponding author), MIT, Dept Earth Atmospher & Planetary Sci, Cambridge, MA 02139 USA.
EM rsummons@mit.edu
FU Agouron Institute Geobiology Fellowship; Simons Foundation Collaboration on the Origins of Life; National Science Foundation programme 'Frontiers of Earth System Dynamics' [EAR-1338810]; National Science Foundation programme 'Integrated Earth Systems' [IES-1615426]; Directorate For Geosciences; Division Of Earth Sciences [1615426] Funding Source: National Science Foundation; Division Of Earth Sciences; Directorate For Geosciences [1338810] Funding Source: National Science Foundation
NR 33
TC 84
Z9 99
U1 1
U2 70
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 16
PY 2017
VL 543
IS 7645
BP 420
EP +
DI 10.1038/nature21412
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN9RN
UT WOS:000396337400050
PM 28264195
DA 2026-03-09
ER

PT J
AU Cau, A
   Beyrand, V
   Voeten, DFAE
   Fernandez, V
   Tafforeau, P
   Stein, K
   Barsbold, R
   Tsogtbaatar, K
   Currie, PJ
   Godefroit, P
AF Cau, Andrea
   Beyrand, Vincent
   Voeten, Dennis F. A. E.
   Fernandez, Vincent
   Tafforeau, Paul
   Stein, Koen
   Barsbold, Rinchen
   Tsogtbaatar, Khishigjav
   Currie, Philip J.
   Godefroit, Pascal
TI Synchrotron scanning reveals amphibious ecomorphology in a new clade of bird-like dinosaurs
SO NATURE
LA English
DT Article
ID evolution; theropod; osteology
AB Maniraptora includes birds and their closest relatives among theropod dinosaurs(1-5). During the Cretaceous period, several maniraptoran lineages diverged from the ancestral coelurosaurian bauplan and evolved novel ecomorphologies, including active flight(2), gigantism(3), cursoriality(4) and herbivory(5). Propagation X-ray phase-contrast synchrotron microtomography of a well-preserved maniraptoran from Mongolia, still partially embedded in the rock matrix, revealed a mosaic of features, most of them absent among non-avian maniraptorans but shared by reptilian and avian groups with aquatic or semiaquatic ecologies(6-14). This new theropod, Halszkaraptor escuilliei gen. et sp. nov., is related to other enigmatic Late Cretaceous maniraptorans from Mongolia(15,16) in a novel clade at the root of Dromaeosauridae(17). This lineage adds an amphibious ecomorphology to those evolved by maniraptorans: it acquired a predatory mode that relied mainly on neck hyperelongation for food procurement, it coupled the obligatory bipedalism of theropods with forelimb proportions that may support a swimming function, and it developed postural adaptations convergent with short-tailed birds.
C1 [Cau, Andrea] Geol & Palaeontol Museum Giovanni Capellini, I-40126 Bologna, Italy.
   [Beyrand, Vincent; Voeten, Dennis F. A. E.; Fernandez, Vincent; Tafforeau, Paul] European Synchrotron Radiat Facil, F-38043 Grenoble, France.
   [Beyrand, Vincent; Voeten, Dennis F. A. E.] Palacky Univ, Dept Zool, CS-40220 Olomouc, Czech Republic.
   [Beyrand, Vincent; Voeten, Dennis F. A. E.] Palacky Univ, Lab Ornithol, CS-40220 Olomouc, Czech Republic.
   [Stein, Koen] Vrije Univ Brussel, Earth Syst Sci AMGC, B-1050 Brussels, Belgium.
   [Barsbold, Rinchen] Mongolian Acad Sci, Palaeontol Ctr, Ulaanbaatar 201351, Mongolia.
   [Tsogtbaatar, Khishigjav] Mongolian Acad Sci, Inst Palaeontol & Geol, Ulaanbaatar 210351, Mongolia.
   [Currie, Philip J.] Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E9, Canada.
   [Godefroit, Pascal] Royal Belgian Inst Nat Sci, Directorate Earth & Hist Life, B-1000 Brussels, Belgium.
C3 European Synchrotron Radiation Facility (ESRF); Palacky University Olomouc; Palacky University Olomouc; Vrije Universiteit Brussel; Mongolian Academy of Sciences; Mongolian Academy of Sciences; University of Alberta; Royal Belgian Institute of Natural Sciences
RP Cau, A (corresponding author), Geol & Palaeontol Museum Giovanni Capellini, I-40126 Bologna, Italy.
EM cauand@gmail.com
FU Willi Hennig Society
NR 30
TC 128
Z9 143
U1 4
U2 56
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 21
PY 2017
VL 552
IS 7685
BP 395
EP +
DI 10.1038/nature24679
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ7RI
UT WOS:000418559800057
PM 29211712
DA 2026-03-09
ER

PT J
AU Hangauer, MJ
   Viswanathan, VS
   Ryan, MJ
   Bole, D
   Eaton, JK
   Matov, A
   Galeas, J
   Dhruv, HD
   Berens, ME
   Schreiber, SL
   McCormick, F
   McManus, MT
AF Hangauer, Matthew J.
   Viswanathan, Vasanthi S.
   Ryan, Matthew J.
   Bole, Dhruv
   Eaton, John K.
   Matov, Alexandre
   Galeas, Jacqueline
   Dhruv, Harshil D.
   Berens, Michael E.
   Schreiber, Stuart L.
   McCormick, Frank
   McManus, Michael T.
TI Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition
SO NATURE
LA English
DT Article
ID death; resistance; ferroptosis; state
AB Acquired drug resistance prevents cancer therapies from achieving stable and complete responses(1). Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells(2-4). The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse(5). We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival(6). Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance.
C1 [Hangauer, Matthew J.; McManus, Michael T.] Univ Calif San Francisco, Dept Microbiol & Immunol, 513 Parnassus Ave, San Francisco, CA 94143 USA.
   [Hangauer, Matthew J.; McManus, Michael T.] Univ Calif San Francisco, Ctr Diabet, 513 Parnassus Ave, San Francisco, CA 94143 USA.
   [Hangauer, Matthew J.; Bole, Dhruv; Galeas, Jacqueline; McCormick, Frank] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 1450 3rd St, San Francisco, CA 94143 USA.
   [Viswanathan, Vasanthi S.; Ryan, Matthew J.; Eaton, John K.; Schreiber, Stuart L.] Broad Inst, 415 Main St, Cambridge, MA 02142 USA.
   [Matov, Alexandre] DataSet Anal LLC, 155 Jackson St, San Francisco, CA 94111 USA.
   [Dhruv, Harshil D.; Berens, Michael E.] Translat Genom Res Inst, Canc & Cell Biol Div, 445 N 5th St, Phoenix, AZ 85004 USA.
   [Schreiber, Stuart L.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
   [Schreiber, Stuart L.] Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA.
C3 University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Translational Genomics Research Institute; Howard Hughes Medical Institute; Harvard University
RP McManus, MT (corresponding author), Univ Calif San Francisco, Dept Microbiol & Immunol, 513 Parnassus Ave, San Francisco, CA 94143 USA.; McManus, MT (corresponding author), Univ Calif San Francisco, Ctr Diabet, 513 Parnassus Ave, San Francisco, CA 94143 USA.; McCormick, F (corresponding author), Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 1450 3rd St, San Francisco, CA 94143 USA.
EM frank.mccormick@ucsf.edu; michael.mcmanus@ucsf.edu
FU National Cancer Institute (NCI) of the National Institutes of Health (NIH) (Cancer Target Discovery and Development Network) [U01CA168370, U01CA217882, U01CA176152, U01CA168397, R01CA212767]; Susan G. Komen for Cure Postdoctoral Fellowship [KG1101214]; Howard Hughes Medical Institute; National Cancer Institute [U01CA217882, R01CA212767, U01CA217848] Funding Source: NIH RePORTER
NR 23
TC 1359
Z9 1528
U1 10
U2 393
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 9
PY 2017
VL 551
IS 7679
BP 247
EP +
DI 10.1038/nature24297
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM1KF
UT WOS:000414734200051
PM 29088702
DA 2026-03-09
ER

PT J
AU Zhang, Y
   Ptacin, JL
   Fischer, EC
   Aerni, HR
   Caffaro, CE
   Jose, KS
   Feldman, AW
   Turner, CR
   Romesberg, FE
AF Zhang, Yorke
   Ptacin, Jerod L.
   Fischer, Emil C.
   Aerni, Hans R.
   Caffaro, Carolina E.
   Jose, Kristine San
   Feldman, Aaron W.
   Turner, Court R.
   Romesberg, Floyd E.
TI A semi-synthetic organism that stores and retrieves increased genetic information
SO NATURE
LA English
DT Article
ID green fluorescent protein; escherichia-coli; click chemistry; code; proteomics; purification; mutagenesis; expansion; platform; peptide
AB Since at least the last common ancestor of all life on Earth, genetic information has been stored in a four-letter alphabet that is propagated and retrieved by the formation of two base pairs. The central goal of synthetic biology is to create new life forms and functions(1), and the most general route to this goal is the creation of semi-synthetic organisms whose DNA harbours two additional letters that form a third, unnatural base pair. Previous efforts to generate such semi-synthetic organisms(2) culminated in the creation of a strain of Escherichia coli that, by virtue of a nucleoside triphosphate transporter from Phaeodactylum tricornutum, imports the requisite unnatural triphosphates from its medium and then uses them to replicate a plasmid containing the unnatural base pair dNaM-dTPT3. Although the semi-synthetic organism stores increased information when compared to natural organisms, retrieval of the information requires in vivo transcription of the unnatural base pair into mRNA and tRNA, aminoacylation of the tRNA with a non-canonical amino acid, and efficient participation of the unnatural base pair in decoding at the ribosome. Here we report the in vivo transcription of DNA containing dNaM and dTPT3 into mRNAs with two different unnatural codons and tRNAs with cognate unnatural anticodons, and their efficient decoding at the ribosome to direct the site-specific incorporation of natural or non-canonical amino acids into superfolder green fluorescent protein. The results demonstrate that interactions other than hydrogen bonding can contribute to every step of information storage and retrieval. The resulting semi-synthetic organism both encodes and retrieves increased information and should serve as a platform for the creation of new life forms and functions.
C1 [Zhang, Yorke; Fischer, Emil C.; Feldman, Aaron W.; Romesberg, Floyd E.] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA.
   [Ptacin, Jerod L.; Aerni, Hans R.; Caffaro, Carolina E.; Jose, Kristine San; Turner, Court R.] Synthorx Inc, La Jolla, CA 92037 USA.
C3 Scripps Research Institute
RP Romesberg, FE (corresponding author), Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA.
EM floyd@scripps.edu
FU National Institutes of Health [GM118178]; National Science Foundation [NSF/DGE-1346837]
NR 28
TC 274
Z9 359
U1 4
U2 379
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 30
PY 2017
VL 551
IS 7682
BP 644
EP +
DI 10.1038/nature24659
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FO1KW
UT WOS:000416520400046
PM 29189780
DA 2026-03-09
ER

PT J
AU Wang, P
   Erma, PV
   Xia, GQ
   Shi, J
   Qiao, JX
   Tao, SW
   Cheng, PTW
   Poss, MA
   Farmer, ME
   Yeung, KS
   Yu, JQ
AF Wang, Peng
   Erma, Pritha V.
   Xia, Guoqin
   Shi, Jun
   Qiao, Jennifer X.
   Tao, Shiwei
   Cheng, Peter T. W.
   Poss, Michael A.
   Farmer, Marcus E.
   Yeung, Kap-Sun
   Yu, Jin-Quan
TI Ligand-accelerated non-directed C-H functionalization of arenes
SO NATURE
LA English
DT Article
ID palladium; activation; arylation; bonds; alkenylation; olefination
AB The directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups(1-6). Palladium-catalysed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts(7,8). Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used(9-18), which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.
C1 [Wang, Peng; Erma, Pritha V.; Xia, Guoqin; Farmer, Marcus E.; Yu, Jin-Quan] Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA.
   [Shi, Jun; Tao, Shiwei; Cheng, Peter T. W.] Bristol Myers Squibb Co, Discovery Chem, 350 Carter Rd, Princeton, NJ 08540 USA.
   [Qiao, Jennifer X.; Poss, Michael A.] Bristol Myers Squibb Co, Discovery Chem, POB 4000, Princeton, NJ 08543 USA.
   [Yeung, Kap-Sun] Bristol Myers Squibb Co, Discovery Chem, 5 Res Pkwy, Wallingford, CT 06492 USA.
C3 Scripps Research Institute; Bristol-Myers Squibb; Bristol-Myers Squibb; Bristol-Myers Squibb
RP Yu, JQ (corresponding author), Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA.
EM yu200@scripps.edu
FU Scripps Research Institute; NIH (NIGMS) [2R01 GM102265]; Bristol-Myers Squibb; Shanghai RAAS Blood Products Co., Ltd.; National Institute of General Medical Sciences [R01GM102265] Funding Source: NIH RePORTER
NR 30
TC 344
Z9 385
U1 9
U2 242
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 23
PY 2017
VL 551
IS 7681
BP 489
EP +
DI 10.1038/nature24632
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FN5JO
UT WOS:000416043700042
PM 29168802
DA 2026-03-09
ER

PT J
AU Mcrae, JF
   Clayton, S
   Fitzgerald, TW
   Kaplanis, J
   Prigmore, E
   Rajan, D
   Sifrim, A
   Aitken, S
   Akawi, N
   Alvi, M
   Ambridge, K
   Barrett, DM
   Bayzetinova, T
   Jones, P
   Jones, WD
   King, D
   Krishnappa, N
   Mason, LE
   Singh, T
   Tivey, AR
   Ahmed, M
   Anjum, U
   Archer, H
   Armstrong, R
   Awada, J
   Balasubramanian, M
   Banka, S
   Baralle, D
   Barnicoat, A
   Batstone, P
   Baty, D
   Bennett, C
   Berg, J
   Bernhard, B
   Bevan, AP
   Bitner-Glindzicz, M
   Blair, E
   Blyth, M
   Bohanna, D
   Bourdon, L
   Bourn, D
   Bradley, L
   Brady, A
   Brent, S
   Brewer, C
   Brunstrom, K
   Bunyan, DJ
   Burn, J
   Canham, N
   Castle, B
   Chandler, K
   Chatzimichali, E
   Cilliers, D
   Clarke, A
   Clasper, S
   Clayton-Smith, J
   Clowes, V
   Coates, A
   Cole, T
   Colgiu, I
   Collins, A
   Collinson, MN
   Connell, F
   Cooper, N
   Cox, H
   Cresswell, L
   Cross, G
   Crow, Y
   D'Alessandro, M
   Dabir, T
   Davidson, R
   Davies, S
   de Vries, D
   Dean, J
   Deshpande, C
   Devlin, G
   Dixit, A
   Dobbie, A
   Donaldson, A
   Donnai, D
   Donnelly, D
   Donnelly, C
   Douglas, A
   Douzgou, S
   Duncan, A
   Eason, J
   Ellard, S
   Ellis, I
   Elmslie, F
   Evans, K
   Everest, S
   Fendick, T
   Fisher, R
   Flinter, F
   Foulds, N
   Fry, A
   Fryer, A
   Gardiner, C
   Gaunt, L
   Ghali, N
   Gibbons, R
   Gill, H
   Goodship, J
   Goudie, D
   Gray, E
   Green, A
   Greene, P
   Greenhalgh, L
   Gribble, S
   Harrison, R
   Harrison, L
   Harrison, V
   Hawkins, R
   He, L
   Hellens, S
   Henderson, A
   Hewitt, S
   Hildyard, L
   Hobson, E
   Holden, S
   Holder, M
   Holder, S
   Hollingsworth, G
   Homfray, T
   Humphreys, M
   Hurst, J
   Hutton, B
   Ingram, S
   Irving, M
   Islam, L
   Jackson, A
   Jarvis, J
   Jenkins, L
   Johnson, D
   Jones, E
   Josifova, D
   Joss, S
   Kaemba, B
   Kazembe, S
   Kelsell, R
   Kerr, B
   Kingston, H
   Kini, U
   Kinning, E
   Kirby, G
   Kirk, C
   Kivuva, E
   Kraus, A
   Kumar, D
   Kumar, VKA
   Lachlan, K
   Lam, W
   Lampe, A
   Langman, C
   Lees, M
   Lim, D
   Longman, C
   Lowther, G
   Lynch, SA
   Magee, A
   Maher, E
   Male, A
   Mansour, S
   Marks, K
   Martin, K
   Maye, U
   McCann, E
   McConnell, V
   McEntagart, M
   McGowan, R
   McKay, K
   McKee, S
   McMullan, DJ
   McNerlan, S
   McWilliam, C
   Mehta, S
   Metcalfe, K
   Middleton, A
   Miedzybrodzka, Z
   Miles, E
   Mohammed, S
   Montgomery, T
   Moore, D
   Morgan, S
   Morton, J
   Mugalaasi, H
   Murday, V
   Murphy, H
   Naik, S
   Nemeth, A
   Nevitt, L
   Newbury-Ecob, R
   Norman, A
   O'Shea, R
   Ogilvie, C
   Ong, KR
   Park, SM
   Parker, MJ
   Patel, C
   Paterson, J
   Payne, S
   Perrett, D
   Phipps, J
   Pilz, DT
   Pollard, M
   Pottinger, C
   Poulton, J
   Pratt, N
   Prescott, K
   Price, S
   Pridham, A
   Procter, A
   Purnell, H
   Quarrell, O
   Ragge, N
   Rahbari, R
   Randall, J
   Rankin, J
   Raymond, L
   Rice, D
   Robert, L
   Roberts, E
   Roberts, J
   Roberts, P
   Roberts, G
   Ross, A
   Rosser, E
   Saggar, A
   Samant, S
   Sampson, J
   Sandford, R
   Sarkar, A
   Schweiger, S
   Scott, R
   Scurr, I
   Selby, A
   Seller, A
   Sequeira, C
   Shannon, N
   Sharif, S
   Shaw-Smith, C
   Shearing, E
   Shears, D
   Sheridan, E
   Simonic, I
   Singzon, R
   Skitt, Z
   Smith, A
   Smith, K
   Smithson, S
   Sneddon, L
   Splitt, M
   Squires, M
   Stewart, F
   Stewart, H
   Straub, V
   Suri, M
   Sutton, V
   Swaminathan, GJ
   Sweeney, E
   Tatton-Brown, K
   Taylor, C
   Taylor, R
   Tein, M
   Temple, K
   Thomson, J
   Tischkowitz, M
   Tomkins, S
   Torokwa, A
   Treacy, B
   Turner, C
   Turnpenny, P
   Tysoe, C
   Vandersteen, A
   Varghese, V
   Vasudevan, P
   Vijayarangakannan, P
   Vogt, J
   Wakeling, E
   Wallwark, S
   Waters, J
   Weber, A
   Wellesley, D
   Whiteford, M
   Widaa, S
   Wilcox, S
   Wilkinson, E
   Williams, D
   Williams, N
   Wilson, L
   Woods, G
   Wragg, C
   Wright, M
   Yates, L
   Yau, M
   Nellåker, C
   Parker, M
   Firth, HV
   Wright, CF
   FitzPatrick, DR
   Barrett, JC
   Hurles, ME
AF McRae, Jeremy F.
   Clayton, Stephen
   Fitzgerald, Tomas W.
   Kaplanis, Joanna
   Prigmore, Elena
   Rajan, Diana
   Sifrim, Alejandro
   Aitken, Stuart
   Akawi, Nadia
   Alvi, Mohsan
   Ambridge, Kirsty
   Barrett, Daniel M.
   Bayzetinova, Tanya
   Jones, Philip
   Jones, Wendy D.
   King, Daniel
   Krishnappa, Netravathi
   Mason, Laura E.
   Singh, Tarjinder
   Tivey, Adrian R.
   Ahmed, Munaza
   Anjum, Uruj
   Archer, Hayley
   Armstrong, Ruth
   Awada, Jana
   Balasubramanian, Meena
   Banka, Siddharth
   Baralle, Diana
   Barnicoat, Angela
   Batstone, Paul
   Baty, David
   Bennett, Chris
   Berg, Jonathan
   Bernhard, Birgitta
   Bevan, A. Paul
   Bitner-Glindzicz, Maria
   Blair, Edward
   Blyth, Moira
   Bohanna, David
   Bourdon, Louise
   Bourn, David
   Bradley, Lisa
   Brady, Angela
   Brent, Simon
   Brewer, Carole
   Brunstrom, Kate
   Bunyan, David J.
   Burn, John
   Canham, Natalie
   Castle, Bruce
   Chandler, Kate
   Chatzimichali, Elena
   Cilliers, Deirdre
   Clarke, Angus
   Clasper, Susan
   Clayton-Smith, Jill
   Clowes, Virginia
   Coates, Andrea
   Cole, Trevor
   Colgiu, Irina
   Collins, Amanda
   Collinson, Morag N.
   Connell, Fiona
   Cooper, Nicola
   Cox, Helen
   Cresswell, Lara
   Cross, Gareth
   Crow, Yanick
   D'Alessandro, Mariella
   Dabir, Tabib
   Davidson, Rosemarie
   Davies, Sally
   de Vries, Dylan
   Dean, John
   Deshpande, Charu
   Devlin, Gemma
   Dixit, Abhijit
   Dobbie, Angus
   Donaldson, Alan
   Donnai, Dian
   Donnelly, Deirdre
   Donnelly, Carina
   Douglas, Angela
   Douzgou, Sofia
   Duncan, Alexis
   Eason, Jacqueline
   Ellard, Sian
   Ellis, Ian
   Elmslie, Frances
   Evans, Karenza
   Everest, Sarah
   Fendick, Tina
   Fisher, Richard
   Flinter, Frances
   Foulds, Nicola
   Fry, Andrew
   Fryer, Alan
   Gardiner, Carol
   Gaunt, Lorraine
   Ghali, Neeti
   Gibbons, Richard
   Gill, Harinder
   Goodship, Judith
   Goudie, David
   Gray, Emma
   Green, Andrew
   Greene, Philip
   Greenhalgh, Lynn
   Gribble, Susan
   Harrison, Rachel
   Harrison, Lucy
   Harrison, Victoria
   Hawkins, Rose
   He, Liu
   Hellens, Stephen
   Henderson, Alex
   Hewitt, Sarah
   Hildyard, Lucy
   Hobson, Emma
   Holden, Simon
   Holder, Muriel
   Holder, Susan
   Hollingsworth, Georgina
   Homfray, Tessa
   Humphreys, Mervyn
   Hurst, Jane
   Hutton, Ben
   Ingram, Stuart
   Irving, Melita
   Islam, Lily
   Jackson, Andrew
   Jarvis, Joanna
   Jenkins, Lucy
   Johnson, Diana
   Jones, Elizabeth
   Josifova, Dragana
   Joss, Shelagh
   Kaemba, Beckie
   Kazembe, Sandra
   Kelsell, Rosemary
   Kerr, Bronwyn
   Kingston, Helen
   Kini, Usha
   Kinning, Esther
   Kirby, Gail
   Kirk, Claire
   Kivuva, Emma
   Kraus, Alison
   Kumar, Dhavendra
   Kumar, V. K. Ajith
   Lachlan, Katherine
   Lam, Wayne
   Lampe, Anne
   Langman, Caroline
   Lees, Melissa
   Lim, Derek
   Longman, Cheryl
   Lowther, Gordon
   Lynch, Sally A.
   Magee, Alex
   Maher, Eddy
   Male, Alison
   Mansour, Sahar
   Marks, Karen
   Martin, Katherine
   Maye, Una
   McCann, Emma
   McConnell, Vivienne
   McEntagart, Meriel
   McGowan, Ruth
   McKay, Kirsten
   McKee, Shane
   McMullan, Dominic J.
   McNerlan, Susan
   McWilliam, Catherine
   Mehta, Sarju
   Metcalfe, Kay
   Middleton, Anna
   Miedzybrodzka, Zosia
   Miles, Emma
   Mohammed, Shehla
   Montgomery, Tara
   Moore, David
   Morgan, Sian
   Morton, Jenny
   Mugalaasi, Hood
   Murday, Victoria
   Murphy, Helen
   Naik, Swati
   Nemeth, Andrea
   Nevitt, Louise
   Newbury-Ecob, Ruth
   Norman, Andrew
   O'Shea, Rosie
   Ogilvie, Caroline
   Ong, Kai-Ren
   Park, Soo-Mi
   Parker, Michael J.
   Patel, Chirag
   Paterson, Joan
   Payne, Stewart
   Perrett, Daniel
   Phipps, Julie
   Pilz, Daniela T.
   Pollard, Martin
   Pottinger, Caroline
   Poulton, Joanna
   Pratt, Norman
   Prescott, Katrina
   Price, Sue
   Pridham, Abigail
   Procter, Annie
   Purnell, Hellen
   Quarrell, Oliver
   Ragge, Nicola
   Rahbari, Raheleh
   Randall, Josh
   Rankin, Julia
   Raymond, Lucy
   Rice, Debbie
   Robert, Leema
   Roberts, Eileen
   Roberts, Jonathan
   Roberts, Paul
   Roberts, Gillian
   Ross, Alison
   Rosser, Elisabeth
   Saggar, Anand
   Samant, Shalaka
   Sampson, Julian
   Sandford, Richard
   Sarkar, Ajoy
   Schweiger, Susann
   Scott, Richard
   Scurr, Ingrid
   Selby, Ann
   Seller, Anneke
   Sequeira, Cheryl
   Shannon, Nora
   Sharif, Saba
   Shaw-Smith, Charles
   Shearing, Emma
   Shears, Debbie
   Sheridan, Eamonn
   Simonic, Ingrid
   Singzon, Roldan
   Skitt, Zara
   Smith, Audrey
   Smith, Kath
   Smithson, Sarah
   Sneddon, Linda
   Splitt, Miranda
   Squires, Miranda
   Stewart, Fiona
   Stewart, Helen
   Straub, Volker
   Suri, Mohnish
   Sutton, Vivienne
   Swaminathan, Ganesh Jawahar
   Sweeney, Elizabeth
   Tatton-Brown, Kate
   Taylor, Cat
   Taylor, Rohan
   Tein, Mark
   Temple, Karen
   Thomson, Jenny
   Tischkowitz, Marc
   Tomkins, Susan
   Torokwa, Audrey
   Treacy, Becky
   Turner, Claire
   Turnpenny, Peter
   Tysoe, Carolyn
   Vandersteen, Anthony
   Varghese, Vinod
   Vasudevan, Pradeep
   Vijayarangakannan, Parthiban
   Vogt, Julie
   Wakeling, Emma
   Wallwark, Sarah
   Waters, Jonathon
   Weber, Astrid
   Wellesley, Diana
   Whiteford, Margo
   Widaa, Sara
   Wilcox, Sarah
   Wilkinson, Emily
   Williams, Denise
   Williams, Nicola
   Wilson, Louise
   Woods, Geoff
   Wragg, Christopher
   Wright, Michael
   Yates, Laura
   Yau, Michael
   Nellaker, Chris
   Parker, Michael
   Firth, Helen V.
   Wright, Caroline F.
   FitzPatrick, David R.
   Barrett, Jeffrey C.
   Hurles, Matthew E.
TI Prevalence and architecture of de novo mutations in developmental disorders
SO NATURE
LA English
DT Article
ID intellectual disability; heart-defects; discovery; genetics; genome; genes; metaanalysis; framework; variants; age
AB The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year.
C1 [McRae, Jeremy F.; Clayton, Stephen; Fitzgerald, Tomas W.; Kaplanis, Joanna; Prigmore, Elena; Rajan, Diana; Sifrim, Alejandro; Akawi, Nadia; Ambridge, Kirsty; Barrett, Daniel M.; Bayzetinova, Tanya; Jones, Philip; Jones, Wendy D.; King, Daniel; Krishnappa, Netravathi; Mason, Laura E.; Singh, Tarjinder; Tivey, Adrian R.; Awada, Jana; Bevan, A. Paul; Brent, Simon; Chatzimichali, Elena; Colgiu, Irina; de Vries, Dylan; Gray, Emma; Gribble, Susan; He, Liu; Hildyard, Lucy; Hutton, Ben; Kelsell, Rosemary; Middleton, Anna; Perrett, Daniel; Pollard, Martin; Rahbari, Raheleh; Randall, Josh; Saggar, Anand; Swaminathan, Ganesh Jawahar; Vijayarangakannan, Parthiban; Widaa, Sara; Wilkinson, Emily; Firth, Helen V.; Wright, Caroline F.; FitzPatrick, David R.; Barrett, Jeffrey C.; Hurles, Matthew E.] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England.
   [Aitken, Stuart; Greene, Philip; Jackson, Andrew; Lampe, Anne; Maher, Eddy; Moore, David; FitzPatrick, David R.] Univ Edinburgh, Western Gen Hosp, MRC Human Genet Unit, MRC IGMM, Edinburgh EH4 2XU, Midlothian, Scotland.
   [Alvi, Mohsan] Univ Oxford, Dept Engn Sci, Parks Rd, Oxford OX1 3PJ, England.
   [Ahmed, Munaza; Baralle, Diana; Bunyan, David J.; Collins, Amanda; Collinson, Morag N.; Harrison, Lucy; Harrison, Victoria; Lachlan, Katherine; Temple, Karen; Torokwa, Audrey; Wellesley, Diana] Southampton Univ Hosp, Princess Anne Hosp, Wessex Clin Genet Serv, Coxford Rd, Southampton SO16 5YA, Hants, England.
   [Ahmed, Munaza; Baralle, Diana; Bunyan, David J.; Collins, Amanda; Collinson, Morag N.; Foulds, Nicola; Harrison, Lucy; Harrison, Victoria; Lachlan, Katherine; Temple, Karen; Torokwa, Audrey; Wellesley, Diana] Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Odstock Rd, Salisbury SP2 8BJ, Wilts, England.
   [Ahmed, Munaza; Bunyan, David J.; Collins, Amanda; Harrison, Lucy; Harrison, Victoria; Lachlan, Katherine; Temple, Karen; Torokwa, Audrey; Wellesley, Diana] Univ Southampton, Fac Med, Bldg 85,Life Sci Bldg,Highfield Campus, Southampton SO17, Hants, England.
   [Anjum, Uruj; Elmslie, Frances; Homfray, Tessa; Mansour, Sahar; Marks, Karen; Tatton-Brown, Kate; Taylor, Rohan] Univ London, South West Thames Reg Genet Ctr, St Georges Healthcare NHS Trust, Cranmer Terrace, London SW17 0RE, England.
   [Archer, Hayley; Clarke, Angus; Davies, Sally; Evans, Karenza; Fry, Andrew; Morgan, Sian; Mugalaasi, Hood; Procter, Annie; Sampson, Julian; Varghese, Vinod] Univ Wales Hosp, Inst Med Genet, Heath Pk, Cardiff CF14 4XW, Wales.
   [Archer, Hayley; Clarke, Angus; Davies, Sally; Evans, Karenza; Fry, Andrew; Morgan, Sian; Mugalaasi, Hood; Procter, Annie; Sampson, Julian; Varghese, Vinod] Glan Clwyd Gen Hosp, Dept Clin Genet, Block 12, Rhyl, Denbigh, Wales.
   [Armstrong, Ruth; Holden, Simon; Mehta, Sarju; Park, Soo-Mi; Raymond, Lucy; Sandford, Richard; Simonic, Ingrid; Tischkowitz, Marc; Treacy, Becky; Wallwark, Sarah; Wilcox, Sarah; Woods, Geoff; Firth, Helen V.] East Anglian Med Genet Serv, Cambridge Univ Hosp, NHS Fdn Trust, Box 134,Cambridge Biomed Campus, Cambridge CB2 0QQ, England.
   [Balasubramanian, Meena; Ingram, Stuart; Johnson, Diana; Nevitt, Louise; Parker, Michael J.; Smith, Kath; Taylor, Cat] Sheffield Reg Genet Serv, Sheffield Childrens NHS Trust, Western Bank, Sheffield S10 2TH, S Yorkshire, England.
   [Banka, Siddharth; Chandler, Kate; Clayton-Smith, Jill; Donnelly, Carina; Douzgou, Sofia; Gaunt, Lorraine; Jones, Elizabeth; Kingston, Helen; Metcalfe, Kay; Miles, Emma; Murphy, Helen] Manchester Acad Hlth Sci Ctr, St Marys Hosp, Manchester Ctr Genom Med, Cent Manchester Univ Hosp NHS Fdn Trust, Manchester M13 9WL, Lancs, England.
   [Barnicoat, Angela; Bitner-Glindzicz, Maria; Brunstrom, Kate; Hollingsworth, Georgina; Hurst, Jane; Jenkins, Lucy; Kumar, V. K. Ajith; Male, Alison; Rosser, Elisabeth; Scott, Richard] Hosp Children NHS Fdn Trust, Great Ormond St Hosp, North East Thames Reg Genet Serv, Great Ormond St, London WC1N 3JH, England.
   [Batstone, Paul; D'Alessandro, Mariella; Dean, John; McGowan, Ruth; McWilliam, Catherine; Miedzybrodzka, Zosia; Ross, Alison; Samant, Shalaka] Dept Med Genet Med Sch, North Scotland Reg Genet Serv, NHS Grampian, Foresterhill, Aberdeen AB25 2ZD, Scotland.
   [Baty, David; Berg, Jonathan; Pratt, Norman; Rice, Debbie; Schweiger, Susann] Ninewells Hosp, East Scotland Reg Genet Serv, Dept Pathol, Human Genet Unit NHS Tayside, Dundee DD1 9SY, Scotland.
   [Bennett, Chris; Blyth, Moira; Coates, Andrea; Dobbie, Angus; Hobson, Emma; Kraus, Alison; Roberts, Paul; Sheridan, Eamonn; Smith, Audrey; Squires, Miranda; Thomson, Jenny] Leeds Teaching Hosp NHS Trust, Chapel Allerton Hosp, Dept Clin Genet, Yorkshire Reg Genet Serv, Chapeltown Rd, Leeds LS7 4SA, W Yorkshire, England.
   [Bernhard, Birgitta; Bourdon, Louise; Brady, Angela; Canham, Natalie; Clowes, Virginia; Holder, Muriel; Sequeira, Cheryl; Singzon, Roldan; Vandersteen, Anthony; Wakeling, Emma] North West London Hosp NHS Trust, North West Thames Reg Genet Ctr, Kennedy Galton Ctr, Northwick Pk & St Marks NHS Trust Watford Rd, Harrow HA1 3UJ, Middx, England.
   [Blair, Edward; Cilliers, Deirdre; Clasper, Susan; Gibbons, Richard; Kini, Usha; Phipps, Julie; Poulton, Joanna; Price, Sue; Pridham, Abigail; Purnell, Hellen; Seller, Anneke; Shears, Debbie; Stewart, Helen] Oxford Radcliffe Hosp NHS Trust, Oxford Reg Genet Serv, Churchill Old Rd, Oxford OX3 7LJ, England.
   [Bohanna, David; Cooper, Nicola; Cox, Helen; Islam, Lily; Jarvis, Joanna; Kirby, Gail; Lim, Derek; McMullan, Dominic J.; Morton, Jenny; Naik, Swati; Norman, Andrew; Ong, Kai-Ren; Patel, Chirag; Ragge, Nicola; Sharif, Saba; Tein, Mark; Vogt, Julie; Williams, Denise] Birmingham Womens Hosp, Birmingham Womens NHS Fdn Trust, West Midlands Reg Genet Serv, Birmingham B15 2TG, W Midlands, England.
   [Bourn, David; Burn, John; Fisher, Richard; Goodship, Judith; Hellens, Stephen; Henderson, Alex; Montgomery, Tara; Splitt, Miranda; Straub, Volker; Wright, Michael; Yates, Laura] Newcastle Tyne Hosp NHS Fdn Trust, Inst Human Genet, Int Ctr Life, Northern Genet Serv, Cent Pkwy, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England.
   [Bradley, Lisa; Dabir, Tabib; Donnelly, Deirdre; Humphreys, Mervyn; Kirk, Claire; McConnell, Vivienne; McKee, Shane; McNerlan, Susan; Stewart, Fiona] Belfast City Hosp, Northern Ireland Reg Genet Ctr, Belfast Hlth & Social Care Trust, Lisburn Rd, Belfast, Antrim, North Ireland.
   [Brewer, Carole; Castle, Bruce; Devlin, Gemma; Ellard, Sian; Everest, Sarah; Kivuva, Emma; Rankin, Julia; Shaw-Smith, Charles; Turner, Claire; Turnpenny, Peter; Tysoe, Carolyn] Royal Devon & Exeter Hosp Heavitree, Royal Devon & Exeter NHS Fdn Trust, Peninsula Clin Genet Serv, Dept Clin Genet, Gladstone Rd, Exeter EX1 2ED, Devon, England.
   [Flinter, Frances; Irving, Melita; Josifova, Dragana; Langman, Caroline; Ogilvie, Caroline; Robert, Leema; Yau, Michael] Guys Hosp, Guys & St Thomas NHS Fdn Trust, South East Thames Reg Genet Ctr, Great Maze Pond, London SE1 9RT, England.
   [Cresswell, Lara; Kaemba, Beckie; Kazembe, Sandra; Vasudevan, Pradeep] Univ Hosp Leicester NHS Trust, Leicester Genet Ctr, Leicester Royal Infirm NHS Trust, Leicester LE1 5WW, Leics, England.
   [Cross, Gareth; Dixit, Abhijit; Eason, Jacqueline; Harrison, Rachel; Martin, Katherine; Sarkar, Ajoy; Shannon, Nora; Suri, Mohnish] Nottingham Univ Hosp NHS Trust, City Hosp Campus, Nottingham Reg Genet Serv, Hucknall Rd, Nottingham NG5, England.
   [Duncan, Alexis; Gardiner, Carol; Joss, Shelagh; Kinning, Esther; Murday, Victoria; Pilz, Daniela T.; Whiteford, Margo; Williams, Nicola] West Scotland Reg Genet Serv, Inst Med Genet, Yorkhill Hosp, NHS Greater Glasgow & Clyde, Glasgow G3 8SJ, Lanark, Scotland.
   [Donaldson, Alan; Hawkins, Rose; Newbury-Ecob, Ruth; Wragg, Christopher] St Michaels Hosp, Univ Hosp Bristol NHS Fdn Trust, Bristol Genet Serv Avon, St Michaels Hill, Somerset, NJ USA.
   [Douglas, Angela; Fryer, Alan; Greenhalgh, Lynn; Maye, Una; Roberts, Gillian; Sutton, Vivienne; Sweeney, Elizabeth] Royal Liverpool Childrens Hosp Alder Hey, Dept Clin Genet, Liverpool Womens NHS Fdn Trust, Merseyside & Cheshire Genet Serv, Eaton Rd, Liverpool L12 2AP, Merseyside, England.
   [Gill, Harinder; Green, Andrew; Lynch, Sally A.; O'Shea, Rosie] Our Ladys Childrens Hosp, Natl Ctr Med Genet, Dublin 12, Ireland.
   Glan Clwyd Gen Hosp, Dept Clin Genet, Block 12, Rhyl LL18 5UJ, Denbigh, Wales.
   [Nellaker, Chris] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Obstet Gynaecol, Womens Ctr, Oxford OX3 9DU, England.
   [Nellaker, Chris] Univ Oxford, Dept Engn Sci, Inst Biomed Engn, Old Rd Campus Res Bldg, Oxford OX3 7DQ, England.
   [Nellaker, Chris] Univ Oxford, Big Data Inst, Roosevelt Dr, Oxford OX3 7LF, England.
   [Parker, Michael] Univ Oxford, Nuffield Dept Populat Hlth, Ethox Ctr, Old Rd Campus, Oxford OX3 7LF, England.
C3 Wellcome Trust Sanger Institute; University of Edinburgh; University of Oxford; University of Southampton; Salisbury District Hospital; University of Southampton; City St Georges, University of London; University of London; Oxford University Hospitals NHS Foundation Trust; University of Cambridge; Sheffield Children's NHS Foundation Trust; University of Manchester; University of London; University College London; Great Ormond Street Hospital for Children NHS Foundation Trust; University of Dundee; Chapel Allerton Hospital; University of Leeds; Oxford University Hospitals NHS Foundation Trust; University of Oxford; Birmingham Women's Hospital; Newcastle Upon Tyne Hospitals NHS Foundation Trust; Newcastle University - UK; Belfast City Hospital; University of Exeter; Guy's & St Thomas' NHS Foundation Trust; University of Leicester; University Hospitals of Leicester NHS Trust; Nottingham University Hospital NHS Trust; University of Glasgow; Alder Hey Children's NHS Foundation Trust; Alder Hey Children's Hospital; Our Ladys Children Hospital Crumlin; National Children's Research Centre (NCRC); University of Oxford; University of Oxford; University of Oxford; University of Oxford
EM meh@sanger.ac.uk
FU Health Innovation Challenge Fund [HICF-1009-003]; Wellcome Trust; UK Department of Health; Wellcome Trust Sanger Institute [WT098051]; National Institutes for Health Research, through the Comprehensive Clinical Research Network; MRC Human Genetics Unit; MRC [MC_PC_U127561093, MR/M014568/1, G0800674] Funding Source: UKRI; Engineering and Physical Sciences Research Council [1380788] Funding Source: researchfish; Medical Research Council [G0800270, G0800674, MR/M014568/1, MC_PC_U127561093] Funding Source: researchfish; National Institute for Health Research [NF-SI-0515-10035] Funding Source: researchfish
NR 52
TC 981
Z9 1084
U1 1
U2 164
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 23
PY 2017
VL 542
IS 7642
BP 433
EP +
DI 10.1038/nature21062
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1RG
UT WOS:000395094100027
PM 28135719
DA 2026-03-09
ER

PT J
AU Hu, J
   Dziumbla, S
   Lin, JH
   Bibli, SI
   Zukunft, S
   de Mos, J
   Awwad, K
   Frömel, T
   Jungmann, A
   Devraj, K
   Cheng, ZX
   Wang, LY
   Fauser, S
   Eberhart, CG
   Sodhi, A
   Hammock, BD
   Liebner, S
   Müller, OJ
   Glaubitz, C
   Hammes, HP
   Popp, R
   Fleming, I
AF Hu, Jiong
   Dziumbla, Sarah
   Lin, Jihong
   Bibli, Sofia-Iris
   Zukunft, Sven
   de Mos, Julian
   Awwad, Khader
   Froemel, Timo
   Jungmann, Andreas
   Devraj, Kavi
   Cheng, Zhixing
   Wang, Liya
   Fauser, Sascha
   Eberhart, Charles G.
   Sodhi, Akrit
   Hammock, Bruce D.
   Liebner, Stefan
   Mueller, Oliver J.
   Glaubitz, Clemens
   Hammes, Hans-Peter
   Popp, Ruediger
   Fleming, Ingrid
TI Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy
SO NATURE
LA English
DT Article
ID blood-retinal barrier; ve-cadherin; dependent endocytosis; endothelial-cells; acid; angiogenesis; association; cholesterol; stability; membranes
AB Diabetic retinopathy is an important cause of blindness in adults(1,2), and is characterized by progressive loss of vascular cells and slow dissolution of inter-vascular junctions, which result in vascular leakage and retinal oedema(3). Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization(4,5). Here we identify soluble epoxide hydrolase (sEH) as a key enzyme that initiates pericyte loss and breakdown of endothelial barrier function by generating the diol 19,20-dihydroxydocosapentaenoic acid, derived from docosahexaenoic acid. The expression of sEH and the accumulation of 19,20-dihydroxydocosapentaenoic acid were increased in diabetic mouse retinas and in the retinas and vitreous humour of patients with diabetes. Mechanistically, the diol targeted the cell membrane to alter the localization of cholesterol-binding proteins, and prevented the association of presenilin 1 with N-cadherin and VE-cadherin, thereby compromising pericyte-endothelial cell interactions and inter-endothelial cell junctions. Treating diabetic mice with a specific sEH inhibitor prevented the pericyte loss and vascular permeability that are characteristic of non-proliferative diabetic retinopathy. Conversely, overexpression of sEH in the retinal Muller glial cells of non-diabetic mice resulted in similar vessel abnormalities to those seen in diabetic mice with retinopathy. Thus, increased expression of sEH is a key determinant in the pathogenesis of diabetic retinopathy, and inhibition of sEH can prevent progression of the disease.
C1 [Hu, Jiong; Dziumbla, Sarah; Bibli, Sofia-Iris; Zukunft, Sven; Awwad, Khader; Froemel, Timo; Popp, Ruediger; Fleming, Ingrid] Goethe Univ, Ctr Mol Med, Inst Vasc Signalling, Frankfurt, Germany.
   [Hu, Jiong; Dziumbla, Sarah; Bibli, Sofia-Iris; Froemel, Timo; Liebner, Stefan; Popp, Ruediger; Fleming, Ingrid] German Ctr Cardiovasc Res DZHK, Partner Site Rhein Main, Berlin, Germany.
   [Lin, Jihong; Hammes, Hans-Peter] Heidelberg Univ, Univ Med Mannheim, Med Dept 5, Mannheim, Germany.
   [de Mos, Julian; Glaubitz, Clemens] Goethe Univ, Inst Biophys Chem, Frankfurt, Germany.
   [de Mos, Julian; Glaubitz, Clemens] Goethe Univ, Ctr Biomol Magnet Resonance, Frankfurt, Germany.
   [Jungmann, Andreas; Mueller, Oliver J.] Univ Heidelberg Hosp, Internal Med 3, Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
   [Jungmann, Andreas; Mueller, Oliver J.] German Ctr Cardiovasc Res DZHK, Partner Site Heidelberg, Mannheim, Germany.
   [Devraj, Kavi; Liebner, Stefan] Goethe Univ, Inst Neurol, Edinger Inst, Frankfurt, Germany.
   [Cheng, Zhixing; Wang, Liya] Henan Eye Inst, Zhengzhou, Henan, Peoples R China.
   [Cheng, Zhixing; Wang, Liya] Henan Eye Hosp, Zhengzhou, Henan, Peoples R China.
   [Fauser, Sascha] Univ Hosp Cologne, Dept Ophthalmol, Cologne, Germany.
   [Eberhart, Charles G.; Sodhi, Akrit] Johns Hopkins Sch Med, Wilmer Eye Inst, Baltimore, MD USA.
   [Hammock, Bruce D.] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA.
   [Hammock, Bruce D.] Univ Calif Davis, Comprehens Canc Ctr, Davis, CA 95616 USA.
   [Mueller, Oliver J.] Univ Kiel, Dept Internal Med 3, Arnold Heller Str 3, D-24105 Kiel, Germany.
C3 Goethe University Frankfurt; German Centre for Cardiovascular Research; Ruprecht Karls University Heidelberg; Goethe University Frankfurt; Goethe University Frankfurt; Ruprecht Karls University Heidelberg; German Centre for Cardiovascular Research; Goethe University Frankfurt; University of Cologne; Johns Hopkins University; Johns Hopkins Medicine; University of California System; University of California Davis; University of California System; University of California Davis; University of Kiel
RP Fleming, I (corresponding author), Goethe Univ, Ctr Mol Med, Inst Vasc Signalling, Frankfurt, Germany.; Fleming, I (corresponding author), German Ctr Cardiovasc Res DZHK, Partner Site Rhein Main, Berlin, Germany.
EM fleming@em.uni-frankfurt.de
FU Deutsche Forschungsgemeinschaft [SFB-TR 23/A6, B7, SFB 1118/C03, GRK 1874/1, 147]; NIEHS [R01 ES002710]; Deutsche Forschungsgemeinschaft Graduate School CLIC; Bayer
NR 38
TC 141
Z9 156
U1 0
U2 102
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 14
PY 2017
VL 552
IS 7684
BP 248
EP +
DI 10.1038/nature25013
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ0FK
UT WOS:000418029500046
PM 29211719
DA 2026-03-09
ER

PT J
AU Kim, Y
   Cruz, SS
   Lee, K
   Alawode, BO
   Choi, C
   Song, Y
   Johnson, JM
   Heidelberger, C
   Kong, W
   Choi, S
   Qiao, K
   Almansouri, I
   Fitzgerald, EA
   Kong, J
   Kolpak, AM
   Hwang, J
   Kim, J
AF Kim, Yunjo
   Cruz, Samuel S.
   Lee, Kyusang
   Alawode, Babatunde O.
   Choi, Chanyeol
   Song, Yi
   Johnson, Jared M.
   Heidelberger, Christopher
   Kong, Wei
   Choi, Shinhyun
   Qiao, Kuan
   Almansouri, Ibraheem
   Fitzgerald, Eugene A.
   Kong, Jing
   Kolpak, Alexie M.
   Hwang, Jinwoo
   Kim, Jeehwan
TI Remote epitaxy through graphene enables two-dimensional material-based layer transfer
SO NATURE
LA English
DT Article
ID substrate surface reconstruction; der-waals epitaxy; growth; transition; films; fe
AB Epitaxy-the growth of a crystalline material on a substrate-is crucial for the semiconductor industry, but is often limited by the need for lattice matching between the two material systems. This strict requirement is relaxed for van der Waals epitaxy(1-10), in which epitaxy on layered or two-dimensional (2D) materials is mediated by weak van der Waals interactions, and which also allows facile layer release from 2D surfaces(3,8). It has been thought that 2D materials are the only seed layers for van der Waals epitaxy(3-10). However, the substrates below 2D materials may still interact with the layers grown during epitaxy (epilayers), as in the case of the so-called wetting transparency documented for graphene(11-13). Here we show that the weak van der Waals potential of graphene cannot completely screen the stronger potential field of many substrates, which enables epitaxial growth to occur despite its presence. We use density functional theory calculations to establish that adatoms will experience remote epitaxial registry with a substrate through a substrate-epilayer gap of up to nine angstroms; this gap can accommodate a monolayer of graphene. We confirm the predictions with homoepitaxial growth of GaAs(001) on GaAs(001) substrates through monolayer graphene, and show that the approach is also applicable to InP and GaP. The grown single-crystalline films are rapidly released from the graphene-coated substrate and perform as well as conventionally prepared films when incorporated in light-emitting devices. This technique enables any type of semiconductor film to be copied from underlying substrates through 2D materials, and then the resultant epilayer to be rapidly released and transferred to a substrate of interest. This process is particularly attractive in the context of non-silicon electronics and photonics, where the ability to re-use the graphene-coated substrates(8) allows savings on the high cost of non-silicon substrates.
C1 [Kim, Yunjo; Cruz, Samuel S.; Lee, Kyusang; Alawode, Babatunde O.; Choi, Chanyeol; Kong, Wei; Choi, Shinhyun; Qiao, Kuan; Almansouri, Ibraheem; Kolpak, Alexie M.; Kim, Jeehwan] MIT, Dept Mech Engn, Cambridge, MA 02139 USA.
   [Song, Yi; Kong, Jing] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA.
   [Johnson, Jared M.; Hwang, Jinwoo] Ohio State Univ, Dept Mat Sci & Engn, 116 W 19Th Ave, Columbus, OH 43210 USA.
   [Heidelberger, Christopher; Fitzgerald, Eugene A.; Kim, Jeehwan] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA.
   [Almansouri, Ibraheem] Masdar Inst Sci & Technol, Dept Elect Engn & Comp Sci, Abu Dhabi 54224, U Arab Emirates.
   [Kong, Jing; Kim, Jeehwan] MIT, Elect Res Lab, Cambridge, MA 02139 USA.
C3 Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); University System of Ohio; Ohio State University; Massachusetts Institute of Technology (MIT); Khalifa University of Science & Technology; Masdar Institute of Science & Technology; Massachusetts Institute of Technology (MIT)
RP Kim, J (corresponding author), MIT, Dept Mech Engn, Cambridge, MA 02139 USA.; Kim, J (corresponding author), MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA.; Kim, J (corresponding author), MIT, Elect Res Lab, Cambridge, MA 02139 USA.
EM jeehwan@mit.edu
FU One to One Joint Research Project of the MI/MIT Cooperative Program; LG Electronics RD Center; National Science Foundation [1122374]; NSF [DMR/ECCS - 1509197, MRSEC DMR-1420451]
NR 27
TC 518
Z9 591
U1 36
U2 843
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 20
PY 2017
VL 544
IS 7650
BP 340
EP +
DI 10.1038/nature22053
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ES4SG
UT WOS:000399524400034
PM 28426001
DA 2026-03-09
ER

PT J
AU Chen, C
   Liu, S
   Shi, XQ
   Chaté, H
   Wu, YL
AF Chen, Chong
   Liu, Song
   Shi, Xia-qing
   Chate, Hugues
   Wu, Yilin
TI Weak synchronization and large-scale collective oscillation in dense bacterial suspensions
SO NATURE
LA English
DT Article
ID self-organization; active matter; dynamics; microtubules; motion; quorum; system; swarm
AB Collective oscillatory behaviour is ubiquitous in nature(1), having a vital role in many biological processes from embryogenesis(2) and organ development(3) to pace-making in neuron networks(4). Elucidating the mechanisms that give rise to synchronization is essential to the understanding of biological self-organization. Collective oscillations in biological multicellular systems often arise from long-range coupling mediated by diffusive chemicals(2,5-9), by electrochemical mechanisms(4,10), or by biomechanical interaction between cells and their physical environment(11). In these examples, the phase of some oscillatory intracellular degree of freedom is synchronized. Here, in contrast, we report the discovery of a weak synchronization mechanism that does not require long-range coupling or inherent oscillation of individual cells. We find that millions of motile cells in dense bacterial suspensions can self organize into highly robust collective oscillatory motion, while individual cells move in an erratic manner, without obvious periodic motion but with frequent, abrupt and random directional changes. So erratic are individual trajectories that uncovering the collective oscillations of our micrometre-sized cells requires individual velocities to be averaged over tens or hundreds of micrometres. On such large scales, the oscillations appear to be in phase and the mean position of cells typically describes a regular elliptic trajectory. We found that the phase of the oscillations is organized into a centimetre-scale travelling wave. We present a model of noisy self-propelled particles with strictly local interactions that accounts faithfully for our observations, suggesting that self-organized collective oscillatory motion results from spontaneous chiral and rotational symmetry breaking. These findings reveal a previously unseen type of long-range order in active matter systems (those in which energy is spent locally to produce non-random motion)(12,13). This mechanism of collective oscillation may inspire new strategies to control the self-organization of active matter(14-18) and swarming robots.
C1 [Chen, Chong; Liu, Song; Wu, Yilin] Chinese Univ Hong Kong, Dept Phys, Shatin, Hong Kong, Peoples R China.
   [Chen, Chong; Liu, Song; Wu, Yilin] Chinese Univ Hong Kong, Shenzhen Res Inst, Shatin, Hong Kong, Peoples R China.
   [Shi, Xia-qing] Soochow Univ, Ctr Soft Condensed Matter Phys, Suzhou 215006, Peoples R China.
   [Chate, Hugues] Univ Paris Saclay, CNRS, CEA, Serv Phys Etat Condense,CEA Saclay, F-91191 Gif Sur Yvette, France.
   [Chate, Hugues] Beijing Computat Sci Res Ctr, Beijing 100094, Peoples R China.
C3 Chinese University of Hong Kong; CUHK Shenzhen Research Institute; Chinese University of Hong Kong; Soochow University - China; CEA; Centre National de la Recherche Scientifique (CNRS); Universite Paris Saclay; Chinese Academy of Engineering Physics; Beijing Computational Science Research Center (CSRC)
RP Wu, YL (corresponding author), Chinese Univ Hong Kong, Dept Phys, Shatin, Hong Kong, Peoples R China.; Wu, YL (corresponding author), Chinese Univ Hong Kong, Shenzhen Res Inst, Shatin, Hong Kong, Peoples R China.; Shi, XQ (corresponding author), Soochow Univ, Ctr Soft Condensed Matter Phys, Suzhou 215006, Peoples R China.; Chaté, H (corresponding author), Univ Paris Saclay, CNRS, CEA, Serv Phys Etat Condense,CEA Saclay, F-91191 Gif Sur Yvette, France.; Chaté, H (corresponding author), Beijing Computat Sci Res Ctr, Beijing 100094, Peoples R China.
EM xqshi@suda.edu.cn; hugues.chate@cea.fr; ylwu@phy.cuhk.edu.hk
FU Research Grants Council of Hong Kong SAR (RGC) [2191031, 2130439]; Research Grants Council of Hong Kong SAR (CUHK) [3132738, 3132739]; National Natural Science Foundation of China (NSFC) [21473152, 11635002, 11474210, 11674236, 91427302]; Agence Nationale de la Recherche
NR 30
TC 184
Z9 205
U1 2
U2 274
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 9
PY 2017
VL 542
IS 7640
BP 210
EP 214
DI 10.1038/nature20817
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK2DJ
UT WOS:000393737500036
PM 28114301
DA 2026-03-09
ER

PT J
AU Luo, MC
   Gu, YQ
   Puiu, D
   Wang, H
   Twardziok, SO
   Deal, KR
   Huo, NX
   Zhu, TT
   Wang, L
   Wang, Y
   McGuire, PE
   Liu, SY
   Long, H
   Ramasamy, RK
   Rodriguez, JC
   Van, SL
   Yuan, LX
   Wang, ZZ
   Xia, ZQ
   Xiao, LC
   Anderson, OD
   Ouyang, SH
   Liang, Y
   Zimin, AV
   Pertea, G
   Qi, P
   Ennetzen, JLB
   Dai, XT
   Dawson, MW
   Müller, HG
   Kugler, K
   Rivarola-Duarte, L
   Spannagl, M
   Mayer, KFX
   Lu, FH
   Bevan, MW
   Leroy, P
   Li, PC
   You, FM
   Sun, QX
   Liu, ZY
   Lyons, E
   Wicker, T
   Salzberg, SL
   Devos, KM
   Dvorák, J
AF Luo, Ming-Cheng
   Gu, Yong Q.
   Puiu, Daniela
   Wang, Hao
   Twardziok, Sven O.
   Deal, Karin R.
   Huo, Naxin
   Zhu, Tingting
   Wang, Le
   Wang, Yi
   McGuire, Patrick E.
   Liu, Shuyang
   Long, Hai
   Ramasamy, Ramesh K.
   Rodriguez, Juan C.
   Van, Sonny L.
   Yuan, Luxia
   Wang, Zhenzhong
   Xia, Zhiqiang
   Xiao, Lichan
   Anderson, Olin D.
   Ouyang, Shuhong
   Liang, Yong
   Zimin, Aleksey V.
   Pertea, Geo
   Qi, Peng
   Ennetzen, Jeffrey L. B.
   Dai, Xiongtao
   Dawson, Matthew W.
   Mueller, Hans-Georg
   Kugler, Karl
   Rivarola-Duarte, Lorena
   Spannagl, Manuel
   Mayer, Klaus F. X.
   Lu, Fu-Hao
   Bevan, Michael W.
   Leroy, Philippe
   Li, Pingchuan
   You, Frank M.
   Sun, Qixin
   Liu, Zhiyong
   Lyons, Eric
   Wicker, Thomas
   Salzberg, Steven L.
   Devos, Katrien M.
   Dvorak, Jan
TI Genome sequence of the progenitor of the wheat D genome Aegilops tauschii
SO NATURE
LA English
DT Article
ID polyploid wheat; oryza-sativa; gene; evolution; recombination; resistance; family; identification; annotation; divergence
AB Aegilops tauschii is the diploid progenitor of the D genome of hexaploid wheat(1) (Triticum aestivum, genomes AABBDD) and an important genetic resource for wheat(2-4). The large size and highly repetitive nature of the Ae. tauschii genome has until now precluded the development of a reference-quality genome sequence(5). Here we use an array of advanced technologies, including ordered-clone genome sequencing, whole-genome shotgun sequencing, and BioNano optical genome mapping, to generate a reference-quality genome sequence for Ae. tauschii ssp. strangulata accession AL8/78, which is closely related to the wheat D genome. We show that compared to other sequenced plant genomes, including a much larger conifer genome, the Ae. tauschii genome contains unprecedented amounts of very similar repeated sequences. Our genome comparisons reveal that the Ae. tauschii genome has a greater number of dispersed duplicated genes than other sequenced genomes and its chromosomes have been structurally evolving an order of magnitude faster than those of other grass genomes. The decay of colinearity with other grass genomes correlates with recombination rates along chromosomes. We propose that the vast amounts of very similar repeated sequences cause frequent errors in recombination and lead to gene duplications and structural chromosome changes that drive fast genome evolution.
C1 [Luo, Ming-Cheng; Deal, Karin R.; Huo, Naxin; Zhu, Tingting; Wang, Le; Wang, Yi; McGuire, Patrick E.; Liu, Shuyang; Long, Hai; Ramasamy, Ramesh K.; Rodriguez, Juan C.; Van, Sonny L.; Yuan, Luxia; Wang, Zhenzhong; Xia, Zhiqiang; Xiao, Lichan; Dvorak, Jan] Univ Calif Davis, Dept Plant Sci, Davis, CA 95616 USA.
   [Gu, Yong Q.; Huo, Naxin; Wang, Yi; Anderson, Olin D.; Ouyang, Shuhong; Liang, Yong] USDA ARS, Crop Improvement & Genet Res, Albany, CA USA.
   [Puiu, Daniela; Zimin, Aleksey V.; Pertea, Geo; Salzberg, Steven L.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Computat Biol, Baltimore, MD 21218 USA.
   [Wang, Hao; Qi, Peng; Devos, Katrien M.] Univ Georgia, Dept Crop & Soil Sci, Inst Plant Breeding Genet & Genom, Athens, GA 30602 USA.
   [Wang, Hao; Qi, Peng; Devos, Katrien M.] Univ Georgia, Dept Plant Sci, Athens, GA 30602 USA.
   [Wang, Hao; Ennetzen, Jeffrey L. B.] Univ Georgia, Dept Genet, Athens, GA 30602 USA.
   [Twardziok, Sven O.; Kugler, Karl; Rivarola-Duarte, Lorena; Spannagl, Manuel; Mayer, Klaus F. X.] Helmholtz Zentrum M nchen, Plant Genome & Syst Biol, Neuherberg, Germany.
   [Wang, Zhenzhong; Ouyang, Shuhong; Liang, Yong; Sun, Qixin; Liu, Zhiyong] China Agr Univ, Beijing, Peoples R China.
   [Dai, Xiongtao; Dawson, Matthew W.; Mueller, Hans-Georg] Univ Calif Davis, Dept Stat, Davis, CA 95616 USA.
   [Mayer, Klaus F. X.] Tech Univ Munich, Sch Life Sci Weihenstephan, Munich, Germany.
   [Lu, Fu-Hao; Bevan, Michael W.] Norwich Res Pk, John Innes Ctr, Dept Cell & Dev Biol, Norwich, Norfolk, England.
   [Leroy, Philippe] INRA, UBP, UMR 1095, GDEC, Clermont Ferrand, France.
   [Li, Pingchuan; You, Frank M.] Agr & Agri Food Canada, Morden, MB, Canada.
   [Lyons, Eric] Univ Arizona, CyVerse, Tucson, AZ USA.
   [Wicker, Thomas] Univ Zurich, Dept Plant & Microbial Biol, Zurich, Switzerland.
   [Salzberg, Steven L.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA.
   [Salzberg, Steven L.] Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA.
   [Salzberg, Steven L.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA.
C3 University of California System; University of California Davis; United States Department of Agriculture (USDA); Johns Hopkins University; University System of Georgia; University of Georgia; University System of Georgia; University of Georgia; University System of Georgia; University of Georgia; China Agricultural University; University of California System; University of California Davis; Technical University of Munich; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); John Innes Centre; INRAE; Universite Clermont Auvergne (UCA); Agriculture & Agri Food Canada; University of Arizona; University of Zurich; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University
RP Dvorák, J (corresponding author), Univ Calif Davis, Dept Plant Sci, Davis, CA 95616 USA.; Salzberg, SL (corresponding author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Computat Biol, Baltimore, MD 21218 USA.; Devos, KM (corresponding author), Univ Georgia, Dept Crop & Soil Sci, Inst Plant Breeding Genet & Genom, Athens, GA 30602 USA.; Devos, KM (corresponding author), Univ Georgia, Dept Plant Sci, Athens, GA 30602 USA.; Salzberg, SL (corresponding author), Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA.; Salzberg, SL (corresponding author), Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA.; Salzberg, SL (corresponding author), Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA.
EM salzberg@jhu.edu; kdevos@uga.edu; jdvorak@ucdavis.edu
FU National Science Foundation (NSF) [IOS-1238231]; NSF [DMS-1407852]; Biological and Biotechnological Sciences Research Council (BBSRC) LOLA [BB/J003913/1]; Biotechnology and Biological Sciences Research Council [BB/J003743/1, BB/P004857/1, BB/E004725/1, BB/J003557/1, BBS/E/J/00000584, BBS/E/J/000PR9773, BB/J003913/1, BB/J019739/1] Funding Source: researchfish; BBSRC [BB/J003913/1, BB/J019739/1, BB/E004725/1, BB/J003557/1, BB/J003743/1, BB/P004857/1, BBS/E/J/000PR9773] Funding Source: UKRI
NR 75
TC 476
Z9 544
U1 11
U2 252
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 23
PY 2017
VL 551
IS 7681
BP 498
EP +
DI 10.1038/nature24486
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FN5JO
UT WOS:000416043700044
PM 29143815
DA 2026-03-09
ER

PT J
AU Gabuchian, V
   Rosakis, AJ
   Bhat, HS
   Madariaga, R
   Kanamori, H
AF Gabuchian, Vahe
   Rosakis, Ares J.
   Bhat, Harsha S.
   Madariaga, Raul
   Kanamori, Hiroo
TI Experimental evidence that thrust earthquake ruptures might open faults
SO NATURE
LA English
DT Article
ID tohoku-oki earthquake; 1999 chi-chi; ground motions; half-space; taiwan; slip; transition; model
AB Many of Earth's great earthquakes occur on thrust faults(1). These earthquakes predominantly occur within subduction zones, such as the 2011 moment magnitude 9.0 eathquake in Tohoku-Oki, Japan, or along large collision zones, such as the 1999 moment magnitude 7.7 earthquake in Chi-Chi, Taiwan(2). Notably, these two earthquakes had a maximum slip that was very close to the surface(3,4). This contributed to the destructive tsunami that occurred during the Tohoku-Oki event and to the large amount of structural damage caused by the Chi-Chi event. The mechanism that results in such large slip near the surface is poorly understood as shallow parts of thrust faults are considered to be frictionally stable(5). Here we use earthquake rupture experiments to reveal the existence of a torquing mechanism of thrust fault ruptures near the free surface that causes them to unclamp and slip large distances. Complementary numerical modelling of the experiments confirms that the hanging-wall wedge undergoes pronounced rotation in one direction as the earthquake rupture approaches the free surface, and this torque is released as soon as the rupture breaks the free surface, resulting in the unclamping and violent 'flapping' of the hanging-wall wedge. Our results imply that the shallow extent of the seismogenic zone of a subducting interface is not fixed and can extend up to the trench during great earthquakes through a torquing mechanism.
C1 [Gabuchian, Vahe; Rosakis, Ares J.] CALTECH, Grad Aerosp Labs, 1200 East Calif Blvd 105-50, Pasadena, CA 91105 USA.
   [Bhat, Harsha S.; Madariaga, Raul] PSL Res Univ, Lab Geol, Ecole Normale Super, CNRS UMR 8538, F-75005 Paris, France.
   [Kanamori, Hiroo] CALTECH, Seismol Lab, 1200 East Calif Blvd 252-21, Pasadena, CA 91105 USA.
C3 California Institute of Technology; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Universite PSL; Ecole Normale Superieure (ENS); California Institute of Technology
RP Bhat, HS (corresponding author), PSL Res Univ, Lab Geol, Ecole Normale Super, CNRS UMR 8538, F-75005 Paris, France.
EM bhat@geologie.ens.fr
FU National Science Foundation [EAR-1321655]
NR 27
TC 47
Z9 56
U1 6
U2 61
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 18
PY 2017
VL 545
IS 7654
BP 336
EP +
DI 10.1038/nature22045
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV0WF
UT WOS:000401466500060
PM 28460375
DA 2026-03-09
ER

PT J
AU Dann, GP
   Liszczak, GP
   Bagert, JD
   Müller, MM
   Nguyen, UTT
   Wojcik, F
   Brown, ZZ
   Bos, J
   Panchenko, T
   Pihl, R
   Pollock, SB
   Diehl, KL
   Allis, CD
   Muir, TW
AF Dann, Geoffrey P.
   Liszczak, Glen P.
   Bagert, John D.
   Mueller, Manuel M.
   Nguyen, Uyen T. T.
   Wojcik, Felix
   Brown, Zachary Z.
   Bos, Jeffrey
   Panchenko, Tatyana
   Pihl, Rasmus
   Pollock, Samuel B.
   Diehl, Katharine L.
   Allis, C. David
   Muir, Tom W.
TI ISWI chromatin remodellers sense nucleosome modifications to determine substrate preference
SO NATURE
LA English
DT Article
ID histone modifications; angstrom resolution; crystal-structure; structural basis; core particle; recognition; acetylation; peptide; complex; reconstitution
AB ATP-dependent chromatin remodellers regulate access to genetic information by controlling nucleosome positions in vivo(1). However, the mechanism by which remodellers discriminate between different nucleosome substrates is poorly understood. Many chromatin remodelling proteins possess conserved protein domains that interact with nucleosomal features(2). Here we used a quantitative high-throughput approach, based on the use of a DNA-barcoded mononucleosome library, to profile the biochemical activity of human ISWI family remodellers in response to a diverse set of nucleosome modifications. We show that accessory (non-ATPase) subunits of ISWI remodellers can distinguish between differentially modified nucleosomes, directing remodelling activity towards specific nucleosome substrates according to their modification state. Unexpectedly, we show that the nucleosome acidic patch3 is necessary for maximum activity of all ISWI remodellers evaluated. This dependence also extends to CHD and SWI/SNF family remodellers, suggesting that the acidic patch may be generally required for chromatin remodelling. Critically, remodelling activity can be regulated by modifications neighbouring the acidic patch, signifying that it may act as a tunable interaction hotspot for ATP-dependent chromatin remodellers and, by extension, many other chromatin effectors that engage this region of the nucleosome surface(4-9).
C1 [Dann, Geoffrey P.; Liszczak, Glen P.; Bagert, John D.; Mueller, Manuel M.; Nguyen, Uyen T. T.; Wojcik, Felix; Brown, Zachary Z.; Bos, Jeffrey; Pihl, Rasmus; Pollock, Samuel B.; Diehl, Katharine L.; Muir, Tom W.] Princeton Univ, Frick Lab, Dept Chem, Princeton, NJ 08544 USA.
   [Panchenko, Tatyana; Allis, C. David] Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA.
   [Mueller, Manuel M.] Kings Coll London, Dept Chem, 7 Trinity St, London SE1 1DB, England.
   [Nguyen, Uyen T. T.] Bayer Pharma AG, Berlin, Germany.
   [Panchenko, Tatyana] NYU, Langone Med Ctr, Perlmutter Canc Ctr, 430 East 29th St, New York, NY 10016 USA.
   [Pihl, Rasmus] Aarhus Univ, Dept Biomed, Aarhus, Denmark.
   [Pollock, Samuel B.] Univ Calif San Francisco, 505 Parnassus Ave, San Francisco, CA 94143 USA.
C3 Princeton University; Rockefeller University; University of London; King's College London; Bayer AG; Bayer Healthcare Pharmaceuticals; NYU Langone Medical Center; New York University; Aarhus University; University of California System; University of California San Francisco
RP Muir, TW (corresponding author), Princeton Univ, Frick Lab, Dept Chem, Princeton, NJ 08544 USA.
EM muir@princeton.edu
FU German Research Foundation (DFG); US National Institutes of Health [GM112365, P01 CA196539, R37 GM086868, R01 GM107047]; National Cancer Institute [P01CA196539] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R37GM086868, T32GM007388, R01GM086868] Funding Source: NIH RePORTER
NR 45
TC 138
Z9 183
U1 1
U2 61
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 31
PY 2017
VL 548
IS 7669
BP 607
EP +
DI 10.1038/nature23671
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FF2BO
UT WOS:000408703100043
PM 28767641
DA 2026-03-09
ER

PT J
AU Zhang, S
   Takaku, M
   Zou, LY
   Gu, AD
   Chou, WC
   Zhang, G
   Wu, B
   Kong, Q
   Thomas, SY
   Serody, JS
   Chen, X
   Xu, XJ
   Wade, PA
   Cook, DN
   Ting, JPY
   Wan, YSY
AF Zhang, Song
   Takaku, Motoki
   Zou, Liyun
   Gu, Ai-di
   Chou, Wei-chun
   Zhang, Ge
   Wu, Bing
   Kong, Qing
   Thomas, Seddon Y.
   Serody, Jonathan S.
   Chen, Xian
   Xu, Xiaojiang
   Wade, Paul A.
   Cook, Donald N.
   Ting, Jenny P. Y.
   Wan, Yisong Y.
TI Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation
SO NATURE
LA English
DT Article
ID growth-factor-beta; tgf-beta; ski; generation; smad4; repression; cytokines; pathways; il-17; snon
AB T helper 17 (T(H)17) cells are critically involved in host defence, inflammation, and autoimmunity(1-5). Transforming growth factor beta (TGF beta) is instrumental in T(H)17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGF beta enables T(H)17 cell differentiation remains elusive. Here we reveal that TGF beta enables T(H)17 cell differentiation by reversing SKISMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor gamma t (ROR gamma t). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGF beta signalling in a ROR gamma t-dependent manner. Ectopic SMAD4 expression suppresses ROR gamma t expression and T(H)17 cell differentiation of SMAD4-deficient T cells. However, TGF beta neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGF beta stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and T(H)17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and T(H)17 cell differentiation in a SMAD4-dependent manner. Therefore, TGF beta-induced disruption of SKI reverses SKISMAD4-mediated suppression of ROR gamma t to enable T(H)17 cell differentiation. This study reveals a critical mechanism by which TGF beta controls T(H)17 cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating T(H)17-related diseases.
C1 [Zhang, Song; Zou, Liyun; Gu, Ai-di; Chou, Wei-chun; Zhang, Ge; Wu, Bing; Kong, Qing; Serody, Jonathan S.; Chen, Xian; Ting, Jenny P. Y.; Wan, Yisong Y.] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA.
   [Zhang, Song; Zou, Liyun; Gu, Ai-di; Chou, Wei-chun; Zhang, Ge; Wu, Bing; Kong, Qing; Serody, Jonathan S.; Ting, Jenny P. Y.; Wan, Yisong Y.] Univ North Carolina Chapel Hill, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA.
   [Takaku, Motoki; Wade, Paul A.] NIEHS, Epigenet & Stem Cell Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA.
   [Chou, Wei-chun; Ting, Jenny P. Y.] Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC 27599 USA.
   [Zhang, Ge] Dalian Med Univ, Dept Immunol, Dalian 116044, Peoples R China.
   [Kong, Qing; Chen, Xian] Univ North Carolina Chapel Hill, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA.
   [Thomas, Seddon Y.; Cook, Donald N.] NIEHS, Immun Inflammat & Dis Lab, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA.
   [Xu, Xiaojiang] NIEHS, Integrat Bioinformat, POB 12233, Res Triangle Pk, NC 27709 USA.
C3 University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS); University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; Dalian Medical University; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS); National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS)
RP Wan, YSY (corresponding author), Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA.; Wan, YSY (corresponding author), Univ North Carolina Chapel Hill, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA.
EM wany@email.unc.edu
FU National Natural Science Foundation of China [81402549, LJQ2015033]; National Institutes of Health (NIH) [AI029564, AI097392, AI123193]; National Multiple Sclerosis Society [CA10068, RG4654]; Intramural Research Program of the National Institute of Environmental Health Science [ES101965, ES102025]; Yang Family Biomedical Scholars Award; National Cancer Institute [P30CA016086] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [R01AI029564, R01AI123193] Funding Source: NIH RePORTER; National Institute of Environmental Health Sciences [ZIAES102025, ZIAES101965] Funding Source: NIH RePORTER
NR 30
TC 95
Z9 104
U1 1
U2 58
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 2
PY 2017
VL 551
IS 7678
BP 105
EP +
DI 10.1038/nature24283
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FL4SY
UT WOS:000414222900054
PM 29072299
DA 2026-03-09
ER

PT J
AU Kuchay, S
   Giorgi, C
   Simoneschi, D
   Pagan, J
   Missiroli, S
   Saraf, A
   Florens, L
   Washburn, MP
   Collazo-Lorduy, A
   Castillo-Martin, M
   Cordon-Cardo, C
   Sebti, SM
   Pinton, P
   Pagano, M
AF Kuchay, Shafi
   Giorgi, Carlotta
   Simoneschi, Daniele
   Pagan, Julia
   Missiroli, Sonia
   Saraf, Anita
   Florens, Laurence
   Washburn, Michael P.
   Collazo-Lorduy, Ana
   Castillo-Martin, Mireia
   Cordon-Cardo, Carlos
   Sebti, Said M.
   Pinton, Paolo
   Pagano, Michele
TI PTEN counteracts FBXL2 to promote IP3R3-and Ca2+-mediated apoptosis limiting tumour growth
SO NATURE
LA English
DT Article
ID inositol 1,4,5-trisphosphate receptors; f-mediated degradation; liver epithelial-cells; endoplasmic-reticulum; trisphosphate receptors; calcium-release; down-regulation; cancer-therapy; ca2+ release; er
AB In response to environmental cues that promote IP3 (inositol 1,4,5-trisphosphate) generation, IP3 receptors (IP3Rs) located on the endoplasmic reticulum allow the 'quasisynaptical' feeding of calcium to the mitochondria to promote oxidative phosphorylation(1). However, persistent Ca2+ release results in mitochondrial Ca2+ overload and consequent apoptosis(2). Among the three mammalian IP3Rs, IP3R3 appears to be the major player in Ca2+-dependent apoptosis. Here we show that the F-box protein FBXL2 (the receptor subunit of one of 69 human SCF (SKP1, CUL1, F-box protein) ubiquitin ligase complexes(3)) binds IP3R3 and targets it for ubiquitin-, p97- and proteasome-mediated degradation to limit Ca2+ influx into mitochondria. FBXL2-knockdown cells and FBXL2-insensitive IP3R3 mutant knock-in clones display increased cytosolic Ca2+ release from the endoplasmic reticulum and sensitization to Ca2+-dependent apoptotic stimuli. The phosphatase and tensin homologue (PTEN) gene is frequently mutated or lost in human tumours and syndromes that predispose individuals to cancer(4). We found that PTEN competes with FBXL2 for IP3R3 binding, and the FBXL2-dependent degradation of IP3R3 is accelerated in Pten(-/-) mouse embryonic fibroblasts and PTEN-null cancer cells. Reconstitution of PTEN-null cells with either wild-type PTEN or a catalytically dead mutant stabilizes IP3R3 and induces persistent Ca2+ mobilization and apoptosis. IP3R3 and PTEN protein levels directly correlate in human prostate cancer. Both in cell culture and xenograft models, a non-degradable IP3R3 mutant sensitizes tumour cells with low or no PTEN expression to photodynamic therapy, which is based on the ability of photosensitizer drugs to cause Ca2+-dependent cytotoxicity after irradiation with visible light(5,6). Similarly, disruption of FBXL2 localization with GGTi-2418, a geranylgeranyl transferase inhibitor(7), sensitizes xenotransplanted tumours to photodynamic therapy. In summary, we identify a novel molecular mechanism that limits mitochondrial Ca2+ overload to prevent cell death. Notably, we provide proof-of-principle that inhibiting IP3R3 degradation in PTEN-deregulated cancers represents a valid therapeutic strategy.
C1 [Kuchay, Shafi; Giorgi, Carlotta; Simoneschi, Daniele; Pagan, Julia; Pagano, Michele] NYU, Sch Med, Dept Biochem & Mol Pharmacol, 522 First Ave,SRB 1107, New York, NY 10016 USA.
   [Kuchay, Shafi; Giorgi, Carlotta; Simoneschi, Daniele; Pagan, Julia; Pagano, Michele] NYU, Sch Med, Perlmutter Canc Ctr, 522 First Ave,SRB 1107, New York, NY 10016 USA.
   [Kuchay, Shafi; Pagan, Julia; Pagano, Michele] NYU, Sch Med, Howard Hughes Med Inst, 522 First Ave,SRB 1107, New York, NY 10016 USA.
   [Giorgi, Carlotta; Missiroli, Sonia; Pinton, Paolo] Univ Ferrara, Sect Pathol Oncol & Expt Biol, Lab Technol Adv Therapies LTTA, Dept Morphol Surg & Expt Med, Ferrara, Italy.
   [Saraf, Anita; Florens, Laurence; Washburn, Michael P.] Stowers Inst Med Res, 1000 East 50th St, Kansas City, MO 64110 USA.
   [Washburn, Michael P.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, 3901 Rainbow Blvd, Kansas City, KS 66160 USA.
   [Collazo-Lorduy, Ana; Castillo-Martin, Mireia; Cordon-Cardo, Carlos] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA.
   [Collazo-Lorduy, Ana] Spanish Soc Med Oncol, Madrid, Spain.
   [Castillo-Martin, Mireia] Champalimaud Ctr Unknown, Dept Pathol, Lisbon, Portugal.
   [Sebti, Said M.] Univ S Florida, Moffitt Canc Ctr, Drug Discovery Dept, Tampa, FL 33612 USA.
   [Sebti, Said M.] Univ S Florida, Dept Oncol Sci, Tampa, FL 33612 USA.
C3 New York University; New York University; Howard Hughes Medical Institute; New York University; University of Ferrara; Stowers Institute for Medical Research; University of Kansas; University of Kansas Medical Center; Icahn School of Medicine at Mount Sinai; Fundacao Champalimaud; H Lee Moffitt Cancer Center & Research Institute; State University System of Florida; University of South Florida; State University System of Florida; University of South Florida
RP Pagano, M (corresponding author), NYU, Sch Med, Dept Biochem & Mol Pharmacol, 522 First Ave,SRB 1107, New York, NY 10016 USA.; Pagano, M (corresponding author), NYU, Sch Med, Perlmutter Canc Ctr, 522 First Ave,SRB 1107, New York, NY 10016 USA.; Pagano, M (corresponding author), NYU, Sch Med, Howard Hughes Med Inst, 522 First Ave,SRB 1107, New York, NY 10016 USA.; Pinton, P (corresponding author), Univ Ferrara, Sect Pathol Oncol & Expt Biol, Lab Technol Adv Therapies LTTA, Dept Morphol Surg & Expt Med, Ferrara, Italy.
EM paolo.pinton@unife.it; michele.pagano@nyumc.org
FU NIH; AIRC [IG-18624, MFAG-13521]; Ferrara's University; Italian Ministry of Health; Cariplo; Stowers Institute for Medical Research; National Cancer Institute [R35CA197731, P30CA016087, R01CA076584] Funding Source: NIH RePORTER
NR 44
TC 211
Z9 225
U1 2
U2 117
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 22
PY 2017
VL 546
IS 7659
BP 554
EP +
DI 10.1038/nature22965
PG 27
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY2QK
UT WOS:000403814100043
PM 28614300
DA 2026-03-09
ER

PT J
AU Coates, MI
   Gess, RW
   Finarelli, JA
   Criswell, KE
   Tietjen, K
AF Coates, Michael I.
   Gess, Robert W.
   Finarelli, John A.
   Criswell, Katharine E.
   Tietjen, Kristen
TI A symmoriiform chondrichthyan braincase and the origin of chimaeroid fishes
SO NATURE
LA English
DT Article
ID bayesian phylogenetic inference; shark; placoderm; diversity; anatomy; biology; limits
AB Chimaeroid fishes (Holocephali) are one of the four principal divisions of modern gnathostomes (jawed vertebrates). Despite only 47 described living species(1), chimaeroids are the focus of resurgent interest as potential archives of genomic data(2) and for the unique perspective they provide on chondrichthyan and gnathostome ancestral conditions. Chimaeroids are also noteworthy for their highly derived body plan(1,3,4). However, like other living groups with distinctive anatomies(5), fossils have been of limited use in unravelling their evolutionary origin, as the earliest recognized examples already exhibit many of the specializations present in modern forms(6,7). Here we report the results of a computed tomography analysis of Dwykaselachus, an enigmatic chondrichthyan braincase from the similar to 280 million year old Karoo sediments of South Africa(8). Externally, the braincase is that of a symmoriid shark(9-13) and is by far the most complete uncrushed example yet discovered. Internally, the morphology exhibits otherwise characteristically chimaeroid specializations, including the otic labyrinth arrangement and the brain space configuration relative to exceptionally large orbits. These results have important implications for our view of modern chondrichthyan origins, add robust structure to the phylogeny of early crown group gnathostomes, reveal preconditions that suggest an initial morpho-functional basis for the derived chimaeroid cranium, and shed new light on the chondrichthyan response to the extinction at the end of the Devonian period.
C1 [Coates, Michael I.; Criswell, Katharine E.; Tietjen, Kristen] Univ Chicago, Dept Organismal Biol & Anat, Chicago, IL 60637 USA.
   [Gess, Robert W.] Rhodes Univ, Dept Geol, ZA-6139 Grahamstown, South Africa.
   [Gess, Robert W.] Rhodes Univ, Albany Museum, ZA-6139 Grahamstown, South Africa.
   [Finarelli, John A.] Univ Coll Dublin, UCD Sci Educ & Res Ctr, UCD Sch Biol & Environm Sci, Dublin 4, Ireland.
   [Finarelli, John A.] Univ Coll Dublin, UCD Earth Inst, Dublin 4, Ireland.
C3 University of Chicago; Rhodes University; Rhodes University; Albany Museum; University College Dublin; University College Dublin
RP Coates, MI (corresponding author), Univ Chicago, Dept Organismal Biol & Anat, Chicago, IL 60637 USA.
EM mcoates@uchicago.edu
FU National Science Foundation [DEB-0917922, DEB-1541491]; National Research Foundation/Department of Science and Technology South African Centre of Excellence in Palaeosciences; Direct For Biological Sciences; Division Of Environmental Biology [1501749, 1541547] Funding Source: National Science Foundation; Division Of Earth Sciences; Directorate For Geosciences [1561622] Funding Source: National Science Foundation
NR 56
TC 59
Z9 64
U1 0
U2 32
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 12
PY 2017
VL 541
IS 7636
BP 208
EP +
DI 10.1038/nature20806
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6PI
UT WOS:000396125500039
PM 28052054
DA 2026-03-09
ER

PT J
AU Norimatsu, Y
   Hasegawa, K
   Shimizu, N
   Toyoshima, C
AF Norimatsu, Yoshiyuki
   Hasegawa, Kazuya
   Shimizu, Nobutaka
   Toyoshima, Chikashi
TI Protein-phospholipid interplay revealed with crystals of a calcium pump
SO NATURE
LA English
DT Article
ID x-ray-diffraction; molecular-dynamics; membrane-protein; ca2+-atpase; translocation; resolution; mechanism; multiple; bilayer; binding
AB The lipid bilayer has so far eluded visualization by conventional crystallographic methods, severely limiting our understanding of phospholipid-and protein-phospholipid interactions. Here we describe electron density maps for crystals of Ca2+-ATPase in four different states obtained by X-ray solvent contrast modulation. These maps resolve the entire first layer of phospholipids surrounding the transmembrane helices, although less than half of them are hydrogen-bonded to protein residues. Phospholipids follow the movements of associated residues, causing local distortions and changes in thickness of the bilayer. Unexpectedly, the entire protein tilts during the reaction cycle, governed primarily by a belt of Trp residues, to minimize energy costs accompanying the large perpendicular movements of the transmembrane helices. A class of Arg residues extend their side chains through the cytoplasm to exploit phospholipids as anchors for conformational switching. Thus, phospholipid-Arg/Lys and phospholipid-Trp interactions have distinct functional roles in the dynamics of ion pumps and, presumably, membrane proteins in general.
C1 [Norimatsu, Yoshiyuki; Toyoshima, Chikashi] Univ Tokyo, Inst Mol & Cellular Biosci, Tokyo 1130032, Japan.
   [Hasegawa, Kazuya; Shimizu, Nobutaka] Japan Synchrotron Radiat Res Inst JASRI, Prot Crystal Anal Div, 1-1-1 Kouto, Sayo, Hyogo 6795198, Japan.
   [Shimizu, Nobutaka] High Energy Accelerator Res Org KEK, Inst Mat Struct Sci, 1-1 Oho, Tsukuba, Ibaraki 3050801, Japan.
C3 University of Tokyo; Japan Synchrotron Radiation Research Institute; High Energy Accelerator Research Organization (KEK)
RP Toyoshima, C (corresponding author), Univ Tokyo, Inst Mol & Cellular Biosci, Tokyo 1130032, Japan.
EM ct@iam.u-tokyo.ac.jp
FU SPring-8 [2009B0025, 2012B1486, 2013A0049]; Ministry of Education, Culture, Sports, Science and Technology of Japan; Grants-in-Aid for Scientific Research [16H02499, 23000014] Funding Source: KAKEN
NR 47
TC 115
Z9 120
U1 0
U2 61
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 11
PY 2017
VL 545
IS 7653
BP 193
EP +
DI 10.1038/nature22357
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EU3XG
UT WOS:000400963800028
PM 28467821
DA 2026-03-09
ER

PT J
AU Greber, BJ
   Nguyen, THD
   Fang, J
   Afonine, PV
   Adams, PD
   Nogales, E
AF Greber, Basil J.
   Nguyen, Thi Hoang Duong
   Fang, Jie
   Afonine, Pavel V.
   Adams, Paul D.
   Nogales, Eva
TI The cryo-electron microscopy structure of human transcription factor IIH
SO NATURE
LA English
DT Article
ID nucleotide excision-repair; cryo-em structure; dna-repair; crystal-structure; xpd helicase; general transcription; xeroderma-pigmentosum; molecular-replacement; tfiih; domain
AB Human transcription factor IIH (TFIIH) is part of the general transcriptional machinery required by RNA polymerase II for the initiation of eukaryotic gene transcription(1). Composed of ten subunits that add up to a molecular mass of about 500 kDa, TFIIH is also essential for nucleotide excision repair(1). The seven-subunit TFIIH core complex formed by XPB, XPD, p62, p52, p44, p34, and p8 is competent for DNA repair(2), while the CDK-activating kinase subcomplex, which includes the kinase activity of CDK7 as well as the cyclin H and MAT1 subunits, is additionally required for transcription initiation(1,2). Mutations in the TFIIH subunits XPB, XPD, and p8 lead to severe premature ageing and cancer propensity in the genetic diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy, highlighting the importance of TFIIH for cellular physiology(3). Here we present the cryo-electron microscopy structure of human TFIIH at 4.4 angstrom resolution. The structure reveals the molecular architecture of the TFIIH core complex, the detailed structures of its constituent XPB and XPD ATPases, and how the core and kinase subcomplexes of TFIIH are connected. Additionally, our structure provides insight into the conformational dynamics of TFIIH and the regulation of its activity.
C1 [Greber, Basil J.; Nguyen, Thi Hoang Duong; Nogales, Eva] Univ Calif Berkeley, Calif Inst Quantitat Biol QB3, Berkeley, CA 94720 USA.
   [Greber, Basil J.; Nguyen, Thi Hoang Duong; Afonine, Pavel V.; Adams, Paul D.; Nogales, Eva] Lawrence Berkeley Natl Lab, Mol Biophys & Integrat Bioimaging Div, Berkeley, CA 94720 USA.
   [Nguyen, Thi Hoang Duong] Univ Calif Berkeley, Miller Inst Basic Res Sci, Berkeley, CA 94720 USA.
   [Fang, Jie; Nogales, Eva] Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA.
   [Adams, Paul D.] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA.
   [Nogales, Eva] Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA.
C3 University of California System; University of California Berkeley; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; University of California System; University of California Berkeley; University of California System; University of California Berkeley; Howard Hughes Medical Institute; University of California System; University of California Berkeley; University of California System; University of California Berkeley
RP Nogales, E (corresponding author), Univ Calif Berkeley, Calif Inst Quantitat Biol QB3, Berkeley, CA 94720 USA.; Nogales, E (corresponding author), Lawrence Berkeley Natl Lab, Mol Biophys & Integrat Bioimaging Div, Berkeley, CA 94720 USA.; Nogales, E (corresponding author), Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA.; Nogales, E (corresponding author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA.
EM enogales@lbl.gov
FU Office of Science of the US Department of Energy [DE-AC02-05CH11231]; NIGMS [R01-GM63072, P01-GM063210]; Swiss National Science Foundation [P300PA_160983, P300PA_174355]; National Institute of General Medical Sciences [P01GM063210] Funding Source: NIH RePORTER; Swiss National Science Foundation (SNF) [P300PA_174355, P300PA_160983] Funding Source: Swiss National Science Foundation (SNF)
NR 66
TC 85
Z9 115
U1 0
U2 22
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 21
PY 2017
VL 549
IS 7672
BP 414
EP +
DI 10.1038/nature23903
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FH7PB
UT WOS:000411381300041
PM 28902838
DA 2026-03-09
ER

PT J
AU Lagos, MJ
   Trügler, A
   Hohenester, U
   Batson, PE
AF Lagos, Maureen J.
   Truegler, Andreas
   Hohenester, Ulrich
   Batson, Philip E.
TI Mapping vibrational surface and bulk modes in a single nanocube
SO NATURE
LA English
DT Article
ID lattice-dynamics; magnesium-oxide; fast electrons; thin-films; crystal; scattering; phonons; nanoparticles; spectroscopy; microscope
AB Imaging of vibrational excitations in and near nanostructures is essential for developing low-loss infrared nanophotonics(1), controlling heat transport in thermal nanodevices(2,3), inventing new thermoelectric materials4 and understanding nanoscale energy transport. Spatially resolved electron energy loss spectroscopy has previously been used to image plasmonic behaviour in nanostructures in an electron microscope(5,6), but hitherto it has not been possible to map vibrational modes directly in a single nanostructure, limiting our understanding of phonon coupling with photons(7) and plasmons(8). Here we present spatial mapping of optical and acoustic, bulk and surface vibrational modes in magnesium oxide nanocubes using an atom-wide electron beam. We find that the energy and the symmetry of the surface polariton phonon modes depend on the size of the nanocubes, and that they are localized to the surfaces of the nanocube. We also observe a limiting of bulk phonon scattering in the presence of surface phonon modes. Most phonon spectroscopies are selectively sensitive to either surface or bulk excitations; therefore, by demonstrating the excitation of both bulk and surface vibrational modes using a single probe, our work represents advances in the detection and visualization of spatially confined surface and bulk phonons in nanostructures.
C1 [Lagos, Maureen J.; Batson, Philip E.] Rutgers State Univ, Inst Adv Mat, Dept Mat & Sci Engn, Dept Phys & Astron, Piscataway, NJ 08854 USA.
   [Truegler, Andreas; Hohenester, Ulrich] Graz Univ, Inst Phys, Univ 5, A-8010 Graz, Austria.
C3 Rutgers University System; Rutgers University New Brunswick; University of Graz
RP Lagos, MJ (corresponding author), Rutgers State Univ, Inst Adv Mat, Dept Mat & Sci Engn, Dept Phys & Astron, Piscataway, NJ 08854 USA.
EM maureen.lagos@rutgers.edu
FU US Department of Energy, Office of Science, Basic Energy Sciences [DE-SC0005132]; Austrian Science Fund FWF [P27299-N27, SFB F49 NextLite (F4906-N23)]; Austrian Science Fund (FWF) [P27299] Funding Source: Austrian Science Fund (FWF)
NR 39
TC 223
Z9 279
U1 7
U2 317
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 23
PY 2017
VL 543
IS 7646
BP 529
EP +
DI 10.1038/nature21699
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EO9OM
UT WOS:000397018000046
PM 28332537
DA 2026-03-09
ER

PT J
AU Fischer-Gödde, M
   Kleine, T
AF Fischer-Goedde, Mario
   Kleine, Thorsten
TI Ruthenium isotopic evidence for an inner Solar System origin of the late veneer
SO NATURE
LA English
DT Article
ID primitive upper-mantle; terrestrial planets; osmium isotope; core formation; s-process; siderophile elements; protoplanetary disk; earths mantle; giant impact; moon
AB The excess of highly siderophile elements in the Earth's mantle is thought to reflect the addition of primitive meteoritic material after core formation ceased(1-4). This 'late veneer' either comprises material remaining in the terrestrial planet region after the main stages of the Earth's accretion(5,6), or derives from more distant asteroidal(7) or cometary(8) sources. Distinguishing between these disparate origins is important because a late veneer consisting of carbonaceous chondrite-like asteroids(7) or comets(8) could be the principal source of the Earth's volatiles and water. Until now, however, a 'genetic' link between the late veneer and such volatile-rich materials has not been established or ruled out. Such genetic links can be determined using ruthenium (Ru) isotopes, because the Ru in the Earth's mantle predominantly derives from the late veneer(9), and because meteorites exhibit Ru isotope variations arising from the heterogeneous distribution of stellar-derived dust(10,11). Although Ru isotopic data and the correlation of Ru and molybdenum (Mo) isotope anomalies in meteorites were previously used to argue that the late veneer derives from the same type of inner Solar System material as do Earth's main building blocks(6), the Ru isotopic composition of carbonaceous chondrites has not been determined sufficiently well to rule them out as a source of the late veneer. Here we show that all chondrites, including carbonaceous chondrites, have Ru isotopic compositions distinct from that of the Earth's mantle. The Ru isotope anomalies increase from enstatite to ordinary to carbonaceous chondrites, demonstrating that material formed at greater heliocentric distance contains larger Ru isotope anomalies. Therefore, these data refute an outer Solar System origin for the late veneer and imply that the late veneer was not the primary source of volatiles and water on the Earth.
C1 [Fischer-Goedde, Mario; Kleine, Thorsten] Univ Munster, Inst Planetol, Wilhelm Klemm Str 10, D-48149 Munster, Germany.
C3 University of Munster
RP Fischer-Gödde, M; Kleine, T (corresponding author), Univ Munster, Inst Planetol, Wilhelm Klemm Str 10, D-48149 Munster, Germany.
EM m.fischer-goedde@uni-muenster.de; thorsten.kleine@uni-muenster.de
FU Deutsche Forschungsgemeinschaft [SFB-TRR 170]
NR 34
TC 168
Z9 180
U1 1
U2 80
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 26
PY 2017
VL 541
IS 7638
BP 525
EP 527
DI 10.1038/nature21045
PG 3
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6LX
UT WOS:000396116600049
PM 28128236
DA 2026-03-09
ER

PT J
AU Hirschi, M
   Johnson, ZL
   Lee, SY
AF Hirschi, Marscha
   Johnson, Zachary Lee
   Lee, Seok-Yong
TI Visualizing multistep elevator-like transitions of a nucleoside transporter
SO NATURE
LA English
DT Article
ID conserved glutamate residues; crystal-structure; cotransport; mechanisms; complexes; unlocking; model
AB Membrane transporters move substrates across the membrane by alternating access of their binding sites between the opposite sides of the membrane. An emerging model of this process is the elevator mechanism, in which a substrate-binding transport domain moves a large distance across the membrane. This mechanism has been characterized by a transition between two states, but the conformational path that leads to the transition is not yet known, largely because the available structural information has been limited to the two end states. Here we present crystal structures of the inward-facing, intermediate, and outward-facing states of a concentrative nucleoside transporter from Neisseria wadsworthii. Notably, we determined the structures of multiple intermediate conformations, in which the transport domain is captured halfway through its elevator motion. Our structures present a trajectory of the conformational transition in the elevator model, revealing multiple intermediate steps and state-dependent conformational changes within the transport domain that are associated with the elevator-like motion.
C1 [Hirschi, Marscha; Johnson, Zachary Lee; Lee, Seok-Yong] Duke Univ, Med Ctr, Dept Biochem, 303 Res Dr, Durham, NC 27710 USA.
C3 Duke University
RP Lee, SY (corresponding author), Duke Univ, Med Ctr, Dept Biochem, 303 Res Dr, Durham, NC 27710 USA.
EM seok-yong.lee@duke.edu
FU NIH [R01 GM100984, R35 NS097241];  [P41GM103403];  [S10 RR029205];  [P41 GM116799]; National Institute of Neurological Disorders and Stroke [R35NS097241] Funding Source: NIH RePORTER
NR 41
TC 42
Z9 47
U1 0
U2 23
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 4
PY 2017
VL 545
IS 7652
BP 66
EP +
DI 10.1038/nature22057
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET7MK
UT WOS:000400480400031
PM 28424521
DA 2026-03-09
ER

PT J
AU Schmiege, P
   Fine, M
   Blobel, G
   Li, XC
AF Schmiege, Philip
   Fine, Michael
   Blobel, Gunter
   Li, Xiaochun
TI Human TRPML1 channel structures in open and closed conformations
SO NATURE
LA English
DT Article
ID mucolipidosis type-iv; ion-channel; trpv1 structures; mutations; model; identification; refinement; mechanism; system; cells
AB Transient receptor potential mucolipin 1 (TRPML1) is a Ca2+-releasing cation channel that mediates the calcium signalling and homeostasis of lysosomes. Mutations in TRPML1 lead to mucolipidosis type IV, a severe lysosomal storage disorder. Here we report two electron cryo-microscopy structures of full-length human TRPML1: a 3.72-A apo structure at pH 7.0 in the closed state, and a 3.49-A agonist-bound structure at pH 6.0 in an open state. Several aromatic and hydrophobic residues in pore helix 1, helices S5 and S6, and helix S6 of a neighbouring subunit, form a hydrophobic cavity to house the agonist, suggesting a distinct agonist-binding site from that found in TRPV1, a TRP channel from a different subfamily. The opening of TRPML1 is associated with distinct dilations of its lower gate together with a slight structural movement of pore helix 1. Our work reveals the regulatory mechanism of TRPML channels, facilitates better understanding of TRP channel activation, and provides insights into the molecular basis of mucolipidosis type IV pathogenesis.
C1 [Schmiege, Philip; Blobel, Gunter; Li, Xiaochun] Rockefeller Univ, Howard Hughes Med Inst, Lab Cell Biol, New York, NY 10065 USA.
   [Schmiege, Philip; Li, Xiaochun] Univ Texas Southwestern Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA.
   [Fine, Michael] Univ Texas Southwestern Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA.
   [Li, Xiaochun] Univ Texas Southwestern Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA.
C3 Rockefeller University; Howard Hughes Medical Institute; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center
RP Blobel, G; Li, XC (corresponding author), Rockefeller Univ, Howard Hughes Med Inst, Lab Cell Biol, New York, NY 10065 USA.; Li, XC (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA.; Li, XC (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA.
EM blobel@rockefeller.edu; xiaochun.li@utsouthwestern.edu
FU Howard Hughes Medical Institute; Endowed Scholars Program in Medical Science of University of Texas Southwestern Medical Center; National Institutes of Health [T32DK007257, HL119843]; National Heart Lung and Blood Institute [R01HL119843] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [T32DK007257] Funding Source: NIH RePORTER
NR 59
TC 121
Z9 137
U1 1
U2 31
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 19
PY 2017
VL 550
IS 7676
BP 366
EP +
DI 10.1038/nature24036
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FY4NV
UT WOS:000426802700001
PM 29019983
DA 2026-03-09
ER

PT J
AU Beagrie, RA
   Scialdone, A
   Schueler, M
   Kraemer, DCA
   Chotalia, M
   Xie, SQ
   Barbieri, M
   de Santiago, I
   Lavitas, LM
   Branco, MR
   Fraser, J
   Dostie, J
   Game, L
   Dillon, N
   Edwards, PAW
   Nicodemi, M
   Pombo, A
AF Beagrie, Robert A.
   Scialdone, Antonio
   Schueler, Markus
   Kraemer, Dorothee C. A.
   Chotalia, Mita
   Xie, Sheila Q.
   Barbieri, Mariano
   de Santiago, Ines
   Lavitas, Liron-Mark
   Branco, Miguel R.
   Fraser, James
   Dostie, Josee
   Game, Laurence
   Dillon, Niall
   Edwards, Paul A. W.
   Nicodemi, Mario
   Pombo, Ana
TI Complex multi-enhancer contacts captured by genome architecture mapping
SO NATURE
LA English
DT Article
ID rna-polymerase-ii; chromosome conformation capture; embryonic stem-cells; hi-c data; organization; transcription; genes; reveals; domains; principles
AB The organization of the genome in the nucleus and the interactions of genes with their regulatory elements are key features of transcriptional control and their disruption can cause disease. Here we report a genome-wide method, genome architecture mapping (GAM), for measuring chromatin contacts and other features of three-dimensional chromatin topology on the basis of sequencing DNA from a large collection of thin nuclear sections. We apply GAM to mouse embryonic stem cells and identify enrichment for specific interactions between active genes and enhancers across very large genomic distances using a mathematical model termed SLICE (statistical inference of co-segregation). GAM also reveals an abundance of three-way contacts across the genome, especially between regions that are highly transcribed or contain super-enhancers, providing a level of insight into genome architecture that, owing to the technical limitations of current technologies, has previously remained unattainable. Furthermore, GAM highlights a role for gene-expressionspecific contacts in organizing the genome in mammalian nuclei.
C1 [Beagrie, Robert A.; Schueler, Markus; Kraemer, Dorothee C. A.; Barbieri, Mariano; Lavitas, Liron-Mark; Pombo, Ana] Max Delbruck Ctr Mol Med, Berlin Inst Med Syst Biol, Epigenet Regulat & Chromatin Architecture Grp, Robert Rossle St, D-13125 Berlin, Germany.
   [Beagrie, Robert A.; Chotalia, Mita; Xie, Sheila Q.; de Santiago, Ines; Lavitas, Liron-Mark; Branco, Miguel R.; Pombo, Ana] Imperial Coll London, MRC London Inst Med Sci, Genome Funct Grp, Hammersmith Hosp Campus, London W12 0NN, England.
   [Beagrie, Robert A.] Imperial Coll London, MRC London Inst Med Sci, Gene Regulat & Chromatin Grp, Hammersmith Hosp Campus, London W12 0NN, England.
   [Scialdone, Antonio; Nicodemi, Mario] Univ Napoli Fed II INFN Napoli, Complesso Univ Monte, Dipartimento Fis, I-80126 Naples, Italy.
   [Pombo, Ana] BIH, D-10117 Berlin, Germany.
   [Fraser, James; Dostie, Josee] McGill Univ, Goodman Canc Res Ctr, Dept Biochem, Montreal, PQ H3G 1Y6, Canada.
   [Game, Laurence] Imperial Coll London, MRC London Inst Med Sci, Genom Lab, Hammersmith Hosp Campus, London W12 0NN, England.
   [Edwards, Paul A. W.] Univ Cambridge, Hutchison MRC Res Ctr, Dept Pathol, Cambridge CB2 0XZ, England.
   [Pombo, Ana] Humboldt Univ, Inst Biol, D-10115 Berlin, Germany.
   [Scialdone, Antonio] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge, England.
   [Xie, Sheila Q.] Imperial Coll London, MRC London Inst Med Sci, Single Mol Imaging Grp, Hammersmith Hosp Campus, London W12 0NN, England.
   [de Santiago, Ines] Univ Cambridge, Canc Res UK Cambridge Inst, Li Ka Shing Ctr,Robinson Way, Cambridge CB2 1TN, England.
   [Branco, Miguel R.] Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London E1 2AT, England.
C3 Helmholtz Association; Max Delbruck Center for Molecular Medicine; Imperial College London; Imperial College London; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; McGill University; Imperial College London; University of Cambridge; Humboldt University of Berlin; Wellcome Trust Sanger Institute; Imperial College London; CRUK Cambridge Institute; University of Cambridge; Cancer Research UK; University of London; Queen Mary University London
RP Pombo, A (corresponding author), Max Delbruck Ctr Mol Med, Berlin Inst Med Syst Biol, Epigenet Regulat & Chromatin Architecture Grp, Robert Rossle St, D-13125 Berlin, Germany.; Pombo, A (corresponding author), Imperial Coll London, MRC London Inst Med Sci, Genome Funct Grp, Hammersmith Hosp Campus, London W12 0NN, England.; Nicodemi, M (corresponding author), Univ Napoli Fed II INFN Napoli, Complesso Univ Monte, Dipartimento Fis, I-80126 Naples, Italy.; Pombo, A (corresponding author), BIH, D-10117 Berlin, Germany.; Pombo, A (corresponding author), Humboldt Univ, Inst Biol, D-10115 Berlin, Germany.
EM mario.nicodemi@na.infn.it; ana.pombo@mdc-berlin.de
FU Medical Research Council, UK; Helmholtz Foundation; MRC-Technology; Berlin Institute of Health (BIH); Breast Cancer Campaign; Cancer Research UK; Canadian Institutes of Health Research (CIHR) [MOP-86716, CAP-120350]; CINECA ISCRA [HP10CYFPS5, HP10CRTY8P]; MRC [MC_U120061476, MC_U120036884] Funding Source: UKRI; Medical Research Council [MC_U120061476, 1116071, MC_U120036884] Funding Source: researchfish
NR 63
TC 515
Z9 625
U1 1
U2 91
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 23
PY 2017
VL 543
IS 7646
BP 519
EP +
DI 10.1038/nature21411
PG 25
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EO9OM
UT WOS:000397018000044
PM 28273065
DA 2026-03-09
ER

PT J
AU Chen, WJ
   Özdemir, SK
   Zhao, GM
   Wiersig, J
   Yang, L
AF Chen, Weijian
   Ozdemir, Sahin Kaya
   Zhao, Guangming
   Wiersig, Jan
   Yang, Lan
TI Exceptional points enhance sensing in an optical microcavity
SO NATURE
LA English
DT Article
ID nanoparticles; chip; degeneracy; lasers
AB Sensors play an important part in many aspects of daily life such as infrared sensors in home security systems, particle sensors for environmental monitoring and motion sensors in mobile phones. High-quality optical microcavities are prime candidates for sensing applications because of their ability to enhance light-matter interactions in a very confined volume. Examples of such devices include mechanical transducers(1), magnetometers(2), single-particle absorption spectrometers(3), and microcavity sensors for sizing single particles(4) and detecting nanometre-scale objects such as single nanoparticles and atomic ions(5-7). Traditionally, a very small perturbation near an optical microcavity introduces either a change in the linewidth or a frequency shift or splitting of a resonance that is proportional to the strength of the perturbation. Here we demonstrate an alternative sensing scheme, by which the sensitivity of microcavities can be enhanced when operated at non-Hermitian spectral degeneracies known as exceptional points(8-16). In our experiments, we use two nanoscale scatterers to tune a whispering-gallery-mode micro-toroid cavity, in which light propagates along a concave surface by continuous total internal reflection, in a precise and controlled manner to exceptional points(12,13). A target nanoscale object that subsequently enters the evanescent field of the cavity perturbs the system from its exceptional point, leading to frequency splitting. Owing to the complex-square-root topology near an exceptional point, this frequency splitting scales as the square root of the perturbation strength and is therefore larger (for sufficiently small perturbations) than the splitting observed in traditional non-exceptional-point sensing schemes. Our demonstration of exceptional-point-enhanced sensitivity paves the way for sensors with unprecedented sensitivity.
C1 [Chen, Weijian; Ozdemir, Sahin Kaya; Zhao, Guangming; Yang, Lan] Washington Univ, Dept Elect & Syst Engn, St Louis, MO 63130 USA.
   [Wiersig, Jan] Otto von Guericke Univ, Inst Theoret Phys, D-39016 Magdeburg, Germany.
C3 Washington University (WUSTL); Otto von Guericke University
RP Yang, L (corresponding author), Washington Univ, Dept Elect & Syst Engn, St Louis, MO 63130 USA.
EM yang@seas.wustl.edu
FU National Science Foundation [EFMA1641109]; Army Research Office [W911NF1210026, W911NF1710189, W911NF1610339]; DFG [WI1986/6-1]; U.S. Department of Defense (DOD) [W911NF1710189, W911NF1610339] Funding Source: U.S. Department of Defense (DOD)
NR 33
TC 1699
Z9 1884
U1 55
U2 922
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 10
PY 2017
VL 548
IS 7666
BP 192
EP +
DI 10.1038/nature23281
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD1GB
UT WOS:000407284300039
PM 28796206
DA 2026-03-09
ER

PT J
AU Burr, ML
   Sparbier, CE
   Chan, YC
   Williamson, JC
   Woods, K
   Beavis, PA
   Lam, EYN
   Henderson, MA
   Bell, CC
   Stolzenburg, S
   Gilan, O
   Bloor, S
   Noori, T
   Morgens, DW
   Bassik, MC
   Neeson, PJ
   Behren, A
   Darcy, PK
   Dawson, SJ
   Voskoboinik, I
   Trapani, JA
   Cebon, J
   Lehner, PJ
   Dawson, MA
AF Burr, Marian L.
   Sparbier, Christina E.
   Chan, Yih-Chih
   Williamson, James C.
   Woods, Katherine
   Beavis, Paul A.
   Lam, Enid Y. N.
   Henderson, Melissa A.
   Bell, Charles C.
   Stolzenburg, Sabine
   Gilan, Omer
   Bloor, Stuart
   Noori, Tahereh
   Morgens, David W.
   Bassik, Michael C.
   Neeson, Paul J.
   Behren, Andreas
   Darcy, Phillip K.
   Dawson, Sarah-Jane
   Voskoboinik, Ilia
   Trapani, Joseph A.
   Cebon, Jonathan
   Lehner, Paul J.
   Dawson, Mark A.
TI CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity
SO NATURE
LA English
DT Article
ID infection; membrane
AB Cancer cells exploit the expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) to subvert T-cell-mediated immunosurveillance(1,2). The success of therapies that disrupt PD-L1-mediated tumour tolerance has highlighted the need to understand the molecular regulation of PD-L1 expression(1). Here we identify the uncharacterized protein CMTM6 as a critical regulator of PD-L1 in a broad range of cancer cells, by using a genome-wide CRISPR-Cas9 screen. CMTM6 is a ubiquitously expressed protein that binds PD-L1 and maintains its cell surface expression. CMTM6 is not required for PD-L1 maturation but co-localizes with PD-L1 at the plasma membrane and in recycling endosomes, where it prevents PD-L1 from being targeted for lysosome-mediated degradation. Using a quantitative approach to profile the entire plasma membrane proteome, we find that CMTM6 displays specificity for PD-L1. Notably, CMTM6 depletion decreases PD-L1 without compromising cell surface expression of MHC class I. CMTM6 depletion, via the reduction of PD-L1, significantly alleviates the suppression of tumour-specific T cell activity in vitro and in vivo. These findings provide insights into the biology of PD-L1 regulation, identify a previously unrecognized master regulator of this critical immune checkpoint and highlight a potential therapeutic target to overcome immune evasion by tumour cells.
C1 [Burr, Marian L.; Sparbier, Christina E.; Chan, Yih-Chih; Beavis, Paul A.; Lam, Enid Y. N.; Henderson, Melissa A.; Bell, Charles C.; Stolzenburg, Sabine; Gilan, Omer; Noori, Tahereh; Neeson, Paul J.; Darcy, Phillip K.; Dawson, Sarah-Jane; Voskoboinik, Ilia; Trapani, Joseph A.; Dawson, Mark A.] Peter MacCallum Canc Ctr, Canc Res Div, Melbourne, Vic 3000, Australia.
   [Burr, Marian L.; Beavis, Paul A.; Lam, Enid Y. N.; Henderson, Melissa A.; Bell, Charles C.; Gilan, Omer; Neeson, Paul J.; Darcy, Phillip K.; Dawson, Sarah-Jane; Voskoboinik, Ilia; Trapani, Joseph A.; Dawson, Mark A.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia.
   [Burr, Marian L.; Williamson, James C.; Bloor, Stuart; Lehner, Paul J.] Cambridge Inst Med Res, Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0XY, England.
   [Woods, Katherine; Behren, Andreas; Cebon, Jonathan] La Trobe Univ, Sch Canc Med, Melbourne, Vic 3086, Australia.
   [Woods, Katherine; Behren, Andreas; Cebon, Jonathan] Olivia Newton John Canc Res Inst, Heidelberg, Vic 3084, Australia.
   [Morgens, David W.; Bassik, Michael C.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
   [Dawson, Sarah-Jane; Dawson, Mark A.] Univ Melbourne, Ctr Canc Res, Melbourne, Vic, Australia.
   [Dawson, Mark A.] Peter MacCallum Canc Ctr, Dept Haematol, Melbourne, Vic, Australia.
C3 Peter Maccallum Cancer Center; University of Melbourne; Peter Maccallum Cancer Center; University of Cambridge; La Trobe University; La Trobe University; Olivia Newton-John Cancer Research Institute; Stanford University; University of Melbourne; Peter Maccallum Cancer Center
RP Dawson, MA (corresponding author), Peter MacCallum Canc Ctr, Canc Res Div, Melbourne, Vic 3000, Australia.; Dawson, MA (corresponding author), Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia.; Lehner, PJ (corresponding author), Cambridge Inst Med Res, Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0XY, England.; Dawson, MA (corresponding author), Univ Melbourne, Ctr Canc Res, Melbourne, Vic, Australia.; Dawson, MA (corresponding author), Peter MacCallum Canc Ctr, Dept Haematol, Melbourne, Vic, Australia.
EM marian.burr@petermac.org; pjl30@cam.ac.uk; mark.dawson@petermac.org
FU Cancer Research UK Fellowship; Addenbrooke's Charitable Trust award; NIHR fellowship; Senior Leukaemia Foundation Australia Fellowship; NHMRC [1085015, 1106444, 1106447]; Cancer Council Victoria; Leukaemia Foundation Australia; Wellcome Trust PRF [101835/Z/13/Z]; NHSBT; NIHR Cambridge BRC; Wellcome Trust Strategic Award; Addenbrooke's Charitable Trust; Wellcome Trust [101835/Z/13/Z] Funding Source: Wellcome Trust; National Health and Medical Research Council (NHMRC) [1106447, 1085015, 1106444] Funding Source: National Health and Medical Research Council (NHMRC); National Health and Medical Research Council of Australia [1106447, 1085015, 1106444] Funding Source: NHMRC; National Human Genome Research Institute [T32HG000044] Funding Source: NIH RePORTER; Cancer Research UK [20097] Funding Source: researchfish; National Institute for Health Research [ACF-2012-14-003] Funding Source: researchfish
NR 19
TC 755
Z9 854
U1 9
U2 284
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 7
PY 2017
VL 549
IS 7670
BP 101
EP 105
DI 10.1038/nature23643
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG0DH
UT WOS:000409388700041
PM 28813417
DA 2026-03-09
ER

PT J
AU Thompson, JD
   Nicholson, TL
   Liang, QY
   Cantu, SH
   Venkatramani, AV
   Choi, S
   Fedorov, IA
   Viscor, D
   Pohl, T
   Lukin, MD
   Vuletic, V
AF Thompson, Jeff D.
   Nicholson, Travis L.
   Liang, Qi-Yu
   Cantu, Sergio H.
   Venkatramani, Aditya V.
   Choi, Soonwon
   Fedorov, Ilya A.
   Viscor, Daniel
   Pohl, Thomas
   Lukin, Mikhail D.
   Vuletic, Vladan
TI Symmetry-protected collisions between strongly interacting photons
SO NATURE
LA English
DT Article
ID quantum nonlinear optics; majorana fermions; rydberg atoms
AB Realizing robust quantum phenomena in strongly interacting systems is one of the central challenges in modern physical science. Approaches ranging from topological protection to quantum error correction are currently being explored across many different experimental platforms, including electrons in condensed-matter systems', trapped atoms' and photons'. Although photon-photon interactions are typically negligible in conventional optical media, strong interactions between individual photons have recently been engineered in several systems(4-10). Here, using coherent coupling between light and Rydberg excitations in an ultracold atomic gas, we demonstrate a controlled and coherent exchange collision between two photons that is accompanied by a pi/2 phase shift. The effect is robust in that the value of the phase shift is determined by the interaction symmetry rather than the precise experimental parameters(7,10-13), and in that it occurs under conditions where photon absorption is minimal. The measured phase shift of 0.48(3)pi is in excellent agreement with a theoretical model. These observations open a route to realizing robust single-photon switches and all-optical quantum logic gates, and to exploring novel quantum many-body phenomena with strongly interacting photons.
C1 [Thompson, Jeff D.; Venkatramani, Aditya V.; Choi, Soonwon; Lukin, Mikhail D.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.
   [Thompson, Jeff D.] Princeton Univ, Dept Elect Engn, Princeton, NJ 08544 USA.
   [Nicholson, Travis L.; Liang, Qi-Yu; Cantu, Sergio H.; Vuletic, Vladan] MIT, Dept Phys, Cambridge, MA 02139 USA.
   [Nicholson, Travis L.; Liang, Qi-Yu; Cantu, Sergio H.; Vuletic, Vladan] MIT, Elect Res Lab, Cambridge, MA 02139 USA.
   [Fedorov, Ilya A.] Russian Quantum Ctr, Moscow 143025, Russia.
   [Viscor, Daniel; Pohl, Thomas] Max Planck Inst Phys Komplexer Syst, D-01187 Dresden, Germany.
   [Pohl, Thomas] Aarhus Univ, Dept Phys & Astron, DK-8000 Aarhus, Denmark.
C3 Harvard University; Princeton University; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Russian Quantum Center; Max Planck Society; Aarhus University
RP Lukin, MD (corresponding author), Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.; Vuletic, V (corresponding author), MIT, Dept Phys, Cambridge, MA 02139 USA.; Vuletic, V (corresponding author), MIT, Elect Res Lab, Cambridge, MA 02139 USA.
EM lukin@physics.harvard.edu; vuletic@mit.edu
FU NSF; Center for Ultracold Atoms; DARPA; ARO; ARO MURI; AFOSR MURI; ARL; U-FET [512862]; H-FETPROACT [640378]; DFG [SPP 1929]; Kwanjeong Educational Foundation; Direct For Mathematical & Physical Scien; Division Of Physics [1506284, 1505862, 1125846] Funding Source: National Science Foundation
NR 30
TC 71
Z9 83
U1 2
U2 64
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 9
PY 2017
VL 542
IS 7640
BP 206
EP 209
DI 10.1038/nature20823
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK2DJ
UT WOS:000393737500035
PM 28117443
DA 2026-03-09
ER

PT J
AU Compagno, M
   Wang, Q
   Pighi, C
   Cheong, TC
   Meng, FL
   Poggio, T
   Yeap, LS
   Karaca, E
   Blasco, RB
   Langellotto, F
   Ambrogio, C
   Voena, C
   Wiestner, A
   Kasar, SN
   Brown, JR
   Sun, J
   Wu, CJ
   Gostissa, M
   Alt, FW
   Chiarle, R
AF Compagno, Mara
   Wang, Qi
   Pighi, Chiara
   Cheong, Taek-Chin
   Meng, Fei-Long
   Poggio, Teresa
   Yeap, Leng-Siew
   Karaca, Elif
   Blasco, Rafael B.
   Langellotto, Fernanda
   Ambrogio, Chiara
   Voena, Claudia
   Wiestner, Adrian
   Kasar, Siddha N.
   Brown, Jennifer R. .
   Sun, Jing
   Wu, Catherine J.
   Gostissa, Monica
   Alt, Frederick W.
   Chiarle, Roberto
TI Phosphatidylinositol 3-kinase δ blockade increases genomic instability in B cells
SO NATURE
LA English
DT Article
ID induced cytidine deaminase; class-switch recombination; sequencing reveals; super-enhancers; targeting btk; aid; dna; transcription; mechanisms; ibrutinib
AB Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation(1). In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma(2). AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation3. The phosphatidylinositol 3-kinase delta (PI3K delta) pathway regulates AID by suppressing its expression in B cells4. Drugs for leukaemia or lymphoma therapy such as idelalisib, duvelisib and ibrutinib block PI3K delta activity directly or indirectly(5-8), potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both of these effects were completely abrogated in AID-deficient B cells. PI3K delta inhibitors or ibrutinib increased the formation of AID-dependent tumours in pristane-treated mice. Consistently, PI3K delta inhibitors enhanced AID expression and translocation frequency to IGH and AID off-target sites in human chronic lymphocytic leukaemia and mantle cell lymphoma cell lines, and patients treated with idelalisib, but not ibrutinib, showed increased somatic hypermutation in AID off-targets. In summary, we show that PI3K delta or Bruton's tyrosine kinase inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism. This effect should be carefully considered, as such inhibitors can be administered to patients for years.
C1 [Compagno, Mara; Wang, Qi; Pighi, Chiara; Cheong, Taek-Chin; Karaca, Elif; Blasco, Rafael B.; Langellotto, Fernanda; Voena, Claudia; Chiarle, Roberto] Childrens Hosp Boston, Dept Pathol, Boston, MA 02115 USA.
   [Compagno, Mara; Wang, Qi; Pighi, Chiara; Cheong, Taek-Chin; Karaca, Elif; Blasco, Rafael B.; Langellotto, Fernanda; Voena, Claudia; Chiarle, Roberto] Harvard Med Sch, Boston, MA 02115 USA.
   [Meng, Fei-Long; Yeap, Leng-Siew; Gostissa, Monica; Alt, Frederick W.] Boston Childrens Hosp, Howard Hughes Med Inst, Program Cellular & Mol Med, Boston, MA 02115 USA.
   [Meng, Fei-Long; Yeap, Leng-Siew; Gostissa, Monica; Alt, Frederick W.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.
   [Poggio, Teresa; Voena, Claudia; Chiarle, Roberto] Univ Torino, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy.
   [Kasar, Siddha N.; Brown, Jennifer R. .; Sun, Jing] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.
   [Wiestner, Adrian] Natl Heart Lung & Blood Inst, Hematol Branch, Bethesda, MD USA.
   [Meng, Fei-Long] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China.
   [Yeap, Leng-Siew] Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Immunol, Shanghai 200025, Peoples R China.
   [Langellotto, Fernanda; Gostissa, Monica] Agenus Inc, 3 Forbes Rd, Lexington, MA 02421 USA.
C3 Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Program in Cellular & Molecular Medicine (PCMM); Harvard University; Harvard Medical School; University of Turin; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard Medical School; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI); Chinese Academy of Sciences; Center for Excellence in Molecular Cell Science, CAS; Chinese Academy of Sciences; Shanghai Jiao Tong University; Agenus Inc
RP Chiarle, R (corresponding author), Childrens Hosp Boston, Dept Pathol, Boston, MA 02115 USA.; Chiarle, R (corresponding author), Harvard Med Sch, Boston, MA 02115 USA.; Chiarle, R (corresponding author), Univ Torino, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy.
EM roberto.chiarle@childrens.harvard.edu
FU NIH [R01 CA196703-01, 1U10CA180861-01, R01AI077595]; Associazione Italiana per la Ricerca sul Cancro [IG-12023, MFAG 10708]; Worldwide Cancer Research grant [12-0216]; Compagnia di San Paolo-Comitato Gigi Ghirotti; American Cancer Society [RSG-13-002-01-CCE]; National Research Foundation of Korea(NRF); PhRMA Foundation; NHLBI, NIH; National Cancer Institute [P01CA206978, R01CA196703, R01CA216273] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [ZIAHL002346] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [R37AI077595] Funding Source: NIH RePORTER
NR 43
TC 109
Z9 127
U1 0
U2 57
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 23
PY 2017
VL 542
IS 7642
BP 489
EP +
DI 10.1038/nature21406
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1RG
UT WOS:000395094100039
PM 28199309
DA 2026-03-09
ER

PT J
AU Larson, AG
   Elnatan, D
   Keenen, MM
   Trnka, MJ
   Ohnston, JBJ
   Burlingame, AL
   Agard, DA
   Redding, S
   Narlikar, GJ
AF Larson, Adam G.
   Elnatan, Daniel
   Keenen, Madeline M.
   Trnka, Michael J.
   Ohnston, Jonathan B. J.
   Burlingame, Alma L.
   Agard, David A.
   Redding, Sy
   Narlikar, Geeta J.
TI Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin
SO NATURE
LA English
DT Article
ID analytical ultracentrifugation; histone h3; chromatin; proteins; mass; spectra; deconvolution; recognition; association; specificity
AB Gene silencing by heterochromatin is proposed to occur in part as a result of the ability of heterochromatin protein 1 (HP1) proteins to spread across large regions of the genome, compact the underlying chromatin and recruit diverse ligands(1-3). Here we identify a new property of the human HP1 alpha protein: the ability to form phase-separated droplets. While unmodified HP1 alpha is soluble, either phosphorylation of its N-terminal extension or DNA binding promotes the formation of phase-separated droplets. Phosphorylation-driven phase separation can be promoted or reversed by specific HP1 alpha ligands. Known components of heterochromatin such as nucleosomes and DNA preferentially partition into the HP1 alpha droplets, but molecules such as the transcription factor TFIIB show no preference. Using a single-molecule DNA curtain assay, we find that both unmodified and phosphorylated HP1 alpha induce rapid compaction of DNA strands into puncta, although with different characteristics(4). We show by direct protein delivery into mammalian cells that an HP1 alpha mutant incapable of phase separation in vitro forms smaller and fewer nuclear puncta than phosphorylated HP1 alpha. These findings suggest that heterochromatin-mediated gene silencing may occur in part through sequestration of compacted chromatin in phase-separated HP1 droplets, which are dissolved or formed by specific ligands on the basis of nuclear context.
C1 [Larson, Adam G.; Elnatan, Daniel; Keenen, Madeline M.; Agard, David A.; Redding, Sy; Narlikar, Geeta J.] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA.
   [Larson, Adam G.; Elnatan, Daniel; Keenen, Madeline M.] Univ Calif San Francisco, Tetrad Grad Program, San Francisco, CA 94158 USA.
   [Trnka, Michael J.; Ohnston, Jonathan B. J.; Burlingame, Alma L.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA.
   [Agard, David A.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA.
C3 University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Howard Hughes Medical Institute
RP Narlikar, GJ (corresponding author), Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA.
EM Geeta.narlikar@ucsf.edu
FU NSF; UCSF Program for Breakthrough Biomedical Research (PBBR) by Sandler Foundation; NIH [8P41GM103481, 1S10D016229, R01GM108455]; PBBR (New Frontier Research Award); National Institute of General Medical Sciences [R35GM118099] Funding Source: NIH RePORTER
NR 37
TC 1268
Z9 1522
U1 6
U2 256
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 13
PY 2017
VL 547
IS 7662
BP 236
EP +
DI 10.1038/nature22822
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FA3AX
UT WOS:000405314500043
PM 28636604
DA 2026-03-09
ER

PT J
AU Fitzpatrick, AWP
   Falcon, B
   He, S
   Murzin, AG
   Murshudov, G
   Garringer, HJ
   Crowther, RA
   Ghetti, B
   Goedert, M
   Scheres, SHW
AF Fitzpatrick, Anthony W. P.
   Falcon, Benjamin
   He, Shaoda
   Murzin, Alexey G.
   Murshudov, Garib
   Garringer, Holly J.
   Crowther, R. Anthony
   Ghetti, Bernardino
   Goedert, Michel
   Scheres, Sjors H. W.
TI Cryo-EM structures of tau filaments from Alzheimer's disease
SO NATURE
LA English
DT Article
ID paired helical filaments; atomic-resolution structure; amyloid fibrils; neurofibrillary tangles; frontotemporal dementia; fine-structure; protein-tau; in-vitro; brain; antibody
AB Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 angstrom resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-beta/beta-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.
C1 [Fitzpatrick, Anthony W. P.; Falcon, Benjamin; He, Shaoda; Murzin, Alexey G.; Murshudov, Garib; Crowther, R. Anthony; Goedert, Michel; Scheres, Sjors H. W.] MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England.
   [Garringer, Holly J.; Ghetti, Bernardino] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA.
C3 MRC Laboratory Molecular Biology; Indiana University System; Indiana University Bloomington
RP Goedert, M; Scheres, SHW (corresponding author), MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England.
EM mg@mrc-lmb.cam.ac.uk; scheres@mrc-lmb.cam.ac.uk
FU UK Medical Research Council [MC_UP_A025_1012, MC_U105184291, MC_UP_A025_1013]; European Union; US National Institutes of Health [P30-AG010133]; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine; Medical Research Council [MC_UP_A025_1013, MC_UP_A025_1012, MC_U105184291, MC_EX_MR/N027892/1, G0600724] Funding Source: researchfish; MRC [MC_UP_A025_1013, MC_EX_MR/N027892/1, G0600724, MC_UP_A025_1012] Funding Source: UKRI
CR Åslund A, 2009, ACS CHEM BIOL, V4, P673, DOI 10.1021/cb900112v
   Berriman J, 2003, P NATL ACAD SCI USA, V100, P9034, DOI 10.1073/pnas.1530287100
   Bibow S, 2011, ANGEW CHEM INT EDIT, V50, P11520, DOI 10.1002/anie.201105493
   Braak H, 2016, CSH PERSPECT BIOL, V8, P0, DOI 10.1101/cshperspect.a023630
   Carmel G, 1996, J BIOL CHEM, V271, P32789, DOI 10.1074/jbc.271.51.32789
   Chen SX, 2013, ULTRAMICROSCOPY, V135, P24, DOI 10.1016/j.ultramic.2013.06.004
   Chen VB, 2010, ACTA CRYSTALLOGR D, V66, P12, DOI 10.1107/S0907444909042073
   Chiti F, 2006, ANNU REV BIOCHEM, V75, P333, DOI 10.1146/annurev.biochem.75.101304.123901
   Clavaguera F, 2013, P NATL ACAD SCI USA, V110, P9535, DOI 10.1073/pnas.1301175110
   Colvin MT, 2016, J AM CHEM SOC, V138, P9663, DOI 10.1021/jacs.6b05129
   CRICK FHC, 1955, NATURE, V176, P780, DOI 10.1038/176780a0
   Crowther RA, 2000, J STRUCT BIOL, V130, P271, DOI 10.1006/jsbi.2000.4270
   CROWTHER RA, 1991, P NATL ACAD SCI USA, V88, P2288, DOI 10.1073/pnas.88.6.2288
   Dan A, 2013, ACTA NEUROPATHOL COM, V1, P0, DOI 10.1186/2051-5960-1-54
   Emsley P, 2010, ACTA CRYSTALLOGR D, V66, P486, DOI 10.1107/S0907444910007493
   Falcon B, 2015, J BIOL CHEM, V290, P1049, DOI 10.1074/jbc.M114.589309
   Fitzpatrick AWP, 2013, P NATL ACAD SCI USA, V110, P5468, DOI 10.1073/pnas.1219476110
   Ghetti B, 2015, NEUROPATH APPL NEURO, V41, P24, DOI 10.1111/nan.12213
   GOEDERT M, 1992, NEURON, V8, P159, DOI 10.1016/0896-6273(92)90117-V
   GOEDERT M, 1989, NEURON, V3, P519, DOI 10.1016/0896-6273(89)90210-9
   Govaerts C, 2004, P NATL ACAD SCI USA, V101, P8342, DOI 10.1073/pnas.0402254101
   Guo JL, 2016, J EXP MED, V213, P2635, DOI 10.1084/jem.20160833
   GUSTKE N, 1994, BIOCHEMISTRY-US, V33, P9511, DOI 10.1021/bi00198a017
   Hayashi S, 2002, ANN NEUROL, V51, P525, DOI 10.1002/ana.10163
   He SD, 2017, J STRUCT BIOL, V198, P163, DOI 10.1016/j.jsb.2017.02.003
   Herrmann US, 2015, SCI TRANSL MED, V7, P0, DOI 10.1126/scitranslmed.aab1923
   Iverson TM, 2000, BIOCHEMISTRY-US, V39, P9222, DOI 10.1021/bi000204s
   Jackson SJ, 2016, J NEUROSCI, V36, P762, DOI 10.1523/JNEUROSCI.3542-15.2016
   JAKES R, 1991, EMBO J, V10, P2725, DOI 10.1002/j.1460-2075.1991.tb07820.x
   Jicha GA, 1997, J NEUROSCI RES, V48, P128, DOI 10.1002/(SICI)1097-4547(19970415)48:2<128::AID-JNR5>3.0.CO;2-E
   Kadavath H, 2015, ANGEW CHEM INT EDIT, V54, P10347, DOI 10.1002/ange.201501714
   Kajava AV, 2006, ADV PROTEIN CHEM, V73, P55, DOI 10.1016/S0065-3233(06)73003-0
   Kaufman SK, 2016, NEURON, V92, P796, DOI 10.1016/j.neuron.2016.09.055
   KIDD M, 1963, NATURE, V197, P192, DOI 10.1038/197192b0
   Kolb HC, 2017, CSH PERSPECT BIOL, V9, P0, DOI 10.1101/cshperspect.a023721
   Lu JX, 2013, CELL, V154, P1257, DOI 10.1016/j.cell.2013.08.035
   McEwan WA, 2017, P NATL ACAD SCI USA, V114, P574, DOI 10.1073/pnas.1607215114
   Murshudov GN, 1997, ACTA CRYSTALLOGR D, V53, P240, DOI 10.1107/S0907444996012255
   Poorkaj P, 2002, ANN NEUROL, V52, P511, DOI 10.1002/ana.10340
   Riek R, 2016, NATURE, V539, P227, DOI 10.1038/nature20416
   Sawaya MR, 2007, NATURE, V447, P453, DOI 10.1038/nature05695
   Schmidt M, 2015, P NATL ACAD SCI USA, V112, P11858, DOI 10.1073/pnas.1503455112
   Spina S, 2008, BRAIN, V131, P72, DOI 10.1093/brain/awm280
   Sunde M, 1997, J MOL BIOL, V273, P729, DOI 10.1006/jmbi.1997.1348
   Taniguchi-Watanabe S, 2016, ACTA NEUROPATHOL, V131, P267, DOI 10.1007/s00401-015-1503-3
   TERRY RD, 1963, J NEUROPATH EXP NEUR, V22, P629, DOI 10.1097/00005072-196310000-00005
   Tuttle MD, 2016, NAT STRUCT MOL BIOL, V23, P409, DOI 10.1038/nsmb.3194
   von Bergen M, 2000, P NATL ACAD SCI USA, V97, P5129, DOI 10.1073/pnas.97.10.5129
   Wälti MA, 2016, P NATL ACAD SCI USA, V113, PE4976, DOI 10.1073/pnas.1600749113
   Wasmer C, 2008, SCIENCE, V319, P1523, DOI 10.1126/science.1151839
   WILCOCK GK, 1982, J NEUROL SCI, V56, P343, DOI 10.1016/0022-510X(82)90155-1
   WISCHIK CM, 1988, P NATL ACAD SCI USA, V85, P4884, DOI 10.1073/pnas.85.13.4884
   WISCHIK CM, 1988, P NATL ACAD SCI USA, V85, P4506, DOI 10.1073/pnas.85.12.4506
   Xie C, 2015, J NEUROCHEM, V135, P19, DOI 10.1111/jnc.13228
   YAGISHITA S, 1981, ACTA NEUROPATHOL, V54, P239, DOI 10.1007/BF00687747
   Zhang K, 2016, J STRUCT BIOL, V193, P1, DOI 10.1016/j.jsb.2015.11.003
   Zheng SQ, 2017, NAT METHODS, V14, P331, DOI 10.1038/nmeth.4193
NR 57
TC 1453
Z9 1690
U1 15
U2 593
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 13
PY 2017
VL 547
IS 7662
BP 185
EP +
DI 10.1038/nature23002
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FA3AX
UT WOS:000405314500032
PM 28678775
DA 2026-03-09
ER

PT J
AU Panigrahi, P
   Parida, S
   Nanda, NC
   Satpathy, R
   Pradhan, L
   Chandel, DS
   Baccaglini, L
   Mohapatra, A
   Mohapatra, SS
   Misra, PR
   Chaudhry, R
   Chen, HGH
   Johnson, JA
   Morris, JG
   Paneth, N
   Gewolb, IH
AF Panigrahi, Pinaki
   Parida, Sailajanandan
   Nanda, Nimai C.
   Satpathy, Radhanath
   Pradhan, Lingaraj
   Chandel, Dinesh S.
   Baccaglini, Lorena
   Mohapatra, Arjit
   Mohapatra, Subhranshu S.
   Misra, Pravas R.
   Chaudhry, Rama
   Chen, Hegang H.
   Johnson, Judith A.
   Morris, J. Glenn, Jr.
   Paneth, Nigel
   Gewolb, Ira H.
TI A randomized synbiotic trial to prevent sepsis among infants in rural India
SO NATURE
LA English
DT Article
ID community-acquired pneumonia; late-onset sepsis; necrotizing enterocolitis; lactobacillus-plantarum; preterm infants; colonization; microflora; infection; country; plasmid
AB Sepsis in early infancy results in one million annual deaths worldwide, most of them in developing countries. No efficient means of prevention is currently available. Here we report on a randomized, double-blind, placebo-controlled trial of an oral synbiotic preparation (Lactobacillus plantarum plus fructooligosaccharide) in rural Indian newborns. We enrolled 4,556 infants that were at least 2,000 g at birth, at least 35 weeks of gestation, and with no signs of sepsis or other morbidity, and monitored them for 60 days. We show a significant reduction in the primary outcome (combination of sepsis and death) in the treatment arm (risk ratio 0.60, 95% confidence interval 0.48-0.74), with few deaths (4 placebo, 6 synbiotic). Significant reductions were also observed for culture-positive and culture-negative sepsis and lower respiratory tract infections. These findings suggest that a large proportion of neonatal sepsis in developing countries could be effectively prevented using a synbiotic containing L. plantarum ATCC-202195.
C1 [Panigrahi, Pinaki; Baccaglini, Lorena] Univ Nebraska Med Ctr, Coll Publ Hlth, Ctr Global Hlth & Dev, Dept Epidemiol, Omaha, NE 68198 USA.
   [Panigrahi, Pinaki] Univ Nebraska Med Ctr, Coll Publ Hlth, Ctr Global Hlth & Dev, Dept Pediat, Omaha, NE 68198 USA.
   [Parida, Sailajanandan] SCB Med Coll, Dept Pediat, Cuttack, Odisha, India.
   [Nanda, Nimai C.] Ispat Gen Hosp, Dept Pediat, Rourkela, Odisha, India.
   [Satpathy, Radhanath; Mohapatra, Arjit; Mohapatra, Subhranshu S.; Misra, Pravas R.] Asian Inst Publ Hlth, Bhubaneswar, Odisha, India.
   [Pradhan, Lingaraj] Capital Hosp, Dept Pediat, Bhubaneswar, Odisha, India.
   [Chandel, Dinesh S.] Univ Nebraska Med Ctr, Coll Publ Hlth, Ctr Global Hlth & Dev, Dept Environm Agr & Occupat Hlth, Omaha, NE USA.
   [Chaudhry, Rama] All India Inst Med Sci, Dept Microbiol, New Delhi, India.
   [Chen, Hegang H.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA.
   [Johnson, Judith A.; Morris, J. Glenn, Jr.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA.
   [Paneth, Nigel] Michigan State Univ, Coll Human Med, Dept Epidemiol, E Lansing, MI 48824 USA.
   [Paneth, Nigel] Michigan State Univ, Coll Human Med, Dept Pediat, E Lansing, MI 48824 USA.
   [Paneth, Nigel] Michigan State Univ, Coll Human Med, Dept Human Dev, E Lansing, MI 48824 USA.
   [Gewolb, Ira H.] Michigan State Univ, Coll Human Med, Div Neonatol, E Lansing, MI 48824 USA.
C3 University of Nebraska System; University of Nebraska Medical Center; University of Nebraska System; University of Nebraska Medical Center; Srirama Chandra Bhanja Medical College & Hospital; University of Nebraska System; University of Nebraska Medical Center; All India Institute of Medical Sciences (AIIMS) New Delhi; University System of Maryland; University of Maryland Baltimore; State University System of Florida; University of Florida; Michigan State University; Michigan State University College of Human Medicine; Michigan State University; Michigan State University College of Human Medicine; Michigan State University; Michigan State University College of Human Medicine; Michigan State University; Michigan State University College of Human Medicine
RP Panigrahi, P (corresponding author), Univ Nebraska Med Ctr, Coll Publ Hlth, Ctr Global Hlth & Dev, Dept Epidemiol, Omaha, NE 68198 USA.; Panigrahi, P (corresponding author), Univ Nebraska Med Ctr, Coll Publ Hlth, Ctr Global Hlth & Dev, Dept Pediat, Omaha, NE 68198 USA.
EM ppanigrahi@unmc.edu
FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, USA [U01 HD 40574, R01 HD 53719]
NR 51
TC 393
Z9 458
U1 5
U2 85
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 24
PY 2017
VL 548
IS 7668
BP 407
EP +
DI 10.1038/nature23480
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FE5VI
UT WOS:000408279000029
PM 28813414
DA 2026-03-09
ER

PT J
AU Ho, TT
   Warr, MR
   Adelman, ER
   Lansinger, OM
   Flach, J
   Verovskaya, EV
   Figueroa, ME
   Passegué, E
AF Ho, Theodore T.
   Warr, Matthew R.
   Adelman, Emmalee R.
   Lansinger, Olivia M.
   Flach, Johanna
   Verovskaya, Evgenia V.
   Figueroa, Maria E.
   Passegue, Emmanuelle
TI Autophagy maintains the metabolism and function of young and old stem cells
SO NATURE
LA English
DT Article
ID progenitors; modulation; mechanisms
AB With age, haematopoietic stem cells lose their ability to regenerate the blood system, and promote disease development. Autophagy is associated with health and longevity, and is critical for protecting haematopoietic stem cells from metabolic stress. Here we show that loss of autophagy in haematopoietic stem cells causes accumulation of mitochondria and an activated metabolic state, which drives accelerated myeloid differentiation mainly through epigenetic deregulations, and impairs haematopoietic stem-cell self-renewal activity and regenerative potential. Strikingly, most haematopoietic stem cells in aged mice share these altered metabolic and functional features. However, approximately one-third of aged haematopoietic stem cells exhibit high autophagy levels and maintain a low metabolic state with robust long-term regeneration potential similar to healthy young haematopoietic stem cells. Our results demonstrate that autophagy actively suppresses haematopoietic stem-cell metabolism by clearing active, healthy mitochondria to maintain quiescence and stemness, and becomes increasingly necessary with age to preserve the regenerative capacity of old haematopoietic stem cells.
C1 [Ho, Theodore T.; Warr, Matthew R.; Lansinger, Olivia M.; Flach, Johanna; Verovskaya, Evgenia V.; Passegue, Emmanuelle] Univ Calif San Francisco, Dept Med, Hem Onc Div, Eli & Edythe Broad,Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA.
   [Adelman, Emmalee R.; Figueroa, Maria E.] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA.
   [Figueroa, Maria E.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Dept Human Genet, Miami, FL 33136 USA.
   [Passegue, Emmanuelle] Columbia Univ, Dept Genet & Dev, Sch Med, Columbia Stem Cell Initiat, New York, NY 10032 USA.
C3 University of California System; University of California San Francisco; University of Michigan System; University of Michigan; University of Miami; Columbia University
RP Passegué, E (corresponding author), Univ Calif San Francisco, Dept Med, Hem Onc Div, Eli & Edythe Broad,Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA.; Passegué, E (corresponding author), Columbia Univ, Dept Genet & Dev, Sch Med, Columbia Stem Cell Initiat, New York, NY 10032 USA.
EM passeguee@stemcell.ucsf.edu
FU AHA [T32GM008284]; LLS Special Fellow Award; Netherlands Organisation for Scientific Research (NWO) Rubicon Fellowship; BD Biosciences Stem Cell grant; National Institutes of Health [R01CA184014, P30DK063720]; Program for Breakthrough Biomedical Research New Frontier Research Award; Glenn Foundation Research Award; Leukemia & Lymphoma Society;  [T32AG000114]; National Institute of General Medical Sciences [T32GM008284] Funding Source: NIH RePORTER; National Institute on Aging [T32AG000114] Funding Source: NIH RePORTER
NR 41
TC 698
Z9 798
U1 6
U2 279
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 9
PY 2017
VL 543
IS 7644
BP 205
EP +
DI 10.1038/nature21388
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0GQ
UT WOS:000395688700031
PM 28241143
DA 2026-03-09
ER

PT J
AU Browning, TJ
   Achterberg, EP
   Rapp, I
   Engel, A
   Bertrand, EM
   Tagliabue, A
   Moore, CM
AF Browning, Thomas J.
   Achterberg, Eric P.
   Rapp, Insa
   Engel, Anja
   Bertrand, Erin M.
   Tagliabue, Alessandro
   Moore, C. Mark
TI Nutrient co-limitation at the boundary of an oceanic gyre
SO NATURE
LA English
DT Article
ID limiting resources; iron; phytoplankton; phosphorus; nitrogen; cobalt; vitamin-b-12; productivity; colimitation; framework
AB Nutrient limitation of oceanic primary production exerts a fundamental control on marine food webs and the flux of carbon into the deep ocean(1). The extensive boundaries of the oligotrophic sub-tropical gyres collectively define the most extreme transition in ocean productivity, but little is known about nutrient limitation in these zones(1-4). Here we present the results of full-factorial nutrient amendment experiments conducted at the eastern boundary of the South Atlantic gyre. We find extensive regions in which the addition of nitrogen or iron individually resulted in no significant phytoplankton growth over 48 hours. However, the addition of both nitrogen and iron increased concentrations of chlorophyll a by up to approximately 40-fold, led to diatom proliferation, and reduced community diversity. Once nitrogen-iron co-limitation had been alleviated, the addition of cobalt or cobalt-containing vitamin B12 could further enhance chlorophyll a yields by up to threefold. Our results suggest that nitrogen-iron co-limitation is pervasive in the ocean, with other micronutrients also approaching co-deficiency. Such multi-nutrient limitations potentially increase phytoplankton community diversity.
C1 [Browning, Thomas J.; Achterberg, Eric P.; Rapp, Insa; Engel, Anja] GEOMAR Helmholtz Ctr Ocean Res, Marine Biogeochem Div, D-24148 Kiel, Germany.
   [Bertrand, Erin M.] Dalhousie Univ, Dept Biol, Halifax, NS B3H 4R2, Canada.
   [Tagliabue, Alessandro] Univ Liverpool, Sch Environm Sci, Dept Earth Ocean & Ecol Sci, Liverpool L69 3GP, Merseyside, England.
   [Moore, C. Mark] Univ Southampton, Natl Oceanog Ctr Southampton, Ocean & Earth Sci, Southampton SO14 3ZH, Hants, England.
C3 Helmholtz Association; GEOMAR Helmholtz Center for Ocean Research Kiel; Dalhousie University; University of Liverpool; NERC National Oceanography Centre; University of Southampton
RP Browning, TJ (corresponding author), GEOMAR Helmholtz Ctr Ocean Res, Marine Biogeochem Div, D-24148 Kiel, Germany.
EM tbrowning@geomar.de
FU Marie Sklodowska-Curie Postdoctoral European Fellowship (OceanLiNES) [658035]; European Commission (OCEAN-CERTAIN) [603773]; Deutsche Forschungsgemeinschaft (DFG); European Research Council [724289]; Marie Curie Actions (MSCA) [658035] Funding Source: Marie Curie Actions (MSCA); European Research Council (ERC) [724289] Funding Source: European Research Council (ERC)
NR 30
TC 167
Z9 193
U1 8
U2 200
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 9
PY 2017
VL 551
IS 7679
BP 242
EP +
DI 10.1038/nature24063
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM1KF
UT WOS:000414734200050
PM 29088696
DA 2026-03-09
ER

PT J
AU Kodigala, A
   Lepetit, T
   Gu, Q
   Bahari, B
   Fainman, Y
   Kanté, B
AF Kodigala, Ashok
   Lepetit, Thomas
   Gu, Qing
   Bahari, Babak
   Fainman, Yeshaiahu
   Kante, Boubacar
TI Lasing action from photonic bound states in continuum
SO NATURE
LA English
DT Article
ID light; laser
AB In 1929, only three years after the advent of quantum mechanics, von Neumann and Wigner showed that Schrodinger's equation can have bound states above the continuum threshold(1). These peculiar states, called bound states in the continuum (BICs), manifest themselves as resonances that do not decay. For several decades afterwards the idea lay dormant, regarded primarily as a mathematical curiosity. In 1977, Herrick and Stillinger revived interest in BICs when they suggested that BICs could be observed in semiconductor superlattices(2,3). BICs arise naturally from Feshbach's quantum mechanical theory of resonances, as explained by Friedrich and Wintgen, and are thus more physical than initially realized(4). Recently, it was realized that BICs are intrinsically a wave phenomenon and are thus not restricted to the realm of quantum mechanics. They have since been shown to occur in many different fields of wave physics including acoustics, microwaves and nanophotonics(5-16). However, experimental observations of BICs have been limited to passive systems and the realization of BIC lasers has remained elusive. Here we report, at room temperature, lasing action from an optically pumped BIC cavity. Our results show that the lasing wavelength of the fabricated BIC cavities, each made of an array of cylindrical nanoresonators suspended in air, scales with the radii of the nanoresonators according to the theoretical prediction for the BIC mode. Moreover, lasing action from the designed BIC cavity persists even after scaling down the array to as few as 8-by-8 nanoresonators. BIC lasers open up new avenues in the study of light-matter interaction because they are intrinsically connected to topological charges(17) and represent natural vector beam sources (that is, there are several possible beam shapes)(18), which are highly sought after in the fields of optical trapping, biological sensing and quantum information.
C1 [Kodigala, Ashok; Lepetit, Thomas; Gu, Qing; Bahari, Babak; Fainman, Yeshaiahu; Kante, Boubacar] Univ Calif San Diego, Dept Elect & Comp Engn, La Jolla, CA 92093 USA.
C3 University of California System; University of California San Diego
RP Kanté, B (corresponding author), Univ Calif San Diego, Dept Elect & Comp Engn, La Jolla, CA 92093 USA.
FU National Science Foundation Career Award [ECCS-1554021]; Office of Naval Research Multi-University Research Initiative [N00014-13-1-0678]; University of California San Diego; National Science Foundation [ECCS-1542148]; Directorate For Engineering; Div Of Electrical, Commun & Cyber Sys [1507146, 1405234] Funding Source: National Science Foundation
NR 29
TC 1199
Z9 1325
U1 68
U2 818
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 12
PY 2017
VL 541
IS 7636
BP 196
EP 199
DI 10.1038/nature20799
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6PI
UT WOS:000396125500036
PM 28079064
DA 2026-03-09
ER

PT J
AU Zhang, H
   Dasbiswas, K
   Ludwig, NB
   Han, G
   Lee, B
   Vaikuntanathan, S
   Talapin, DV
AF Zhang, Hao
   Dasbiswas, Kinjal
   Ludwig, Nicholas B.
   Han, Gang
   Lee, Byeongdu
   Vaikuntanathan, Suri
   Talapin, Dmitri V.
TI Stable colloids in molten inorganic salts
SO NATURE
LA English
DT Article
ID surface; nanocrystals; semiconductor; nanoparticles; stability; hydration; halide; route
AB A colloidal solution is a homogeneous dispersion of particles or droplets of one phase (solute) in a second, typically liquid, phase (solvent). Colloids are ubiquitous in biological, chemical and technological processes(1,2), homogenizing highly dissimilar constituents. To stabilize a colloidal system against coalescence and aggregation, the surface of each solute particle is engineered to impose repulsive forces strong enough to overpower van der Waals attraction and keep the particles separated from each other(2). Electrostatic stabilization(3,4) of charged solutes works well in solvents with high dielectric constants, such as water (dielectric constant of 80). In contrast, colloidal stabilization in solvents with low polarity, such as hexane (dielectric constant of about 2), can be achieved by decorating the surface of each particle of the solute with molecules (surfactants) containing flexible, brush-like chains(2,5). Here we report a class of colloidal systems in which solute particles (including metals, semiconductors and magnetic materials) form stable colloids in various molten inorganic salts. The stability of such colloids cannot be explained by traditional electrostatic and steric mechanisms. Screening of many solute-solvent combinations shows that colloidal stability can be traced to the strength of chemical bonding at the solute-solvent interface. Theoretical analysis and molecular dynamics modelling suggest that a layer of surface-bound solvent ions produces long-ranged charge-density oscillations in the molten salt around solute particles, preventing their aggregation. Colloids composed of inorganic particles in inorganic melts offer opportunities for introducing colloidal techniques to solid-state science and engineering applications.
C1 [Zhang, Hao; Dasbiswas, Kinjal; Ludwig, Nicholas B.; Vaikuntanathan, Suri; Talapin, Dmitri V.] Univ Chicago, Dept Chem, Chicago, IL 60637 USA.
   [Zhang, Hao; Dasbiswas, Kinjal; Ludwig, Nicholas B.; Vaikuntanathan, Suri; Talapin, Dmitri V.] Univ Chicago, James Franck Inst, Chicago, IL 60637 USA.
   [Han, Gang] Univ Massachusetts, Sch Med, Dept Mol Pharmacol & Biochem, Worcester, MA 01605 USA.
   [Lee, Byeongdu] Argonne Natl Lab, Adv Photon Source, Argonne, IL 60439 USA.
   [Talapin, Dmitri V.] Argonne Natl Lab, Ctr Nanoscale Mat, Argonne, IL 60439 USA.
C3 University of Chicago; University of Chicago; University of Massachusetts System; University of Massachusetts Worcester; United States Department of Energy (DOE); Argonne National Laboratory; United States Department of Energy (DOE); Argonne National Laboratory
RP Talapin, DV (corresponding author), Univ Chicago, Dept Chem, Chicago, IL 60637 USA.; Talapin, DV (corresponding author), Univ Chicago, James Franck Inst, Chicago, IL 60637 USA.; Talapin, DV (corresponding author), Argonne Natl Lab, Ctr Nanoscale Mat, Argonne, IL 60439 USA.
EM dvtalapin@uchicago.edu
FU National Science Foundation (NSF) [DMR-1611371]; Air Force Office of Scientific Research (AFOSR) [FA9550-14-1-0367]; Department of Defense (DOD) Office of Naval Research [N00014-13-1-0490]; II-VI Foundation; National Institutes of Health (NIH) [R01 MH103133]; Human Frontier Science Program [RGY-0090/2014]; University of Chicago Research Computing Center; NSF MRSEC [DMR-14-20703]; Center for Nanoscale Materials and Advanced Photon Source; DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]; Division Of Materials Research; Direct For Mathematical & Physical Scien [1611371] Funding Source: National Science Foundation
NR 37
TC 188
Z9 219
U1 8
U2 466
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 16
PY 2017
VL 542
IS 7641
BP 328
EP +
DI 10.1038/nature21041
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2LQ
UT WOS:000394451600032
PM 28202966
DA 2026-03-09
ER

PT J
AU Jeon, MY
   Kim, D
   Kumar, P
   Lee, PS
   Rangnekar, N
   Bai, P
   Shete, M
   Elyassi, B
   Lee, HS
   Narasimharao, K
   Basahel, SN
   Al-Thabaiti, S
   Xu, WQ
   Cho, HJ
   Fetisov, EO
   Thyagarajan, R
   DeJaco, RF
   Fan, W
   Mkhoyan, KA
   Siepmann, JI
   Tsapatsis, M
AF Jeon, Mi Young
   Kim, Donghun
   Kumar, Prashant
   Lee, Pyung Soo
   Rangnekar, Neel
   Bai, Peng
   Shete, Meera
   Elyassi, Bahman
   Lee, Han Seung
   Narasimharao, Katabathini
   Basahel, Sulaiman Nasir
   Al-Thabaiti, Shaeel
   Xu, Wenqian
   Cho, Hong Je
   Fetisov, Evgenii O.
   Thyagarajan, Raghuram
   DeJaco, Robert F.
   Fan, Wei
   Mkhoyan, K. Andre
   Siepmann, J. Ilja
   Tsapatsis, Michael
TI Ultra-selective high-flux membranes from directly synthesized zeolite nanosheets
SO NATURE
LA English
DT Article
ID oriented mfi membranes; hydrothermal synthesis; secondary growth; crystal-growth; intergrowth; performance; permeation; silicalite; nucleation
AB A zeolite with structure type MFI1,2 is an aluminosilicate or silicate material that has a three-dimensionally connected pore network, which enables molecular recognition in the size range 0.5-0.6 nm. These micropore dimensions are relevant for many valuable chemical intermediates, and therefore MFI-type zeolites are widely used in the chemical industry as selective catalysts or adsorbents(3-5). As with all zeolites, strategies to tailor them for specific applications include controlling their crystal size and shape(5-8). Nanometre-thick MFI crystals (nanosheets) have been introduced in pillared(9) and self-pillared (intergrown)(10) architectures, offering improved mass-transfer characteristics for certain adsorption and catalysis applications(11-14). Moreover, single (non-intergrown and nonlayered) nanosheets have been used to prepare thin membranes(15,16) that could be used to improve the energy efficiency of separation processes(17). However, until now, single MFI nanosheets have been prepared using a multi-step approach based on the exfoliation of layered MFI9,15, followed by centrifugation to remove non-exfoliated particles(18). This top-down method is time-consuming, costly and low-yield and it produces fragmented nanosheets with submicrometre lateral dimensions. Alternatively, direct (bottom-up) synthesis could produce high-aspect-ratio zeolite nanosheets, with improved yield and at lower cost. Here we use a nanocrystal-seeded growth method triggered by a single rotational intergrowth to synthesize high-aspect-ratio MFI nanosheets with a thickness of 5 nanometres (2.5 unit cells). These high-aspect-ratio nanosheets allow the fabrication of thin and defect-free coatings that effectively cover porous substrates. These coatings can be intergrown to produce high-flux and ultra-selective MFI membranes that compare favourably with other MFI membranes prepared from existing MFI materials (such as exfoliated nanosheets or nanocrystals).
C1 [Jeon, Mi Young; Kim, Donghun; Kumar, Prashant; Lee, Pyung Soo; Rangnekar, Neel; Bai, Peng; Shete, Meera; Elyassi, Bahman; Lee, Han Seung; DeJaco, Robert F.; Mkhoyan, K. Andre; Tsapatsis, Michael] Univ Minnesota, Dept Chem Engn & Mat Sci, 421 Washington Ave SE, Minneapolis, MN 55455 USA.
   [Bai, Peng; Fetisov, Evgenii O.; Thyagarajan, Raghuram; Siepmann, J. Ilja] Univ Minnesota, Dept Chem, 207 Pleasant St SE, Minneapolis, MN 55455 USA.
   [Bai, Peng; Fetisov, Evgenii O.; Thyagarajan, Raghuram; Siepmann, J. Ilja] Univ Minnesota, Chem Theory Ctr, Minneapolis, MN 55455 USA.
   [Narasimharao, Katabathini; Basahel, Sulaiman Nasir; Al-Thabaiti, Shaeel] King Abdulaziz Univ, Dept Chem, Fac Sci, Jeddah 21589, Saudi Arabia.
   [Xu, Wenqian] Argonne Natl Lab, Adv Photon Source, Xray Sci Div, Argonne, IL 60439 USA.
   [Cho, Hong Je; Fan, Wei] Univ Massachusetts, Dept Chem Engn, Amherst, MA 01003 USA.
   [Lee, Pyung Soo] KRICT, Ctr Membrane, Adv Green Chem Mat Div, Daejeon 34114, South Korea.
C3 University of Minnesota System; University of Minnesota Twin Cities; University of Minnesota System; University of Minnesota Twin Cities; University of Minnesota System; University of Minnesota Twin Cities; King Abdulaziz University; United States Department of Energy (DOE); Argonne National Laboratory; University of Massachusetts System; University of Massachusetts Amherst; Korea Research Institute of Chemical Technology (KRICT)
RP Kim, D; Lee, PS; Tsapatsis, M (corresponding author), Univ Minnesota, Dept Chem Engn & Mat Sci, 421 Washington Ave SE, Minneapolis, MN 55455 USA.; Lee, PS (corresponding author), KRICT, Ctr Membrane, Adv Green Chem Mat Div, Daejeon 34114, South Korea.
EM kimx1408@umn.edu; zeolite@krict.re.kr; tsapa001@umn.edu
FU ARPA-E programme of the US Department of Energy [DE-AR0000338 (0670-3240)]; Center for Gas Separations Relevant to Clean Energy Technologies, an Energy Frontier Research Center - US Department of Energy, Office of Science, Basic Energy Sciences [DE-SC0001015]; US Department of Energy, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences and Biosciences [DEFG02-12ER16362]; NSF through the MRSEC programme; DOE Office of Science [DE-AC02-06CH11357]; Office of Science of the Department of Energy [DE-AC02-06CH11357]
NR 53
TC 487
Z9 554
U1 32
U2 1344
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 30
PY 2017
VL 543
IS 7647
BP 690
EP +
DI 10.1038/nature21421
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EP8IS
UT WOS:000397619700050
PM 28297708
DA 2026-03-09
ER

PT J
AU Niewoehner, O
   Garcia-Doval, C
   Rostol, JT
   Berk, C
   Schwede, F
   Bigler, L
   Hall, J
   Marraffini, LA
   Jinek, M
AF Niewoehner, Ole
   Garcia-Doval, Carmela
   Rostol, Jakob T.
   Berk, Christian
   Schwede, Frank
   Bigler, Laurent
   Hall, Jonathan
   Marraffini, Luciano A.
   Jinek, Martin
TI Type III CRISPR-Cas systems produce cyclic oligoadenylate second messengers
SO NATURE
LA English
DT Article
ID effector complex; thermus-thermophilus; dna cleavage; protein; immunity; recognition; endoribonuclease; classification; degradation; bacteria
AB In many prokaryotes, type III clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated (Cas) systems detect and degrade invasive genetic elements by an RNA-guided, RNA-targeting multisubunit interference complex. The CRISPR-associated protein Csm6 additionally contributes to interference by functioning as a standalone RNase that degrades invader RNA transcripts, but the mechanism linking invader sensing to Csm6 activity is not understood. Here we show that Csm6 proteins are activated through a second messenger generated by the type III interference complex. Upon target RNA binding by the interference complex, its Cas10 subunit converts ATP into a cyclic oligoadenylate product, which allosterically activates Csm6 by binding to its CRISPR-associated Rossmann fold (CARF) domain. CARF domain mutations that abolish allosteric activation inhibit Csm6 activity in vivo, and mutations in the Cas10 Palm domain phenocopy loss of Csm6. Together, these results point to an unprecedented mechanism for regulation of CRISPR interference that bears striking conceptual similarity to oligoadenylate signalling in mammalian innate immunity.
C1 [Niewoehner, Ole; Garcia-Doval, Carmela; Jinek, Martin] Univ Zurich, Dept Biochem, Winterthurerstr 190, CH-8057 Zurich, Switzerland.
   [Rostol, Jakob T.; Marraffini, Luciano A.] Rockefeller Univ, Bacteriol Lab, 1230 York Ave, New York, NY 10065 USA.
   [Berk, Christian; Hall, Jonathan] Inst Pharmaceut Sci, Dept Chem & Appl Biosci, Vladimir Prelog Weg 1-5-10, CH-8093 Zurich, Switzerland.
   [Schwede, Frank] BIOLOG Life Sci Inst GmbH, Flughafendamm 9a, D-28199 Bremen, Germany.
   [Bigler, Laurent] Univ Zurich, Dept Chem, Winterthurerstr 190, CH-8057 Zurich, Switzerland.
C3 University of Zurich; Rockefeller University; University of Zurich
RP Jinek, M (corresponding author), Univ Zurich, Dept Biochem, Winterthurerstr 190, CH-8057 Zurich, Switzerland.
EM jinek@bioc.uzh.ch
FU Swiss National Science Foundation [SNSF 31003A_149393]; Swiss National Competence Center for Research (NCCR) 'RNA Disease'; European Molecular Biology Organization; Boehringer Ingelheim Fonds PhD fellowship; Rita Allen Scholars Program; Burroughs Wellcome Fund PATH award; National Institutes of Health Director's New Innovator Award [1DP2AI104556-01]; Howard Hughes Medical Institute-Simons Faculty Scholar Award
NR 41
TC 358
Z9 441
U1 1
U2 78
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 31
PY 2017
VL 548
IS 7669
BP 543
EP +
DI 10.1038/nature23467
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FF2BO
UT WOS:000408703100029
PM 28722012
DA 2026-03-09
ER

PT J
AU Lefrançais, E
   Ortiz-Muñoz, G
   Caudrillier, A
   Mallavia, B
   Liu, FC
   Sayah, DM
   Thornton, EE
   Headley, MB
   David, T
   Coughlin, SR
   Krummel, MF
   Leavitt, AD
   Passegué, E
   Looney, MR
AF Lefrancais, Emma
   Ortiz-Munoz, Guadalupe
   Caudrillier, Axelle
   Mallavia, Benat
   Liu, Fengchun
   Sayah, David M.
   Thornton, Emily E.
   Headley, Mark B.
   David, Tovo
   Coughlin, Shaun R.
   Krummel, Matthew F.
   Leavitt, Andrew D.
   Passegue, Emmanuelle
   Looney, Mark R.
TI The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors
SO NATURE
LA English
DT Article
ID circulating megakaryocytes; mature megakaryocytes; cells; visualization
AB Platelets are critical for haemostasis, thrombosis, and inflammatory responses(1,2), but the events that lead to mature platelet production remain incompletely understood(3). The bone marrow has been proposed to be a major site of platelet production, although there is indirect evidence that the lungs might also contribute to platelet biogenesis(4-7). Here, by directly imaging the lung microcirculation in mice(8), we show that a large number of megakaryocytes circulate through the lungs, where they dynamically release platelets. Megakaryocytes that release platelets in the lungs originate from extrapulmonary sites such as the bone marrow; we observed large megakaryocytes migrating out of the bone marrow space. The contribution of the lungs to platelet biogenesis is substantial, accounting for approximately 50% of total platelet production or 10 million platelets per hour. Furthermore, we identified populations of mature and immature megakaryocytes along with haematopoietic progenitors in the extravascular spaces of the lungs. Under conditions of thrombocytopenia and relative stem cell deficiency in the bone marrow(9), these progenitors can migrate out of the lungs, repopulate the bone marrow, completely reconstitute blood platelet counts, and contribute to multiple haematopoietic lineages. These results identify the lungs as a primary site of terminal platelet production and an organ with considerable haematopoietic potential.
C1 [Lefrancais, Emma; Ortiz-Munoz, Guadalupe; Caudrillier, Axelle; Mallavia, Benat; Liu, Fengchun; Leavitt, Andrew D.; Passegue, Emmanuelle; Looney, Mark R.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.
   [Sayah, David M.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA.
   [Thornton, Emily E.; Headley, Mark B.; Krummel, Matthew F.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA.
   [David, Tovo; Coughlin, Shaun R.] Univ Calif San Francisco, Inst Cardiovasc Res, San Francisco, CA 94143 USA.
   [Looney, Mark R.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA.
C3 University of California System; University of California San Francisco; University of California System; University of California Los Angeles; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco
RP Looney, MR (corresponding author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.; Looney, MR (corresponding author), Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA.
EM mark.looney@ucsf.edu
FU NIH [HL092471, HL107386, HL130324]; UCSF Nina Ireland Program in Lung Health; UCSF Program for Breakthrough Biomedical Research; National Heart Lung and Blood Institute [R35HL135763] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [T32AI007334] Funding Source: NIH RePORTER
NR 30
TC 851
Z9 1035
U1 7
U2 237
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 6
PY 2017
VL 544
IS 7648
BP 105
EP +
DI 10.1038/nature21706
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EQ8GQ
UT WOS:000398323300042
PM 28329764
DA 2026-03-09
ER

PT J
AU Hirsch, T
   Rothoeft, T
   Teig, N
   Bauer, JW
   Pellegrini, G
   De Rosa, L
   Scaglione, D
   Reichelt, J
   Klausegger, A
   Kneisz, D
   Romano, O
   Seconetti, AS
   Contin, R
   Enzo, E
   Jurman, I
   Carulli, S
   Jacobsen, F
   Luecke, T
   Lehnhardt, M
   Fischer, M
   Kueckelhaus, M
   Quaglino, D
   Morgante, M
   Bicciato, S
   Bondanza, S
   De Luca, M
AF Hirsch, Tobias
   Rothoeft, Tobias
   Teig, Norbert
   Bauer, Johann W.
   Pellegrini, Graziella
   De Rosa, Laura
   Scaglione, Davide
   Reichelt, Julia
   Klausegger, Alfred
   Kneisz, Daniela
   Romano, Oriana
   Seconetti, Alessia Secone
   Contin, Roberta
   Enzo, Elena
   Jurman, Irena
   Carulli, Sonia
   Jacobsen, Frank
   Luecke, Thomas
   Lehnhardt, Marcus
   Fischer, Meike
   Kueckelhaus, Maximilian
   Quaglino, Daniela
   Morgante, Michele
   Bicciato, Silvio
   Bondanza, Sergio
   De Luca, Michele
TI Regeneration of the entire human epidermis using transgenic stem cells
SO NATURE
LA English
DT Article
ID gene-therapy; epidermolysis-bullosa; clonal analysis; transplantation; burns; keratinocyte; package; cancer; safety
AB Junctional epidermolysis bullosa (JEB) is a severe and often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving patients with JEB develop chronic wounds to the skin and mucosa, which impair their quality of life and lead to skin cancer. Here we show that autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of JEB. The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection. Clonal tracing showed that the human epidermis is sustained not by equipotent progenitors, but by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew in vitro and in vivo and produce progenitors that replenish terminally differentiated keratinocytes. This study provides a blueprint that can be applied to other stem cell-mediated combined ex vivo cell and gene therapies.
C1 [Hirsch, Tobias; Lehnhardt, Marcus; Kueckelhaus, Maximilian] Ruhr Univ Bochum, BG Univ Hosp Bergmannsheil, Burn Ctr, Dept Plast Surg, D-44789 Bochum, Germany.
   [Rothoeft, Tobias; Teig, Norbert; Fischer, Meike] Ruhr Univ Bochum, Univ Childrens Hosp, Dept Neonatol & Pediat Intens Care, D-44791 Bochum, Germany.
   [Bauer, Johann W.; Reichelt, Julia; Klausegger, Alfred; Kneisz, Daniela] Paracelsus Med Univ, Univ Hosp, EB House Austria & Dept Dermatol, A-5020 Salzburg, Austria.
   [Pellegrini, Graziella] Univ Modena & Reggio Emilia, Dept Surg Med Dent & Morphol Sci, I-41124 Modena, Italy.
   [Pellegrini, Graziella; De Rosa, Laura; Seconetti, Alessia Secone; Contin, Roberta; Enzo, Elena; De Luca, Michele] Univ Modena & Reggio Emilia, Dept Life Sci, Ctr Regenerat Med Stefano Ferrari, I-41125 Modena, Italy.
   [Scaglione, Davide] IGA Technol Serv Srl, I-33100 Udine, Italy.
   [Romano, Oriana; Quaglino, Daniela; Bicciato, Silvio] Univ Modena & Reggio Emilia, Dept Life Sci, I-41125 Modena, Italy.
   [Jurman, Irena; Morgante, Michele] Univ Udine, Ist Genom Appl, I-33100 Udine, Italy.
   [Jurman, Irena; Morgante, Michele] Univ Udine, Dipartimento Sci Agroalimentari Ambientail & Anim, I-33100 Udine, Italy.
   [Carulli, Sonia; Bondanza, Sergio] Holostem Terapie Avanzate Srl, I-41125 Modena, Italy.
   [Luecke, Thomas] Ruhr Univ Bochum, Univ Childrens Hosp, Dept Neuropediat, D-44791 Bochum, Germany.
C3 Ruhr University Bochum; Ruhr University Bochum; Paracelsus Private Medical University; Universita di Modena e Reggio Emilia; Universita di Modena e Reggio Emilia; Universita di Modena e Reggio Emilia; University of Udine; University of Udine; Ruhr University Bochum
RP De Luca, M (corresponding author), Univ Modena & Reggio Emilia, Dept Life Sci, Ctr Regenerat Med Stefano Ferrari, I-41125 Modena, Italy.
EM michele.deluca@unimore.it
FU Italian Ministry of Education, University and Research (MIUR) [CTN01_00177_888744]; Regione Emilia-Romagna, Asse 1 POR-FESR; Fondazione Cassa di Risparmio di Modena; DEBRA Sudtirol - Alto Adige; DEBRA Austria; European Research Council (ERC) under European Union [670126-DENOVOSTEM]; ERC under European Union's Seventh Framework Programme [294780-NOVABREED]; Epigenetics Flagship project CNR-MIUR grants
NR 43
TC 513
Z9 597
U1 2
U2 307
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 16
PY 2017
VL 551
IS 7680
BP 327
EP +
DI 10.1038/nature24487
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM8UK
UT WOS:000415365500032
PM 29144448
DA 2026-03-09
ER

PT J
AU Chen, JS
   Dagdas, YS
   Kleinstiver, BP
   Welch, MM
   Sousa, AA
   Harrington, LB
   Sternberg, SH
   Joung, JK
   Yildiz, A
   Doudna, JA
AF Chen, Janice S.
   Dagdas, Yavuz S.
   Kleinstiver, Benjamin P.
   Welch, Moira M.
   Sousa, Alexander A.
   Harrington, Lucas B. .
   Sternberg, Samuel H.
   Joung, J. Keith
   Yildiz, Ahmet
   Doudna, Jennifer A.
TI Enhanced proofreading governs CRISPR-Cas9 targeting accuracy
SO NATURE
LA English
DT Article
ID molecular simulations; dna recognition; cas nucleases; rna; cleavage; complex; endonuclease; specificity
AB The RNA-guided CRISPR-Cas9 nuclease from Streptococcus pyogenes (SpCas9) has been widely repurposed for genome editing1-4. High-fidelity (SpCas9-HF1) and enhanced specificity (eSpCas9(1.1)) variants exhibit substantially reduced off-target cleavage in human cells, but the mechanism of target discrimination and the potential to further improve fidelity are unknown5-9. Here, using single-molecule Frster resonance energy transfer experiments, we show that both SpCas9-HF1 and eSpCas9(1.1) are trapped in an inactive state10 when bound to mismatched targets. We find that a non-catalytic domain within Cas9, REC3, recognizes target complementarity and governs the HNH nuclease to regulate overall catalytic competence. Exploiting this observation, we design a new hyper-accurate Cas9 variant (HypaCas9) that demonstrates high genome-wide specificity without compromising on-target activity in human cells. These results offer a more comprehensive model to rationalize and modify the balance between target recognition and nuclease activation for precision genome editing.
C1 [Chen, Janice S.; Harrington, Lucas B. .; Yildiz, Ahmet; Doudna, Jennifer A.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
   [Dagdas, Yavuz S.] Univ Calif Berkeley, Biophys Grad Grp, Berkeley, CA 94720 USA.
   [Kleinstiver, Benjamin P.; Welch, Moira M.; Sousa, Alexander A.; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Canc Res, Charlestown, MA 02129 USA.
   [Kleinstiver, Benjamin P.; Welch, Moira M.; Sousa, Alexander A.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA 02129 USA.
   [Kleinstiver, Benjamin P.; Joung, J. Keith] Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA.
   [Sternberg, Samuel H.; Doudna, Jennifer A.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
   [Yildiz, Ahmet] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Doudna, Jennifer A.] Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA.
   [Doudna, Jennifer A.] Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA.
   [Sternberg, Samuel H.] Columbia Univ, Dept Biochem & Mol Biophys, 630 W 168th St, New York, NY 10032 USA.
C3 University of California System; University of California Berkeley; University of California System; University of California Berkeley; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; University of California System; University of California Berkeley; University of California System; University of California Berkeley; Howard Hughes Medical Institute; University of California System; University of California Berkeley; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; Columbia University
RP Doudna, JA (corresponding author), Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.; Doudna, JA (corresponding author), Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.; Doudna, JA (corresponding author), Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA.; Doudna, JA (corresponding author), Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA.
EM doudna@berkeley.edu
FU National Science Foundation Graduate Research Fellowships; Banting (Natural Sciences and Engineering Research Council of Canada); Charles A. King Trust Postdoctoral Fellowships; National Institutes of Health [GM094522, GM118773, R35 GM118158]; National Science Foundation [MCB-1617028, MCB-1244557]; Desmond and Ann Heathwood MGH Research Scholar Award; National Human Genome Research Institute [RM1HG009490] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R35GM118158] Funding Source: NIH RePORTER
NR 22
TC 913
Z9 1150
U1 9
U2 347
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 19
PY 2017
VL 550
IS 7676
BP 407
EP +
DI 10.1038/nature24268
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK1NF
UT WOS:000413247900063
PM 28931002
DA 2026-03-09
ER

PT J
AU Prouteau, M
   Desfosses, A
   Sieben, C
   Bourgoint, C
   Mozaffari, NL
   Demurtas, D
   Mitra, AK
   Guichard, P
   Manley, S
   Loewith, R
AF Prouteau, Manoel
   Desfosses, Ambroise
   Sieben, Christian
   Bourgoint, Clelia
   Mozaffari, Nour Lydia
   Demurtas, Davide
   Mitra, Alok K.
   Guichard, Paul
   Manley, Suliana
   Loewith, Robbie
TI TORC1 organized in inhibited domains (TOROIDs) regulate TORC1 activity
SO NATURE
LA English
DT Article
ID 3-dimensional reconstruction; superresolution microscopy; complex; target; growth; cells
AB The target of rapamycin (TOR) is a eukaryotic serine/threonine protein kinase that functions in two distinct complexes, TORC1 and TORC2, to regulate growth and metabolism(1,2). GTPases, responding to signals generated by abiotic stressors, nutrients, and, in metazoans, growth factors, play an important(3) but poorly understood role in TORC1 regulation. Here we report that, in budding yeast, glucose withdrawal (which leads to an acute loss of TORC1 kinase activity(4)) triggers a similarly rapid Rag GTPase-dependent redistribution of TORC1 from being semi-uniform around the vacuolar membrane to a single, vacuole-associated cylindrical structure visible by super-resolution optical microscopy. Three-dimensional reconstructions of cryo-electron micrograph images of these purified cylinders demonstrate that TORC1 oligomerizes into a higher-level hollow helical assembly, which we name a TOROID (TORC1 organized in inhibited domain). Fitting of the recently described mammalian TORC1 structure into our helical map reveals that oligomerization leads to steric occlusion of the active site. Guided by the implications from our reconstruction, we present a TOR1 allele that prevents both TOROID formation and TORC1 inactivation in response to glucose withdrawal, demonstrating that oligomerization is necessary for TORC1 inactivation. Our results reveal a novel mechanism by which Rag GTPases regulate TORC1 activity and suggest that the reversible assembly and/or disassembly of higher-level structures may be an underappreciated mechanism for the regulation of protein kinases.
C1 [Prouteau, Manoel; Bourgoint, Clelia; Mozaffari, Nour Lydia; Loewith, Robbie] Univ Geneva, Dept Mol Biol, 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
   [Prouteau, Manoel; Bourgoint, Clelia; Mozaffari, Nour Lydia; Loewith, Robbie] Univ Geneva, Inst Genet & Genom Geneva iGE3, 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
   [Desfosses, Ambroise; Mitra, Alok K.] Univ Auckland, Sch Biol Sci, Private Bag 92019, Auckland 1010, New Zealand.
   [Sieben, Christian; Mozaffari, Nour Lydia; Manley, Suliana] Ecole Polytech Fed Lausanne, Inst Phys, Lab Expt Biophys, CH-1015 Lausanne, Switzerland.
   [Sieben, Christian; Mozaffari, Nour Lydia; Manley, Suliana; Loewith, Robbie] Univ Geneva, Swiss Natl Ctr Competence Res NCCR Chem Biol, Sci 2, Room 3-308,30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
   [Demurtas, Davide] Ecole Polytech Fed Lausanne, Interdisciplinary Ctr Electron Microscopy, CH-1015 Lausanne, Switzerland.
   [Guichard, Paul] Univ Geneva, Dept Cell Biol, 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
C3 University of Geneva; University of Geneva; University of Auckland; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; University of Geneva; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; University of Geneva
RP Loewith, R (corresponding author), Univ Geneva, Dept Mol Biol, 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.; Loewith, R (corresponding author), Univ Geneva, Inst Genet & Genom Geneva iGE3, 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.; Loewith, R (corresponding author), Univ Geneva, Swiss Natl Ctr Competence Res NCCR Chem Biol, Sci 2, Room 3-308,30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
EM Robbie.Loewith@unige.ch
FU NeSI's collaborator institutions; Ministry of Business, Innovation & Employment's Research Infrastructure programme; Royal Society of New Zealand Marsden; Canton of Geneva; SystemsX; SNSF; European Research Council Consolidator grant program; National Centre for Competence in Research in Chemical Biology
NR 40
TC 85
Z9 97
U1 0
U2 37
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 12
PY 2017
VL 550
IS 7675
BP 265
EP +
DI 10.1038/nature24021
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FJ5YG
UT WOS:000412829500050
PM 28976958
DA 2026-03-09
ER

PT J
AU Wu, CY
   Wolf, WJ
   Levartovsky, Y
   Bechtel, HA
   Martin, MC
   Toste, FD
   Gross, E
AF Wu, Chung-Yeh
   Wolf, William J. .
   Levartovsky, Yehonatan
   Bechtel, Hans A. .
   Martin, Michael C.
   Toste, F. Dean
   Gross, Elad
TI High-spatial-resolution mapping of catalytic reactions on single particles
SO NATURE
LA English
DT Article
ID self-assembled monolayers; n-heterocyclic carbenes; near-field; spectroscopy; nanoparticles; surfaces; gold; reactivity; dynamics; time
AB The critical role in surface reactions and heterogeneous catalysis of metal atoms with low coordination numbers, such as found at atomic steps and surface defects, is firmly established(1,2). But despite the growing availability of tools that enable detailed in situ characterization(3), so far it has not been possible to document this role directly. Surface properties can be mapped with high spatial resolution, and catalytic conversion can be tracked with a clear chemical signature; however, the combination of the two, which would enable high-spatial-resolution detection of reactions on catalytic surfaces, has rarely been achieved. Single-molecule fluorescence spectroscopy has been used to image and characterize single turnover sites at catalytic surfaces(4,5), but is restricted to reactions that generate highly fluorescing product molecules. Herein the chemical conversion of N-heterocyclic carbene molecules attached to catalytic particles is mapped using synchrotron-radiation-based infrared nanospectroscopy(6,7) with a spatial resolution of 25 nanometres, which enabled particle regions that differ in reactivity to be distinguished. These observations demonstrate that, compared to the flat regions on top of the particles, the peripheries of the particles-which contain metal atoms with low coordination numbers-are more active in catalysing oxidation and reduction of chemically active groups in surface-anchored N-heterocyclic carbene molecules.
C1 [Wu, Chung-Yeh; Wolf, William J. .; Toste, F. Dean] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
   [Wu, Chung-Yeh; Wolf, William J. .; Toste, F. Dean] Lawrence Berkeley Natl Lab, Div Chem Sci, 1 Cyclotron Rd, Berkeley, CA 94720 USA.
   [Levartovsky, Yehonatan; Gross, Elad] Hebrew Univ Jerusalem, Inst Chem, IL-91904 Jerusalem, Israel.
   [Levartovsky, Yehonatan; Gross, Elad] Hebrew Univ Jerusalem, Ctr Nanosci & Nanotechnol, IL-91904 Jerusalem, Israel.
   [Bechtel, Hans A. .; Martin, Michael C.] Lawrence Berkeley Natl Lab, Adv Light Source, 1 Cyclotron Rd, Berkeley, CA 94720 USA.
C3 University of California System; University of California Berkeley; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; Hebrew University of Jerusalem; Hebrew University of Jerusalem; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory
RP Toste, FD (corresponding author), Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.; Toste, FD (corresponding author), Lawrence Berkeley Natl Lab, Div Chem Sci, 1 Cyclotron Rd, Berkeley, CA 94720 USA.; Gross, E (corresponding author), Hebrew Univ Jerusalem, Inst Chem, IL-91904 Jerusalem, Israel.; Gross, E (corresponding author), Hebrew Univ Jerusalem, Ctr Nanosci & Nanotechnol, IL-91904 Jerusalem, Israel.
EM fdtoste@berkeley.edu; elad.gross@mail.huji.ac.il
FU Office of Science, Office of Basic Energy Sciences and the Division of Chemical Sciences, Geosciences, and Biosciences of the US Department of Energy at LBNL [DE-AC02-05CH11231]; Office of Science, Office of Basic Energy Sciences, of the US Department of Energy [DE-AC02-05CH11231]; NSF [DGE 1106400]
NR 30
TC 202
Z9 230
U1 5
U2 332
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 26
PY 2017
VL 541
IS 7638
BP 511
EP 515
DI 10.1038/nature20795
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6LX
UT WOS:000396116600046
PM 28068671
DA 2026-03-09
ER

PT J
AU Kolkowitz, S
   Bromley, SL
   Bothwell, T
   Wall, ML
   Marti, GE
   Koller, AP
   Zhang, X
   Rey, AM
   Ye, J
AF Kolkowitz, S.
   Bromley, S. L.
   Bothwell, T.
   Wall, M. L.
   Marti, G. E.
   Koller, A. P.
   Zhang, X.
   Rey, A. M.
   Ye, J.
TI Spin-orbit-coupled fermions in an optical lattice clock
SO NATURE
LA English
DT Article
ID edge states; atoms
AB Engineered spin-orbit coupling (SOC) in cold-atom systems can enable the study of new synthetic materials and complex condensed matter phenomena1-8. However, spontaneous emission in alkali-atom spin-orbit-coupled systems is hindered by heating, limiting the observation of many-body effects(1,2,5) and motivating research into potential alternatives(9-11). Here we demonstrate that spin-orbit-coupled fermions can be engineered to occur naturally in a one-dimensional optical lattice clock(12). In contrast to previous SOC experiments(1-11), here the SOC is both generated and probed using a direct ultra-narrow optical clock transition between two electronic orbital states in Sr-87 atoms. We use clock spectroscopy to prepare lattice band populations, internal electronic states and quasi-momenta, and to produce spin-orbit-coupled dynamics. The exceptionally long lifetime of the excited clock state (160 seconds) eliminates decoherence and atom loss from spontaneous emission at all relevant experimental timescales, allowing subsequent momentum-and spin-resolved in situ probing of the SOC band structure and eigenstates. We use these capabilities to study Bloch oscillations, spin-momentum locking and Van Hove singularities in the transition density of states. Our results lay the groundwork for using fermionic optical lattice clocks to probe new phases of matter.
C1 [Kolkowitz, S.; Bromley, S. L.; Bothwell, T.; Wall, M. L.; Marti, G. E.; Koller, A. P.; Zhang, X.; Rey, A. M.; Ye, J.] Univ Colorado, NIST, JILA, Boulder, CO 80309 USA.
   [Kolkowitz, S.; Bromley, S. L.; Bothwell, T.; Wall, M. L.; Marti, G. E.; Koller, A. P.; Zhang, X.; Rey, A. M.; Ye, J.] Univ Colorado, Dept Phys, Boulder, CO 80309 USA.
   [Wall, M. L.] Johns Hopkins Appl Phys Lab, Laurel, MD 20723 USA.
   [Zhang, X.] Peking Univ, Sch Phys, Int Ctr Quantum Mat, Beijing 100871, Peoples R China.
C3 National Institute of Standards & Technology (NIST) - USA; University of Colorado System; University of Colorado Boulder; University of Colorado System; University of Colorado Boulder; Johns Hopkins University; Johns Hopkins University Applied Physics Laboratory; Peking University
RP Kolkowitz, S (corresponding author), Univ Colorado, NIST, JILA, Boulder, CO 80309 USA.; Kolkowitz, S (corresponding author), Univ Colorado, Dept Phys, Boulder, CO 80309 USA.
EM shimonk@jila.colorado.edu
FU NIST; NSF Physics Frontier Center at JILA [NSF-PFC-1125844]; AFOSR-MURI; AFOSR; DARPA; ARO; NRC
NR 38
TC 240
Z9 277
U1 0
U2 118
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 2
PY 2017
VL 542
IS 7639
BP 66
EP +
DI 10.1038/nature20811
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6MY
UT WOS:000396119300032
PM 28002409
DA 2026-03-09
ER

PT J
AU Hublin, JJ
   Ben-Ncer, A
   Bailey, SE
   Freidline, SE
   Neubauer, S
   Skinner, MM
   Bergmann, I
   Le Cabec, A
   Benazzi, S
   Harvati, K
   Gunz, P
AF Hublin, Jean-Jacques
   Ben-Ncer, Abdelouahed
   Bailey, Shara E. .
   Freidline, Sarah E.
   Neubauer, Simon
   Skinner, Matthew M.
   Bergmann, Inga
   Le Cabec, Adeline
   Benazzi, Stefano
   Harvati, Katerina
   Gunz, Philipp
TI New fossils from Jebel Irhoud, Morocco and the pan-African origin of Homo sapiens
SO NATURE
LA English
DT Article
ID modern humans; facial morphology; genome sequence; dental remains; lower molars; neanderthal; evolution; hominid; spain; site
AB Fossil evidence points to an African origin of Homo sapiens from a group called either H. heidelbergensis or H. rhodesiensis. However, the exact place and time of emergence of H. sapiens remain obscure because the fossil record is scarce and the chronological age of many key specimens remains uncertain. In particular, it is unclear whether the present day 'modern' morphology rapidly emerged approximately 200 thousand years ago (ka) among earlier representatives of H. sapiens(1) or evolved gradually over the last 400 thousand years(2). Here we report newly discovered human fossils from Jebel Irhoud, Morocco, and interpret the affinities of the hominins from this site with other archaic and recent human groups. We identified a mosaic of features including facial, mandibular and dental morphology that aligns the Jebel Irhoud material with early or recent anatomically modern humans and more primitive neurocranial and endocranial morphology. In combination with an age of 315 +/- 34 thousand years (as determined by thermoluminescence dating)(3), this evidence makes Jebel Irhoud the oldest and richest African Middle Stone Age hominin site that documents early stages of the H. sapiens clade in which key features of modern morphology were established. Furthermore, it shows that the evolutionary processes behind the emergence of H. sapiens involved the whole African continent.
C1 [Hublin, Jean-Jacques; Freidline, Sarah E.; Neubauer, Simon; Bergmann, Inga; Le Cabec, Adeline; Gunz, Philipp] Max Planck Inst Evolutionary Anthropol, Dept Human Evolut, Deutsch Pl 6, D-04103 Leipzig, Germany.
   [Hublin, Jean-Jacques] Coll France, Chaire Int Paleoanthropol, Paris, France.
   [Ben-Ncer, Abdelouahed] Inst Natl Sci Archeol & Patrimoine, Rabat, Morocco.
   [Bailey, Shara E. .] NYU, Dept Anthropol, Ctr Study Human Origins, New York, NY 10003 USA.
   [Skinner, Matthew M.] Univ Kent, Sch Anthropol & Conservat, Canterbury CT2 7NR, Kent, England.
   [Benazzi, Stefano] Univ Bologna, Dept Cultural Heritage, I-48121 Ravenna, Italy.
   [Harvati, Katerina] Eberhard Karls Univ Tubingen, Paleoanthropol, Senckenberg Ctr Human Evolut & Paleoenvironm, Tubingen, Germany.
   [Harvati, Katerina] Eberhard Karls Univ Tubingen, DFG Ctr Adv Studies Words Bones Genes Tools, Tubingen, Germany.
C3 Max Planck Society; Universite PSL; College de France; New York University; University of Kent; University of Bologna; Eberhard Karls University of Tubingen; Leibniz Association; Senckenberg Gesellschaft fur Naturforschung (SGN); Eberhard Karls University of Tubingen
RP Hublin, JJ; Gunz, P (corresponding author), Max Planck Inst Evolutionary Anthropol, Dept Human Evolut, Deutsch Pl 6, D-04103 Leipzig, Germany.; Hublin, JJ (corresponding author), Coll France, Chaire Int Paleoanthropol, Paris, France.
EM hublin@eva.mpg.de; gunz@eva.mpg.de
FU Moroccan Institut National des Sciences de l'Archeologie et du Patrimoine; Department of Human Evolution of the Max Planck Institute for Evolutionary Anthropology
NR 106
TC 695
Z9 862
U1 4
U2 273
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 8
PY 2017
VL 546
IS 7657
BP 289
EP +
DI 10.1038/nature22336
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW9FY
UT WOS:000402823400037
PM 28593953
DA 2026-03-09
ER

PT J
AU Smorra, C
   Sellner, S
   Borchert, MJ
   Harrington, JA
   Higuchi, T
   Nagahama, H
   Tanaka, T
   Mooser, A
   Schneider, G
   Bohman, M
   Blaum, K
   Matsuda, Y
   Ospelkaus, C
   Quint, W
   Walz, J
   Yamazaki, Y
   Ulmer, S
AF Smorra, C.
   Sellner, S.
   Borchert, M. J.
   Harrington, J. A.
   Higuchi, T.
   Nagahama, H.
   Tanaka, T.
   Mooser, A.
   Schneider, G.
   Bohman, M.
   Blaum, K.
   Matsuda, Y.
   Ospelkaus, C.
   Quint, W.
   Walz, J.
   Yamazaki, Y.
   Ulmer, S.
TI A parts-per-billion measurement of the antiproton magnetic moment
SO NATURE
LA English
DT Article
ID penning trap technique; electron; cpt; ion
AB Precise comparisons of the fundamental properties of matter-antimatter conjugates provide sensitive tests of charge-parity-time (CPT) invariance(1), which is an important symmetry that rests on basic assumptions of the standard model of particle physics. Experiments on mesons(2), leptons(3,4) and baryons(5,6) have compared different properties of matter-antimatter conjugates with fractional uncertainties at the parts-per-billion level or better. One specific quantity, however, has so far only been known to a fractional uncertainty at the parts-per-million level(7,8): the magnetic moment of the antiproton, mu((p) over bar). The extraordinary difficulty in measuring mu((p) over bar) with high precision is caused by its intrinsic smallness; for example, it is 660 times smaller than the magnetic moment of the positron(3). Here we report a high-precision measurement of mu((p) over bar) in units of the nuclear magneton mu N with a fractional precision of 1.5 parts per billion (68% confidence level). We use a two-particle spectroscopy method in an advanced cryogenic multi-Penning trap system. Our result mu((p) over bar) = -2.7928473441(42) mu(N) (where the number in parentheses represents the 68% confidence interval on the last digits of the value) improves the precision of the previous best mu((p) over bar) measurement(8) by a factor of approximately 350. The measured value is consistent with the proton magnetic moment(9), mu((p) over bar) = 2.792847350(9) mu(N), and is in agreement with CPT invariance. Consequently, this measurement constrains the magnitude of certain CPT-violating effects(10) to below 1.8 x 10(-24) gigaelectronvolts, and a possible splitting of the protonantiproton magnetic moments by CPT-odd dimension-five interactions to below 6 x 10(-12) Bohr magnetons(11).
C1 [Smorra, C.; Sellner, S.; Borchert, M. J.; Higuchi, T.; Nagahama, H.; Tanaka, T.; Mooser, A.; Schneider, G.; Bohman, M.; Yamazaki, Y.; Ulmer, S.] RIKEN, Ulmer Fundamental Symmetries Lab, 2-1 Hirosawa, Wako, Saitama 3510198, Japan.
   [Smorra, C.] CERN, CH-1211 Geneva, Switzerland.
   [Borchert, M. J.; Ospelkaus, C.] Leibniz Univ Hannover, Inst Quantenopt, Welfengarten 1, D-30167 Hannover, Germany.
   [Harrington, J. A.; Bohman, M.; Blaum, K.] Max Planck Inst Kernphys, Saupfercheckweg 1, D-69117 Heidelberg, Germany.
   [Higuchi, T.; Tanaka, T.; Matsuda, Y.] Univ Tokyo, Grad Sch Arts & Sci, Tokyo 1538902, Japan.
   [Schneider, G.; Walz, J.] Johannes Gutenberg Univ Mainz, Inst Phys, D-55099 Mainz, Germany.
   [Ospelkaus, C.] Phys Tech Bundesanstalt, D-38116 Braunschweig, Germany.
   [Quint, W.] GSI Helmholtzzentrum Schwerionenforsch GmbH, D-64291 Darmstadt, Germany.
   [Walz, J.] Helmholtz Inst, D-55099 Mainz, Germany.
C3 RIKEN; European Organization for Nuclear Research (CERN); Leibniz University Hannover; Max Planck Society; University of Tokyo; Johannes Gutenberg University of Mainz; Physikalisch-Technische Bundesanstalt (PTB); Helmholtz Association; GSI Helmholtz-Center for Heavy Ion Research; Helmholtz Association
RP Smorra, C; Ulmer, S (corresponding author), RIKEN, Ulmer Fundamental Symmetries Lab, 2-1 Hirosawa, Wako, Saitama 3510198, Japan.; Smorra, C (corresponding author), CERN, CH-1211 Geneva, Switzerland.
EM Christian.Smorra@cern.ch; Stefan.Ulmer@cern.ch
FU RIKEN; MEXT [24000008]; Max-Planck Society; EU (ERC) [290870-MEFUCO]; Helmholtz-Gemeinschaft; CERN Fellowship program; Grants-in-Aid for Scientific Research [24000008] Funding Source: KAKEN
NR 36
TC 108
Z9 127
U1 1
U2 22
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 19
PY 2017
VL 550
IS 7676
BP 371
EP +
DI 10.1038/nature24048
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK1NF
UT WOS:000413247900055
PM 29052625
DA 2026-03-09
ER

PT J
AU Wan, W
   Kolesnikova, L
   Clarke, M
   Koehler, A
   Noda, T
   Becker, S
   Briggs, JAG
AF Wan, William
   Kolesnikova, Larissa
   Clarke, Mairi
   Koehler, Alexander
   Noda, Takeshi
   Becker, Stephan
   Briggs, John A. G.
TI Structure and assembly of the Ebola virus nucleocapsid
SO NATURE
LA English
DT Article
ID nucleoprotein-rna complex; crystal-structure; molecular-dynamics; visualization; resolution; toolbox; domain; model
AB Ebola and Marburg viruses are filoviruses: filamentous, enveloped viruses that cause haemorrhagic fever(1). Filoviruses are within the order Mononegavirales(2), which also includes rabies virus, measles virus, and respiratory syncytial virus. Mononegaviruses have non-segmented, single-stranded negative-sense RNA genomes that are encapsidated by nucleoprotein and other viral proteins to form a helical nucleocapsid. The nucleocapsid acts as a scaffold for virus assembly and as a template for genome transcription and replication. Insights into nucleoprotein-nucleoprotein interactions have been derived from structural studies of oligomerized, RNA-encapsidating nucleoprotein(3-6), and cryo-electron microscopy of nucleocapsid(7-12) or nucleocapsid-like structures(11-13). There have been no high-resolution reconstructions of complete mononegavirus nucleocapsids. Here we apply cryo-electron tomography and subtomogram averaging to determine the structure of Ebola virus nucleocapsid within intact viruses and recombinant nucleocapsid-like assemblies. These structures reveal the identity and arrangement of the nucleocapsid components, and suggest that the formation of an extended a-helix from the disordered carboxy-terminal region of nucleoprotein-core links nucleoprotein oligomerization, nucleocapsid condensation, RNA encapsidation, and accessory protein recruitment.
C1 [Wan, William; Clarke, Mairi; Briggs, John A. G.] European Mol Biol Lab, Struct & Computat Biol Unit, Meyerhofstr 1, D-69117 Heidelberg, Germany.
   [Kolesnikova, Larissa; Koehler, Alexander; Becker, Stephan] Philipps Univ Marburg, Inst Virol, Hans Meerwein Str 2, D-35043 Marburg, Germany.
   [Noda, Takeshi] Kyoto Univ, Inst Frontier Life & Med Sci, Lab Ultrastruct Virol, Kyoto 6068507, Japan.
   [Noda, Takeshi] Japan Sci & Technol Agcy, PRESTO, Saitama 3320012, Japan.
   [Briggs, John A. G.] MRC Lab Mol Biol, Struct Studies Div, Francis Crick Ave, Cambridge CB2 0QH, England.
   [Wan, William] Max Planck Inst Biochem, Dept Mol Struct Biol, Klopferspitz 18, D-82152 Martinsried, Germany.
C3 European Molecular Biology Laboratory (EMBL); Philipps University Marburg; Kyoto University; Japan Science & Technology Agency (JST); MRC Laboratory Molecular Biology; Max Planck Society
RP Briggs, JAG (corresponding author), European Mol Biol Lab, Struct & Computat Biol Unit, Meyerhofstr 1, D-69117 Heidelberg, Germany.; Briggs, JAG (corresponding author), MRC Lab Mol Biol, Struct Studies Div, Francis Crick Ave, Cambridge CB2 0QH, England.
EM john.briggs@mrc-lmb.cam.ac.uk
FU European Molecular Biology Laboratory; European Research Council (ERC) under European Union's Horizon research and innovation programme [ERC-CoG-648432 MEMBRANEFUSION]; Deutsche Forschungsgemeinschaft [Sonderforschungsbereich 1021]; German Center for Infection Research (DZIF); EMBO [ALTF 748-2014]; MRC [MC_UP_1201/16] Funding Source: UKRI
NR 45
TC 151
Z9 177
U1 0
U2 74
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 16
PY 2017
VL 551
IS 7680
BP 394
EP +
DI 10.1038/nature24490
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM8UK
UT WOS:000415365500045
PM 29144446
DA 2026-03-09
ER

PT J
AU Zhu, S
   Ding, SY
   Wang, PH
   Wei, Z
   Pan, W
   Palm, NW
   Yang, Y
   Yu, H
   Li, HB
   Wang, G
   Lei, XQ
   de Zoete, MR
   Zhao, J
   Zheng, YJ
   Chen, HW
   Zhao, YJ
   Jurado, KA
   Feng, NG
   Shan, L
   Kluger, Y
   Lu, J
   Abraham, C
   Fikrig, E
   Greenberg, HB
   Flavell, RA
AF Zhu, Shu
   Ding, Siyuan
   Wang, Penghua
   Wei, Zheng
   Pan, Wen
   Palm, Noah W.
   Yang, Yi
   Yu, Hua
   Li, Hua-Bing
   Wang, Geng
   Lei, Xuqiu
   de Zoete, Marcel R.
   Zhao, Jun
   Zheng, Yunjiang
   Chen, Haiwei
   Zhao, Yujiao
   Jurado, Kellie A.
   Feng, Ningguo
   Shan, Liang
   Kluger, Yuval
   Lu, Jun
   Abraham, Clara
   Fikrig, Erol
   Greenberg, Harry B.
   Flavell, Richard A.
TI Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells
SO NATURE
LA English
DT Article
ID double-stranded-rna; heterologous rotavirus; aim2 inflammasome; immune-responses; caspase-1; replication; secretion; flagellin; innate; death
AB Rotavirus, a leading cause of severe gastroenteritis and diarrhoea in young children, accounts for around 215,000 deaths annually worldwide(1). Rotavirus specifically infects the intestinal epithelial cells in the host small intestine and has evolved strategies to antagonize interferon and NF-kappa B signalling(2-5), raising the question as to whether other host factors participate in antiviral responses in intestinal mucosa. The mechanism by which enteric viruses are sensed and restricted in vivo, especially by NOD-like receptor (NLR) inflammasomes, is largely unknown. Here we uncover and mechanistically characterize the NLR Nlrp9b that is specifically expressed in intestinal epithelial cells and restricts rotavirus infection. Our data show that, via RNA helicase Dhx9, Nlrp9b recognizes short double-stranded RNA stretches and forms inflammasome complexes with the adaptor proteins Asc and caspase-1 to promote the maturation of interleukin (Il)-18 and gasdermin D (Gsdmd)-induced pyroptosis. Conditional depletion of Nlrp9b or other inflammasome components in the intestine in vivo resulted in enhanced susceptibility of mice to rotavirus replication. Our study highlights an important innate immune signalling pathway that functions in intestinal epithelial cells and may present useful targets in the modulation of host defences against viral pathogens.
C1 [Zhu, Shu; Wei, Zheng; Palm, Noah W.; Yang, Yi; Yu, Hua; Li, Hua-Bing; Wang, Geng; Lei, Xuqiu; de Zoete, Marcel R.; Zhao, Jun; Zheng, Yunjiang; Chen, Haiwei; Shan, Liang; Flavell, Richard A.] Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06520 USA.
   [Ding, Siyuan; Feng, Ningguo; Greenberg, Harry B.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA.
   [Ding, Siyuan; Feng, Ningguo; Greenberg, Harry B.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA.
   [Ding, Siyuan; Greenberg, Harry B.] VA Palo Alto Hlth Care Syst, Palo Alto Vet Inst Res, Palo Alto, CA 94304 USA.
   [Wang, Penghua; Zhao, Yujiao] New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA.
   [Pan, Wen; Lu, Jun] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA.
   [Zhao, Jun; Kluger, Yuval] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA.
   [Jurado, Kellie A.; Abraham, Clara; Fikrig, Erol] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA.
   [Fikrig, Erol; Flavell, Richard A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
C3 Yale University; Stanford University; Stanford University; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Palo Alto Health Care System; New York Medical College; Yale University; Yale University; Yale University; Howard Hughes Medical Institute
RP Flavell, RA (corresponding author), Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06520 USA.; Flavell, RA (corresponding author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
EM richard.flavell@yale.edu
FU Helen Hay Whitney Foundation-Howard Hughes Medical Institute; Walter V. and Idun Berry Postdoctoral Fellowship; Thrasher Research Fund; VA Merit Review grant [I01BX000158]; NIH [R01AI021362, U19AI116484];  [R21AI103807];  [R01DK099097];  [R01DK106593];  [R01AI120369];  [U19AI089992]; National Center for Advancing Translational Sciences [UL1TR001863] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [R01AI127865, R01AI125249, T32AI007019, U19AI089992, U19AI116484] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK099097] Funding Source: NIH RePORTER
NR 41
TC 307
Z9 350
U1 2
U2 143
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 29
PY 2017
VL 546
IS 7660
BP 667
EP +
DI 10.1038/nature22967
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY9QB
UT WOS:000404332000050
PM 28636595
DA 2026-03-09
ER

PT J
AU Andersen, PR
   Tirian, L
   Vunjak, M
   Rennecke, JB
AF Andersen, Peter Refsing
   Tirian, Laszlo
   Vunjak, Milica
   Rennecke, Julius B.
TI A heterochromatin-dependent transcription machinery drives piRNA expression
SO NATURE
LA English
DT Article
ID polymerase-ii transcription; tbp-like factor; small rnas; crystal-structure; mice lacking; pol ii; tfiia; trf2; complex; chromatin
AB Nuclear small RNA pathways safeguard genome integrity by establishing transcription-repressing heterochromatin at transposable elements. This inevitably also targets the transposon-rich source loci of the small RNAs themselves. How small RNA source loci are efficiently transcribed while transposon promoters are potently silenced is not understood. Here we show that, in Drosophila, transcription of PIWI-interacting RNA (piRNA) clusters-small RNA source loci in animal gonads-is enforced through RNA polymerase II pre-initiation complex formation within repressive heterochromatin. This is accomplished through Moonshiner, a paralogue of a basal transcription factor IIA (TFIIA) subunit, which is recruited to piRNA clusters via the heterochromatin protein-1 variant Rhino. Moonshiner triggers transcription initiation within piRNA clusters by recruiting the TATA-box binding protein (TBP)-related factor TRF2, an animal TFIID core variant. Thus, transcription of heterochromatic small RNA source loci relies on direct recruitment of the core transcriptional machinery to DNA via histone marks rather than sequence motifs, a concept that we argue is a recurring theme in evolution.
C1 [Andersen, Peter Refsing; Tirian, Laszlo; Vunjak, Milica; Rennecke, Julius B.] Austrian Acad Sci IMBA, Vienna Bioctr VBC, Inst Mol Biotechnol, Dr Bohrgasse 3, A-1030 Vienna, Austria.
C3 Austrian Academy of Sciences; Vienna Biocenter (VBC); Institute of Molecular Biotechnology (IMBA)
RP Andersen, PR; Rennecke, JB (corresponding author), Austrian Acad Sci IMBA, Vienna Bioctr VBC, Inst Mol Biotechnol, Dr Bohrgasse 3, A-1030 Vienna, Austria.
EM peter.andersen@imba.oeaw.ac.at; julius.brennecke@imba.oeaw.ac.at
FU Austrian Academy of Sciences; European Community (ERC) [260711EU, ERC-2015-CoG-682181]; Alfred Benzon Foundation; Novo Nordisk Foundation; Novo Nordisk Fonden [NNF14OC0009189] Funding Source: researchfish
NR 81
TC 195
Z9 222
U1 0
U2 57
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 7
PY 2017
VL 549
IS 7670
BP 54
EP +
DI 10.1038/nature23482
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG0DH
UT WOS:000409388700031
PM 28847004
DA 2026-03-09
ER

PT J
AU Wise, MG
   Dowdeswell, JA
   Jakobsson, M
   Larter, RD
AF Wise, Matthew G.
   Dowdeswell, Julian A.
   Jakobsson, Martin
   Larter, Robert D.
TI Evidence of marine ice-cliff instability in Pine Island Bay from iceberg-keel plough marks
SO NATURE
LA English
DT Article
ID grounding line retreat; sea-level rise; west antarctica; geological record; calving glaciers; outer shelf; holocene; thwaites; disintegration; widespread
AB Marine ice-cliff instability (MICI) processes could accelerate future retreat of the Antarctic Ice Sheet if ice shelves that buttress grounding lines more than 800 metres below sea level are lost(1,2). The present-day grounding zones of the Pine Island and Thwaites glaciers in West Antarctica need to retreat only short distances before they reach extensive retrograde slopes(3,4). When grounding zones of glaciers retreat onto such slopes, theoretical considerations and modelling results indicate that the retreat becomes unstable (marine ice-sheet instability) and thus accelerates(5). It is thought(1,2) that MICI is triggered when this retreat produces ice cliffs above the water line with heights approaching about 90 metres. However, observational evidence confirming the action of MICI has not previously been reported. Here we present observational evidence that rapid deglacial ice-sheet retreat into Pine Island Bay proceeded in a similar manner to that simulated in a recent modelling study(1), driven by MICI. Iceberg-keel plough marks on the sea-floor provide geological evidence of past and present iceberg morphology, keel depth(6) and drift direction(7). From the planform shape and cross-sectional morphologies of iceberg-keel plough marks, we find that iceberg calving during the most recent deglaciation was not characterized by small numbers of large, tabular icebergs as is observed today(8,9), which would produce wide, flat-based plough marks(10) or toothcomb-like multi-keeled plough marks(11,12). Instead, it was characterized by large numbers of smaller icebergs with V-shaped keels. Geological evidence of the form and water-depth distribution of the plough marks indicates calving-margin thicknesses equivalent to the threshold that is predicted to trigger ice-cliff structural collapse as a result of MICI13. We infer rapid and sustained ice-sheet retreat driven by MICI, commencing around 12,300 years ago and terminating before about 11,200 years ago, which produced large numbers of icebergs smaller than the typical tabular icebergs produced today. Our findings demonstrate the effective operation of MICI in the past, and highlight its potential contribution to accelerated future retreat of the Antarctic Ice Sheet.
C1 [Wise, Matthew G.; Dowdeswell, Julian A.] Univ Cambridge, Scott Polar Res Inst, Lensfield Rd, Cambridge CB2 1ER, England.
   [Jakobsson, Martin] Stockholm Univ, Dept Geol Sci, S-10691 Stockholm, Sweden.
   [Jakobsson, Martin] Stockholm Univ, Bolin Ctr Climate Res, S-10691 Stockholm, Sweden.
   [Larter, Robert D.] British Antarctic Survey, NERC, Madingley Rd, Cambridge CB3 0ET, England.
C3 University of Cambridge; Stockholm University; Stockholm University; UK Research & Innovation (UKRI); Natural Environment Research Council (NERC); NERC British Antarctic Survey
RP Wise, MG; Dowdeswell, JA (corresponding author), Univ Cambridge, Scott Polar Res Inst, Lensfield Rd, Cambridge CB2 1ER, England.
EM mgw37@cam.ac.uk; jd16@cam.ac.uk
FU UK Natural Environment Research Council (NERC) [LCAG/247 RG72013]; UK NERC; Natural Environment Research Council [1366310, bas0100030] Funding Source: researchfish; NERC [bas0100030] Funding Source: UKRI
NR 44
TC 54
Z9 71
U1 0
U2 43
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 26
PY 2017
VL 550
IS 7677
BP 506
EP +
DI 10.1038/nature24458
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK7OW
UT WOS:000413697800040
PM 29072274
DA 2026-03-09
ER

PT J
AU Britschgi, A
   Duss, S
   Kim, S
   Couto, JP
   Brinkhaus, H
   Koren, S
   De Silva, D
   Mertz, KD
   Kaup, D
   Varga, Z
   Voshol, H
   Vissieres, A
   Leroy, C
   Roloff, T
   Stadler, MB
   Scheel, CH
   Miraglia, LJ
   Orth, AP
   Bonamy, GMC
   Reddy, VA
   Bentires-Alj, M
AF Britschgi, Adrian
   Duss, Stephan
   Kim, Sungeun
   Couto, Joana Pinto
   Brinkhaus, Heike
   Koren, Shany
   De Silva, Duvini
   Mertz, Kirsten D.
   Kaup, Daniela
   Varga, Zsuzsanna
   Voshol, Hans
   Vissieres, Alexandra
   Leroy, Cedric
   Roloff, Tim
   Stadler, Michael B.
   Scheel, Christina H.
   Miraglia, Loren J.
   Orth, Anthony P.
   Bonamy, Ghislain M. C.
   Reddy, Venkateshwar A.
   Bentires-Alj, Mohamed
TI The Hippo kinases LATS1 and 2 control human breast cell fate via crosstalk with ERα
SO NATURE
LA English
DT Article
ID mammary epithelial-cells; stem-cell; yap pathway; cancer; differentiation; tumorigenesis; growth; gland; taz; mouse
AB Cell fate perturbations underlie many human diseases, including breast cancer(1,2). Unfortunately, the mechanisms by which breast cell fate are regulated are largely unknown. The mammary gland epithelium consists of differentiated luminal epithelial and basal myoepithelial cells, as well as undifferentiated stem cells and more restricted progenitors(3,4). Breast cancer originates from this epithelium, but the molecular mechanisms that underlie breast epithelial hierarchy remain ill-defined. Here, we use a high-content confocal image-based short hairpin RNA screen to identify tumour suppressors that regulate breast cell fate in primary human breast epithelial cells. We show that ablation of the large tumour suppressor kinases (LATS) 1 and 2 (refs 5, 6), which are part of the Hippo pathway, promotes the luminal phenotype and increases the number of bipotent and luminal progenitors, the proposed cells-of-origin of most human breast cancers. Mechanistically, we have identified a direct interaction between Hippo and oestrogen receptor-alpha (ER alpha) signalling. In the presence of LATS, ERa was targeted for ubiquitination and Ddb1-cullin4-associated-factor 1 (DCAF1)-dependent proteasomal degradation. Absence of LATS stabilized ERa and the Hippo effectors YAP and TAZ (hereafter YAP/TAZ), which together control breast cell fate through intrinsic and paracrine mechanisms. Our findings reveal a non-canonical (that is, YAP/TAZ-independent) effect of LATS in the regulation of human breast cell fate.
C1 [Britschgi, Adrian; Duss, Stephan; Couto, Joana Pinto; Brinkhaus, Heike; Koren, Shany; De Silva, Duvini; Leroy, Cedric; Roloff, Tim; Stadler, Michael B.; Bentires-Alj, Mohamed] Friedrich Miescher Inst Biomed Res, CH-4058 Basel, Switzerland.
   [Kim, Sungeun; Miraglia, Loren J.; Orth, Anthony P.; Bonamy, Ghislain M. C.; Reddy, Venkateshwar A.] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA.
   [Couto, Joana Pinto; Koren, Shany; De Silva, Duvini; Bentires-Alj, Mohamed] Univ Basel, Univ Basel Hosp, Dept Biomed, CH-4031 Basel, Switzerland.
   [Mertz, Kirsten D.; Kaup, Daniela] Cantonal Hosp Baselland, Inst Pathol Liestal, CH-4410 Liestal, Switzerland.
   [Varga, Zsuzsanna] Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland.
   [Voshol, Hans; Vissieres, Alexandra; Leroy, Cedric] Novartis Inst Biomed Res, CH-4058 Basel, Switzerland.
   [Stadler, Michael B.] Swiss Inst Bioinformat, CH-4058 Basel, Switzerland.
   [Scheel, Christina H.] German Res Ctr Environm Hlth, Inst Stem Cell Res, D-85764 Neuherberg, Germany.
C3 Friedrich Miescher Institute for Biomedical Research; Novartis; Novartis USA; University of Basel; Kantonsspital Baselland; University of Zurich; University Zurich Hospital; Novartis; Swiss Institute of Bioinformatics; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health
RP Bentires-Alj, M (corresponding author), Friedrich Miescher Inst Biomed Res, CH-4058 Basel, Switzerland.; Bentires-Alj, M (corresponding author), Univ Basel, Univ Basel Hosp, Dept Biomed, CH-4031 Basel, Switzerland.
EM m.bentires-alj@unibas.ch
FU Novartis Research Foundation; European Research Council; Swiss National Science Foundation; Krebsliga Beider Basel; Swiss Cancer League; Department of Surgery of the University Hospital of Basel; Swiss Initiative for Systems Biology (SystemsX.ch)
NR 52
TC 118
Z9 140
U1 1
U2 47
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 26
PY 2017
VL 541
IS 7638
BP 541
EP 545
DI 10.1038/nature20829
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6LX
UT WOS:000396116600053
PM 28068668
DA 2026-03-09
ER

PT J
AU Garabato, ACN
   Forryan, A
   Dutrieux, P
   Brannigan, L
   Biddle, LC
   Heywood, KJ
   Jenkins, A
   Firing, YL
   Kimura, S
AF Garabato, Alberto C. Naveira
   Forryan, Alexander
   Dutrieux, Pierre
   Brannigan, Liam
   Biddle, Louise C.
   Heywood, Karen J.
   Jenkins, Adrian
   Firing, Yvonne L.
   Kimura, Satoshi
TI Vigorous lateral export of the meltwater outflow from beneath an Antarctic ice shelf
SO NATURE
LA English
DT Article
ID glacial meltwater; sea-ice; sheet; instability; amundsen; ocean; water; helium; neon; melt
AB The instability and accelerated melting of the Antarctic Ice Sheet are among the foremost elements of contemporary global climate change la. The increased freshwater output from Antarctica is important in determining sea level rise(1,3), the fate of Antarctic sea ice and its effect on the Earth's albedo(4,5), ongoing changes in global deep-ocean ventilation(3,6), and the evolution of Southern Ocean ecosystems and carbon cycling(7,8). A key uncertainty in assessing and predicting the impacts of Antarctic Ice Sheet melting concerns the vertical distribution of the exported meltwater. This is usually represented by climate-scale models(3-5,9) as a near-surface freshwater input to the ocean, yet measurements around Antarctica reveal the meltwater to be concentrated at deeper levels(10-14). Here we use observations of the turbulent properties of the meltwater outflows from beneath a rapidly melting Antarctic ice shelf to identify the mechanism responsible for the depth of the meltwater. We show that the initial ascent of the meltwater outflow from the ice shelf cavity triggers a centrifugal overturning instability that grows by extracting kinetic energy from the lateral shear of the background oceanic flow. The instability promotes vigorous lateral export, rapid dilution by turbulent mixing, and finally settling of meltwater at depth. We use an idealized ocean circulation model to show that this mechanism is relevant to a broad spectrum of Antarctic ice shelves. Our findings demonstrate that the mechanism producing meltwater at depth is a dynamically robust feature of Antarctic melting that should be incorporated into climate-scale models.
C1 [Garabato, Alberto C. Naveira; Forryan, Alexander] Univ Southampton, Ocean & Earth Sci, Natl Oceanog Ctr, Southampton SO14 3ZH, Hants, England.
   [Dutrieux, Pierre; Jenkins, Adrian; Kimura, Satoshi] British Antarctic Survey, Cambridge CB3 0ET, England.
   [Dutrieux, Pierre] Columbia Univ, Lamont Doherty Earth Observ, Palisades, NY 10964 USA.
   [Brannigan, Liam] Stockholm Univ, Dept Meteorol, SE-10691 Stockholm, Sweden.
   [Biddle, Louise C.; Heywood, Karen J.] Univ East Anglia, Sch Environm Sci, Ctr Ocean & Atmospher Sci, Norwich NR4 7TJ, Norfolk, England.
   [Firing, Yvonne L.] Natl Inst Oceanog, Southampton SO14 3ZH, Hants, England.
C3 University of Southampton; NERC National Oceanography Centre; UK Research & Innovation (UKRI); Natural Environment Research Council (NERC); NERC British Antarctic Survey; Columbia University; Stockholm University; University of East Anglia; NERC National Oceanography Centre
RP Garabato, ACN (corresponding author), Univ Southampton, Ocean & Earth Sci, Natl Oceanog Ctr, Southampton SO14 3ZH, Hants, England.
EM acng@noc.soton.ac.uk
FU Natural Environment Research Council of the UK [NE/J005703/1, NE/J005746/1, NE/J005770/1]; Philip Leverhulme Prize; Royal Society; Wolfson Foundation; NERC [bas0100033, NE/J005711/1, NE/J005770/1, NE/J005703/1, NE/J005746/1] Funding Source: UKRI; Natural Environment Research Council [NE/J005703/1, NE/J005746/1, noc010012, bas0100033, 1210192, NE/J005711/1, NE/J005770/1] Funding Source: researchfish
NR 28
TC 64
Z9 72
U1 0
U2 44
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 9
PY 2017
VL 542
IS 7640
BP 219
EP 222
DI 10.1038/nature20825
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK2DJ
UT WOS:000393737500038
PM 28135723
DA 2026-03-09
ER

PT J
AU McGovern, N
   Shin, A
   Low, G
   Low, D
   Duan, KB
   Yao, LJ
   Msallam, R
   Low, I
   Shadan, NB
   Sumatoh, HR
   Soon, E
   Lum, J
   Mok, E
   Hubert, S
   See, P
   Kunxiang, EH
   Lee, YH
   Janela, B
   Choolani, M
   Mattar, CNZ
   Fan, YP
   Lim, TKH
   Chan, DKH
   Tan, KK
   Tam, JKC
   Schuster, C
   Elbe-Bürger, A
   Wang, XN
   Bigley, V
   Collin, M
   Haniffa, M
   Schlitzer, A
   Poidinger, M
   Albani, S
   Larbi, A
   Newell, EW
   Chan, JKY
   Ginhoux, F
AF McGovern, Naomi
   Shin, Amanda
   Low, Gillian
   Low, Donovan
   Duan, Kaibo
   Yao, Leong Jing
   Msallam, Rasha
   Low, Ivy
   Shadan, Nurhidaya Binte
   Sumatoh, Hermi R.
   Soon, Erin
   Lum, Josephine
   Mok, Esther
   Hubert, Sandra
   See, Peter
   Kunxiang, Edwin Huang
   Lee, Yie Hou
   Janela, Baptiste
   Choolani, Mahesh
   Mattar, Citra Nurfarah Zaini
   Fan, Yiping
   Lim, Tony Kiat Hon
   Chan, Dedrick Kok Hong
   Tan, Ker-Kan
   Tam, John Kit Chung
   Schuster, Christopher
   Elbe-Buerger, Adelheid
   Wang, Xiao-nong
   Bigley, Venetia
   Collin, Matthew
   Haniffa, Muzlifah
   Schlitzer, Andreas
   Poidinger, Michael
   Albani, Salvatore
   Larbi, Anis
   Newell, Evan W.
   Chan, Jerry Kok Yen
   Ginhoux, Florent
TI Human fetal dendritic cells promote prenatal T-cell immune suppression through arginase-2
SO NATURE
LA English
DT Article
ID maternal hla antigens; stem-cells; expression; tolerance; responses; survival; behavior; tissue; skin; ccr7
AB During gestation the developing human fetus is exposed to a diverse range of potentially immune-stimulatory molecules including semi-allogeneic antigens from maternal cells(1,2), substances from ingested amniotic fluid(3,4), food antigens(5), and microbes(6). Yet the capacity of the fetal immune system, including antigen-presenting cells, to detect and respond to such stimuli remains unclear. In particular, dendritic cells, which are crucial for effective immunity and tolerance, remain poorly characterized in the developing fetus. Here we show that subsets of antigen-presenting cells can be identified in fetal tissues and are related to adult populations of antigen-presenting cells. Similar to adult dendritic cells, fetal dendritic cells migrate to lymph nodes and respond to toll-like receptor ligation; however, they differ markedly in their response to allogeneic antigens, strongly promoting regulatory T-cell induction and inhibiting T-cell tumour-necrosis factor-a production through arginase-2 activity. Our results reveal a previously unappreciated role of dendritic cells within the developing fetus and indicate that they mediate homeostatic immune-suppressive responses during gestation.
C1 [McGovern, Naomi; Shin, Amanda; Low, Gillian; Low, Donovan; Duan, Kaibo; Msallam, Rasha; Low, Ivy; Shadan, Nurhidaya Binte; Sumatoh, Hermi R.; Soon, Erin; Lum, Josephine; Mok, Esther; Hubert, Sandra; See, Peter; Janela, Baptiste; Schlitzer, Andreas; Poidinger, Michael; Larbi, Anis; Newell, Evan W.; Chan, Jerry Kok Yen; Ginhoux, Florent] ASTAR, Singapore Immunol Network SIgN, 8A Biomed Grove,Immunos Bldg,Level 3 & 4, Singapore 138648, Singapore.
   [Shin, Amanda] Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Immunol, Shanghai 200025, Peoples R China.
   [Yao, Leong Jing; Albani, Salvatore] STIIC, 20 Coll Rd,Level 8 Discovery Tower, Singapore 169856, Singapore.
   [Kunxiang, Edwin Huang; Fan, Yiping; Chan, Jerry Kok Yen] KK Womens & Childrens Hosp, Dept Reprod Med, Singapore 229899, Singapore.
   [Lee, Yie Hou] KK Womens & Childrens Hosp, KK Res Ctr, 100 Bukit Timah Rd, Singapore 229899, Singapore.
   [Lee, Yie Hou] Duke NUS Med Sch, OBGYN Acad Clin Program, Duke NUS, 8 Coll Rd, Singapore 169857, Singapore.
   [Choolani, Mahesh; Mattar, Citra Nurfarah Zaini] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Obstet & Gynaecol, NUHS Tower Block,1E Kent Ridge Rd, Singapore 119228, Singapore.
   [Choolani, Mahesh; Mattar, Citra Nurfarah Zaini; Fan, Yiping; Chan, Jerry Kok Yen] Natl Univ Singapore, Yong Loo Lin Sch Med, Expt Fetal Med Grp, Singapore 119077, Singapore.
   [Lim, Tony Kiat Hon] Singapore Gen Hosp, Dept Pathol, 20 Coll Rd, Singapore 169856, Singapore.
   [Chan, Dedrick Kok Hong; Tan, Ker-Kan] Natl Univ Hlth Syst, Univ Surg Cluster, Div Colorectal Surg, Singapore 119074, Singapore.
   [Tan, Ker-Kan; Tam, John Kit Chung; Schlitzer, Andreas] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, 1E Kent Ridge Rd, Singapore 119228, Singapore.
   [Schuster, Christopher; Elbe-Buerger, Adelheid] Med Univ Vienna, DIAID, Dept Dermatol, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.
   [Wang, Xiao-nong; Bigley, Venetia; Collin, Matthew; Haniffa, Muzlifah] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
   [Schlitzer, Andreas] Univ Bonn, Myeloid Cell Biol Life & Med Sci Inst, D-53115 Bonn, Germany.
   [Schlitzer, Andreas] German Ctr Neurodegenerat Dis, Single Cell Genom & Epigen Unit, D-53175 Bonn, Germany.
   [Schlitzer, Andreas] Univ Bonn, D-53175 Bonn, Germany.
   [Chan, Jerry Kok Yen] Duke NUS Grad Med Sch, Canc & Stem Cell Biol Program, Singapore 119077, Singapore.
C3 Agency for Science Technology & Research (A*STAR); A*STAR - Singapore Immunology Network (SIgN); Shanghai Jiao Tong University; Chinese Academy of Sciences; KK Women's & Children's Hospital; KK Women's & Children's Hospital; National University of Singapore; National University of Singapore; National University of Singapore; Singapore General Hospital; National University of Singapore; National University of Singapore; Medical University of Vienna; Newcastle University - UK; University of Bonn; Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE); University of Bonn; National University of Singapore
RP Chan, JKY; Ginhoux, F (corresponding author), ASTAR, Singapore Immunol Network SIgN, 8A Biomed Grove,Immunos Bldg,Level 3 & 4, Singapore 138648, Singapore.; Chan, JKY (corresponding author), KK Womens & Childrens Hosp, Dept Reprod Med, Singapore 229899, Singapore.; Chan, JKY (corresponding author), Natl Univ Singapore, Yong Loo Lin Sch Med, Expt Fetal Med Grp, Singapore 119077, Singapore.; Chan, JKY (corresponding author), Duke NUS Grad Med Sch, Canc & Stem Cell Biol Program, Singapore 119077, Singapore.
EM jerrychan@duke.nus.edu.sg; Florent_Ginhoux@immunol.a-star.edu.sg
FU Singapore Immunology Network; Biomedical Research Council (BMRC); Austrian Science Fund [P19474-B13, W1248-B30]; BMRC [SPF2014/00]; Singapore Ministry of Health's National Medical Research Council [CSIRG/1383/2014, CSA(SI)/008/2016/]; Austrian Science Fund (FWF) [P19474] Funding Source: Austrian Science Fund (FWF)
NR 29
TC 199
Z9 223
U1 0
U2 79
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 29
PY 2017
VL 546
IS 7660
BP 662
EP +
DI 10.1038/nature22795
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY9QB
UT WOS:000404332000049
PM 28614294
DA 2026-03-09
ER

PT J
AU Powers, RE
   Wang, SY
   Liu, TY
   Rapoport, TA
AF Powers, Robert E.
   Wang, Songyu
   Liu, Tina Y.
   Rapoport, Tom A.
TI Reconstitution of the tubular endoplasmic reticulum network with purified components
SO NATURE
LA English
DT Article
ID homotypic er fusion; membrane-proteins; amphipathic helix; provide insight; atlastin; generation; cells
AB Organelles display characteristic morphologies that are intimately tied to their cellular function, but how organelles are shaped is poorly understood. The endoplasmic reticulum is particularly intriguing, as it comprises morphologically distinct domains, including a dynamic network of interconnected membrane tubules. Several membrane proteins have been implicated in network formation(1-5), but how exactly they mediate network formation and whether they are all required are unclear. Here we reconstitute a dynamic tubular membrane network with purified endoplasmic reticulum proteins. Proteoliposomes containing the membrane-fusing GTPase Sey1p (refs 6, 7) and the curvature-stabilizing protein Yop1p (refs 8, 9) from Saccharomyces cerevisiae form a tubular network upon addition of GTP. The tubules rapidly fragment when GTP hydrolysis of Sey1p is inhibited, indicating that network maintenance requires continuous membrane fusion and that Yop1p favours the generation of highly curved membrane structures. Sey1p also forms networks with other curvature-stabilizing proteins, including reticulon(8) and receptor expression-enhancing proteins (REEPs)(10) from different species. Atlastin, the vertebrate orthologue of Sey1p(6,11), forms a GTP-hydrolysis-dependent network on its own, serving as both a fusion and curvature-stabilizing protein. Our results show that organelle shape can be generated by a surprisingly small set of proteins and represents an energy-dependent steady state between formation and disassembly.
C1 [Powers, Robert E.; Wang, Songyu; Liu, Tina Y.; Rapoport, Tom A.] Harvard Med Sch, Howard Hughes Med Inst, 240 Longwood Ave, Boston, MA 02115 USA.
   [Powers, Robert E.; Wang, Songyu; Liu, Tina Y.; Rapoport, Tom A.] Harvard Med Sch, Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 USA.
   [Liu, Tina Y.] Univ Calif Berkeley, 731 Stanley Hall,MS 3220, Berkeley, CA 94720 USA.
C3 Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Harvard University; Harvard Medical School; University of California System; University of California Berkeley
RP Rapoport, TA (corresponding author), Harvard Med Sch, Howard Hughes Med Inst, 240 Longwood Ave, Boston, MA 02115 USA.; Rapoport, TA (corresponding author), Harvard Med Sch, Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 USA.
EM tom_rapoport@hms.harvard.edu
FU National Institutes of Health/National Institute of General Medical Sciences [T32 GM008313]; Charles King Trust; National Institute of General Medical Sciences [T32GM008313] Funding Source: NIH RePORTER
NR 25
TC 88
Z9 103
U1 0
U2 52
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 9
PY 2017
VL 543
IS 7644
BP 257
EP +
DI 10.1038/nature21387
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0GQ
UT WOS:000395688700042
PM 28225760
DA 2026-03-09
ER

PT J
AU Waldron, A
   Miller, DC
   Redding, D
   Mooers, A
   Kuhn, TS
   Nibbelink, N
   Roberts, JT
   Tobias, JA
   Gittleman, JL
AF Waldron, Anthony
   Miller, Daniel C.
   Redding, Dave
   Mooers, Arne
   Kuhn, Tyler S.
   Nibbelink, Nate
   Roberts, J. Timmons
   Tobias, Joseph A.
   Gittleman, John L.
TI Reductions in global biodiversity loss predicted from conservation spending
SO NATURE
LA English
DT Article
ID red list index; international aid; economic-growth; extinction; governance; progress; impacts; models; trends
AB Halting global biodiversity loss is central to the Convention on Biological Diversity and United Nations Sustainable Development Goals(1,2), but success to date has been very limited(3-5). A critical determinant of success in achieving these goals is the financing that is committed to maintaining biodiversity(6-9); however, financing decisions are hindered by considerable uncertainty over the likely impact of any conservation investment(6-9). For greater effectiveness, we need an evidence-based model(10-12) that shows how conservation spending quantitatively reduces the rate of biodiversity loss. Here we demonstrate such a model, and empirically quantify how conservation investment between 1996 and 2008 reduced biodiversity loss in 109 countries (signatories to the Convention on Biological Diversity and Sustainable Development Goals), by a median average of 29% per country. We also show that biodiversity changes in signatory countries can be predicted with high accuracy, using a dual model that balances the effects of conservation investment against those of economic, agricultural and population growth (human development pressures)(13-18). Decision-makers can use this model to forecast the improvement that any proposed biodiversity budget would achieve under various scenarios of human development pressure, and then compare these forecasts to any chosen policy target. We find that the impact of spending decreases as human development pressures grow, which implies that funding may need to increase over time. The model offers a flexible tool for balancing the Sustainable Development Goals of human development and maintaining biodiversity, by predicting the dynamic changes in conservation finance that will be needed as human development proceeds.
C1 [Waldron, Anthony; Tobias, Joseph A.] Univ Oxford, Dept Zool, Edward Grey Inst, Oxford OX1 3PS, England.
   [Waldron, Anthony; Miller, Daniel C.] Univ Illinois, Dept Nat Resources & Environm Sci, Urbana, IL 61801 USA.
   [Redding, Dave] UCL, Dept Genet Evolut & Environm, London WC1E 6BT, England.
   [Mooers, Arne] Simon Fraser Univ, Biol Dept, Burnaby, BC V5A 1S6, Canada.
   [Kuhn, Tyler S.] Scimitar Sci, Whitehorse, YT Y1A 6V6, Canada.
   [Nibbelink, Nate] Univ Georgia, Warnell Sch Forestry & Nat Resources, Athens, GA 30602 USA.
   [Roberts, J. Timmons] Brown Univ, Inst Brown Environm & Soc, Providence, RI 02912 USA.
   [Tobias, Joseph A.] Imperial Coll London, Dept Life Sci, Silwood Pk,Buckhurst Rd, Ascot SL5 7PY, Berks, England.
   [Gittleman, John L.] Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA.
C3 University of Oxford; University of Illinois System; University of Illinois Urbana-Champaign; University of London; University College London; Simon Fraser University; University System of Georgia; University of Georgia; Brown University; Imperial College London; University System of Georgia; University of Georgia
RP Waldron, A (corresponding author), Univ Oxford, Dept Zool, Edward Grey Inst, Oxford OX1 3PS, England.; Waldron, A (corresponding author), Univ Illinois, Dept Nat Resources & Environm Sci, Urbana, IL 61801 USA.
EM anthonywaldron@hotmail.com
FU UKDWP; USDA National Institute of Food and Agriculture [1009327]; MacArthur Foundation through Advancing Conservation in a Social Context research initiative; Natural Sciences and Engineering Research Council Canada; UK Natural Environment Research Council [NE/I028068/1, NE/K016431/1]; Odum School of Ecology; Medical Research Council [MR/R02491X/1] Funding Source: researchfish; Natural Environment Research Council [NE/I028068/1, NE/K016431/1] Funding Source: researchfish; MRC [MR/R02491X/1] Funding Source: UKRI; NERC [NE/I028068/1, NE/K016431/1] Funding Source: UKRI
NR 85
TC 265
Z9 306
U1 7
U2 235
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 16
PY 2017
VL 551
IS 7680
BP 364
EP +
DI 10.1038/nature24295
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM8UK
UT WOS:000415365500039
PM 29072294
DA 2026-03-09
ER

PT J
AU Gill, DA
   Mascia, MB
   Ahmadia, GN
   Glew, L
   Lester, SE
   Barnes, M
   Craigie, I
   Darling, ES
   Free, CM
   Geldmann, J
   Holst, S
   Jensen, OP
   White, AT
   Basurto, X
   Coad, L
   Gates, RD
   Guannel, G
   Mumby, PJ
   Thomas, H
   Whitmee, S
   Woodley, S
   Fox, HE
AF Gill, David A.
   Mascia, Michael B.
   Ahmadia, Gabby N.
   Glew, Louise
   Lester, Sarah E.
   Barnes, Megan
   Craigie, Ian
   Darling, Emily S.
   Free, Christopher M.
   Geldmann, Jonas
   Holst, Susie
   Jensen, Olaf P.
   White, Alan T.
   Basurto, Xavier
   Coad, Lauren
   Gates, Ruth D.
   Guannel, Greg
   Mumby, Peter J.
   Thomas, Hannah
   Whitmee, Sarah
   Woodley, Stephen
   Fox, Helen E.
TI Capacity shortfalls hinder the performance of marine protected areas globally
SO NATURE
LA English
DT Article
ID reserves; science
AB Marine protected areas (MPAs) are increasingly being used globally to conserve marine resources. However, whether many MPAs are being effectively and equitably managed, and how MPA management influences substantive outcomes remain unknown. We developed a global database of management and fish population data (433 and 218 MPAs, respectively) to assess: MPA management processes; the effects of MPAs on fish populations; and relationships between management processes and ecological effects. Here we report that many MPAs failed to meet thresholds for effective and equitable management processes, with widespread shortfalls in staff and financial resources. Although 71% of MPAs positively influenced fish populations, these conservation impacts were highly variable. Staff and budget capacity were the strongest predictors of conservation impact: MPAs with adequate staff capacity had ecological effects 2.9 times greater than MPAs with inadequate capacity. Thus, continued global expansion of MPAs without adequate investment in human and financial capacity is likely to lead to sub-optimal conservation outcomes.
C1 [Gill, David A.] Natl Socioenvironm Synth Ctr SESYNC, Annapolis, MD 21401 USA.
   [Gill, David A.] World Wildlife Fund Int, Luc Hoffmann Inst, CH-1196 Gland, Switzerland.
   [Mascia, Michael B.] Conservat Int, Moore Ctr Sci, Arlington, VA 22202 USA.
   [Ahmadia, Gabby N.; Glew, Louise; Fox, Helen E.] World Wildlife Fund US, Washington, DC 20037 USA.
   [Lester, Sarah E.] Florida State Univ, Dept Geog, Tallahassee, FL 32306 USA.
   [Barnes, Megan] Univ Queensland, Ctr Biodivers & Conservat Sci, St Lucia Campus, Brisbane, Qld 4072, Australia.
   [Barnes, Megan] Univ Hawaii, Dept Nat Resources & Environm Management, Honolulu, HI 96822 USA.
   [Craigie, Ian] James Cook Univ, ARC Ctr Excellence Coral Reef Studies, Townsville, Qld 4811, Australia.
   [Darling, Emily S.] Wildlife Conservat Soc, Bronx, NY 10460 USA.
   [Free, Christopher M.; Jensen, Olaf P.] Rutgers State Univ, Dept Marine & Coastal Sci, New Brunswick, NJ 08901 USA.
   [Geldmann, Jonas] Univ Cambridge, Dept Zool, Conservat Sci Grp, Downing St, Cambridge CB2 3EJ, England.
   [Geldmann, Jonas] Univ Copenhagen, Nat Hist Museum Denmark, Ctr Macroecol Evolut & Climate, Univ Pk 15, DK-2100 Copenhagen E, Denmark.
   [Holst, Susie] NOAA, Coral Reef Conservat Program, Silver Spring, MD 20910 USA.
   [White, Alan T.] Nature Conservancy, Indo Pacific Div, Honolulu, HI 96817 USA.
   [Basurto, Xavier] Duke Univ, Nicholas Sch Environm, Beaufort, NC 28516 USA.
   [Coad, Lauren] Univ Oxford, Environm Change Inst, South Parks Rd, Oxford OX1 3QY, England.
   [Coad, Lauren] Ctr Int Forestry Res, Bogor 16115, Barat, Indonesia.
   [Gates, Ruth D.] Univ Hawaii Manoa, Hawaii Inst Marine Biol, Kaneohe, HI 96744 USA.
   [Guannel, Greg] Stanford Univ, Nat Capital Project, 371 Serra Mall, Stanford, CA 94305 USA.
   [Mumby, Peter J.] Univ Queensland, Marine Spatial Ecol Lab, Sch Biol Sci, St Lucia Campus, Brisbane, Qld 4072, Australia.
   [Mumby, Peter J.] Univ Queensland, ARC Ctr Excellence Coral Reef Studies, St Lucia Campus, Brisbane, Qld 4072, Australia.
   [Thomas, Hannah] UNEP World Conservat Monitoring Ctr, Cambridge CB3 0DL, England.
   [Whitmee, Sarah] UCL, CBER, London WC1E 6BT, England.
   [Woodley, Stephen] IUCN, WCPA SSC Joint Task Force Biodivers & Protected A, Quebec City, PQ J9B 1T3, Canada.
   [Fox, Helen E.] Natl Geog Soc, Washington, DC 20036 USA.
   [Gill, David A.] Conservat Int, Moore Ctr Sci, Arlington, VA 22202 USA.
   [Gill, David A.] George Mason Univ, Fairfax, VA 22030 USA.
C3 World Wildlife Fund; Conservation International; State University System of Florida; Florida State University; University of Queensland; University of Hawaii System; James Cook University; ARC Centre of Excellence for Coral Reef Studies; Wildlife Conservation Society; Rutgers University System; Rutgers University New Brunswick; University of Cambridge; University of Copenhagen; National Oceanic Atmospheric Admin (NOAA) - USA; Nature Conservancy; Duke University; University of Oxford; CGIAR; Center for International Forestry Research (CIFOR); University of Hawaii System; University of Hawaii Manoa; Stanford University; University of Queensland; University of Queensland; James Cook University; ARC Centre of Excellence for Coral Reef Studies; University of London; University College London; National Geographic Society; Conservation International; George Mason University
RP Gill, DA (corresponding author), Natl Socioenvironm Synth Ctr SESYNC, Annapolis, MD 21401 USA.; Gill, DA (corresponding author), World Wildlife Fund Int, Luc Hoffmann Inst, CH-1196 Gland, Switzerland.; Gill, DA (corresponding author), Conservat Int, Moore Ctr Sci, Arlington, VA 22202 USA.; Gill, DA (corresponding author), George Mason Univ, Fairfax, VA 22030 USA.
EM dgill@conservation.org
FU National Socio-Environmental Synthesis Center (SESYNC) under National Science Foundation [DBI-1052875]; Luc Hoffmann Institute; SESYNC; Direct For Biological Sciences; Div Of Biological Infrastructure [1052875] Funding Source: National Science Foundation
NR 49
TC 673
Z9 763
U1 16
U2 366
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 30
PY 2017
VL 543
IS 7647
BP 665
EP +
DI 10.1038/nature21708
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EP8IS
UT WOS:000397619700045
PM 28329771
DA 2026-03-09
ER

PT J
AU Viswanathan, VS
   Ryan, MJ
   Dhruv, HD
   Gill, S
   Eichhoff, OM
   Seashore-Ludlow, B
   Kaffenberger, SD
   Eaton, JK
   Shimada, K
   Aguirre, AJ
   Viswanathan, SR
   Chattopadhyay, S
   Tamayo, P
   Yang, WS
   Rees, MG
   Chen, SX
   Boskovic, ZV
   Javaid, S
   Huang, C
   Wu, XY
   Tseng, YY
   Roider, EM
   Gao, D
   Cleary, JM
   Wolpin, BM
   Mesirov, JP
   Haber, DA
   Engelman, JA
   Boehm, JS
   Kotz, JD
   Hon, CS
   Chen, Y
   Hahn, WC
   Levesque, MP
   Doench, JG
   Berens, ME
   Shamji, AF
   Clemons, PA
   Stockwell, BR
   Schreiber, SL
AF Viswanathan, Vasanthi S.
   Ryan, Matthew J.
   Dhruv, Harshil D.
   Gill, Shubhroz
   Eichhoff, Ossia M.
   Seashore-Ludlow, Brinton
   Kaffenberger, Samuel D.
   Eaton, John K.
   Shimada, Kenichi
   Aguirre, Andrew J.
   Viswanathan, Srinivas R.
   Chattopadhyay, Shrikanta
   Tamayo, Pablo
   Yang, Wan Seok
   Rees, Matthew G.
   Chen, Sixun
   Boskovic, Zarko V.
   Javaid, Sarah
   Huang, Cherrie
   Wu, Xiaoyun
   Tseng, Yuen-Yi
   Roider, Elisabeth M.
   Gao, Dong
   Cleary, James M.
   Wolpin, Brian M.
   Mesirov, Jill P.
   Haber, Daniel A.
   Engelman, Jeffrey A.
   Boehm, Jesse S.
   Kotz, Joanne D.
   Hon, Cindy S.
   Chen, Yu
   Hahn, William C.
   Levesque, Mitchell P.
   Doench, John G.
   Berens, Michael E.
   Shamji, Alykhan F.
   Clemons, Paul A.
   Stockwell, Brent R.
   Schreiber, Stuart L.
TI Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway
SO NATURE
LA English
DT Article
ID epithelial-mesenchymal transition; human-melanoma cells; prostate-cancer; expression; inhibitor; reveals; death; sensitivity; metabolism; signature
AB Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness(1-4). A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood(1-6). Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a nonapoptotic form of cell death induced by the build-up of toxic lipid peroxides(7,8). We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes(8,9). This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death(8). Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGF beta-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.
C1 [Viswanathan, Vasanthi S.; Ryan, Matthew J.; Gill, Shubhroz; Seashore-Ludlow, Brinton; Eaton, John K.; Aguirre, Andrew J.; Viswanathan, Srinivas R.; Chattopadhyay, Shrikanta; Tamayo, Pablo; Rees, Matthew G.; Chen, Sixun; Boskovic, Zarko V.; Huang, Cherrie; Wu, Xiaoyun; Tseng, Yuen-Yi; Mesirov, Jill P.; Boehm, Jesse S.; Kotz, Joanne D.; Hon, Cindy S.; Hahn, William C.; Doench, John G.; Shamji, Alykhan F.; Clemons, Paul A.; Schreiber, Stuart L.] Broad Inst, 415 Main St, Cambridge, MA 02142 USA.
   [Dhruv, Harshil D.; Berens, Michael E.] Translat Genom Res Inst, Canc & Cell Biol Div, 445 N 5th St, Phoenix, AZ 85004 USA.
   [Eichhoff, Ossia M.; Roider, Elisabeth M.; Levesque, Mitchell P.] Univ Zurich, Univ Zurich Hosp, Dept Dermatol, Wagistr 14, CH-8952 Zurich, Switzerland.
   [Kaffenberger, Samuel D.; Gao, Dong; Chen, Yu] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA.
   [Shimada, Kenichi] Harvard Med Sch, Lab Syst Pharmacol, 200 Longwood Ave, Boston, MA 02115 USA.
   [Aguirre, Andrew J.; Viswanathan, Srinivas R.; Cleary, James M.; Wolpin, Brian M.; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.
   [Tamayo, Pablo; Mesirov, Jill P.] Univ Calif San Diego, Sch Med, Moores Canc Ctr, La Jolla, CA 92093 USA.
   [Tamayo, Pablo; Mesirov, Jill P.] Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA.
   [Yang, Wan Seok] St Johns Univ, Dept Biol Sci, 8000 Utopia Pkwy, Queens, NY 11439 USA.
   [Javaid, Sarah; Haber, Daniel A.] Massachusetts Gen Hosp, Ctr Canc, 149 13th St, Charlestown, MA 02129 USA.
   [Haber, Daniel A.; Schreiber, Stuart L.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
   [Engelman, Jeffrey A.] Novartis Inst Biomed Res, Oncol Dis Area, Cambridge, MA 02139 USA.
   [Stockwell, Brent R.] Columbia Univ, Dept Chem, Dept Biol Sci, 550 West 120th St, New York, NY 10027 USA.
   [Schreiber, Stuart L.] Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA.
C3 Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Translational Genomics Research Institute; University of Zurich; University Zurich Hospital; Memorial Sloan Kettering Cancer Center; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; University of California System; University of California San Diego; University of California System; University of California San Diego; St. John's University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Howard Hughes Medical Institute; Novartis; Novartis USA; Columbia University; Harvard University
RP Schreiber, SL (corresponding author), Broad Inst, 415 Main St, Cambridge, MA 02142 USA.; Schreiber, SL (corresponding author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.; Schreiber, SL (corresponding author), Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA.
EM stuart_schreiber@harvard.edu
FU National Cancer Institute (Cancer Target Discovery and Development Network) [U01CA176152, U01CA168397, 5R01CA097061, R01CA161061, NCI-CA129933, P30CA008748]; National Institutes of Health [R01GM038627, 5R01GM085081]; Swiss National Fund [310030_149946]; Howard Hughes Medical Institute; Swiss National Science Foundation (SNF) [310030_149946] Funding Source: Swiss National Science Foundation (SNF); National Cancer Institute [P50CA092629, U01CA176058, U01CA217848, R01CA193837, P30CA008748, R01CA129933, R35CA209896, R01CA208100, K08CA218420] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK043351] Funding Source: NIH RePORTER
NR 35
TC 1317
Z9 1477
U1 13
U2 424
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 27
PY 2017
VL 547
IS 7664
BP 453
EP +
DI 10.1038/nature23007
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB7ZK
UT WOS:000406358300036
PM 28678785
DA 2026-03-09
ER

PT J
AU Gutjahr, M
   Ridgwell, A
   Sexton, PF
   Anagnostou, E
   Pearson, PN
   Pälike, H
   Norris, RD
   Thomas, E
   Foster, GL
AF Gutjahr, Marcus
   Ridgwell, Andy
   Sexton, Philip F.
   Anagnostou, Eleni
   Pearson, Paul N.
   Paelike, Heiko
   Norris, Richard D.
   Thomas, Ellen
   Foster, Gavin L.
TI Very large release of mostly volcanic carbon during the Palaeocene-Eocene Thermal Maximum
SO NATURE
LA English
DT Article
ID boron isotopic composition; atmospheric co2; ph; constraints; seawater; methane; foraminifera; excursion; climate; events
AB The Palaeocene-Eocene Thermal Maximum(1,2) (PETM) was a global warming event that occurred about 56 million years ago, and is commonly thought to have been driven primarily by the destabilization of carbon from surface sedimentary reservoirs such as methane hydrates(3). However, it remains controversial whether such reservoirs were indeed the source of the carbon that drove the warming(1,3-5). Resolving this issue is key to understanding the proximal cause of the warming, and to quantifying the roles of triggers versus feedbacks. Here we present boron isotope data-a proxy for seawater pH-that show that the ocean surface pH was persistently low during the PETM. We combine our pH data with a paired carbon isotope record in an Earth system model in order to reconstruct the unfolding carbon-cycle dynamics during the event(6,7). We find strong evidence for a much larger (more than 10,000 petagrams)-and, on average, isotopically heavier-carbon source than considered previously(8,9). This leads us to identify volcanism associated with the North Atlantic Igneous Province(10,11), rather than carbon from a surface reservoir, as the main driver of the PETM. This finding implies that climate-driven amplification of organic carbon feedbacks probably played only a minor part in driving the event. However, we find that enhanced burial of organic matter seems to have been important in eventually sequestering the released carbon and accelerating the recovery of the Earth system(12).
C1 [Gutjahr, Marcus; Anagnostou, Eleni; Foster, Gavin L.] Univ Southampton, Natl Oceanog Ctr Southampton, Ocean & Earth Sci, Southampton SO17 1BJ, Hants, England.
   [Gutjahr, Marcus] GEOMAR Helmholtz Ctr Ocean Res Kiel, Wischhofstr 1-3, D-24148 Kiel, Germany.
   [Ridgwell, Andy] Univ Bristol, Sch Geog Sci, Bristol BS8 1SS, Avon, England.
   [Ridgwell, Andy] Univ Calif Riverside, Dept Earth Sci, Riverside, CA 92521 USA.
   [Sexton, Philip F.] Open Univ, Sch Environm Earth & Ecosyst Sci, Milton Keynes MK7 6AA, Bucks, England.
   [Pearson, Paul N.] Cardiff Univ, Sch Earth & Ocean Sci, Cardiff CF10 3AT, S Glam, Wales.
   [Paelike, Heiko] Univ Bremen, Ctr Marine Environm Sci, MARUM, D-28359 Bremen, Germany.
   [Norris, Richard D.] Univ Calif San Diego, Scripps Inst Oceanog, La Jolla, CA 92037 USA.
   [Thomas, Ellen] Yale Univ, Dept Geol & Geophys, POB 6666, New Haven, CT 06520 USA.
   [Thomas, Ellen] Wesleyan Univ, Dept Earth & Environm Sci, Middletown, CT 06459 USA.
C3 University of Southampton; NERC National Oceanography Centre; Helmholtz Association; GEOMAR Helmholtz Center for Ocean Research Kiel; University of Bristol; University of California System; University of California Riverside; Open University - UK; Cardiff University; University of Bremen; University of California System; University of California San Diego; Scripps Institution of Oceanography; Yale University; Wesleyan University
RP Gutjahr, M (corresponding author), Univ Southampton, Natl Oceanog Ctr Southampton, Ocean & Earth Sci, Southampton SO17 1BJ, Hants, England.; Gutjahr, M (corresponding author), GEOMAR Helmholtz Ctr Ocean Res Kiel, Wischhofstr 1-3, D-24148 Kiel, Germany.
EM mgutjahr@geomar.de
FU UK Ocean Acidification Research Program NERC/DEFRA/DECC grant [NE/H017518/1]; Heising-Simons Foundation award; EU [ERC 2013-CoG-617313]; National Science Foundation Division of Ocean Sciences [NSF OCE 1536611]; ERC [2013-CoG-617462]; NERC [NE/H017518/1, NE/I005595/1, NE/H017356/1, NE/D00876X/2] Funding Source: UKRI; Natural Environment Research Council [NE/H017356/1, NE/I005595/1, NE/D00876X/2, NE/H017518/1] Funding Source: researchfish
NR 74
TC 305
Z9 358
U1 20
U2 307
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 31
PY 2017
VL 548
IS 7669
BP 573
EP +
DI 10.1038/nature23646
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FF2BO
UT WOS:000408703100036
PM 28858305
DA 2026-03-09
ER

PT J
AU Moore, SJ
   Sowa, ST
   Schuchardt, C
   Deery, E
   Lawrence, AD
   Ramos, JV
   Billig, S
   Birkemeyer, C
   Chivers, PT
   Howard, MJ
   Rigby, SEJ
   Layer, G
   Warren, MJ
AF Moore, Simon J.
   Sowa, Sven T.
   Schuchardt, Christopher
   Deery, Evelyne
   Lawrence, Andrew D.
   Ramos, Jose Vazquez
   Billig, Susan
   Birkemeyer, Claudia
   Chivers, Peter T.
   Howard, Mark J.
   Rigby, Stephen E. J.
   Layer, Gunhild
   Warren, Martin J.
TI Elucidation of the biosynthesis of the methane catalyst coenzyme F430
SO NATURE
LA English
DT Article
ID yellow metal-free; m reductase; crystal-structure; methanogenic bacteria; anaerobic oxidation; nickel uptake; enzyme; identification; heme; biochemistry
AB Methane biogenesis in methanogens is mediated by methyl-coenzyme M reductase, an enzyme that is also responsible for the utilization of methane through anaerobic methane oxidation. The enzyme uses an ancillary factor called coenzyme F-430, a nickel-containing modified tetrapyrrole that promotes catalysis through a methyl radical/Ni( ii)-thiolate intermediate. However, it is unclear how coenzyme F-430 is synthesized from the common primogenitor uroporphyrinogen iii, incorporating 11 steric centres into the macrocycle, although the pathway must involve chelation, amidation, macrocyclic ring reduction, lactamization and carbocyclic ring formation. Here we identify the proteins that catalyse the biosynthesis of coenzyme F-430 from sirohydrochlorin, termed CfbA-CfbE, and demonstrate their activity. The research completes our understanding of how the repertoire of tetrapyrrole-based pigments are constructed, permitting the development of recombinant systems to use these metalloprosthetic groups more widely.
C1 [Moore, Simon J.; Deery, Evelyne; Lawrence, Andrew D.; Howard, Mark J.; Warren, Martin J.] Univ Kent, Sch Biosci, Giles Lane, Canterbury CT2 7NJ, Kent, England.
   [Sowa, Sven T.; Schuchardt, Christopher; Ramos, Jose Vazquez; Layer, Gunhild] Univ Leipzig, Inst Biochem, Bruderstr 34, D-04103 Leipzig, Germany.
   [Billig, Susan; Birkemeyer, Claudia] Univ Leipzig, Inst Analyt Chem, Linnestr 3, D-04103 Leipzig, Germany.
   [Chivers, Peter T.] Univ Durham, Dept Chem, Durham DH1 3LE, England.
   [Chivers, Peter T.] Univ Durham, Dept Biosci, Durham DH1 3LE, England.
   [Rigby, Stephen E. J.] Univ Manchester, Sch Chem, Manchester Inst Biotechnol, 131 Princess St, Manchester M1 7DN, Lancs, England.
C3 University of Kent; Leipzig University; Leipzig University; Durham University; Durham University; University of Manchester
RP Warren, MJ (corresponding author), Univ Kent, Sch Biosci, Giles Lane, Canterbury CT2 7NJ, Kent, England.; Layer, G (corresponding author), Univ Leipzig, Inst Biochem, Bruderstr 34, D-04103 Leipzig, Germany.
EM gunhild.layer@uni-leipzig.de; m.j.warren@kent.ac.uk
FU Boehringer Ingelheim Foundation; Deutsche Forschungsgemeinschaft [LA2412/6-1]; Biotechnology and Biological Sciences Research Council (BBSRC) [68/B19356, BB/I012079]; BBSRC [B19356/2, BB/L010208/1, BB/E013007/1, BB/K009249/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/K009249/1, BB/E013007/1, BB/L010208/1, B19356/2] Funding Source: researchfish
NR 42
TC 103
Z9 123
U1 3
U2 122
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 2
PY 2017
VL 543
IS 7643
BP 78
EP +
DI 10.1038/nature21427
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0AA
UT WOS:000395671500035
PM 28225763
DA 2026-03-09
ER

PT J
AU Lloyd-Price, J
   Mahurkar, A
   Ahnavard, GR
   Rabtree, JC
   Rvis, JO
   Hall, ABR
   Rady, AB
   Reasy, HHC
   McCracken, C
   Giglio, MG
   McDonald, D
   Franzosa, EA
   Knight, R
   White, O
   Huttenhower, C
AF Lloyd-Price, Jason
   Mahurkar, Anup
   Ahnavard, Gholamali R.
   Rabtree, Jonathan C.
   Rvis, Joshua O.
   Hall, A. B. Rantley
   Rady, Arthur B.
   Reasy, Heather H. C.
   McCracken, Carrie
   Giglio, Michelle G.
   McDonald, Daniel
   Franzosa, Eric A.
   Knight, Rob
   White, Owen
   Huttenhower, Curtis
TI Strains, functions and dynamics in the expanded Human Microbiome Project
SO NATURE
LA English
DT Article
ID metabolic pathways; biocyc collection; metacyc database; single-cell; catalog; uniprot; enzymes; search; uniref; life
AB The characterization of baseline microbial and functional diversity in the human microbiome has enabled studies of microbiome-related disease, diversity, biogeography, and molecular function. The National Institutes of Health Human Microbiome Project has provided one of the broadest such characterizations so far. Here we introduce a second wave of data from the study, comprising 1,631 new metagenomes (2,355 total) targeting diverse body sites with multiple time points in 265 individuals. We applied updated profiling and assembly methods to provide new characterizations of microbiome personalization. Strain identification revealed subspecies clades specific to body sites; it also quantified species with phylogenetic diversity under-represented in isolate genomes. Body-wide functional profiling classified pathways into universal, human-enriched, and body site-enriched subsets. Finally, temporal analysis decomposed microbial variation into rapidly variable, moderately variable, and stable subsets. This study furthers our knowledge of baseline human microbial diversity and enables an understanding of personalized microbiome function and dynamics.
C1 [Lloyd-Price, Jason; Ahnavard, Gholamali R.; Franzosa, Eric A.; Huttenhower, Curtis] Harvard TH Chan Sch Publ Hlth, Biostat Dept, Boston, MA 02115 USA.
   [Lloyd-Price, Jason; Ahnavard, Gholamali R.; Hall, A. B. Rantley; Franzosa, Eric A.; Huttenhower, Curtis] Broad Inst, Cambridge, MA 02142 USA.
   [Mahurkar, Anup; Rabtree, Jonathan C.; Rvis, Joshua O.; Rady, Arthur B.; Reasy, Heather H. C.; McCracken, Carrie; Giglio, Michelle G.; White, Owen] Univ Maryland, Sch Med, Inst Gnome Sci, Baltimore, MD 21201 USA.
   [McDonald, Daniel; Knight, Rob] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA.
   [Knight, Rob] Univ Calif San Diego, Dept Comp Sci & Engn, La Jolla, CA 92093 USA.
C3 Harvard University; Harvard T.H. Chan School of Public Health; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University System of Maryland; University of Maryland Baltimore; University of California System; University of California San Diego; University of California System; University of California San Diego
RP Huttenhower, C (corresponding author), Harvard TH Chan Sch Publ Hlth, Biostat Dept, Boston, MA 02115 USA.; Huttenhower, C (corresponding author), Broad Inst, Cambridge, MA 02142 USA.
EM chuttenh@hsph.harvard.edu
FU National Institutes of Health (NIH) grants [U54DK102557, U54HG004969, U54HG004973, U54AI084844, U54HG004968, U54HG003079, U01HG006537, R01HG004872, U01HG004866]; Crohn's & Colitis Foundation of America (CCFA) award [3162]; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK043351] Funding Source: NIH RePORTER
NR 68
TC 897
Z9 1090
U1 4
U2 223
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 5
PY 2017
VL 550
IS 7674
BP 61
EP +
DI 10.1038/nature23889
PG 25
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI7XU
UT WOS:000412214100044
PM 28953883
DA 2026-03-09
ER

PT J
AU Adamczyk, L
   Adkins, JK
   Agakishiev, G
   Aggarwal, MM
   Ahammed, Z
   Ajitanand, NN
   Alekseev, I
   Anderson, DM
   Aoyama, R
   Aparin, A
   Arkhipkin, D
   Aschenauer, EC
   Ashraf, MU
   Attri, A
   Averichev, GS
   Bai, X
   Bairathi, V
   Behera, A
   Bellwied, R
   Bhasin, A
   Bhati, AK
   Bhattarai, P
   Bielcik, J
   Bielcikova, J
   Bland, LC
   Bordyuzhin, IG
   Bouchet, J
   Brandenburg, JD
   Brandin, AV
   Brown, D
   Bunzarov, I
   Butterworth, J
   Caines, H
   Sanchez, MCDLB
   Campbell, JM
   Cebra, D
   Chakaberia, I
   Chaloupka, P
   Chang, Z
   Chankova-Bunzarova, N
   Chatterjee, A
   Chattopadhyay, S
   Chen, X
   Chen, JH
   Chen, X
   Cheng, J
   Cherney, M
   Christie, W
   Contin, G
   Crawford, HJ
   Das, S
   De Silva, LC
   Debbe, RR
   Dedovich, TG
   Deng, J
   Derevschikov, AA
   Didenko, L
   Dilks, C
   Dong, X
   Drachenberg, JL
   Draper, JE
   Dunkelberger, LE
   Dunlop, JC
   Efimov, LG
   Elsey, N
   Engelage, J
   Eppley, G
   Esha, R
   Esumi, S
   Evdokimov, O
   Ewigleben, J
   Eyser, O
   Fatemi, R
   Fazio, S
   Federic, P
   Federicova, P
   Fedorisin, J
   Feng, Z
   Filip, P
   Finch, E
   Fisyak, Y
   Flores, CE
   Fulek, L
   Gagliardi, CA
   Garand, D
   Geurts, F
   Gibson, A
   Girard, M
   Grosnick, D
   Gunarathne, DS
   Guo, Y
   Gupta, A
   Gupta, S
   Guryn, W
   Hamad, AI
   Hamed, A
   Harlenderova, A
   Harris, JW
   He, L
   Heppelmann, S
   Heppelmann, S
   Hirsch, A
   Hoffmann, GW
   Horvat, S
   Huang, T
   Huang, B
   Huang, X
   Huang, HZ
   Humanic, TJ
   Huo, P
   Igo, G
   Jacobs, WW
   Jentsch, A
   Jia, J
   Jiang, K
   Jowzaee, S
   Judd, EG
   Kabana, S
   Kalinkin, D
   Kang, K
   Kauder, K
   Ke, HW
   Keane, D
   Kechechyan, A
   Khan, Z
   Kikola, DP
   Kisel, I
   Kisiel, A
   Kochenda, L
   Kocmanek, M
   Kollegger, T
   Kosarzewski, LK
   Kraishan, AF
   Kravtsov, P
   Krueger, K
   Kulathunga, N
   Kumar, L
   Kvapil, J
   Kwasizur, JH
   Lacey, R
   Landgraf, JM
   Landry, KD
   Lauret, J
   Lebedev, A
   Lednicky, R
   Lee, JH
   Li, X
   Li, C
   Li, W
   Li, Y
   Lidrych, J
   Lin, T
   Lisa, MA
   Liu, H
   Liu, P
   Liu, Y
   Liu, F
   Ljubicic, T
   Llope, WJ
   Lomnitz, M
   Longacre, RS
   Luo, S
   Luo, X
   Ma, GL
   Ma, L
   Ma, YG
   Ma, R
   Magdy, N
   Majka, R
   Mallick, D
   Margetis, S
   Markert, C
   Matis, HS
   Meehan, K
   Mei, JC
   Miller, ZW
   Minaev, NG
   Mioduszewski, S
   Mishra, D
   Mizuno, S
   Mohanty, B
   Mondal, MM
   Morozov, DA
   Mustafa, MK
   Nasim, M
   Nayak, TK
   Nelson, JM
   Nie, M
   Nigmatkulov, G
   Niida, T
   Nogach, LV
   Nonaka, T
   Nurushev, SB
   Odyniec, G
   Ogawa, A
   Oh, K
   Okorokov, VA
   Olvitt, D
   Page, BS
   Pak, R
   Pandit, Y
   Panebratsev, Y
   Pawlik, B
   Pei, H
   Perkins, C
   Pile, P
   Pluta, J
   Poniatowska, K
   Porter, J
   Posik, M
   Poskanzer, AM
   Pruthi, NK
   Przybycien, M
   Putschke, J
   Qiu, H
   Quintero, A
   Ramachandran, S
   Ray, RL
   Reed, R
   Rehbein, MJ
   Ritter, HG
   Roberts, JB
   Rogachevskiy, OV
   Romero, JL
   Roth, JD
   Ruan, L
   Rusnak, J
   Rusnakova, O
   Sahoo, NR
   Sahu, PK
   Salur, S
   Sandweiss, J
   Saur, M
   Schambach, J
   Schmah, AM
   Schmidke, WB
   Schmitz, N
   Schweid, BR
   Seger, J
   Sergeeva, M
   Seyboth, P
   Shah, N
   Shahaliev, E
   Shanmuganathan, PV
   Shao, M
   Sharma, A
   Sharma, MK
   Shen, WQ
   Shi, Z
   Shi, SS
   Shou, QY
   Sichtermann, EP
   Sikora, R
   Simko, M
   Singha, S
   Skoby, MJ
   Smirnov, N
   Smirnov, D
   Solyst, W
   Song, L
   Sorensen, P
   Spinka, HM
   Srivastava, B
   Stanislaus, TDS
   Strikhanov, M
   Stringfellow, B
   Sugiura, T
   Sumbera, M
   Summa, B
   Sun, Y
   Sun, XM
   Sun, X
   Surrow, B
   Svirida, DN
   Tang, AH
   Tang, Z
   Taranenko, A
   Tarnowsky, T
   Tawfik, A
   Thader, J
   Thomas, JH
   Timmins, AR
   Tlusty, D
   Todoroki, T
   Tokarev, M
   Trentalange, S
   Tribble, RE
   Tribedy, P
   Tripathy, SK
   Trzeciak, BA
   Tsai, OD
   Ullrich, T
   Underwood, DG
   Upsal, I
   Van Buren, G
   Van Nieuwenhuizen, G
   Vasiliev, AN
   Videbaek, F
   Vokal, S
   Voloshin, SA
   Vossen, A
   Wang, G
   Wang, Y
   Wang, F
   Wang, Y
   Webb, JC
   Webb, G
   Wen, L
   Westfall, GD
   Wieman, H
   Wissink, SW
   Witt, R
   Wu, Y
   Xiao, ZG
   Xie, W
   Xie, G
   Xu, J
   Xu, N
   Xu, QH
   Xu, YF
   Xu, Z
   Yang, Y
   Yang, Q
   Yang, C
   Yang, S
   Ye, Z
   Ye, Z
   Yi, L
   Yip, K
   Yoo, IK
   Yu, N
   Zbroszczyk, H
   Zha, W
   Zhang, Z
   Zhang, XP
   Zhang, JB
   Zhang, S
   Zhang, J
   Zhang, Y
   Zhang, J
   Zhang, S
   Zhao, J
   Zhong, C
   Zhou, L
   Zhou, C
   Zhu, X
   Zhu, Z
   Zyzak, M
AF Adamczyk, L.
   Adkins, J. K.
   Agakishiev, G.
   Aggarwal, M. M.
   Ahammed, Z.
   Ajitanand, N. N.
   Alekseev, I.
   Anderson, D. M.
   Aoyama, R.
   Aparin, A.
   Arkhipkin, D.
   Aschenauer, E. C.
   Ashraf, M. U.
   Attri, A.
   Averichev, G. S.
   Bai, X.
   Bairathi, V.
   Behera, A.
   Bellwied, R.
   Bhasin, A.
   Bhati, A. K.
   Bhattarai, P.
   Bielcik, J.
   Bielcikova, J.
   Bland, L. C.
   Bordyuzhin, I. G.
   Bouchet, J.
   Brandenburg, J. D.
   Brandin, A. V.
   Brown, D.
   Bunzarov, I.
   Butterworth, J.
   Caines, H.
   Sanchez, M. Calderon De la Barca
   Campbell, J. M.
   Cebra, D.
   Chakaberia, I.
   Chaloupka, P.
   Chang, Z.
   Chankova-Bunzarova, N.
   Chatterjee, A.
   Chattopadhyay, S.
   Chen, X.
   Chen, J. H.
   Chen, X.
   Cheng, J.
   Cherney, M.
   Christie, W.
   Contin, G.
   Crawford, H. J.
   Das, S.
   De Silva, L. C.
   Debbe, R. R.
   Dedovich, T. G.
   Deng, J.
   Derevschikov, A. A.
   Didenko, L.
   Dilks, C.
   Dong, X.
   Drachenberg, J. L.
   Draper, J. E.
   Dunkelberger, L. E.
   Dunlop, J. C.
   Efimov, L. G.
   Elsey, N.
   Engelage, J.
   Eppley, G.
   Esha, R.
   Esumi, S.
   Evdokimov, O.
   Ewigleben, J.
   Eyser, O.
   Fatemi, R.
   Fazio, S.
   Federic, P.
   Federicova, P.
   Fedorisin, J.
   Feng, Z.
   Filip, P.
   Finch, E.
   Fisyak, Y.
   Flores, C. E.
   Fulek, L.
   Gagliardi, C. A.
   Garand, D.
   Geurts, F.
   Gibson, A.
   Girard, M.
   Grosnick, D.
   Gunarathne, D. S.
   Guo, Y.
   Gupta, A.
   Gupta, S.
   Guryn, W.
   Hamad, A. I.
   Hamed, A.
   Harlenderova, A.
   Harris, J. W.
   He, L.
   Heppelmann, S.
   Heppelmann, S.
   Hirsch, A.
   Hoffmann, G. W.
   Horvat, S.
   Huang, T.
   Huang, B.
   Huang, X.
   Huang, H. Z.
   Humanic, T. J.
   Huo, P.
   Igo, G.
   Jacobs, W. W.
   Jentsch, A.
   Jia, J.
   Jiang, K.
   Jowzaee, S.
   Judd, E. G.
   Kabana, S.
   Kalinkin, D.
   Kang, K.
   Kauder, K.
   Ke, H. W.
   Keane, D.
   Kechechyan, A.
   Khan, Z.
   Kikola, D. P.
   Kisel, I.
   Kisiel, A.
   Kochenda, L.
   Kocmanek, M.
   Kollegger, T.
   Kosarzewski, L. K.
   Kraishan, A. F.
   Kravtsov, P.
   Krueger, K.
   Kulathunga, N.
   Kumar, L.
   Kvapil, J.
   Kwasizur, J. H.
   Lacey, R.
   Landgraf, J. M.
   Landry, K. D.
   Lauret, J.
   Lebedev, A.
   Lednicky, R.
   Lee, J. H.
   Li, X.
   Li, C.
   Li, W.
   Li, Y.
   Lidrych, J.
   Lin, T.
   Lisa, M. A.
   Liu, H.
   Liu, P.
   Liu, Y.
   Liu, F.
   Ljubicic, T.
   Llope, W. J.
   Lomnitz, M.
   Longacre, R. S.
   Luo, S.
   Luo, X.
   Ma, G. L.
   Ma, L.
   Ma, Y. G.
   Ma, R.
   Magdy, N.
   Majka, R.
   Mallick, D.
   Margetis, S.
   Markert, C.
   Matis, H. S.
   Meehan, K.
   Mei, J. C.
   Miller, Z. W.
   Minaev, N. G.
   Mioduszewski, S.
   Mishra, D.
   Mizuno, S.
   Mohanty, B.
   Mondal, M. M.
   Morozov, D. A.
   Mustafa, M. K.
   Nasim, Md.
   Nayak, T. K.
   Nelson, J. M.
   Nie, M.
   Nigmatkulov, G.
   Niida, T.
   Nogach, L. V.
   Nonaka, T.
   Nurushev, S. B.
   Odyniec, G.
   Ogawa, A.
   Oh, K.
   Okorokov, V. A.
   Olvitt, D., Jr.
   Page, B. S.
   Pak, R.
   Pandit, Y.
   Panebratsev, Y.
   Pawlik, B.
   Pei, H.
   Perkins, C.
   Pile, P.
   Pluta, J.
   Poniatowska, K.
   Porter, J.
   Posik, M.
   Poskanzer, A. M.
   Pruthi, N. K.
   Przybycien, M.
   Putschke, J.
   Qiu, H.
   Quintero, A.
   Ramachandran, S.
   Ray, R. L.
   Reed, R.
   Rehbein, M. J.
   Ritter, H. G.
   Roberts, J. B.
   Rogachevskiy, O. V.
   Romero, J. L.
   Roth, J. D.
   Ruan, L.
   Rusnak, J.
   Rusnakova, O.
   Sahoo, N. R.
   Sahu, P. K.
   Salur, S.
   Sandweiss, J.
   Saur, M.
   Schambach, J.
   Schmah, A. M.
   Schmidke, W. B.
   Schmitz, N.
   Schweid, B. R.
   Seger, J.
   Sergeeva, M.
   Seyboth, P.
   Shah, N.
   Shahaliev, E.
   Shanmuganathan, P. V.
   Shao, M.
   Sharma, A.
   Sharma, M. K.
   Shen, W. Q.
   Shi, Z.
   Shi, S. S.
   Shou, Q. Y.
   Sichtermann, E. P.
   Sikora, R.
   Simko, M.
   Singha, S.
   Skoby, M. J.
   Smirnov, N.
   Smirnov, D.
   Solyst, W.
   Song, L.
   Sorensen, P.
   Spinka, H. M.
   Srivastava, B.
   Stanislaus, T. D. S.
   Strikhanov, M.
   Stringfellow, B.
   Sugiura, T.
   Sumbera, M.
   Summa, B.
   Sun, Y.
   Sun, X. M.
   Sun, X.
   Surrow, B.
   Svirida, D. N.
   Tang, A. H.
   Tang, Z.
   Taranenko, A.
   Tarnowsky, T.
   Tawfik, A.
   Thader, J.
   Thomas, J. H.
   Timmins, A. R.
   Tlusty, D.
   Todoroki, T.
   Tokarev, M.
   Trentalange, S.
   Tribble, R. E.
   Tribedy, P.
   Tripathy, S. K.
   Trzeciak, B. A.
   Tsai, O. D.
   Ullrich, T.
   Underwood, D. G.
   Upsal, I.
   Van Buren, G.
   Van Nieuwenhuizen, G.
   Vasiliev, A. N.
   Videbaek, F.
   Vokal, S.
   Voloshin, S. A.
   Vossen, A.
   Wang, G.
   Wang, Y.
   Wang, F.
   Wang, Y.
   Webb, J. C.
   Webb, G.
   Wen, L.
   Westfall, G. D.
   Wieman, H.
   Wissink, S. W.
   Witt, R.
   Wu, Y.
   Xiao, Z. G.
   Xie, W.
   Xie, G.
   Xu, J.
   Xu, N.
   Xu, Q. H.
   Xu, Y. F.
   Xu, Z.
   Yang, Y.
   Yang, Q.
   Yang, C.
   Yang, S.
   Ye, Z.
   Ye, Z.
   Yi, L.
   Yip, K.
   Yoo, I-K.
   Yu, N.
   Zbroszczyk, H.
   Zha, W.
   Zhang, Z.
   Zhang, X. P.
   Zhang, J. B.
   Zhang, S.
   Zhang, J.
   Zhang, Y.
   Zhang, J.
   Zhang, S.
   Zhao, J.
   Zhong, C.
   Zhou, L.
   Zhou, C.
   Zhu, X.
   Zhu, Z.
   Zyzak, M.
TI Global Λ hyperon polarization in nuclear collisions
SO NATURE
LA English
DT Article
ID vorticity
AB The extreme energy densities generated by ultra-relativistic collisions between heavy atomic nuclei produce a state of matter that behaves surprisingly like a fluid, with exceptionally high temperature and low viscosity(1). Non-central collisions have angular momenta of the order of 1,000., and the resulting fluid may have a strong vortical structure(2-4) that must be understood to describe the fluid properly. The vortical structure is also of particular interest because the restoration of fundamental symmetries of quantum chromodynamics is expected to produce novel physical effects in the presence of strong vorticity(5). However, no experimental indications of fluid vorticity in heavy ion collisions have yet been found. Since vorticity represents a local rotational structure of the fluid, spin-orbit coupling can lead to preferential orientation of particle spins along the direction of rotation. Here we present measurements of an alignment between the global angular momentum of a non-central collision and the spin of emitted particles (in this case the collision occurs between gold nuclei and produces Lambda baryons), revealing that the fluid produced in heavy ion collisions is the most vortical system so far observed. (At high energies, this fluid is a quark-gluon plasma.) We find that Lambda and (Lambda) over bar hyperons show a positive polarization of the order of a few per cent, consistent with some hydrodynamic predictions(6). (A hyperon is a particle composed of three quarks, at least one of which is a strange quark; the remainder are up and down quarks, found in protons and neutrons.) A previous measurement(7) that reported a null result, that is, zero polarization, at higher collision energies is seen to be consistent with the trend of our observations, though with larger statistical uncertainties. These data provide experimental access to the vortical structure of the nearly ideal liquid(8) created in a heavy ion collision and should prove valuable in the development of hydrodynamic models that quantitatively connect observations to the theory of the strong force.
C1 [Adamczyk, L.; Fulek, L.; Przybycien, M.; Sikora, R.] AGH Univ Sci & Technol, FPACS, PL-30059 Krakow, Poland.
   [Adkins, J. K.; Fatemi, R.; Ramachandran, S.] Univ Kentucky, Lexington, KY 40506 USA.
   [Agakishiev, G.; Aparin, A.; Averichev, G. S.; Bunzarov, I.; Chankova-Bunzarova, N.; Dedovich, T. G.; Efimov, L. G.; Fedorisin, J.; Filip, P.; Kechechyan, A.; Lednicky, R.; Panebratsev, Y.; Rogachevskiy, O. V.; Shahaliev, E.; Tokarev, M.; Vokal, S.] Joint Inst Nucl Res, Dubna 141980, Russia.
   [Aggarwal, M. M.; Attri, A.; Bhati, A. K.; Kumar, L.; Pruthi, N. K.] Panjab Univ, Chandigarh 160014, India.
   [Ahammed, Z.; Chatterjee, A.; Chattopadhyay, S.; Nayak, T. K.] Variable Energy Cyclotron Ctr, Kolkata 700064, India.
   [Ajitanand, N. N.; Behera, A.; Huo, P.; Jia, J.; Lacey, R.; Liu, P.; Magdy, N.; Schweid, B. R.] SUNY Stony Brook, Stony Brook, NY 11794 USA.
   [Alekseev, I.; Bordyuzhin, I. G.; Svirida, D. N.] Alikhanov Inst Theoret & Expt Phys, Moscow 117218, Russia.
   [Alekseev, I.; Brandin, A. V.; Kochenda, L.; Kravtsov, P.; Nigmatkulov, G.; Okorokov, V. A.; Strikhanov, M.; Taranenko, A.] Natl Res Nucl Univ, MEPhI, Moscow 115409, Russia.
   [Anderson, D. M.; Chang, Z.; Gagliardi, C. A.; Hamed, A.; Liu, Y.; Mioduszewski, S.; Sahoo, N. R.; Tribble, R. E.] Texas A&M Univ, College Stn, TX 77843 USA.
   [Aoyama, R.; Ashraf, M. U.; Esumi, S.; Nonaka, T.; Sugiura, T.] Univ Tsukuba, Tsukuba, Ibaraki, Japan.
   [Arkhipkin, D.; Aschenauer, E. C.; Bland, L. C.; Chakaberia, I.; Christie, W.; Debbe, R. R.; Didenko, L.; Dunlop, J. C.; Eyser, O.; Fazio, S.; Fisyak, Y.; Guryn, W.; Jia, J.; Ke, H. W.; Landgraf, J. M.; Lauret, J.; Lebedev, A.; Lee, J. H.; Ljubicic, T.; Longacre, R. S.; Ma, R.; Ogawa, A.; Page, B. S.; Pak, R.; Pile, P.; Ruan, L.; Schmidke, W. B.; Smirnov, D.; Sorensen, P.; Tang, A. H.; Todoroki, T.; Tribedy, P.; Ullrich, T.; Van Buren, G.; Van Nieuwenhuizen, G.; Videbaek, F.; Webb, J. C.; Webb, G.; Xu, Z.; Yang, S.; Yip, K.] Brookhaven Natl Lab, Upton, NY 11973 USA.
   [Cheng, J.; Huang, X.; Kang, K.; Li, Y.; Wang, Y.; Xiao, Z. G.; Zhang, X. P.; Zhu, X.] Tsinghua Univ, Beijing 100084, Peoples R China.
   [Bai, X.; Das, S.; Feng, Z.; Liu, F.; Luo, X.; Pei, H.; Shi, S. S.; Sun, X. M.; Sun, X.; Wang, Y.; Xu, J.; Yu, N.; Zhang, J. B.] Cent China Normal Univ, Wuhan 430079, Hubei, Peoples R China.
   [Bairathi, V.; Mallick, D.; Mishra, D.; Mohanty, B.] Natl Inst Sci Educ & Res, Bhubaneswar 751005, Orissa, India.
   [Bellwied, R.; Kulathunga, N.; Song, L.; Timmins, A. R.] Univ Houston, Houston, TX 77204 USA.
   [Bhasin, A.; Gupta, A.; Gupta, S.; Sharma, A.; Sharma, M. K.] Univ Jammu, Jammu 180001, India.
   [Bhattarai, P.; Hoffmann, G. W.; Jentsch, A.; Markert, C.; Ray, R. L.; Schambach, J.] Univ Texas Austin, Austin, TX 78712 USA.
   [Bielcik, J.; Chaloupka, P.; Federicova, P.; Harlenderova, A.; Kvapil, J.; Lidrych, J.; Rusnakova, O.; Trzeciak, B. A.] Czech Tech Univ, FNSPE, Prague 11519, Czech Republic.
   [Bielcikova, J.; Federic, P.; Kocmanek, M.; Rusnak, J.; Saur, M.; Simko, M.; Sumbera, M.] Nucl Phys Inst AS CR, Prague 25068, Czech Republic.
   [Bouchet, J.; Guo, Y.; Hamad, A. I.; Kabana, S.; Keane, D.; Margetis, S.; Singha, S.; Wu, Y.] Kent State Univ, Kent, OH 44242 USA.
   [Brandenburg, J. D.; Butterworth, J.; Eppley, G.; Geurts, F.; Roberts, J. B.; Tlusty, D.] Rice Univ, Houston, TX 77251 USA.
   [Brown, D.; Ewigleben, J.; Reed, R.; Shanmuganathan, P. V.] Lehigh Univ, Bethlehem, PA 18015 USA.
   [Caines, H.; Harris, J. W.; Horvat, S.; Majka, R.; Sandweiss, J.; Smirnov, N.; Yi, L.] Yale Univ, New Haven, CT 06520 USA.
   [Sanchez, M. Calderon De la Barca; Cebra, D.; Draper, J. E.; Flores, C. E.; Heppelmann, S.; Meehan, K.; Romero, J. L.] Univ Calif Davis, Davis, CA 95616 USA.
   [Campbell, J. M.; Humanic, T. J.; Lisa, M. A.; Upsal, I.] Ohio State Univ, Columbus, OH 43210 USA.
   [Chen, X.; Jiang, K.; Li, X.; Li, C.; Shao, M.; Sun, Y.; Tang, Z.; Xie, G.; Yang, Q.; Zha, W.; Zhang, S.; Zhang, Y.; Zhou, L.] Univ Sci & Technol China, Hefei 230026, Anhui, Peoples R China.
   [Chen, J. H.; Li, W.; Ma, G. L.; Ma, L.; Ma, Y. G.; Nie, M.; Shah, N.; Shen, W. Q.; Shou, Q. Y.; Xu, Y. F.; Zhang, Z.; Zhang, S.; Zhong, C.; Zhou, C.] Chinese Acad Sci, Shanghai Inst Appl Phys, Shanghai 201800, Peoples R China.
   [Chen, X.; Zhang, J.] Chinese Acad Sci, Inst Modern Phys, Lanzhou 730000, Gansu, Peoples R China.
   [Cherney, M.; De Silva, L. C.; Rehbein, M. J.; Roth, J. D.; Seger, J.] Creighton Univ, Omaha, NE 68178 USA.
   [Contin, G.; Dong, X.; Lomnitz, M.; Matis, H. S.; Mizuno, S.; Mustafa, M. K.; Odyniec, G.; Porter, J.; Poskanzer, A. M.; Ritter, H. G.; Salur, S.; Schmah, A. M.; Shi, Z.; Sichtermann, E. P.; Thader, J.; Thomas, J. H.; Wieman, H.; Xu, N.; Zhang, J.] Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA.
   [Crawford, H. J.; Engelage, J.; Judd, E. G.; Nelson, J. M.; Perkins, C.] Univ Calif Berkeley, Berkeley, CA 94720 USA.
   [Deng, J.; Mei, J. C.; Xu, Q. H.; Yang, C.; Zhu, Z.] Shandong Univ, Jinan 250100, Shandong, Peoples R China.
   [Derevschikov, A. A.; Minaev, N. G.; Morozov, D. A.; Nogach, L. V.; Nurushev, S. B.; Vasiliev, A. N.] Inst High Energy Phys, Protvino 142281, Russia.
   [Dilks, C.; Heppelmann, S.; Summa, B.] Penn State Univ, University Pk, PA 16802 USA.
   [Drachenberg, J. L.] Lamar Univ, Dept Phys, Beaumont, TX 77710 USA.
   [Dunkelberger, L. E.; Esha, R.; Huang, H. Z.; Igo, G.; Landry, K. D.; Nasim, Md.; Sergeeva, M.; Trentalange, S.; Tsai, O. D.; Wang, G.; Wen, L.] Univ Calif Los Angeles, Los Angeles, CA 90095 USA.
   [Elsey, N.; Jowzaee, S.; Kauder, K.; Llope, W. J.; Niida, T.; Putschke, J.; Voloshin, S. A.] Wayne State Univ, Detroit, MI 48201 USA.
   [Evdokimov, O.; Huang, B.; Khan, Z.; Luo, S.; Miller, Z. W.; Pandit, Y.; Ye, Z.; Ye, Z.] Univ Illinois, Chicago, IL 60607 USA.
   [Finch, E.] Southern Connecticut State Univ, New Haven, CT 06515 USA.
   [Garand, D.; He, L.; Hirsch, A.; Qiu, H.; Srivastava, B.; Stringfellow, B.; Wang, F.; Xie, W.; Zhao, J.] Purdue Univ, W Lafayette, IN 47907 USA.
   [Gibson, A.; Grosnick, D.; Stanislaus, T. D. S.] Valparaiso Univ, Valparaiso, IN 46383 USA.
   [Girard, M.; Kikola, D. P.; Kisiel, A.; Kosarzewski, L. K.; Pluta, J.; Poniatowska, K.; Zbroszczyk, H.] Warsaw Univ Technol, PL-00661 Warsaw, Poland.
   [Gunarathne, D. S.; Kraishan, A. F.; Olvitt, D., Jr.; Posik, M.; Quintero, A.; Surrow, B.] Temple Univ, Philadelphia, PA 19122 USA.
   [Huang, T.; Yang, Y.] Natl Cheng Kung Univ, Tainan 70101, Taiwan.
   [Jacobs, W. W.; Kalinkin, D.; Kwasizur, J. H.; Lin, T.; Liu, H.; Skoby, M. J.; Solyst, W.; Vossen, A.; Wissink, S. W.] Indiana Univ, Bloomington, IN 47408 USA.
   [Kisel, I.; Kollegger, T.; Zyzak, M.] FIAS, D-60438 Frankfurt, Germany.
   [Krueger, K.; Spinka, H. M.; Underwood, D. G.] Argonne Natl Lab, 9700 S Cass Ave, Argonne, IL 60439 USA.
   [Mondal, M. M.] Inst Phys, Bhubaneswar 751005, Orissa, India.
   [Oh, K.; Yoo, I-K.] Pusan Natl Univ, Pusan 46241, South Korea.
   [Pawlik, B.] PAN, Inst Nucl Phys, PL-31342 Krakow, Poland.
   [Schmitz, N.; Seyboth, P.] Max Planck Inst Phys & Astrophys, D-80805 Munich, Germany.
   [Tarnowsky, T.; Westfall, G. D.] Michigan State Univ, E Lansing, MI 48824 USA.
   [Tawfik, A.] World Lab Cosmol & Particle Phys WLCAPP, Cairo 11571, Egypt.
   [Witt, R.] US Naval Acad, Annapolis, MD 21402 USA.
C3 AGH University of Krakow; University of Kentucky; Joint Institute for Nuclear Research - Russia; Panjab University; Variable Energy Cyclotron Centre; State University of New York (SUNY) System; Stony Brook University; National Research Centre - Kurchatov Institute; Alikhanov Institute for Theoretical & Experimental Physics; National Research Nuclear University MEPhI (Moscow Engineering Physics Institute); Texas A&M University System; Texas A&M University College Station; University of Tsukuba; United States Department of Energy (DOE); Brookhaven National Laboratory; Tsinghua University; Central China Normal University; National Institute of Science Education & Research (NISER); University of Houston System; University of Houston; University of Jammu; University of Texas System; University of Texas Austin; Czech Technical University Prague; Czech Academy of Sciences; Nuclear Physics Institute of the Czech Academy of Sciences; University System of Ohio; Kent State University; Kent State University Kent; Kent State University Salem; Rice University; Lehigh University; Yale University; University of California System; University of California Davis; University System of Ohio; Ohio State University; Chinese Academy of Sciences; University of Science & Technology of China, CAS; Chinese Academy of Sciences; Shanghai Institute of Applied Physics, CAS; Chinese Academy of Sciences; Institute of Modern Physics, CAS; Creighton University; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; University of California System; University of California Berkeley; Shandong University; National Research Centre - Kurchatov Institute; Institute of High Energy Physics - IHEP; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Texas State University System; Lamar University; University of California System; University of California Los Angeles; Wayne State University; University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital; Connecticut State University System; Southern Connecticut State University; Purdue University System; Purdue University; Valparaiso University; Warsaw University of Technology; Pennsylvania Commonwealth System of Higher Education (PCSHE); Temple University; National Cheng Kung University; Indiana University System; Indiana University Bloomington; United States Department of Energy (DOE); Argonne National Laboratory; Institute of Physics Bhubaneswar (IOPB); Pusan National University; Polish Academy of Sciences; Institute of Nuclear Physics - Polish Academy of Sciences; Max Planck Society; Michigan State University; United States Department of Defense; United States Navy; United States Naval Academy
RP Adamczyk, L (corresponding author), AGH Univ Sci & Technol, FPACS, PL-30059 Krakow, Poland.
FU RHIC Operations Group; RCF at Brookhaven National Laboratory; NERSC Center at Lawrence Berkeley National Laboratory; Open Science Grid consortium; Office of Nuclear Physics within the US Department of Energy Office of Science; US National Science Foundation; Ministry of Education and Science of the Russian Federation; National Natural Science Foundation of China; Chinese Academy of Science; Ministry of Science and Technology of China; Chinese Ministry of Education; National Research Foundation of Korea; GA of the Czech Republic; MSMT of the Czech Republic; Department of Atomic Energy; Department of Science and Technology of the Government of India; National Science Centre of Poland; National Research Foundation; Ministry of Science, Education and Sports of Croatia; RosAtom of Russia; Direct For Mathematical & Physical Scien; Division Of Physics [1613939, 1614835] Funding Source: National Science Foundation; Direct For Mathematical & Physical Scien; Division Of Physics [1307188] Funding Source: National Science Foundation
NR 30
TC 735
Z9 821
U1 0
U2 104
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 3
PY 2017
VL 548
IS 7665
BP 62
EP +
DI 10.1038/nature23004
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FC4SU
UT WOS:000406831700036
PM 28770839
DA 2026-03-09
ER

PT J
AU Zhao, WX
   Steinfeld, JB
   Liang, FS
   Chen, XY
   Maranon, DG
   Ma, CJ
   Kwon, Y
   Rao, T
   Wang, WB
   Sheng, C
   Song, XM
   Deng, YH
   Jimenez-Sainz, J
   Lu, L
   Jensen, RB
   Xiong, Y
   Kupfer, GM
   Wiese, C
   Greene, EC
   Sung, P
AF Zhao, Weixing
   Steinfeld, Justin B.
   Liang, Fengshan
   Chen, Xiaoyong
   Maranon, David G.
   Ma, Chu Jian
   Kwon, Youngho
   Rao, Timsi
   Wang, Weibin
   Sheng, Chen
   Song, Xuemei
   Deng, Yanhong
   Jimenez-Sainz, Judit
   Lu, Lucy
   Jensen, Ryan B.
   Xiong, Yong
   Kupfer, Gary M.
   Wiese, Claudia
   Greene, Eric C.
   Sung, Patrick
TI BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing
SO NATURE
LA English
DT Article
ID domain bard1 gene; genomic stability; tumor suppression; strand exchange; cancer genomics; primary breast; brca1; recombination; repair; ovarian
AB The tumour suppressor complex BRCA1-BARD1 functions in the repair of DNA double-stranded breaks by homologous recombination. During this process, BRCA1-BARD1 facilitates the nucleolytic resection of DNA ends to generate a single-stranded template for the recruitment of another tumour suppressor complex, BRCA2-PALB2, and the recombinase RAD51. Here, by examining purified wild-type and mutant BRCA1-BARD1, we show that both BRCA1 and BARD1 bind DNA and interact with RAD51, and that BRCA1-BARD1 enhances the recombinase activity of RAD51. Mechanistically, BRCA1-BARD1 promotes the assembly of the synaptic complex, an essential intermediate in RAD51-mediated DNA joint formation. We provide evidence that BRCA1 and BARD1 are indispensable for RAD51 stimulation. Notably, BRCA1-BARD1 mutants with weakened RAD51 interactions show compromised DNA joint formation and impaired mediation of homologous recombination and DNA repair in cells. Our results identify a late role of BRCA1-BARD1 in homologous recombination, an attribute of the tumour suppressor complex that could be targeted in cancer therapy.
C1 [Zhao, Weixing; Liang, Fengshan; Kwon, Youngho; Rao, Timsi; Wang, Weibin; Sheng, Chen; Lu, Lucy; Xiong, Yong; Sung, Patrick] Yale Univ, Dept Mol Biophys & Biochem, Sch Med, POB 6666, New Haven, CT 06520 USA.
   [Steinfeld, Justin B.; Ma, Chu Jian; Greene, Eric C.] Columbia Univ, Dept Biochem & Mol Biophys, 630 W 168th St, New York, NY 10032 USA.
   [Liang, Fengshan; Chen, Xiaoyong; Kupfer, Gary M.] Yale Univ, Sch Med, Dept Pediat, Sect Hematol Oncol, 333 Cedar St, New Haven, CT 06520 USA.
   [Liang, Fengshan; Chen, Xiaoyong; Kupfer, Gary M.] Yale Univ, Sch Med, Dept Pathol, 333 Cedar St, New Haven, CT 06520 USA.
   [Maranon, David G.; Wiese, Claudia] Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA.
   [Song, Xuemei; Deng, Yanhong] Yale Sch Publ Hlth, Yale Ctr Analyt Sci, New Haven, CT USA.
   [Jimenez-Sainz, Judit; Jensen, Ryan B.; Sung, Patrick] Yale Univ, Sch Med, Dept Therapeut Radiol, 333 Cedar St, New Haven, CT 06520 USA.
   [Sheng, Chen] Sichuan Univ, West China Hosp, Chengdu 610041, Sichuan, Peoples R China.
C3 Yale University; Columbia University; Yale University; Yale University; Colorado State University System; Colorado State University Fort Collins; Yale University; Yale University; Sichuan University
RP Zhao, WX; Sung, P (corresponding author), Yale Univ, Dept Mol Biophys & Biochem, Sch Med, POB 6666, New Haven, CT 06520 USA.; Greene, EC (corresponding author), Columbia Univ, Dept Biochem & Mol Biophys, 630 W 168th St, New York, NY 10032 USA.; Sung, P (corresponding author), Yale Univ, Sch Med, Dept Therapeut Radiol, 333 Cedar St, New Haven, CT 06520 USA.
EM weixing.zhao@yale.edu; ecg2108@cumc.columbia.edu; patrick.sung@yale.edu
FU US National Institutes of Health [ES007061, CA220123, CA168635, CA92584, ES021454, CA215990, R35GM118026]; NIH [F31CA210663]; Basser Innovation Award from the Basser Center for BRCA at Penn Medicine's Abramson Cancer Center; National Cancer Institute [R01CA168635, R01CA215990, P01CA092584] Funding Source: NIH RePORTER; National Center for Advancing Translational Sciences [UL1TR001863] Funding Source: NIH RePORTER; National Institute of Environmental Health Sciences [R01ES007061] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R35GM118026] Funding Source: NIH RePORTER
NR 55
TC 288
Z9 364
U1 2
U2 90
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 19
PY 2017
VL 550
IS 7676
BP 360
EP 365
DI 10.1038/nature24060
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK1NF
UT WOS:000413247900054
PM 28976962
DA 2026-03-09
ER

PT J
AU Baik, S
   Kim, DW
   Park, Y
   Lee, TJ
   Bhang, SH
   Pang, C
AF Baik, Sangyul
   Kim, Da Wan
   Park, Youngjin
   Lee, Tae-Jin
   Bhang, Suk Ho
   Pang, Changhyun
TI A wet-tolerant adhesive patch inspired by protuberances in suction cups of octopi
SO NATURE
LA English
DT Article
ID polymer; mold
AB Adhesion strategies that rely on mechanical interlocking or molecular attractions between surfaces can suffer when coming into contact with liquids(1,2). Thus far, artificial wet and dry adhesives have included hierarchical mushroom-shaped or porous structures that allow suction or capillarity(3-6), supramolecular structures comprising nanoparticles(7), and chemistry-based attractants that use various protein polyelectrolytes(8-10). However, it is challenging to develop adhesives that are simple to make and also perform well- and repeatedly-under both wet and dry conditions, while avoiding non-chemical contamination on the adhered surfaces(11). Here we present an artificial, biologically inspired, reversible wet/dry adhesion system that is based on the dome-like protuberances found in the suction cups of octopi. To mimic the architecture of these protuberances(12-14), we use a simple, solution-based, air-trap technique that involves fabricating a patterned structure as a polymeric master, and using it to produce a reversed architecture, without any sophisticated chemical syntheses or surface modifications. The micrometre-scale domes in our artificial adhesive enhance the suction stress. This octopus-inspired system exhibits strong, reversible, highly repeatable adhesion to silicon wafers, glass, and rough skin surfaces under various conditions (dry, moist, under water and under oil). To demonstrate a potential application, we also used our adhesive to transport a large silicon wafer in air and under water without any resulting surface contamination.
C1 [Baik, Sangyul; Kim, Da Wan; Park, Youngjin; Lee, Tae-Jin; Bhang, Suk Ho; Pang, Changhyun] Sungkyunkwan Univ, Sch Chem Engn, Suwon 16419, Kyunggi Do, South Korea.
   [Pang, Changhyun] Sungkyunkwan Univ, SKKU Adv Inst Nanotechnol SAINT, Suwon 16419, Kyunggi Do, South Korea.
   [Pang, Changhyun] Sungkyunkwan Univ, SAIHST, Suwon 16419, Kyunggi Do, South Korea.
C3 Sungkyunkwan University (SKKU); Sungkyunkwan University (SKKU); Sungkyunkwan University (SKKU)
RP Pang, C (corresponding author), Sungkyunkwan Univ, Sch Chem Engn, Suwon 16419, Kyunggi Do, South Korea.; Pang, C (corresponding author), Sungkyunkwan Univ, SKKU Adv Inst Nanotechnol SAINT, Suwon 16419, Kyunggi Do, South Korea.; Pang, C (corresponding author), Sungkyunkwan Univ, SAIHST, Suwon 16419, Kyunggi Do, South Korea.
EM chpang@skku.edu
FU National Research Foundation of Korea [NRF-2014R1A1A1007162, NRF-2016H1A2A1908670]; Korea Health Technology RD Project [HI17C1728]; Institute for Information and Communications Technology Promotion; Korea government [B0132-15-1003]; National Research Foundation of Korea; Ministry of Science, ICT and Future Planning [NRF-2015R1C1A1A01055224]
NR 20
TC 517
Z9 567
U1 25
U2 893
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 15
PY 2017
VL 546
IS 7658
BP 396
EP +
DI 10.1038/nature22382
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EX5BK
UT WOS:000403250900033
PM 28617467
DA 2026-03-09
ER

PT J
AU Risca, VI
   Denny, SK
   Straight, AF
   Greenleaf, WJ
AF Risca, Viviana I.
   Denny, Sarah K.
   Straight, Aaron F.
   Greenleaf, William J. .
TI Variable chromatin structure revealed by in situ spatially correlated DNA cleavage mapping
SO NATURE
LA English
DT Article
ID nucleosome; fiber; resolution; architecture; chromosm; cells; model; organization; sequence; compact
AB Chromatin structure at the length scale encompassing local nucleosome-nucleosome interactions is thought to play a crucial role in regulating transcription and access to DNA(1-3). However, this secondary structure of chromatin remains poorly understood compared with the primary structure of single nucleosomes or the tertiary structure of long-range looping interactions(4). Here we report the first genome-wide map of chromatin conformation in human cells at the 1-3 nucleosome (50-500 bp) scale, obtained using ionizing radiation-induced spatially correlated cleavage of DNA with sequencing (RICC-seq) to identify DNA-DNA contacts that are spatially proximal. Unbiased analysis of RICC-seq signal reveals regional enrichment of DNA fragments characteristic of alternating rather than adjacent nucleosome interactions in tri-nucleosome units, particularly in H3K9me3-marked heterochromatin. We infer differences in the likelihood of nucleosome-nucleosome contacts among open chromatin, H3K27me3-marked, and H3K9me3-marked repressed chromatin regions. After calibrating RICC-seq signal to three-dimensional distances, we show that compact two-start helical fibre structures with stacked alternating nucleosomes are consistent with RICC-seq fragmentation patterns from H3K9me3-marked chromatin, while non-compact structures and solenoid structures are consistent with open chromatin. Our data support a model of chromatin architecture in intact interphase nuclei consistent with variable longitudinal compaction of two-start helical fibres.
C1 [Risca, Viviana I.; Greenleaf, William J. .] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
   [Denny, Sarah K.; Greenleaf, William J. .] Stanford Univ, Biophys Program, Stanford, CA 94305 USA.
   [Straight, Aaron F.] Stanford Univ, Dept Biochem, Sch Med, Stanford, CA 94305 USA.
   [Straight, Aaron F.] Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 USA.
   [Greenleaf, William J. .] Stanford Univ, Dept Appl Phys, Sch Med, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; Stanford University; Stanford University; Stanford University
RP Greenleaf, WJ (corresponding author), Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.; Greenleaf, WJ (corresponding author), Stanford Univ, Biophys Program, Stanford, CA 94305 USA.; Greenleaf, WJ (corresponding author), Stanford Univ, Dept Appl Phys, Sch Med, Stanford, CA 94305 USA.
EM wjg@stanford.edu
FU Walter V. and Idun Berry Postdoctoral Fellowship; National Institutes of Health (NIH) Predoctoral Molecular Biophysics Training Program; National Science Foundation Graduate Fellowship; National Institutes of Health (NIH) [R01GM106005]; NIH [R21HG007726, P50HG00773501]; Rita Allen Foundation; Baxter Foundation; Human Frontier Science Program
NR 48
TC 121
Z9 143
U1 1
U2 27
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 12
PY 2017
VL 541
IS 7636
BP 237
EP +
DI 10.1038/nature20781
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6PI
UT WOS:000396125500045
PM 28024297
DA 2026-03-09
ER

PT J
AU Kasen, D
   Metzger, B
   Barnes, J
   Quataert, E
   Ramirez-Ruiz, E
AF Kasen, Daniel
   Metzger, Brian
   Barnes, Jennifer
   Quataert, Eliot
   Ramirez-Ruiz, Enrico
TI Origin of the heavy elements in binary neutron-star mergers from a gravitational-wave event
SO NATURE
LA English
DT Article
ID r-process; light curves; driven winds; nucleosynthesis; supernovae; outflows; opacity
AB The cosmic origin of elements heavier than iron has long been uncertain. Theoretical modelling(1-7) shows that the matter that is expelled in the violent merger of two neutron stars can assemble into heavy elements such as gold and platinum in a process known as rapid neutron capture (r-process) nucleosynthesis. The radioactive decay of isotopes of the heavy elements is predicted(8-12) to power a distinctive thermal glow (a 'kilonova'). The discovery of an electromagnetic counterpart to the gravitational-wave source(13) GW170817 represents the first opportunity to detect and scrutinize a sample of freshly synthesized r-process elements(14-18). Here we report models that predict the electromagnetic emission of kilonovae in detail and enable the mass, velocity and composition of ejecta to be derived from observations. We compare the models to the optical and infrared radiation associated with the GW170817 event to argue that the observed source is a kilonova. We infer the presence of two distinct components of ejecta, one composed primarily of light (atomic mass number less than 140) and one of heavy (atomic mass number greater than 140) r-process elements. The ejected mass and a merger rate inferred from GW170817 imply that such mergers are a dominant mode of r-process production in the Universe.
C1 [Kasen, Daniel; Quataert, Eliot] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Kasen, Daniel; Quataert, Eliot] Univ Calif Berkeley, Dept Astron, 601 Campbell Hall, Berkeley, CA 94720 USA.
   [Kasen, Daniel; Quataert, Eliot] Univ Calif Berkeley, Theoret Astrophys Ctr, Berkeley, CA 94720 USA.
   [Kasen, Daniel] Lawrence Berkeley Natl Lab, Nucl Sci Div, Berkeley, CA 94720 USA.
   [Metzger, Brian; Barnes, Jennifer] Columbia Univ, Dept Phys, 538 W 120th St, New York, NY 10027 USA.
   [Metzger, Brian; Barnes, Jennifer] Columbia Univ, Columbia Astrophys Lab, 538 W 120th St, New York, NY 10027 USA.
   [Ramirez-Ruiz, Enrico] Univ Santa Cruz, Dept Astron, Santa Cruz, CA USA.
   [Ramirez-Ruiz, Enrico] Univ Copenhagen, Niels Bohr Inst, DARK, Blegdamsvej 17, DK-2100 Copenhagen, Denmark.
C3 University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of California System; University of California Berkeley; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; Columbia University; Columbia University; University of California System; University of California Santa Cruz; University of Copenhagen; Niels Bohr Institute
RP Kasen, D (corresponding author), Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.; Kasen, D (corresponding author), Univ Calif Berkeley, Dept Astron, 601 Campbell Hall, Berkeley, CA 94720 USA.; Kasen, D (corresponding author), Univ Calif Berkeley, Theoret Astrophys Ctr, Berkeley, CA 94720 USA.; Kasen, D (corresponding author), Lawrence Berkeley Natl Lab, Nucl Sci Div, Berkeley, CA 94720 USA.
EM kasen@berkeley.edu
FU Department of Energy (DOE) Office early career award [DE-SC0008067]; DOE Office of Nuclear Physics [DE-SC0017616]; Office of Energy Research, Office of High Energy and Nuclear Physics, Divisions of Nuclear Physics, of the US DOE [DE-AC02-05CH11231]; DOE SciDAC [DE-SC0018297]; Niels Bohr Professorship - DNRF; UCMEXUS; David and Lucile Packard Foundation; Gordon and Betty Moore Foundation [GBMF5076]; Simons Foundation through a Simons Investigator Award; National Aeronautics and Space Administration (NASA) through the Einstein Fellowship Program [PF7-180162]; National Aeronautics Space Administration [NAS8-03060]; Office of Science of the US DOE [DE AC02-05CH11231]; U.S. Department of Energy (DOE) [DE-SC0008067, DE-SC0017616] Funding Source: U.S. Department of Energy (DOE)
NR 68
TC 904
Z9 1017
U1 2
U2 74
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 2
PY 2017
VL 551
IS 7678
BP 80
EP +
DI 10.1038/nature24453
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FL4SY
UT WOS:000414222900048
PM 29094687
DA 2026-03-09
ER

PT J
AU Mancio-Silva, L
   Slavic, K
   Ruivo, MTG
   Grosso, AR
   Modrzynska, KK
   Vera, IM
   Sales-Dias, J
   Gomes, AR
   MacPherson, CR
   Crozet, P
   Adamo, M
   Baena-Gonzalez, E
   Tewari, R
   Llinás, M
   Billker, O
   Mota, MM
AF Mancio-Silva, Liliana
   Slavic, Ksenija
   Ruivo, Margarida T. Grilo
   Grosso, Ana Rita
   Modrzynska, Katarzyna K.
   Vera, Iset Medina
   Sales-Dias, Joana
   Gomes, Ana Rita
   MacPherson, Cameron Ross
   Crozet, Pierre
   Adamo, Mattia
   Baena-Gonzalez, Elena
   Tewari, Rita
   Llinas, Manuel
   Billker, Oliver
   Mota, Maria M.
TI Nutrient sensing modulates malaria parasite virulence
SO NATURE
LA English
DT Article
ID differential expression analysis; activated protein-kinase; plasmodium-falciparum; calorie restriction; cerebral malaria; structural basis; blood stages; yeast; ancient; berghei
AB The lifestyle of intracellular pathogens, such as malaria parasites, is intimately connected to that of their host, primarily for nutrient supply. Nutrients act not only as primary sources of energy but also as regulators of gene expression, metabolism and growth, through various signalling networks that enable cells to sense and adapt to varying environmental conditions(1,2). Canonical nutrient-sensing pathways are presumed to be absent from the causative agent of malaria, Plasmodium(3-5), thus raising the question of whether these parasites can sense and cope with fluctuations in host nutrient levels. Here we show that Plasmodium blood-stage parasites actively respond to host dietary calorie alterations through rearrangement of their transcriptome accompanied by substantial adjustment of their multiplication rate. A kinome analysis combined with chemical and genetic approaches identified KIN as a critical regulator that mediates sensing of nutrients and controls a transcriptional response to the host nutritional status. KIN shares homology with SNF1/AMPK alpha, and yeast complementation studies suggest that it is part of a functionally conserved cellular energy-sensing pathway. Overall, these findings reveal a key parasite nutrient-sensing mechanism that is critical for modulating parasite replication and virulence.
C1 [Mancio-Silva, Liliana; Slavic, Ksenija; Ruivo, Margarida T. Grilo; Grosso, Ana Rita; Vera, Iset Medina; Sales-Dias, Joana; Mota, Maria M.] Univ Lisbon, Fac Med, Inst Med Mol, P-1649028 Lisbon, Portugal.
   [Modrzynska, Katarzyna K.; Gomes, Ana Rita; Billker, Oliver] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.
   [MacPherson, Cameron Ross] Inst Pasteur, F-75724 Paris, France.
   [Crozet, Pierre; Adamo, Mattia; Baena-Gonzalez, Elena] Inst Gulbenkian Ciencias, Oeiras, Portugal.
   [Tewari, Rita] Univ Nottingham, Sch Life Sci, Queens Med Ctr, Nottingham, England.
   [Llinas, Manuel] Penn State Univ, Ctr Malaria Res, Dept Chem, Dept Biochem & Mol Biol, State Coll, PA 16802 USA.
   [Llinas, Manuel] Penn State Univ, Ctr Infect Dis Dynam, State Coll, PA 16802 USA.
C3 Universidade de Lisboa; Wellcome Trust Sanger Institute; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Instituto Gulbenkian de Ciencia; University of Nottingham; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park
RP Mota, MM (corresponding author), Univ Lisbon, Fac Med, Inst Med Mol, P-1649028 Lisbon, Portugal.
EM mmota@medicina.ulisboa.pt
FU European Research Council [311502]; Fundacao para a Ciencia e Tecnologia (FCT) [EXCL/IMI-MIC/0056/2012, PTDC/SAU-MET/118199/2010]; European Commission (FP7) [EVIMALAR 242095]; EMBO LTF [ALTF 960-2009]; FCT fellowship [SFRH/BPD/111788/2015]; EMBO [LTF 712-2012]; NIH NRSA [5F32AI104252-03]; Wellcome Trust [098051]; Medical Research Council (MRC) [G0501670]; FCT [SFRH-BPD79255-2011, UID/Multi/04551/2013]; MRC [G0900109, MR/K011782/1]; Burroughs Wellcome Fund; NIH Director's New Innovators award [1DP2OD001315-01]; European Research Council [311502]; Fundacao para a Ciencia e Tecnologia (FCT) [EXCL/IMI-MIC/0056/2012, PTDC/SAU-MET/118199/2010]; European Commission (FP7) [EVIMALAR 242095]; EMBO LTF [ALTF 960-2009]; FCT fellowship [SFRH/BPD/111788/2015]; EMBO [LTF 712-2012]; NIH NRSA [5F32AI104252-03]; Wellcome Trust [098051]; Medical Research Council (MRC) [G0501670]; FCT [SFRH-BPD79255-2011, UID/Multi/04551/2013]; MRC [G0900109, MR/K011782/1]; Burroughs Wellcome Fund; NIH Director's New Innovators award [1DP2OD001315-01]; Biotechnology and Biological Sciences Research Council [BB/N017609/1] Funding Source: researchfish; Medical Research Council [MR/N023048/1, G0501670, G0900109, MR/K011782/1] Funding Source: researchfish; BBSRC [BB/N017609/1] Funding Source: UKRI; MRC [MR/N023048/1, G0501670] Funding Source: UKRI; MRC [G0900109, MR/K011782/1] Funding Source: UKRI; Fundação para a Ciência e a Tecnologia [SFRH/BPD/111788/2015, PTDC/SAU-MET/118199/2010] Funding Source: FCT; European Research Council (ERC) [311502] Funding Source: European Research Council (ERC)
NR 38
TC 134
Z9 147
U1 1
U2 35
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 13
PY 2017
VL 547
IS 7662
BP 213
EP +
DI 10.1038/nature23009
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FA3AX
UT WOS:000405314500038
PM 28678779
DA 2026-03-09
ER

PT J
AU Aage, N
   Andreassen, E
   Lazarov, BS
   Sigmund, O
AF Aage, Niels
   Andreassen, Erik
   Lazarov, Boyan S.
   Sigmund, Ole
TI Giga-voxel computational morphogenesis for structural design
SO NATURE
LA English
DT Article
ID topology optimization
AB In the design of industrial products ranging from hearing aids to automobiles and aeroplanes, material is distributed so as to maximize the performance and minimize the cost. Historically, human intuition and insight have driven the evolution of mechanical design, recently assisted by computer-aided design approaches. The computer-aided approach known as topology optimization enables unrestricted design freedom and shows great promise with regard to weight savings, but its applicability has so far been limited to the design of single components or simple structures, owing to the resolution limits of current optimization methods(1,2).Here we report a computational morphogenesis tool, implemented on a supercomputer, that produces designs with giga-voxel resolutionmore than two orders of magnitude higher than previously reported. Such resolution provides insights into the optimal distribution of material within a structure that were hitherto unachievable owing to the challenges of scaling up existing modelling and optimization frameworks. As an example, we apply the tool to the design of the internal structure of a full-scale aeroplane wing. The optimized full-wing design has unprecedented structural detail at length scales ranging from tens of metres to millimetres and, intriguingly, shows remarkable similarity to naturally occurring bone structures in, for example, bird beaks. We estimate that our optimized design corresponds to a reduction in mass of 2-5 per cent compared to currently used aeroplane wing designs, which translates into a reduction in fuel consumption of about 40-200 tonnes per year per aeroplane. Our morphogenesis process is generally applicable, not only to mechanical design, but also to flow systems(3), antennas(4), nano-optics(5) and micro-systems(6,7).
C1 [Aage, Niels; Andreassen, Erik; Lazarov, Boyan S.; Sigmund, Ole] Tech Univ Denmark, Dept Mech Engn, Nils Koppels Alle,Bldg 404, DK-2800 Lyngby, Denmark.
   [Aage, Niels] Tech Univ Denmark, Ctr Acoust Mech Microsyst, DK-2800 Lyngby, Denmark.
C3 Technical University of Denmark; Technical University of Denmark
RP Aage, N (corresponding author), Tech Univ Denmark, Dept Mech Engn, Nils Koppels Alle,Bldg 404, DK-2800 Lyngby, Denmark.; Aage, N (corresponding author), Tech Univ Denmark, Ctr Acoust Mech Microsyst, DK-2800 Lyngby, Denmark.
EM naage@mek.dtu.dk
FU Villum Foundation through the NextTop project; PRACE (Partnership for Advanced Computing in Europe) grant TopWING giving access to the Curie supercomputer (GENCI@CEA, France); Visualization Cluster at Copenhagen University
NR 30
TC 610
Z9 720
U1 25
U2 411
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 5
PY 2017
VL 550
IS 7674
BP 84
EP +
DI 10.1038/nature23911
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI7XU
UT WOS:000412214100049
PM 28980645
DA 2026-03-09
ER

PT J
AU Stogsdill, JA
   Ramirez, J
   Liu, D
   Kim, YH
   Baldwin, KT
   Enustun, E
   Ejikeme, T
   Ji, RR
   Eroglu, C
AF Stogsdill, Jeff A.
   Ramirez, Juan
   Liu, Di
   Kim, Yong Ho
   Baldwin, Katherine T.
   Enustun, Eray
   Ejikeme, Tiffany
   Ji, Ru-Rong
   Eroglu, Cagla
TI Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis
SO NATURE
LA English
DT Article
ID cns synaptogenesis; secreted proteins; schizophrenia; maturation; synapses; cortex; mouse; transcriptome; mechanisms; database
AB Astrocytes are complex glial cells with numerous fine cellular processes that infiltrate the neuropil and interact with synapses. The mechanisms that control the establishment of astrocyte morphology are unknown, and it is unclear whether impairing astrocytic infiltration of the neuropil alters synaptic connectivity. Here we show that astrocyte morphogenesis in the mouse cortex depends on direct contact with neuronal processes and occurs in parallel with the growth and activity of synaptic circuits. The neuroligin family cell adhesion proteins NL1, NL2, and NL3, which are expressed by cortical astrocytes, control astrocyte morphogenesis through interactions with neuronal neurexins. Furthermore, in the absence of astrocytic NL2, the formation and function of cortical excitatory synapses are diminished, whereas inhibitory synaptic function is enhanced. Our findings highlight a previously undescribed mechanism of action for neuroligins and link astrocyte morphogenesis to synaptogenesis. Because neuroligin mutations have been implicated in various neurological disorders, these findings also point towards an astrocyte- based mechanism of neural pathology.
C1 [Stogsdill, Jeff A.; Ramirez, Juan; Baldwin, Katherine T.; Enustun, Eray; Ejikeme, Tiffany; Eroglu, Cagla] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA.
   [Liu, Di; Kim, Yong Ho; Ji, Ru-Rong] Duke Univ, Med Ctr, Dept Anesthesiol, Durham, NC 27710 USA.
   [Ji, Ru-Rong; Eroglu, Cagla] Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27710 USA.
   [Ji, Ru-Rong; Eroglu, Cagla] Duke Inst Brain Sci, Durham, NC 27710 USA.
C3 Duke University; Duke University; Duke University
RP Eroglu, C (corresponding author), Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA.
EM cagla.eroglu@dm.duke.du
FU National Institutes of Health [R01 DA031833, R01 DE022743, F31 NS092419]; Holland Trice Brain Research Award; Foerster-Bernstein Family; Hartwell Foundation
NR 41
TC 349
Z9 424
U1 3
U2 81
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 9
PY 2017
VL 551
IS 7679
BP 192
EP +
DI 10.1038/nature24638
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM1KF
UT WOS:000414734200040
PM 29120426
DA 2026-03-09
ER

PT J
AU Taylor, NMI
   Manolaridis, I
   Jackson, SM
   Kowal, J
   Stahlberg, H
   Locher, KP
AF Taylor, Nicholas M. I. .
   Manolaridis, Ioannis
   Jackson, Scott M.
   Kowal, Julia
   Stahlberg, Henning
   Locher, Kaspar P.
TI Structure of the human multidrug transporter ABCG2
SO NATURE
LA English
DT Article
ID binding cassette transporter; resistance-associated protein; p-glycoprotein; monoclonal-antibody; atpase subunit; cancer; expression; substrate; reconstitution; identification
AB ABCG2 is a constitutively expressed ATP-binding cassette (ABC) transporter that protects many tissues against xenobiotic molecules. Its activity affects the pharmacokinetics of commonly used drugs and limits the delivery of therapeutics into tumour cells, thus contributing to multidrug resistance. Here we present the structure of human ABCG2 determined by cryo-electron microscopy, providing the first high-resolution insight into a human multidrug transporter. We visualize ABCG2 in complex with two antigen-binding fragments of the human-specific, inhibitory antibody 5D3 that recognizes extracellular loops of the transporter. We observe two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between the transmembrane domains. Combined with functional in vitro analyses, our results suggest a multidrug recognition and transport mechanism of ABCG2, rationalize disease-causing single nucleotide polymorphisms and the allosteric inhibition by the 5D3 antibody, and provide the structural basis of cholesterol recognition by other G-subfamily ABC transporters.
C1 [Taylor, Nicholas M. I. .; Stahlberg, Henning] Univ Basel, Ctr Cellular Imaging & NanoAnalyt C CINA, Biozentrum, Mattenstr 26, CH-4058 Basel, Switzerland.
   [Manolaridis, Ioannis; Jackson, Scott M.; Kowal, Julia; Locher, Kaspar P.] Swiss Fed Inst Technol, Inst Mol Biol & Biophys, Otto Stern Weg 5, CH-8093 Zurich, Switzerland.
C3 University of Basel; Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Stahlberg, H (corresponding author), Univ Basel, Ctr Cellular Imaging & NanoAnalyt C CINA, Biozentrum, Mattenstr 26, CH-4058 Basel, Switzerland.; Locher, KP (corresponding author), Swiss Fed Inst Technol, Inst Mol Biol & Biophys, Otto Stern Weg 5, CH-8093 Zurich, Switzerland.
EM henning.stahlberg@unibas.ch; locher@mol.biol.ethz.ch
FU Swiss National Science Foundation through the National Centre of Competence in Research (NCCR) TransCure; Swiss Federal Institute of Technology Zurich (ETH Zurich) [ETH-22-14-1]
NR 76
TC 348
Z9 393
U1 5
U2 130
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 22
PY 2017
VL 546
IS 7659
BP 504
EP +
DI 10.1038/nature22345
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY2QK
UT WOS:000403814100033
PM 28554189
DA 2026-03-09
ER

PT J
AU Dauphas, N
AF Dauphas, Nicolas
TI The isotopic nature of the Earth's accreting material through time
SO NATURE
LA English
DT Article
ID core formation; terrestrial planets; moon; origin; differentiation
AB The Earth formed by accretion of Moon-to Mars-size embryos coming from various heliocentric distances. The isotopic nature of these bodies is unknown. However, taking meteorites as a guide, most models assume that the Earth must have formed from a heterogeneous assortment of embryos with distinct isotopic compositions(1-3). High-precision measurements, however, show that the Earth, the Moon and enstatite meteorites have almost indistinguishable isotopic compositions(4-10). Models have been proposed that reconcile the Earth-Moon similarity with the inferred heterogeneous nature of Earth-forming material, but these models either require specific geometries for the Moon-forming impact(11,12) or can explain only one aspect of the Earth-Moon similarity (that is, O-17)(1-3). Here I show that elements with distinct affinities for metal can be used to decipher the isotopic nature of the Earth's accreting material through time. I find that the mantle signatures of lithophile O, Ca, Ti and Nd, moderately siderophile Cr, Ni and Mo, and highly siderophile Ru record different stages of the Earth's accretion; yet all those elements point to material that was isotopically most similar to enstatite meteorites. This isotopic similarity indicates that the material accreted by the Earth always comprised a large fraction of enstatite-type impactors (about half were E-type in the first 60 per cent of the accretion and all of the impactors were E-type after that). Accordingly, the giant impactor that formed the Moon probably had an isotopic composition similar to that of the Earth, hence relaxing the constraints on models of lunar formation. Enstatite meteorites and the Earth were formed from the same isotopic reservoir but they diverged in their chemical evolution owing to subsequent fractionation by nebular and planetary processes(13).
C1 [Dauphas, Nicolas] Univ Chicago, Origins Lab, Dept Geophys Sci, 5734 South Ellis Ave, Chicago, IL 60637 USA.
   [Dauphas, Nicolas] Univ Chicago, Enrico Fermi Inst, 5734 South Ellis Ave, Chicago, IL 60637 USA.
C3 University of Chicago; University of Chicago
RP Dauphas, N (corresponding author), Univ Chicago, Origins Lab, Dept Geophys Sci, 5734 South Ellis Ave, Chicago, IL 60637 USA.; Dauphas, N (corresponding author), Univ Chicago, Enrico Fermi Inst, 5734 South Ellis Ave, Chicago, IL 60637 USA.
EM dauphas@uchicago.edu
FU NSF (CSEDI) [EAR1502591]; NSF (Petrology and Geochemistry) [EAR1444951]; NASA (LARS) [NNX14AK09G]; NASA [678332, NNX14AK09G] Funding Source: Federal RePORTER; Directorate For Geosciences; Division Of Earth Sciences [1444951, 1502591] Funding Source: National Science Foundation
NR 32
TC 363
Z9 400
U1 11
U2 156
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 26
PY 2017
VL 541
IS 7638
BP 521
EP 524
DI 10.1038/nature20830
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6LX
UT WOS:000396116600048
PM 28128239
DA 2026-03-09
ER

PT J
AU Wehrenberg, CE
   McGonegle, D
   Bolme, C
   Higginbotham, A
   Lazicki, A
   Lee, HJ
   Nagler, B
   Park, HS
   Remington, BA
   Rudd, RE
   Sliwa, M
   Suggit, M
   Swift, D
   Tavella, F
   Zepeda-Ruiz, L
   Wark, JS
AF Wehrenberg, C. E.
   McGonegle, D.
   Bolme, C.
   Higginbotham, A.
   Lazicki, A.
   Lee, H. J.
   Nagler, B.
   Park, H. -S.
   Remington, B. A.
   Rudd, R. E.
   Sliwa, M.
   Suggit, M.
   Swift, D.
   Tavella, F.
   Zepeda-Ruiz, L.
   Wark, J. S.
TI In situ X-ray diffraction measurement of shock-wave-driven twinning and lattice dynamics
SO NATURE
LA English
DT Article
ID molecular-dynamics; tantalum; deformation; compression; transformation; plasticity
AB Pressure-driven shock waves in solid materials can cause extreme damage and deformation. Understanding this deformation and the associated defects that are created in the material is crucial in the study of a wide range of phenomena, including planetary formation and asteroid impact sites(1-3), the formation of interstellar dust clouds(4), ballistic penetrators(5), spacecraft shielding(6) and ductility in high-performance ceramics(7). At the lattice level, the basic mechanisms of plastic deformation are twinning (whereby crystallites with a mirror-image lattice form) and slip (whereby lattice dislocations are generated and move), but determining which of these mechanisms is active during deformation is challenging. Experiments that characterized lattice defects(8-11) have typically examined the microstructure of samples after deformation, and so are complicated by post-shock annealing(12) and reverberations. In addition, measurements have been limited to relatively modest pressures (less than 100 gigapascals). In situ X-ray diffraction experiments can provide insights into the dynamic behaviour of materials(13), but have only recently been applied to plasticity during shock compression(14-17) and have yet to provide detailed insight into competing deformation mechanisms. Here we present X-ray diffraction experiments with femtosecond resolution that capture in situ, lattice-level information on the microstructural processes that drive shock-wave-driven deformation. To demonstrate this method we shock-compress the body-centred-cubic material tantalum-an important material for high-energy-density physics owing to its high shock impedance and high X-ray opacity. Tantalum is also a material for which previous shock compression simulations(18-20) and experiments(8-12) have provided conflicting information about the dominant deformation mechanism. Our experiments reveal twinning and related lattice rotation occurring on the timescale of tens of picoseconds. In addition, despite the common association between twinning and strong shocks(21), we find a transition from twinning to dislocation-slip-dominated plasticity at high pressure (more than 150 gigapascals), a regime that recovery experiments cannot accurately access. The techniques demonstrated here will be useful for studying shock waves and other high-strain-rate phenomena, as well as a broad range of processes induced by plasticity.
C1 [Wehrenberg, C. E.; Lazicki, A.; Park, H. -S.; Remington, B. A.; Rudd, R. E.; Swift, D.; Zepeda-Ruiz, L.] Lawrence Livermore Natl Lab, 7000 East Ave, Livermore, CA 94550 USA.
   [McGonegle, D.; Sliwa, M.; Suggit, M.; Wark, J. S.] Univ Oxford, Dept Phys, Clarendon Lab, Parks Rd, Oxford OX1 3PU, England.
   [Bolme, C.] Los Alamos Natl Lab, Bikini Atoll Rd,SM-30, Los Alamos, NM 87545 USA.
   [Higginbotham, A.] Univ York, Dept Phys, York YO10 5DD, N Yorkshire, England.
   [Lee, H. J.; Nagler, B.; Tavella, F.] SLAC Natl Accelerator Lab, 2575 Sand Hill Rd, Menlo Pk, CA 94025 USA.
C3 United States Department of Energy (DOE); Lawrence Livermore National Laboratory; University of Oxford; United States Department of Energy (DOE); Los Alamos National Laboratory; University of York - UK; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory
RP Wehrenberg, CE (corresponding author), Lawrence Livermore Natl Lab, 7000 East Ave, Livermore, CA 94550 USA.
EM wehrenberg1@llnl.gov
FU US Department of Energy by Lawrence Livermore National Laboratory [DE-AC52-07NA27344]; Los Alamos National Laboratory [DE-AC52-06NA25396]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]; US Department of Energy, Office of Science, Office of Fusion Energy Sciences [SF00515, DE-SCW-1507]; UK EPSRC [EP/J017256/1]; LLNS [B595954, B609694]; EPSRC [EP/J017256/1] Funding Source: UKRI; Engineering and Physical Sciences Research Council [EP/J017256/1] Funding Source: researchfish
NR 34
TC 137
Z9 157
U1 5
U2 142
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 26
PY 2017
VL 550
IS 7677
BP 496
EP +
DI 10.1038/nature24061
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK7OW
UT WOS:000413697800038
PM 29072261
DA 2026-03-09
ER

PT J
AU Azurenko, AM
   Chiu, CS
   Ji, G
   Parsons, MF
   Kanasz-Nagy, M
   Schmidt, R
   Grusdt, F
   Demler, E
   Greif, D
   Greiner, M
AF Azurenko, Anton M.
   Chiu, Christie S.
   Ji, Geoffrey
   Parsons, Maxwell F.
   Kanasz-Nagy, Marton
   Schmidt, Richard
   Grusdt, Fabian
   Demler, Eugene
   Greif, Daniel
   Greiner, Markus
TI A cold-atom Fermi-Hubbard antiferromagnet
SO NATURE
LA English
DT Article
ID 2-dimensional heisenberg-model; optical lattice; quantum simulation; fractional charge; spin correlations; mott insulator; ground-state; trapped ions; magnetism; noise
AB Exotic phenomena in systems with strongly correlated electrons emerge from the interplay between spin and motional degrees of freedom. For example, doping an antiferromagnet is expected to give rise to pseudogap states and high-temperature superconductors(1). Quantum simulation(2-8) using ultracold fermions in optical lattices could help to answer open questions about the doped Hubbard Hamiltonian(9-14), and has recently been advanced by quantum gas microscopy(15-20). Here we report the realization of an antiferromagnet in a repulsively interacting Fermi gas on a two-dimensional square lattice of about 80 sites at a temperature of 0.25 times the tunnelling energy. The antiferromagnetic long-range order manifests through the divergence of the correlation length, which reaches the size of the system, the development of a peak in the spin structure factor and a staggered magnetization that is close to the ground-state value. We hole-dope the system away from half-filling, towards a regime in which complex many-body states are expected, and find that strong magnetic correlations persist at the antiferromagnetic ordering vector up to dopings of about 15 per cent. In this regime, numerical simulations are challenging(21) and so experiments provide a valuable benchmark. Our results demonstrate that microscopy of cold atoms in optical lattices can help us to understand the low-temperature Fermi-Hubbard model.
C1 [Azurenko, Anton M.; Chiu, Christie S.; Ji, Geoffrey; Parsons, Maxwell F.; Kanasz-Nagy, Marton; Schmidt, Richard; Grusdt, Fabian; Demler, Eugene; Greif, Daniel; Greiner, Markus] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.
C3 Harvard University
RP Greiner, M (corresponding author), Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.
EM greiner@physics.harvard.edu
FU AFOSR (MURI); ARO (MURI); ARO (NDSEG); Gordon and Betty Moore foundation EPiQS initiative; HQOC; NSF (CUA); NSF (ITAMP); NSF (GRFP); NSF (SAO); SNSF; Direct For Mathematical & Physical Scien; Division Of Physics [1506203, 1125846] Funding Source: National Science Foundation
CR Blanter YM, 2000, PHYS REP, V336, P1, DOI 10.1016/S0370-1573(99)00123-4
   Bloch I, 2008, REV MOD PHYS, V80, P885, DOI 10.1103/RevModPhys.80.885
   Boll M, 2016, SCIENCE, V353, P1257, DOI 10.1126/science.aag1635
   Braungardt S, 2011, PHYS REV A, V83, P0, DOI 10.1103/PhysRevA.83.013601
   Braungardt S, 2008, PHYS REV A, V78, P0, DOI 10.1103/PhysRevA.78.063613
   Brown PA, 2016, PREPRINT, V0, P0
   CAFFAREL M, 1994, EUROPHYS LETT, V26, P493, DOI 10.1209/0295-5075/26/7/003
   CHAKRAVARTY S, 1989, PHYS REV B, V39, P2344, DOI 10.1103/PhysRevB.39.2344
   Chang CC, 2015, PHILOS MAG, V95, P1260, DOI 10.1080/14786435.2013.845314
   Cherng RW, 2007, NEW J PHYS, V9, P0, DOI 10.1088/1367-2630/9/1/007
   Cheuk LW, 2016, SCIENCE, V353, P1260, DOI 10.1126/science.aag3349
   CHUBUKOV AV, 1994, PHYS REV B, V49, P11919, DOI 10.1103/PhysRevB.49.11919
   Denteneer PJH, 1993, EUROPHYS LETT, V22, P413
   dePicciotto R, 1997, NATURE, V389, P162, DOI 10.1038/38241
   Drewes JH, 2017, PHYS REV LETT, V118, P0, DOI 10.1103/PhysRevLett.118.170401
   Edge GJA, 2015, PHYS REV A, V92, P0, DOI 10.1103/PhysRevA.92.063406
   Friedenauer A, 2008, NAT PHYS, V4, P757, DOI 10.1038/nphys1032
   Gaunt AL, 2012, SCI REP-UK, V2, P0, DOI 10.1038/srep00721
   Gogolenko S, 2014, LECT NOTES COMPUT SC, V8632, P524, DOI 10.1007/978-3-319-09873-9_44
   GOLDMAN VJ, 1995, SCIENCE, V267, P1010, DOI 10.1126/science.267.5200.1010
   Gorelik EV, 2012, PHYS REV A, V85, P0, DOI 10.1103/PhysRevA.85.061602
   Greif D, 2013, SCIENCE, V340, P1307, DOI 10.1126/science.1236362
   Gritsev V, 2006, NAT PHYS, V2, P705, DOI 10.1038/nphys410
   Haller E, 2015, NAT PHYS, V11, P738, DOI 10.1038/NPHYS3403
   Hart RA, 2015, NATURE, V519, P211, DOI 10.1038/nature14223
   Ho T-L, 2009, PREPRINT, V0, P0
   Hofferberth S, 2008, NAT PHYS, V4, P489, DOI 10.1038/nphys941
   Hofstetter W, 2002, PHYS REV LETT, V89, P0, DOI 10.1103/PhysRevLett.89.220407
   HOHENBERG PC, 1967, PHYS REV, V158, P383, DOI 10.1103/PhysRev.158.383
   HUBBARD J, 1963, PROC R SOC LON SER-A, V276, P238, DOI 10.1098/rspa.1963.0204
   Hueck K, 2017, REV SCI INSTRUM, V88, P0, DOI 10.1063/1.4973969
   Jiang C, 2016, P 30 IEEE INT PAR DI, V0, P0
   Jördens R, 2008, NATURE, V455, P204, DOI 10.1038/nature07244
   Khatami E, 2011, PHYS REV A, V84, P0, DOI 10.1103/PhysRevA.84.053611
   Kim K, 2010, NATURE, V465, P590, DOI 10.1038/nature09071
   Lamacraft A, 2007, PHYS REV A, V76, P011603
   LeBlanc JPF, 2015, PHYS REV X, V5, P0, DOI 10.1103/PhysRevX.5.041041
   LeBlanc JPF, 2013, PHYS REV B, V88, P0, DOI 10.1103/PhysRevB.88.155108
   Lee PA, 2006, REV MOD PHYS, V78, P17, DOI 10.1103/RevModPhys.78.17
   Liang JY, 2010, APPL OPTICS, V49, P1323, DOI 10.1364/AO.49.001323
   MACHIDA K, 1989, PHYSICA C, V158, P192, DOI 10.1016/0921-4534(89)90316-X
   MANOUSAKIS E, 1991, REV MOD PHYS, V63, P1, DOI 10.1103/RevModPhys.63.1
   MERMIN ND, 1966, PHYS REV LETT, V17, P1133, DOI 10.1103/PhysRevLett.17.1133
   Murmann S, 2015, PHYS REV LETT, V115, P0, DOI 10.1103/PhysRevLett.115.215301
   Paiva T, 2010, PHYS REV LETT, V104, P0, DOI 10.1103/PhysRevLett.104.066406
   Parsons MF, 2016, SCIENCE, V353, P1253, DOI 10.1126/science.aag1430
   Parsons MF, 2015, PHYS REV LETT, V114, P0, DOI 10.1103/PhysRevLett.114.213002
   Polkovnikov A, 2006, P NATL ACAD SCI USA, V103, P6125, DOI 10.1073/pnas.0510276103
   Saminadayar L, 1997, PHYS REV LETT, V79, P2526, DOI 10.1103/PhysRevLett.79.2526
   Sandvik AW, 1999, PHYS REV B, V59, P14157, DOI 10.1103/PhysRevB.59.R14157
   Sandvik AW, 1997, PHYS REV B, V56, P11678, DOI 10.1103/PhysRevB.56.11678
   Schneider U, 2008, SCIENCE, V322, P1520, DOI 10.1126/science.1165449
   Schulz HJ, 1995, NATO ADV SCI I B-PHY, V343, P89
   SCHULZ HJ, 1990, PHYS REV LETT, V64, P1445, DOI 10.1103/PhysRevLett.64.1445
   Simon J, 2011, NATURE, V472, P307, DOI 10.1038/nature09994
   Staar P, 2013, PHYS REV B, V88, P0, DOI 10.1103/PhysRevB.88.115101
   Struck J, 2011, SCIENCE, V333, P996, DOI 10.1126/science.1207239
   Yamada K, 1998, PHYS REV B, V57, P6165, DOI 10.1103/PhysRevB.57.6165
   Yan B, 2013, NATURE, V501, P521, DOI 10.1038/nature12483
   Zupancic P, 2016, OPT EXPRESS, V24, P13881, DOI 10.1364/OE.24.013881
NR 60
TC 628
Z9 716
U1 4
U2 148
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 25
PY 2017
VL 545
IS 7655
BP 462
EP +
DI 10.1038/nature22362
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV6TH
UT WOS:000401906500048
PM 28541324
DA 2026-03-09
ER

PT J
AU Assawaworrarit, S
   Yu, XF
   Fan, SH
AF Assawaworrarit, Sid
   Yu, Xiaofang
   Fan, Shanhui
TI Robust wireless power transfer using a nonlinear parity-time-symmetric circuit
SO NATURE
LA English
DT Article
ID transfer system; microimplants; microcavity; frequency; breaking; design; lasers
AB Considerable progress in wireless power transfer has been made in the realm of non-radiative transfer, which employs magnetic-field coupling in the near field(1-4). A combination of circuit resonance and impedance transformation is often used to help to achieve efficient transfer of power over a predetermined distance of about the size of the resonators(3,4). The development of non-radiative wireless power transfer has paved the way towards real-world applications such as wireless powering of implantable medical devices and wireless charging of stationary electric vehicles(1,2,5-8). However, it remains a fundamental challenge to create a wireless power transfer system in which the transfer efficiency is robust against the variation of operating conditions. Here we propose theoretically and demonstrate experimentally that a parity-time-symmetric circuit incorporating a nonlinear gain saturation element provides robust wireless power transfer. Our results show that the transfer efficiency remains near unity over a distance variation of approximately one metre, without the need for any tuning. This is in contrast with conventional methods where high transfer efficiency can only be maintained by constantly tuning the frequency or the internal coupling parameters as the transfer distance or the relative orientation of the source and receiver units is varied. The use of a nonlinear parity-time-symmetric circuit should enable robust wireless power transfer to moving devices or vehicles(9,10).
C1 [Assawaworrarit, Sid; Yu, Xiaofang; Fan, Shanhui] Stanford Univ, Dept Elect Engn, Ginzton Lab, Stanford, CA 94305 USA.
C3 Stanford University
RP Fan, SH (corresponding author), Stanford Univ, Dept Elect Engn, Ginzton Lab, Stanford, CA 94305 USA.
EM shanhui@stanford.edu
FU TomKat Center for Sustainable Energy at Stanford
NR 34
TC 633
Z9 735
U1 41
U2 684
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 15
PY 2017
VL 546
IS 7658
BP 387
EP +
DI 10.1038/nature22404
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EX5BK
UT WOS:000403250900031
PM 28617463
DA 2026-03-09
ER

PT J
AU Long, Y
   Tahl, YS
   Weidtkamp-Peters, S
   Postma, M
   Zhou, W
   Oedhart, JG
   Sánchez-Pérez, MI
   Adella, TWJG
   Simon, R
   Scheres, B
   Blilou, I
AF Long, Yuchen
   Tahl, Yvonne S.
   Weidtkamp-Peters, Stefanie
   Postma, Marten
   Zhou, Wenkun
   Oedhart, Joachim G.
   Sanchez-Perez, Maria-Isabel
   Adella, Theodorus W. J. G., Jr.
   Simon, Ruediger
   Scheres, Ben
   Blilou, Ikram
TI In vivo FRET-FLIM reveals cell-type-specific protein interactions in Arabidopsis roots
SO NATURE
LA English
DT Article
ID stabilize tissue boundary; transcription factors; fluorescence; shr; instrumentation; identification; resolution; scarecrow; movement; cyan
AB During multicellular development, specification of distinct cell fates is often regulated by the same transcription factors operating differently in distinct cis-regulatory modules(1-3), either through different protein complexes, conformational modification of protein complexes, or combinations of both. Direct visualization of different transcription factor complex states guiding specific gene expression programs has been challenging. Here we use in vivo FRET-FLIM (Forster resonance energy transfer measured by fluorescence lifetime microscopy) to reveal spatial partitioning of protein interactions in relation to specification of cell fate. We show that, in Arabidopsis roots, three fully functional fluorescently tagged cell fate regulators establish cell-type-specific interactions at endogenous expression levels and can form higher order complexes. We reveal that cell-type-specific in vivo FRET-FLIM distributions reflect conformational changes of these complexes to differentially regulate target genes and specify distinct cell fates.
C1 [Long, Yuchen; Zhou, Wenkun; Scheres, Ben; Blilou, Ikram] Wageningen Univ & Res Ctr, Plant Dev Biol, Droevendaalsesteeg 1, NL-6708 PB Wageningen, Netherlands.
   [Long, Yuchen; Blilou, Ikram] Univ Utrecht, Dept Biol, Mol Genet, Padualaan 8, NL-3581 CH Utrecht, Netherlands.
   [Tahl, Yvonne S.; Simon, Ruediger] Heinrich Heine Univ, CEPLAS Cluster Excellence Plant Sci, Univ Str 1, D-40225 Dusseldorf, Germany.
   [Tahl, Yvonne S.; Simon, Ruediger] Heinrich Heine Univ, Inst Dev Genet, Univ Str 1, D-40225 Dusseldorf, Germany.
   [Weidtkamp-Peters, Stefanie] Heinrich Heine Univ, Ctr Adv Imaging, Univ Str 1, D-40225 Dusseldorf, Germany.
   [Postma, Marten; Oedhart, Joachim G.; Adella, Theodorus W. J. G., Jr.] Univ Amsterdam, van Leeuwenhoek Ctr Adv Microscopy, Sect Mol Cytol, Swammerdam Inst Life Sci, Sci Pk 904, NL-1098 XH Amsterdam, Netherlands.
   [Sanchez-Perez, Maria-Isabel] UAM, Dept Bioquim, Inst Invest Biomed Alberto Sols, CSIC, Arturo Duperier 4, Madrid 28029, Spain.
   [Long, Yuchen] UCB Lyon 1, ENS Lyon, Lab Reprod & Dev Plantes RDP, CNRS,INRA, F-69342 Lyon, France.
C3 Wageningen University & Research; Utrecht University; Heinrich Heine University Dusseldorf; Heinrich Heine University Dusseldorf; Heinrich Heine University Dusseldorf; University of Amsterdam; Autonomous University of Madrid; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Investigaciones Biomedicas Alberto Sols (IIBM); INRAE; Ecole Normale Superieure de Lyon (ENS de LYON); Universite Lyon 1; Centre National de la Recherche Scientifique (CNRS)
RP Blilou, I (corresponding author), Wageningen Univ & Res Ctr, Plant Dev Biol, Droevendaalsesteeg 1, NL-6708 PB Wageningen, Netherlands.; Blilou, I (corresponding author), Univ Utrecht, Dept Biol, Mol Genet, Padualaan 8, NL-3581 CH Utrecht, Netherlands.
EM ikram.blilou@wur.nl
FU NWO VIDI grant; ERC Advanced Grant SysArc; NWO Spinoza Grant; NWO ALW-VIDI grant [864.09.015]; DFG [WE 5343/1-1]
NR 41
TC 133
Z9 151
U1 2
U2 159
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 3
PY 2017
VL 548
IS 7665
BP 97
EP +
DI 10.1038/nature23317
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FC4SU
UT WOS:000406831700044
PM 28746306
DA 2026-03-09
ER

PT J
AU Kim, YC
   Kim, KH
   Son, DY
   Jeong, DN
   Seo, JY
   Choi, YS
   Han, IT
   Lee, SY
   Park, NG
AF Kim, Yong Churl
   Kim, Kwang Hee
   Son, Dae-Yong
   Jeong, Dong-Nyuk
   Seo, Ja-Young
   Choi, Yeong Suk
   Han, In Taek
   Lee, Sang Yoon
   Park, Nam-Gyu
TI Printable organometallic perovskite enables large-area, low-dose X-ray imaging
SO NATURE
LA English
DT Article
ID solar-cells; single-crystals; amorphous selenium; efficiency; detectors; radiation; photons
AB Medical X-ray imaging procedures require digital flat detectors operating at low doses to reduce radiation health risks(1,2). Solutionprocessed organic-inorganic hybrid perovskites have characteristics that make them good candidates for the photoconductive layer of such sensitive detectors(3-7). However, such detectors have not yet been built on thin-film transistor arrays because it has been difficult to prepare thick perovskite films (more than a few hundred micrometres) over large areas (a detector is typically 50 centimetres by 50 centimetres). We report here an all-solutionbased (in contrast to conventional vacuum processing) synthetic route to producing printable polycrystalline perovskites with sharply faceted large grains having morphologies and optoelectronic properties comparable to those of single crystals. High sensitivities of up to 11 microcoulombs per air KERMA of milligray per square centimetre (mu C mGyair(-1) cm(-2)) are achieved under irradiation with a 100-kilovolt bremsstrahlung source, which are at least one order of magnitude higher than the sensitivities achieved with currently used amorphous selenium or thallium-doped cesium iodide detectors. We demonstrate X-ray imaging in a conventional thin-film transistor substrate by embedding an 830-micrometrethick perovskite film and an additional two interlayers of polymer/perovskite composites to provide conformal interfaces between perovskite films and electrodes that control dark currents and temporal charge carrier transportation. Such an all-solution-based perovskite detector could enable low-dose X-ray imaging, and could also be used in photoconductive devices for radiation imaging, sensing and energy harvesting.
C1 [Kim, Yong Churl; Kim, Kwang Hee; Choi, Yeong Suk; Han, In Taek; Lee, Sang Yoon] SAIT, Samsung Elect Mat Res Complex, Suwon 443803, South Korea.
   [Son, Dae-Yong; Jeong, Dong-Nyuk; Seo, Ja-Young; Park, Nam-Gyu] Sungkyunkwan Univ, Sch Chem Engn, Suwon 440746, South Korea.
   [Son, Dae-Yong; Jeong, Dong-Nyuk; Seo, Ja-Young; Park, Nam-Gyu] Sungkyunkwan Univ, Dept Energy Sci, Suwon 440746, South Korea.
C3 Sungkyunkwan University (SKKU); Sungkyunkwan University (SKKU)
RP Han, IT (corresponding author), SAIT, Samsung Elect Mat Res Complex, Suwon 443803, South Korea.; Park, NG (corresponding author), Sungkyunkwan Univ, Sch Chem Engn, Suwon 440746, South Korea.; Park, NG (corresponding author), Sungkyunkwan Univ, Dept Energy Sci, Suwon 440746, South Korea.
EM intaek.han@samsung.com; npark@skku.edu
FU National Research Foundation of Korea (NRF) grants; Ministry of Science, ICT Future Planning (MSIP) of Korea under contract (Global Frontier R&D Program on Center for Multiscale Energy System) [NRF-2012M3A6A7054861, NRF-2014M3A6A7060583]; Ministry of Science, ICT Future Planning (MSIP) of Korea under contract (Future Materials Discovery Program) [NRF-2016M3D1A1027664]
NR 30
TC 1035
Z9 1131
U1 29
U2 1235
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 5
PY 2017
VL 550
IS 7674
BP 87
EP +
DI 10.1038/nature24032
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI7XU
UT WOS:000412214100050
PM 28980632
DA 2026-03-09
ER

PT J
AU Knop, E
   Zoller, L
   Ryser, R
   Erpe, CG
   Hörler, M
   Fontaine, C
AF Knop, Eva
   Zoller, Leana
   Ryser, Remo
   Erpe, Christopher G.
   Horler, Maurin
   Fontaine, Colin
TI Artificial light at night as a new threat to pollination
SO NATURE
LA English
DT Article
ID animal mutualistic networks; nocturnal pollen-transport; plants; community; systems
AB Pollinators are declining worldwide(1) and this has raised concerns for a parallel decline in the essential pollination service they provide to both crops and wild plants(2,3). Anthropogenic drivers linked to this decline include habitat changes, intensive agriculture, pesticides, invasive alien species, spread of pathogens and climate change(1). Recently, the rapid global increase in artificial light at night(4) has been proposed to be a new threat to terrestrial ecosystems; the consequences of this increase for ecosystem function are mostly unknown(5,6). Here we show that artificial light at night disrupts nocturnal pollination networks and has negative consequences for plant reproductive success. In artificially illuminated plant-pollinator communities, nocturnal visits to plants were reduced by 62% compared to dark areas. Notably, this resulted in an overall 13% reduction in fruit set of a focal plant even though the plant also received numerous visits by diurnal pollinators. Furthermore, by merging diurnal and nocturnal pollination sub-networks, we show that the structure of these combined networks tends to facilitate the spread of the negative consequences of disrupted nocturnal pollination to daytime pollinator communities. Our findings demonstrate that artificial light at night is a threat to pollination and that the negative effects of artificial light at night on nocturnal pollination are predicted to propagate to the diurnal community, thereby aggravating the decline of the diurnal community. We provide perspectives on the functioning of plant-pollinator communities, showing that nocturnal pollinators are not redundant to diurnal communities and increasing our understanding of the human-induced decline in pollinators and their ecosystem service.
C1 [Knop, Eva; Zoller, Leana; Ryser, Remo; Erpe, Christopher G.; Horler, Maurin] Univ Bern, Inst Ecol & Evolut, Baltzerstr 6, CH-3012 Bern, Switzerland.
   [Fontaine, Colin] CNRS, UMR 7204, MNHN, Ctr Ecol & Sci Conservat, 61 Rue Buffon, F-75005 Paris, France.
C3 University of Bern; Museum National d'Histoire Naturelle (MNHN); Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Ecology & Environment (INEE); Sorbonne Universite
RP Knop, E (corresponding author), Univ Bern, Inst Ecol & Evolut, Baltzerstr 6, CH-3012 Bern, Switzerland.
EM evaknop@gmx.ch
FU Swiss National Sciences Foundation
NR 35
TC 340
Z9 386
U1 21
U2 551
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 10
PY 2017
VL 548
IS 7666
BP 206
EP +
DI 10.1038/nature23288
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD1GB
UT WOS:000407284300042
PM 28783730
DA 2026-03-09
ER

PT J
AU Bakker, P
   Clark, PU
   Golledge, NR
   Schmittner, A
   Weber, ME
AF Bakker, Pepijn
   Clark, Peter U.
   Golledge, Nicholas R.
   Schmittner, Andreas
   Weber, Michael E.
TI Centennial-scale Holocene climate variations amplified by Antarctic Ice Sheet discharge
SO NATURE
LA English
DT Article
ID southern-ocean; last deglaciation; variability; model; sea; hemisphere; atlantic
AB Proxy-based indicators of past climate change show that current global climate models systematically underestimate Holocene-epoch climate variability on centennial to multi-millennial timescales, with the mismatch increasing for longer periods(1-5). Proposed explanations for the discrepancy include ocean-atmosphere coupling that is too weak in models(6), insufficient energy cascades from smaller to larger spatial and temporal scales(7), or that global climate models do not consider slow climate feedbacks related to the carbon cycle or interactions between ice sheets and climate(4). Such interactions, however, are known to have strongly affected centennial-to orbital-scale climate variability during past glaciations(8-11), and are likely to be important in future climate change(12-14). Here we show that fluctuations in Antarctic Ice Sheet discharge caused by relatively small changes in subsurface ocean temperature can amplify multi-centennial climate variability regionally and globally, suggesting that a dynamic Antarctic Ice Sheet may have driven climate fluctuations during the Holocene. We analysed high-temporal-resolution records of iceberg-rafted debris derived from the Antarctic Ice Sheet, and performed both high-spatial-resolution ice-sheet modelling of the Antarctic Ice Sheet and multi-millennial global climate model simulations. Ice-sheet responses to decadal-scale ocean forcing appear to be less important, possibly indicating that the future response of the Antarctic Ice Sheet will be governed more by long-term anthropogenic warming combined with multi-centennial natural variability than by annual or decadal climate oscillations.
C1 [Bakker, Pepijn; Clark, Peter U.; Schmittner, Andreas] Oregon State Univ, Coll Earth Ocean & Atmospher Sci, Corvallis, OR 97331 USA.
   [Golledge, Nicholas R.] Victoria Univ Wellington, Antarct Res Ctr, Wellington, New Zealand.
   [Golledge, Nicholas R.] GNS Sci, Lower Hutt, New Zealand.
   [Weber, Michael E.] Univ Bonn, Steinmann Inst, Bonn, Germany.
   [Weber, Michael E.] Univ Cambridge, Dept Earth Sci, Cambridge, England.
C3 Oregon State University; Victoria University Wellington; Earth Sciences New Zealand; GNS Science - New Zealand; University of Bonn; University of Cambridge
RP Bakker, P (corresponding author), Univ Bremen, Ctr Marine Environm Sci, MARUM, Bremen, Germany.
EM pbakker@marum.de
FU National Oceanographic and Atmospheric Administration [NA15OAR4310239]; Antarctic Glaciology Program of the National Science Foundation [1043517]; Royal Society of New Zealand's Marsden Fund [VUW1203]; Deutsche Forschungsgemeinschaft (DFG) [We2039/8-1]; NASA [NNX13AM16G, NNX13AK27G]; Directorate For Geosciences; Office of Polar Programs (OPP) [1043517] Funding Source: National Science Foundation
NR 34
TC 64
Z9 70
U1 0
U2 75
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 5
PY 2017
VL 541
IS 7635
BP 72
EP +
DI 10.1038/nature20582
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6NA
UT WOS:000396119500031
PM 27951585
DA 2026-03-09
ER

PT J
AU Chen, L
   Shi, GS
   Shen, J
   Peng, BQ
   Zhang, BW
   Wang, YZ
   Bian, FG
   Wang, JJ
   Li, DY
   Qian, Z
   Xu, G
   Liu, GP
   Zeng, JR
   Zhang, LJ
   Yang, YZ
   Zhou, GQ
   Wu, MH
   Jin, WQ
   Li, JY
   Fang, HP
AF Chen, Liang
   Shi, Guosheng
   Shen, Jie
   Peng, Bingquan
   Zhang, Bowu
   Wang, Yuzhu
   Bian, Fenggang
   Wang, Jiajun
   Li, Deyuan
   Qian, Zhe
   Xu, Gang
   Liu, Gongping
   Zeng, Jianrong
   Zhang, Lijuan
   Yang, Yizhou
   Zhou, Guoquan
   Wu, Minghong
   Jin, Wanqin
   Li, Jingye
   Fang, Haiping
TI Ion sieving in graphene oxide membranes via cationic control of interlayer spacing
SO NATURE
LA English
DT Article
ID carbon nanotubes; layered graphene; porous graphene; transport; separation; mechanism; ultrathin; future
AB Graphene oxide membranes-partially oxidized, stacked sheets of graphene(1)-can provide ultrathin, high-flux and energy-efficient membranes for precise ionic and molecular sieving in aqueous solution(2-6). These materials have shown potential in a variety of applications, including water desalination and purification(7-9), gas and ion separation(10-13), biosensors(14), proton conductors(15), lithium-based batteries(16) and super-capacitors(17). Unlike the pores of carbon nanotube membranes, which have fixed sizes(18-20), the pores of graphene oxide membranes-that is, the interlayer spacing between graphene oxide sheets (a sheet is a single flake inside the membrane)-are of variable size. Furthermore, it is difficult to reduce the interlayer spacing sufficiently to exclude small ions and to maintain this spacing against the tendency of graphene oxide membranes to swell when immersed in aqueous solution(21-25). These challenges hinder the potential ion filtration applications of graphene oxide membranes. Here we demonstrate cationic control of the interlayer spacing of graphene oxide membranes with angstrom precision using K+, Na+, Ca2+, Li+ or Mg2+ ions. Moreover, membrane spacings controlled by one type of cation can efficiently and selectively exclude other cations that have larger hydrated volumes. First-principles calculations and ultraviolet absorption spectroscopy reveal that the location of the most stable cation adsorption is where oxide groups and aromatic rings coexist. Previous density functional theory computations show that other cations (Fe2+, Co2+, Cu2+, Cd2+, Cr2+ and Pb2+) should have a much stronger cation-pi interaction with the graphene sheet than Na+ has(26), suggesting that other ions could be used to produce a wider range of interlayer spacings.
C1 [Chen, Liang; Peng, Bingquan; Wang, Jiajun; Li, Deyuan; Qian, Zhe; Xu, Gang; Wu, Minghong] Shanghai Univ, Shanghai Appl Radiat Inst, Shanghai 200444, Peoples R China.
   [Chen, Liang; Shi, Guosheng; Zhang, Bowu; Wang, Yuzhu; Bian, Fenggang; Li, Deyuan; Zeng, Jianrong; Zhang, Lijuan; Yang, Yizhou; Li, Jingye; Fang, Haiping] Chinese Acad Sci, Shanghai Inst Appl Phys, Div Interfacial Water, Key Lab Interfacial Phys & Technol, Shanghai 201800, Peoples R China.
   [Chen, Liang; Shi, Guosheng; Zhang, Bowu; Wang, Yuzhu; Bian, Fenggang; Li, Deyuan; Zeng, Jianrong; Zhang, Lijuan; Yang, Yizhou; Li, Jingye; Fang, Haiping] Chinese Acad Sci, Shanghai Inst Appl Phys, Shanghai Synchrotron Radiat Facil, Shanghai 201800, Peoples R China.
   [Chen, Liang; Zhou, Guoquan] Zhejiang A&F Univ, Zhejiang Prov Key Lab Chem Utilizat Forestry Biom, Linan 311300, Zhejiang, Peoples R China.
   [Shen, Jie; Liu, Gongping; Jin, Wanqin] Nanjing Tech Univ, Jiangsu Natl Synerget Innovat Ctr Adv Mat, State Key Lab Mat Oriented Chem Engn, 5 Xinmofan Rd, Nanjing 210009, Jiangsu, Peoples R China.
C3 Shanghai University; Chinese Academy of Sciences; Shanghai Institute of Applied Physics, CAS; Chinese Academy of Sciences; Shanghai Institute of Applied Physics, CAS; Zhejiang A&F University; Nanjing Tech University
RP Wu, MH (corresponding author), Shanghai Univ, Shanghai Appl Radiat Inst, Shanghai 200444, Peoples R China.; Li, JY; Fang, HP (corresponding author), Chinese Acad Sci, Shanghai Inst Appl Phys, Div Interfacial Water, Key Lab Interfacial Phys & Technol, Shanghai 201800, Peoples R China.; Li, JY; Fang, HP (corresponding author), Chinese Acad Sci, Shanghai Inst Appl Phys, Shanghai Synchrotron Radiat Facil, Shanghai 201800, Peoples R China.; Jin, WQ (corresponding author), Nanjing Tech Univ, Jiangsu Natl Synerget Innovat Ctr Adv Mat, State Key Lab Mat Oriented Chem Engn, 5 Xinmofan Rd, Nanjing 210009, Jiangsu, Peoples R China.
EM mhwu@mail.shu.edu.cn; wqjin@njtech.edu.cn; lijingye@sinap.ac.cn; fanghaiping@sinap.ac.cn
FU National Natural Science Foundation of China [11290164, 41430644, 21490585, 11574339, 11404361, 21476107]; National Science Fund for Outstanding Young Scholars [11722548]; Key Research Program of the Chinese Academy of Sciences [KJZD-EW-M03]; Deepcomp7000 and ScGrid of the Supercomputing Center; Computer Network Information Center of the Chinese Academy of Sciences; Special Program for Applied Research on SuperComputation of the NSFC-Guangdong Joint Fund; Shanghai Supercomputer Center of China
NR 31
TC 1558
Z9 1688
U1 86
U2 4035
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 19
PY 2017
VL 550
IS 7676
BP 415
EP 418
DI 10.1038/nature24044
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK1NF
UT WOS:000413247900057
PM 28992630
DA 2026-03-09
ER

PT J
AU Guimaraes, PR
   Pires, MM
   Jordano, P
   Bascompte, J
   Thompson, JN
AF Guimaraes, Paulo R. ., Jr.
   Pires, Mathias M.
   Jordano, Pedro
   Bascompte, Jordi
   Thompson, John N.
TI Indirect effects drive coevolution in mutualistic networks
SO NATURE
LA English
DT Article
ID evolution; behavior
AB Ecological interactions have been acknowledged to play a key role in shaping biodiversity(1,2). Yet a major challenge for evolutionary biology is to understand the role of ecological interactions in shaping trait evolution when progressing from pairs of interacting species to multispecies interaction networks(2). Here we introduce an approach that integrates coevolutionary dynamics and network structure. Our results show that non-interacting species can be as important as directly interacting species in shaping coevolution within mutualistic assemblages. The contribution of indirect effects differs among types of mutualism. Indirect effects are more likely to predominate in nested, species-rich networks formed by multiple-partner mutualisms, such as pollination or seed dispersal by animals, than in small and modular networks formed by intimate mutualisms, such as those between host plants and their protective ants. Coevolutionary pathways of indirect effects favour ongoing trait evolution by promoting slow but continuous reorganization of the adaptive landscape of mutualistic partners under changing environments. Our results show that coevolution can be a major process shaping species traits throughout ecological networks. These findings expand our understanding of how evolution driven by interactions occurs through the interplay of selection pressures moving along multiple direct and indirect pathways.
C1 [Guimaraes, Paulo R. ., Jr.] Univ Sao Paulo, Inst Biociencias, Dept Ecol, Rua Matao 321,Travessa 14, BR-05508090 Sao Paulo, SP, Brazil.
   [Pires, Mathias M.] Univ Estadual Campinas, Inst Biol, Dept Biol Anim, Rua Monteiro Lobato 255, BR-13083862 Campinas, SP, Brazil.
   [Jordano, Pedro] Estn Biol Donana EBD CSIC, Ave Americo Vespucio 26, Seville 41092, Spain.
   [Bascompte, Jordi] Univ Zurich, Dept Evolutionary Biol & Environm Studies, Winterthurerstr 190, CH-8057 Zurich, Switzerland.
   [Thompson, John N.] Univ Calif Santa Cruz, Dept Ecol & Evolutionary Biol, Santa Cruz, CA 95064 USA.
C3 Universidade de Sao Paulo; Universidade Estadual de Campinas; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Estacion Biologica de Donana (EBD); University of Zurich; University of California System; University of California Santa Cruz
RP Guimaraes, PR (corresponding author), Univ Sao Paulo, Inst Biociencias, Dept Ecol, Rua Matao 321,Travessa 14, BR-05508090 Sao Paulo, SP, Brazil.
EM prguima@usp.br
FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2016/20739-9]; CNPq; FAPESP [2013/22016-6]; European Research Council; Swiss National Science Foundation [31003A_160671]; Severo Ochoa Excellence Award (Spanish Ministerio de Ciencia e Innovacion) [SEV-2012-0262]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [13/22016-6, 16/20739-9] Funding Source: FAPESP
NR 30
TC 209
Z9 230
U1 2
U2 187
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 26
PY 2017
VL 550
IS 7677
BP 511
EP +
DI 10.1038/nature24273
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK7OW
UT WOS:000413697800041
PM 29045396
DA 2026-03-09
ER

PT J
AU Zhang, X
   Strobel, DF
   Imanaka, H
AF Zhang, Xi
   Strobel, Darrell F.
   Imanaka, Hiroshi
TI Haze heats Pluto's atmosphere yet explains its cold temperature
SO NATURE
LA English
DT Article
ID new-horizons observations; thermal structure; optical-constants; titans atmosphere; stratospheric aerosols; refractive-index; jupiter; density; rates; constraints
AB Pluto's atmosphere is cold and hazy(1-3). Recent observations(1) have shown it to be much colder than predicted theoretically(4), suggesting an unknown cooling mechanism(1). Atmospheric gas molecules, particularly water vapour, have been proposed as a coolant; however, because Pluto's thermal structure is expected to be in radiative-conductive equilibrium(4-9), the required water vapour would need to be supersaturated by many orders of magnitude under thermodynamic equilibrium conditions(9). Here we report that atmospheric hazes, rather than gases, can explain Pluto's temperature profile. We find that haze particles have substantially larger solar heating and thermal cooling rates than gas molecules, dominating the atmospheric radiative balance from the ground to an altitude of 700 kilometres, above which heat conduction maintains an isothermal atmosphere. We conclude that Pluto's atmosphere is unique among Solar System planetary atmospheres, as its radiative energy equilibrium is controlled primarily by haze particles instead of gas molecules. We predict that Pluto is therefore several orders of magnitude brighter at mid-infrared wavelengths than previously thought-a brightness that could be detected by future telescopes.
C1 [Zhang, Xi] Univ Calif Santa Cruz, Dept Earth & Planetary Sci, Santa Cruz, CA 95064 USA.
   [Strobel, Darrell F.] Johns Hopkins Univ, Dept Earth & Planetary Sci & Phys & Astron, Baltimore, MD 21218 USA.
   [Imanaka, Hiroshi] SETI Inst, 189 North Bernardo Ave,Suite 100, Mountain View, CA 94043 USA.
   [Imanaka, Hiroshi] NASA, Ames Res Ctr, Moffett Field, CA 94035 USA.
C3 University of California System; University of California Santa Cruz; Johns Hopkins University; SETI Institute; National Aeronautics & Space Administration (NASA); NASA Ames Research Center
RP Zhang, X (corresponding author), Univ Calif Santa Cruz, Dept Earth & Planetary Sci, Santa Cruz, CA 95064 USA.
EM xiz@ucsc.edu
FU NASA [NNX16AG08G, NNX14AF61G, NNX15AQ73G]; NASA's New Horizons Mission; NASA [797489, NNX15AQ73G, 684144, NNX16AG08G, NNX14AF61G, 905117] Funding Source: Federal RePORTER
NR 40
TC 61
Z9 70
U1 0
U2 37
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 16
PY 2017
VL 551
IS 7680
BP 352
EP +
DI 10.1038/nature24465
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM8UK
UT WOS:000415365500036
PM 29144464
DA 2026-03-09
ER

PT J
AU Wei, L
   Chen, ZX
   Shi, LX
   Long, R
   Anzalone, AV
   Zhang, LY
   Hu, FH
   Yuste, R
   Cornish, VW
   Min, W
AF Wei, Lu
   Chen, Zhixing
   Shi, Lixue
   Long, Rong
   Anzalone, Andrew V.
   Zhang, Luyuan
   Hu, Fanghao
   Yuste, Rafael
   Cornish, Virginia W.
   Min, Wei
TI Super-multiplex vibrational imaging
SO NATURE
LA English
DT Article
ID stimulated raman-scattering; resonance raman; spectroscopy; microscopy; biomolecules; proteins
AB The ability to visualize directly a large number of distinct molecular species inside cells is increasingly essential for understanding complex systems and processes. Even though existing methods have successfully been used to explore structure-function relationships in nervous systems, to profile RNA in situ, to reveal the heterogeneity of tumour microenvironments and to study dynamic macromolecular assembly(1-4), it remains challenging to image many species with high selectivity and sensitivity under biological conditions. For instance, fluorescence microscopy faces a 'colour barrier', owing to the intrinsically broad (about 1,500 inverse centimetres) and featureless nature of fluorescence spectra(5) that limits the number of resolvable colours to two to five (or seven to nine if using complicated instrumentation and analysis)(6-8). Spontaneous Raman microscopy probes vibrational transitions with much narrower resonances (peak width of about 10 inverse centimetres) and so does not suffer from this problem, but weak signals make many bio-imaging applications impossible. Although surface-enhanced Raman scattering offers high sensitivity and multiplicity, it cannot be readily used to image specific molecular targets quantitatively inside live cells(9). Here we use stimulated Raman scattering under electronic pre-resonance conditions to image target molecules inside living cells with very high vibrational selectivity and sensitivity (down to 250 nanomolar with a time constant of 1 millisecond). We create a palette of triple-bond-conjugated near-infrared dyes that each displays a single peak in the cell-silent Raman spectral window; when combined with available fluorescent probes, this palette provides 24 resolvable colours, with the potential for further expansion. Proof-of-principle experiments on neuronal co-cultures and brain tissues reveal cell-type-dependent heterogeneities in DNA and protein metabolism under physiological and pathological conditions, underscoring the potential of this 24-colour (super-multiplex) optical imaging approach for elucidating intricate interactions in complex biological systems.
C1 [Wei, Lu; Chen, Zhixing; Shi, Lixue; Long, Rong; Anzalone, Andrew V.; Zhang, Luyuan; Hu, Fanghao; Cornish, Virginia W.; Min, Wei] Columbia Univ, Dept Chem, New York, NY 10027 USA.
   [Yuste, Rafael; Cornish, Virginia W.; Min, Wei] Columbia Univ, NeuroTechnol Ctr, New York, NY 10027 USA.
   [Yuste, Rafael] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA.
   [Yuste, Rafael] Columbia Univ, Dept Neurosci, New York, NY 10027 USA.
   [Min, Wei] Columbia Univ, Kavli Inst Brain Sci, New York, NY 10032 USA.
C3 Columbia University; Columbia University; Columbia University; Columbia University; Columbia University
RP Min, W (corresponding author), Columbia Univ, Dept Chem, New York, NY 10027 USA.; Min, W (corresponding author), Columbia Univ, NeuroTechnol Ctr, New York, NY 10027 USA.; Min, W (corresponding author), Columbia Univ, Kavli Inst Brain Sci, New York, NY 10032 USA.
EM wm2256@columbia.edu
FU NIH [1DP2EB016573, EB020892]; US Army Research Office [W911NF-12-1-0594]; Alfred P. Sloan Foundation; Camille and Henry Dreyfus Foundation; NEI [EY024503, EY011787]; NIMH [MH101218, MH100561]; National Eye Institute [R01EY011787] Funding Source: NIH RePORTER
NR 32
TC 422
Z9 506
U1 9
U2 576
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 27
PY 2017
VL 544
IS 7651
BP 465
EP +
DI 10.1038/nature22051
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET1TN
UT WOS:000400051900040
PM 28424513
DA 2026-03-09
ER

PT J
AU Sutherland, R
   Townend, J
   Toy, V
   Upton, P
   Coussens, J
   Allen, M
   Baratin, LM
   Barth, N
   Becroft, L
   Boese, C
   Boles, A
   Boulton, C
   Broderick, NGR
   Janku-Capova, L
   Carpenter, BM
   Célérier, B
   Chamberlain, C
   Cooper, A
   Coutts, A
   Cox, S
   Craw, L
   Doan, ML
   Eccles, J
   Faulkner, D
   Grieve, J
   Grochowski, J
   Gulley, A
   Hartog, A
   Howarth, J
   Jacobs, K
   Jeppson, T
   Kato, N
   Keys, S
   Kirilova, M
   Kometani, Y
   Langridge, R
   Lin, WR
   Little, T
   Lukacs, A
   Mallyon, D
   Mariani, E
   Massiot, C
   Mathewson, L
   Melosh, B
   Menzies, C
   Moore, J
   Morales, L
   Morgan, C
   Mori, H
   Niemeijer, A
   Nishikawa, O
   Prior, D
   Sauer, K
   Savage, M
   Schleicher, A
   Schmitt, DR
   Shigematsu, N
   Taylor-Offord, S
   Teagle, D
   Tobin, H
   Valdez, R
   Weaver, K
   Wiersberg, T
   Williams, J
   Woodman, N
   Zimmer, M
AF Sutherland, Rupert
   Townend, John
   Toy, Virginia
   Upton, Phaedra
   Coussens, Jamie
   Allen, Michael
   Baratin, Laura-May
   Barth, Nicolas
   Becroft, Leeza
   Boese, Carolin
   Boles, Austin
   Boulton, Carolyn
   Broderick, Neil G. R.
   Janku-Capova, Lucie
   Carpenter, Brett M.
   Celerier, Bernard
   Chamberlain, Calum
   Cooper, Alan
   Coutts, Ashley
   Cox, Simon
   Craw, Lisa
   Mai-Linh Doan
   Eccles, Jennifer
   Faulkner, Dan
   Grieve, Jason
   Grochowski, Julia
   Gulley, Anton
   Hartog, Arthur
   Howarth, Jamie
   Jacobs, Katrina
   Jeppson, Tamara
   Kato, Naoki
   Keys, Steven
   Kirilova, Martina
   Kometani, Yusuke
   Langridge, Rob
   Lin, Weiren
   Little, Timothy
   Lukacs, Adrienn
   Mallyon, Deirdre
   Mariani, Elisabetta
   Massiot, Cecile
   Mathewson, Loren
   Melosh, Ben
   Menzies, Catriona
   Moore, Jo
   Morales, Luiz
   Morgan, Chance
   Mori, Hiroshi
   Niemeijer, Andre
   Nishikawa, Osamu
   Prior, David
   Sauer, Katrina
   Savage, Martha
   Schleicher, Anja
   Schmitt, Douglas R.
   Shigematsu, Norio
   Taylor-Offord, Sam
   Teagle, Damon
   Tobin, Harold
   Valdez, Robert
   Weaver, Konrad
   Wiersberg, Thomas
   Williams, Jack
   Woodman, Nick
   Zimmer, Martin
TI Extreme hydrothermal conditions at an active plate-bounding fault
SO NATURE
LA English
DT Article
ID san-andreas fault; alpine fault; heat-flow; south island; new-zealand; slip zone; earthquake; permeability; temperature; friction
AB Temperature and fluid pressure conditions control rock deformation and mineralization on geological faults, and hence the distribution of earthquakes(1). Typical intraplate continental crust has hydrostatic fluid pressure and a near-surface thermal gradient of 31 +/- 15 degrees Celsius per kilometre(2,3). At temperatures above 300-450 degrees Celsius, usually found at depths greater than 10-15 kilometres, the intra-crystalline plasticity of quartz and feldspar relieves stress by aseismic creep and earthquakes are infrequent. Hydrothermal conditions control the stability of mineral phases and hence frictional-mechanical processes associated with earthquake rupture cycles, but there are few temperature and fluid pressure data from active plate-bounding faults. Here we report results from a borehole drilled into the upper part of the Alpine Fault, which is late in its cycle of stress accumulation and expected to rupture in a magnitude 8 earthquake in the coming decades(4,5). The borehole (depth 893 metres) revealed a pore fluid pressure gradient exceeding 9 +/- 1 per cent above hydrostatic levels and an average geothermal gradient of 125 +/- 55 degrees Celsius per kilometre within the hanging wall of the fault. These extreme hydrothermal conditions result from rapid fault movement, which transports rock and heat from depth, and topographically driven fluid movement that concentrates heat into valleys. Shear heating may occur within the fault but is not required to explain our observations. Our data and models show that highly anomalous fluid pressure and temperature gradients in the upper part of the seismogenic zone can be created by positive feedbacks between processes of fault slip, rock fracturing and alteration, and landscape development at plate-bounding faults.
C1 [Sutherland, Rupert; Upton, Phaedra; Howarth, Jamie; Langridge, Rob; Massiot, Cecile] GNS Sci, POB 30368, Lower Hutt, New Zealand.
   [Sutherland, Rupert; Townend, John; Baratin, Laura-May; Boese, Carolin; Janku-Capova, Lucie; Chamberlain, Calum; Grochowski, Julia; Jacobs, Katrina; Keys, Steven; Little, Timothy; Massiot, Cecile; Savage, Martha; Taylor-Offord, Sam] Victoria Univ Wellington, SGEES, POB 600, Wellington, New Zealand.
   [Toy, Virginia; Becroft, Leeza; Cooper, Alan; Craw, Lisa; Grieve, Jason; Lukacs, Adrienn; Mathewson, Loren; Prior, David; Sauer, Katrina; Williams, Jack] Univ Otago, Dept Geol, POB 56, Dunedin 9054, New Zealand.
   [Coussens, Jamie; Menzies, Catriona; Teagle, Damon; Woodman, Nick] Univ Southampton, Dept Ocean & Earth Sci, Southampton SO14 3ZH, Hants, England.
   [Allen, Michael; Faulkner, Dan; Mariani, Elisabetta] Univ Liverpool, Sch Environm Sci, Liverpool L69 3GP, Merseyside, England.
   [Barth, Nicolas] Univ Calif Riverside, Dept Earth Sci, Riverside, CA 92521 USA.
   [Boles, Austin] Univ Michigan, Dept Earth & Environm Sci, Ann Arbor, MI 48109 USA.
   [Broderick, Neil G. R.; Coutts, Ashley; Eccles, Jennifer; Gulley, Anton] Univ Auckland, Private Bag 92019, Auckland 1142, New Zealand.
   [Carpenter, Brett M.] Univ Oklahoma, Sch Geol & Geophys, Norman, OK 73019 USA.
   [Celerier, Bernard] Univ Montpellier, CNRS, F-34095 Montpellier, France.
   [Cox, Simon] GNS Sci, Private Bag 1930, Dunedin 9054, New Zealand.
   [Mai-Linh Doan] Univ Grenoble Alpes, Univ Savoie Mont Blanc, CNRS, IRD,IFSTTAR,ISTerre, F-38000 Grenoble, France.
   [Hartog, Arthur] Schlumberger Fiber Opt Technol Ctr, Romsey SO51 9DL, Hants, England.
   [Jeppson, Tamara; Tobin, Harold] Univ Wisconsin, Dept Geosci, Madison, WI 53706 USA.
   [Kato, Naoki] Osaka Univ, Dept Earth & Space Sci, Osaka 5650871, Japan.
   [Kometani, Yusuke] Yamaguchi Univ, Dept Geosphere Sci, Yamaguchi 7538511, Japan.
   [Lin, Weiren] Kyoto Univ, Grad Sch Engn, Kyoto 6158540, Japan.
   [Lin, Weiren] Japan Agcy Marine Earth Sci & Technol, Kochi Inst Core Sample Res, Kochi 7838502, Japan.
   [Mallyon, Deirdre; Schmitt, Douglas R.] Univ Alberta, Dept Phys, Edmonton, AB T6G 2R3, Canada.
   [Melosh, Ben] McGill Univ, Dept Earth & Planetary Sci, Montreal, PQ H3A 0G4, Canada.
   [Moore, Jo] Macquarie Univ, Dept Earth & Planetary Sci, Sydney, NSW 2109, Australia.
   [Morales, Luiz] ETH, ScopeM, CH-8093 Zurich, Switzerland.
   [Mori, Hiroshi] Shinshu Univ, Dept Geol, Asahi 3-1-1, Matsumoto, Nagano, Japan.
   [Niemeijer, Andre] Univ Utrecht, Fac Geosci, HPT Lab, NL-3584 CD Utrecht, Netherlands.
   [Nishikawa, Osamu] Akita Univ, Dept Earth Sci & Technol, Akita 0108502, Japan.
   [Schleicher, Anja; Wiersberg, Thomas; Zimmer, Martin] GFZ German Res Ctr Geosci, D-14473 Potsdam, Germany.
   [Shigematsu, Norio] Geol Survey Japan, AIST, Tsukuba, Ibaraki, Japan.
   [Valdez, Robert] Penn State Univ, Dept Geosci, University Pk, PA 16802 USA.
C3 Earth Sciences New Zealand; GNS Science - New Zealand; Victoria University Wellington; University of Otago; NERC National Oceanography Centre; University of Southampton; University of Liverpool; University of California System; University of California Riverside; University of Michigan System; University of Michigan; University of Auckland; University of Oklahoma System; University of Oklahoma - Norman; Universite de Montpellier; Centre National de la Recherche Scientifique (CNRS); Earth Sciences New Zealand; GNS Science - New Zealand; Universite Gustave-Eiffel; Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Centre National de la Recherche Scientifique (CNRS); Institut de Recherche pour le Developpement (IRD); Universite Savoie Mont Blanc; Schlumberger; University of Wisconsin System; University of Wisconsin Madison; University of Osaka; Yamaguchi University; Kyoto University; Japan Agency for Marine-Earth Science & Technology (JAMSTEC); University of Alberta; McGill University; Macquarie University; Swiss Federal Institutes of Technology Domain; ETH Zurich; Shinshu University; Utrecht University; Akita University; Helmholtz Association; GFZ Helmholtz Centre for Geosciences; National Institute of Advanced Industrial Science & Technology (AIST); Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park
RP Sutherland, R (corresponding author), GNS Sci, POB 30368, Lower Hutt, New Zealand.; Sutherland, R (corresponding author), Victoria Univ Wellington, SGEES, POB 600, Wellington, New Zealand.
EM rupert.sutherland@vuw.ac.nz
FU Westland community; International Continental Scientific Drilling Program (ICDP); NZ Marsden Fund; GNS Science; Victoria University of Wellington; University of Otago; NZ Ministry for Business Innovation and Employment; NERC [NE/J022128/1, NE/J024449/1]; Netherlands Organization for Scientific Research VIDI grant [854.12.011]; ERC [SEISMIC 335915]; NERC [NE/H012842/1, NE/J022128/1, NE/J024449/1] Funding Source: UKRI; Directorate For Geosciences; Division Of Earth Sciences [1215711] Funding Source: National Science Foundation; Natural Environment Research Council [1364056, 1544352, NE/J024449/1, NE/H012842/1, NE/J022128/1] Funding Source: researchfish; Grants-in-Aid for Scientific Research [16H04065, 26109004] Funding Source: KAKEN
NR 36
TC 97
Z9 106
U1 1
U2 104
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 1
PY 2017
VL 546
IS 7656
BP 137
EP +
DI 10.1038/nature22355
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW3CR
UT WOS:000402372800043
PM 28514440
DA 2026-03-09
ER

PT J
AU Joung, J
   Engreitz, JM
   Konermann, S
   Abudayyeh, OO
   Verdine, VK
   Aguet, F
   Gootenberg, JS
   Sanjana, NE
   Wright, JB
   Fulco, CP
   Tseng, YY
   Yoon, CH
   Boehm, JS
   Lander, ES
   Zhang, F
AF Joung, Julia
   Engreitz, Jesse M.
   Konermann, Silvana
   Abudayyeh, Omar O.
   Verdine, Vanessa K.
   Aguet, Francois
   Gootenberg, Jonathan S.
   Sanjana, Neville E.
   Wright, Jason B.
   Fulco, Charles P.
   Tseng, Yuen-Yi
   Yoon, Charles H.
   Boehm, Jesse S.
   Lander, Eric S.
   Zhang, Feng
TI Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood
SO NATURE
LA English
DT Article
ID noncoding rnas; transcriptional activation; chromatin; reveals; expression; interference; sensitivity; seq; map
AB Mammalian genomes contain thousands of loci that transcribe long noncoding RNAs (lncRNAs)(1,2), some of which are known to carry out critical roles in diverse cellular processes through a variety of mechanisms(3-8). Although some lncRNA loci encode RNAs that act non-locally (in trans)(5), there is emerging evidence that many lncRNA loci act locally (in cis) to regulate the expression of nearby genes-for example, through functions of the lncRNA promoter, transcription, or transcript itself(3,6-8). Despite their potentially important roles, it remains challenging to identify functional lncRNA loci and distinguish among these and other mechanisms. Here, to address these challenges, we developed a genome-scale CRISPR-Cas9 activation screen that targets more than 10,000 lncRNA transcriptional start sites to identify noncoding loci that influence a phenotype of interest. We found 11 lncRNA loci that, upon recruitment of an activator, mediate resistance to BRAF inhibitors in human melanoma cells. Most candidate loci appear to regulate nearby genes. Detailed analysis of one candidate, termed EMICERI, revealed that its transcriptional activation resulted in dosage-dependent activation of four neighbouring protein-coding genes, one of which confers the resistance phenotype. Our screening and characterization approach provides a CRISPR toolkit with which to systematically discover the functions of noncoding loci and elucidate their diverse roles in gene regulation and cellular function.
C1 [Joung, Julia; Zhang, Feng] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Joung, Julia; Engreitz, Jesse M.; Konermann, Silvana; Abudayyeh, Omar O.; Verdine, Vanessa K.; Aguet, Francois; Gootenberg, Jonathan S.; Sanjana, Neville E.; Wright, Jason B.; Fulco, Charles P.; Tseng, Yuen-Yi; Boehm, Jesse S.; Lander, Eric S.; Zhang, Feng] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Joung, Julia; Konermann, Silvana; Abudayyeh, Omar O.; Verdine, Vanessa K.; Gootenberg, Jonathan S.; Sanjana, Neville E.; Wright, Jason B.; Zhang, Feng] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Joung, Julia; Konermann, Silvana; Abudayyeh, Omar O.; Gootenberg, Jonathan S.; Sanjana, Neville E.; Wright, Jason B.; Zhang, Feng] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA.
   [Abudayyeh, Omar O.] MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA.
   [Gootenberg, Jonathan S.; Fulco, Charles P.; Lander, Eric S.] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA.
   [Yoon, Charles H.] Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA.
   [Lander, Eric S.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Konermann, Silvana] Salk Inst Biol Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA.
   [Sanjana, Neville E.] New York Genome Ctr, New York, NY USA.
   [Sanjana, Neville E.] NYU, Dept Biol, New York, NY 10003 USA.
C3 Massachusetts Institute of Technology (MIT); Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Massachusetts Institute of Technology (MIT); Salk Institute; New York University
RP Zhang, F (corresponding author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Lander, ES; Zhang, F (corresponding author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Zhang, F (corresponding author), MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Zhang, F (corresponding author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA.; Lander, ES (corresponding author), Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA.; Lander, ES (corresponding author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
EM lander@broadinstitute.org; zhang@broadinstitute.org
FU Fannie and John Hertz Foundation; Paul and Daisy Soros Fellowship; National Defense Science and Engineering Fellowship; DOE Computational Science Graduate Fellowship; NIH through NHGRI [R00-HG008171]; NIH through NIDDK [F32-DK096822]; National Defense Science and Engineering Graduate Fellowship; Broad Institute; NIH through NIMH [5DP1-MH100706, 1R01-MH110049]; NSF; Howard Hughes Medical Institute; New York Stem Cell; Simons Foundation; Paul G. Allen Family Foundation; Vallee Foundation;  [UM1HG008895]
NR 28
TC 335
Z9 412
U1 3
U2 130
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 17
PY 2017
VL 548
IS 7667
BP 343
EP +
DI 10.1038/nature23451
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD8AU
UT WOS:000407748400035
PM 28792927
DA 2026-03-09
ER

PT J
AU Emmett, MJ
   Lim, HW
   Jager, J
   Richter, HJ
   Adlanmerini, M
   Peed, LC
   Briggs, ER
   Steger, DJ
   Ma, T
   Sims, CA
   Baur, JA
   Pei, LM
   Won, KJ
   Seale, P
   Gerhart-Hines, Z
   Lazar, MA
AF Emmett, Matthew J.
   Lim, Hee-Woong
   Jager, Jennifer
   Richter, Hannah J.
   Adlanmerini, Marine
   Peed, Lindsey C.
   Briggs, Erika R.
   Steger, David J.
   Ma, Tao
   Sims, Carrie A.
   Baur, Joseph A.
   Pei, Liming
   Won, Kyoung-Jae
   Seale, Patrick
   Gerhart-Hines, Zachary
   Lazar, Mitchell A.
TI Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge
SO NATURE
LA English
DT Article
ID integrative genomics viewer; energy-expenditure; adipocyte identity; beige fat; in-vivo; gene; mice; transcription; metabolism; macrophage
AB Brown adipose tissue is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease(1). However, the transcriptional mechanisms that determine the thermogenic capacity of brown adipose tissue before environmental cold are unknown. Here we show that histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Mice with brown adipose tissue-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. Uncoupling protein 1 (UCP1) is nearly absent in brown adipose tissue lacking HDAC3, and there is also marked downregulation of mitochondrial oxidative phosphorylation genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor(2), it functions as a coactivator of oestrogen-related receptor alpha (ERR alpha) in brown adipose tissue. HDAC3 coactivation of ERR alpha is mediated by deacetylation of PGC-1 alpha and is required for the transcription of Ucp1, Ppargc1a (encoding PGC-1 alpha), and oxidative phosphorylation genes. Importantly, HDAC3 promotes the basal transcription of these genes independently of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in brown adipose tissue that can be rapidly engaged upon exposure to dangerously cold temperature.
C1 [Emmett, Matthew J.; Lim, Hee-Woong; Jager, Jennifer; Richter, Hannah J.; Adlanmerini, Marine; Peed, Lindsey C.; Briggs, Erika R.; Steger, David J.; Sims, Carrie A.; Baur, Joseph A.; Pei, Liming; Won, Kyoung-Jae; Seale, Patrick; Lazar, Mitchell A.] Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA.
   [Emmett, Matthew J.; Jager, Jennifer; Richter, Hannah J.; Adlanmerini, Marine; Peed, Lindsey C.; Briggs, Erika R.; Steger, David J.; Lazar, Mitchell A.] Univ Penn, Perelman Sch Med, Dept Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA.
   [Lim, Hee-Woong; Won, Kyoung-Jae; Lazar, Mitchell A.] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA.
   [Ma, Tao; Gerhart-Hines, Zachary] Univ Copenhagen, Novo Nordisk Fdn, Sect Metab Receptol, Ctr Basic Metab Res, DK-2200 Copenhagen, Denmark.
   [Ma, Tao; Gerhart-Hines, Zachary] Univ Copenhagen, Inst Neurosci & Pharmacol, DK-2200 Copenhagen, Denmark.
   [Sims, Carrie A.] Univ Penn, Perelman Sch Med, Dept Surg, Trauma Ctr Penn, Philadelphia, PA 19104 USA.
   [Baur, Joseph A.] Univ Penn, Perelman Sch Med, Dept Physiol, Philadelphia, PA 19104 USA.
   [Pei, Liming] Childrens Hosp Philadelphia, Ctr Mitochondrial & Epigenom Med, Philadelphia, PA 19104 USA.
   [Pei, Liming] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA.
   [Seale, Patrick] Univ Penn, Perelman Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA.
C3 University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; Novo Nordisk Foundation; University of Copenhagen; University of Copenhagen; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; University of Pennsylvania
RP Lazar, MA (corresponding author), Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA.; Lazar, MA (corresponding author), Univ Penn, Perelman Sch Med, Dept Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA.; Lazar, MA (corresponding author), Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA.
EM lazar@mail.med.upenn.edu
FU NIH [R01 DK45586, F30 DK104513, R01 DK106027]; JPB Foundation; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK111495, R01DK045586, R01DK043806, P30DK019525, P30DK050306] Funding Source: NIH RePORTER; NNF Center for Basic Metabolic Research [Gerhart-Hines Group] Funding Source: researchfish
NR 58
TC 151
Z9 187
U1 2
U2 42
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 22
PY 2017
VL 546
IS 7659
BP 544
EP +
DI 10.1038/nature22819
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY2QK
UT WOS:000403814100041
PM 28614293
DA 2026-03-09
ER

PT J
AU Ong, LL
   Hanikel, N
   Yaghi, OK
   Grun, C
   Strauss, MT
   Bron, P
   Lai-Kee-Him, J
   Schueder, F
   Wang, B
   Wang, PF
   Kishi, JY
   Myhrvold, C
   Zhu, A
   Jungmann, R
   Bellot, G
   Ke, YG
   Yin, P
AF Ong, Luvena L.
   Hanikel, Nikita
   Yaghi, Omar K.
   Grun, Casey
   Strauss, Maximilian T.
   Bron, Patrick
   Lai-Kee-Him, Josephine
   Schueder, Florian
   Wang, Bei
   Wang, Pengfei
   Kishi, Jocelyn Y.
   Myhrvold, Cameron
   Zhu, Allen
   Jungmann, Ralf
   Bellot, Gaetan
   Ke, Yonggang
   Yin, Peng
TI Programmable self-assembly of three-dimensional nanostructures from 10,000 unique components
SO NATURE
LA English
DT Article
ID single-stranded-dna; nanoscale shapes; rational design; origami; reconstruction; image
AB Nucleic acids (DNA and RNA) are widely used to construct nanometre-scale structures with ever increasing complexity(1-14), with possible application in fields such as structural biology, biophysics, synthetic biology and photonics. The nanostructures are formed through one-pot self-assembly, with early kilodalton-scale examples containing typically tens of unique DNA strands. The introduction of DNA origami(4), which uses many staple strands to fold one long scaffold strand into a desired structure, has provided access to megadalton-scale nanostructures that contain hundreds of unique DNA strands(6,7,10-14). Even larger DNA origami structures are possible(15,16), but manufacturing and manipulating an increasingly long scaffold strand remains a challenge. An alternative and more readily scalable approach involves the assembly of DNA bricks, which each consist of four short binding domains arranged so that the bricks can interlock(8,9). This approach does not require a scaffold; instead, the short DNA brick strands self-assemble according to specific inter-brick interactions. First-generation bricks used to create three-dimensional structures are 32 nucleotides long, consisting of four eight-nucleotide binding domains. Protocols have been designed to direct the assembly of hundreds of distinct bricks into well formed structures, but attempts to create larger structures have encountered practical challenges and had limited success(9). Here we show that DNA bricks with longer, 13-nucleotide binding domains make it possible to self-assemble 0.1-1-gigadalton, three-dimensional nanostructures from tens of thousands of unique components, including a 0.5-gigadalton cuboid containing about 30,000 unique bricks and a 1-gigadalton rotationally symmetric tetramer. We also assembled a cuboid that contains around 10,000 bricks and about 20,000 uniquely addressable, 13-base-pair 'voxels' that serves as a molecular canvas for three-dimensional sculpting. Complex, user-prescribed, three-dimensional cavities can be produced within this molecular canvas, enabling the creation of shapes such as letters, a helicoid and a teddy bear. We anticipate that with further optimization of structure design, strand synthesis and assembly procedure even larger structures could be accessible, which could be useful for applications such as positioning functional components.
C1 [Ong, Luvena L.; Hanikel, Nikita; Yaghi, Omar K.; Grun, Casey; Strauss, Maximilian T.; Schueder, Florian; Wang, Bei; Kishi, Jocelyn Y.; Myhrvold, Cameron; Zhu, Allen; Yin, Peng] Harvard Univ, Wyss Inst Biologically Inspired Engn, Boston, MA 02115 USA.
   [Ong, Luvena L.] MIT, Harvard MIT Program Hlth Sci & Technol, Cambridge, MA 02139 USA.
   [Strauss, Maximilian T.; Schueder, Florian; Jungmann, Ralf] Max Planck Inst Biochem, D-82152 Martinsried Munich, Germany.
   [Strauss, Maximilian T.; Schueder, Florian; Jungmann, Ralf] Ludwig Maximilians Univ Munchen, Dept Phys, D-80539 Munich, Germany.
   [Strauss, Maximilian T.; Schueder, Florian; Jungmann, Ralf] Ludwig Maximilians Univ Munchen, Ctr Nanosci, D-80539 Munich, Germany.
   [Bron, Patrick; Lai-Kee-Him, Josephine] Ctr Biochim Struct, CNRS, INSERM, UMR 5048,U1054, F-34000 Montpellier, France.
   [Wang, Bei] Univ Sci & Technol China, Dept Polymer Sci & Engn, Hefei 230026, Anhui, Peoples R China.
   [Wang, Pengfei; Ke, Yonggang] Emory Univ, Dept Biomed Engn, Atlanta, GA 30322 USA.
   [Wang, Pengfei; Ke, Yonggang] Georgia Inst Technol, Atlanta, GA 30322 USA.
   [Kishi, Jocelyn Y.; Myhrvold, Cameron; Yin, Peng] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA.
   [Bellot, Gaetan] Inst Genom Fonct, CNRS, INSERM, U1191,UMR 5203, F-34000 Montpellier, France.
   [Ke, Yonggang] Emory Univ, Dept Chem, Atlanta, GA 30322 USA.
C3 Harvard University; Massachusetts Institute of Technology (MIT); Max Planck Society; University of Munich; University of Munich; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Montpellier; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Chinese Academy of Sciences; University of Science & Technology of China, CAS; Emory University; University System of Georgia; Georgia Institute of Technology; Harvard University; Harvard Medical School; Universite de Montpellier; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Institut National de la Sante et de la Recherche Medicale (Inserm); Emory University
RP Yin, P (corresponding author), Harvard Univ, Wyss Inst Biologically Inspired Engn, Boston, MA 02115 USA.; Ke, YG (corresponding author), Emory Univ, Dept Biomed Engn, Atlanta, GA 30322 USA.; Ke, YG (corresponding author), Georgia Inst Technol, Atlanta, GA 30322 USA.; Yin, P (corresponding author), Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA.; Bellot, G (corresponding author), Inst Genom Fonct, CNRS, INSERM, U1191,UMR 5203, F-34000 Montpellier, France.; Ke, YG (corresponding author), Emory Univ, Dept Chem, Atlanta, GA 30322 USA.
EM gaetan.bellot@igf.cnrs.fr; yonggang.ke@emory.edu; py@hms.harvard.edu
FU Office of Naval Research grants [N000141010827, N000141310593, N000141410610, N000141612182, N000141612410]; Army Research Office grant [W911NF1210238]; National Science Foundation [CCF-1054898, CCF-1162459, CCF-1317291, CMMI-1333215, CMMI-1334109, CMMI-1344915]; Air Force Office of Scientific Research grant [AFA9550-15- 1-0514]; National Institute of Health [1DP2OD007292, 1R01EB018659, 167814]; Emory Biomedical Engineering Department Startup Fund; Emory Winship Cancer Institute Billi and Bernie Marcus Research Award; Winship Cancer Institute from American Cancer Society [IRG-14-188-0]; National Science Foundation CAREER Award [DMR-1654485]; French National Research Agency [ANR-16- CE09-0004-01, ANR-15-CE09-0003-02, ANR-10-INBS-05]; NSF graduate research fellowship; German National Academic Foundation; German Academic Exchange Service; International Max Planck Research School for Molecular and Cellular Life Sciences (IMPRS-LS); U.S. Department of Defense (DOD) [N000141612182, N000141612410, W911NF1210238] Funding Source: U.S. Department of Defense (DOD); Div Of Civil, Mechanical, & Manufact Inn; Directorate For Engineering [1344915] Funding Source: National Science Foundation; Div Of Civil, Mechanical, & Manufact Inn; Directorate For Engineering [1333215] Funding Source: National Science Foundation; Agence Nationale de la Recherche (ANR) [ANR-16-CE09-0004, ANR-15-CE09-0003] Funding Source: Agence Nationale de la Recherche (ANR)
NR 37
TC 318
Z9 389
U1 14
U2 538
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 7
PY 2017
VL 552
IS 7683
BP 72
EP +
DI 10.1038/nature24648
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FP4BA
UT WOS:000417560500045
PM 29219968
DA 2026-03-09
ER

PT J
AU Guo, ZCV
   Inagaki, HK
   Daie, K
   Druckmann, S
   Gerfen, CR
   Svoboda, K
AF Guo, Zengcai V.
   Inagaki, Hidehiko K.
   Daie, Kayvon
   Druckmann, Shaul
   Gerfen, Charles R.
   Svoboda, Karel
TI Maintenance of persistent activity in a frontal thalamocortical loop
SO NATURE
LA English
DT Article
ID basal ganglia; prefrontal cortex; working-memory; motor cortex; transgenic mice; single neurons; thalamus; rat; movement; nucleus
AB Persistent neural activity maintains information that connects past and future events. Models of persistent activity often invoke reverberations within local cortical circuits, but long-range circuits could also contribute. Neurons in the mouse anterior lateral motor cortex (ALM) have been shown to have selective persistent activity that instructs future actions. The ALM is connected bidirectionally with parts of the thalamus, including the ventral medial and ventral anterior-lateral nuclei. We recorded spikes from the ALM and thalamus during tactile discrimination with a delayed directional response. Here we show that, similar to ALM neurons, thalamic neurons exhibited selective persistent delay activity that predicted movement direction. Unilateral photoinhibition of delay activity in the ALM or thalamus produced contralesional neglect. Photoinhibition of the thalamus caused a short-latency and near-complete collapse of ALM activity. Similarly, photoinhibition of the ALM diminished thalamic activity. Our results show that the thalamus is a circuit hub in motor preparation and suggest that persistent activity requires reciprocal excitation across multiple brain areas.
C1 [Guo, Zengcai V.; Inagaki, Hidehiko K.; Daie, Kayvon; Druckmann, Shaul; Svoboda, Karel] HHMI, Janelia Res Campus, Ashburn, VA 20147 USA.
   [Gerfen, Charles R.] NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA.
   [Guo, Zengcai V.] Tsinghua Univ, Sch Med, Beijing 100084, Peoples R China.
C3 Howard Hughes Medical Institute; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH); Tsinghua University
RP Svoboda, K (corresponding author), HHMI, Janelia Res Campus, Ashburn, VA 20147 USA.
EM svobodak@janelia.hhmi.org
FU Howard Hughes Medical Institute; Simons Collaboration on the Global Brain; National Institute of Mental Health [ZIAMH002497] Funding Source: NIH RePORTER
NR 60
TC 349
Z9 414
U1 4
U2 94
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 11
PY 2017
VL 545
IS 7653
BP 181
EP +
DI 10.1038/nature22324
PG 25
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EU3XG
UT WOS:000400963800026
PM 28467817
DA 2026-03-09
ER

PT J
AU Schubert, AF
   Gladkova, C
   Pardon, E
   Wagstaff, JL
   Freund, SMV
   Steyaert, J
   Maslen, SL
   Komander, D
AF Schubert, Alexander F.
   Gladkova, Christina
   Pardon, Els
   Wagstaff, Jane L.
   Freund, Stefan M. V.
   Steyaert, Jan
   Maslen, Sarah L.
   Komander, David
TI Structure of PINK1 in complex with its substrate ubiquitin
SO NATURE
LA English
DT Article
ID dependent protein-kinase; parkinsons-disease; crystal-structure; pink1-dependent phosphorylation; catalytic-activity; activate parkin; recognition; mechanism; drosophila-pink1; ubiquitylation
AB Autosomal-recessive juvenile Parkinsonism (AR-JP) is caused by mutations in a number of PARK genes, in particular the genes encoding the E3 ubiquitin ligase Parkin (PARK2, also known as PRKN) and its upstream protein kinase PINK1 (also known as PARK6). PINK1 phosphorylates both ubiquitin and the ubiquitin-like domain of Parkin on structurally protected Ser65 residues, triggering mitophagy. Here we report a crystal structure of a nanobody-stabilized complex containing Pediculus humanus corporis (Ph) PINK1 bound to ubiquitin in the 'C-terminally retracted' (Ub-CR) conformation. The structure reveals many peculiarities of PINK1, including the architecture of the C-terminal region, and reveals how the N lobe of PINK1 binds ubiquitin via a unique insertion. The flexible Ser65 loop in the Ub-CR conformation contacts the activation segment, facilitating placement of Ser65 in a phosphate-accepting position. The structure also explains how autophosphorylation in the N lobe stabilizes structurally and functionally important insertions, and reveals the molecular basis of AR-JP-causing mutations, some of which disrupt ubiquitin binding.
C1 [Schubert, Alexander F.; Gladkova, Christina; Wagstaff, Jane L.; Freund, Stefan M. V.; Maslen, Sarah L.; Komander, David] Med Res Council Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England.
   [Pardon, Els; Steyaert, Jan] VIB, VIB VUB Ctr Struct Biol, B-1050 Brussels, Belgium.
   [Steyaert, Jan] Vrije Univ Brussel, Struct Biol Brussels, B-1050 Brussels, Belgium.
C3 MRC Laboratory Molecular Biology; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); Flanders Institute for Biotechnology (VIB); Vrije Universiteit Brussel
RP Komander, D (corresponding author), Med Res Council Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England.
EM dk@mrc-lmb.cam.ac.uk
FU INSTRUCT; European Strategy Forum on Research Infrastructures (ESFRI); Research Foundation - Flanders (FWO); EU FP7 infrastructure grant BIOSTRUCT-X [283570]; Medical Research Council [U105192732]; European Research Council [309756, 724804]; Michael J. Fox Foundation; Lister Institute for Preventive Medicine; European Research Council (ERC) [724804] Funding Source: European Research Council (ERC); Medical Research Council [1662760, MC_U105192732, 1571029] Funding Source: researchfish; MRC [MC_U105192732] Funding Source: UKRI
NR 62
TC 133
Z9 159
U1 2
U2 62
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 7
PY 2017
VL 552
IS 7683
BP 51
EP +
DI 10.1038/nature24645
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FP4BA
UT WOS:000417560500041
PM 29160309
DA 2026-03-09
ER

PT J
AU Yan, KS
   Janda, CY
   Chang, JL
   Zheng, GXY
   Larkin, KA
   Luca, VC
   Chia, LA
   Mah, AT
   Han, A
   Terry, JM
   Ootani, A
   Roelf, K
   Lee, M
   Yuan, J
   Li, X
   Bolen, CR
   Wilhelmy, J
   Davies, PS
   Ueno, H
   von Furstenberg, RJ
   Belgrader, P
   Ziraldo, SB
   Ordonez, H
   Henning, SJ
   Wong, MH
   Snyder, MP
   Weissman, IL
   Hsueh, AJ
   Mikkelsen, TS
   Garcia, KC
   Kuo, CJ
AF Yan, Kelley S.
   Janda, Claudia Y.
   Chang, Junlei
   Zheng, Grace X. Y.
   Larkin, Kathryn A.
   Luca, Vincent C.
   Chia, Luis A.
   Mah, Amanda T.
   Han, Arnold
   Terry, Jessica M.
   Ootani, Akifumi
   Roelf, Kelly
   Lee, Mark
   Yuan, Jenny
   Li, Xiao
   Bolen, Christopher R.
   Wilhelmy, Julie
   Davies, Paige S.
   Ueno, Hiroo
   von Furstenberg, Richard J.
   Belgrader, Phillip
   Ziraldo, Solongo B.
   Ordonez, Heather
   Henning, Susan J.
   Wong, Melissa H.
   Snyder, Michael P.
   Weissman, Irving L.
   Hsueh, Aaron J.
   Mikkelsen, Tarjei S.
   Garcia, K. Christopher
   Kuo, Calvin J.
TI Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal
SO NATURE
LA English
DT Article
ID rna-seq experiments; wnt/beta-catenin; in-vitro; crypt; expression; receptors; marker; growth; colon; lgr4
AB The canonical Wnt/beta-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling beta-catenin nuclear translocation and TCF/LEF-dependent gene transactivation(1-3). Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors(1) and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands(2,3). For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium(4)-an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5(+) intestinal stem cells (ISCs)(5-9). R-spondin ligands (RSPO1-RSPO4) engage distinct LGR4-LGR6, RNF43 and ZNRF3 receptor classes(10-13), markedly potentiate canonical Wnt/beta-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5(+) ISCs in vivo(8,14-17). However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5(+) ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5(+) ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration.
C1 [Yan, Kelley S.; Chang, Junlei; Larkin, Kathryn A.; Chia, Luis A.; Mah, Amanda T.; Han, Arnold; Ootani, Akifumi; Roelf, Kelly; Lee, Mark; Yuan, Jenny; Wilhelmy, Julie; Kuo, Calvin J.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA.
   [Yan, Kelley S.] Columbia Univ, Columbia Ctr Human Dev, Div Digest & Liver Dis, Dept Med,Dept Genet & Dev,Med Ctr, New York, NY 10032 USA.
   [Janda, Claudia Y.; Luca, Vincent C.; Garcia, K. Christopher] Stanford Univ, Howard Hughes Med Inst, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA.
   [Zheng, Grace X. Y.; Terry, Jessica M.; Belgrader, Phillip; Ziraldo, Solongo B.; Ordonez, Heather; Mikkelsen, Tarjei S.] 10x Genom Inc, Pleasanton, CA 94566 USA.
   [Han, Arnold] Columbia Univ, Columbia Ctr Translat Immunol, Dept Microbiol & Immunol, Dept Med,Div Digest & Liver Dis,Med Ctr, New York, NY 10032 USA.
   [Li, Xiao; Snyder, Michael P.] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
   [Bolen, Christopher R.] Stanford Univ, Dept Microbiol & Immunol, Sch Med, Stanford, CA 94305 USA.
   [Davies, Paige S.; Wong, Melissa H.] Oregon Hlth & Sci Univ, Dept Cell Dev & Canc Biol, Portland, OR 97239 USA.
   [Ueno, Hiroo; Weissman, Irving L.] Stanford Univ, Sch Med, Inst Stem Cell Biol, Stanford, CA 94305 USA.
   [von Furstenberg, Richard J.; Henning, Susan J.] Univ North Carolina Chapel Hill, Dept Med, Chapel Hill, NC 27599 USA.
   [Hsueh, Aaron J.] Stanford Univ, Sch Med, Dept Gynecol & Obstet, Stanford, CA 94305 USA.
C3 Stanford University; Columbia University; Howard Hughes Medical Institute; Stanford University; Columbia University; Stanford University; Stanford University; Oregon Health & Science University; Stanford University; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; Stanford University
RP Kuo, CJ (corresponding author), Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA.
EM cjkuo@stanford.edu
FU CIRM MD Scholar Fellowships; AHA Postdoctoral Fellowship; Cancer Research Institute Irvington Fellowship; Burroughs Wellcome Fund CAMS; NIH [K08DK096048, K08DK100739, K99CA204738, R01GM097015, U01CA176299, U19AI116484, U01CA151920]; Ludwig Fund for Cancer Research; Intestinal Stem Cell Consortium - NIDDK [NIH U01DK085527, U01DK085547, U01DK085525]; NIAID; HHMI; Stinehart/Reed Foundation; AHA Innovative Science Award; National Cancer Institute [U01CA217851, P30CA124435] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [U19AI116484] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [U01DK085527] Funding Source: NIH RePORTER
NR 43
TC 341
Z9 421
U1 3
U2 144
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 11
PY 2017
VL 545
IS 7653
BP 238
EP +
DI 10.1038/nature22313
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EU3XG
UT WOS:000400963800037
PM 28467820
DA 2026-03-09
ER

PT J
AU Althoff, T
   Sosic, R
   Hicks, JL
   King, AC
   Delp, SL
   Leskovec, J
AF Althoff, Tim
   Sosic, Rok
   Hicks, Jennifer L.
   King, Abby C.
   Delp, Scott L.
   Leskovec, Jure
TI Large-scale physical activity data reveal worldwide activity inequality
SO NATURE
LA English
DT Article
ID income inequality; health; validation; inactivity; behaviors; mortality; tracking; progress; sleep; steps
AB To be able to curb the global pandemic of physical inactivity(1-7) and the associated 5.3 million deaths per year(2), we need to understand the basic principles that govern physical activity. However, there is a lack of large-scale measurements of physical activity patterns across free-living populations worldwide(1,6). Here we leverage the wide usage of smartphones with built-in accelerometry to measure physical activity at the global scale. We study a dataset consisting of 68 million days of physical activity for 717,527 people, giving us a window into activity in 111 countries across the globe. We find inequality in how activity is distributed within countries and that this inequality is a better predictor of obesity prevalence in the population than average activity volume. Reduced activity in females contributes to a large portion of the observed activity inequality. Aspects of the built environment, such as the walkability of a city, are associated with a smaller gender gap in activity and lower activity inequality. In more walkable cities, activity is greater throughout the day and throughout the week, across age, gender, and body mass index (BMI) groups, with the greatest increases in activity found for females. Our findings have implications for global public health policy and urban planning and highlight the role of activity inequality and the built environment in improving physical activity and health.
C1 [Althoff, Tim; Sosic, Rok; Leskovec, Jure] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA.
   [Hicks, Jennifer L.; Delp, Scott L.] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.
   [King, Abby C.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA.
   [King, Abby C.] Stanford Univ, Sch Med, Stanford Prevent Res Ctr, Dept Med, Stanford, CA 94305 USA.
   [Delp, Scott L.] Stanford Univ, Dept Mech Engn, Stanford, CA 94305 USA.
   [Leskovec, Jure] Chan Zuckerberg Biohub, San Francisco, CA 94158 USA.
C3 Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Chan Zuckerberg Initiative (CZI)
RP Leskovec, J (corresponding author), Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA.; Leskovec, J (corresponding author), Chan Zuckerberg Biohub, San Francisco, CA 94158 USA.
EM jure@cs.stanford.edu
FU National Institutes of Health (NIH) [U54 EB020405]; SAP Stanford Graduate Fellowship; NIH National Center for Simulation in Rehabilitation Research [R24 HD065690, P2C HD065690]; NSF [IIS-1149837]; Stanford Data Science Initiative
NR 45
TC 705
Z9 841
U1 14
U2 441
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 20
PY 2017
VL 547
IS 7663
BP 336
EP +
DI 10.1038/nature23018
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB0OR
UT WOS:000405844900031
PM 28693034
DA 2026-03-09
ER

PT J
AU Tzedakis, PC
   Crucifix, M
   Mitsui, T
   Wolff, EW
AF Tzedakis, P. C. .
   Crucifix, M.
   Mitsui, T.
   Wolff, E. W.
TI A simple rule to determine which insolation cycles lead to interglacials
SO NATURE
LA English
DT Article
ID middle pleistocene transition; glacial cycles; ice-sheet; climate; evolution; obliquity; model; variability; precession; ocean
AB The pacing of glacial-interglacial cycles during the Quaternary period (the past 2.6 million years) is attributed to astronomically driven changes in high-latitude insolation. However, it has not been clear how astronomical forcing translates into the observed sequence of interglacials. Here we show that before one million years ago interglacials occurred when the energy related to summer insolation exceeded a simple threshold, about every 41,000 years. Over the past one million years, fewer of these insolation peaks resulted in deglaciation (that is, more insolation peaks were 'skipped'), implying that the energy threshold for deglaciation had risen, which led to longer glacials. However, as a glacial lengthens, the energy needed for deglaciation decreases. A statistical model that combines these observations correctly predicts every complete deglaciation of the past million years and shows that the sequence of interglacials that has occurred is one of a small set of possibilities. The model accounts for the dominance of obliquity-paced glacial-interglacial cycles early in the Quaternary and for the change in their frequency about one million years ago. We propose that the appearance of larger ice sheets over the past million years was a consequence of an increase in the deglaciation threshold and in the number of skipped insolation peaks.
C1 [Tzedakis, P. C. .] UCL, Dept Geog, Environm Change Res Ctr, London, England.
   [Crucifix, M.; Mitsui, T.] Catholic Univ Louvain, Earth & Life Inst, Georges Lemaitre Ctr Earth & Climate Res, Louvain La Neuve, Belgium.
   [Wolff, E. W.] Univ Cambridge, Dept Earth Sci, Cambridge, England.
C3 University of London; University College London; Universite Catholique Louvain; University of Cambridge
RP Tzedakis, PC (corresponding author), UCL, Dept Geog, Environm Change Res Ctr, London, England.
EM p.c.tzedakis@ucl.ac.uk
FU Leverhulme Trust [RPG-2014-417]; Belgian Policy Office [BR/121/A2/STOCHCLIM]; Royal Society; Directorate For Geosciences; ICER [1450554] Funding Source: National Science Foundation; Division Of Earth Sciences; Directorate For Geosciences [1440015] Funding Source: National Science Foundation; ICER; Directorate For Geosciences [1450657] Funding Source: National Science Foundation
NR 56
TC 107
Z9 123
U1 5
U2 76
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 23
PY 2017
VL 542
IS 7642
BP 427
EP +
DI 10.1038/nature21364
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1RG
UT WOS:000395094100026
PM 28230118
DA 2026-03-09
ER

PT J
AU Snow, RW
   Sartorius, B
   Kyalo, D
   Maina, J
   Amratia, P
   Mundia, CW
   Bejon, P
   Noor, AM
AF Snow, Robert W.
   Sartorius, Benn
   Kyalo, David
   Maina, Joseph
   Amratia, Punam
   Mundia, Clara W.
   Bejon, Philip
   Noor, Abdisalan M.
TI The prevalence of Plasmodium falciparum in sub-Saharan Africa since 1900
SO NATURE
LA English
DT Article
ID malaria eradication
AB Malaria transmission is influenced by climate, land use and deliberate interventions. Recent declines have been observed in malaria transmission. Here we show that the African continent has witnessed a long-term decline in the prevalence of Plasmodium falciparum from 40% prevalence in the period 1900-1929 to 24% prevalence in the period 2010-2015, a trend that has been interrupted by periods of rapidly increasing or decreasing transmission. The cycles and trend over the past 115 years are inconsistent with explanations in terms of climate or deliberate intervention alone. Previous global initiatives have had minor impacts on malaria transmission, and a historically unprecedented decline has been observed since 2000. However, there has been little change in the high transmission belt that covers large parts of West and Central Africa. Previous efforts to model the changing patterns of P. falciparum transmission intensity in Africa have been limited to the past 15 years(1,2) or have used maps drawn from historical expert opinions(3). We provide quantitative data, from 50,424 surveys at 36,966 geocoded locations, that covers 115 years of malaria history in sub-Saharan Africa; inferring from these data to future trends, we would expect continued reductions in malaria transmission, punctuated with resurgences.
C1 [Snow, Robert W.; Kyalo, David; Maina, Joseph; Amratia, Punam; Mundia, Clara W.; Bejon, Philip; Noor, Abdisalan M.] Kenya Med Res Inst Wellcome Trust Collaborat Prog, Nairobi, Kenya.
   [Snow, Robert W.; Bejon, Philip] Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.
   [Sartorius, Benn] Univ KwaZulu Natal, Sch Nursing & Publ Hlth, Publ Hlth Med, Durban, South Africa.
C3 Kenya Medical Research Institute; University of Oxford; University of Kwazulu Natal
RP Snow, RW (corresponding author), Kenya Med Res Inst Wellcome Trust Collaborat Prog, Nairobi, Kenya.; Snow, RW (corresponding author), Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.
EM rsnow@kemri-wellcome.org
FU International Development Research Centre, Canada; Wellcome Trust, UK through Mapping Malaria Risk in Africa (MARA/ARMA) project [1996-1997: 048335]; Wellcome Trust through Malaria Atlas Project (MAP) [034694, 079080, 103602]; Wellcome Trust [095127, 077092, 203077]; Department for International Development (UK) [203155]; MRC [G1002624] Funding Source: UKRI; Wellcome Trust [103602/Z/14/Z] Funding Source: Wellcome Trust; Medical Research Council [G1002624] Funding Source: researchfish
NR 20
TC 151
Z9 178
U1 0
U2 38
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 26
PY 2017
VL 550
IS 7677
BP 515
EP +
DI 10.1038/nature24059
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK7OW
UT WOS:000413697800042
PM 29019978
DA 2026-03-09
ER

PT J
AU Xu, GY
   Greene, GH
   Yoo, HJ
   Liu, LJ
   Marques, J
   Motley, J
   Dong, XN
AF Xu, Guoyong
   Greene, George H.
   Yoo, Heejin
   Liu, Lijing
   Marques, Jorge
   Motley, Jonathan
   Dong, Xinnian
TI Global translational reprogramming is a fundamental layer of immune regulation in plants
SO NATURE
LA English
DT Article
ID ethylene-insensitive mutants; messenger-rna; arabidopsis-thaliana; in-vivo; landscape; vectors; genes
AB In the absence of specialized immune cells, the need for plants to reprogram transcription to transition from growth-related activities to defence is well understood(1,2). However, little is known about translational changes that occur during immune induction. Using ribosome footprinting, here we perform global translatome profiling on Arabidopsis exposed to the microbe-associated molecular pattern elf18. We find that during this pattern-triggered immunity, translation is tightly regulated and poorly correlated with transcription. Identification of genes with altered translational efficiency leads to the discovery of novel regulators of this immune response. Further investigation of these genes shows that messenger RNA sequence features are major determinants of the observed translational efficiency changes. In the 5' leader sequences of transcripts with increased translational efficiency, we find a highly enriched messenger RNA consensus sequence, R-motif, consisting of mostly purines. We show that R-motif regulates translation in response to pattern-triggered immunity induction through interaction with poly(A)-binding proteins. Therefore, this study provides not only strong evidence, but also a molecular mechanism, for global translational reprogramming during pattern-triggered immunity in plants.
C1 [Xu, Guoyong; Greene, George H.; Yoo, Heejin; Liu, Lijing; Marques, Jorge; Motley, Jonathan; Dong, Xinnian] Duke Univ, Dept Biol, Howard Hughes Med Inst, Gordon & Betty Moore Fdn, Durham, NC 27708 USA.
C3 Duke University; Howard Hughes Medical Institute
RP Dong, XN (corresponding author), Duke Univ, Dept Biol, Howard Hughes Med Inst, Gordon & Betty Moore Fdn, Durham, NC 27708 USA.
EM xdong@duke.edu
FU National Institutes of Health [5R01 GM069594-11]; Howard Hughes Medical Institute; Gordon and Betty Moore Foundation [GBMF3032]; Gordon and Betty Moore Foundation (GBMF) [GBMF3032] Funding Source: Gordon and Betty Moore Foundation (GBMF); National Institute of General Medical Sciences [R35GM118036] Funding Source: NIH RePORTER
NR 38
TC 185
Z9 228
U1 9
U2 152
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 25
PY 2017
VL 545
IS 7655
BP 487
EP +
DI 10.1038/nature22371
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV6TH
UT WOS:000401906500053
PM 28514447
DA 2026-03-09
ER

PT J
AU Chen, CC
   Itakura, E
   Nelson, GM
   Sheng, M
   Laurent, P
   Fenk, LA
   Butcher, RA
   Hegde, RS
   de Bono, M
AF Chen, Changchun
   Itakura, Eisuke
   Nelson, Geoffrey M.
   Sheng, Ming
   Laurent, Patrick
   Fenk, Lorenz A.
   Butcher, Rebecca A.
   Hegde, Ramanujan S.
   de Bono, Mario
TI IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses
SO NATURE
LA English
DT Article
ID kappa-b-zeta; c-elegans; natural variation; genetic-analysis; social-behavior; neural circuit; pathways; protein; family; expression
AB Interleukin-17 (IL-17) is a major pro-inflammatory cytokine: it mediates responses to pathogens or tissue damage, and drives autoimmune diseases. Little is known about its role in the nervous system. Here we show that IL-17 has neuromodulator-like properties in Caenorhabditis elegans. IL-17 can act directly on neurons to alter their response properties and contribution to behaviour. Using unbiased genetic screens, we delineate an IL-17 signalling pathway and show that it acts in the RMG hub interneurons. Disrupting IL-17 signalling reduces RMG responsiveness to input from oxygen sensors, and renders sustained escape from 21% oxygen transient and contingent on additional stimuli. Over-activating IL-17 receptors abnormally heightens responses to 21% oxygen in RMG neurons and whole animals. IL-17 deficiency can be bypassed by optogenetic stimulation of RMG. Inducing IL-17 expression in adults can rescue mutant defects within 6 h. These findings reveal a non-immunological role of IL-17 modulating circuit function and behaviour.
C1 [Chen, Changchun; Itakura, Eisuke; Nelson, Geoffrey M.; Sheng, Ming; Laurent, Patrick; Fenk, Lorenz A.; Hegde, Ramanujan S.; de Bono, Mario] MRC, Mol Biol Lab, Francis Crick Ave, Cambridge CB2 0QH, England.
   [Butcher, Rebecca A.] Univ Florida, Dept Chem, Gainesville, FL 32611 USA.
   [Itakura, Eisuke] Chiba Univ, Grad Sch Adv Integrat Sci, Dept Nanobiol, Chiba 2638522, Japan.
   [Laurent, Patrick] Univ Libre Bruxelles, Neurophysiol Lab, Campus Erasme,808 Route Lenn, B-1070 Brussels, Belgium.
C3 MRC Laboratory Molecular Biology; State University System of Florida; University of Florida; Chiba University; Universite Libre de Bruxelles
RP de Bono, M (corresponding author), MRC, Mol Biol Lab, Francis Crick Ave, Cambridge CB2 0QH, England.
EM debono@mrc-lmb.cam.ac.uk
FU National Institutes of Health [P40 OD010440]; European Molecular Biology Organization; Japan Society for the Promotion of Science; Medical Research Council, UK; European Research Council [269058]; European Research Council (ERC) [269058] Funding Source: European Research Council (ERC); National Institute of General Medical Sciences; NIH Office of the Director [P40OD010440] Funding Source: NIH RePORTER; Grants-in-Aid for Scientific Research [16H01194, 16H06167] Funding Source: KAKEN; MRC [MC_UP_A022_1007, MC_U105178786] Funding Source: UKRI; Medical Research Council [MC_U105178786, MC_UP_A022_1007] Funding Source: researchfish
NR 47
TC 101
Z9 120
U1 0
U2 44
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 2
PY 2017
VL 542
IS 7639
BP 43
EP +
DI 10.1038/nature20818
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6MY
UT WOS:000396119300029
PM 28099418
DA 2026-03-09
ER

PT J
AU Nayak, AK
   Kumar, V
   Ma, TP
   Werner, P
   Pippel, E
   Sahoo, R
   Damay, F
   Rössler, UK
   Felser, C
   Parkin, SSP
AF Nayak, Ajaya K.
   Kumar, Vivek
   Ma, Tianping
   Werner, Peter
   Pippel, Eckhard
   Sahoo, Roshnee
   Damay, Francoise
   Roessler, Ulrich K.
   Felser, Claudia
   Parkin, Stuart S. P.
TI Magnetic antiskyrmions above room temperature in tetragonal Heusler materials
SO NATURE
LA English
DT Article
ID real-space observation; skyrmion lattice; chiral magnet; driven
AB Magnetic skyrmions are topologically stable, vortex-like objects surrounded by chiral boundaries that separate a region of reversed magnetization from the surrounding magnetized material(1-3). They are closely related to nanoscopic chiral magnetic domain walls, which could be used as memory and logic elements for conventional and neuromorphic computing applications that go beyond Moore's law. Of particular interest is 'racetrack memory', which is composed of vertical magnetic nanowires, each accommodating of the order of 100 domain walls, and that shows promise as a solid state, nonvolatile memory with exceptional capacity and performance(4,5). Its performance is derived from the very high speeds (up to one kilometre per second) at which chiral domain walls can be moved with nanosecond current pulses in synthetic antiferromagnet racetracks. Because skyrmions are essentially composed of a pair of chiral domain walls closed in on themselves, but are, in principle, more stable to perturbations than the component domain walls themselves, they are attractive for use in spintronic applications, notably racetrack memory. Stabilization of skyrmions has generally been achieved in systems with broken inversion symmetry, in which the asymmetric Dzyaloshinskii-Moriya interaction modifies the uniform magnetic state to a swirling state(6,7). Depending on the crystal symmetry, two distinct types of skyrmions have been observed experimentally, namely, Bloch(7,8) and Neel skyrmions(9). Here we present the experimental manifestation of another type of skyrmion-the magnetic antiskyrmion-in acentric tetragonal Heusler compounds with D-2d crystal symmetry. Antiskyrmions are characterized by boundary walls that have alternating Bloch and Neel type as one traces around the boundary. A spiral magnetic ground-state, which propagates in the tetragonal basal plane, is transformed into an antiskyrmion lattice state under magnetic fields applied along the tetragonal axis over a wide range of temperatures. Direct imaging by Lorentz transmission electron microscopy shows field-stabilized antiskyrmion lattices and isolated antiskyrmions from 100 kelvin to well beyond room temperature, and zero-field metastable antiskyrmions at low temperatures. These results enlarge the family of magnetic skyrmions and pave the way to the engineering of complex bespoke designed skyrmionic structures.
C1 [Nayak, Ajaya K.; Ma, Tianping; Werner, Peter; Pippel, Eckhard; Parkin, Stuart S. P.] Max Planck Inst Microstruct Phys, Weinberg 2, D-06120 Halle, Germany.
   [Kumar, Vivek; Sahoo, Roshnee; Felser, Claudia] Max Planck Inst Chem Phys Solids, Nothnitzer Str 40, D-01187 Dresden, Germany.
   [Damay, Francoise] CEA Saclay, CNRS, Lab Leon Brillouin, CEA, F-91191 Gif Sur Yvette, France.
   [Roessler, Ulrich K.] IFW Dresden, POB 270116, D-01171 Dresden, Germany.
   [Nayak, Ajaya K.] NISER, Sch Phys Sci, Bhubaneswar 752050, Jatni, India.
C3 Max Planck Society; Max Planck Society; CEA; Centre National de la Recherche Scientifique (CNRS); Universite Paris Saclay; Institute for Integrative Nanosciences (IIN); Leibniz Association; Leibniz Institute for Solid State & Materials Research Dresden; National Institute of Science Education & Research (NISER)
RP Parkin, SSP (corresponding author), Max Planck Inst Microstruct Phys, Weinberg 2, D-06120 Halle, Germany.
EM stuart.parkin@mpi-halle.mpg.de
FU ERC [670166, 291472]; European Research Council (ERC) [670166] Funding Source: European Research Council (ERC)
NR 36
TC 625
Z9 670
U1 4
U2 601
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 31
PY 2017
VL 548
IS 7669
BP 561
EP +
DI 10.1038/nature23466
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FF2BO
UT WOS:000408703100034
PM 28846999
DA 2026-03-09
ER

PT J
AU Teixeira, FK
   Okuniewska, M
   Malone, CD
   Coux, RX
   Rio, DC
   Lehmann, R
AF Teixeira, Felipe Karam
   Okuniewska, Martyna
   Malone, Colin D.
   Coux, Remi-Xavier
   Rio, Donald C.
   Lehmann, Ruth
TI piRNA-mediated regulation of transposon alternative splicing in the soma and germ line
SO NATURE
LA English
DT Article
ID drosophila-melanogaster; hybrid dysgenesis; p-element; gene-expression; epigenetic regulation; read alignment; chip-seq; rna-seq; piwi; mechanism
AB Transposable elements can drive genome evolution, but their enhanced activity is detrimental to the host and therefore must be tightly regulated(1). The Piwi-interacting small RNA (piRNA) pathway is vital for the regulation of transposable elements, by inducing transcriptional silencing or post-transcriptional decay of mRNAs(2). Here we show that piRNAs and piRNA biogenesis components regulate precursor mRNA splicing of P-transposable element transcripts in vivo, leading to the production of the non-transposase-encoding mature mRNA isoform in Drosophila germ cells. Unexpectedly, we show that the piRNA pathway components do not act to reduce transcript levels of the P-element transposon during P-M hybrid dysgenesis, a syndrome that affects germline development in Drosophila(3,4). Instead, splicing regulation is mechanistically achieved together with piRNA-mediated changes to repressive chromatin states, and relies on the function of the Piwi-piRNA complex proteins Asterix (also known as Gtsf1)(5-7) and Panoramix (Silencio)(8,9), as well as Heterochromatin protein 1a (HP1a; encoded by Su(var) 205). Furthermore, we show that this machinery, together with the piRNA Flamenco cluster(10), not only controls the accumulation of Gypsy retrotransposon transcripts(11) but also regulates the splicing of Gypsy mRNAs in cultured ovarian somatic cells, a process required for the production of infectious particles that can lead to heritable transposition events(12,13). Our findings identify splicing regulation as a new role and essential function for the Piwi pathway in protecting the genome against transposon mobility, and provide a model system for studying the role of chromatin structure in modulating alternative splicing during development.
C1 [Teixeira, Felipe Karam; Okuniewska, Martyna; Malone, Colin D.; Coux, Remi-Xavier; Lehmann, Ruth] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA.
   [Teixeira, Felipe Karam; Okuniewska, Martyna; Malone, Colin D.; Coux, Remi-Xavier; Lehmann, Ruth] NYU, Sch Med, Kimmel Ctr Biol & Med, Skirball Inst,Dept Cell Biol, New York, NY 10016 USA.
   [Rio, Donald C.] Univ Calif Berkeley, Dept Mol & Cell Biol, Ctr RNA Syst Biol, Berkeley, CA 94720 USA.
   [Rio, Donald C.] Univ Calif Berkeley, Calif Inst Quantitat Biosci, Berkeley, CA 94720 USA.
   [Teixeira, Felipe Karam] Univ Cambridge, Dept Genet, Downing St, Cambridge CB2 3EH, England.
   [Malone, Colin D.] Columbia Univ, Med Ctr, Inst Genom Med, New York, NY 10032 USA.
C3 Howard Hughes Medical Institute; New York University; New York University; University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of Cambridge; Columbia University
RP Teixeira, FK; Lehmann, R (corresponding author), NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA.; Teixeira, FK; Lehmann, R (corresponding author), NYU, Sch Med, Kimmel Ctr Biol & Med, Skirball Inst,Dept Cell Biol, New York, NY 10016 USA.
EM fk319@cam.ac.uk; ruth.lehmann@med.nyu.edu
FU NIH [P30CA016087, R37HD41900, R35-118121-02, NIH R01-097352]; HHWF fellowship; EMBO fellowship; HFSP fellowship; Wellcome Trust [206257/Z/17/Z]; HHMI investigator; Wellcome Trust [206257/Z/17/Z] Funding Source: Wellcome Trust; Eunice Kennedy Shriver National Institute of Child Health and Human Development [R37HD041900] Funding Source: NIH RePORTER; National Cancer Institute [P30CA016087] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R35GM118121] Funding Source: NIH RePORTER
NR 54
TC 103
Z9 122
U1 1
U2 57
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 14
PY 2017
VL 552
IS 7684
BP 268
EP +
DI 10.1038/nature25018
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ0FK
UT WOS:000418029500050
PM 29211718
DA 2026-03-09
ER

PT J
AU Parker, JL
   Newstead, S
AF Parker, Joanne L.
   Newstead, Simon
TI Structural basis of nucleotide sugar transport across the Golgi membrane
SO NATURE
LA English
DT Article
ID gdp-mannose transporter; sialic acid transporter; endoplasmic-reticulum; identification; glycosylation; apparatus; yeast; purification; mechanisms; proteins
AB Glycosylation is a fundamental cellular process that, in eukaryotes, occurs in the lumen of both the Golgi apparatus and the endoplasmic reticulum(1). Nucleotide sugar transporters (NSTs) are an essential component of the glycosylation pathway, providing the diverse range of substrates required for the glycosyltransferases(2,3). NSTs are linked to several developmental and immune disorders in humans, and in pathogenic microbes they have an important role in virulence(4-8). How NSTs recognize and transport activated monosaccharides, however, is currently unclear. Here we present the crystal structure of an NST, the GDP-mannose transporter Vrg4, in both the substrate-free and the bound states. A hitherto unobserved requirement of short-chain lipids in activating the transporter supports a model for regulation within the highly dynamic membranes of the Golgi apparatus. Our results provide a structural basis for understanding nucleotide sugar recognition, and provide insights into the transport and regulatory mechanism of this family of intracellular transporters.
C1 [Parker, Joanne L.; Newstead, Simon] Univ Oxford, Dept Biochem, South Parks Rd, Oxford OX1 3QU, England.
C3 University of Oxford
RP Parker, JL; Newstead, S (corresponding author), Univ Oxford, Dept Biochem, South Parks Rd, Oxford OX1 3QU, England.
EM joanne.parker@bioch.ox.ac.uk; simon.newstead@bioch.ox.ac.uk
FU Wellcome awards [102890/Z/13/Z, 102890/Z/13/A]; Wellcome Trust [102890/Z/13/A, 102890/Z/13/Z] Funding Source: Wellcome Trust; Wellcome Trust [102890/Z/13/Z] Funding Source: researchfish
NR 42
TC 67
Z9 80
U1 1
U2 57
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 23
PY 2017
VL 551
IS 7681
BP 521
EP +
DI 10.1038/nature24464
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FN5JO
UT WOS:000416043700049
PM 29143814
DA 2026-03-09
ER

PT J
AU Erez, Z
   Steinberger-Levy, I
   Shamir, M
   Doron, S
   Stokar-Avihail, A
   Peleg, Y
   Melamed, S
   Leavitt, A
   Savidor, A
   Albeck, S
   Amitai, G
   Sorek, R
AF Erez, Zohar
   Steinberger-Levy, Ida
   Shamir, Maya
   Doron, Shany
   Stokar-Avihail, Avigail
   Peleg, Yoav
   Melamed, Sarah
   Leavitt, Azita
   Savidor, Alon
   Albeck, Shira
   Amitai, Gil
   Sorek, Rotem
TI Communication between viruses guides lysis-lysogeny decisions
SO NATURE
LA English
DT Article
ID bacillus-subtilis; bacteria; mechanism; infection; receptor; complex; system; gene; plcr
AB Temperate viruses can become dormant in their host cells, a process called lysogeny. In every infection, such viruses decide between the lytic and the lysogenic cycles, that is, whether to replicate and lyse their host or to lysogenize and keep the host viable. Here we show that viruses (phages) of the SPbeta group use a small-molecule communication system to coordinate lysis-lysogeny decisions. During infection of its Bacillus host cell, the phage produces a six aminoacids-long communication peptide that is released into the medium. In subsequent infections, progeny phages measure the concentration of this peptide and lysogenize if the concentration is sufficiently high. We found that different phages encode different versions of the communication peptide, demonstrating a phage-specific peptide communication code for lysogeny decisions. We term this communication system the 'arbitrium' system, and further show that it is encoded by three phage genes: aimP, which produces the peptide; aimR, the intracellular peptide receptor; and aimX, a negative regulator of lysogeny. The arbitrium system enables a descendant phage to 'communicate' with its predecessors, that is, to estimate the amount of recent previous infections and hence decide whether to employ the lytic or lysogenic cycle.
C1 [Erez, Zohar; Steinberger-Levy, Ida; Shamir, Maya; Doron, Shany; Stokar-Avihail, Avigail; Melamed, Sarah; Leavitt, Azita; Amitai, Gil; Sorek, Rotem] Weizmann Inst Sci, Dept Mol Genet, IL-7610001 Rehovot, Israel.
   [Steinberger-Levy, Ida] Israel Inst Biol Res, Dept Biochem & Mol Genet, Ness Ziona, Israel.
   [Peleg, Yoav; Albeck, Shira] Weizmann Inst Sci, Fac Biochem, ISPC, IL-7610001 Rehovot, Israel.
   [Savidor, Alon] Weizmann Inst Sci, Nancy & Stephen Grand Israel Natl Ctr Personalize, de Botton Inst Prot Profiling, IL-7610001 Rehovot, Israel.
C3 Weizmann Institute of Science; Weizmann Institute of Science; Weizmann Institute of Science
RP Amitai, G; Sorek, R (corresponding author), Weizmann Inst Sci, Dept Mol Genet, IL-7610001 Rehovot, Israel.
EM gil.amitai@weizmann.ac.il; rotem.sorek@weizmann.ac.il
FU Israel Science Foundation [1303/12, 1360/16, 1796/12]; European Research Council (ERC) [ERC-StG 260432, ERC-CoG 681203]; Human Frontier Science Program (HFSP) [RGP0011/2013]; Abisch-Frenkel foundation; Pasteur-Weizmann council; Minerva Foundation; Leona M. and Harry B. Helmsley Charitable Trust; DFG; Dana and Yossie Holander Center for Structural Proteomics
NR 25
TC 446
Z9 538
U1 14
U2 325
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 26
PY 2017
VL 541
IS 7638
BP 488
EP 493
DI 10.1038/nature21049
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6LX
UT WOS:000396116600042
PM 28099413
DA 2026-03-09
ER

PT J
AU Chevalier, A
   Silva, DA
   Rocklin, GJ
   Hicks, DR
   Vergara, R
   Murapa, P
   Bernard, SM
   Zhang, L
   Lam, KH
   Yao, GR
   Bahl, CD
   Miyashita, SI
   Goreshnik, I
   Fuller, JT
   Koday, MT
   Jenkins, CM
   Colvin, T
   Carter, L
   Bohn, A
   Bryan, CM
   Fernández-Velasco, DA
   Stewart, L
   Dong, M
   Huang, XH
   Jin, RS
   Wilson, IA
   Fuller, DH
   Baker, D
AF Chevalier, Aaron
   Silva, Daniel-Adriano
   Rocklin, Gabriel J.
   Hicks, Derrick R.
   Vergara, Renan
   Murapa, Patience
   Bernard, Steffen M.
   Zhang, Lu
   Lam, Kwok-Ho
   Yao, Guorui
   Bahl, Christopher D.
   Miyashita, Shin-Ichiro
   Goreshnik, Inna
   Fuller, James T.
   Koday, Merika T.
   Jenkins, Cody M.
   Colvin, Tom
   Carter, Lauren
   Bohn, Alan
   Bryan, Cassie M.
   Alejandro Fernandez-Velasco, D.
   Stewart, Lance
   Dong, Min
   Huang, Xuhui
   Jin, Rongsheng
   Wilson, Ian A.
   Fuller, Deborah H.
   Baker, David
TI Massively parallel de novo protein design for targeted therapeutics
SO NATURE
LA English
DT Article
ID influenza hemagglutinin; high-affinity; specificity; library; peptides; software; receptor; cells; size
AB De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37-43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.
C1 [Chevalier, Aaron; Silva, Daniel-Adriano; Rocklin, Gabriel J.; Hicks, Derrick R.; Vergara, Renan; Bahl, Christopher D.; Goreshnik, Inna; Colvin, Tom; Carter, Lauren; Bryan, Cassie M.; Baker, David] Univ Washington, Dept Biochem, Seattle, WA 98195 USA.
   [Chevalier, Aaron; Silva, Daniel-Adriano; Rocklin, Gabriel J.; Hicks, Derrick R.; Vergara, Renan; Bahl, Christopher D.; Carter, Lauren; Bryan, Cassie M.; Stewart, Lance; Baker, David] Univ Washington, Inst Prot Design, Seattle, WA 98195 USA.
   [Hicks, Derrick R.] Univ Washington, Mol & Cellular Biol Program, Seattle, WA 98195 USA.
   [Vergara, Renan; Alejandro Fernandez-Velasco, D.] Univ Nacl Autonoma Mexico, Fac Med, Ciudad Univ, Mexico City 04510, DF, Mexico.
   [Murapa, Patience; Fuller, James T.; Koday, Merika T.; Jenkins, Cody M.; Bohn, Alan; Fuller, Deborah H.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA.
   [Bernard, Steffen M.; Wilson, Ian A.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA.
   [Bernard, Steffen M.; Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA.
   [Zhang, Lu] Chinese Acad Sci, Fujian Inst Res Struct Matter, State Key Lab Struct Chem, Fuzhou 350002, Fujian, Peoples R China.
   [Zhang, Lu; Huang, Xuhui] Hong Kong Univ Sci & Technol, Dept Chem, Kowloon, Hong Kong, Peoples R China.
   [Zhang, Lu; Huang, Xuhui] Hong Kong Univ Sci & Technol, State Key Lab Mol Neurosci, Kowloon, Hong Kong, Peoples R China.
   [Lam, Kwok-Ho; Yao, Guorui; Jin, Rongsheng] Univ Calif Irvine, Dept Physiol & Biophys, Irvine, CA 92697 USA.
   [Miyashita, Shin-Ichiro; Dong, Min] Boston Childrens Hosp, Dept Urol, Boston, MA 02115 USA.
   [Miyashita, Shin-Ichiro; Dong, Min] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA.
   [Miyashita, Shin-Ichiro; Dong, Min] Harvard Med Sch, Dept Surg, Boston, MA 02115 USA.
   [Koday, Merika T.] Virvio Inc, Seattle, WA 98195 USA.
C3 University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Universidad Nacional Autonoma de Mexico; University of Washington; University of Washington Seattle; Scripps Research Institute; Scripps Research Institute; Chinese Academy of Sciences; Fujian Institute of Research on the Structure of Matter, CAS; Hong Kong University of Science & Technology; Hong Kong University of Science & Technology; University of California System; University of California Irvine; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School
RP Baker, D (corresponding author), Univ Washington, Dept Biochem, Seattle, WA 98195 USA.; Baker, D (corresponding author), Univ Washington, Inst Prot Design, Seattle, WA 98195 USA.
EM dabaker@uw.edu
FU Life Sciences Discovery Fund Launch grant [9598385]; PEW Latin-American fellow in the biomedical sciences; CONACyT postdoctoral fellowship; Merck fellow of the Life Sciences Research Foundation; CONACyT; Doctorado en Ciencias Bioquimicas UNAM; NIH [R56AI117675, 1R01NS080833]; Molecular Basis of Viral Pathogenesis Training Grant [T32AI007354-26A1]; Investigator in the Pathogenesis of Infectious Disease award from the Burroughs Wellcome Fund; CoMotion Mary Gates Innovation Fellow program; Shenzhen Science and Technology Innovation Committee [JCYJ20170413173837121]; Hong Kong Research Grant Council [C6009-15G, AoE/P-705/16]; PAPIIT UNAM [IN220516]; CONACyT [254514]; Facultad de Medicina UNAM; NIAID [AI091823, AI123920, AI125704, 1R41AI122431, 1R21AI119258]; Life Sciences Discovery Fund grant [20040757]; STF at the University of Washington; NIH; NIGMS; HHMI; DOE Office of Science User Facility [DE-AC02-05CH11231]; NIGMS [P41 GM103403]; NIH-ORIP HEI grant [S100D021527]; U.S. DOE Office of Science User Facility [DE-AC02-06CH11357]; National Institute of Neurological Disorders and Stroke [R01NS080833] Funding Source: NIH RePORTER
NR 46
TC 347
Z9 469
U1 6
U2 276
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 5
PY 2017
VL 550
IS 7674
BP 74
EP +
DI 10.1038/nature23912
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI7XU
UT WOS:000412214100047
PM 28953867
DA 2026-03-09
ER

PT J
AU Folco, HD
   Chalamcharla, VR
   Sugiyama, T
   Thillainadesan, G
   Zofall, M
   Balachandran, V
   Dhakshnamoorthy, J
   Mizuguchi, T
   Grewal, SIS
AF Folco, H. Diego
   Chalamcharla, Venkata R.
   Sugiyama, Tomoyasu
   Thillainadesan, Gobi
   Zofall, Martin
   Balachandran, Vanivilasini
   Dhakshnamoorthy, Jothy
   Mizuguchi, Takeshi
   Grewal, Shiv I. S.
TI Untimely expression of gametogenic genes in vegetative cells causes uniparental disomy
SO NATURE
LA English
DT Article
ID facultative heterochromatin formation; fission yeast; schizosaccharomyces-pombe; chromosome segregation; rapid method; meiosis-i; cohesion; centromeres; elimination; attachment
AB Uniparental disomy (UPD), in which an individual contains a pair of homologous chromosomes originating from only one parent, is a frequent phenomenon that is linked to congenital disorders and various cancers(1,2). UPD is thought to result mostly from pre- or post-zygotic chromosome missegregation(2). However, the factors that drive UPD remain unknown. Here we use the fission yeast Schizosaccharomyces pombe as a model to investigate UPD, and show that defects in the RNA interference (RNAi) machinery or in the YTH domain-containing RNA elimination factor Mmi1 cause high levels of UPD in vegetative diploid cells. This phenomenon is not due to defects in heterochromatin assembly at centromeres. Notably, in cells lacking RNAi components or Mmi1, UPD is associated with the untimely expression of gametogenic genes. Deletion of the upregulated gene encoding the meiotic cohesin Rec8 or the cyclin Crs1 suppresses UPD in both RNAi and mmi1 mutants. Moreover, overexpression of Rec8 is sufficient to trigger UPD in wild-type cells. Rec8 expressed in vegetative cells localizes to chromosomal arms and to the centromere core, where it is required for localization of the cohesin subunit Psc3. The centromeric localization of Rec8 and Psc3 promotes UPD by uniquely affecting chromosome segregation, causing a reductional segregation of one homologue. Together, these findings establish the untimely vegetative expression of gametogenic genes as a causative factor of UPD, and provide a solid foundation for understanding this phenomenon, which is linked to diverse human diseases.
C1 [Folco, H. Diego; Chalamcharla, Venkata R.; Sugiyama, Tomoyasu; Thillainadesan, Gobi; Zofall, Martin; Balachandran, Vanivilasini; Dhakshnamoorthy, Jothy; Mizuguchi, Takeshi; Grewal, Shiv I. S.] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA.
   [Mizuguchi, Takeshi] Yokohama City Univ, Grad Sch Med, Dept Human Genet, Fukuura 3-9, Yokohama, Kanagawa 2360004, Japan.
C3 National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Yokohama City University
RP Grewal, SIS (corresponding author), NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA.
EM grewals@mail.nih.gov
FU National Institutes of Health, National Cancer Institute; National Cancer Institute [ZIABC011208] Funding Source: NIH RePORTER
NR 43
TC 32
Z9 37
U1 0
U2 17
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 2
PY 2017
VL 543
IS 7643
BP 126
EP +
DI 10.1038/nature21372
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0AA
UT WOS:000395671500046
PM 28199302
DA 2026-03-09
ER

PT J
AU Scheele, CLGJ
   Hannezo, E
   Muraro, MJ
   Zomer, A
   Langedijk, NSM
   van Oudenaarden, A
   Simons, BD
   van Rheenen, J
AF Scheele, Colinda L. G. J.
   Hannezo, Edouard
   Muraro, Mauro J.
   Zomer, Anoek
   Langedijk, Nathalia S. M.
   van Oudenaarden, Alexander
   Simons, Benjamin D.
   van Rheenen, Jacco
TI Identity and dynamics of mammary stem cells during branching morphogenesis
SO NATURE
LA English
DT Article
ID gland development; basal lamina; differentiation; hierarchy
AB During puberty, the mouse mammary gland develops into a highly branched epithelial network. Owing to the absence of exclusive stem cell markers, the location, multiplicity, dynamics and fate of mammary stem cells (MaSCs), which drive branching morphogenesis, are unknown. Here we show that morphogenesis is driven by proliferative terminal end buds that terminate or bifurcate with near equal probability, in a stochastic and time-invariant manner, leading to a heterogeneous epithelial network. We show that the majority of terminal end bud cells function as highly proliferative, lineage-committed MaSCs that are heterogeneous in their expression profile and short-term contribution to ductal extension. Yet, through cell rearrangements during terminal end bud bifurcation, each MaSC is able to contribute actively to long-term growth. Our study shows that the behaviour of MaSCs is not directly linked to a single expression profile. Instead, morphogenesis relies upon lineage-restricted heterogeneous MaSC populations that function as single equipotent pools in the long term.
C1 [Scheele, Colinda L. G. J.; Muraro, Mauro J.; Zomer, Anoek; Langedijk, Nathalia S. M.; van Oudenaarden, Alexander; van Rheenen, Jacco] Hubrecht Inst KNAW, Canc Genom Netherlands, Utrecht, Netherlands.
   [Scheele, Colinda L. G. J.; Muraro, Mauro J.; Zomer, Anoek; Langedijk, Nathalia S. M.; van Oudenaarden, Alexander; van Rheenen, Jacco] Univ Med Ctr Utrecht, Utrecht, Netherlands.
   [Hannezo, Edouard; Simons, Benjamin D.] Univ Cambridge, Dept Phys, Cavendish Lab, Cambridge, England.
   [Hannezo, Edouard; Simons, Benjamin D.] Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge, England.
   [Hannezo, Edouard; Simons, Benjamin D.] Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge CB2 1TN, England.
C3 Royal Netherlands Academy of Arts & Sciences; Hubrecht Institute (KNAW); Utrecht University; Utrecht University Medical Center; University of Cambridge; University of Cambridge; University of Cambridge
RP van Rheenen, J (corresponding author), Hubrecht Inst KNAW, Canc Genom Netherlands, Utrecht, Netherlands.; van Rheenen, J (corresponding author), Univ Med Ctr Utrecht, Utrecht, Netherlands.; Simons, BD (corresponding author), Univ Cambridge, Dept Phys, Cavendish Lab, Cambridge, England.; Simons, BD (corresponding author), Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge, England.; Simons, BD (corresponding author), Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge CB2 1TN, England.
EM bds10@cam.ac.uk; j.vanrheenen@hubrecht.eu
FU European Research Council [648804]; Worldwide Cancer Research [13-0297]; Wellcome Trust [098357/Z/12/Z, 110326/Z/15/Z]; Trinity College, Cambridge; Wellcome Trust; Bettencourt-Schueller Young Researcher Prize; Boehringer Ingelheim Fonds PhD Fellowship; Medical Research Council [MC_PC_12009] Funding Source: researchfish; Wellcome Trust [098357/Z/12/Z] Funding Source: researchfish
NR 35
TC 155
Z9 180
U1 0
U2 40
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 16
PY 2017
VL 542
IS 7641
BP 313
EP +
DI 10.1038/nature21046
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2LQ
UT WOS:000394451600029
PM 28135720
DA 2026-03-09
ER

PT J
AU Verhalen, B
   Dastvan, R
   Thangapandian, S
   Peskova, Y
   Koteiche, HA
   Nakamoto, RK
   Tajkhorshid, E
   Mchaourab, HS
AF Verhalen, Brandy
   Dastvan, Reza
   Thangapandian, Sundarapandian
   Peskova, Yelena
   Koteiche, Hanane A.
   Nakamoto, Robert K.
   Tajkhorshid, Emad
   Mchaourab, Hassane S.
TI Energy transduction and alternating access of the mammalian ABC transporter P-glycoprotein
SO NATURE
LA English
DT Article
ID nucleotide-binding domains; gui membrane-builder; atp hydrolysis; catalytic cycle; distance measurements; glutamate residues; molecular-dynamics; force-field; charmm; conformation
AB ATP binding cassette (ABC) transporters of the exporter class harness the energy of ATP hydrolysis in the nucleotide-binding domains (NBDs) to power the energetically uphill efflux of substrates by a dedicated transmembrane domain (TMD)(1-4). Although numerous investigations have described the mechanism of ATP hydrolysis and defined the architecture of ABC exporters, a detailed structural dynamic understanding of the transduction of ATP energy to the work of substrate translocation remains elusive. Here we used double electron-electron resonance(5,6) and molecular dynamics simulations to describe the ATP- and substrate-coupled conformational cycle of the mouse ABC efflux transporter P-glycoprotein (Pgp; also known as ABCB1), which has a central role in the clearance of xenobiotics and in cancer resistance to chemotherapy(7). Pairs of spin labels were introduced at residues selected to track the putative inward-facing to outward-facing transition. Our findings illuminate how ATP energy is harnessed in the NBDs in a two-stroke cycle and elucidate the consequent conformational motion that reconfigures the TMD, two critical aspects of Pgp transport mechanism. Along with a fully atomistic model of the outward-facing conformation in membranes, the insight into Pgp conformational dynamics harmonizes mechanistic and structural data into a novel perspective on ATP-coupled transport and reveals mechanistic divergence within the efflux class of ABC transporters.
C1 [Verhalen, Brandy; Dastvan, Reza; Koteiche, Hanane A.; Mchaourab, Hassane S.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA.
   [Thangapandian, Sundarapandian; Tajkhorshid, Emad] Univ Illinois, Dept Biochem, Ctr Biophys & Quantitat Biol, Urbana, IL 61801 USA.
   [Thangapandian, Sundarapandian; Tajkhorshid, Emad] Univ Illinois, Beckman Inst Adv Sci & Technol, Urbana, IL 61801 USA.
   [Peskova, Yelena; Nakamoto, Robert K.] Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA.
   [Verhalen, Brandy] Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA.
C3 Vanderbilt University; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; University of Virginia; University of Texas System; University of Texas Southwestern Medical Center
RP Mchaourab, HS (corresponding author), Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA.
EM hassane.mchaourab@vanderbilt.edu
FU National Institutes of Health [U54-GM087519, P41-GM104601]; Extreme Science and Engineering Discovery Environment [TG-MCA06N060]; National Institute of General Medical Sciences [P41GM104601] Funding Source: NIH RePORTER
NR 46
TC 183
Z9 211
U1 0
U2 102
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 30
PY 2017
VL 543
IS 7647
BP 738
EP +
DI 10.1038/nature21414
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EP8IS
UT WOS:000397619700060
PM 28289287
DA 2026-03-09
ER

PT J
AU Cannon, KM
   Parman, SW
   Mustard, JF
AF Cannon, Kevin M.
   Parman, Stephen W.
   Mustard, John F.
TI Primordial clays on Mars formed beneath a steam or supercritical atmosphere
SO NATURE
LA English
DT Article
ID hydrous minerals; history; water; differentiation; diversity; component; impacts; origin; growth; model
AB On Mars, clay minerals are widespread in terrains that date back to the Noachian period (4.1 billion to 3.7 billion years ago)(1-5). It is thought that the Martian basaltic crust reacted with liquid water during this time to form hydrated clay minerals(3,6). Here we propose, however, that a substantial proportion of these clays was formed when Mars' primary crust reacted with a dense steam or supercritical atmosphere of water and carbon dioxide that was outgassed during magma ocean cooling(7-9). We present experimental evidence that shows rapid clay formation under conditions that would have been present at the base of such an atmosphere and also deeper in the porous crust. Furthermore, we explore the fate of a primordial clay-rich layer with the help of a parameterized crustal evolution model; we find that the primordial clay is locally disrupted by impacts and buried by impact-ejected material and by erupted volcanic material, but that it survives as a mostly coherent layer at depth, with limited surface exposures. These exposures are similar to those observed in remotely sensed orbital data from Mars(1-5). Our results can explain the present distribution of many clays on Mars, and the anomalously low density of the Martian crust in comparison with expectations.
C1 [Cannon, Kevin M.; Parman, Stephen W.; Mustard, John F.] Brown Univ, Dept Earth Environm & Planetary Sci, Providence, RI 02912 USA.
   [Cannon, Kevin M.] Univ Cent Florida, Dept Phys, Orlando, FL 32816 USA.
C3 Brown University; State University System of Florida; University of Central Florida
RP Cannon, KM (corresponding author), Brown Univ, Dept Earth Environm & Planetary Sci, Providence, RI 02912 USA.; Cannon, KM (corresponding author), Univ Cent Florida, Dept Phys, Orlando, FL 32816 USA.
EM cannon@ucf.edu
NR 40
TC 42
Z9 51
U1 0
U2 29
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 7
PY 2017
VL 552
IS 7683
BP 88
EP +
DI 10.1038/nature24657
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FP4BA
UT WOS:000417560500048
PM 29219967
DA 2026-03-09
ER

PT J
AU Livneh, Y
   Ramesh, RN
   Burgess, CR
   Levandowski, KM
   Madara, JC
   Fenselau, H
   Goldey, GJ
   Diaz, VE
   Jikomes, N
   Resch, JM
   Lowell, BB
   Andermann, ML
AF Livneh, Yoav
   Ramesh, Rohan N.
   Burgess, Christian R.
   Levandowski, Kirsten M.
   Madara, Joseph C.
   Fenselau, Henning
   Goldey, Glenn J.
   Diaz, Veronica E.
   Jikomes, Nick
   Resch, Jon M.
   Lowell, Bradford B.
   Andermann, Mark L.
TI Homeostatic circuits selectively gate food cue responses in insular cortex
SO NATURE
LA English
DT Article
ID basolateral amygdala; gustatory cortex; neurons; nucleus; rats; representations; thalamus; behavior; seeking; reward
AB Physiological needs bias perception and attention to relevant sensory cues. This process is 'hijacked' by drug addiction, causing cue-induced cravings and relapse. Similarly, its dysregulation contributes to failed diets, obesity, and eating disorders. Neuroimaging studies in humans have implicated insular cortex in these phenomena. However, it remains unclear how 'cognitive' cortical representations of motivationally relevant cues are biased by subcortical circuits that drive specific motivational states. Here we develop a microprism-based cellular imaging approach to monitor visual cue responses in the insular cortex of behaving mice across hunger states. Insular cortex neurons demonstrate food-cuebiased responses that are abolished during satiety. Unexpectedly, while multiple satiety-related visceral signals converge in insular cortex, chemogenetic activation of hypothalamic 'hunger neurons' (expressing agouti-related peptide (AgRP)) bypasses these signals to restore hunger-like response patterns in insular cortex. Circuit mapping and pathwayspecific manipulations uncover a pathway from AgRP neurons to insular cortex via the paraventricular thalamus and basolateral amygdala. These results reveal a neural basis for state-specific biased processing of motivationally relevant cues.
C1 [Livneh, Yoav; Ramesh, Rohan N.; Burgess, Christian R.; Levandowski, Kirsten M.; Madara, Joseph C.; Fenselau, Henning; Goldey, Glenn J.; Diaz, Veronica E.; Jikomes, Nick; Resch, Jon M.; Lowell, Bradford B.; Andermann, Mark L.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA.
   [Ramesh, Rohan N.; Jikomes, Nick; Lowell, Bradford B.; Andermann, Mark L.] Harvard Med Sch, Program Neurosci, Boston, MA 02115 USA.
C3 Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard University; Harvard Medical School
RP Lowell, BB; Andermann, ML (corresponding author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA.; Lowell, BB; Andermann, ML (corresponding author), Harvard Med Sch, Program Neurosci, Boston, MA 02115 USA.
EM blowell@bidmc.harvard.edu; manderma@bidmc.harvard.edu
FU Center for Neuroanatomy with Neurotropic Viruses [P40RR018604]; European Molecular Biology Organization postdoctoral fellowship; Edmond and Lily Safra Center for Brain Sciences postdoctoral award; Davis Family Foundation postdoctoral fellowship; National Science Foundation Graduate Research Fellowship Program; Sackler Scholars Program; National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) NRSA [F31 DK105678, F32 DK103387]; NIH New Innovator Award [DP2 DK105570, R01 DK109930]; Klarman Family Foundation; McKnight Scholar Award; Pew Scholar Award; Smith Family Foundation; NIH [R01 DK075632, R01 DK096010, R01 DK089044, R01 DK111401, P30 DK046200, P30 DK057521]; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK089044, R01DK096010, R01DK075632, P30DK020572, P30DK046200] Funding Source: NIH RePORTER
NR 49
TC 223
Z9 270
U1 1
U2 46
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 29
PY 2017
VL 546
IS 7660
BP 611
EP +
DI 10.1038/nature22375
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY9QB
UT WOS:000404332000039
PM 28614299
DA 2026-03-09
ER

PT J
AU Adinolfi, V
   Sargent, EH
AF Adinolfi, Valerio
   Sargent, Edward H.
TI Photovoltage field-effect transistors
SO NATURE
LA English
DT Article
ID quantum-dot photodetectors; solar-cells; silicon; optoelectronics; recombination
AB The detection of infrared radiation enables night vision, health monitoring, optical communications and three-dimensional object recognition. Silicon is widely used in modern electronics, but its electronic bandgap prevents the detection of light at wavelengths longer than about 1,100 nanometres. It is therefore of interest to extend the performance of silicon photodetectors into the infrared spectrum, beyond the bandgap of silicon(1,2). Here we demonstrate a photovoltage field-effect transistor that uses silicon for charge transport, but is also sensitive to infrared light owing to the use of a quantum dot light absorber. The photovoltage generated at the interface between the silicon and the quantum dot, combined with the high transconductance provided by the silicon device, leads to high gain (more than 10(4) electrons per photon at 1,500 nanometres), fast time response (less than 10 microseconds) and a widely tunable spectral response. Our photovoltage field-effect transistor has a responsivity that is five orders of magnitude higher at a wavelength of 1,500 nanometres than that of previous infrared-sensitized silicon detectors(3). The sensitization is achieved using a room-temperature solution process and does not rely on traditional high-temperature epitaxial growth of semiconductors (such as is used for germanium and III-V semiconductors)(4,5). Our results show that colloidal quantum dots can be used as an efficient platform for silicon-based infrared detection, competitive with state-of-the-art epitaxial semiconductors.
C1 [Adinolfi, Valerio; Sargent, Edward H.] Univ Toronto, Dept Elect & Comp Engn, 10 Kings Coll Rd, Toronto, ON M5S 3G4, Canada.
C3 University of Toronto
RP Sargent, EH (corresponding author), Univ Toronto, Dept Elect & Comp Engn, 10 Kings Coll Rd, Toronto, ON M5S 3G4, Canada.
EM ted.sargent@utoronto.com
FU Natural Sciences and Engineering Research Council (NSERC) of Canada
NR 23
TC 260
Z9 282
U1 9
U2 608
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 16
PY 2017
VL 542
IS 7641
BP 324
EP +
DI 10.1038/nature21050
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2LQ
UT WOS:000394451600031
PM 28178236
DA 2026-03-09
ER

PT J
AU Mi, W
   Li, YY
   Yoon, SH
   Ernst, RK
   Walz, T
   Liao, MF
AF Mi, Wei
   Li, Yanyan
   Yoon, Sung Hwan
   Ernst, Robert K.
   Walz, Thomas
   Liao, Maofu
TI Structural basis of MsbA-mediated lipopolysaccharide transport
SO NATURE
LA English
DT Article
ID binding cassette transporter; abc transporter; molecular-mechanism; alternating access; biosynthesis; recognition; diversity; resonance; flippase; complex
AB Lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria is critical for the assembly of their cell envelopes. LPS synthesized in the cytoplasmic leaflet of the inner membrane is flipped to the periplasmic leaflet by MsbA, an ATP-binding cassette transporter. Despite substantial efforts, the structural mechanisms underlying MsbA-driven LPS flipping remain elusive. Here we use single-particle cryo-electron microscopy to elucidate the structures of lipid-nanodisc-embedded MsbA in three functional states. The 4.2 angstrom-resolution structure of the transmembrane domains of nucleotide-free MsbA reveals that LPS binds deep inside MsbA at the height of the periplasmic leaflet, establishing extensive hydrophilic and hydrophobic interactions with MsbA. Two sub-nanometre-resolution structures of MsbA with ADP-vanadate and ADP reveal an unprecedented closed and an inward-facing conformation, respectively. Our study uncovers the structural basis for LPS recognition, delineates the conformational transitions of MsbA to flip LPS, and paves the way for structural characterization of other lipid flippases.
C1 [Mi, Wei; Liao, Maofu] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
   [Li, Yanyan] Jiangnan Univ, State Key Lab Food Sci & Technol, Wuxi 214122, Peoples R China.
   [Yoon, Sung Hwan; Ernst, Robert K.] Univ Maryland, Sch Dent, Dept Microbial Pathogenesis, Baltimore, MD 21201 USA.
   [Walz, Thomas] Rockefeller Univ, Lab Mol Electron Microscopy, 1230 York Ave, New York, NY 10065 USA.
C3 Harvard University; Harvard Medical School; Jiangnan University; University System of Maryland; University of Maryland Baltimore; Rockefeller University
RP Liao, MF (corresponding author), Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
EM maofu_liao@hms.harvard.edu
FU NIGMS NIH HHS [R01 GM122797] Funding Source: Medline; National Institute of General Medical Sciences [R01GM122797] Funding Source: NIH RePORTER
NR 66
TC 200
Z9 240
U1 3
U2 93
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 14
PY 2017
VL 549
IS 7671
BP 233
EP +
DI 10.1038/nature23649
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG7AE
UT WOS:000410555900037
PM 28869968
DA 2026-03-09
ER

PT J
AU Good, BH
   McDonald, MJ
   Barrick, JE
   Lenski, RE
   Desai, MM
AF Good, Benjamin H.
   McDonald, Michael J.
   Barrick, Jeffrey E.
   Lenski, Richard E.
   Desai, Michael M.
TI The dynamics of molecular evolution over 60,000 generations
SO NATURE
LA English
DT Article
ID rapidly adapting populations; term experimental evolution; escherichia-coli; clonal interference; beneficial mutations; yeast populations; genome evolution; key innovation; genetic draft; adaptation
AB The outcomes of evolution are determined by a stochastic dynamical process that governs how mutations arise and spread through a population. However, it is difficult to observe these dynamics directly over long periods and across entire genomes. Here we analyse the dynamics of molecular evolution in twelve experimental populations of Escherichia coli, using whole-genome metagenomic sequencing at five hundred-generation intervals through sixty thousand generations. Although the rate of fitness gain declines over time, molecular evolution is characterized by signatures of rapid adaptation throughout the duration of the experiment, with multiple beneficial variants simultaneously competing for dominance in each population. Interactions between ecological and evolutionary processes play an important role, as long-term quasi-stable coexistence arises spontaneously in most populations, and evolution continues within each clade. We also present evidence that the targets of natural selection change over time, as epistasis and historical contingency alter the strength of selection on different genes. Together, these results show that long-term adaptation to a constant environment can be a more complex and dynamic process than is often assumed.
C1 [Good, Benjamin H.; McDonald, Michael J.; Desai, Michael M.] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA.
   [Good, Benjamin H.; McDonald, Michael J.; Desai, Michael M.] Harvard Univ, FAS Ctr Syst Biol, Cambridge, MA 02138 USA.
   [Good, Benjamin H.; Desai, Michael M.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.
   [Good, Benjamin H.] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Good, Benjamin H.] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA.
   [McDonald, Michael J.] Monash Univ, Ctr Geometr Biol, Sch Biol Sci, Clayton, Vic 3800, Australia.
   [Barrick, Jeffrey E.] Univ Texas Austin, Dept Mol Biosci, Austin, TX 78712 USA.
   [Lenski, Richard E.] Michigan State Univ, BEACON Ctr Study Evolut Act, E Lansing, MI 48824 USA.
   [Lenski, Richard E.] Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA.
C3 Harvard University; Harvard University; Harvard University; University of California System; University of California Berkeley; University of California System; University of California Berkeley; Monash University; University of Texas System; University of Texas Austin; Michigan State University; Michigan State University
RP Desai, MM (corresponding author), Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA.; Desai, MM (corresponding author), Harvard Univ, FAS Ctr Syst Biol, Cambridge, MA 02138 USA.; Desai, MM (corresponding author), Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.
EM mmdesai@fas.harvard.edu
FU US National Science Foundation [DEB-1501580, DEB-1451740, PHY-1313638]; Miller Institute for Basic Research in Science at the University of California Berkeley; BEACON Center for the Study of Evolution in Action [DBI-0939454]; Simons Foundation [376196]; US National Institutes of Health; Research Computing Group at Harvard University; Direct For Biological Sciences; Division Of Environmental Biology [1451740] Funding Source: National Science Foundation; National Institute of General Medical Sciences [R01GM104239] Funding Source: NIH RePORTER
NR 37
TC 446
Z9 576
U1 10
U2 242
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 2
PY 2017
VL 551
IS 7678
BP 45
EP +
DI 10.1038/nature24287
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FL4SY
UT WOS:000414222900041
PM 29045390
DA 2026-03-09
ER

PT J
AU Erclik, T
   Li, X
   Courgeon, M
   Bertet, C
   Chen, ZQ
   Baumert, R
   Ng, J
   Koo, C
   Arain, U
   Behnia, R
   Rodriguez, AD
   Senderowicz, L
   Negre, N
   White, KP
   Desplan, C
AF Erclik, Ted
   Li, Xin
   Courgeon, Maximilien
   Bertet, Claire
   Chen, Zhenqing
   Baumert, Ryan
   Ng, June
   Koo, Clara
   Arain, Urfa
   Behnia, Rudy
   Rodriguez, Alberto Del Valle
   Senderowicz, Lionel
   Negre, Nicolas
   White, Kevin P.
   Desplan, Claude
TI Integration of temporal and spatial patterning generates neural diversity
SO NATURE
LA English
DT Article
ID drosophila optic lobe; central-nervous-system; gene-expression; visual center; neuroblasts; identity; notch; melanogaster; medulla; brain
AB In the Drosophila optic lobes, 800 retinotopically organized columns in the medulla act as functional units for processing visual information. The medulla contains over 80 types of neuron, which belong to two classes: uni-columnar neurons have a stoichiometry of one per column, while multi-columnar neurons contact multiple columns. Here we show that combinatorial inputs from temporal and spatial axes generate this neuronal diversity: all neuroblasts switch fates over time to produce different neurons; the neuroepithelium that generates neuroblasts is also subdivided into six compartments by the expression of specific factors. Uni-columnar neurons are produced in all spatial compartments independently of spatial input; they innervate the neuropil where they are generated. Multi-columnar neurons are generated in smaller numbers in restricted compartments and require spatial input; the majority of their cell bodies subsequently move to cover the entire medulla. The selective integration of spatial inputs by a fixed temporal neuroblast cascade thus acts as a powerful mechanism for generating neural diversity, regulating stoichiometry and the formation of retinotopy.
C1 [Erclik, Ted; Li, Xin; Courgeon, Maximilien; Bertet, Claire; Chen, Zhenqing; Baumert, Ryan; Ng, June; Koo, Clara; Behnia, Rudy; Desplan, Claude] NYU, Dept Biol, New York, NY 10003 USA.
   [Erclik, Ted; Arain, Urfa] Univ Toronto, Dept Biol, Mississauga, ON L5L 1C6, Canada.
   [Rodriguez, Alberto Del Valle; Desplan, Claude] New York Univ Abu Dhabi, Ctr Genom & Syst Biol, Abu Dhabi, U Arab Emirates.
   [Senderowicz, Lionel; Negre, Nicolas; White, Kevin P.] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA.
   [Senderowicz, Lionel; Negre, Nicolas; White, Kevin P.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA.
   [Li, Xin] Univ Illinois, Dept Cell & Dev Biol, Urbana, IL 61801 USA.
C3 New York University; University of Toronto; University Toronto Mississauga; New York University; New York University Abu Dhabi; University of Chicago; University of Chicago; University of Illinois System; University of Illinois Urbana-Champaign
RP Desplan, C (corresponding author), NYU, Dept Biol, New York, NY 10003 USA.; Desplan, C (corresponding author), New York Univ Abu Dhabi, Ctr Genom & Syst Biol, Abu Dhabi, U Arab Emirates.
EM cd38@nyu.edu
FU National Institutes of Health (NIH) [R01 EY017916]; Canadian Institutes of Health Research (CIHR); Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-2015-06457]; Robert Leet and Clara Guthrie Patterson Trust Postdoctoral Fellowship; EMBO [ALTF 680-2009]; HFSPO [LT000077/2010-L]; NIH [U01HG004264]; National Eye Institute [R01EY017916, P30EY013079] Funding Source: NIH RePORTER
NR 29
TC 95
Z9 122
U1 0
U2 33
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 19
PY 2017
VL 541
IS 7637
BP 365
EP +
DI 10.1038/nature20794
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6QP
UT WOS:000396128800036
PM 28077877
DA 2026-03-09
ER

PT J
AU Takenaka, H
   Grinberg, I
   Liu, S
   Rappe, AM
AF Takenaka, Hiroyuki
   Grinberg, Ilya
   Liu, Shi
   Rappe, Andrew M.
TI Slush-like polar structures in single-crystal relaxors
SO NATURE
LA English
DT Article
ID glassy polarization behavior; lead magnesium niobate; molecular-dynamics; ferroelectrics; water; model; oxides; order; ice
AB Despite more than 50 years of investigation, it is still unclear how the underlying structure of relaxor ferroelectrics gives rise to their defining properties, such as ultrahigh piezoelectric coefficients, high permittivity over a broad temperature range, diffuse phase transitions, strong frequency dependence in dielectric response, and phonon anomalies(1-10). The model of polar nanoregions inside a non-polar matrix has been widely used to describe the structure of relaxor ferroelectrics(11). However, the lack of precise knowledge about the shapes, growth and dipole patterns of polar nanoregions has led to the characterization of relaxors as "hopeless messes"(12), and no predictive model for relaxor behaviour is currently available. Here we use molecular dynamics simulations of the prototypical Pb(Mg-1/3, Nb-2/3)O-3-PbTiO3 relaxor material to examine its structure and the spatial and temporal polarization correlations. Our simulations show that the unusual properties of relaxors stem from the presence of a multi-domain state with extremely small domain sizes (2-10 nanometres), and no non-polar matrix, owing to the local dynamics. We find that polar structures in the multidomain state in relaxors are analogous to those of the slush state of water. The multi-domain structure of relaxors that is revealed by our molecular dynamics simulations is consistent with recent experimental diffuse scattering results and indicates that relaxors have a high density of low-angle domain walls. This insight explains the recently discovered classes of relaxors(13) that cannot be described by the polar nanoregion model, and provides guidance for the design and synthesis of new relaxor materials.
C1 [Takenaka, Hiroyuki; Grinberg, Ilya; Liu, Shi; Rappe, Andrew M.] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA.
   [Grinberg, Ilya] Bar Ilan Univ, Dept Chem, Ramat Gan, Israel.
C3 University of Pennsylvania; Bar Ilan University
RP Takenaka, H; Rappe, AM (corresponding author), Univ Penn, Dept Chem, Philadelphia, PA 19104 USA.
EM htakenaka@carnegiescience.edu; rappe@sas.upenn.edu
FU ONR [N00014-12-1-1033]; HPCMO
NR 56
TC 260
Z9 294
U1 18
U2 338
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 15
PY 2017
VL 546
IS 7658
BP 391
EP +
DI 10.1038/nature22068
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EX5BK
UT WOS:000403250900032
PM 28617453
DA 2026-03-09
ER

PT J
AU Scaringi, S
   Maccarone, TJ
   D'Angelo, C
   Knigge, C
   Groot, PJ
AF Scaringi, S.
   Maccarone, T. J.
   D'Angelo, C.
   Knigge, C.
   Groot, P. J.
TI Magnetically gated accretion in an accreting 'non-magnetic' white dwarf
SO NATURE
LA English
DT Article
ID vy sculptoris stars; short cadence data; rms-flux relation; mv-lyrae; low state; cataclysmic variables; rapid burster; black-holes; ex-lupi; variability
AB White dwarfs are often found in binary systems with orbital periods ranging from tens of minutes to hours in which they can accrete gas from their companion stars. In about 15 per cent of these binaries, the magnetic field of the white dwarf is strong enough (at 106 gauss or more) to channel the accreted matter along field lines onto the magnetic poles(1,2). The remaining systems are referred to as 'non-magnetic', because until now there has been no evidence that they have a magnetic field that is strong enough to affect the accretion dynamics. Here we report an analysis of archival optical observations of the 'non-magnetic' accreting white dwarf in the binary system MV Lyrae, whose light curve displays quasi-periodic bursts of about 30 minutes duration roughly every 2 hours. The timescale and amplitude of these bursts indicate the presence of an unstable, magnetically regulated accretion mode, which in turn implies the existence of magnetically gated accretion(3-5), in which disk material builds up around the magnetospheric boundary (at the co-rotation radius) and then accretes onto the white dwarf, producing bursts powered by the release of gravitational potential energy. We infer a surface magnetic field strength for the white dwarf in MV Lyrae of between 2 x 10(4) gauss and 1 x 105 gauss, too low to be detectable by other current methods. Our discovery provides a new way of studying the strength and evolution of magnetic fields in accreting white dwarfs and extends the connections between accretion onto white dwarfs, young stellar objects and neutron stars, for which similar magnetically gated accretion cycles have been identified(6-9).
C1 [Scaringi, S.] Univ Canterbury, Sch Phys & Chem Sci, Christchurch 8041, New Zealand.
   [Maccarone, T. J.] Texas Tech Univ, Dept Phys & Astron, Lubbock, TX 79409 USA.
   [D'Angelo, C.] Leiden Univ, Leiden Observ, NL-2300 RA Leiden, Netherlands.
   [Knigge, C.] Univ Southampton, Sch Phys & Astron, Southampton SO17 1BJ, Hants, England.
   [Groot, P. J.] Radboud Univ Nijmegen, Dept Astrophys IMAPP, POB 9010, NL-6500 GL Nijmegen, Netherlands.
C3 University of Canterbury; Texas Tech University System; Texas Tech University; Leiden University - Excl LUMC; Leiden University; University of Southampton; Radboud University Nijmegen
RP Scaringi, S (corresponding author), Univ Canterbury, Sch Phys & Chem Sci, Christchurch 8041, New Zealand.
EM simone.scaringi@canterbury.ac.nz
FU NASA Science Mission directorate; NASA [NAS5-26555]; NASA Office of Space Science [NNX09AF08G]; Erskine programme run by the University of Canterbury
NR 46
TC 35
Z9 37
U1 0
U2 10
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 14
PY 2017
VL 552
IS 7684
BP 210
EP +
DI 10.1038/nature24653
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ0FK
UT WOS:000418029500038
PM 29239355
DA 2026-03-09
ER

PT J
AU Goel, S
   DeCristo, MJ
   Watt, AC
   BrinJones, H
   Sceneay, J
   Li, BB
   Khan, N
   Ubellacker, JM
   Xie, SZ
   Metzger-Filho, O
   Hoog, J
   Ellis, MJ
   Ma, CX
   Ramm, S
   Krop, IE
   Winer, EP
   Roberts, TM
   Kim, HJ
   McAllister, SS
   Zhao, JJ
AF Goel, Shom
   DeCristo, Molly J.
   Watt, April C.
   BrinJones, Haley
   Sceneay, Jaclyn
   Li, Ben B.
   Khan, Naveed
   Ubellacker, Jessalyn M.
   Xie, Shaozhen
   Metzger-Filho, Otto
   Hoog, Jeremy
   Ellis, Matthew J.
   Ma, Cynthia X.
   Ramm, Susanne
   Krop, Ian E.
   Winer, Eric P.
   Roberts, Thomas M.
   Kim, Hye-Jung
   McAllister, Sandra S.
   Zhao, Jean J.
TI CDK4/6 inhibition triggers anti-tumour immunity
SO NATURE
LA English
DT Article
ID breast-cancer; requirement; methylation; senescence; expression; cells
AB Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies(1,2). Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours(3,4). Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells(5). Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity. We confirm this phenomenon through transcriptomic analysis of serial biopsies from a clinical trial of CDK4/6 inhibitor treatment for breast cancer. The enhanced antitumour immune response has two underpinnings. First, CDK4/6 inhibitors activate tumour cell expression of endogenous retroviral elements, thus increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and hence enhances tumour antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells. Mechanistically, the effects of CDK4/6 inhibitors both on tumour cells and on regulatory T cells are associated with reduced activity of the E2F target, DNA methyltransferase 1. Ultimately, these events promote cytotoxic T-cell-mediated clearance of tumour cells, which is further enhanced by the addition of immune checkpoint blockade. Our findings indicate that CDK4/6 inhibitors increase tumour immunogenicity and provide a rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti-cancer treatment.
C1 [Goel, Shom; Watt, April C.; BrinJones, Haley; Li, Ben B.; Khan, Naveed; Xie, Shaozhen; Roberts, Thomas M.; Zhao, Jean J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.
   [Goel, Shom; Metzger-Filho, Otto; Krop, Ian E.; Winer, Eric P.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.
   [DeCristo, Molly J.; Sceneay, Jaclyn; Ubellacker, Jessalyn M.; McAllister, Sandra S.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA.
   [DeCristo, Molly J.; Sceneay, Jaclyn; Ubellacker, Jessalyn M.; McAllister, Sandra S.] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA.
   [Hoog, Jeremy; Ma, Cynthia X.] Washington Univ, Sch Med, Dept Internal Med, Div Oncol, St Louis, MO 63110 USA.
   [Ellis, Matthew J.] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA.
   [Ramm, Susanne] Harvard Med Sch, Harvard Program Therapeut Sci, Lab Syst Pharmacol, Boston, MA 02115 USA.
   [Ramm, Susanne] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA.
   [Kim, Hye-Jung] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA.
   [Kim, Hye-Jung] Harvard Med Sch, Div Immunol, Dept Microbiol & Immunobiol, Boston, MA 02115 USA.
   [McAllister, Sandra S.] Harvard Med Sch, Harvard Stem Cell Inst, Boston, MA 02115 USA.
   [McAllister, Sandra S.; Zhao, Jean J.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.
   [Zhao, Jean J.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.
C3 Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Washington University (WUSTL); Baylor College of Medicine; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School
RP Goel, S; Zhao, JJ (corresponding author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.; Goel, S (corresponding author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; McAllister, SS (corresponding author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA.; McAllister, SS (corresponding author), Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA.; McAllister, SS (corresponding author), Harvard Med Sch, Harvard Stem Cell Inst, Boston, MA 02115 USA.; McAllister, SS; Zhao, JJ (corresponding author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.; Zhao, JJ (corresponding author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.
EM shom_goel@dfci.harvard.edu; smcallister1@bwh.harvard.edu; jean_zhao@dfci.harvard.edu
FU DF/HCC SPORE in Breast Cancer (National Institutes of Health (NIH) [2015 P50 CA]; Landry Cancer Biology Research Fellowship; DOD Era of Hope award [W81XWH-14-1-0191]; NIH (NCI) [RO1 CA166284]; Presidential Early Career Award for Scientists and Engineers; Breast Cancer Research Foundation; DF/HCC SPORE in Breast Cancer [P50 CA168504]; NIH [CA187918-02, CA210057-01, CA172461-04]; National Cancer Institute [R35CA210057, P50CA168504] Funding Source: NIH RePORTER
NR 30
TC 1147
Z9 1301
U1 7
U2 268
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 24
PY 2017
VL 548
IS 7668
BP 471
EP +
DI 10.1038/nature23465
PG 26
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FE5VI
UT WOS:000408279000042
PM 28813415
DA 2026-03-09
ER

PT J
AU Higuchi, T
   Heide, C
   Ullmann, K
   Weber, HB
   Hommelhoff, P
AF Higuchi, Takuya
   Heide, Christian
   Ullmann, Konrad
   Weber, Heiko B.
   Hommelhoff, Peter
TI Light-field-driven currents in graphene
SO NATURE
LA English
DT Article
ID gaas; wave
AB The ability to steer electrons using the strong electromagnetic field of light has opened up the possibility of controlling electron dynamics on the sub-femtosecond (less than 10(-15) seconds) timescale. In dielectrics and semiconductors, various light-field-driven effects have been explored, including high-harmonic generation(1-4), sub-optical-cycle interband population transfer(5) and the non-perturbative change of the transient polarizability(6,7). In contrast, much less is known about light-field-driven electron dynamics in narrow-bandgap systems or in conductors, in which screening due to free carriers or light absorption hinders the application of strong optical fields(6,8). Graphene is a promising platform with which to achieve light-field-driven control of electrons in a conducting material, because of its broadband and ultrafast optical response, weak screening and high damage threshold(9,10). Here we show that a current induced in monolayer graphene by two-cycle laser pulses is sensitive to the electric-field waveform, that is, to the exact shape of the optical carrier field of the pulse, which is controlled by the carrier envelope phase, with a precision on the attosecond (10(-18) seconds) timescale. Such a current, dependent on the carrier-envelope phase, shows a striking reversal of the direction of the current as a function of the driving field amplitude at about two volts per nanometre. This reversal indicates a transition of light-matter interaction from the weak-field (photon-driven) regime to the strong-field (light-field driven) regime, where the intraband dynamics influence interband transitions. We show that in this strong-field regime the electron dynamics are governed by sub-optical-cycle Landau-Zener-Stuckelberg interference(11), composed of coherent repeated Landau-Zener transitions on the femtosecond timescale. Furthermore, the influence of this sub-optical-cycle interference can be controlled with the laser polarization state. These coherent electron dynamics in graphene take place on a hitherto unexplored timescale, faster than electron-electron scattering (tens of femtoseconds) and electron-phonon scattering (hundreds of femtoseconds)(12-14). We expect these results to have direct ramifications for band-structure to mography2 and light-field-driven petahertz electronics(8).
C1 [Higuchi, Takuya; Heide, Christian; Hommelhoff, Peter] Friedrich Alexander Univ Erlangen Nurnberg FAU, Dept Phys, Laser Phys, Staudtstr 1, D-91058 Erlangen, Germany.
   [Ullmann, Konrad; Weber, Heiko B.] Friedrich Alexander Univ Erlangen Nurnberg FAU, Dept Phys, Appl Phys, Staudtstr 7, D-91058 Erlangen, Germany.
C3 University of Erlangen Nuremberg; University of Erlangen Nuremberg
RP Hommelhoff, P (corresponding author), Friedrich Alexander Univ Erlangen Nurnberg FAU, Dept Phys, Laser Phys, Staudtstr 1, D-91058 Erlangen, Germany.
EM takuya.higuchi@fau.de; peter.hommelhoff@fau.de
FU European Research Council (Consolidator Grant NearFieldAtto); Deutsche Forschungsgemeinschaft [SFB 953]
NR 30
TC 356
Z9 382
U1 14
U2 346
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 12
PY 2017
VL 550
IS 7675
BP 224
EP +
DI 10.1038/nature23900
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FJ5YG
UT WOS:000412829500042
PM 28953882
DA 2026-03-09
ER

PT J
AU Abbosh, C
   Birkbak, NJ
   Wilson, GA
   Jamal-Hanjani, M
   Constantin, T
   Salari, R
   Le Quesne, J
   Moore, DA
   Veeriah, S
   Rosenthal, R
   Marafioti, T
   Kirkizlar, E
   Watkins, TBK
   McGranahan, N
   Ward, S
   Martinson, L
   Riley, J
   Fraioli, F
   Al Bakir, M
   Gronroos, E
   Zambrana, F
   Endozo, R
   Bi, WL
   Fennessy, FM
   Sponer, N
   Johnson, D
   Laycock, J
   Shafi, S
   Czyzewska-Khan, J
   Rowan, A
   Chambers, T
   Matthews, N
   Turajlic, S
   Hiley, C
   Lee, SM
   Forster, MD
   Ahmad, T
   Falzon, M
   Borg, E
   Lawrence, D
   Hayward, M
   Kolvekar, S
   Panagiotopoulos, N
   Janes, SM
   Thakrar, R
   Ahmed, A
   Blackhall, F
   Summers, Y
   Hafez, D
   Naik, A
   Ganguly, A
   Kareht, S
   Shah, R
   Joseph, L
   Quinn, AM
   Crosbie, PA
   Naidu, B
   Middleton, G
   Langman, G
   Trotter, S
   Nicolson, M
   Remmen, H
   Kerr, K
   Chetty, M
   Gomersall, L
   Fennell, DA
   Nakas, A
   Rathinam, S
   Anand, G
   Khan, S
   Russell, P
   Ezhil, V
   Ismail, B
   Irvin-Sellers, M
   Prakash, V
   Lester, JF
   Kornaszewska, M
   Attanoos, R
   Adams, H
   Davies, H
   Oukrif, D
   Akarca, AU
   Hartley, JA
   Lowe, HL
   Lock, S
   Iles, N
   Bell, H
   Ngai, Y
   Elgar, G
   Szallasi, Z
   Schwarz, RF
   Herrero, J
   Stewart, A
   Quezada, SA
   Peggs, KS
   Van Loo, P
   Dive, C
   Lin, CJ
   Rabinowitz, M
   Aerts, HJWL
   Hackshaw, A
   Shaw, JA
   Zimmermann, BG
   Swanton, C
   Jamal-Hanjani, M
   Abbosh, C
   Veeriah, S
   Shafi, S
   Czyzewska-Khan, J
   Johnson, D
   Laycock, J
   Bosshard-Carter, L
   Goh, G
   Rosenthal, R
   Gorman, P
   Murugaesu, N
   Hynds, RE
   Wilson, GA
   Birkbak, NJ
   Watkins, TBK
   McGranahan, N
   Horswell, S
   Al Bakir, M
   Gronroos, E
   Mitter, R
   Escudero, M
   Stewart, A
   Van Loo, P
   Rowan, A
   Xu, H
   Turajlic, S
   Hiley, C
   Goldman, J
   Stone, RK
   Denner, T
   Matthews, N
   Elgar, G
   Ward, S
   Biggs, J
   Costa, M
   Begum, S
   Phillimore, B
   Chambers, T
   Nye, E
   Graca, S
   Joshi, K
   Furness, A
   Ben Aissa, A
   Wong, YNS
   Georgiou, A
   Quezada, SA
   Peggs, KS
   Hartley, JA
   Lowe, HL
   Herrero, J
   Lawrence, D
   Hayward, M
   Panagiotopoulos, N
   Kolvekar, S
   Falzon, M
   Borg, E
   Marafioti, T
   Simeon, C
   Hector, G
   Smith, A
   Aranda, M
   Novelli, M
   Oukrif, D
   Akarca, AU
   Janes, SM
   Thakrar, R
   Forster, MD
   Ahmad, T
   Lee, SM
   Papadatos-Pastos, D
   Carnell, D
   Mendes, R
   George, J
   Navani, N
   Ahmed, A
   Taylor, M
   Choudhary, J
   Summers, Y
   Califano, R
   Taylor, P
   Shah, R
   Krysiak, P
   Rammohan, K
   Fontaine, E
   Booton, R
   Evison, M
   Crosbie, PA
   Moss, S
   Idries, F
   Joseph, L
   Bishop, P
   Chaturvedi, A
   Quinn, AM
   Doran, H
   Leek, A
   Harrison, P
   Moore, K
   Waddington, R
   Novasio, J
   Blackhall, F
   Rogan, J
   Smith, E
   Dive, C
   Tugwood, J
   Brady, G
   Rothwell, DG
   Chemi, F
   Pierce, J
   Gulati, S
   Naidu, B
   Langman, G
   Trotter, S
   Bellamy, M
   Bancroft, H
   Kerr, A
   Kadiri, S
   Webb, J
   Middleton, G
   Djearaman, M
   Fennell, DA
   Shaw, JA
   Le Quesne, J
   Moore, DA
   Thomas, A
   Walter, H
   Riley, J
   Martinson, L
   Nakas, A
   Rathinam, S
   Monteiro, W
   Marshall, H
   Nelson, L
   Bennett, J
   Primrose, L
   Anand, G
   Khan, S
   Amadi, A
   Nicolson, M
   Kerr, K
   Palmer, S
   Remmen, H
   Miller, J
   Buchan, K
   Chetty, M
   Gomersall, L
   Lester, JF
   Edwards, A
   Morgan, F
   Adams, H
   Davies, H
   Kornaszewska, M
   Attanoos, R
   Lock, S
   Verjee, A
   MacKenzie, M
   Wilcox, M
   Bell, H
   Iles, N
   Hackshaw, A
   Ngai, Y
   Smith, S
   Gower, N
   Ottensmeier, C
   Chee, S
   Johnson, B
   Alzetani, A
   Shaw, E
   Lim, E
   De Sousa, P
   Barbosa, MT
   Bowman, A
   Jordan, S
   Rice, A
   Raubenheimer, H
   Proli, C
   Cufari, ME
   Ronquillo, JC
   Kwayie, A
   Bhayani, H
   Hamilton, M
   Bakar, Y
   Mensah, N
   Ambrose, L
   Devaraj, A
   Buderi, S
   Finch, J
   Azcarate, L
   Chavan, H
   Green, S
   Mashinga, H
   Nicholson, AG
   Lau, K
   Sheaff, M
   Schmid, P
   Conibear, J
   Ezhil, V
   Ismail, B
   Irvin-Sellers, M
   Prakash, V
   Russell, P
   Light, T
   Horey, T
   Danson, S
   Bury, J
   Edwards, J
   Hill, J
   Matthews, S
   Kitsanta, Y
   Suvarna, K
   Fisher, P
   Keerio, AD
   Shackcloth, M
   Gosney, J
   Postmus, P
   Feeney, S
   Asante-Siaw, J
   Constantin, T
   Salari, R
   Sponer, N
   Naik, A
   Zimmermann, BG
   Rabinowitz, M
   Aerts, HJWL
   Dentro, S
   Dessimoz, C
AF Abbosh, Christopher
   Birkbak, Nicolai J.
   Wilson, Gareth A.
   Jamal-Hanjani, Mariam
   Constantin, Tudor
   Salari, Raheleh
   Le Quesne, John
   Moore, David A.
   Veeriah, Selvaraju
   Rosenthal, Rachel
   Marafioti, Teresa
   Kirkizlar, Eser
   Watkins, Thomas B. K.
   McGranahan, Nicholas
   Ward, Sophia
   Martinson, Luke
   Riley, Joan
   Fraioli, Francesco
   Al Bakir, Maise
   Gronroos, Eva
   Zambrana, Francisco
   Endozo, Raymondo
   Bi, Wenya Linda
   Fennessy, Fiona M.
   Sponer, Nicole
   Johnson, Diana
   Laycock, Joanne
   Shafi, Seema
   Czyzewska-Khan, Justyna
   Rowan, Andrew
   Chambers, Tim
   Matthews, Nik
   Turajlic, Samra
   Hiley, Crispin
   Lee, Siow Ming
   Forster, Martin D.
   Ahmad, Tanya
   Falzon, Mary
   Borg, Elaine
   Lawrence, David
   Hayward, Martin
   Kolvekar, Shyam
   Panagiotopoulos, Nikolaos
   Janes, Sam M.
   Thakrar, Ricky
   Ahmed, Asia
   Blackhall, Fiona
   Summers, Yvonne
   Hafez, Dina
   Naik, Ashwini
   Ganguly, Apratim
   Kareht, Stephanie
   Shah, Rajesh
   Joseph, Leena
   Quinn, Anne Marie
   Crosbie, Phil A.
   Naidu, Babu
   Middleton, Gary
   Langman, Gerald
   Trotter, Simon
   Nicolson, Marianne
   Remmen, Hardy
   Kerr, Keith
   Chetty, Mahendran
   Gomersall, Lesley
   Fennell, Dean A.
   Nakas, Apostolos
   Rathinam, Sridhar
   Anand, Girija
   Khan, Sajid
   Russell, Peter
   Ezhil, Veni
   Ismail, Babikir
   Irvin-Sellers, Melanie
   Prakash, Vineet
   Lester, Jason F.
   Kornaszewska, Malgorzata
   Attanoos, Richard
   Adams, Haydn
   Davies, Helen
   Oukrif, Dahmane
   Akarca, Ayse U.
   Hartley, John A.
   Lowe, Helen L.
   Lock, Sara
   Iles, Natasha
   Bell, Harriet
   Ngai, Yenting
   Elgar, Greg
   Szallasi, Zoltan
   Schwarz, Roland F.
   Herrero, Javier
   Stewart, Aengus
   Quezada, Sergio A.
   Peggs, Karl S.
   Van Loo, Peter
   Dive, Caroline
   Lin, C. Jimmy
   Rabinowitz, Matthew
   Aerts, Hugo J. W. L.
   Hackshaw, Allan
   Shaw, Jacqui A.
   Zimmermann, Bernhard G.
   Swanton, Charles
   Jamal-Hanjani, Mariam
   Abbosh, Christopher
   Veeriah, Selvaraju
   Shafi, Seema
   Czyzewska-Khan, Justyna
   Johnson, Diana
   Laycock, Joanne
   Bosshard-Carter, Leticia
   Goh, Gerald
   Rosenthal, Rachel
   Gorman, Pat
   Murugaesu, Nirupa
   Hynds, Robert E.
   Wilson, Gareth A.
   Birkbak, Nicolai J.
   Watkins, Thomas B. K.
   McGranahan, Nicholas
   Horswell, Stuart
   Al Bakir, Maise
   Gronroos, Eva
   Mitter, Richard
   Escudero, Mickael
   Stewart, Aengus
   Van Loo, Peter
   Rowan, Andrew
   Xu, Hang
   Turajlic, Samra
   Hiley, Crispin
   Goldman, Jacki
   Stone, Richard Kevin
   Denner, Tamara
   Matthews, Nik
   Elgar, Greg
   Ward, Sophia
   Biggs, Jennifer
   Costa, Marta
   Begum, Sharmin
   Phillimore, Ben
   Chambers, Tim
   Nye, Emma
   Graca, Sofia
   Joshi, Kroopa
   Furness, Andrew
   Ben Aissa, Assma
   Wong, Yien Ning Sophia
   Georgiou, Andy
   Quezada, Sergio A.
   Peggs, Karl S.
   Hartley, John A.
   Lowe, Helen L.
   Herrero, Javier
   Lawrence, David
   Hayward, Martin
   Panagiotopoulos, Nikolaos
   Kolvekar, Shyam
   Falzon, Mary
   Borg, Elaine
   Marafioti, Teresa
   Simeon, Celia
   Hector, Gemma
   Smith, Amy
   Aranda, Marie
   Novelli, Marco
   Oukrif, Dahmane
   Akarca, Ayse U.
   Janes, Sam M.
   Thakrar, Ricky
   Forster, Martin D.
   Ahmad, Tanya
   Lee, Siow Ming
   Papadatos-Pastos, Dionysis
   Carnell, Dawn
   Mendes, Ruheena
   George, Jeremy
   Navani, Neal
   Ahmed, Asia
   Taylor, Magali
   Choudhary, Junaid
   Summers, Yvonne
   Califano, Raffaele
   Taylor, Paul
   Shah, Rajesh
   Krysiak, Piotr
   Rammohan, Kendadai
   Fontaine, Eustace
   Booton, Richard
   Evison, Matthew
   Crosbie, Phil A.
   Moss, Stuart
   Idries, Faiza
   Joseph, Leena
   Bishop, Paul
   Chaturvedi, Anshuman
   Quinn, Anne Marie
   Doran, Helen
   Leek, Angela
   Harrison, Phil
   Moore, Katrina
   Waddington, Rachael
   Novasio, Juliette
   Blackhall, Fiona
   Rogan, Jane
   Smith, Elaine
   Dive, Caroline
   Tugwood, Jonathan
   Brady, Ged
   Rothwell, Dominic G.
   Chemi, Francesca
   Pierce, Jackie
   Gulati, Sakshi
   Naidu, Babu
   Langman, Gerald
   Trotter, Simon
   Bellamy, Mary
   Bancroft, Hollie
   Kerr, Amy
   Kadiri, Salma
   Webb, Joanne
   Middleton, Gary
   Djearaman, Madava
   Fennell, Dean A.
   Shaw, Jacqui A.
   Le Quesne, John
   Moore, David A.
   Thomas, Anne
   Walter, Harriet
   Riley, Joan
   Martinson, Luke
   Nakas, Apostolos
   Rathinam, Sridhar
   Monteiro, William
   Marshall, Hilary
   Nelson, Louise
   Bennett, Jonathan
   Primrose, Lindsay
   Anand, Girija
   Khan, Sajid
   Amadi, Anita
   Nicolson, Marianne
   Kerr, Keith
   Palmer, Shirley
   Remmen, Hardy
   Miller, Joy
   Buchan, Keith
   Chetty, Mahendran
   Gomersall, Lesley
   Lester, Jason F.
   Edwards, Alison
   Morgan, Fiona
   Adams, Haydn
   Davies, Helen
   Kornaszewska, Malgorzata
   Attanoos, Richard
   Lock, Sara
   Verjee, Azmina
   MacKenzie, Mairead
   Wilcox, Maggie
   Bell, Harriet
   Iles, Natasha
   Hackshaw, Allan
   Ngai, Yenting
   Smith, Sean
   Gower, Nicole
   Ottensmeier, Christian
   Chee, Serena
   Johnson, Benjamin
   Alzetani, Aiman
   Shaw, Emily
   Lim, Eric
   De Sousa, Paulo
   Barbosa, Monica Tavares
   Bowman, Alex
   Jordan, Simon
   Rice, Alexandra
   Raubenheimer, Hilgardt
   Proli, Chiara
   Cufari, Maria Elena
   Ronquillo, John Carlo
   Kwayie, Angela
   Bhayani, Harshil
   Hamilton, Morag
   Bakar, Yusura
   Mensah, Natalie
   Ambrose, Lyn
   Devaraj, Anand
   Buderi, Silviu
   Finch, Jonathan
   Azcarate, Leire
   Chavan, Hema
   Green, Sophie
   Mashinga, Hillaria
   Nicholson, Andrew G.
   Lau, Kelvin
   Sheaff, Michael
   Schmid, Peter
   Conibear, John
   Ezhil, Veni
   Ismail, Babikir
   Irvin-Sellers, Melanie
   Prakash, Vineet
   Russell, Peter
   Light, Teresa
   Horey, Tracey
   Danson, Sarah
   Bury, Jonathan
   Edwards, John
   Hill, Jennifer
   Matthews, Sue
   Kitsanta, Yota
   Suvarna, Kim
   Fisher, Patricia
   Keerio, Allah Dino
   Shackcloth, Michael
   Gosney, John
   Postmus, Pieter
   Feeney, Sarah
   Asante-Siaw, Julius
   Constantin, Tudor
   Salari, Raheleh
   Sponer, Nicole
   Naik, Ashwini
   Zimmermann, Bernhard G.
   Rabinowitz, Matthew
   Aerts, Hugo J. W. L.
   Dentro, Stefan
   Dessimoz, Christophe
TI Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution
SO NATURE
LA English
DT Article
ID circulating tumor dna; uptake ratio; mutations; impact
AB The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.
C1 [Abbosh, Christopher; Birkbak, Nicolai J.; Wilson, Gareth A.; Jamal-Hanjani, Mariam; Veeriah, Selvaraju; Rosenthal, Rachel; Marafioti, Teresa; Watkins, Thomas B. K.; McGranahan, Nicholas; Ward, Sophia; Zambrana, Francisco; Johnson, Diana; Laycock, Joanne; Shafi, Seema; Czyzewska-Khan, Justyna; Hiley, Crispin; Lee, Siow Ming; Forster, Martin D.; Janes, Sam M.; Oukrif, Dahmane; Akarca, Ayse U.; Dive, Caroline; Swanton, Charles; Jamal-Hanjani, Mariam; Abbosh, Christopher; Veeriah, Selvaraju; Shafi, Seema; Czyzewska-Khan, Justyna; Johnson, Diana; Laycock, Joanne; Bosshard-Carter, Leticia; Goh, Gerald; Rosenthal, Rachel; Gorman, Pat; Murugaesu, Nirupa; Hynds, Robert E.; Wilson, Gareth A.; Birkbak, Nicolai J.; Watkins, Thomas B. K.; McGranahan, Nicholas; Hiley, Crispin; Ward, Sophia; Joshi, Kroopa; Furness, Andrew; Ben Aissa, Assma; Wong, Yien Ning Sophia; Georgiou, Andy; Oukrif, Dahmane; Akarca, Ayse U.; Janes, Sam M.; Forster, Martin D.; Lee, Siow Ming; Dive, Caroline] UCL, Canc Inst, Canc Res UK Lung Canc Ctr Excellence London & Man, Paul OGorman Bldg,72 Huntley St, London WC1E 6DD, England.
   [Birkbak, Nicolai J.; Wilson, Gareth A.; Watkins, Thomas B. K.; McGranahan, Nicholas; Ward, Sophia; Al Bakir, Maise; Gronroos, Eva; Rowan, Andrew; Chambers, Tim; Turajlic, Samra; Hiley, Crispin; Elgar, Greg; Swanton, Charles; Wilson, Gareth A.; Birkbak, Nicolai J.; Watkins, Thomas B. K.; McGranahan, Nicholas; Horswell, Stuart; Al Bakir, Maise; Gronroos, Eva; Mitter, Richard; Escudero, Mickael; Rowan, Andrew; Xu, Hang; Turajlic, Samra; Hiley, Crispin; Goldman, Jacki; Stone, Richard Kevin; Denner, Tamara; Elgar, Greg; Ward, Sophia; Biggs, Jennifer; Costa, Marta; Begum, Sharmin; Phillimore, Ben; Chambers, Tim; Nye, Emma; Graca, Sofia] Francis Crick Inst, Translat Canc Therapeut Lab, 1 Midland Rd, London NW1 1AT, England.
   [Constantin, Tudor; Salari, Raheleh; Kirkizlar, Eser; Sponer, Nicole; Hafez, Dina; Naik, Ashwini; Ganguly, Apratim; Kareht, Stephanie; Lin, C. Jimmy; Rabinowitz, Matthew; Zimmermann, Bernhard G.; Constantin, Tudor; Salari, Raheleh; Sponer, Nicole; Naik, Ashwini; Zimmermann, Bernhard G.; Rabinowitz, Matthew] Natera Inc, 201 Ind Rd, San Carlos, CA 94070 USA.
   [Le Quesne, John; Moore, David A.; Martinson, Luke; Riley, Joan; Fennell, Dean A.; Shaw, Jacqui A.; Fennell, Dean A.; Shaw, Jacqui A.; Le Quesne, John; Moore, David A.; Thomas, Anne; Walter, Harriet; Riley, Joan; Martinson, Luke] Univ Leicester, Canc Studies, Leicester LE2 7LX, Leics, England.
   [Marafioti, Teresa; Falzon, Mary; Borg, Elaine; Falzon, Mary; Borg, Elaine; Marafioti, Teresa; Novelli, Marco] Univ Coll London Hosp, Dept Pathol, 21 Univ St, London WC1 6JJ, England.
   [Ward, Sophia; Chambers, Tim; Matthews, Nik; Elgar, Greg; Matthews, Nik; Elgar, Greg; Ward, Sophia; Biggs, Jennifer; Chambers, Tim] Francis Crick Inst, Adv Sequencing Facil, 1 Midland Rd, London NW1 1AT, England.
   [Fraioli, Francesco; Endozo, Raymondo] Univ Coll London Hosp, Dept Nucl Med, 235 Euston Rd, London NW1 2BU, England.
   [Bi, Wenya Linda; Fennessy, Fiona M.; Aerts, Hugo J. W. L.; Aerts, Hugo J. W. L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.
   [Bi, Wenya Linda; Fennessy, Fiona M.; Aerts, Hugo J. W. L.; Aerts, Hugo J. W. L.] Harvard Med Sch, Boston, MA 02115 USA.
   [Matthews, Nik; Matthews, Nik] Inst Canc Res, Tumour Profiling Unit, Genom Facil, 237 Fulham Rd, London SW3 6JB, England.
   [Turajlic, Samra; Turajlic, Samra] Royal Marsden Hosp, Renal Unit, London SW3, England.
   [Turajlic, Samra; Turajlic, Samra] Royal Marsden Hosp, Skin Unit, London SW3, England.
   [Lee, Siow Ming; Forster, Martin D.; Ahmad, Tanya; Forster, Martin D.; Ahmad, Tanya; Lee, Siow Ming; Papadatos-Pastos, Dionysis] Univ Coll London Hosp, Dept Oncol, 250 Euston Rd, London NW1 2BU, England.
   [Lawrence, David; Hayward, Martin; Kolvekar, Shyam; Panagiotopoulos, Nikolaos; Lawrence, David; Hayward, Martin; Panagiotopoulos, Nikolaos; Kolvekar, Shyam] Univ Coll London Hosp, Dept Cardiothorac Surg, 235 Euston Rd, London NW1 2BU, England.
   [Janes, Sam M.; Thakrar, Ricky; Janes, Sam M.; Thakrar, Ricky] Univ Coll London Hosp, Dept Resp Med, 235 Euston Rd, London NW1 2BU, England.
   [Janes, Sam M.; Hynds, Robert E.; Janes, Sam M.] UCL, Div Med, Lungs Living Res Ctr, UCL Resp, Rayne Bldg,5 Univ St, London WC1E 6JF, England.
   [Ahmed, Asia; Ahmed, Asia] Univ Coll London Hosp, Dept Radiol, 235 Euston Rd, London NW1 2BU, England.
   [Blackhall, Fiona; Blackhall, Fiona] Univ Manchester, Inst Canc Studies, Oxford Rd, Manchester M13 9PL, Lancs, England.
   [Blackhall, Fiona; Summers, Yvonne; Summers, Yvonne; Blackhall, Fiona] Christie Hosp, Manchester M20 4BX, Lancs, England.
   [Shah, Rajesh; Shah, Rajesh] Univ Hosp South Manchester, Dept Cardiothorac Surg, Manchester M23 9LT, Lancs, England.
   [Joseph, Leena; Quinn, Anne Marie; Joseph, Leena; Quinn, Anne Marie] Univ Hosp South Manchester, Dept Pathol, Manchester M23 9LT, Lancs, England.
   [Crosbie, Phil A.; Crosbie, Phil A.] Univ Hosp South Manchester, North West Lung Ctr, Manchester M23 9LT, Lancs, England.
   [Naidu, Babu; Naidu, Babu] Birmingham Heartlands Hosp, Dept Thorac Surg, Birmingham B9 5SS, W Midlands, England.
   [Middleton, Gary; Middleton, Gary] Univ Birmingham, Inst Immunol & Immunotherapy, Birmingham B15 2TT, W Midlands, England.
   [Langman, Gerald; Trotter, Simon; Langman, Gerald; Trotter, Simon] Birmingham Heartlands Hosp, Dept Cellular Pathol, Birmingham B9 5SS, W Midlands, England.
   [Nicolson, Marianne; Nicolson, Marianne] Univ Aberdeen, Dept Med Oncol, Med Sch, Aberdeen AB25 2ZN, Scotland.
   [Nicolson, Marianne; Chetty, Mahendran; Gomersall, Lesley; Nicolson, Marianne; Palmer, Shirley; Miller, Joy; Buchan, Keith; Chetty, Mahendran; Gomersall, Lesley] Aberdeen Royal Infirm, Aberdeen AB25 2ZN, Scotland.
   [Remmen, Hardy; Remmen, Hardy] Univ Aberdeen, Dept Cardiothorac Surg, Med Sch, Aberdeen AB25 2ZD, Scotland.
   [Remmen, Hardy; Kerr, Keith; Kerr, Keith; Remmen, Hardy] Aberdeen Royal Infirm, Aberdeen AB25 2ZD, Scotland.
   [Kerr, Keith; Kerr, Keith] Univ Aberdeen, Dept Pathol, Med Sch, Aberdeen AB25 2ZD, Scotland.
   [Chetty, Mahendran; Chetty, Mahendran] Univ Aberdeen, Dept Resp Med, Med Sch, Aberdeen AB25 2ZN, Scotland.
   [Gomersall, Lesley; Gomersall, Lesley] Univ Aberdeen, Dept Radiol, Med Sch, Aberdeen AB25 2ZN, Scotland.
   [Nakas, Apostolos; Rathinam, Sridhar; Nakas, Apostolos; Rathinam, Sridhar] Glenfield Hosp, Dept Thorac Surg, Leicester LE3 9QP, Leics, England.
   [Anand, Girija; Anand, Girija] North Middlesex Univ Hosp, Dept Radiotherapy, London N18, England.
   [Khan, Sajid; Khan, Sajid] Royal Free Hosp, Dept Resp Med, Pond St, London NW3 2QG, England.
   [Khan, Sajid; Khan, Sajid] Barnet Hosp, Dept Resp Med, Wellhouse Lane, Barnet EN5 3DJ, England.
   [Khan, Sajid; Khan, Sajid] Chase Farm Hosp, Dept Resp Med, Wellhouse Lane, Barnet EN5 3DJ, England.
   [Russell, Peter; Russell, Peter] Princess Alexandra Hosp, Dept Resp Med, Hamstel Rd, Harlow CM20 1QX, Essex, England.
   [Ezhil, Veni; Ezhil, Veni] Royal Surrey Cty Hosp, St Lukes Canc Ctr, Dept Clin Oncol, Guildford GU2 7XX, Surrey, England.
   [Ismail, Babikir; Ismail, Babikir] Ashford & St Peters Hosp, Dept Pathol, Guildford Rd, Chertsey KT16 0PZ, Surrey, England.
   [Irvin-Sellers, Melanie; Irvin-Sellers, Melanie] Ashford & St Peters Hosp, Dept Resp Med, Guildford Rd, Chertsey KT16 0PZ, Surrey, England.
   [Prakash, Vineet; Prakash, Vineet] Ashford & St Peters Hosp, Dept Radiol, Guildford Rd, Chertsey KT16 0PZ, Surrey, England.
   [Lester, Jason F.; Lester, Jason F.] Velindre Hosp, Dept Clin Oncol, Cardiff CF14 2TL, S Glam, Wales.
   [Kornaszewska, Malgorzata; Kornaszewska, Malgorzata] Univ Hosp Wales, Dept Cardiothorac Surg, Cardiff CF14 4XW, S Glam, Wales.
   [Attanoos, Richard; Attanoos, Richard] Univ Hosp Wales, Dept Cellular Pathol, Heath Pk, Cardiff, S Glam, Wales.
   [Attanoos, Richard; Attanoos, Richard] Cardiff Univ, Heath Pk, Cardiff, S Glam, Wales.
   [Adams, Haydn; Adams, Haydn] Univ Hosp Llandough, Dept Radiol, Cardiff CF64 2XX, S Glam, Wales.
   [Davies, Helen] Univ Hosp Llandough, Dept Resp Med, Cardiff CF64 2XX, S Glam, Wales.
   [Hartley, John A.; Lowe, Helen L.; Hartley, John A.; Lowe, Helen L.] UCL, Expt Canc Med Ctr, GCLP Facil, Canc Inst, Paul OGorman Bldg,72 Huntley St, London WC1E 6DD, England.
   [Lock, Sara; Lock, Sara; Verjee, Azmina] Whittington Hosp NHS Trust, Dept Resp Med, London N19 5NF, England.
   [Iles, Natasha; Bell, Harriet; Ngai, Yenting; Hackshaw, Allan; Bell, Harriet; Iles, Natasha; Hackshaw, Allan; Ngai, Yenting; Smith, Sean; Gower, Nicole] UCL, Canc Res UK & UCL Canc Trials Ctr, London W1T 4TJ, England.
   [Szallasi, Zoltan] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark.
   [Szallasi, Zoltan] Harvard Med Sch, Boston Childrens Hosp, Computat Hlth Informat Program CHIP, Boston, MA USA.
   [Szallasi, Zoltan] Semmelweis Univ, Dept Pathol 2, Brain Metastasis Res Grp, MTA SE NAP, H-1091 Budapest, Hungary.
   [Schwarz, Roland F.] Max Delbrueck Ctr Mol Med, Berlin Inst Med Syst Biol, Berlin, Germany.
   [Herrero, Javier; Herrero, Javier] UCL, Bill Lyons Informat Ctr, Canc Inst, Paul OGorman Bldg,72 Huntley St, London WC1E 6DD, England.
   [Stewart, Aengus; Stewart, Aengus] Francis Crick Inst, Dept Bioinformat & Biostat, 1 Midland Rd, London NW1 1AT, England.
   [Quezada, Sergio A.; Peggs, Karl S.; Quezada, Sergio A.; Peggs, Karl S.] UCL, Canc Immunol Unit, Canc Inst, Paul OGorman Bldg,72 Huntley St, London WC1E 6DD, England.
   [Van Loo, Peter; Van Loo, Peter] Francis Crick Inst, Canc Genom Lab, 1 Midland Rd, London NW1 1AT, England.
   [Van Loo, Peter; Van Loo, Peter] Univ Leuven, Dept Human Genet, B-3000 Leuven, Belgium.
   [Dive, Caroline; Dive, Caroline; Tugwood, Jonathan; Brady, Ged; Rothwell, Dominic G.; Chemi, Francesca; Pierce, Jackie; Gulati, Sakshi] Univ Manchester, Canc Res UK Manchester Inst, Wilmslow Rd, Manchester M20 4BX, Lancs, England.
   [Aerts, Hugo J. W. L.; Aerts, Hugo J. W. L.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA.
   [Naidu, Babu; Simeon, Celia; Hector, Gemma; Smith, Amy; Aranda, Marie; Carnell, Dawn; Mendes, Ruheena; George, Jeremy; Navani, Neal; Taylor, Magali; Choudhary, Junaid] Univ Birmingham, Inst Inflammat & Ageing, Birmingham B15 2TT, W Midlands, England.
   [Naidu, Babu; Simeon, Celia; Hector, Gemma; Smith, Amy; Aranda, Marie; Carnell, Dawn; Mendes, Ruheena; George, Jeremy; Navani, Neal; Taylor, Magali; Choudhary, Junaid] Univ Coll London Hosp NHS Fdn Trust, London, England.
   [Califano, Raffaele; Taylor, Paul; Krysiak, Piotr; Rammohan, Kendadai; Fontaine, Eustace; Booton, Richard; Evison, Matthew; Moss, Stuart; Idries, Faiza; Bishop, Paul; Chaturvedi, Anshuman; Doran, Helen; Smith, Elaine] Univ Hosp South Manchester, Manchester M23 9LT, Lancs, England.
   [Leek, Angela; Harrison, Phil; Moore, Katrina; Waddington, Rachael; Novasio, Juliette; Rogan, Jane] Univ Manchester, Manchester Canc Res Ctr Biobank, Wilmslow Rd, Manchester M20 4BX, Lancs, England.
   [Bellamy, Mary; Bancroft, Hollie; Kerr, Amy; Kadiri, Salma; Webb, Joanne; Djearaman, Madava] Heart England NHS Fdn Trust, Birmingham, W Midlands, England.
   [Monteiro, William; Marshall, Hilary] Glenfield Hosp, NIHR Leicester Resp Biomed Res Unit, Groby Rd, Leicester LE3 9QP, Leics, England.
   [Nelson, Louise; Bennett, Jonathan; Primrose, Lindsay] Univ Hosp Leicester NHS Trust, Leicester, Leics, England.
   [Amadi, Anita] Barnet Hosp, Wellhouse Lane, Barnet EN5 3DJ, England.
   [Amadi, Anita] Chase Farm Hosp, Wellhouse Lane, Barnet EN5 3DJ, England.
   [Edwards, Alison] Velindre Canc Ctr, Clin Trials Unit, Cardiff CF14 2TL, S Glam, Wales.
   [Morgan, Fiona; Davies, Helen] Cardiff & Vale Univ Hlth Board, Cardiff, S Glam, Wales.
   [MacKenzie, Mairead; Wilcox, Maggie] Independent Canc Patients Voice, 17 Woodbridge St, London EC1R 0LL, England.
   [Ottensmeier, Christian; Chee, Serena; Johnson, Benjamin; Alzetani, Aiman; Shaw, Emily] Univ Southampton, Southampton, Hants, England.
   [Ottensmeier, Christian; Chee, Serena; Johnson, Benjamin; Alzetani, Aiman; Shaw, Emily] Southampton Univ Hosp, Southampton, Hants, England.
   [Lim, Eric; De Sousa, Paulo; Barbosa, Monica Tavares; Bowman, Alex; Jordan, Simon; Rice, Alexandra; Raubenheimer, Hilgardt; Proli, Chiara; Cufari, Maria Elena; Ronquillo, John Carlo; Kwayie, Angela; Bhayani, Harshil; Hamilton, Morag; Bakar, Yusura; Mensah, Natalie; Ambrose, Lyn; Devaraj, Anand; Buderi, Silviu; Finch, Jonathan; Azcarate, Leire; Chavan, Hema; Green, Sophie; Mashinga, Hillaria; Nicholson, Andrew G.] Royal Brompton & Harefield NHS Fdn Trust, London, England.
   [Nicholson, Andrew G.] Imperial Coll, Natl Heart & Lung Inst, Sydney St, London, England.
   [Lau, Kelvin; Sheaff, Michael; Schmid, Peter; Conibear, John] Barts Hlth NHS Trust, London, England.
   [Light, Teresa; Horey, Tracey] Princess Alexandra Hosp NHS Trust, Harlow, Essex, England.
   [Danson, Sarah; Bury, Jonathan; Edwards, John; Hill, Jennifer; Matthews, Sue; Kitsanta, Yota; Suvarna, Kim; Fisher, Patricia; Keerio, Allah Dino] Sheffield Teaching Hosp NHS Fdn Trust, Sheffield, S Yorkshire, England.
   [Shackcloth, Michael; Gosney, John; Postmus, Pieter; Feeney, Sarah; Asante-Siaw, Julius] Liverpool Heart & Chest Hosp NHS Fdn Trust, Liverpool, Merseyside, England.
   [Dentro, Stefan] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, Cambs, England.
   [Dessimoz, Christophe] UCL, Dept Comp Sci, Bioinformat Grp, London, England.
   [Dessimoz, Christophe] Univ Lausanne, CH-1015 Lausanne, Switzerland.
   [Dessimoz, Christophe] SIB Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland.
   [Peggs, Karl S.; Peggs, Karl S.] UCL, Canc Inst, Res Dept Haematol, London WC1E 6DD, England.
C3 University of London; University College London; Francis Crick Institute; Natera, Inc.; University of Leicester; University of London; University College London; University College London Hospitals NHS Foundation Trust; Francis Crick Institute; University College London Hospitals NHS Foundation Trust; University of London; University College London; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; University of London; Institute of Cancer Research - UK; Royal Marsden NHS Foundation Trust; Royal Marsden NHS Foundation Trust; Royal Marsden NHS Foundation Trust; University of London; University College London; University College London Hospitals NHS Foundation Trust; University College London Hospitals NHS Foundation Trust; University of London; University College London; University College London Hospitals NHS Foundation Trust; University of London; University College London; University of London; University College London; University of London; University College London; University College London Hospitals NHS Foundation Trust; University of Manchester; Christie NHS Foundation Trust; Christie Hospital; Wythenshawe Hospital NHS Foundation Trust; Wythenshawe Hospital NHS Foundation Trust; Wythenshawe Hospital NHS Foundation Trust; University of Birmingham; Heart of England NHS Foundation Trust; Heartlands Hospital; University of Birmingham; Heart of England NHS Foundation Trust; Heartlands Hospital; University of Birmingham; University of Aberdeen; University of Aberdeen; University of Aberdeen; University of Aberdeen; University of Aberdeen; University of Aberdeen; University of Aberdeen; University Hospitals of Leicester NHS Trust; University of Leicester; Glenfield Hospital; University of London; University College London; UCL Medical School; Royal Free London NHS Foundation Trust; Princess Alexandra Hospital NHS Trust; Royal Surrey County Hospital; Velindre Cancer Centre; Cardiff University; Cardiff University; Cardiff University; University of London; University College London; University of London; University College London; Cancer Research UK; Technical University of Denmark; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; Semmelweis University; Helmholtz Association; Max Delbruck Center for Molecular Medicine; University of London; University College London; Francis Crick Institute; University of London; University College London; Francis Crick Institute; KU Leuven; University of Manchester; Cancer Research UK; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; University of Birmingham; University of London; University College London; University College London Hospitals NHS Foundation Trust; Wythenshawe Hospital NHS Foundation Trust; University of Manchester; Heart of England NHS Foundation Trust; University Hospitals of Leicester NHS Trust; University of Leicester; Glenfield Hospital; University of Leicester; University Hospitals of Leicester NHS Trust; Velindre Cancer Centre; University of Southampton; University of Southampton; Royal Brompton & Harefield NHS Foundation Trust; Imperial College London; Barts Health NHS Trust; Princess Alexandra Hospital NHS Trust; University of Sheffield; Liverpool Heart & Chest Hospital; Wellcome Trust Sanger Institute; University of London; University College London; University of Lausanne; Swiss Institute of Bioinformatics; University of London; University College London
RP Swanton, C (corresponding author), UCL, Canc Inst, Canc Res UK Lung Canc Ctr Excellence London & Man, Paul OGorman Bldg,72 Huntley St, London WC1E 6DD, England.; Swanton, C (corresponding author), Francis Crick Inst, Translat Canc Therapeut Lab, 1 Midland Rd, London NW1 1AT, England.
EM Charles.Swanton@crick.ac.uk
FU Francis Crick Institute - Cancer Research UK [FC001169, FC001202]; UK Medical Research Council [FC001169, FC001202]; Wellcome Trust [FC001169, FC001202]; Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network); CRUK Lung Cancer Centre of Excellence; Stand Up 2 Cancer (SU2C); Rosetrees Trust; NovoNordisk Foundation [16584]; Prostate Cancer Foundation; Breast Cancer Research Foundation; European Research Council (THESEUS); National Institute for Health Research; University College London Hospitals Biomedical Research Centre; Cancer Research UK University College London Experimental Cancer Medicine Centre; University College London [UCL/12/0279, UCL/13/0165]; Cancer Research UK [C11496/A17786, C416/A21999]; MRC [G108/596, MC_UP_1203/1] Funding Source: UKRI; Wellcome Trust [107963/Z/15/Z] Funding Source: Wellcome Trust; National Center for Advancing Translational Sciences [UL1TR001863] Funding Source: NIH RePORTER; Cancer Research UK [18176, 23896, 19278, 17786, 21999, 15951, 20466, 20274, 22795, 17891, 20275, 19310, 19740, 20276, 15954, 20465] Funding Source: researchfish; Cancer Research UK; Versus Arthritis [20265, 22246, 20613, 18892] Funding Source: researchfish; Medical Research Council [MC_UP_1203/1, G108/596] Funding Source: researchfish; National Institute for Health Research [CL-2015-18-009, CL-2015-17-002] Funding Source: researchfish; Novo Nordisk Fonden [NNF15OC0016584] Funding Source: researchfish; Rosetrees [M35-F1-CD1, M35-F2, M179, M630, M510-CD1] Funding Source: researchfish; The Francis Crick Institute [10002, 10202, 10169] Funding Source: researchfish; Wellcome Trust [107963/Z/15/Z] Funding Source: researchfish
NR 28
TC 1438
Z9 1637
U1 10
U2 396
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 25
PY 2017
VL 545
IS 7655
BP 446
EP +
DI 10.1038/nature22364
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV6TH
UT WOS:000401906500045
PM 28445469
DA 2026-03-09
ER

PT J
AU Richter, MF
   Drown, BS
   Riley, AP
   Garcia, A
   Shirai, T
   Svec, RL
   Hergenrother, PJ
AF Richter, Michelle F.
   Drown, Bryon S.
   Riley, Andrew P.
   Garcia, Alfredo
   Shirai, Tomohiro
   Svec, Riley L.
   Hergenrother, Paul J.
TI Predictive compound accumulation rules yield a broad - spectrum antibiotic
SO NATURE
LA English
DT Article
ID molecular-dynamics simulation; drug-like molecules; escherichia-coli; antibacterial activity; ring-distortion; outer-membrane; ompf porin; poly(adp-ribose) glycohydrolase; diverse compounds; free-energy
AB Most small molecules are unable to rapidly traverse the outer membrane of Gram-negative bacteria and accumulate inside these cells, making the discovery of much-needed drugs against these pathogens challenging. Current understanding of the physicochemical properties that dictate small-molecule accumulation in Gram-negative bacteria is largely based on retrospective analyses of antibacterial agents, which suggest that polarity and molecular weight are key factors. Here we assess the ability of over 180 diverse compounds to accumulate in Escherichia coli. Computational analysis of the results reveals major differences from the retrospective studies, namely that the small molecules that are most likely to accumulate contain an amine, are amphiphilic and rigid, and have low globularity. These guidelines were then applied to convert deoxynybomycin, a natural product that is active only against Gram-positive organisms, into an antibiotic with activity against a diverse panel of multi-drug-resistant Gram-negative pathogens. We anticipate that these findings will aid in the discovery and development of antibiotics against Gram-negative bacteria.
C1 [Richter, Michelle F.; Drown, Bryon S.; Riley, Andrew P.; Garcia, Alfredo; Shirai, Tomohiro; Svec, Riley L.; Hergenrother, Paul J.] Univ Illinois, Dept Chem, Urbana, IL 61801 USA.
   [Richter, Michelle F.; Drown, Bryon S.; Riley, Andrew P.; Garcia, Alfredo; Shirai, Tomohiro; Svec, Riley L.; Hergenrother, Paul J.] Inst Genom Biol, Urbana, IL 61801 USA.
C3 University of Illinois System; University of Illinois Urbana-Champaign
RP Hergenrother, PJ (corresponding author), Univ Illinois, Dept Chem, Urbana, IL 61801 USA.; Hergenrother, PJ (corresponding author), Inst Genom Biol, Urbana, IL 61801 USA.
EM hergenro@illinois.edu
FU UIUC through the Office of Technology Management Proof-of-Concept award; NIH [NRSA 1-T32-GM070421]; Kao Corporation; NSF [TG-CHE160050]
NR 63
TC 720
Z9 858
U1 7
U2 337
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 18
PY 2017
VL 545
IS 7654
BP 299
EP +
DI 10.1038/nature22308
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV0WF
UT WOS:000401466500053
PM 28489819
DA 2026-03-09
ER

PT J
AU Schilbach, S
   Hantsche, M
   Tegunov, D
   Dienemann, C
   Wigge, C
   Urlaub, H
   Cramer, P
AF Schilbach, S.
   Hantsche, M.
   Tegunov, D.
   Dienemann, C.
   Wigge, C.
   Urlaub, H.
   Cramer, P.
TI Structures of transcription pre-initiation complex with TFIIH and Mediator
SO NATURE
LA English
DT Article
ID rna-polymerase-ii; cdk-activating kinase; c-terminal domain; crystal-structure; general transcription; protein-structure; dna-repair; xeroderma-pigmentosum; preinitiation complex; helicase
AB For the initiation of transcription, RNA polymerase II (Pol II) assembles with general transcription factors on promoter DNA to form the pre-initiation complex (PIC). Here we report cryo-electron microscopy structures of the Saccharomyces cerevisiae PIC and PIC-core Mediator complex at nominal resolutions of 4.7 angstrom and 5.8 angstrom, respectively. The structures reveal transcription factor IIH (TFIIH), and suggest how the core and kinase TFIIH modules function in the opening of promoter DNA and the phosphorylation of Pol II, respectively. The TFIIH core subunit Ssl2 (a homologue of human XPB) is positioned on downstream DNA by the 'E-bridge' helix in TFIIE, consistent with TFIIE-stimulated DNA opening. The TFIIH kinase module subunit Tfb3 (MAT1 in human) anchors the kinase Kin28 (CDK7), which is mobile in the PIC but preferentially located between the Mediator hook and shoulder in the PIC-core Mediator complex. Open spaces between the Mediator head and middle modules may allow access of the kinase to its substrate, the C-terminal domain of Pol II.
C1 [Schilbach, S.; Hantsche, M.; Tegunov, D.; Dienemann, C.; Wigge, C.; Urlaub, H.; Cramer, P.] Max Planck Inst Biophys Chem, Dept Mol Biol, Fassberg 11, D-37077 Gottingen, Germany.
   [Urlaub, H.] Univ Med Ctr Groningen, Inst Clin Chem, Bioanalyt Grp, Robert Koch Str 40, D-37075 Gottingen, Germany.
C3 Max Planck Society; University of Gottingen; University of Gottingen Hospital
RP Cramer, P (corresponding author), Max Planck Inst Biophys Chem, Dept Mol Biol, Fassberg 11, D-37077 Gottingen, Germany.
EM patrick.cramer@mpibpc.mpg.de
FU Deutsche Forschungsgemeinschaft [SFB860, SPP1935]; Advanced Grant TRANSREGULON of the European Research Council [693023]; Volkswagen Foundation
NR 94
TC 200
Z9 245
U1 3
U2 47
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 9
PY 2017
VL 551
IS 7679
BP 204
EP +
DI 10.1038/nature24282
PG 26
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM1KF
UT WOS:000414734200042
PM 29088706
DA 2026-03-09
ER

PT J
AU Manukyan, L
   Montandon, SA
   Fofonjka, A
   Smirnov, S
   Milinkovitch, MC
AF Manukyan, Liana
   Montandon, Sophie A.
   Fofonjka, Anamarija
   Smirnov, Stanislav
   Milinkovitch, Michel C.
TI A living mesoscopic cellular automaton made of skin scales
SO NATURE
LA English
DT Article
ID carotenoid-based coloration; pigment pattern; genetics; lizards; chromatophores; convergence; iridophores; evolution; model; fish
AB In vertebrates, skin colour patterns emerge from nonlinear dynamical microscopic systems of cell interactions. Here we show that in ocellated lizards a quasi-hexagonal lattice of skin scales, rather than individual chromatophore cells, establishes a green and black labyrinthine pattern of skin colour. We analysed time series of lizard scale colour dynamics over four years of their development and demonstrate that this pattern is produced by a cellular automaton ( a grid of elements whose states are iterated according to a set of rules based on the states of neighbouring elements) that dynamically computes the colour states of individual mesoscopic skin scales to produce the corresponding macroscopic colour pattern. Using numerical simulations and mathematical derivation, we identify how a discrete von Neumann cellular automaton emerges from a continuous Turing reaction-diffusion system. Skin thickness variation generated by three-dimensional morphogenesis of skin scales causes the underlying reaction-diffusion dynamics to separate into microscopic and mesoscopic spatial scales, the latter generating a cellular automaton. Our study indicates that cellular automata are not merely abstract computational systems, but can directly correspond to processes generated by biological evolution.
C1 [Manukyan, Liana; Montandon, Sophie A.; Fofonjka, Anamarija; Milinkovitch, Michel C.] Univ Geneva, Dept Genet & Evolut, LANE, Geneva, Switzerland.
   [Manukyan, Liana; Fofonjka, Anamarija; Milinkovitch, Michel C.] Swiss Inst Bioinformat, Geneva, Switzerland.
   [Smirnov, Stanislav] Univ Geneva, Dept Math, Geneva, Switzerland.
   [Smirnov, Stanislav] Skolkovo Inst Sci & Technol, Skolkovo, Russia.
   [Smirnov, Stanislav] St Petersburg State Univ, Dept Math & Mech, Chebyshev Lab, St Petersburg, Russia.
C3 University of Geneva; Swiss Institute of Bioinformatics; University of Geneva; Skolkovo Institute of Science & Technology; Saint Petersburg State University
RP Manukyan, L (corresponding author), Univ Geneva, Dept Genet & Evolut, LANE, Geneva, Switzerland.; Manukyan, L (corresponding author), Swiss Inst Bioinformat, Geneva, Switzerland.
FU University of Geneva (Switzerland); Swiss National Science Foundation (FNSNF) [31003A_140785, SINERGIA CRSII3_132430]; SystemsX.ch initiative (project EpiPhysX); ERC AG COMPASP; FNSNF; NCCR SwissMAP; Russian Science Foundation; Swiss National Science Foundation (SNF) [31003A_140785] Funding Source: Swiss National Science Foundation (SNF)
NR 59
TC 94
Z9 112
U1 1
U2 86
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 13
PY 2017
VL 544
IS 7649
BP 173
EP +
DI 10.1038/nature22031
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ER6EK
UT WOS:000398897900026
PM 28406206
DA 2026-03-09
ER

PT J
AU Constantino, JN
   Kennon-McGill, S
   Weichselbaum, C
   Marrus, N
   Haider, A
   Glowinski, AL
   Gillespie, S
   Klaiman, C
   Klin, A
   Jones, W
AF Constantino, John N.
   Kennon-McGill, Stefanie
   Weichselbaum, Claire
   Marrus, Natasha
   Haider, Alyzeh
   Glowinski, Anne L.
   Gillespie, Scott
   Klaiman, Cheryl
   Klin, Ami
   Jones, Warren
TI Infant viewing of social scenes is under genetic control and is atypical in autism
SO NATURE
LA English
DT Article
ID frontal eye field; spectrum disorder; visual-attention; general-population; salience; traits; toddlers; behavior; search; adults
AB Long before infants reach, crawl or walk, they explore the world by looking: they look to learn and to engage(1), giving preferential attention to social stimuli, including faces(2), facelike stimuli(3) and biological motion(4). This capacity-social visual engagement-shapes typical infant development from birth(5) and is pathognomonically impaired in children affected by autism(6). Here we show that variation in viewing of social scenes, including levels of preferential attention and the timing, direction and targeting of individual eye movements, is strongly influenced by genetic factors, with effects directly traceable to the active seeking of social information(7). In a series of eye-tracking experiments conducted with 338 toddlers, including 166 epidemiologically ascertained twins (enrolled by representative sampling from the general population), 88 non-twins with autism and 84 singleton controls, we find high monozygotic twin-twin concordance (0.91) and relatively low dizygotic concordance (0.35). Moreover, the characteristics that are the most highly heritable, preferential attention to eye and mouth regions of the face, are also those that are differentially decreased in children with autism (chi(2) = 64.03, P < 0.0001). These results implicate social visual engagement as a neurodevelopmental endophenotype not only for autism, but also for population-wide variation in social-information seeking(8). In addition, these results reveal a means of human biological niche construction, with phenotypic differences emerging from the interaction of individual genotypes with early life experience(7).
C1 [Constantino, John N.; Kennon-McGill, Stefanie; Weichselbaum, Claire; Marrus, Natasha; Haider, Alyzeh; Glowinski, Anne L.] Washington Univ, Dept Psychiat, St Louis, MO 63110 USA.
   [Constantino, John N.] Washington Univ, Dept Pediat, St Louis, MO 63110 USA.
   [Constantino, John N.; Marrus, Natasha] Washington Univ, Intellectual & Dev Disabil Res Ctr, St Louis, MO 63110 USA.
   [Gillespie, Scott] Emory Univ, Sch Med, Pediat Biostat Core, Atlanta, GA 30307 USA.
   [Klaiman, Cheryl; Klin, Ami; Jones, Warren] Childrens Healthcare Atlanta, Marcus Autism Ctr, Atlanta, GA 30329 USA.
   [Klaiman, Cheryl; Klin, Ami; Jones, Warren] Emory Univ, Sch Med, Div Autism & Related Disabil, Dept Pediat, Atlanta, GA 30329 USA.
   [Klin, Ami; Jones, Warren] Emory Univ, Ctr Translat Social Neurosci, Atlanta, GA 30329 USA.
C3 Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Emory University; Children's Healthcare of Atlanta (CHOA); Emory University; Emory University
RP Constantino, JN (corresponding author), Washington Univ, Dept Psychiat, St Louis, MO 63110 USA.; Constantino, JN (corresponding author), Washington Univ, Dept Pediat, St Louis, MO 63110 USA.; Constantino, JN (corresponding author), Washington Univ, Intellectual & Dev Disabil Res Ctr, St Louis, MO 63110 USA.; Jones, W (corresponding author), Childrens Healthcare Atlanta, Marcus Autism Ctr, Atlanta, GA 30329 USA.; Jones, W (corresponding author), Emory Univ, Sch Med, Div Autism & Related Disabil, Dept Pediat, Atlanta, GA 30329 USA.; Jones, W (corresponding author), Emory Univ, Ctr Translat Social Neurosci, Atlanta, GA 30329 USA.
EM constantino@wustl.edu; warren.jones@emory.edu
FU National Institute of Child Health & Human Development [HD068479, U54 HD087011]; National Institute of Mental Health [MH100019, MH100029]; Marcus Foundation; Whitehead Foundation; Georgia Research Alliance; project entitled Early Quantitative Characterization of Reciprocal Social Behavior; National Institute of Mental Health [P50MH100029, K08MH112891, T32MH100019] Funding Source: NIH RePORTER
NR 63
TC 217
Z9 253
U1 2
U2 106
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 20
PY 2017
VL 547
IS 7663
BP 340
EP +
DI 10.1038/nature22999
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB0OR
UT WOS:000405844900032
PM 28700580
DA 2026-03-09
ER

PT J
AU Alvarez, SW
   Sviderskiy, VO
   Terzi, EM
   Papagiannakopoulos, T
   Moreira, AL
   Adams, S
   Sabatini, DM
   Birsoy, K
   Possemato, R
AF Alvarez, Samantha W.
   Sviderskiy, Vladislav O.
   Terzi, Erdem M.
   Papagiannakopoulos, Thales
   Moreira, Andre L.
   Adams, Sylvia
   Sabatini, David M.
   Birsoy, Kivanc
   Possemato, Richard
TI NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis
SO NATURE
LA English
DT Article
ID copy-number alteration; in-vivo; cancer; oxygen; iron; identification; sensitivity; genes; death
AB Environmental nutrient levels impact cancer cell metabolism, resulting in context-dependent gene essentiality(1,2). Here, using loss-of-function screening based on RNA interference, we show that environmental oxygen levels are a major driver of differential essentiality between in vitro model systems and in vivo tumours. Above the 3-8% oxygen concentration typical of most tissues, we find that cancer cells depend on high levels of the iron-sulfur cluster biosynthetic enzyme NFS1. Mammary or subcutaneous tumours grow despite suppression of NFS1, whereas metastatic or primary lung tumours do not. Consistent with a role in surviving the high oxygen environment of incipient lung tumours, NFS1 lies in a region of genomic amplification present in lung adenocarcinoma and is most highly expressed in well-differentiated adenocarcinomas. NFS1 activity is particularly important for maintaining the ironsulfur co-factors present in multiple cell-essential proteins upon exposure to oxygen compared to other forms of oxidative damage. Furthermore, insufficient iron-sulfur cluster maintenance robustly activates the iron-starvation response and, in combination with inhibition of glutathione biosynthesis, triggers ferroptosis, a non-apoptotic form of cell death. Suppression of NFS1 cooperates with inhibition of cysteine transport to trigger ferroptosis in vitro and slow tumour growth. Therefore, lung adenocarcinomas select for expression of a pathway that confers resistance to high oxygen tension and protects cells from undergoing ferroptosis in response to oxidative damage.
C1 [Alvarez, Samantha W.; Sviderskiy, Vladislav O.; Terzi, Erdem M.; Papagiannakopoulos, Thales; Moreira, Andre L.; Adams, Sylvia; Possemato, Richard] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA.
   [Alvarez, Samantha W.; Sviderskiy, Vladislav O.; Terzi, Erdem M.; Papagiannakopoulos, Thales; Moreira, Andre L.; Adams, Sylvia; Possemato, Richard] NYU, Sch Med, Laura & Isaac Perlmutter Canc Ctr, New York, NY 10016 USA.
   [Sabatini, David M.; Birsoy, Kivanc; Possemato, Richard] Whitehead Inst Biomed Res, Nine Cambridge Ctr, Cambridge, MA 02142 USA.
   [Sabatini, David M.; Birsoy, Kivanc; Possemato, Richard] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA.
   [Sabatini, David M.; Birsoy, Kivanc; Possemato, Richard] David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Sabatini, David M.; Birsoy, Kivanc; Possemato, Richard] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Sabatini, David M.; Birsoy, Kivanc; Possemato, Richard] Broad Inst Harvard & Massachusetts Inst Technol, Seven Cambridge Ctr, Cambridge, MA 02142 USA.
   [Birsoy, Kivanc] Rockefeller Univ, Lab Metab Regulat & Genet, 1230 York Ave, New York, NY 10065 USA.
C3 New York University; New York University; Massachusetts Institute of Technology (MIT); Whitehead Institute; Massachusetts Institute of Technology (MIT); Howard Hughes Medical Institute; Massachusetts Institute of Technology (MIT); Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Rockefeller University
RP Possemato, R (corresponding author), NYU, Sch Med, Dept Pathol, New York, NY 10016 USA.; Possemato, R (corresponding author), NYU, Sch Med, Laura & Isaac Perlmutter Canc Ctr, New York, NY 10016 USA.; Sabatini, DM; Birsoy, K; Possemato, R (corresponding author), Whitehead Inst Biomed Res, Nine Cambridge Ctr, Cambridge, MA 02142 USA.; Sabatini, DM; Birsoy, K; Possemato, R (corresponding author), MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA.; Sabatini, DM; Birsoy, K; Possemato, R (corresponding author), David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Sabatini, DM; Birsoy, K; Possemato, R (corresponding author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Sabatini, DM; Birsoy, K; Possemato, R (corresponding author), Broad Inst Harvard & Massachusetts Inst Technol, Seven Cambridge Ctr, Cambridge, MA 02142 USA.; Birsoy, K (corresponding author), Rockefeller Univ, Lab Metab Regulat & Genet, 1230 York Ave, New York, NY 10065 USA.
EM sabatini@wi.mit.edu; kbirsoy@rockefeller.edu; richard.possemato@nyumc.org
FU National Institutes of Health (NIH) [T32GM007308, T32GM115313, CA168940, CA193660, CA103866, CA129105, AI07389]; Starr Cancer Consortium; Broad Institute SPARC; Leukemia and Lymphoma Society; V Foundation; Pew-Stewart Scholar Grant; Susan G. Komen for the Cure; NIH [P30CA016087, S10 OD010584-01, S10 OD018338, S10 OD016304]; National Cancer Institute [R01CA103866, P30CA016087, R01CA129105] Funding Source: NIH RePORTER
NR 34
TC 631
Z9 705
U1 6
U2 195
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 30
PY 2017
VL 551
IS 7682
BP 639
EP +
DI 10.1038/nature24637
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FO1KW
UT WOS:000416520400045
PM 29168506
DA 2026-03-09
ER

PT J
AU Zeng, FX
   Chen, YB
   Remis, J
   Shekhar, M
   Phillips, JC
   Tajkhorshid, E
   Jin, H
AF Zeng, Fuxing
   Chen, Yanbo
   Remis, Jonathan
   Shekhar, Mrinal
   Phillips, James C.
   Tajkhorshid, Emad
   Jin, Hong
TI Structural basis of co-translational quality control by ArfA and RF2 bound to ribosome
SO NATURE
LA English
DT Article
ID cryo-em structure; peptide-bond formation; escherichia-coli; stalled ribosm; messenger-rna; ggq motif; termination complex; release; rescue; expression
AB Quality control mechanisms intervene appropriately when defective translation events occur, in order to preserve the integrity of protein synthesis. Rescue of ribosomes translating on messenger RNAs that lack stop codons is one of the co-translational quality control pathways. In many bacteria, ArfA recognizes stalled ribosomes and recruits the release factor RF2, which catalyses the termination of protein synthesis(1-3). Although an induced-fit mechanism of nonstop mRNA surveillance mediated by ArfA and RF2 has been reported(4), the molecular interaction between ArfA and RF2 in the ribosome that is responsible for the mechanism is unknown. Here we report an electron cryo-microscopy structure of ArfA and RF2 in complex with the 70S ribosome bound to a nonstop mRNA. The structure, which is consistent with our kinetic and biochemical data, reveals the molecular interactions that enable ArfA to specifically recruit RF2, not RF1, into the ribosome and to enable RF2 to release the truncated protein product in this co-translational quality control pathway. The positively charged C-terminal domain of ArfA anchors in the mRNA entry channel of the ribosome. Furthermore, binding of ArfA and RF2 induces conformational changes in the ribosomal decoding centre that are similar to those seen in other protein-involved decoding processes. Specific interactions between residues in the N-terminal domain of ArfA and RF2 help RF2 to adopt a catalytically competent conformation for peptide release. Our findings provide a framework for understanding recognition of the translational state of the ribosome by new proteins, and expand our knowledge of the decoding potential of the ribosome.
C1 [Zeng, Fuxing; Chen, Yanbo; Tajkhorshid, Emad; Jin, Hong] Univ Illinois, Dept Biochem, Urbana, IL 61801 USA.
   [Remis, Jonathan] Northwestern Univ, Dept Mol Biosci, Evanston, IL 60208 USA.
   [Shekhar, Mrinal; Tajkhorshid, Emad; Jin, Hong] Univ Illinois, Ctr Biophys & Quantitat Biol, Urbana, IL 61801 USA.
   [Shekhar, Mrinal; Phillips, James C.; Tajkhorshid, Emad] Univ Illinois, Beckman Inst Adv Sci & Technol, Urbana, IL 61801 USA.
C3 University of Illinois System; University of Illinois Urbana-Champaign; Northwestern University; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign
RP Jin, H (corresponding author), Univ Illinois, Dept Biochem, Urbana, IL 61801 USA.; Jin, H (corresponding author), Univ Illinois, Ctr Biophys & Quantitat Biol, Urbana, IL 61801 USA.
EM hjin@illinois.edu
FU National Institute of General Medical Sciences of the NIH [R01-GM120552]; National Institute of General Medical Sciences [P41GM104601] Funding Source: NIH RePORTER
NR 65
TC 34
Z9 91
U1 1
U2 25
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 26
PY 2017
VL 541
IS 7638
BP 554
EP 557
DI 10.1038/nature21053
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6LX
UT WOS:000396116600056
PM 28077875
DA 2026-03-09
ER

PT J
AU de Lavergne, C
   Madec, G
   Roquet, F
   Holmes, RM
   McDougall, TJ
AF de lavergne, C.
   Madec, G.
   Roquet, F.
   Holmes, R. M.
   McDougall, T. J.
TI Abyssal ocean overturning shaped by seafloor distribution
SO NATURE
LA English
DT Article
ID large-scale circulation; antarctic bottom water; south-pacific ocean; mid-atlantic ridge; global ocean; deep-water; north pacific; indian-ocean; world ocean; turbulent dissipation
AB The abyssal ocean is broadly characterized by northward flow of the densest waters and southward flow of less-dense waters above them. Understanding what controls the strength and structure of these interhemispheric flows-referred to as the abyssal overturning circulation-is key to quantifying the ocean's ability to store carbon and heat on timescales exceeding a century. Here we show that, north of 32 degrees S, the depth distribution of the seafloor compels dense southernorigin waters to flow northward below a depth of about 4 kilometres and to return southward predominantly at depths greater than 2.5 kilometres. Unless ventilated from the north, the overlying mid-depths (1 to 2.5 kilometres deep) host comparatively weak mean meridional flow. Backed by analysis of historical radiocarbon measurements, the findings imply that the geometry of the Pacific, Indian and Atlantic basins places a major external constraint on the overturning structure.
C1 [de lavergne, C.; Holmes, R. M.; McDougall, T. J.] Univ New South Wales, Sch Math & Stat, Sydney, NSW 2052, Australia.
   [de lavergne, C.; Madec, G.] Univ Pierre & Marie Curie Paris 6, CNRS, IRD, MNHN,Sorbonne Univ,LOCEAN Lab, F-75005 Paris, France.
   [Roquet, F.] Stockholm Univ, Dept Meteorol MISU, S-11418 Stockholm, Sweden.
   [Holmes, R. M.] Univ New South Wales, Climate Change Res Ctr, Sydney, NSW 2052, Australia.
   [Holmes, R. M.] Univ New South Wales, ARC Ctr Excellence Climate Syst Sci, Sydney, NSW 2052, Australia.
C3 University of New South Wales Sydney; Institut de Recherche pour le Developpement (IRD); Sorbonne Universite; Museum National d'Histoire Naturelle (MNHN); Centre National de la Recherche Scientifique (CNRS); Stockholm University; University of New South Wales Sydney; University of New South Wales Sydney; ARC Centre of Excellence for Climate System Science
RP de Lavergne, C (corresponding author), Univ New South Wales, Sch Math & Stat, Sydney, NSW 2052, Australia.; de Lavergne, C (corresponding author), Univ Pierre & Marie Curie Paris 6, CNRS, IRD, MNHN,Sorbonne Univ,LOCEAN Lab, F-75005 Paris, France.
EM casimir.delavergne@gmail.com
FU Australian Research Council [FL150100090]; Australian Research Council [FL150100090] Funding Source: Australian Research Council
NR 96
TC 93
Z9 98
U1 2
U2 62
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 9
PY 2017
VL 551
IS 7679
BP 181
EP +
DI 10.1038/nature24472
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM1KF
UT WOS:000414734200038
PM 29120416
DA 2026-03-09
ER

PT J
AU Burstein, D
   Harrington, LB
   Strutt, SC
   Probst, AJ
   Anantharaman, K
   Thomas, BC
   Doudna, JA
   Banfield, JF
AF Burstein, David
   Harrington, Lucas B.
   Strutt, Steven C.
   Probst, Alexander J.
   Anantharaman, Karthik
   Thomas, Brian C.
   Doudna, Jennifer A.
   Banfield, Jillian F.
TI New CRISPR-Cas systems from uncultivated microbes
SO NATURE
LA English
DT Article
ID provides acquired-resistance; spacer acquisition; adaptive immunity; dna elements; small rna; archaea; endonuclease; genm; classification; recognition
AB CRISPR-Cas systems provide microbes with adaptive immunity by employing short DNA sequences, termed spacers, that guide Cas proteins to cleave foreign DNA(1,2). Class 2 CRISPR-Cas systems are streamlined versions, in which a single RNA-bound Cas protein recognizes and cleaves target sequences(3,4). The programmable nature of these minimal systems has enabled researchers to repurpose them into a versatile technology that is broadly revolutionizing biological and clinical research(5). However, current CRISPR-Cas technologies are based solely on systems from isolated bacteria, leaving the vast majority of enzymes from organisms that have not been cultured untapped. Metagenomics, the sequencing of DNA extracted directly from natural microbial communities, provides access to the genetic material of a huge array of uncultivated organisms(6,7). Here, using genome-resolved metagenomics, we identify a number of CRISPR-Cas systems, including the first reported Cas9 in the archaeal domain of life, to our knowledge. This divergent Cas9 protein was found in little studied nanoarchaea as part of an active CRISPR-Cas system. In bacteria, we discovered two previously unknown systems, CRISPR-CasX and CRISPR-CasY, which are among the most compact systems yet discovered. Notably, all required functional components were identified by metagenomics, enabling validation of robust in vivo RNA-guided DNA interference activity in Escherichia coli. Interrogation of environmental microbial communities combined with in vivo experiments allows us to access an unprecedented diversity of genomes, the content of which will expand the repertoire of microbe-based biotechnologies.
C1 [Burstein, David; Probst, Alexander J.; Anantharaman, Karthik; Thomas, Brian C.; Banfield, Jillian F.] Univ Calif Berkeley, Dept Earth & Planetary Sci, Berkeley, CA 94720 USA.
   [Harrington, Lucas B.; Strutt, Steven C.; Doudna, Jennifer A.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
   [Doudna, Jennifer A.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
   [Doudna, Jennifer A.] Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA.
   [Doudna, Jennifer A.] Univ Calif Berkeley, Innovat Genom Initiat, Berkeley, CA 94720 USA.
   [Doudna, Jennifer A.] Lawrence Berkeley Natl Lab, MBIB Div, Berkeley, CA 94720 USA.
   [Banfield, Jillian F.] Univ Calif Berkeley, Dept Environm Sci Policy & Management, Berkeley, CA 94720 USA.
C3 University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of California System; University of California Berkeley; Howard Hughes Medical Institute; University of California System; University of California Berkeley; University of California System; University of California Berkeley; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; University of California System; University of California Berkeley
RP Banfield, JF (corresponding author), Univ Calif Berkeley, Dept Earth & Planetary Sci, Berkeley, CA 94720 USA.; Doudna, JA (corresponding author), Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.; Doudna, JA (corresponding author), Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.; Doudna, JA (corresponding author), Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA.; Doudna, JA (corresponding author), Univ Calif Berkeley, Innovat Genom Initiat, Berkeley, CA 94720 USA.; Doudna, JA (corresponding author), Lawrence Berkeley Natl Lab, MBIB Div, Berkeley, CA 94720 USA.; Banfield, JF (corresponding author), Univ Calif Berkeley, Dept Environm Sci Policy & Management, Berkeley, CA 94720 USA.
EM doudna@berkeley.edu; jbanfield@berkeley.edu
FU EMBO fellowship; US National Science Foundation; German Science Foundation [DFG PR 1603/1-1]; Allen Distinguished Investigator Program, through The Paul G. Allen Frontiers Group; National Science Foundation [MCB-1244557]; Lawrence Berkeley National Laboratory's Sustainable Systems Scientific Focus Area - US Department of Energy [DE-AC02-05CH11231]
NR 35
TC 425
Z9 685
U1 6
U2 343
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 9
PY 2017
VL 542
IS 7640
BP 237
EP 241
DI 10.1038/nature21059
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK2DJ
UT WOS:000393737500042
PM 28005056
DA 2026-03-09
ER

PT J
AU Zhang, SC
   Kang, LX
   Wang, X
   Tong, LM
   Yang, LW
   Wang, ZQ
   Qi, K
   Deng, SB
   Li, QW
   Bai, XD
   Ding, F
   Zhang, J
AF Zhang, Shuchen
   Kang, Lixing
   Wang, Xiao
   Tong, Lianming
   Yang, Liangwei
   Wang, Zequn
   Qi, Kuo
   Deng, Shibin
   Li, Qingwen
   Bai, Xuedong
   Ding, Feng
   Zhang, Jin
TI Arrays of horizontal carbon nanotubes of controlled chirality grown using designed catalysts
SO NATURE
LA English
DT Article
ID selective growth; oxide catalysts; diameter; raman
AB The semiconductor industry is increasingly of the view that Moore's law-which predicts the biennial doubling of the number of transistors per microprocessor chip-is nearing its end(1). Consequently, the pursuit of alternative semiconducting materials for nanoelectronic devices, including single-walled carbon nanotubes (SWNTs), continues(2-4). Arrays of horizontal nanotubes are particularly appealing for technological applications because they optimize current output. However, the direct growth of horizontal SWNT arrays with controlled chirality, that would enable the arrays to be adapted for a wider range of applications and ensure the uniformity of the fabricated devices, has not yet been achieved. Here we show that horizontal SWNT arrays with predicted chirality can be grown from the surfaces of solid carbide catalysts by controlling the symmetries of the active catalyst surface. We obtained horizontally aligned metallic SWNT arrays with an average density of more than 20 tubes per micrometre in which 90 per cent of the tubes had chiral indices of (12, 6), and semiconducting SWNT arrays with an average density of more than 10 tubes per micrometre in which 80 per cent of the nanotubes had chiral indices of (8, 4). The nanotubes were grown using uniform size Mo2C and WC solid catalysts. Thermodynamically, the SWNT was selectively nucleated by matching its structural symmetry and diameter with those of the catalyst. We grew nanotubes with chiral indices of (2m, m) (where m is a positive integer), the yield of which could be increased by raising the concentration of carbon to maximize the kinetic growth rate in the chemical vapour deposition process. Compared to previously reported methods, such as cloning(5,6), seeding(7,8) and specific-structure-matching growth(9-11), our strategy of controlling the thermodynamics and kinetics offers more degrees of freedom, enabling the chirality of as-grown SWNTs in an array to be tuned, and can also be used to predict the growth conditions required to achieve the desired chiralities.
C1 [Zhang, Shuchen; Kang, Lixing; Tong, Lianming; Yang, Liangwei; Wang, Zequn; Deng, Shibin; Zhang, Jin] Peking Univ, Beijing Sci & Engn Ctr Nanocarbons, Coll Chem & Mol Engn, Ctr Nanochem,Beijing Natl Lab Mol Sci,Key Lab Phy, Beijing 100871, Peoples R China.
   [Kang, Lixing; Li, Qingwen] Chinese Acad Sci, Suzhou Inst Nanotech & Nanobion, Suzhou 215123, Peoples R China.
   [Wang, Xiao; Ding, Feng] Inst Basic Sci, Ctr Multidimens Carbon Mat, Ulsan 689798, South Korea.
   [Wang, Xiao; Ding, Feng] Hong Kong Polytech Univ, Inst Text & Clothing, Hong Kong, Hong Kong, Peoples R China.
   [Qi, Kuo; Bai, Xuedong] Chinese Acad Sci, Inst Phys, Beijing 100190, Peoples R China.
   [Ding, Feng] Ulsan Natl Inst Sci & Technol, Sch Mat Sci & Engn, Ulsan 689798, South Korea.
C3 Peking University; Chinese Academy of Sciences; Chinese Academy of Sciences; Suzhou Institute of Nano-Tech & Nano-Bionics, CAS; Institute for Basic Science - Korea (IBS); Hong Kong Polytechnic University; Chinese Academy of Sciences; Institute of Physics, CAS; Ulsan National Institute of Science & Technology (UNIST)
RP Zhang, J (corresponding author), Peking Univ, Beijing Sci & Engn Ctr Nanocarbons, Coll Chem & Mol Engn, Ctr Nanochem,Beijing Natl Lab Mol Sci,Key Lab Phy, Beijing 100871, Peoples R China.
EM jinzhang@pku.edu.cn
FU Ministry of Science and Technology of China [2016YFA0200101, 2016YFA0200104]; National Natural Science Foundation of China [51432002, 21129001, 21233001]
NR 30
TC 383
Z9 410
U1 26
U2 1231
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 9
PY 2017
VL 543
IS 7644
BP 234
EP +
DI 10.1038/nature21051
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0GQ
UT WOS:000395688700037
PM 28199307
DA 2026-03-09
ER

PT J
AU Faria, NR
   Quick, J
   Claro, IM
   Thézé, J
   de Jesus, JG
   Giovanetti, M
   Kraemer, MUG
   Hill, SC
   Black, A
   da Costa, AC
   Franco, LC
   Silva, SP
   Wu, CH
   Raghwani, J
   Cauchemez, S
   du Plessis, L
   Verotti, MP
   de Oliveira, WK
   Carmo, EH
   Coelho, GE
   Santelli, ACFS
   Vinhal, LC
   Henriques, CM
   Simpson, JT
   Loose, M
   Andersen, KG
   Grubaugh, ND
   Somasekar, S
   Chiu, CY
   Muñoz-Medina, JE
   Gonzalez-Bonilla, CR
   Arias, CF
   Lewis-Ximenez, LL
   Baylis, SA
   Chieppe, AO
   Aguiar, SF
   Fernandes, CA
   Lemos, PS
   Nascimento, BLS
   Monteiro, HAO
   Siqueira, IC
   de Queiroz, MG
   de Souza, TR
   Bezerra, JF
   Lemos, MR
   Pereira, GF
   Loudal, D
   Moura, LC
   Dhalia, R
   França, RF
   Magalhaes, T
   Marques, ET
   Jaenisch, T
   Wallau, GL
   de Lima, MC
   Nascimento, V
   de Cerqueira, EM
   de Lima, MM
   Mascarenhas, DL
   Neto, JPM
   Levin, AS
   Tozetto-Mendoza, TR
   Fonseca, SN
   Mendes-Correa, MC
   Milagres, FP
   Segurado, A
   Holmes, EC
   Rambaut, A
   Bedford, T
   Nunes, MRT
   Sabino, EC
   Alcantara, LCJ
   Loman, NJ
   Pybus, OG
AF Faria, N. R.
   Quick, J.
   Claro, I. M.
   Theze, J.
   de Jesus, J. G.
   Giovanetti, M.
   Kraemer, M. U. G.
   Hill, S. C.
   Black, A.
   da Costa, A. C.
   Franco, L. C.
   Silva, S. P.
   Wu, C. -H.
   Raghwani, J.
   Cauchemez, S.
   du Plessis, L.
   Verotti, M. P.
   de Oliveira, W. K.
   Carmo, E. H.
   Coelho, G. E.
   Santelli, A. C. F. S.
   Vinhal, L. C.
   Henriques, C. M.
   Simpson, J. T.
   Loose, M.
   Andersen, K. G.
   Grubaugh, N. D.
   Somasekar, S.
   Chiu, C. Y.
   Munoz-Medina, J. E.
   Gonzalez-Bonilla, C. R.
   Arias, C. F.
   Lewis-Ximenez, L. L.
   Baylis, S. A.
   Chieppe, A. O.
   Aguiar, S. F.
   Fernandes, C. A.
   Lemos, P. S.
   Nascimento, B. L. S.
   Monteiro, H. A. O.
   Siqueira, I. C.
   de Queiroz, M. G.
   de Souza, T. R.
   Bezerra, J. F.
   Lemos, M. R.
   Pereira, G. F.
   Loudal, D.
   Moura, L. C.
   Dhalia, R.
   Franca, R. F.
   Magalhaes, T.
   Marques, E. T., Jr.
   Jaenisch, T.
   Wallau, G. L.
   de Lima, M. C.
   Nascimento, V.
   de Cerqueira, E. M.
   de Lima, M. M.
   Mascarenhas, D. L.
   Moura Neto, J. P.
   Levin, A. S.
   Tozetto-Mendoza, T. R.
   Fonseca, S. N.
   Mendes-Correa, M. C.
   Milagres, F. P.
   Segurado, A.
   Holmes, E. C.
   Rambaut, A.
   Bedford, T.
   Nunes, M. R. T.
   Sabino, E. C.
   Alcantara, L. C. J.
   Loman, N. J.
   Pybus, O. G.
TI Establishment and cryptic transmission of Zika virus in Brazil and the Americas
SO NATURE
LA English
DT Article
ID time; evolution; models; dengue; bahia; emergence; selection; outbreak; accurate; salvador
AB Transmission of Zika virus (ZIKV) in the Americas was first confirmed in May 2015 in northeast Brazil(1). Brazil has had the highest number of reported ZIKV cases worldwide (more than 200,000 by 24 December 20162) and the most cases associated with microcephaly and other birth defects (2,366 confirmed by 31 December 20162). Since the initial detection of ZIKV in Brazil, more than 45 countries in the Americas have reported local ZIKV transmission, with 24 of these reporting severe ZIKV-associated disease(3). However, the origin and epidemic history of ZIKV in Brazil and the Americas remain poorly understood, despite the value of this information for interpreting observed trends in reported microcephaly. Here we address this issue by generating 54 complete or partial ZIKV genomes, mostly from Brazil, and reporting data generated by a mobile genomics laboratory that travelled across northeast Brazil in 2016. One sequence represents the earliest confirmed ZIKV infection in Brazil. Analyses of viral genomes with ecological and epidemiological data yield an estimate that ZIKV was present in northeast Brazil by February 2014 and is likely to have disseminated from there, nationally and internationally, before the first detection of ZIKV in the Americas. Estimated dates for the international spread of ZIKV from Brazil indicate the duration of pre-detection cryptic transmission in recipient regions. The role of northeast Brazil in the establishment of ZIKV in the Americas is further supported by geographic analysis of ZIKV transmission potential and by estimates of the basic reproduction number of the virus.
C1 [Faria, N. R.; Theze, J.; Kraemer, M. U. G.; Hill, S. C.; Raghwani, J.; du Plessis, L.; Pybus, O. G.] Univ Oxford, Dept Zool, Oxford OX1 3SY, England.
   [Faria, N. R.; Franco, L. C.; Silva, S. P.; Lemos, P. S.; Nascimento, B. L. S.; Monteiro, H. A. O.; Nunes, M. R. T.] Minist Hlth, Evandro Chagas Inst, Ananindeua, Brazil.
   [Quick, J.; Loman, N. J.] Univ Birmingham, Inst Microbiol & Infect, Birmingham, W Midlands, England.
   [Claro, I. M.; da Costa, A. C.; Levin, A. S.; Tozetto-Mendoza, T. R.; Mendes-Correa, M. C.; Segurado, A.; Sabino, E. C.] Univ Sao Paulo, Sch Med, Dept Infect Dis, Sao Paulo, Brazil.
   [Claro, I. M.; da Costa, A. C.; Levin, A. S.; Tozetto-Mendoza, T. R.; Mendes-Correa, M. C.; Segurado, A.; Sabino, E. C.] Univ Sao Paulo, Inst Trop Med, Sao Paulo, Brazil.
   [de Jesus, J. G.; Giovanetti, M.; Siqueira, I. C.; Alcantara, L. C. J.] Fiocruz MS, Fundacao Oswaldo Cruz, Salvador, BA, Brazil.
   [Giovanetti, M.] Univ Roma Tor Vergata, Rome, Italy.
   [Kraemer, M. U. G.] Harvard Med Sch, Boston, MA USA.
   [Kraemer, M. U. G.] Boston Childrens Hosp, Boston, MA USA.
   [Black, A.; Bedford, T.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA.
   [Black, A.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.
   [Wu, C. -H.] Univ Oxford, Dept Stat, Oxford OX1 3LB, England.
   [Cauchemez, S.] Inst Pasteur, Math Modelling Infect Dis, Paris, France.
   [Cauchemez, S.] Inst Pasteur, Ctr Bioinformat Biostat & Integrat Biol, Paris, France.
   [Cauchemez, S.] Ctr Natl Rech Sci, URA3012, Paris, France.
   [Verotti, M. P.] Minist Hlth, Coordena Lab Saude CGLAB DEVIT SVS, Brasilia, DF, Brazil.
   [de Oliveira, W. K.] Minist Hlth, Coordena Geral Vigilincia & Resposta Emergencias, Brasilia, DF, Brazil.
   [de Oliveira, W. K.] Fundacao Oswaldo Cruz FIOCRUZ, Ctr Data & Knowledge Integrat Hlth CIDACS, Salvador, BA, Brazil.
   [Carmo, E. H.; Henriques, C. M.] Minist Hlth, Dept Vigilincia Doencas Transmissiveis, Brasilia, DF, Brazil.
   [Coelho, G. E.; Santelli, A. C. F. S.; Vinhal, L. C.] Minist Hlth, Coordena Geral Programas Controle & Preven Malari, Brasilia, DF, Brazil.
   [Coelho, G. E.] PAHO, Buenos Aires, DF, Argentina.
   [Santelli, A. C. F. S.] Fundacao Oswaldo Cruz FIOCRUZ, Rio De Janeiro, Brazil.
   [Simpson, J. T.] Ontario Inst Canc Res, Toronto, ON, Canada.
   [Loose, M.] Univ Nottingham, Nottingham, England.
   [Andersen, K. G.; Grubaugh, N. D.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA.
   [Somasekar, S.; Chiu, C. Y.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA.
   [Somasekar, S.; Chiu, C. Y.] Univ Calif San Francisco, Dept Med Infect & Dis, San Francisco, CA 94143 USA.
   [Munoz-Medina, J. E.; Gonzalez-Bonilla, C. R.] Inst Mexicano Seguro Social, Div Labs Vigilancia & Invest Epidemiol, Mexico City, DF, Mexico.
   [Arias, C. F.] Univ Nacl Autonoma Mexico, Inst Biotecnol, Cuernavaca, Morelos, Mexico.
   [Lewis-Ximenez, L. L.] Inst Oswaldo Cruz FIOCRUZ, Rio De Janeiro, Brazil.
   [Baylis, S. A.] Paul Ehrlich Inst, Langen, Germany.
   [Chieppe, A. O.; Aguiar, S. F.; Fernandes, C. A.] Lab Cent Saude Publ Noel Nutels, Rio De Janeiro, Brazil.
   [de Queiroz, M. G.; de Souza, T. R.; Bezerra, J. F.] Labo Cent Saude Publ Estado Rio Grande Norte, Natal, RN, Brazil.
   [de Souza, T. R.] Univ Potiguar Rio Grande Norte, Natal, RN, Brazil.
   [Bezerra, J. F.] Fundacao Natalense Ensino & Cultura, Natal, RN, Brazil.
   [Lemos, M. R.; Pereira, G. F.; Loudal, D.; Moura, L. C.] Lab Cent Saude Publ Estado Paraiba, Joao Pessoa, Paraiba, Brazil.
   [Dhalia, R.; Franca, R. F.; Magalhaes, T.; Marques, E. T., Jr.; Wallau, G. L.] Fundacao Oswaldo Cruz FIOCRUZ, Recife, PE, Brazil.
   [Magalhaes, T.] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA.
   Univ Pittsburgh, Grad Sch Publ Hlth, Ctr Vaccine Res, Pittsburgh, PA USA.
   [Jaenisch, T.] Univ Heidelberg Hosp, Dept Infect Dis, Sect Clin Trop Med, Heidelberg, Germany.
   [de Lima, M. C.; Nascimento, V.; de Cerqueira, E. M.] Lab Cent Saude Publ Estado Alagoas, Maceio, Brazil.
   [de Lima, M. M.] Univ Estadual Feira de Santana, Feira Santana, Bahia, Argentina.
   [Mascarenhas, D. L.] Secretaria Saude Feira Santana, Feira De Santana, Bahia, Brazil.
   [Moura Neto, J. P.] Univ Fed Amazonas, Manaus, Amazonas, Brazil.
   [Fonseca, S. N.] Hosp Sao Francisco, Ribeirao Preto, Brazil.
   [Milagres, F. P.] Univ Fed Tocantins, Palmas, Brazil.
   [Holmes, E. C.] Univ Sydney, Sydney, NSW, Australia.
   [Rambaut, A.] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH9 3FL, Midlothian, Scotland.
   [Rambaut, A.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA.
   [Nunes, M. R. T.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA.
   [Pybus, O. G.] Metabiota, San Francisco, CA 94104 USA.
C3 University of Oxford; Instituto Evandro Chagas; University of Birmingham; Universidade de Sao Paulo; Universidade de Sao Paulo; Fundacao Oswaldo Cruz; University of Rome Tor Vergata; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Fred Hutchinson Cancer Center; University of Washington; University of Washington Seattle; University of Oxford; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Centre National de la Recherche Scientifique (CNRS); Fundacao Oswaldo Cruz; Fundacao Oswaldo Cruz; University of Toronto; Ontario Institute for Cancer Research; University of Nottingham; Scripps Research Institute; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Instituto Mexicano del Seguro Social; Universidad Nacional Autonoma de Mexico; Fundacao Oswaldo Cruz; Paul Ehrlich Institute; Universidade Potiguar; Fundacao Oswaldo Cruz; Colorado State University System; Colorado State University Fort Collins; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Ruprecht Karls University Heidelberg; Universidade Federal de Amazonas; Universidade Federal do Tocantins (UFT); University of Sydney; University of Edinburgh; National Institutes of Health (NIH) - USA; NIH Fogarty International Center (FIC); University of Texas System; University of Texas Medical Branch Galveston
RP Pybus, OG (corresponding author), Univ Oxford, Dept Zool, Oxford OX1 3SY, England.; Loman, NJ (corresponding author), Univ Birmingham, Inst Microbiol & Infect, Birmingham, W Midlands, England.; Sabino, EC (corresponding author), Univ Sao Paulo, Sch Med, Dept Infect Dis, Sao Paulo, Brazil.; Sabino, EC (corresponding author), Univ Sao Paulo, Inst Trop Med, Sao Paulo, Brazil.; Alcantara, LCJ (corresponding author), Fiocruz MS, Fundacao Oswaldo Cruz, Salvador, BA, Brazil.; Pybus, OG (corresponding author), Metabiota, San Francisco, CA 94104 USA.
EM sabinoec@usp.br; lalcan@bahia.fiocruz.br; n.j.loman@bham.ac.uk; oliver.pybus@zoo.ox.ac.uk
FU MRC/Wellcome Trust/Newton Fund Zika Rapid Response grant [MC_PC_15100/ZK/16-078]; USAID Emerging Pandemic Threats Program-2 PREDICT-2 [AID-OAA-A-14-00102]; MRC Bioinformatics Fellowship; Sir Henry Dale Fellowship [204311/Z/16/Z]; CNPq [457480/2014-9, 302584/2015-3, 439975/2016-6]; FAPESP [2012/03417-7]; NIH [R35 GM119774, R01 HL105704]; NSF [DGE-1256082]; Abbott Laboratories, Inc.; National Health and Medical Research Council [GNT1037231]; MRC; CRUK [ANR00310]; Wellcome Trust; Royal Society [101237/Z/13/Z]; ERC [614725-PATHPHYLODYN, 278433-PREDEMICS]; EU [643476-COMPARE, 734548-ZIKAlliance]; IDAMS; DENFREE; DengueTools; PPSUSFACEPE [APQ-0302-4.01/13]; FACEPE [APQ-0044.2.11/16, APQ-0055.2.11/16]; German Ministry of Health; Medical Research Council [MR/L015080/1, MC_PC_15100, MR/M501621/1] Funding Source: researchfish; National Institute of Allergy and Infectious Diseases [T32AI007244] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R35GM119774] Funding Source: NIH RePORTER; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [12/03417-7] Funding Source: FAPESP; MRC [MR/M501621/1, MR/L015080/1, MC_PC_15100] Funding Source: UKRI
NR 62
TC 426
Z9 481
U1 2
U2 115
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 15
PY 2017
VL 546
IS 7658
BP 406
EP +
DI 10.1038/nature22401
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EX5BK
UT WOS:000403250900035
PM 28538727
DA 2026-03-09
ER

PT J
AU Pardo, JD
   Szostakiwskyj, M
   Ahlberg, PE
   Anderson, JS
AF Pardo, Jason D.
   Szostakiwskyj, Matt
   Ahlberg, Per E.
   Anderson, Jason S.
TI Hidden morphological diversity among early tetrapods
SO NATURE
LA English
DT Article
ID cranial morphology; computed-tomography; devonian tetrapod; east kirkton; lepospondyli; evolution; scotland; amphibians; anatomy; genus
AB Phylogenetic analysis of early tetrapod evolution has resulted in a consensus across diverse data sets(1-3) in which the tetrapod stem group is a relatively homogenous collection of medium-to large-sized animals showing a progressive loss of 'fish' characters as they become increasingly terrestrial(4,5), whereas the crown group demonstrates marked morphological diversity and disparity(6). The oldest fossil attributed to the tetrapod crown group is the highly specialized astopod Lethiscus stocki(7,8), which shows a small size, extreme axial elongation, loss of limbs, spool-shaped vertebral centra, and a skull with reduced centres of ossification, in common with an otherwise disparate group of small animals known as lepospondyls. Here we use micro-computed tomography of the only known specimen of Lethiscus to provide new information that strongly challenges this consensus. Digital dissection reveals extremely primitive cranial morphology, including a spiracular notch, a large remnant of the notochord within the braincase, an open ventral cranial fissure, an anteriorly restricted parasphenoid element, and Meckelian ossifications. The braincase is elongate and lies atop a dorsally projecting septum of the parasphenoid bone, similar to stem tetrapods such as embolomeres. This morphology is consistent in a second astopod, Coloraderpeton, although the details differ. Phylogenetic analysis, including critical new braincase data, places astopods deep on the tetrapod stem, whereas another major lepospondyl lineage is displaced into the amniotes. These results show that stem group tetrapods were much more diverse in their body plans than previously thought. Our study requires a change in commonly used calibration dates for molecular analyses, and emphasizes the importance of character sampling for early tetrapod evolutionary relationships.
C1 [Pardo, Jason D.; Anderson, Jason S.] Univ Calgary, Dept Comparat Biol & Expt Med, 3330 Hosp Dr, Calgary, AB T2N 4N1, Canada.
   [Szostakiwskyj, Matt] Univ Calgary, Dept Biol Sci, 2500 Univ Dr, Calgary, AB T2N 1N4, Canada.
   [Ahlberg, Per E.] Uppsala Univ, Dept Organismal Biol, Uppsala, Sweden.
C3 University of Calgary; University of Calgary; Uppsala University
RP Anderson, JS (corresponding author), Univ Calgary, Dept Comparat Biol & Expt Med, 3330 Hosp Dr, Calgary, AB T2N 4N1, Canada.
EM janders@ucalgary.ca
FU Natural Sciences and Engineering Research Council of Canada; Directorate For Geosciences; Division Of Earth Sciences [1561622] Funding Source: National Science Foundation
NR 30
TC 121
Z9 134
U1 0
U2 55
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 29
PY 2017
VL 546
IS 7660
BP 642
EP +
DI 10.1038/nature22966
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY9QB
UT WOS:000404332000045
PM 28636600
DA 2026-03-09
ER

PT J
AU Meech, KJ
   Weryk, R
   Micheli, M
   Kleyna, JT
   Hainaut, OR
   Jedicke, R
   Wainscoat, RJ
   Chambers, KC
   Keane, JV
   Petric, A
   Denneau, L
   Magnier, E
   Berger, T
   Huber, ME
   Flewelling, H
   Waters, C
   Schunova-Lilly, E
   Chastel, S
AF Meech, Karen J.
   Weryk, Robert
   Micheli, Marco
   Kleyna, Jan T.
   Hainaut, Olivier R.
   Jedicke, Robert
   Wainscoat, Richard J.
   Chambers, Kenneth C.
   Keane, Jacqueline V.
   Petric, Andreea
   Denneau, Larry
   Magnier, Eugene
   Berger, Travis
   Huber, Mark E.
   Flewelling, Heather
   Waters, Chris
   Schunova-Lilly, Eva
   Chastel, Serge
TI A brief visit from a red and extremely elongated interstellar asteroid
SO NATURE
LA English
DT Article
ID system; comets; debris; stars
AB None of the approximately 750,000 known asteroids and comets in the Solar System is thought to have originated outside it, despite models of the formation of planetary systems suggesting that orbital migration of giant planets ejects a large fraction of the original planetesimals into interstellar space(1). The high predicted number density(2) of icy interstellar objects (2.4 x 10(-4) per cubic astronomical unit) suggests that some should have been detected, yet hitherto none has been seen. Many decades of asteroid and comet characterization have yielded formation models that explain the mass distribution, chemical abundances and planetary configuration of the Solar System today, but there has been no way of telling whether the Solar System is typical of planetary systems. Here we report observations and analysis of the object 1I/2017 U1 ('Oumuamua) that demonstrate its extrasolar trajectory, and that thus enable comparisons to be made between material from another planetary system and from our own. Our observations during the brief visit by the object to the inner Solar System reveal it to be asteroidal, with no hint of cometary activity despite an approach within 0.25 astronomical units of the Sun. Spectroscopic measurements show that the surface of the object is spectrally red, consistent with comets or organic-rich asteroids that reside within the Solar System. Light-curve observations indicate that the object has an extremely oblong shape, with a length about ten times its width, and a mean radius of about 102 metres assuming an albedo of 0.04. No known objects in the Solar System have such extreme dimensions. The presence of 'Oumuamua in the Solar System suggests that previous estimates of the number density of interstellar objects, based on the assumption that all such objects were cometary, were pessimistically low. Planned upgrades to contemporary asteroid survey instruments and improved data processing techniques are likely to result in the detection of more interstellar objects in the coming years.
C1 [Meech, Karen J.; Weryk, Robert; Kleyna, Jan T.; Jedicke, Robert; Wainscoat, Richard J.; Chambers, Kenneth C.; Keane, Jacqueline V.; Petric, Andreea; Denneau, Larry; Magnier, Eugene; Berger, Travis; Huber, Mark E.; Flewelling, Heather; Waters, Chris; Schunova-Lilly, Eva; Chastel, Serge] Inst Astron, 2680 Woodlawn Dr, Honolulu, HI 96822 USA.
   [Micheli, Marco] ESA SSA NEO Coordinat Ctr, Largo Galileo Galilei 1, I-00044 Frascati, Italy.
   [Micheli, Marco] Osserv Astron Roma, Via Frascati 33, I-00040 Monte Porzio Catone, Italy.
   [Hainaut, Olivier R.] European Southern Observ, Karl Schwarzschild Str 2, D-85748 Garching, Germany.
C3 Istituto Nazionale Astrofisica (INAF); European Southern Observatory
RP Meech, KJ (corresponding author), Inst Astron, 2680 Woodlawn Dr, Honolulu, HI 96822 USA.
EM meech@ifa.hawaii.edu
FU NASA [NNX14AM74G]; NSF [AST1413736, AST1617015]; ESO programme [2100.C-5008(A)]; Gemini Observatory [GS-2017B-DD-7]; W. M. Keck Foundation; Direct For Mathematical & Physical Scien [1617015] Funding Source: National Science Foundation; Division Of Astronomical Sciences [1617015] Funding Source: National Science Foundation
NR 31
TC 320
Z9 358
U1 0
U2 55
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 21
PY 2017
VL 552
IS 7685
BP 378
EP +
DI 10.1038/nature25020
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ7RI
UT WOS:000418559800053
PM 29160305
DA 2026-03-09
ER

PT J
AU Suga, M
   Akita, F
   Sugahara, M
   Kubo, M
   Nakajima, Y
   Nakane, T
   Yamashita, K
   Umena, Y
   Nakabayashi, M
   Yamane, T
   Nakano, T
   Suzuki, M
   Masuda, T
   Inoue, S
   Kimura, T
   Nomura, T
   Yonekura, S
   Yu, LJ
   Sakamoto, T
   Motomura, T
   Chen, JH
   Kato, Y
   Noguchi, T
   Tono, K
   Joti, Y
   Kameshima, T
   Hatsui, T
   Nango, E
   Tanaka, R
   Naitow, H
   Matsuura, Y
   Yamashita, A
   Yamamoto, M
   Nureki, O
   Yabashi, M
   Ishikawa, T
   Iwata, S
   Shen, JR
AF Suga, Michihiro
   Akita, Fusamichi
   Sugahara, Michihiro
   Kubo, Minoru
   Nakajima, Yoshiki
   Nakane, Takanori
   Yamashita, Keitaro
   Umena, Yasufumi
   Nakabayashi, Makoto
   Yamane, Takahiro
   Nakano, Takamitsu
   Suzuki, Mamoru
   Masuda, Tetsuya
   Inoue, Shigeyuki
   Kimura, Tetsunari
   Nomura, Takashi
   Yonekura, Shinichiro
   Yu, Long-Jiang
   Sakamoto, Tomohiro
   Motomura, Taiki
   Chen, Jing-Hua
   Kato, Yuki
   Noguchi, Takumi
   Tono, Kensuke
   Joti, Yasumasa
   Kameshima, Takashi
   Hatsui, Takaki
   Nango, Eriko
   Tanaka, Rie
   Naitow, Hisashi
   Matsuura, Yoshinori
   Yamashita, Ayumi
   Yamamoto, Masaki
   Nureki, Osamu
   Yabashi, Makina
   Ishikawa, Tetsuya
   Iwata, So
   Shen, Jian-Ren
TI Light-induced structural changes and the site of O=O bond formation in PSII caught by XFEL
SO NATURE
LA English
DT Article
ID oxygen-evolving complex; x-ray-diffraction; photosynthetic water oxidation; photosystem-ii; infrared detection; oxidizing complex; proton release; mechanism; state; binding
AB Photosystem II (PSII) is a huge membrane-protein complex consisting of 20 different subunits with a total molecular mass of 350 kDa for a monomer. It catalyses light-driven water oxidation at its catalytic centre, the oxygen-evolving complex (OEC)(1-3). The structure of PSII has been analysed at 1.9 angstrom resolution by synchrotron radiation X-rays, which revealed that the OEC is a Mn4CaO5 cluster organized in an asymmetric, `distorted-chair' form(4). This structure was further analysed with femtosecond X-ray free electron lasers (XFEL), providing the `radiation damage-free'(5) structure. The mechanism of O=O bond formation, however, remains obscure owing to the lack of intermediate-state structures. Here we describe the structural changes in PSII induced by two-flash illumination at room temperature at a resolution of 2.35 angstrom using time-resolved serial femtosecond crystallography with an XFEL provided by the SPring-8 angstrom compact free-electron laser. An isomorphous difference Fourier map between the two-flash and dark-adapted states revealed two areas of apparent changes: around the QB/non-haem iron and the Mn4CaO5 cluster. The changes around the QB/non-haem iron region reflected the electron and proton transfers induced by the two-flash illumination. In the region around the OEC, a water molecule located 3.5 angstrom from the Mn4CaO5 cluster disappeared from the map upon two-flash illumination. This reduced the distance between another water molecule and the oxygen atom O4, suggesting that proton transfer also occurred. Importantly, the two-flash-minus-dark isomorphous difference Fourier map showed an apparent positive peak around O5, a unique mu 4-oxo-bridge located in the quasi-centre of Mn1 and Mn4 (refs 4,5). This suggests the insertion of a new oxygen atom (O6) close to O5, providing an O=O distance of 1.5 angstrom between these two oxygen atoms. This provides a mechanism for the O=O bond formation consistent with that proposed previously(6,7.)
C1 [Suga, Michihiro; Akita, Fusamichi; Nakajima, Yoshiki; Umena, Yasufumi; Nakabayashi, Makoto; Yamane, Takahiro; Nakano, Takamitsu; Yonekura, Shinichiro; Yu, Long-Jiang; Sakamoto, Tomohiro; Motomura, Taiki; Chen, Jing-Hua; Shen, Jian-Ren] Okayama Univ, Res Inst Interdisciplinary Sci, 3-1-1 Tsushima Naka, Okayama 7008530, Japan.
   [Suga, Michihiro; Akita, Fusamichi; Nakajima, Yoshiki; Umena, Yasufumi; Nakabayashi, Makoto; Yamane, Takahiro; Nakano, Takamitsu; Yonekura, Shinichiro; Yu, Long-Jiang; Sakamoto, Tomohiro; Motomura, Taiki; Chen, Jing-Hua; Iwata, So; Shen, Jian-Ren] Okayama Univ, Grad Sch Nat Sci & Technol, 3-1-1 Tsushima Naka, Okayama 7008530, Japan.
   [Akita, Fusamichi; Kubo, Minoru] Japan Sci & Technol Agcy, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 3320012, Japan.
   [Sugahara, Michihiro; Kubo, Minoru; Yamashita, Keitaro; Suzuki, Mamoru; Masuda, Tetsuya; Inoue, Shigeyuki; Kimura, Tetsunari; Nomura, Takashi; Hatsui, Takaki; Nango, Eriko; Tanaka, Rie; Naitow, Hisashi; Matsuura, Yoshinori; Yamashita, Ayumi; Yamamoto, Masaki; Yabashi, Makina; Ishikawa, Tetsuya; Iwata, So] RIKEN, SPring Ctr 8, 1-1-1 Kouto,Sayo Cho, Mikazuki, Hyogo 6795148, Japan.
   [Nakane, Takanori; Nureki, Osamu] Univ Tokyo, Grad Sch Sci, Dept Biol Sci, Bunkyo Ku, 2-11-16 Yayoi, Tokyo 1130032, Japan.
   [Suzuki, Mamoru] Osaka Univ, Inst Prot Res, Suita, Osaka 5650871, Japan.
   [Masuda, Tetsuya] Kyoto Univ, Grad Sch Agr, Div Food Sci & Biotechnol, Uji, Kyoto 6110011, Japan.
   [Inoue, Shigeyuki] Univ Tokyo, Grad Sch Med, Dept Cell Biol & Anat, Bunkyo Ku, Hongo, Tokyo 1130033, Japan.
   [Kimura, Tetsunari] Kobe Univ, Grad Sch Sci, Dept Chem, Nada Ku, 1-1 Rokkodai, Kobe, Hyogo 6578501, Japan.
   [Motomura, Taiki; Shen, Jian-Ren] Univ Hyogo, Grad Sch Life Sci, Dept Picobiol, 3-2-1 Kouto,Kamigori Cho, Kobe, Hyogo 6781297, Japan.
   [Chen, Jing-Hua; Shen, Jian-Ren] Chinese Acad Sci, Inst Bot, Key Lab Photobiol, 20 Nanxincun, Beijing 100093, Peoples R China.
   [Kato, Yuki; Noguchi, Takumi] Nagoya Univ, Grad Sch Sci, Div Mat Sci, Chikusa Ku, Furo Cho, Nagoya, Aichi 4648602, Japan.
   [Tono, Kensuke; Joti, Yasumasa] Japan Synchrotron Radiat Res Inst, 1-1-1 Kouto, Sayo, Hyogo 6795198, Japan.
   [Nango, Eriko] Kyoto Univ, Grad Sch Med, Dept Cell Biol, Sakyo Ku, Yoshidakonoe Cho, Kyoto 6068501, Japan.
C3 Okayama University; Okayama University; Japan Science & Technology Agency (JST); RIKEN; University of Tokyo; University of Osaka; Kyoto University; University of Tokyo; Kobe University; University of Hyogo; Chinese Academy of Sciences; Institute of Botany, CAS; Nagoya University; Japan Synchrotron Radiation Research Institute; Kyoto University
RP Suga, M (corresponding author), Okayama Univ, Res Inst Interdisciplinary Sci, 3-1-1 Tsushima Naka, Okayama 7008530, Japan.
EM s.iwata@mfour.med.kyoto-u.ac.jp; shen@cc.okayama-u.ac.jp
FU Okayama University; JSPS KAKENHI [JP15H01642, JP16H06162, JP16H06296, JP16K21181, JP15H05588, JP15H03841, JP15H01055, JP24000018]; MEXT, Japan; Asahi Glass Foundation; Kato Memorial Bioscience Foundation; Inamori Foundation; Japan Science and Technology agency (JST); PRESTO from JST; Pioneering Project 'Dynamic Structural Biology' of RIKEN; CAS [XDB17030100]; Grants-in-Aid for Scientific Research [15H01642, 26440028, 16H06162, 15H03841, 24000018, 24107003, 15H05476, 15H05588, 17H03662, 15H01055, 17H06435, 16KT0058] Funding Source: KAKEN
NR 45
TC 521
Z9 581
U1 2
U2 503
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 2
PY 2017
VL 543
IS 7643
BP 131
EP +
DI 10.1038/nature21400
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0AA
UT WOS:000395671500047
PM 28219079
DA 2026-03-09
ER

PT J
AU Tian, L
   Goldstein, A
   Wang, H
   Lo, HC
   Kim, IS
   Welte, T
   Sheng, KW
   Dobrolecki, LE
   Zhang, XM
   Utluri, NP
   Hung, TLP
   Mani, SA
   Stossi, F
   Sreekumar, A
   Mancini, MA
   Decker, WK
   Zong, CH
   Lewis, MT
   Zhang, XHF
AF Tian, Lin
   Goldstein, Amit
   Wang, Hai
   Lo, Hin Ching
   Kim, Ik Sun
   Welte, Thomas
   Sheng, Kuanwei
   Dobrolecki, Lacey E.
   Zhang, Xiaomei
   Utluri, Nagireddy P.
   Hung, Thuy L. P.
   Mani, Sendurai A.
   Stossi, Fabio
   Sreekumar, Arun
   Mancini, Michael A.
   Decker, William K.
   Zong, Chenghang
   Lewis, Michael T.
   Zhang, Xiang H. -F.
TI Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming
SO NATURE
LA English
DT Article
ID t-cells; expression; angiogenesis; inhibition; therapy; reveals
AB Blockade of angiogenesis can retard tumour growth, but may also paradoxically increase metastasis(1,2). This paradox may be resolved by vessel normalization(3), which involves increased pericyte coverage, improved tumour vessel perfusion, reduced vascular permeability, and consequently mitigated hypoxia3. Although these processes alter tumour progression, their regulation is poorly understood. Here we show that type 1 T helper (T(H)1) cells play a crucial role in vessel normalization. Bioinformatic analyses revealed that gene expression features related to vessel normalization correlate with immunostimulatory pathways, especially T lymphocyte infiltration or activity. To delineate the causal relationship, we used various mouse models with vessel normalization or T lymphocyte deficiencies. Although disruption of vessel normalization reduced T lymphocyte infiltration as expected(4), reciprocal depletion or inactivation of CD4+ T lymphocytes decreased vessel normalization, indicating a mutually regulatory loop. In addition, activation of CD4+ T lymphocytes by immune checkpoint blockade increased vessel normalization. TH1 cells that secrete interferon-gamma are a major population of cells associated with vessel normalization. Patient-derived xenograft tumours growing in immunodeficient mice exhibited enhanced hypoxia compared to the original tumours in immunocompetent humans, and hypoxia was reduced by adoptive TH1 transfer. Our findings elucidate an unexpected role of TH1 cells in vasculature and immune reprogramming. TH1 cells may be a marker and a determinant of both immune checkpoint blockade and anti-angiogenesis efficacy.
C1 [Tian, Lin; Goldstein, Amit; Wang, Hai; Lo, Hin Ching; Kim, Ik Sun; Welte, Thomas; Dobrolecki, Lacey E.; Zhang, Xiaomei; Lewis, Michael T.; Zhang, Xiang H. -F.] Baylor Coll Med, Lester & Sue Smith Breast Ctr, One Baylor Plaza, Houston, TX 77030 USA.
   [Tian, Lin; Goldstein, Amit; Wang, Hai; Lo, Hin Ching; Kim, Ik Sun; Welte, Thomas; Utluri, Nagireddy P.; Stossi, Fabio; Sreekumar, Arun; Mancini, Michael A.; Decker, William K.; Zong, Chenghang; Lewis, Michael T.; Zhang, Xiang H. -F.] Baylor Coll Med, Dan L Duncan Canc Ctr, One Baylor Plaza, Houston, TX 77030 USA.
   [Tian, Lin; Utluri, Nagireddy P.; Sreekumar, Arun] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, One Baylor Plaza, Houston, TX 77030 USA.
   [Goldstein, Amit; Wang, Hai; Welte, Thomas; Utluri, Nagireddy P.; Stossi, Fabio; Sreekumar, Arun; Mancini, Michael A.; Lewis, Michael T.; Zhang, Xiang H. -F.] Baylor Coll Med, Dept Mol & Cellular Biol, One Baylor Plaza, Houston, TX 77030 USA.
   [Lo, Hin Ching; Kim, Ik Sun; Sheng, Kuanwei; Zong, Chenghang] Baylor Coll Med, Grad Program Integrat Mol & Biomed Sci, One Baylor Plaza, Houston, TX 77030 USA.
   [Sheng, Kuanwei; Zong, Chenghang] Baylor Coll Med, Dept Mol & Human Genet, One Baylor Plaza, Houston, TX 77030 USA.
   [Hung, Thuy L. P.; Decker, William K.] Baylor Coll Med, Dept Pathol & Immunol, One Baylor Plaza, Houston, TX 77030 USA.
   [Mani, Sendurai A.] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, 2130 West Holcombe Blvd, Houston, TX 77030 USA.
   [Decker, William K.] Baylor Coll Med, Ctr Cell & Gene Therapy, One Baylor Plaza, Houston, TX 77030 USA.
   [Zong, Chenghang; Zhang, Xiang H. -F.] Baylor Coll Med, McNair Med Inst, One Baylor Plaza, Houston, TX 77030 USA.
C3 Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; University of Texas System; UTMD Anderson Cancer Center; Baylor College of Medicine; Baylor College Medical Hospital; Baylor College of Medicine
RP Zhang, XHF (corresponding author), Baylor Coll Med, Lester & Sue Smith Breast Ctr, One Baylor Plaza, Houston, TX 77030 USA.; Zhang, XHF (corresponding author), Baylor Coll Med, Dan L Duncan Canc Ctr, One Baylor Plaza, Houston, TX 77030 USA.; Zhang, XHF (corresponding author), Baylor Coll Med, Dept Mol & Cellular Biol, One Baylor Plaza, Houston, TX 77030 USA.; Zhang, XHF (corresponding author), Baylor Coll Med, McNair Med Inst, One Baylor Plaza, Houston, TX 77030 USA.
EM xiangz@bcm.edu
FU Breast Cancer Research Foundation; NCI [CA183878, 2P30CA125123-09]; DoD [W81XWH-16-1-0073]; SGK [CCR14298445]; McNair Medical Institute; CPRIT Core Facility Support Award [RP120092]; NIH [1S10OD016167]; National Cancer Institute [R01CA220297, R01CA183878, P30CA125123] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK056338] Funding Source: NIH RePORTER
NR 36
TC 668
Z9 738
U1 3
U2 245
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 13
PY 2017
VL 544
IS 7649
BP 250
EP +
DI 10.1038/nature21724
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ER6EK
UT WOS:000398897900041
PM 28371798
DA 2026-03-09
ER

PT J
AU Du, ZH
   Zheng, H
   Huang, B
   Ma, R
   Wu, JY
   Zhang, XL
   He, J
   Xiang, YL
   Wang, QJ
   Li, YY
   Ma, J
   Zhang, X
   Zhang, K
   Wang, Y
   Zhang, MQ
   Gao, JT
   Dixon, JR
   Wang, XW
   Zeng, JY
   Xie, W
AF Du, Zhenhai
   Zheng, Hui
   Huang, Bo
   Ma, Rui
   Wu, Jingyi
   Zhang, Xianglin
   He, Jing
   Xiang, Yunlong
   Wang, Qiujun
   Li, Yuanyuan
   Ma, Jing
   Zhang, Xu
   Zhang, Ke
   Wang, Yang
   Zhang, Michael Q.
   Gao, Juntao
   Dixon, Jesse R.
   Wang, Xiaowo
   Zeng, Jianyang
   Xie, Wei
TI Allelic reprogramming of 3D chromatin architecture during early mammalian development
SO NATURE
LA English
DT Article
ID rna-seq; preimplantation embryos; zygotic transition; human genome; reveals; organization; chromosome; reorganization; transcription; expression
AB In mammals, chromatin organization undergoes drastic reprogramming after fertilization(1). However, the three-dimensional structure of chromatin and its reprogramming in preimplantation development remain poorly understood. Here, by developing a low-input Hi-C (genome-wide chromosome conformation capture) approach, we examined the reprogramming of chromatin organization during early development in mice. We found that oocytes in metaphase II show homogeneous chromatin folding that lacks detectable topologically associating domains (TADs) and chromatin compartments. Strikingly, chromatin shows greatly diminished higher-order structure after fertilization. Unexpectedly, the subsequent establishment of chromatin organization is a prolonged process that extends through preimplantation development, as characterized by slow consolidation of TADs and segregation of chromatin compartments. The two sets of parental chromosomes are spatially separated from each other and display distinct compartmentalization in zygotes. Such allele separation and allelic compartmentalization can be found as late as the 8-cell stage. Finally, we show that chromatin compaction in preimplantation embryos can partially proceed in the absence of zygotic transcription and is a multi-level hierarchical process. Taken together, our data suggest that chromatin may exist in a markedly relaxed state after fertilization, followed by progressive maturation of higher-order chromatin architecture during early development.
C1 [Du, Zhenhai; Zheng, Hui; Wu, Jingyi; He, Jing; Xiang, Yunlong; Wang, Qiujun; Li, Yuanyuan; Ma, Jing; Zhang, Ke; Xie, Wei] Tsinghua Univ, Ctr Stem Cell Biol & Regenerat Med, MOE Key Lab Bioinformat, THU PKU Ctr Life Sci,Sch Life Sci, Beijing 100084, Peoples R China.
   [Huang, Bo] Peking Univ, Acad Adv Interdisciplinary Studies, PKU THU Ctr Life Sci, Beijing 100871, Peoples R China.
   [Ma, Rui; Zeng, Jianyang] Tsinghua Univ, Inst Interdisciplinary Informat Sci, Beijing 100084, Peoples R China.
   [Wu, Jingyi; Xie, Wei] Tsinghua Univ, Sch Life Sci, Joint Grad Program Peking Tsinghua NIBS, Beijing 100084, Peoples R China.
   [Zhang, Xianglin; Zhang, Xu; Wang, Yang; Zhang, Michael Q.; Gao, Juntao; Wang, Xiaowo] Tsinghua Univ, MOE Key Lab Bioinformat, Beijing 100084, Peoples R China.
   [Zhang, Xianglin; Zhang, Xu; Wang, Yang; Zhang, Michael Q.; Gao, Juntao; Wang, Xiaowo] Tsinghua Univ, Bioinformat Div, TNLIST, Beijing 100084, Peoples R China.
   [Zhang, Xianglin; Zhang, Xu; Wang, Yang; Zhang, Michael Q.; Gao, Juntao; Wang, Xiaowo] Tsinghua Univ, Ctr Synthet & Syst Biol, Beijing 100084, Peoples R China.
   [Gao, Juntao] Univ Texas Dallas, Ctr Syst Biol, Dept Biol Sci, 800 West Campbell Rd,RL11, Richardson, TX 75080 USA.
   [Dixon, Jesse R.] Salk Inst Biol Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA.
C3 Tsinghua University; Peking University; Tsinghua University; National Institute of Biological Sciences, Beijing; Tsinghua University; Tsinghua University; Tsinghua University; Tsinghua University; University of Texas System; University of Texas Dallas; Salk Institute
RP Xie, W (corresponding author), Tsinghua Univ, Ctr Stem Cell Biol & Regenerat Med, MOE Key Lab Bioinformat, THU PKU Ctr Life Sci,Sch Life Sci, Beijing 100084, Peoples R China.; Xie, W (corresponding author), Tsinghua Univ, Sch Life Sci, Joint Grad Program Peking Tsinghua NIBS, Beijing 100084, Peoples R China.
EM xiewei121@tsinghua.edu.cn
FU National Key R&D Program of China [2016YFC0900301]; National Basic Research Program of China [2015CB856201, 2012CB316503]; National Natural Science Foundation of China [31422031, 61472205, 31371341, 31361163004, 31671383, 91519326, 31671384, 91329000]; THU-PKU Center for Life Sciences; Youth Thousand Scholar Program of China; State Key Research Development Program of China [2016YFC1200303]; TNLIST Cross-discipline Foundation; NIH [MH102616]; Beijing Advanced Innovation Center for Structural Biology
NR 30
TC 414
Z9 483
U1 5
U2 161
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 13
PY 2017
VL 547
IS 7662
BP 232
EP +
DI 10.1038/nature23263
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FA3AX
UT WOS:000405314500042
PM 28703188
DA 2026-03-09
ER

PT J
AU Hsu, JY
   Crawley, S
   Chen, M
   Ayupova, DA
   Lindhout, DA
   Higbee, J
   Kutach, A
   Joo, W
   Gao, ZY
   Fu, DN
   To, C
   Mondal, K
   Li, B
   Kekatpure, A
   Wang, M
   Laird, T
   Horner, G
   Chan, J
   McEntee, M
   Lopez, M
   Lakshminarasimhan, D
   White, A
   Wang, SP
   Yao, J
   Yie, JM
   Matern, H
   Solloway, M
   Haldankar, R
   Parsons, T
   Tang, J
   Shen, WD
   Chen, YA
   Ian, HT
   Allan, BB
AF Hsu, Jer-Yuan
   Crawley, Suzanne
   Chen, Michael
   Ayupova, Dina A.
   Lindhout, Darrin A.
   Higbee, Jared
   Kutach, Alan
   Joo, William
   Gao, Zhengyu
   Fu, Diana
   To, Carmen
   Mondal, Kalyani
   Li, Betty
   Kekatpure, Avantika
   Wang, Marilyn
   Laird, Teresa
   Horner, Geoffrey
   Chan, Jackie
   McEntee, Michele
   Lopez, Manuel
   Lakshminarasimhan, Damodharan
   White, Andre
   Wang, Sheng-Ping
   Yao, Jun
   Yie, Junming
   Matern, Hugo
   Solloway, Mark
   Haldankar, Raj
   Parsons, Thomas
   Tang, Jie
   Shen, Wenyan D.
   Chen, Yu Alice
   Ian, Hui T.
   Allan, Bernard B. .
TI Non - homeostatic body weight regulation through a brainstem-restricted receptor for GDF15
SO NATURE
LA English
DT Article
ID parabrachial nucleus; induced anorexia; anomalous signal; gene-expression; tyrosine kinase; cgrp neurons; food-intake; ret; gdnf; activation
AB Under homeostatic conditions, animals use well-defined hypothalamic neural circuits to help maintain stable body weight, by integrating metabolic and hormonal signals from the periphery to balance food consumption and energy expenditure(1,2). In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand(3). Recent studies have identified brain areas outside the hypothalamus that are activated under these 'non-homeostatic' conditions(4-6), but the molecular nature of the peripheral signals and brain-localized receptors that activate these circuits remains elusive. Here we identify glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as a brainstem-restricted receptor for growth and differentiation factor 15 (GDF15). GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the 'emergency circuit' that shapes feeding responses to stressful conditions(7). GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases(8,9). By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, we identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress. These findings provide opportunities to develop therapeutic agents for the treatment of disorders with altered energy demand.
C1 [Hsu, Jer-Yuan; Crawley, Suzanne; Chen, Michael; Ayupova, Dina A.; Lindhout, Darrin A.; Higbee, Jared; Kutach, Alan; Joo, William; Gao, Zhengyu; Fu, Diana; To, Carmen; Mondal, Kalyani; Li, Betty; Kekatpure, Avantika; Wang, Marilyn; Laird, Teresa; Horner, Geoffrey; Chan, Jackie; McEntee, Michele; Lopez, Manuel; Matern, Hugo; Solloway, Mark; Haldankar, Raj; Parsons, Thomas; Tang, Jie; Shen, Wenyan D.; Chen, Yu Alice; Ian, Hui T.; Allan, Bernard B. .] NGM Biopharmaceut, San Francisco, CA 94080 USA.
   [Lakshminarasimhan, Damodharan; White, Andre] XTAL Biostruct, 12 Michigan Dr, Natick, MA 01760 USA.
   [Wang, Sheng-Ping; Yao, Jun] Merck Res Labs, Kenilworth, NJ 07033 USA.
   [Joo, William] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA.
   [Lopez, Manuel] BioMarin Pharmaceut Inc, San Rafael, CA 94901 USA.
   [Chen, Yu Alice] 23andMe Inc, San Francisco, CA 94080 USA.
C3 Merck & Company; Harvard University; BioMarin Pharmaceutical Inc.; 23andMe, Inc.
RP Hsu, JY; Allan, BB (corresponding author), NGM Biopharmaceut, San Francisco, CA 94080 USA.
EM ahsu@ngmbio.com; ballan@ngmbio.com
NR 40
TC 488
Z9 560
U1 3
U2 70
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 12
PY 2017
VL 550
IS 7675
BP 255
EP +
DI 10.1038/nature24042
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FJ5YG
UT WOS:000412829500048
PM 28953886
DA 2026-03-09
ER

PT J
AU Cardoso, V
   Chesné, J
   Ribeiro, H
   García-Cassani, B
   Carvalho, T
   Bouchery, T
   Shah, K
   Barbosa-Morais, NL
   Harris, N
   Veiga-Fernandes, H
AF Cardoso, Vania
   Chesne, Julie
   Ribeiro, Helder
   Garcia-Cassani, Bethania
   Carvalho, Tania
   Bouchery, Tiffany
   Shah, Kathleen
   Barbosa-Morais, Nuno L.
   Harris, Nicola
   Veiga-Fernandes, Henrique
TI Neuronal regulation of type 2 innate lymphoid cells via neuromedin U
SO NATURE
LA English
DT Article
ID immune interactions; receptor ret; identification; immunoreactivity; expression; intestine; tyrosine; tract; brain; gene
AB Group 2 innate lymphoid cells (ILC2s) regulate inflammation, tissue repair and metabolic homeostasis(1), and are activated by host-derived cytokines and alarmins(1). Discrete subsets of immune cells integrate nervous system cues(2-4), but it remains unclear whether neuron-derived signals control ILC2s. Here we show that neuromedin U (NMU) in mice is a fast and potent regulator of type 2 innate immunity in the context of a functional neuron-ILC2 unit. We found that ILC2s selectively express neuromedin U receptor 1 (Nmur1), and mucosal neurons express NMU. Cell-autonomous activation of ILC2s with NMU resulted in immediate and strong NMUR1-dependent production of innate inflammatory and tissue repair cytokines. NMU controls ILC2s downstream of extracellular signal-regulated kinase and calcium-influx-dependent activation of both calcineurin and nuclear factor of activated T cells (NFAT). NMU treatment in vivo resulted in immediate protective type 2 responses. Accordingly, ILC2-autonomous ablation of Nmur1 led to impaired type 2 responses and poor control of worm infection. Notably, mucosal neurons were found adjacent to ILC2s, and these neurons directly sensed worm products and alarmins to induce NMU and to control innate type 2 cytokines. Our work reveals that neuron-ILC2 cell units confer immediate tissue protection through coordinated neuroimmune sensory responses.
C1 [Cardoso, Vania; Chesne, Julie; Ribeiro, Helder; Garcia-Cassani, Bethania; Carvalho, Tania; Barbosa-Morais, Nuno L.; Veiga-Fernandes, Henrique] Univ Lisbon, Fac Med Lisboa, Inst Med Mol, Ave Prof Egas Moniz,Edificio Egas Moniz, P-1649028 Lisbon, Portugal.
   [Cardoso, Vania; Chesne, Julie; Ribeiro, Helder; Garcia-Cassani, Bethania; Veiga-Fernandes, Henrique] Champalimaud Res, Champalimaud Ctr Unknown, P-1400038 Lisbon, Portugal.
   [Bouchery, Tiffany; Shah, Kathleen; Harris, Nicola] Ecole Polytech Fed Lausanne, Global Hlth Inst, CH-1015 Lausanne, Switzerland.
C3 Universidade de Lisboa; Instituto Superior de Ciencias da Saude Egas Moniz; Fundacao Champalimaud; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne
RP Veiga-Fernandes, H (corresponding author), Univ Lisbon, Fac Med Lisboa, Inst Med Mol, Ave Prof Egas Moniz,Edificio Egas Moniz, P-1649028 Lisbon, Portugal.; Veiga-Fernandes, H (corresponding author), Champalimaud Res, Champalimaud Ctr Unknown, P-1400038 Lisbon, Portugal.
EM henrique.veigafernandes@research.fchampalimaud.org
FU Fundacao para a Ciencia e Tecnologia (FCT), Portugal; Fondation pour la Recherche Medicale (FRM), France; Marie Sklodowska-Curie fellowship, EU [750030]; FP7, EU [289720]; FCT, Portugal; European Molecular Biology Organisation (EMBO); Swiss National Science Foundation [310030_156517]; ERC, EU [647274]; Kenneth Rainin Foundation, USA; Crohn's and Colitis Foundation of America, USA; Marie Curie Actions (MSCA) [750030] Funding Source: Marie Curie Actions (MSCA); European Research Council (ERC) [647274] Funding Source: European Research Council (ERC); Swiss National Science Foundation (SNF) [310030_156517] Funding Source: Swiss National Science Foundation (SNF)
NR 43
TC 478
Z9 544
U1 5
U2 68
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 14
PY 2017
VL 549
IS 7671
BP 277
EP +
DI 10.1038/nature23469
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG7AE
UT WOS:000410555900047
PM 28869974
DA 2026-03-09
ER

PT J
AU Wartewig, T
   Kurgyis, Z
   Keppler, S
   Pechloff, K
   Hameister, E
   Öllinger, R
   Maresch, R
   Buch, T
   Steiger, K
   Winter, C
   Rad, R
   Ruland, J
AF Wartewig, Tim
   Kurgyis, Zsuzsanna
   Keppler, Selina
   Pechloff, Konstanze
   Hameister, Erik
   Oellinger, Rupert
   Maresch, Roman
   Buch, Thorsten
   Steiger, Katja
   Winter, Christof
   Rad, Roland
   Ruland, Juergen
TI PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis
SO NATURE
LA English
DT Article
ID cancer gene discovery; expression; identification; transcriptome; mutagenesis; memory; tool; syk; itk
AB T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes(1). T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules(1-4). Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events. Here we show that the acute enforcement of oncogenic TCR signalling in lymphocytes in a mouse model of human T cell lymphoma drives the strong expansion of these cells in vivo. However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genome-wide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1, which encodes the inhibitory receptor programmed death-1 (PD-1), as a master gene that suppresses oncogenic T cell signalling. Mono-and bi-allelic deletions of PDCD1 are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, the activity of PD-1 enhances levels of the tumour suppressor PTEN and attenuates signalling by the kinases AKT and PKC in pre-malignant cells. By contrast, a homo-or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Thus, the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T cell lymphomas that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation, and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immunooncology.
C1 [Wartewig, Tim; Kurgyis, Zsuzsanna; Keppler, Selina; Pechloff, Konstanze; Hameister, Erik; Winter, Christof; Ruland, Juergen] Tech Univ Munich, Inst Klin Chem & Pathobiochem, Klinikum Rechts Isar, D-81675 Munich, Germany.
   [Wartewig, Tim; Kurgyis, Zsuzsanna; Keppler, Selina; Pechloff, Konstanze; Hameister, Erik; Oellinger, Rupert; Maresch, Roman; Winter, Christof; Rad, Roland; Ruland, Juergen] Tech Univ Munich, Ctr Translat Canc Res, TranslaTUM, D-81675 Munich, Germany.
   [Pechloff, Konstanze; Winter, Christof; Rad, Roland; Ruland, Juergen] German Canc Consortium DKTK, D-69120 Heidelberg, Germany.
   [Oellinger, Rupert; Maresch, Roman; Rad, Roland] Tech Univ Munich, Klinikum Rechts Isar, Dept Med 2, D-81675 Munich, Germany.
   [Buch, Thorsten] Univ Zurich, Inst Lab Anim Sci, Zurich, Switzerland.
   [Steiger, Katja] Tech Univ Munich, Inst Pathol, D-81675 Munich, Germany.
   [Ruland, Juergen] German Ctr Infect Res DZIF, Partner Site Munich, Munich, Germany.
C3 Technical University of Munich; Technical University of Munich; Helmholtz Association; German Cancer Research Center (DKFZ); Technical University of Munich; University of Zurich; Technical University of Munich; German Center for Infection Research
RP Ruland, J (corresponding author), Tech Univ Munich, Inst Klin Chem & Pathobiochem, Klinikum Rechts Isar, D-81675 Munich, Germany.; Ruland, J (corresponding author), Tech Univ Munich, Ctr Translat Canc Res, TranslaTUM, D-81675 Munich, Germany.; Ruland, J (corresponding author), German Canc Consortium DKTK, D-69120 Heidelberg, Germany.; Ruland, J (corresponding author), German Ctr Infect Res DZIF, Partner Site Munich, Munich, Germany.
EM j.ruland@tum.de
FU DFG [SFB 1054/B01, RU 695/6-1]; ERC (FP7) [322865]
NR 41
TC 212
Z9 239
U1 1
U2 30
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 7
PY 2017
VL 552
IS 7683
BP 121
EP +
DI 10.1038/nature24649
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FP4BA
UT WOS:000417560500055
PM 29143824
DA 2026-03-09
ER

PT J
AU Ahmadi, M
   Alves, BXR
   Baker, CJ
   Bertsche, W
   Butler, E
   Capra, A
   Carruth, C
   Cesar, CL
   Charlton, M
   Cohen, S
   Collister, R
   Eriksson, S
   Evans, A
   Evetts, N
   Fajans, J
   Friesen, T
   Fujiwara, MC
   Gill, DR
   Gutierrez, A
   Hangst, JS
   Hardy, WN
   Hayden, ME
   Isaac, CA
   Ishida, A
   Johnson, MA
   Jones, SA
   Jonsell, S
   Kurchaninov, L
   Madsen, N
   Mathers, M
   Maxwell, D
   McKenna, JTK
   Menary, S
   Michan, JM
   Momose, T
   Munich, JJ
   Nolan, P
   Olchanski, K
   Olin, A
   Pusa, P
   Rasmussen, CO
   Robicheaux, F
   Sacramento, RL
   Sameed, M
   Sarid, E
   Silveira, DM
   Stracka, S
   Stutter, G
   So, C
   Tharp, TD
   Thompson, JE
   Thompson, RI
   Van der Werf, DP
   Wurtele, JS
AF Ahmadi, M.
   Alves, B. X. R.
   Baker, C. J.
   Bertsche, W.
   Butler, E.
   Capra, A.
   Carruth, C.
   Cesar, C. L.
   Charlton, M.
   Cohen, S.
   Collister, R.
   Eriksson, S.
   Evans, A.
   Evetts, N.
   Fajans, J.
   Friesen, T.
   Fujiwara, M. C.
   Gill, D. R.
   Gutierrez, A.
   Hangst, J. S.
   Hardy, W. N.
   Hayden, M. E.
   Isaac, C. A.
   Ishida, A.
   Johnson, M. A.
   Jones, S. A.
   Jonsell, S.
   Kurchaninov, L.
   Madsen, N.
   Mathers, M.
   Maxwell, D.
   McKenna, J. T. K.
   Menary, S.
   Michan, J. M.
   Momose, T.
   Munich, J. J.
   Nolan, P.
   Olchanski, K.
   Olin, A.
   Pusa, P.
   Rasmussen, C. O.
   Robicheaux, F.
   Sacramento, R. L.
   Sameed, M.
   Sarid, E.
   Silveira, D. M.
   Stracka, S.
   Stutter, G.
   So, C.
   Tharp, T. D.
   Thompson, J. E.
   Thompson, R. I.
   Van der Werf, D. P.
   Wurtele, J. S.
TI Observation of the hyperfine spectrum of antihydrogen
SO NATURE
LA English
DT Article
ID trapped antihydrogen; magnetic-moment; atomic-hydrogen; deuterium; maser
AB The observation of hyperfine structure in atomic hydrogen by Rabi and co-workers(1-3) and the measurement(4) of the zero-field ground-state splitting at the level of seven parts in 10(13) are important achievements of mid-twentieth-century physics. The work that led to these achievements also provided the first evidence for the anomalous magnetic moment of the electron(5-8), inspired Schwinger's relativistic theory of quantum electrodynamics(9,10) and gave rise to the hydrogen maser(11), which is a critical component of modern navigation, geo-positioning and very-long-baseline interferometry systems. Research at the Antiproton Decelerator at CERN by the ALPHA collaboration extends these enquiries into the antimatter sector. Recently, tools have been developed that enable studies of the hyperfine structure of antihydrogen(12)-the antimatter counterpart of hydrogen. The goal of such studies is to search for any differences that might exist between this archetypal pair of atoms, and thereby to test the fundamental principles on which quantum field theory is constructed. Magnetic trapping of antihydrogen atoms(13,14) provides a means of studying them by combining electromagnetic interaction with detection techniques that are unique to antimatter(12,15). Here we report the results of a microwave spectroscopy experiment in which we probe the response of antihydrogen over a controlled range of frequencies. The data reveal clear and distinct signatures of two allowed transitions, from which we obtain a direct, magnetic-field-independent measurement of the hyperfine splitting. From a set of trials involving 194 detected atoms, we determine a splitting of 1,420.4 +/- 0.5 megahertz, consistent with expectations for atomic hydrogen at the level of four parts in 10(4). This observation of the detailed behaviour of a quantum transition in an atom of antihydrogen exemplifies tests of fundamental symmetries such as charge-parity-time in antimatter, and the techniques developed here will enable more-precise such tests.
C1 [Ahmadi, M.; Nolan, P.; Pusa, P.] Univ Liverpool, Dept Phys, Liverpool L69 7ZE, Merseyside, England.
   [Alves, B. X. R.; Friesen, T.; Hangst, J. S.; Rasmussen, C. O.; Stutter, G.] Aarhus Univ, Dept Phys & Astron, DK-8000 Aarhus C, Denmark.
   [Baker, C. J.; Charlton, M.; Eriksson, S.; Isaac, C. A.; Jones, S. A.; Madsen, N.; Maxwell, D.; Sameed, M.; Van der Werf, D. P.] Swansea Univ, Coll Sci, Dept Phys, Swansea SA2 8PP, W Glam, Wales.
   [Bertsche, W.; Johnson, M. A.] Univ Manchester, Sch Phys & Astron, Manchester M12 9PL, Lancs, England.
   [Bertsche, W.; Johnson, M. A.] Sci Tech Daresbury, Cockcroft Inst, Warrington WA4 4AD, Cheshire, England.
   [Butler, E.] CERN, Dept Phys, CH-1211 Geneva 23, Switzerland.
   [Capra, A.; Collister, R.; Fujiwara, M. C.; Gill, D. R.; Kurchaninov, L.; McKenna, J. T. K.; Michan, J. M.; Olchanski, K.; Olin, A.; Stracka, S.] TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada.
   [Carruth, C.; Fajans, J.; Wurtele, J. S.] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Cesar, C. L.; Sacramento, R. L.; Silveira, D. M.] Univ Fed Rio de Janeiro, Inst Fis, BR-21941972 Rio De Janeiro, Brazil.
   [Cohen, S.] Ben Gurion Univ Negev, Dept Phys, IL-84105 Beer Sheva, Israel.
   [Evans, A.; Thompson, R. I.] Univ Calgary, Dept Phys & Astron, Calgary, AB T2N 1N4, Canada.
   [Evetts, N.; Gutierrez, A.; Hardy, W. N.; Momose, T.] Univ British Columbia, Dept Phys & Astron, Vancouver, BC V6T 1Z1, Canada.
   [Gutierrez, A.] UCL, Dept Med Phys & Biomed Engn, London WC1E 6BT, England.
   [Hayden, M. E.; Munich, J. J.] Simon Fraser Univ, Dept Phys, Burnaby, BC V5A 1S6, Canada.
   [Ishida, A.] Univ Tokyo, Dept Phys, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
   [Jonsell, S.] Stockholm Univ, Dept Phys, SE-10691 Stockholm, Sweden.
   [Mathers, M.; Menary, S.; Thompson, J. E.] York Univ, Dept Phys & Astron, Toronto, ON M3J 1P3, Canada.
   [Michan, J. M.] Ecole Polytech Fed Lausanne, Swiss Plasma Ctr, CH-1015 Lausanne, Switzerland.
   [Olin, A.] Univ Victoria, Dept Phys & Astron, Victoria, BC V8P 5C2, Canada.
   [Robicheaux, F.] Purdue Univ, Dept Phys & Astron, W Lafayette, IN 47907 USA.
   [Sarid, E.] Soreq NRC, IL-81800 Yavne, Israel.
   [Stracka, S.] Univ Pisa, Largo Pontecorvo 3, I-56127 Pisa, Italy.
   [Stracka, S.] Sez INFN Pisa, Largo Pontecorvo 3, I-56127 Pisa, Italy.
   [Tharp, T. D.] Marquette Univ, Dept Phys, POB 1881, Milwaukee, WI 53201 USA.
   [Van der Werf, D. P.] CEA Saclay, IRFU, F-91191 Gif Sur Yvette, France.
C3 University of Liverpool; Aarhus University; Swansea University; University of Manchester; STFC Daresbury Laboratory; European Organization for Nuclear Research (CERN); University of Geneva; University of British Columbia; University of California System; University of California Berkeley; Universidade Federal do Rio de Janeiro; Ben-Gurion University of the Negev; University of Calgary; University of British Columbia; University of London; University College London; Simon Fraser University; University of Tokyo; Stockholm University; York University - Canada; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; University of Victoria; Purdue University System; Purdue University; University of Pisa; Istituto Nazionale di Fisica Nucleare (INFN); Marquette University; CEA; Universite Paris Saclay
RP Friesen, T; Hangst, JS (corresponding author), Aarhus Univ, Dept Phys & Astron, DK-8000 Aarhus C, Denmark.; Hayden, ME (corresponding author), Simon Fraser Univ, Dept Phys, Burnaby, BC V5A 1S6, Canada.
EM Tim.Friesen@cern.ch; jeffrey.hangst@cern.ch; mhayden@sfu.ca
FU European Research Council; CNPq (Brazil); FAPERJ (Brazil); RENAFAE (Brazil); NSERC (Canada); NRC/TRIUMF (Canada); EHPDS/EHDRS (Canada); FQRNT (Canada); FNU (NICE Centre) (Denmark); Carlsberg Foundation (Denmark); JSPS Postdoctoral Fellowships for Research Abroad (Japan); ISF (Israel); STFC (UK); EPSRC (UK); Royal Society (UK); Leverhulme Trust (UK); DOE (USA); NSF (USA); VR (Sweden); Division Of Physics; Direct For Mathematical & Physical Scien [1500470] Funding Source: National Science Foundation; Division Of Physics; Direct For Mathematical & Physical Scien [1500538] Funding Source: National Science Foundation; Engineering and Physical Sciences Research Council [EP/P024769/1, EP/E048951/1, EP/P024785/1, EP/L014769/1, 1422853, EP/H02431X/1, EP/D040108/1, EP/K040235/1, EP/L014734/1, EP/K017373/1, EP/H026932/1, EP/P024734/1, EP/L014718/1, EP/F019785/1] Funding Source: researchfish; Science and Technology Facilities Council [ST/P002056/1, 1686188] Funding Source: researchfish; EPSRC [EP/D040108/1, EP/P024785/1, EP/L014718/1, EP/P024734/1, EP/H026932/1, EP/P024769/1, EP/H02431X/1, EP/K017373/1, EP/F019785/1, EP/L014734/1, EP/L014769/1, EP/E048951/1, EP/K040235/1] Funding Source: UKRI; STFC [1686188, ST/P002056/1] Funding Source: UKRI
NR 25
TC 108
Z9 127
U1 0
U2 45
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 3
PY 2017
VL 548
IS 7665
BP 66
EP +
DI 10.1038/nature23446
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FC4SU
UT WOS:000406831700037
PM 28770838
DA 2026-03-09
ER

PT J
AU Melo, FDE
   Kurtova, AV
   Harnoss, JM
   Kljavin, N
   Hoeck, JD
   Hung, J
   Anderson, JE
   Storm, EE
   Modrusan, Z
   Koeppen, H
   Dijkgraaf, GJP
   Piskol, R
   de Sauvage, FJ
AF de Sousa e Melo, Felipe
   Kurtova, Antonina V.
   Harnoss, Jonathan M.
   Kljavin, Noelyn
   Hoeck, Joerg D.
   Hung, Jeffrey
   Anderson, Jeffrey Eastham
   Storm, Elaine E.
   Modrusan, Zora
   Koeppen, Hartmut
   Dijkgraaf, Gerrit J. P.
   Piskol, Robert
   de Sauvage, Frederic J.
TI A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer
SO NATURE
LA English
DT Article
ID colorectal-cancer; intestinal regeneration; chromosomal instability; initiating cells; sequencing data; model; population; expression; identification; tumorigenesis
AB Cancer stem cells (CSCs) have been hypothesized to represent the driving force behind tumour progression and metastasis, making them attractive cancer targets. However, conclusive experimental evidence for their functional relevance is still lacking for most malignancies. Here we show that the leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) identifies intestinal CSCs in mouse tumours engineered to recapitulate the clinical progression of human colorectal cancer. We demonstrate that selective Lgr5(+) cell ablation restricts primary tumour growth, but does not result in tumour regression. Instead, tumours are maintained by proliferative Lgr5-cells that continuously attempt to replenish the Lgr5+ CSC pool, leading to rapid re-initiation of tumour growth upon treatment cessation. Notably, CSCs are critical for the formation and maintenance of liver metastasis derived from colorectal cancers. Together, our data highlight distinct CSC dependencies for primary versus metastasic tumour growth, and suggest that targeting CSCs may represent a therapeutic opportunity for managing metastatic disease.
C1 [de Sousa e Melo, Felipe; Kurtova, Antonina V.; Kljavin, Noelyn; Hoeck, Joerg D.; Storm, Elaine E.; Dijkgraaf, Gerrit J. P.; de Sauvage, Frederic J.] Genentech Inc, Mol Oncol, 1 DNA Way, San Francisco, CA 94080 USA.
   [Harnoss, Jonathan M.] Genentech Inc, Canc Immunol, 1 DNA Way, San Francisco, CA 94080 USA.
   [Hung, Jeffrey; Anderson, Jeffrey Eastham; Koeppen, Hartmut] Genentech Inc, Res Pathol, 1 DNA Way, San Francisco, CA 94080 USA.
   [Modrusan, Zora] Genentech Inc, Mol Biol, 1 DNA Way, San Francisco, CA 94080 USA.
   [Piskol, Robert] Genentech Inc, Bioinformat & Computat Biol, 1 DNA Way, San Francisco, CA 94080 USA.
C3 Roche Holding; Roche Holding USA; Genentech; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Genentech; Roche Holding USA
RP de Sauvage, FJ (corresponding author), Genentech Inc, Mol Oncol, 1 DNA Way, San Francisco, CA 94080 USA.
EM desauvage.fred@gene.com
NR 48
TC 627
Z9 703
U1 2
U2 187
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 30
PY 2017
VL 543
IS 7647
BP 676
EP +
DI 10.1038/nature21713
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EP8IS
UT WOS:000397619700047
PM 28358093
DA 2026-03-09
ER

PT J
AU Katheder, NS
   Khezri, R
   O'Farrell, F
   Schultz, SW
   Jain, A
   Rahman, MM
   Schink, KO
   Theodossiou, TA
   Johansen, T
   Juhász, G
   Bilder, D
   Brech, A
   Stenmark, H
   Rusten, TE
AF Katheder, Nadja S.
   Khezri, Rojyar
   O'Farrell, Fergal
   Schultz, Sebastian W.
   Jain, Ashish
   Rahman, Mohammed M.
   Schink, Kay O.
   Theodossiou, Theodossis A.
   Johansen, Terje
   Juhasz, Gabor
   Bilder, David
   Brech, Andreas
   Stenmark, Harald
   Rusten, Tor Erik
TI Microenvironmental autophagy promotes tumour growth
SO NATURE
LA English
DT Article
ID cell polarity; oncogenic ras; drosophila; maintenance; progression; overgrowth; activation; expression; invasion; scribble
AB As malignant tumours develop, they interact intimately with their microenvironment and can activate autophagy(1), a catabolic process which provides nutrients during starvation. How tumours regulate autophagy in vivo and whether autophagy affects tumour growth is controversial(2). Here we demonstrate, using a well characterized Drosophila melanogaster malignant tumour model(3,4), that non-cell-autonomous autophagy is induced both in the tumour microenvironment and systemically in distant tissues. Tumour growth can be pharmacologically restrained using autophagy inhibitors, and early-stage tumour growth and invasion are genetically dependent on autophagy within the local tumour microenvironment. Induction of autophagy is mediated by Drosophila tumour necrosis factor and interleukin-6-like signalling from metabolically stressed tumour cells, whereas tumour growth depends on active amino acid transport. We show that dormant growth-impaired tumours from autophagy-deficient animals reactivate tumorous growth when transplanted into autophagy-proficient hosts. We conclude that transformed cells engage surrounding normal cells as active and essential microenvironmental contributors to early tumour growth through nutrient-generating autophagy.
C1 [Katheder, Nadja S.; Khezri, Rojyar; O'Farrell, Fergal; Schultz, Sebastian W.; Jain, Ashish; Rahman, Mohammed M.; Schink, Kay O.; Brech, Andreas; Stenmark, Harald; Rusten, Tor Erik] Oslo Univ Hosp, Inst Canc Res, Dept Mol Cell Biol, N-0379 Oslo, Norway.
   [Katheder, Nadja S.; Khezri, Rojyar; Jain, Ashish; Rahman, Mohammed M.; Schink, Kay O.; Brech, Andreas; Stenmark, Harald; Rusten, Tor Erik] Univ Oslo, Fac Med, Ctr Canc Biomed, N-0379 Oslo, Norway.
   [Jain, Ashish; Johansen, Terje] Arctic Univ Norway, UiT, Inst Med Biol, Mol Canc Res Grp, N-9037 Tromso, Norway.
   [Theodossiou, Theodossis A.] Oslo Univ Hosp, Inst Canc Res, Dept Radiat Med, N-0379 Oslo, Norway.
   [Juhasz, Gabor] Hungarian Acad Sci, Biol Res Ctr, Inst Genet, H-672 Szeged, Hungary.
   [Juhasz, Gabor] Eotvos Lorand Univ, Dept Anat Cell & Dev Biol, H-1117 Budapest, Hungary.
   [Bilder, David] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
C3 University of Oslo; University of Oslo; UiT The Arctic University of Tromso; University of Oslo; Hungarian Academy of Sciences; HUN-REN; HUN-REN Biological Research Center; Institute of Genetics - HAS; Eotvos Lorand University; University of California System; University of California Berkeley
RP Rusten, TE (corresponding author), Oslo Univ Hosp, Inst Canc Res, Dept Mol Cell Biol, N-0379 Oslo, Norway.
EM tor.erik.rusten@rr-research.no
FU Research Council of Norway through its Centres of Excellence funding scheme [179571]; Norwegian Cancer Society [PK01-2009-0386, 145517, 71043-PR-2006-0320]; Southern and Eastern Regional Health Authority [2015016]; Norwegian Research Council [196898, 214448]; NIH [RO1 GM090150]; EU grant from the Simon Fougner Hartmanns Foundation [609020, LP2014-2]
NR 30
TC 384
Z9 423
U1 5
U2 233
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 19
PY 2017
VL 541
IS 7637
BP 417
EP +
DI 10.1038/nature20815
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6QP
UT WOS:000396128800047
PM 28077876
DA 2026-03-09
ER

PT J
AU Bialas, AR
   Presumey, J
   Das, A
   van der Poel, CE
   Lapchak, PH
   Mesin, L
   Victora, G
   Tsokos, GC
   Mawrin, C
   Herbst, R
   Carroll, MC
AF Bialas, Allison R.
   Presumey, Jessy
   Das, Abhishek
   van der Poel, Cees E.
   Lapchak, Peter H.
   Mesin, Luka
   Victora, Gabriel
   Tsokos, George C.
   Mawrin, Christian
   Herbst, Ronald
   Carroll, Michael C.
TI RETRACTED: Microglia-dependent synapse loss in type I interferon-mediated lupus (Retracted article. See vol. 578, pg. 177, 2020)
SO NATURE
LA English
DT Article; Retracted Publication
ID b-cell tolerance; blood-brain; neuropsychiatric manifestations; erythematosus; receptor; diagnosis; alpha; pathogenesis; antibody; profile
AB Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by autoantibody deposition in tissues such as kidney, skin and lungs. Notably, up to 75% of patients with SLE experience neuropsychiatric symptoms that range from anxiety, depression and cognitive impairment to seizures and, in rare cases, psychosis-collectively this is referred to as central nervous system (CNS) lupus(1-4). In some cases, certain autoantibodies, such as anti-NMDAR or anti-phospholipid antibodies(5,6), promote CNS lupus. However, in most patients, the mechanisms that underlie these symptoms are unknown. CNS lupus typically presents at lupus diagnosis or within the first year, suggesting that early factors contributing to peripheral autoimmunity may promote CNS lupus symptoms. Here we report behavioural phenotypes and synapse loss in lupus-prone mice that are prevented by blocking type I interferon (IFN) signalling. Furthermore, we show that type I IFN stimulates microglia to become reactive and engulf neuronal and synaptic material in lupus-prone mice. These findings and our observation of increased type I IFN signalling in post-mortem hippocampal brain sections from patients with SLE may instruct the evaluation of ongoing clinical trials of anifrolumab(7), a type I IFN-receptor antagonist. Moreover, identification of IFN-driven microglia-dependent synapse loss, along with microglia transcriptome data, connects CNS lupus with other CNS diseases and provides an explanation for the neurological symptoms observed in some patients with SLE.
C1 [Bialas, Allison R.; Presumey, Jessy; Das, Abhishek; van der Poel, Cees E.; Carroll, Michael C.] Harvard Med Sch, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.
   [Bialas, Allison R.; Presumey, Jessy; Das, Abhishek; van der Poel, Cees E.; Carroll, Michael C.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA.
   [Lapchak, Peter H.; Tsokos, George C.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA.
   [Mesin, Luka; Victora, Gabriel] Rockefeller Univ, Lab Lymphocyte Dynam, New York, NY USA.
   [Mawrin, Christian] Univ Magdeburg, Dept Neuropathol, Magdeburg, Germany.
   [Mawrin, Christian] Otto von Guericke Univ, Ctr Behav Brain Sci CBBS, Magdeburg, Germany.
   [Herbst, Ronald] MedImmune LLC, Dept Canc Biol, Gaithersburg, MD 20878 USA.
C3 Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; Program in Cellular & Molecular Medicine (PCMM); Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Rockefeller University; Otto von Guericke University; Otto von Guericke University; AstraZeneca; Medimmune
RP Carroll, MC (corresponding author), Harvard Med Sch, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Carroll, MC (corresponding author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA.
EM michael.carroll@childrens.harvard.edu
FU Alliance for Lupus Research [A.L.R.-332527]; NIH [AI039246, AI42269]; MedImmune LLC; NIH T32 training grant [AI74549]; Jeffrey Modell Foundation
NR 39
TC 134
Z9 164
U1 4
U2 55
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 22
PY 2017
VL 546
IS 7659
BP 539
EP +
DI 10.1038/nature22821
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY2QK
UT WOS:000403814100040
PM 28614301
DA 2026-03-09
ER

PT J
AU Wu, LH
   Willis, JJ
   McKay, IS
   Diroll, BT
   Qin, J
   Cargnello, M
   Tassone, CJ
AF Wu, Liheng
   Willis, Joshua J.
   McKay, Ian Salmon
   Diroll, Benjamin T.
   Qin, Jian
   Cargnello, Matteo
   Tassone, Christopher J.
TI High-temperature crystallization of nanocrystals into three-dimensional superlattices
SO NATURE
LA English
DT Article
ID binary nanoparticle superlattices; in-situ; interface; membranes
AB Crystallization of colloidal nanocrystals into superlattices represents a practical bottom-up process with which to create ordered metamaterials with emergent functionalities(1-3). With precise control over the size, shape and composition of individual nanocrystals(4-6), various single-and multi-component nanocrystal superlattices have been produced, the lattice structures and chemical compositions of which can be accurately engineered(7-9). Nanocrystal superlattices are typically prepared by carefully controlling the assembly process through solvent evaporation or destabilization(2,10-15) or through DNA-guided crystallization(16-18). Slow solvent evaporation or cooling of nanocrystal solutions (over hours or days) is the key element for successful crystallization processes(10,18). Here we report the rapid growth (seconds) of micrometre-sized, face-centred-cubic, three-dimensional nanocrystal superlattices during colloidal synthesis at high temperatures (more than 230 degrees Celsius). Using in situ small-angle X-ray scattering, we observe continuous growth of individual nanocrystals within the lattices, which results in simultaneous lattice expansion and fine nanocrystal size control due to the superlattice templates. Thermodynamic models demonstrate that balanced attractive and repulsive interparticle interactions dictated by the ligand coverage on nanocrystal surfaces and nanocrystal core size are responsible for the crystallization process. The interparticle interactions can also be controlled to form different superlattice structures, such as hexagonal close-packed lattices. The rational assembly of various nanocrystal systems into novel materials is thus facilitated for both fundamental research and for practical applications in the fields of magnetics(19), electronics(3) and catalysis(20).
C1 [Wu, Liheng; Tassone, Christopher J.] SLAC Natl Accelerator Lab, Stanford Synchrotron Radiat Lightsource, Menlo Pk, CA 94025 USA.
   [Wu, Liheng; Willis, Joshua J.; McKay, Ian Salmon; Qin, Jian; Cargnello, Matteo] Stanford Univ, Dept Chem Engn, Stanford, CA 94305 USA.
   [Diroll, Benjamin T.] Argonne Natl Lab, Ctr Nanoscale Mat, Lemont, IL 60439 USA.
   [Cargnello, Matteo] Stanford Univ, SUNCAT Ctr Interface Sci & Catalysis, Stanford, CA 94305 USA.
C3 Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; Stanford University; United States Department of Energy (DOE); Argonne National Laboratory; Stanford University
RP Tassone, CJ (corresponding author), SLAC Natl Accelerator Lab, Stanford Synchrotron Radiat Lightsource, Menlo Pk, CA 94025 USA.; Cargnello, M (corresponding author), Stanford Univ, Dept Chem Engn, Stanford, CA 94305 USA.; Cargnello, M (corresponding author), Stanford Univ, SUNCAT Ctr Interface Sci & Catalysis, Stanford, CA 94305 USA.
EM mcargnello@stanford.edu; tassone@slac.stanford.edu
FU US Department of Energy (DOE), Laboratory Directed Research and Development programme at SLAC National Accelerator Laboratory [DE-AC02-76SF00515]; DOE Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]; Department of Defense through the National Defense Science & Engineering Graduate Fellowship Program; Fannie and John Hertz Foundation through a Hertz Foundation Fellowship; School of Engineering at Stanford University; Terman Faculty Fellowship; DOE Office of Science [DE-AC02-06CH11357]
NR 39
TC 126
Z9 141
U1 8
U2 316
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 10
PY 2017
VL 548
IS 7666
BP 197
EP +
DI 10.1038/nature23308
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD1GB
UT WOS:000407284300040
PM 28759888
DA 2026-03-09
ER

PT J
AU Kim, J
   Hu, ZP
   Cai, L
   Li, KL
   Choi, E
   Faubert, B
   Bezwada, D
   Rodriguez-Canales, J
   Villalobos, P
   Lin, YF
   Ni, M
   Huffman, KE
   Girard, L
   Byers, LA
   Unsal-Kacmaz, K
   Peña, CG
   Heymach, JV
   Wauters, E
   Vansteenkiste, J
   Castrillon, DH
   Chen, BPC
   Wistuba, I
   Lambrechts, D
   Xu, J
   Minna, JD
   DeBerardinis, RJ
AF Kim, Jiyeon
   Hu, Zeping
   Cai, Ling
   Li, Kailong
   Choi, Eunhee
   Faubert, Brandon
   Bezwada, Divya
   Rodriguez-Canales, Jaime
   Villalobos, Pamela
   Lin, Yu-Fen
   Ni, Min
   Huffman, Kenneth E.
   Girard, Luc
   Byers, Lauren A.
   Unsal-Kacmaz, Keziban
   Pena, Christopher G.
   Heymach, John V.
   Wauters, Els
   Vansteenkiste, Johan
   Castrillon, Diego H.
   Chen, Benjamin P. C.
   Wistuba, Ignacio
   Lambrechts, Diether
   Xu, Jian
   Minna, John D.
   DeBerardinis, Ralph J.
TI CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells
SO NATURE
LA English
DT Article
ID replication; growth; lkb1; ampk; metabolism; pathway
AB Metabolic reprogramming by oncogenic signals promotes cancer initiation and progression. The oncogene KRAS and tumour suppressor STK11, which encodes the kinase LKB1, regulate metabolism and are frequently mutated in non-small-cell lung cancer (NSCLC). Concurrent occurrence of oncogenic KRAS and loss of LKB1 (KL) in cells specifies aggressive oncological behaviour(1,2). Here we show that human KL cells and tumours share metabolomic signatures of perturbed nitrogen handling. KL cells express the urea cycle enzyme carbamoyl phosphate synthetase-1 (CPS1), which produces carbamoyl phosphate in the mitochondria from ammonia and bicarbonate, initiating nitrogen disposal. Transcription of CPS1 is suppressed by LKB1 through AMPK, and CPS1 expression correlates inversely with LKB1 in human NSCLC. Silencing CPS1 in KL cells induces cell death and reduces tumour growth. Notably, cell death results from pyrimidine depletion rather than ammonia toxicity, as CPS1 enables an unconventional pathway of nitrogen flow from ammonia into pyrimidines. CPS1 loss reduces the pyrimidine to purine ratio, compromises S-phase progression and induces DNA-polymerase stalling and DNA damage. Exogenous pyrimidines reverse DNA damage and rescue growth. The data indicate that the KL oncological genotype imposes a metabolic vulnerability related to a dependence on a cross-compartmental pathway of pyrimidine metabolism in an aggressive subset of NSCLC.
C1 [Kim, Jiyeon; Hu, Zeping; Cai, Ling; Li, Kailong; Faubert, Brandon; Bezwada, Divya; Ni, Min; Xu, Jian; DeBerardinis, Ralph J.] UT Southwestern Med Ctr, Childrens Med Ctr Res Inst, Dallas, TX 75390 USA.
   [Choi, Eunhee] UT Southwestern Med Ctr, Dept Pharmacol, Dallas, TX 75390 USA.
   [Rodriguez-Canales, Jaime; Villalobos, Pamela; Wistuba, Ignacio] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, 2130 West Holcombe Blvd, Houston, TX 77030 USA.
   [Lin, Yu-Fen; Chen, Benjamin P. C.] UT Southwestern Med Ctr, Dept Radiat Oncol, Dallas, TX 75390 USA.
   [Huffman, Kenneth E.; Girard, Luc; Minna, John D.] UT Southwestern Med Ctr, Hamon Ctr Therapeut Oncol, Dallas, TX 75390 USA.
   [Byers, Lauren A.; Heymach, John V.] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, 2130 West Holcombe Blvd, Houston, TX 77030 USA.
   [Unsal-Kacmaz, Keziban] Pfizer, Oncol Res Unit, 401 North Middletown Rd, Pearl River, NY 10965 USA.
   [Pena, Christopher G.; Castrillon, Diego H.] UT Southwestern Med Ctr, Dept Pathol, Dallas, TX 75390 USA.
   [Wauters, Els; Vansteenkiste, Johan] Univ Gasthuisberg, Div Resp, KU Leuven, Herestr 49, B-3000 Leuven, Belgium.
   [Lambrechts, Diether] Katholieke Univ Leuven, Dept Human Genet, Lab Translat Genet, O&N 4 Herestr 49 Box 912, B-3000 Leuven, Belgium.
   [Lambrechts, Diether] Katholieke Univ Leuven, VIB, Ctr Canc Biol, O&N 4 Herestr 49 Box 912, B-3000 Leuven, Belgium.
   [DeBerardinis, Ralph J.] UT Southwestern Med Ctr, Dept Pediat, Dallas, TX 75390 USA.
   [DeBerardinis, Ralph J.] UT Southwestern Med Ctr, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA.
   [Pena, Christopher G.] Univ Texas Hlth Sci Ctr San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA.
C3 University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; UTMD Anderson Cancer Center; Pfizer; Pfizer USA; University of Texas System; University of Texas Southwestern Medical Center; KU Leuven; KU Leuven; KU Leuven; Flanders Institute for Biotechnology (VIB); University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas at San Antonio
RP DeBerardinis, RJ (corresponding author), UT Southwestern Med Ctr, Childrens Med Ctr Res Inst, Dallas, TX 75390 USA.; DeBerardinis, RJ (corresponding author), UT Southwestern Med Ctr, Dept Pediat, Dallas, TX 75390 USA.; DeBerardinis, RJ (corresponding author), UT Southwestern Med Ctr, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA.
EM Ralph.Deberardinis@UTSouthwestern.edu
FU NIH [R01CA157996, 1R01CA196912, CA176284]; Cancer Prevention and Research Institute of Texas [CPRIT RP130272]; Robert A. Welch Foundation [I1733]; H.H.M.I. (Faculty Scholars Program); American Lung Association Senior Research Training Fellowship [RT-306212]; University of Texas Lung Specialized Programs of Research Excellence (SPORE) grant [P50CA70907]; CPRIT [RP120732, RP110708]; National Cancer Institute [P50CA070907] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK111430] Funding Source: NIH RePORTER
NR 30
TC 271
Z9 321
U1 4
U2 118
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 1
PY 2017
VL 546
IS 7656
BP 168
EP +
DI 10.1038/nature22359
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW3CR
UT WOS:000402372800050
PM 28538732
DA 2026-03-09
ER

PT J
AU Sendoel, A
   Dunn, JG
   Rodriguez, EH
   Naik, S
   Gomez, NC
   Hurwitz, B
   Levorse, J
   Dill, BD
   Schramek, D
   Molina, H
   Weissman, JS
   Fuchs, E
AF Sendoel, Ataman
   Dunn, Joshua G.
   Rodriguez, Edwin H.
   Naik, Shruti
   Gomez, Nicholas C.
   Hurwitz, Brian
   Levorse, John
   Dill, Brian D.
   Schramek, Daniel
   Molina, Henrik
   Weissman, Jonathan S.
   Fuchs, Elaine
TI Translation from unconventional 5′ start sites drives tumour initiation
SO NATURE
LA English
DT Article
ID open reading frames; stem-cell; malignant-transformation; protein-synthesis; gene-expression; in-vivo; sox2; identification; populations; regulators
AB We are just beginning to understand how translational control affects tumour initiation and malignancy. Here we use an epidermis-specific, in vivo ribosome profiling strategy to investigate the translational landscape during the transition from normal homeostasis to malignancy. Using a mouse model of inducible SOX2, which is broadly expressed in oncogenic RAS-associated cancers, we show that despite widespread reductions in translation and protein synthesis, certain oncogenic mRNAs are spared. During tumour initiation, the translational apparatus is redirected towards unconventional upstream initiation sites, enhancing the translational efficiency of oncogenic mRNAs. An in vivo RNA interference screen of translational regulators revealed that depletion of conventional eIF2 complexes has adverse effects on normal but not oncogenic growth. Conversely, the alternative initiation factor eIF2A is essential for cancer progression, during which it mediates initiation at these upstream sites, differentially skewing translation and protein expression. Our findings unveil a role for the translation of 5' untranslated regions in cancer, and expose new targets for therapeutic intervention.
C1 [Sendoel, Ataman; Naik, Shruti; Gomez, Nicholas C.; Hurwitz, Brian; Levorse, John; Schramek, Daniel; Fuchs, Elaine] Rockefeller Univ, Robin Chemers Neustein Lab Mammalian Dev & Cell B, Howard Hughes Med Inst, New York, NY 10065 USA.
   [Dunn, Joshua G.; Rodriguez, Edwin H.; Weissman, Jonathan S.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, Howard Hughes Med Inst, San Francisco, CA 94158 USA.
   [Dill, Brian D.; Molina, Henrik] Rockefeller Univ, Prote Resource Ctr, New York, NY 10065 USA.
   [Schramek, Daniel] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada.
C3 Howard Hughes Medical Institute; Rockefeller University; University of California System; University of California San Francisco; Howard Hughes Medical Institute; Rockefeller University; University of Toronto; Sinai Health System Toronto; Lunenfeld Tanenbaum Research Institute
RP Fuchs, E (corresponding author), Rockefeller Univ, Robin Chemers Neustein Lab Mammalian Dev & Cell B, Howard Hughes Med Inst, New York, NY 10065 USA.
EM fuchslb@rockefeller.edu
FU Leona M. and Harry B. Helmsley Charitable Trust; Sohn Conferences Foundation for mass spectrometer instrumentation; Human Frontier Science Program Organization (HFSP) [LT000639-2013]; European Union under REA [629861]; National Institute of General Medical Sciences of the National Institutes of Health [T32GM007739]; National Institutes of Health [R37-AR27883]; NYSTEM [CO29559]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R37AR027883] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007739] Funding Source: NIH RePORTER
NR 57
TC 255
Z9 302
U1 1
U2 49
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 26
PY 2017
VL 541
IS 7638
BP 494
EP 499
DI 10.1038/nature21036
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6LX
UT WOS:000396116600043
PM 28077873
DA 2026-03-09
ER

PT J
AU Bertram, K
   Agafonov, DE
   Liu, WT
   Dybkov, O
   Will, CL
   Hartmuth, K
   Urlaub, H
   Kastner, B
   Stark, H
   Lührmann, R
AF Bertram, Karl
   Agafonov, Dmitry E.
   Liu, Wen-Ti
   Dybkov, Olexandr
   Will, Cindy L.
   Hartmuth, Klaus
   Urlaub, Henning
   Kastner, Berthold
   Stark, Holger
   Luehrmann, Reinhard
TI Cryo-EM structure of a human spliceosome activated for step 2 of splicing
SO NATURE
LA English
DT Article
ID pre-messenger-rna; u4/u6.u5 tri-snrnp; 2nd step; i spliceosome; molecular architecture; crystal-structure; catalytic core; prp8; u5; insights
AB Spliceosome rearrangements facilitated by RNA helicase PRP16 before catalytic step two of splicing are poorly understood. Here we report a 3D cryo-electron microscopy structure of the human spliceosomal C complex stalled directly after PRP16 action (C*). The architecture of the catalytic U2-U6 ribonucleoprotein (RNP) core of the human C* spliceosome is very similar to that of the yeast pre-Prp16 C complex. However, in C* the branched intron region is separated from the catalytic centre by approximately 20 angstrom, and its position close to the U6 small nuclear RNA ACAGA box is stabilized by interactions with the PRP8 RNase H-like and PRP17 WD40 domains. RNA helicase PRP22 is located about 100 angstrom from the catalytic centre, suggesting that it destabilizes the spliced mRNA after step two from a distance. Comparison of the structure of the yeast C and human C* complexes reveals numerous RNP rearrangements that are likely to be facilitated by PRP16, including a large-scale movement of the U2 small nuclear RNP.
C1 [Bertram, Karl; Liu, Wen-Ti; Stark, Holger] MPI Biophys Chem, Dept Struct Dynam, Fassberg 11, D-37077 Gottingen, Germany.
   [Agafonov, Dmitry E.; Dybkov, Olexandr; Will, Cindy L.; Hartmuth, Klaus; Kastner, Berthold; Luehrmann, Reinhard] MPI Biophys Chem, Dept Cellular Biochem, Fassberg 11, D-37077 Gottingen, Germany.
   [Urlaub, Henning] MPI Biophys Chem, Bioanalyt Mass Spectrometry, Fassberg 11, D-37077 Gottingen, Germany.
   [Urlaub, Henning] Univ Med Ctr Gottingen, Bioanalyt Grp, Inst Clin Chem, Robert Koch Str 40, D-37075 Gottingen, Germany.
C3 Max Planck Society; Max Planck Society; Max Planck Society; University of Gottingen; University of Gottingen Hospital
RP Stark, H (corresponding author), MPI Biophys Chem, Dept Struct Dynam, Fassberg 11, D-37077 Gottingen, Germany.; Kastner, B; Lührmann, R (corresponding author), MPI Biophys Chem, Dept Cellular Biochem, Fassberg 11, D-37077 Gottingen, Germany.
EM b.kastner@mpi-bpc.mpg.de; hstark1@gwdg.de; reinhard.luehrmann@mpi-bpc.mpg.de
FU Deutsche Forschungsgemeinschaft [SFB 860]
NR 71
TC 197
Z9 252
U1 3
U2 57
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 16
PY 2017
VL 542
IS 7641
BP 318
EP +
DI 10.1038/nature21079
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2LQ
UT WOS:000394451600030
PM 28076346
DA 2026-03-09
ER

PT J
AU Lukarska, M
   Fournier, G
   Pflug, A
   Resa-Infante, P
   Reich, S
   Naffakh, N
   Cusack, S
AF Lukarska, Maria
   Fournier, Guillaume
   Pflug, Alexander
   Resa-Infante, Patricia
   Reich, Stefan
   Naffakh, Nadia
   Cusack, Stephen
TI Structural basis of an essential interaction between influenza polymerase and Pol II CTD
SO NATURE
LA English
DT Article
ID carboxyl-terminal domain; amino-acid mutation; rna-polymerase; a virus; pa subunit; transcription; degradation; replication; refinement
AB The heterotrimeric influenza polymerase (FluPol), comprising subunits PA, PB1 and PB2, binds to the conserved 5' and 3' termini (the 'promoter') of each of the eight single-stranded viral RNA (vRNA) genome segments and performs both transcription and replication of vRNA in the infected cell nucleus(1-3). To transcribe viral mRNAs, FluPol associates with cellular RNA polymerase II (Pol II)(4-7), which enables it to take 5'-capped primers from nascent Pol II transcripts(8,9). Here we present a co-crystal structure of bat influenza A polymerase bound to a Pol II C-terminal domain (CTD) peptide mimic, which shows two distinct phosphoserine-5 (SeP5)-binding sites in the polymerase PA subunit, accommodating four CTD heptad repeats overall. Mutagenesis of the SeP5-contacting basic residues (PA K289, R454, K635 and R638) weakens CTD repeat binding in vitro without affecting the intrinsic cap-primed (transcription) or unprimed (replication) RNA synthesis activity of recombinant polymerase, whereas in cell-based minigenome assays the same mutations substantially reduce overall polymerase activity. Only recombinant viruses with a single mutation in one of the SeP5-binding sites can be rescued, but these viruses are severely attenuated and genetically unstable. Several previously described mutants that modulate virulence can be rationalized by our results, including a second site mutation (PA(C453R)) that enables the highly attenuated mutant virus (PA(R638A)) to revert to near wildtype infectivity(10). We conclude that direct binding of FluPol to the SeP5 Pol II CTD is fine-tuned to allow efficient viral transcription and propose that the CTD-binding site on FluPol could be targeted for antiviral drug development.
C1 [Lukarska, Maria; Pflug, Alexander; Resa-Infante, Patricia; Reich, Stefan; Cusack, Stephen] European Mol Biol Lab, Grenoble Outstn, 71 Ave Martyrs,CS 90181, F-38042 Grenoble 9, France.
   [Fournier, Guillaume; Naffakh, Nadia] Inst Pasteur, Dept Virol, Unite Genet Mol Virus ARN, F-75015 Paris, France.
   [Fournier, Guillaume; Naffakh, Nadia] CNRS, UMR3569, F-75015 Paris, France.
   [Fournier, Guillaume; Naffakh, Nadia] Univ Paris Diderot, Unite Genet Mol Virus ARN, Sorbonne Paris Cite, EA302, F-75015 Paris, France.
C3 European Molecular Biology Laboratory (EMBL); Universite Paris Cite; Pasteur Network; Institut Pasteur Paris; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Universite Paris Cite
RP Cusack, S (corresponding author), European Mol Biol Lab, Grenoble Outstn, 71 Ave Martyrs,CS 90181, F-38042 Grenoble 9, France.
EM cusack@embl.fr
FU ERC Advanced Grant V-RNA [322586]; Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence; Institut Carnot Pasteur Maladies Infectieuses; EU PREDEMICS project [278433]; European Research Council (ERC) [322586] Funding Source: European Research Council (ERC)
NR 38
TC 106
Z9 125
U1 1
U2 40
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 5
PY 2017
VL 541
IS 7635
BP 117
EP +
DI 10.1038/nature20594
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6NA
UT WOS:000396119500041
PM 28002402
DA 2026-03-09
ER

PT J
AU Goodwin, CAP
   Ortu, F
   Reta, D
   Chilton, NF
   Mills, DP
AF Goodwin, Conrad A. P.
   Ortu, Fabrizio
   Reta, Daniel
   Chilton, Nicholas F.
   Mills, David P.
TI Molecular magnetic hysteresis at 60 kelvin in dysprosocenium
SO NATURE
LA English
DT Article
ID single-ion magnet; spin qubits; relaxation; anisotropy; complexes; blocking
AB Lanthanides have been investigated extensively for potential applications in quantum information processing and high-density data storage at the molecular and atomic scale. Experimental achievements include reading and manipulating single nuclear spins(1,2), exploiting atomic clock transitions for robust qubits(3) and, most recently, magnetic data storage in single atoms(4,5). Single-molecule magnets exhibit magnetic hysteresis of molecular origin(6)-a magnetic memory effect and a prerequisite of data storage-and so far lanthanide examples have exhibited this phenomenon at the highest temperatures. However, in the nearly 25 years since the discovery of single-molecule magnets(7), hysteresis temperatures have increased from 4 kelvin to only about 14 kelvin(8-10) using a consistent magnetic field sweep rate of about 20 oersted per second, although higher temperatures have been achieved by using very fast sweep rates(11,12) (for example, 30 kelvin with 200 oersted per second)(12). Here we report a hexa-tert-butyldysprosocenium complex-[Dy(Cp-ttt)(2)][B(C6F5)(4)], with Cp-ttt = {(C5H2Bu3)-Bu-t-1,2,4} and Bu-t = C(CH3)(3)-which exhibits magnetic hysteresis at temperatures of up to 60 kelvin at a sweep rate of 22 oersted per second. We observe a clear change in the relaxation dynamics at this temperature, which persists in magnetically diluted samples, suggesting that the origin of the hysteresis is the localized metal-ligand vibrational modes that are unique to dysprosocenium. Ab initio calculations of spin dynamics demonstrate that magnetic relaxation at high temperatures is due to local molecular vibrations. These results indicate that, with judicious molecular design, magnetic data storage in single molecules at temperatures above liquid nitrogen should be possible.
C1 [Goodwin, Conrad A. P.; Ortu, Fabrizio; Reta, Daniel; Chilton, Nicholas F.; Mills, David P.] Univ Manchester, Sch Chem, Oxford Rd, Manchester M13 9PL, Lancs, England.
C3 University of Manchester
RP Chilton, NF; Mills, DP (corresponding author), Univ Manchester, Sch Chem, Oxford Rd, Manchester M13 9PL, Lancs, England.
EM nicholas.chilton@manchester.ac.uk; david.mills@manchester.ac.uk
FU Engineering and Physical Sciences Research Council [EP/P002560/1]; Ramsay Memorial Fellowships Trust; University of Manchester; Engineering and Physical Sciences Research Council [1329386, EP/P002560/1] Funding Source: researchfish; EPSRC [EP/P002560/1] Funding Source: UKRI
NR 31
TC 1673
Z9 1768
U1 9
U2 472
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 24
PY 2017
VL 548
IS 7668
BP 439
EP 442
DI 10.1038/nature23447
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FE5VI
UT WOS:000408279000035
PM 28836589
DA 2026-03-09
ER

PT J
AU Shara, MM
   Ilkiewicz, K
   Mikolajewska, J
   Pagnotta, A
   Bode, MF
   Crause, LA
   Drozd, K
   Faherty, J
   Fuentes-Morales, I
   Grindlay, JE
   Moffat, AFJ
   Pretorius, ML
   Schmidtobreick, L
   Stephenson, FR
   Tappert, C
   Zurek, D
AF Shara, M. M.
   Ilkiewicz, K.
   Mikolajewska, J.
   Pagnotta, A.
   Bode, M. F.
   Crause, L. A.
   Drozd, K.
   Faherty, J.
   Fuentes-Morales, I.
   Grindlay, J. E.
   Moffat, A. F. J.
   Pretorius, M. L.
   Schmidtobreick, L.
   Stephenson, F. R.
   Tappert, C.
   Zurek, D.
TI Proper-motion age dating of the progeny of Nova Scorpii ad 1437
SO NATURE
LA English
DT Article
ID dwarf nova; shell; space; spectroscopy; evolution; remnant; models; stars
AB 'Cataclysmic variables' are binary star systems in which one star of the pair is a white dwarf, and which often generate bright and energetic stellar outbursts. Classical novae are one type of outburst: when the white dwarf accretes enough matter from its companion, the resulting hydrogen-rich atmospheric envelope can host a runaway thermonuclear reaction that generates a rapid brightening(1-4). Achieving peak luminosities of up to one million times that of the Sun(5), all classical novae are recurrent, on timescales of months(6) to millennia(7). During the century before and after an eruption, the 'novalike' binary systems that give rise to classical novae exhibit high rates of mass transfer to their white dwarfs(8). Another type of outburst is the dwarf nova: these occur in binaries that have stellar masses and periods indistinguishable from those of novalikes(9) but much lower mass-transfer rates(10), when accretion-disk instabilities(11) drop matter onto the white dwarfs. The coexistence at the same orbital period of novalike binaries and dwarf novae-which are identical but for their widely varying accretion rates-has been a longstanding puzzle(9). Here we report the recovery of the binary star underlying the classical nova eruption of 11 March ad 1437 (refs 12, 13), and independently confirm its age by proper-motion dating. We show that, almost 500 years after a classical-nova event, the system exhibited dwarf-nova eruptions. The three other oldest recovered classical novae(14-16) display nova shells, but lack firm post-eruption ages(17,18), and are also dwarf novae at present. We conclude that many old novae become dwarf novae for part of the millennia between successive nova eruptions(19,20).
C1 [Shara, M. M.; Pagnotta, A.; Faherty, J.; Zurek, D.] Amer Museum Nat Hist, Dept Astrophys, Cent Pk West & 79th St, New York, NY 10024 USA.
   [Shara, M. M.] Inst Astron, Madingley Rd, Cambridge CB3 0HA, England.
   [Ilkiewicz, K.; Mikolajewska, J.; Drozd, K.] Polish Acad Sci, N Copernicus Astron Ctr, Bartycka 18, PL-00716 Warsaw, Poland.
   [Bode, M. F.] Liverpool John Moores Univ, Astrophys Res Inst, IC2 Liverpool Sci Pk, Liverpool L3 5RF, Merseyside, England.
   [Crause, L. A.; Pretorius, M. L.] South African Astron Observ, POB 9, ZA-7935 Cape Town, South Africa.
   [Fuentes-Morales, I.; Tappert, C.] Univ Valparaiso, Inst Fis & Astron, Ave Gran Bretana 1111, Valparaiso 2360102, Chile.
   [Grindlay, J. E.] Harvard Smithsonian Ctr Astrophys, Inst Theory & Computat, 60 Garden St, Cambridge, MA 02138 USA.
   [Moffat, A. F. J.] Univ Montreal, Dept Phys, CP 6128 Succ C-V, Montreal, PQ H3C 3J7, Canada.
   [Moffat, A. F. J.] Univ Montreal, CRAQ, CP 6128 Succ C-V, Montreal, PQ H3C 3J7, Canada.
   [Pretorius, M. L.] Univ Capetown, Dept Astron, Private Bag X3, ZA-7701 Rondebosch, South Africa.
   [Schmidtobreick, L.] European Southern Observ, Alonso de Cordova 3107, Santiago 7630355, Chile.
   [Stephenson, F. R.] Univ Durham, Dept Phys, South Rd, Durham DH1 3LE, England.
C3 American Museum of Natural History (AMNH); University of Cambridge; Polish Academy of Sciences; Liverpool John Moores University; National Research Foundation - South Africa; South African Astronomical Observatory; Universidad de Valparaiso; Smithsonian Institution; Smithsonian Astrophysical Observatory; Harvard University; Universite de Montreal; Universite de Montreal; University of Cape Town; European Southern Observatory; Durham University
RP Shara, MM (corresponding author), Amer Museum Nat Hist, Dept Astrophys, Cent Pk West & 79th St, New York, NY 10024 USA.; Shara, MM (corresponding author), Inst Astron, Madingley Rd, Cambridge CB3 0HA, England.
EM mshara@amnh.org
FU Polish Narodowe Centrum Nauki [DEC-2013/10/M/ST9/00086]; National Sciences and Engineering Research Council of Canada; Fonds de Recherche Nature et Technologies (Quebec); AMNH's Kathryn W. Davis Postdoctoral Scholar program - New York State Education Department; National Science Foundation (NSF) [DRL-1119444, DUE-1340006]; NSF [AST-0407380, AST-0909073, AST-1313370];  [MNiSW DIR/WK/2016/07]; Science and Technology Facilities Council [ST/J001465/1, ST/L00061X/1, PP/E001149/1, ST/F007159/1, ST/M000966/1, ST/H002391/1] Funding Source: researchfish; STFC [ST/F007159/1, ST/H002391/1, ST/J001465/1, PP/E001149/1, ST/L00061X/1] Funding Source: UKRI
NR 43
TC 55
Z9 63
U1 0
U2 8
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 31
PY 2017
VL 548
IS 7669
BP 558
EP +
DI 10.1038/nature23644
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FF2BO
UT WOS:000408703100033
PM 28858302
DA 2026-03-09
ER

PT J
AU Paulino, C
   Kalienkova, V
   Lam, AKM
   Neldner, Y
   Dutzler, R
AF Paulino, Cristina
   Kalienkova, Valeria
   Lam, Andy K. M.
   Neldner, Yvonne
   Dutzler, Raimund
TI Activation mechanism of the calcium-activated chloride channel TMEM16A revealed by cryo-EM
SO NATURE
LA English
DT Article
ID particle electron cryomicroscopy; independent activation; model; permeation; refinement; expression; microscopy; scramblase; program; voltage
AB The calcium-activated chloride channel TMEM16A is a ligand-gated anion channel that opens in response to an increase in intracellular Ca2+ concentration(1-3). The protein is broadly expressed(4) and contributes to diverse physiological processes, including transepithelial chloride transport and the control of electrical signalling in smooth muscles and certain neurons(5-7). As a member of the TMEM16 (or anoctamin) family of membrane proteins, TMEM16A is closely related to paralogues that function as scramblases, which facilitate the bidirectional movement of lipids across membranes(8-11). The unusual functional diversity of the TMEM16 family and the relationship between two seemingly incompatible transport mechanisms has been the focus of recent investigations. Previous breakthroughs were obtained from the X-ray structure of the lipid scramblase of the fungus Nectria haematococca (nhTMEM16)(12,13), and from the cryo-electron microscopy structure of mouse TMEM16A at 6.6 A (ref. 14). Although the latter structure disclosed the architectural differences that distinguish ion channels from lipid scramblases, its low resolution did not permit a detailed molecular description of the protein or provide any insight into its activation by Ca2+. Here we describe the structures of mouse TMEM16A at high resolution in the presence and absence of Ca2+. These structures reveal the differences between ligand-bound and ligand-free states of a calcium-activated chloride channel, and when combined with functional experiments suggest a mechanism for gating. During activation, the binding of Ca2+ to a site located within the transmembrane domain, in the vicinity of the pore, alters the electrostatic properties of the ion conduction path and triggers a conformational rearrangement of an a-helix that comes into physical contact with the bound ligand, and thereby directly couples ligand binding and pore opening. Our study describes a process that is unique among channel proteins, but one that is presumably general for both functional branches of the TMEM16 family.
C1 [Paulino, Cristina; Kalienkova, Valeria; Lam, Andy K. M.; Neldner, Yvonne; Dutzler, Raimund] Univ Zurich, Dept Biochem, Winterthurerstr 190, CH-8057 Zurich, Switzerland.
   [Paulino, Cristina] Univ Groningen, Dept Struct Biol, Groningen Biomol Sci & Biotechnol Inst, Nijenborgh 7, NL-9747 AG Groningen, Netherlands.
C3 University of Zurich; University of Groningen
RP Dutzler, R (corresponding author), Univ Zurich, Dept Biochem, Winterthurerstr 190, CH-8057 Zurich, Switzerland.
EM dutzler@bioc.uzh.ch
FU European Research Council [339116]; University of Zurich; Maxi foundation; European Research Council (ERC) [339116] Funding Source: European Research Council (ERC)
NR 53
TC 234
Z9 266
U1 2
U2 97
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 21
PY 2017
VL 552
IS 7685
BP 421
EP +
DI 10.1038/nature24652
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ7RI
UT WOS:000418559800062
PM 29236691
DA 2026-03-09
ER

PT J
AU Huang, B
   Clark, G
   Navarro-Moratalla, E
   Klein, DR
   Cheng, R
   Seyler, KL
   Zhong, D
   Schmidgall, E
   McGuire, MA
   Cobden, DH
   Yao, W
   Xiao, D
   Jarillo-Herrero, P
   Xu, XD
AF Huang, Bevin
   Clark, Genevieve
   Navarro-Moratalla, Efren
   Klein, Dahlia R.
   Cheng, Ran
   Seyler, Kyle L.
   Zhong, Ding
   Schmidgall, Emma
   McGuire, Michael A.
   Cobden, David H.
   Yao, Wang
   Xiao, Di
   Jarillo-Herrero, Pablo
   Xu, Xiaodong
TI Layer-dependent ferromagnetism in a van der Waals crystal down to the monolayer limit
SO NATURE
LA English
DT Article
ID transition; behavior; phase; superconductivity; nanosheets; magnetism
AB Since the discovery of graphene(1), the family of two-dimensional materials has grown, displaying a broad range of electronic properties. Recent additions include semiconductors with spin-valley coupling(2), Ising superconductors(3-5) that can be tuned into a quantum metal(6), possible Mott insulators with tunable charge-density waves(7), and topological semimetals with edge transport(8,9). However, no two-dimensional crystal with intrinsic magnetism has yet been discovered(10-14); such a crystal would be useful in many technologies from sensing to data storage(15). Theoretically, magnetic order is prohibited in the two-dimensional isotropic Heisenberg model at finite temperatures by the Mermin-Wagner theorem(16). Magnetic anisotropy removes this restriction, however, and enables, for instance, the occurrence of two-dimensional Ising ferromagnetism. Here we use magneto-optical Kerr effect microscopy to demonstrate that monolayer chromium triiodide (CrI3) is an Ising ferromagnet with out-of-plane spin orientation. Its Curie temperature of 45 kelvin is only slightly lower than that of the bulk crystal, 61 kelvin, which is consistent with a weak interlayer coupling. Moreover, our studies suggest a layer-dependent magnetic phase, highlighting thickness-dependent physical properties typical of van der Waals crystals(17-19). Remarkably, bilayer CrI3 displays suppressed magnetization with a metamagnetic effect(20), whereas in trilayer CrI3 the interlayer ferromagnetism observed in the bulk crystal is restored. This work creates opportunities for studying magnetism by harnessing the unusual features of atomically thin materials, such as electrical control for realizing magnetoelectronics(12), and van der Waals engineering to produce interface phenomena(15).
C1 [Huang, Bevin; Seyler, Kyle L.; Zhong, Ding; Schmidgall, Emma; Cobden, David H.; Xu, Xiaodong] Univ Washington, Dept Phys, Seattle, WA 98195 USA.
   [Clark, Genevieve; Xu, Xiaodong] Univ Washington, Dept Mat Sci & Engn, Seattle, WA 98195 USA.
   [Navarro-Moratalla, Efren; Klein, Dahlia R.; Jarillo-Herrero, Pablo] MIT, Dept Phys, Cambridge, MA 02139 USA.
   [Cheng, Ran; Xiao, Di] Carnegie Mellon Univ, Dept Phys, Pittsburgh, PA 15213 USA.
   [McGuire, Michael A.] Oak Ridge Natl Lab, Mat Sci & Technol Div, Oak Ridge, TN 37831 USA.
   [Yao, Wang] Univ Hong Kong, Dept Phys, Hong Kong, Hong Kong, Peoples R China.
   [Yao, Wang] Univ Hong Kong, Ctr Theoret & Computat Phys, Hong Kong, Hong Kong, Peoples R China.
C3 University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Massachusetts Institute of Technology (MIT); Carnegie Mellon University; United States Department of Energy (DOE); Oak Ridge National Laboratory; University of Hong Kong; University of Hong Kong
RP Xu, XD (corresponding author), Univ Washington, Dept Phys, Seattle, WA 98195 USA.; Xu, XD (corresponding author), Univ Washington, Dept Mat Sci & Engn, Seattle, WA 98195 USA.; Jarillo-Herrero, P (corresponding author), MIT, Dept Phys, Cambridge, MA 02139 USA.
EM pjarillo@mit.edu; xuxd@uw.edu
FU Department of Energy, Basic Energy Sciences, Materials Sciences and Engineering Division [DE-SC0008145, SC0012509]; University of Washington Innovation Award; Center for Integrated Quantum Materials under NSF [DMR-1231319]; Gordon and Betty Moore Foundation's EPiQS Initiative [GBMF4541]; Center for Excitonics, an Energy Frontier Research Center - US Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences [DESC0001088]; DOE [BES DE-SC0012509]; Croucher Foundation (Croucher Innovation Award); RGC of Hong Kong [HKU17305914P]; HKU ORA; US Department of Energy, Office of Science, Basic Energy Sciences, Materials Sciences and Engineering Division; Cottrell Scholar Award; Clean Energy Institute; State of Washington; Boeing Distinguished Professorship in Physics;  [DE-SC0002197]
NR 37
TC 5203
Z9 5597
U1 119
U2 3952
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 8
PY 2017
VL 546
IS 7657
BP 270
EP +
DI 10.1038/nature22391
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW9FY
UT WOS:000402823400033
PM 28593970
DA 2026-03-09
ER

PT J
AU Wan, LL
   Wen, H
   Li, YY
   Lyu, J
   Xi, YX
   Hoshii, T
   Joseph, JK
   Wang, XL
   Loh, YHE
   Erb, MA
   Souza, AL
   Bradner, JE
   Shen, L
   Li, W
   Li, HT
   Allis, CD
   Armstrong, SA
   Shi, XB
AF Wan, Liling
   Wen, Hong
   Li, Yuanyuan
   Lyu, Jie
   Xi, Yuanxin
   Hoshii, Takayuki
   Joseph, Julia K.
   Wang, Xiaolu
   Loh, Yong-Hwee E.
   Erb, Michael A.
   Souza, Amanda L.
   Bradner, James E.
   Shen, Li
   Li, Wei
   Li, Haitao
   Allis, C. David
   Armstrong, Scott A.
   Shi, Xiaobing
TI ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia
SO NATURE
LA English
DT Article
ID rna-polymerase-ii; elongation complex; transcription elongation; chromatin; inhibition; resistance; component; tefb
AB Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs(1). Recognition of modified histones by 'reader' proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of bromodomain and extra-terminal (BET) inhibitors(2,3). We recently identified the YEATS domain as an acetyl-lysine-binding module(4), but its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralogue AF9, is required for disease maintenance in acute myeloid leukaemia. CRISPR-Cas9-mediated depletion of ENL led to anti-leukaemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies and chromatin-immunoprecipitation followed by sequencing analyses revealed that ENL binds to acetylated histone H3, and co-localizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemia. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced the recruitment of RNA polymerase II to ENL-target genes, leading to the suppression of oncogenic gene expression programs. Notably, disrupting the functionality of ENL further sensitized leukaemia cells to BET inhibitors. Together, our data identify ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in acute myeloid leukaemia, and suggest that displacement of ENL from chromatin may be a promising epigenetic therapy, alone or in combination with BET inhibitors, for aggressive leukaemia.
C1 [Wan, Liling; Joseph, Julia K.; Allis, C. David] Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA.
   [Wan, Liling; Hoshii, Takayuki; Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA.
   [Wan, Liling; Hoshii, Takayuki; Armstrong, Scott A.] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.
   [Wen, Hong; Wang, Xiaolu; Shi, Xiaobing] Univ Texas MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, Houston, TX 77030 USA.
   [Wen, Hong; Shi, Xiaobing] Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Houston, TX 77030 USA.
   [Li, Yuanyuan; Li, Haitao] Tsinghua Univ, Beijing Adv Innovat Ctr Struct Biol, Sch Med, Dept Basic Med Sci,MOE Key Lab Prot Sci, Beijing 100084, Peoples R China.
   [Li, Yuanyuan; Li, Haitao] Tsinghua Univ, Tsinghua Peking Joint Ctr Life Sci, Beijing 100084, Peoples R China.
   [Lyu, Jie; Xi, Yuanxin; Li, Wei] Baylor Coll Med, Dan L Duncan Canc Ctr, Dept Mol & Cellular Biol, Houston, TX 77030 USA.
   [Loh, Yong-Hwee E.; Shen, Li] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA.
   [Loh, Yong-Hwee E.; Shen, Li] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA.
   [Erb, Michael A.; Souza, Amanda L.; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA.
   [Bradner, James E.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA.
   [Shi, Xiaobing] Univ Texas Houston, Grad Sch Biomed Sci, Genes & Dev & Epigenet & Mol Carcinogenesis Grad, Houston, TX 77030 USA.
   [Souza, Amanda L.; Bradner, James E.] Novartis Inst BioMed Res, Cambridge, MA 02139 USA.
C3 Rockefeller University; Memorial Sloan Kettering Cancer Center; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard Medical School; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; Tsinghua University; Tsinghua University; Baylor College of Medicine; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; University of Texas System; University of Texas Health Science Center Houston; Novartis; Novartis USA
RP Allis, CD (corresponding author), Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA.; Armstrong, SA (corresponding author), Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA.; Armstrong, SA (corresponding author), Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.; Shi, XB (corresponding author), Univ Texas MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, Houston, TX 77030 USA.; Shi, XB (corresponding author), Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Houston, TX 77030 USA.; Shi, XB (corresponding author), Univ Texas Houston, Grad Sch Biomed Sci, Genes & Dev & Epigenet & Mol Carcinogenesis Grad, Houston, TX 77030 USA.
EM alliscd@rockefeller.edu; scott_armstrong@dfci.harvard.edu; xbshi@mdanderson.org
FU NIH [1R01CA204639-01, CA66996, CA140575, R01HG007538, R01CA193466]; Leukaemia and Lymphoma Society [LLS-SCOR 7006-13]; Rockefeller University; NIH/NCI [1R01CA204020-01]; Cancer Prevention and Research Institute of Texas [RP160237, RP170285]; Welch Foundation [G1719]; Major State Basic Research Development Program in China [2016YFA0500700, 2015CB910503]; Tsinghua University Initiative Scientific Research Program; National Cancer Institute [P30CA016672, P01CA066996, P30CA008748, R01CA193466] Funding Source: NIH RePORTER
NR 27
TC 217
Z9 257
U1 3
U2 86
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 9
PY 2017
VL 543
IS 7644
BP 265
EP +
DI 10.1038/nature21687
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0GQ
UT WOS:000395688700044
PM 28241141
DA 2026-03-09
ER

PT J
AU Gelebart, AH
   Mulder, DJ
   Varga, M
   Konya, A
   Vantomme, G
   Meijer, EW
   Selinger, RLB
   Broer, DJ
AF Gelebart, Anne Helene
   Mulder, Dirk Jan
   Varga, Michael
   Konya, Andrew
   Vantomme, Ghislaine
   Meijer, E. W.
   Selinger, Robin L. B.
   Broer, Dirk J.
TI Making waves in a photoactive polymer film
SO NATURE
LA English
DT Article
ID crystal network actuators; self-oscillating gel; peristaltic motion; light; azobenzene; driven; photoisomerization; devices
AB Oscillating materials(1-4) that adapt their shapes in response to external stimuli are of interest for emerging applications in medicine and robotics. For example, liquid-crystal networks can be programmed to undergo stimulus-induced deformations in various geometries, including in response to light(5,6). Azobenzene molecules are often incorporated into liquid-crystal polymer films to make them photoresponsive(7-11); however, in most cases only the bending responses of these films have been studied, and relaxation after photo-isomerization is rather slow. Modifying the core or adding substituents to the azobenzene moiety can lead to marked changes in photophysical and photochemical properties(12-15), providing an opportunity to circumvent the use of a complex set-up that involves multiple light sources, lenses or mirrors. Here, by incorporating azobenzene derivatives with fast cis-to-trans thermal relaxation into liquid-crystal networks, we generate photoactive polymer films that exhibit continuous, directional, macroscopic mechanical waves under constant light illumination, with a feedback loop that is driven by self-shadowing. We explain the mechanism of wave generation using a theoretical model and numerical simulations, which show good qualitative agreement with our experiments. We also demonstrate the potential application of our photoactive films in light-driven locomotion and self-cleaning surfaces, and anticipate further applications in fields such as photomechanical energy harvesting and miniaturized transport.
C1 [Gelebart, Anne Helene; Mulder, Dirk Jan; Broer, Dirk J.] Eindhoven Univ Technol, Lab Funct Organ Mat & Devices SFD, Dept Chem Engn & Chem, Eindhoven, Netherlands.
   [Gelebart, Anne Helene; Vantomme, Ghislaine; Meijer, E. W.; Broer, Dirk J.] Eindhoven Univ Technol, ICMS, Eindhoven, Netherlands.
   [Varga, Michael; Konya, Andrew; Selinger, Robin L. B.] Kent State Univ, Inst Liquid Crystal, Chem Phys Interdisciplinary Program, Kent, OH 44242 USA.
C3 Eindhoven University of Technology; Eindhoven University of Technology; University System of Ohio; Kent State University; Kent State University Salem; Kent State University Kent
RP Broer, DJ (corresponding author), Eindhoven Univ Technol, Lab Funct Organ Mat & Devices SFD, Dept Chem Engn & Chem, Eindhoven, Netherlands.; Broer, DJ (corresponding author), Eindhoven Univ Technol, ICMS, Eindhoven, Netherlands.; Selinger, RLB (corresponding author), Kent State Univ, Inst Liquid Crystal, Chem Phys Interdisciplinary Program, Kent, OH 44242 USA.
EM rselinge@kent.edu; D.Broer@tue.nl
FU Netherlands Organization for Scientific Research (NWO TOP PUNT) [10018944]; European Research Council (Vibrate ERC) [669991]; US National Science Foundation [DMR 1409658, CMMI 1436565]; European Union [607602]; Dutch Polymer Institute (DPI) [776n]; Directorate For Engineering; Div Of Civil, Mechanical, & Manufact Inn [1436565] Funding Source: National Science Foundation; European Research Council (ERC) [669991] Funding Source: European Research Council (ERC)
NR 27
TC 920
Z9 996
U1 33
U2 1220
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 29
PY 2017
VL 546
IS 7660
BP 632
EP +
DI 10.1038/nature22987
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY9QB
UT WOS:000404332000043
PM 28658225
DA 2026-03-09
ER

PT J
AU Heintz, C
   Doktor, TK
   Lanjuin, A
   Escoubas, CC
   Zhang, Y
   Weir, HJ
   Dutta, S
   Silva-García, CG
   Bruun, GH
   Morantte, I
   Hoxhaj, G
   Manning, BD
   Andresen, BS
   Mair, WB
AF Heintz, Caroline
   Doktor, Thomas K.
   Lanjuin, Anne
   Escoubas, Caroline C.
   Zhang, Yue
   Weir, Heather J.
   Dutta, Sneha
   Silva-Garcia, Carlos Giovanni
   Bruun, Gitte H.
   Morantte, Ianessa
   Hoxhaj, Gerta
   Manning, Brendan D.
   Andresen, Brage S.
   Mair, William B.
TI Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans
SO NATURE
LA English
DT Article
ID u2af large subunit; life-span; factor sf1; protein; interacts; genetics; reveals; disease; crtc-1; genes
AB Ageing is driven by a loss of transcriptional and protein homeostasis(1-3) and is the key risk factor for multiple chronic diseases. Interventions that attenuate or reverse systemic dysfunction associated with age therefore have the potential to reduce overall disease risk in the elderly. Precursor mRNA (pre-mRNA) splicing is a fundamental link between gene expression and the proteome, and deregulation of the splicing machinery is linked to several age-related chronic illnesses(4,5). However, the role of splicing homeostasis in healthy ageing remains unclear. Here we demonstrate that pre-mRNA splicing homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans. Using transcriptomics and in-depth splicing analysis in young and old animals fed ad libitum or subjected to dietary restriction, we find defects in global pre-mRNA splicing with age that are reduced by dietary restriction via splicing factor 1 (SFA-1; the C. elegans homologue of SF1, also known as branchpoint binding protein, BBP). We show that SFA-1 is specifically required for lifespan extension by dietary restriction and by modulation of the TORC1 pathway components AMPK, RAGA-1 and RSKS-1/S6 kinase. We also demonstrate that overexpression of SFA-1 is sufficient to extend lifespan. Together, these data demonstrate a role for RNA splicing homeostasis in dietary restriction longevity and suggest that modulation of specific spliceosome components may prolong healthy ageing.
C1 [Heintz, Caroline; Lanjuin, Anne; Escoubas, Caroline C.; Zhang, Yue; Weir, Heather J.; Dutta, Sneha; Silva-Garcia, Carlos Giovanni; Morantte, Ianessa; Hoxhaj, Gerta; Manning, Brendan D.; Mair, William B.] Harvard TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA.
   [Doktor, Thomas K.; Bruun, Gitte H.; Andresen, Brage S.] Univ Southern Denmark, Dept Biochem & Mol Biol, DK-5230 Odense, Denmark.
   [Doktor, Thomas K.; Bruun, Gitte H.; Andresen, Brage S.] Univ Southern Denmark, Villum Ctr Bioanalyt Sci, DK-5230 Odense, Denmark.
   [Escoubas, Caroline C.] Univ Nice Sophia Antipolis, Fac Med, CNRS, IRCAN,INSERM U1081,UMR7284, F-06107 Nice, France.
   [Morantte, Ianessa] Rockefeller Univ, Lab Neurophysiol & Behav, New York, NY 10065 USA.
C3 Harvard University; Harvard T.H. Chan School of Public Health; University of Southern Denmark; University of Southern Denmark; Universite Cote d'Azur; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Rockefeller University
RP Mair, WB (corresponding author), Harvard TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA.
EM wmair@hsph.harvard.edu
FU Swiss National Science Foundation [P2ZHP3_151609]; Fonds National de la Recherche Luxembourg [AFR7883116]; Lawrence Ellison Medical Foundation [U54CA155626]; Glenn Foundation for Medical Research; National Institutes of Health (NIH) [1R01AG044346]; Ligue Nationale contre le Cancer; Novo Nordisk Foundation [NNF13OC0007939]; Swiss National Science Foundation (SNF) [P2ZHP3_151609] Funding Source: Swiss National Science Foundation (SNF); National Institute on Aging [R01AG044346] Funding Source: NIH RePORTER; Novo Nordisk Fonden [NNF13OC0007939] Funding Source: researchfish; Villum Fonden [00007292] Funding Source: researchfish
NR 41
TC 153
Z9 181
U1 1
U2 80
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 5
PY 2017
VL 541
IS 7635
BP 102
EP +
DI 10.1038/nature20789
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6NA
UT WOS:000396119500038
PM 27919065
DA 2026-03-09
ER

PT J
AU Metsky, HC
   Matranga, CB
   Wohl, S
   Schaffner, SF
   Freije, CA
   Winnicki, SM
   West, K
   Qu, J
   Baniecki, ML
   Gladden-Young, A
   Lin, AE
   Tomkins-Tinch, CH
   Ye, SH
   Park, DJ
   Luo, CY
   Barnes, KG
   Shah, RR
   Chak, B
   Barbosa-Lima, G
   Delatorre, E
   Vieira, YR
   Paul, LM
   Tan, AL
   Barcellona, CM
   Porcelli, MC
   Vasquez, C
   Cannons, AC
   Cone, MR
   Hogan, KN
   Kopp, EW
   Anzinger, JJ
   Garcia, KF
   Parham, LA
   Ramírez, RMG
   Montoya, MCM
   Rojas, DP
   Brown, CM
   Hennigan, S
   Sabina, B
   Scotland, S
   Gangavarapu, K
   Grubaugh, ND
   Oliveira, G
   Robles-Sikisaka, R
   Rambaut, A
   Gehrke, L
   Smole, S
   Halloran, ME
   Villar, L
   Mattar, S
   Lorenzana, I
   Cerbino-Neto, J
   Valim, C
   Degrave, W
   Bozza, PT
   Gnirke, A
   Andersen, KG
   Isern, S
   Michael, SF
   Bozza, FA
   Souza, TML
   Bosch, I
   Yozwiak, NL
   MacInnis, BL
   Sabeti, PC
AF Metsky, Hayden C.
   Matranga, Christian B.
   Wohl, Shirlee
   Schaffner, Stephen F.
   Freije, Catherine A.
   Winnicki, Sarah M.
   West, Kendra
   Qu, James
   Baniecki, Mary Lynn
   Gladden-Young, Adrianne
   Lin, Aaron E.
   Tomkins-Tinch, Christopher H.
   Ye, Simon H.
   Park, Daniel J.
   Luo, Cynthia Y.
   Barnes, Kayla G.
   Shah, Rickey R.
   Chak, Bridget
   Barbosa-Lima, Giselle
   Delatorre, Edson
   Vieira, Yasmine R.
   Paul, Lauren M.
   Tan, Amanda L.
   Barcellona, Carolyn M.
   Porcelli, Mario C.
   Vasquez, Chalmers
   Cannons, Andrew C.
   Cone, Marshall R.
   Hogan, Kelly N.
   Kopp, Edgar W.
   Anzinger, Joshua J.
   Garcia, Kimberly F.
   Parham, Leda A.
   Gelvez Ramirez, Rosa M.
   Miranda Montoya, Maria C.
   Rojas, Diana P.
   Brown, Catherine M.
   Hennigan, Scott
   Sabina, Brandon
   Scotland, Sarah
   Gangavarapu, Karthik
   Grubaugh, Nathan D.
   Oliveira, Glenn
   Robles-Sikisaka, Refugio
   Rambaut, Andrew
   Gehrke, Lee
   Smole, Sandra
   Halloran, M. Elizabeth
   Villar, Luis
   Mattar, Salim
   Lorenzana, Ivette
   Cerbino-Neto, Jose
   Valim, Clarissa
   Degrave, Wim
   Bozza, Patricia T.
   Gnirke, Andreas
   Andersen, Kristian G.
   Isern, Sharon
   Michael, Scott F.
   Bozza, Fernando A.
   Souza, Thiago M. L.
   Bosch, Irene
   Yozwiak, Nathan L.
   MacInnis, Bronwyn L.
   Sabeti, Pardis C.
TI Zika virus evolution and spread in the Americas
SO NATURE
LA English
DT Article
ID ebola; transmission; performance; accuracy; database; models
AB Although the recent Zika virus (ZIKV) epidemic in the Americas and its link to birth defects have attracted a great deal of attention(1,2), much remains unknown about ZIKV disease epidemiology and ZIKV evolution, in part owing to a lack of genomic data. Here we address this gap in knowledge by using multiple sequencing approaches to generate 110 ZIKV genomes from clinical and mosquito samples from 10 countries and territories, greatly expanding the observed viral genetic diversity from this outbreak. We analysed the timing and patterns of introductions into distinct geographic regions; our phylogenetic evidence suggests rapid expansion of the outbreak in Brazil and multiple introductions of outbreak strains into Puerto Rico, Honduras, Colombia, other Caribbean islands, and the continental United States. We find that ZIKV circulated undetected in multiple regions for many months before the first locally transmitted cases were confirmed, highlighting the importance of surveillance of viral infections. We identify mutations with possible functional implications for ZIKV biology and pathogenesis, as well as those that might be relevant to the effectiveness of diagnostic tests.
C1 [Metsky, Hayden C.; Matranga, Christian B.; Wohl, Shirlee; Schaffner, Stephen F.; Freije, Catherine A.; Winnicki, Sarah M.; West, Kendra; Qu, James; Baniecki, Mary Lynn; Gladden-Young, Adrianne; Lin, Aaron E.; Tomkins-Tinch, Christopher H.; Ye, Simon H.; Park, Daniel J.; Luo, Cynthia Y.; Barnes, Kayla G.; Shah, Rickey R.; Chak, Bridget; Gnirke, Andreas; Yozwiak, Nathan L.; MacInnis, Bronwyn L.; Sabeti, Pardis C.] Broad Inst MIT & Harvard, Cambridge, MA USA.
   [Metsky, Hayden C.] MIT, Dept Elect Engn & Comp Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Wohl, Shirlee; Schaffner, Stephen F.; Freije, Catherine A.; Lin, Aaron E.; Luo, Cynthia Y.; Barnes, Kayla G.; Chak, Bridget; Yozwiak, Nathan L.; Sabeti, Pardis C.] Harvard Univ, Dept Organism & Evolutionary Biol, Ctr Syst Biol, Cambridge, MA 02138 USA.
   [Schaffner, Stephen F.; Barnes, Kayla G.; Valim, Clarissa; MacInnis, Bronwyn L.; Sabeti, Pardis C.] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA.
   [Ye, Simon H.] MIT, Harvard Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Shah, Rickey R.] Harvard Univ, Extens Sch, Cambridge, MA 02138 USA.
   [Barbosa-Lima, Giselle; Vieira, Yasmine R.; Cerbino-Neto, Jose; Bozza, Fernando A.] Fdn Oswaldo Cruz FIOCRUZ, Natl Inst Infect Dis Evandro Chagas, Rio De Janeiro, Brazil.
   [Delatorre, Edson] Fiocruz MS, Inst Oswaldo Cruz, Lab AIDS & Imunol Mol, Rio De Janeiro, Brazil.
   [Paul, Lauren M.; Tan, Amanda L.; Barcellona, Carolyn M.; Isern, Sharon; Michael, Scott F.] Florida Gulf Coast Univ, Coll Arts & Sci, Dept Biol Sci, Ft Myers, FL USA.
   [Porcelli, Mario C.; Vasquez, Chalmers] Miami Dade Cty Mosquito Control, Miami, FL USA.
   [Cannons, Andrew C.; Cone, Marshall R.; Hogan, Kelly N.; Kopp, Edgar W.] Bur Publ Hlth Labs, Div Dis Control & Hlth Protect, Florida Dept Hlth, Tampa, FL USA.
   [Anzinger, Joshua J.] Univ West Indies, Dept Microbiol, Kingston, Jamaica.
   [Garcia, Kimberly F.; Parham, Leda A.; Lorenzana, Ivette] Univ Nacl Autonoma Honduras, Inst Invest Microbiol, Tegucigalpa, Honduras.
   [Gelvez Ramirez, Rosa M.; Miranda Montoya, Maria C.; Villar, Luis] Univ Ind Santander, Grp Epidemiol Clin, Bucaramanga, Colombia.
   [Rojas, Diana P.] Univ Florida, Dept Epidemiol, Coll Publ Hlth & Hlth Profess, Gainesville, FL USA.
   [Brown, Catherine M.; Hennigan, Scott; Sabina, Brandon; Scotland, Sarah; Smole, Sandra] Massachusetts Dept Publ Hlth, Jamaica, NY USA.
   [Gangavarapu, Karthik; Grubaugh, Nathan D.; Robles-Sikisaka, Refugio; Andersen, Kristian G.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA.
   [Oliveira, Glenn; Andersen, Kristian G.] Scripps Translat Sci Inst, La Jolla, CA USA.
   [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH9 3FL, Midlothian, Scotland.
   [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA.
   [Gehrke, Lee; Bosch, Irene] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Gehrke, Lee] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA USA.
   [Halloran, M. Elizabeth] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA.
   [Halloran, M. Elizabeth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA.
   [Mattar, Salim] Univ Cordoba, Inst Trop Biol Res, Monteria, Cordoba, Colombia.
   [Valim, Clarissa] Michigan State Univ, Dept Osteopath Med Specialties, E Lansing, MI 48824 USA.
   [Degrave, Wim] Fiocruz MS, Inst Oswaldo Cruz, Lab Genem Func & Bioinformat, Rio De Janeiro, Brazil.
   [Bozza, Patricia T.] Inst Oswaldo Cruz, Fdn Oswaldo Cruz, Lab Imunofarmacol, Rio De Janeiro, Brazil.
   [Andersen, Kristian G.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA.
   [Bozza, Fernando A.] DOr Inst Res & Educ, Rio De Janeiro, Brazil.
   [Souza, Thiago M. L.] Fiocruz MS, Natl Inst Sci & Technol Innovat Neglected Dis, Rio De Janeiro, Brazil.
   [Souza, Thiago M. L.] Fiocruz MS, Ctr Technol Dev Hlth, Rio De Janeiro, Brazil.
   [Sabeti, Pardis C.] Howard Hughes Med Inst, Chevy Chase, MD USA.
C3 Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Massachusetts Institute of Technology (MIT); Harvard University; Harvard University; Harvard T.H. Chan School of Public Health; Massachusetts Institute of Technology (MIT); Harvard University; Fundacao Oswaldo Cruz; Fundacao Oswaldo Cruz; State University System of Florida; Florida Gulf Coast University; Florida Department of Health; University West Indies Mona Jamaica; Universidad Nacional Autonoma de Honduras; Universidad Industrial de Santander; State University System of Florida; University of Florida; Massachusetts Department of Public Health; Scripps Research Institute; Scripps Research Institute; University of Edinburgh; National Institutes of Health (NIH) - USA; NIH Fogarty International Center (FIC); Massachusetts Institute of Technology (MIT); Harvard University; Harvard Medical School; Fred Hutchinson Cancer Center; University of Washington; University of Washington Seattle; Michigan State University; Fundacao Oswaldo Cruz; Fundacao Oswaldo Cruz; Scripps Research Institute; IDOR - Instituto D'Or de Ensino e Pesquisa; Fundacao Oswaldo Cruz; Fundacao Oswaldo Cruz; Center for Technological Development in Health (CDTS); Howard Hughes Medical Institute
RP MacInnis, BL (corresponding author), Broad Inst MIT & Harvard, Cambridge, MA USA.; MacInnis, BL (corresponding author), Harvard Univ, Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA.; Souza, TML (corresponding author), Fiocruz MS, Natl Inst Sci & Technol Innovat Neglected Dis, Rio De Janeiro, Brazil.; Souza, TML (corresponding author), Fiocruz MS, Ctr Technol Dev Hlth, Rio De Janeiro, Brazil.
EM tmoreno@cdts.fiocruz.br; bronwyn@broadinstitute.org
FU Marc and Lynne Benioff; NIH NIAID [U19AI110818, 1R01AI099210, AI100190, HHSN272201400048C]; Howard Hughes Medical Institute; Harvard University Burke Global Health Fellowship; Broad Institute BroadNext10 program; AWS Cloud Credits for Research; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [440909/2016-3]; Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro [E 26/201.320/2016, E 26/201.332/2016, E 26/010.000194/2015]; MIDAS National Institute of General Medical Sciences [U54GM111274]; AEDES Network; Colombian Science, Technology and Innovation Fund of Sistema General de Regalias-BPIN [2013000100011]; ASTMH Shope Fellowship; NSF DGE [1144152]; PNPD/CAPES Postdoctoral Fellowship; Fulbright Colciencias Doctoral Scholarship; NIH [5T32AI007244 33]; EU [278433 PREDEMICS, 643476 COMPARE]; NIH NCATS CTSA [UL1TR001114]; Ray Thomas Foundation; Pew Biomedical Scholarship; National Institute of Allergy and Infectious Diseases [U19AI110818, T32AI007244] Funding Source: NIH RePORTER; Direct For Education and Human Resources; Division Of Graduate Education [1144152] Funding Source: National Science Foundation
NR 68
TC 278
Z9 347
U1 2
U2 89
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 15
PY 2017
VL 546
IS 7658
BP 411
EP +
DI 10.1038/nature22402
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EX5BK
UT WOS:000403250900036
PM 28538734
DA 2026-03-09
ER

PT J
AU Karliner, M
   Rosner, JL
AF Karliner, Marek
   Rosner, Jonathan L.
TI Quark-level analogue of nuclear fusion with doubly heavy baryons
SO NATURE
LA English
DT Article
AB The essence of nuclear fusion is that energy can be released by the rearrangement of nucleons between the initial-and final-state nuclei. The recent discovery(1) of the first doubly charmed baryon Xi(++)(cc), which contains two charm quarks (c) and one up quark (u) and has a mass of about 3,621 megaelectronvolts (MeV) (the mass of the proton is 938 MeV) also revealed a large binding energy of about 130 MeV between the two charm quarks. Here we report that this strong binding enables a quark-rearrangement, exothermic reaction in which two heavy baryons (Lambda(c)) undergo fusion to produce the doubly charmed baryon Xi(++)(cc) and a neutron n (Lambda(c)Lambda(c) -> Xi(++)(cc) n), resulting in an energy release of 12 MeV. This reaction is a quark-level analogue of the deuterium-tritium nuclear fusion reaction (DT -> He-4 n). The much larger binding energy (approximately 280 MeV) between two bottom quarks (b) causes the analogous reaction with bottom quarks (Lambda(b)Lambda(b) -> Xi(0)(bb) n) to have a much larger energy release of about 138 MeV. We suggest some experimental setups in which the highly exothermic nature of the fusion of two heavy-quark baryons might manifest itself. At present, however, the very short lifetimes of the heavy bottom and charm quarks preclude any practical applications of such reactions.
C1 [Karliner, Marek] Tel Aviv Univ, Sch Phys & Astron, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel.
   [Rosner, Jonathan L.] Univ Chicago, Enrico Fermi Inst, 5640 South Ellis Ave, Chicago, IL 60637 USA.
   [Rosner, Jonathan L.] Univ Chicago, Dept Phys, 5640 South Ellis Ave, Chicago, IL 60637 USA.
C3 Tel Aviv University; University of Chicago; University of Chicago
RP Karliner, M (corresponding author), Tel Aviv Univ, Sch Phys & Astron, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel.
EM marek@post.tau.ac.il
NR 18
TC 26
Z9 28
U1 0
U2 17
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 2
PY 2017
VL 551
IS 7678
BP 89
EP 91
DI 10.1038/nature24289
PG 3
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FL4SY
UT WOS:000414222900050
PM 29094704
DA 2026-03-09
ER

PT J
AU Gaudi, BS
   Stassun, KG
   Collins, KA
   Beatty, TG
   Zhou, G
   Latham, DW
   Bieryla, A
   Eastman, JD
   Siverd, RJ
   Crepp, JR
   Gonzales, EJ
   Stevens, DJ
   Buchhave, LA
   Pepper, J
   Johnson, MC
   Colon, KD
   Jensen, ELN
   Rodriguez, JE
   Bozza, V
   Novati, SC
   D'Ago, G
   Dumont, MT
   Ellis, T
   Gaillard, C
   Jang-Condell, H
   Kasper, DH
   Fukui, A
   Gregorio, J
   Ito, A
   Kielkopf, JF
   Manner, M
   Matt, K
   Narita, N
   Oberst, TE
   Reed, PA
   Scarpetta, G
   Stephens, DC
   Yeigh, RR
   Zambelli, R
   Fulton, BJ
   Howard, AW
   James, DJ
   Penny, M
   Bayliss, D
   Curtis, IA
   Depoy, DL
   Esquerdo, GA
   Gould, A
   Joner, MD
   Kuhn, RB
   Labadie-Bartz, J
   Lund, MB
   Marshall, JL
   McLeod, KK
   Pogge, RW
   Relles, H
   Stockdale, C
   Tan, TG
   Trueblood, M
   Trueblood, P
AF Gaudi, B. Scott
   Stassun, Keivan G.
   Collins, Karen A.
   Beatty, Thomas G.
   Zhou, George
   Latham, David W.
   Bieryla, Allyson
   Eastman, Jason D.
   Siverd, Robert J. .
   Crepp, Justin R.
   Gonzales, Erica J.
   Stevens, Daniel J.
   Buchhave, Lars A.
   Pepper, Joshua
   Johnson, Marshall C.
   Colon, Knicole D.
   Jensen, Eric L. N.
   Rodriguez, Joseph E.
   Bozza, Valerio
   Novati, Sebastiano Calchi
   D'Ago, Giuseppe
   Dumont, Mary T.
   Ellis, Tyler
   Gaillard, Clement
   Jang-Condell, Hannah
   Kasper, David H.
   Fukui, Akihiko
   Gregorio, Joao
   Ito, Ayaka
   Kielkopf, John F.
   Manner, Mark
   Matt, Kyle
   Narita, Norio
   Oberst, Thomas E.
   Reed, Phillip A.
   Scarpetta, Gaetano
   Stephens, Denice C.
   Yeigh, Rex R.
   Zambelli, Roberto
   Fulton, B. J.
   Howard, Andrew W.
   James, David J.
   Penny, Matthew
   Bayliss, Daniel
   Curtis, Ivan A.
   Depoy, D. L.
   Esquerdo, Gilbert A.
   Gould, Andrew
   Joner, Michael D.
   Kuhn, Rudolf B.
   Labadie-Bartz, Jonathan
   Lund, Michael B.
   Marshall, Jennifer L.
   McLeod, Kim K.
   Pogge, Richard W.
   Relles, Howard
   Stockdale, Christopher
   Tan, T. G.
   Trueblood, Mark
   Trueblood, Patricia
TI A giant planet undergoing extreme-ultraviolet irradiation by its hot massive-star host
SO NATURE
LA English
DT Article
ID line-profile tomography; exoplanet transits; short-period; engulfment; radii; candidates; telescope; velocity; jupiters; catalog
AB The amount of ultraviolet irradiation and ablation experienced by a planet depends strongly on the temperature of its host star. Of the thousands of extrasolar planets now known, only six have been found that transit hot, A-type stars (with temperatures of 7,300-10,000 kelvin), and no planets are known to transit the even hotter B-type stars. For example, WASP-33 is an A-type star with a temperature of about 7,430 kelvin, which hosts the hottest known transiting planet, WASP-33b (ref. 1); the planet is itself as hot as a red dwarf star of type M (ref. 2). WASP-33b displays a large heat differential between its dayside and nightside(2), and is highly inflated-traits that have been linked to high insolation(3,4). However, even at the temperature of its dayside, its atmosphere probably resembles the molecule-dominated atmospheres of other planets and, given the level of ultraviolet irradiation it experiences, its atmosphere is unlikely to be substantially ablated over the lifetime of its star. Here we report observations of the bright star HD 195689 (also known as KELT-9), which reveal a close-in (orbital period of about 1.48 days) transiting giant planet, KELT-9b. At approximately 10,170 kelvin, the host star is at the dividing line between stars of type A and B, and we measure the dayside temperature of KELT-9b to be about 4,600 kelvin. This is as hot as stars of stellar type K4 (ref. 5). The molecules in K stars are entirely dissociated, and so the primary sources of opacity in the dayside atmosphere of KELT-9b are probably atomic metals. Furthermore, KELT-9b receives 700 times more extreme-ultraviolet radiation (that is, with wavelengths shorter than 91.2 nanometres) than WASP-33b, leading to a predicted range of mass-loss rates that could leave the planet largely stripped of its envelope during the main-sequence lifetime of the host star(6).
C1 [Gaudi, B. Scott; Stevens, Daniel J.; Johnson, Marshall C.; Penny, Matthew; Gould, Andrew; Pogge, Richard W.] Ohio State Univ, Dept Astron, 174 W 18Th Ave, Columbus, OH 43210 USA.
   [Stassun, Keivan G.; Collins, Karen A.; Lund, Michael B.] Vanderbilt Univ, Dept Phys & Astron, 6301 Stevenson Ctr, Nashville, TN 37235 USA.
   [Stassun, Keivan G.] Fisk Univ, Dept Phys, 1000 17th Ave North, Nashville, TN 37208 USA.
   [Beatty, Thomas G.] Penn State Univ, Ctr Exoplanets & Habitable Worlds, 525 Davey Lab, University Pk, PA 16802 USA.
   [Beatty, Thomas G.] Penn State Univ, Dept Astron & Astrophys, 525 Davey Lab, University Pk, PA 16802 USA.
   [Zhou, George; Latham, David W.; Bieryla, Allyson; Eastman, Jason D.; Rodriguez, Joseph E.; Esquerdo, Gilbert A.; Relles, Howard] Harvard Smithsonian Ctr Astrophys, 60 Garden St, Cambridge, MA 02138 USA.
   [Siverd, Robert J. .] Las Cumbres Observ Global Telescope Network, 6740 Cortona Dr,Suite 102, Santa Barbara, CA 93117 USA.
   [Crepp, Justin R.; Gonzales, Erica J.] Univ Notre Dame, Dept Phys, 225 Nieuwland Sci Hall, Notre Dame, IN 46556 USA.
   [Buchhave, Lars A.] Univ Copenhagen, Niels Bohr Inst, Juliane Maries Vej 30, DK-21S00 Copenhagen, Denmark.
   [Buchhave, Lars A.] Geol Museum, Ctr Star & Planet Format, Oster Voldgade 5, DK-1350 Copenhagen, Denmark.
   [Pepper, Joshua; Labadie-Bartz, Jonathan] Lehigh Univ, Dept Phys, 16 Mem Dr East, Bethlehem, PA 18015 USA.
   [Colon, Knicole D.] NASA, Ames Res Ctr, M-S 244-30, Moffett Field, CA 94035 USA.
   [Colon, Knicole D.] Bay Area Environm Res Inst, 625 2nd St Ste 209, Petaluma, CA 94952 USA.
   [Jensen, Eric L. N.] Swarthmore Coll, Dept Phys & Astron, Swarthmore, PA 19081 USA.
   [Bozza, Valerio; Novati, Sebastiano Calchi; Scarpetta, Gaetano] Univ Salerno, Dipartimento Fis ER Caianiello, Via Giovanni Paolo 2 132, I-84084 Fisciano, SA, Italy.
   [Bozza, Valerio] Ist Nazl Fis Nucl, Sez Napoli, I-80126 Naples, Italy.
   [Novati, Sebastiano Calchi; Scarpetta, Gaetano] CALTECH, IPAC, Mail Code 100-22,1200 East Calif Blvd, Pasadena, CA 91125 USA.
   [D'Ago, Giuseppe] IIASS, Via G Pellegrino 19, I-84019 Vietri Sul Mare, SA, Italy.
   [D'Ago, Giuseppe] INAF, Observ Capodimonte, Salita Moiariello 16, I-80131 Naples, Italy.
   [Dumont, Mary T.; Gaillard, Clement; Matt, Kyle; Stephens, Denice C.; Joner, Michael D.] Brigham Young Univ, Dept Phys & Astron, Provo, UT 84602 USA.
   [Dumont, Mary T.] Univ Calif Santa Cruz, Dept Astron & Astrophys, Santa Cruz, CA 95064 USA.
   [Ellis, Tyler; Jang-Condell, Hannah; Kasper, David H.; Yeigh, Rex R.] Univ Wyoming, Dept Phys & Astron, 1000 East Univ, Laramie, WY 82071 USA.
   [Ellis, Tyler] Louisiana State Univ, Dept Phys & Astron, 202 Nicholson Hall, Baton Rouge, LA 70803 USA.
   [Fukui, Akihiko] NINS, Natl Astron Observ Japan, Okayama Astrophys Observ, Okayama 7190232, Japan.
   [Gregorio, Joao] Atalaia Grp, Portalegre, Portugal.
   [Gregorio, Joao] Crow Observ, Portalegre, Portugal.
   [Ito, Ayaka; Narita, Norio] NINS, Natl Astron Observ Japan, 2-21-1 Osawa, Mitaka, Tokyo 1818588, Japan.
   [Ito, Ayaka] Hosei Univ, Grad Sch Sci & Engn, 3-7-2 Kajino Cho, Tokyo 1848584, Japan.
   [Kielkopf, John F.] Univ Louisville, Dept Phys & Astron, Louisville, KY 40292 USA.
   [Manner, Mark] Spot Observ, Nashville, TN 37206 USA.
   [Narita, Norio] Univ Tokyo, Dept Astron, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
   [Narita, Norio] NINS, Astrobiol Ctr, 2-21-1 Osawa, Mitaka, Tokyo 1818588, Japan.
   [Oberst, Thomas E.] Westminster Coll, Dept Phys, New Wilmington, PA 16172 USA.
   [Reed, Phillip A.] Kutztown State Univ, Dept Phys Sci, Kutztown, PA 19530 USA.
   [Zambelli, Roberto] Soc Astron Lunae, I-19030 Castelnuovo Magra, Italy.
   [Fulton, B. J.; Howard, Andrew W.] Univ Hawaii, Inst Astron, 2680 Woodlawn Dr, Honolulu, HI 96822 USA.
   [James, David J.] Univ Washington, Astron Dept, Box 351580, Seattle, WA 98195 USA.
   [Bayliss, Daniel] Univ Geneva, Observ Astron, 51 Chemin Maillettes, CH-1290 Chavannes Des Bois, Switzerland.
   [Curtis, Ivan A.] ICO, Adelaide, SA, Australia.
   [Depoy, D. L.; Marshall, Jennifer L.] Texas A&M Univ, George P & Cynthia Woods Mitchell Inst Fundamen P, College Stn, TX 77843 USA.
   [Depoy, D. L.; Marshall, Jennifer L.] Texas A&M Univ, Dept Phys & Astron, College Stn, TX 77843 USA.
   [Gould, Andrew] Max Planck Inst Astron, Konigstuhl 17, D-69117 Heidelberg, Germany.
   [Kuhn, Rudolf B.] South African Astron Observ, POB 9, ZA-7935 Cape Town, South Africa.
   [McLeod, Kim K.] Wellesley Coll, 106 Cent St, Wellesley, MA 02481 USA.
   [Stockdale, Christopher] Hazelwood Observ, Churchill, Vic, Australia.
   [Tan, T. G.] Perth Exoplanet Survey Telescope, Perth, WA, Australia.
   [Trueblood, Mark; Trueblood, Patricia] Winer Observ, Sonoita, AZ 85637 USA.
C3 University System of Ohio; Ohio State University; Vanderbilt University; Fisk University; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Smithsonian Astrophysical Observatory; Harvard University; Smithsonian Institution; University of Notre Dame; University of Copenhagen; Niels Bohr Institute; Lehigh University; National Aeronautics & Space Administration (NASA); NASA Ames Research Center; Swarthmore College; University of Salerno; Istituto Nazionale di Fisica Nucleare (INFN); California Institute of Technology; Istituto Nazionale Astrofisica (INAF); Brigham Young University; University of California System; University of California Santa Cruz; University of Wyoming; Louisiana State University System; Louisiana State University; National Institutes of Natural Sciences (NINS) - Japan; National Astronomical Observatory of Japan (NAOJ); National Institutes of Natural Sciences (NINS) - Japan; National Astronomical Observatory of Japan (NAOJ); Hosei University; University of Louisville; University of Tokyo; National Institutes of Natural Sciences (NINS) - Japan; Astrobiology Center (ABC); Westminster College Pennsylvania; Pennsylvania State System of Higher Education (PASSHE); Kutztown University - Pennsylvania; University of Hawaii System; University of Washington; University of Washington Seattle; University of Geneva; Texas A&M University System; Texas A&M University College Station; Texas A&M University System; Texas A&M University College Station; Max Planck Society; National Research Foundation - South Africa; South African Astronomical Observatory; Wellesley College; Perth Exoplanet Survey Telescope Observatory
RP Gaudi, BS (corresponding author), Ohio State Univ, Dept Astron, 174 W 18Th Ave, Columbus, OH 43210 USA.
EM gaudi.1@osu.edu
FU Ohio State University; Vanderbilt University; Lehigh University; NSF CAREER [AST-1056524]; NSF PAARE [AST-1358862]; Jet Propulsion Laboratory; Exoplanet Exploration Program of the National Aeronautics and Space Administration (NASA); National Science Foundation Graduate Research Fellowship [2014184874]; Harvard Future Faculty Leaders Postdoctoral fellowship; Japan Society for Promotion of Science (JSPS) KAKENHI [JP25247026]; W. M. Keck Foundation; NASA; Two Micron All Sky Survey; American Association of Variable Star Observers (AAVSO) Photometric All-Sky Survey (APASS); Robert Martin Ayers Sciences Fund; AAVSO Endowment; Grants-in-Aid for Scientific Research [17H04574] Funding Source: KAKEN; Division Of Physics; Direct For Mathematical & Physical Scien [1461219] Funding Source: National Science Foundation
NR 57
TC 210
Z9 235
U1 1
U2 17
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 22
PY 2017
VL 546
IS 7659
BP 514
EP +
DI 10.1038/nature22392
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY2QK
UT WOS:000403814100035
PM 28582774
DA 2026-03-09
ER

PT J
AU Gaudelli, NM
   Komor, AC
   Rees, HA
   Packer, MS
   Badran, AH
   Bryson, DI
   Liu, DR
AF Gaudelli, Nicole M.
   Komor, Alexis C.
   Rees, Holly A.
   Packer, Michael S.
   Badran, Ahmed H.
   Bryson, David I.
   Liu, David R.
TI Programmable base editing of A.T to G.C in genomic DNA without DNA cleavage
SO NATURE
LA English
DT Article
ID adenosine-deaminase; cytosine deamination; directed evolution; target base; precise; tada; mutation; rice
AB The spontaneous deamination of cytosine is a major source of transitions from C.G to T.A base pairs, which account for half of known pathogenic point mutations in humans. The ability to efficiently convert targeted A.T base pairs to G.C could therefore advance the study and treatment of genetic diseases. The deamination of adenine yields inosine, which is treated as guanine by polymerases, but no enzymes are known to deaminate adenine in DNA. Here we describe adenine base editors (ABEs) that mediate the conversion of A.T to G.C in genomic DNA. We evolved a transfer RNA adenosine deaminase to operate on DNA when fused to a catalytically impaired CRISPR-Cas9 mutant. Extensive directed evolution and protein engineering resulted in seventh-generation ABEs that convert targeted A.T base pairs efficiently to G.C (approximately 50% efficiency in human cells) with high product purity (typically at least 99.9%) and low rates of indels (typically no more than 0.1%). ABEs introduce point mutations more efficiently and cleanly, and with less off-target genome modification, than a current Cas9 nuclease-based method, and can install disease-correcting or disease-suppressing mutations in human cells. Together with previous base editors, ABEs enable the direct, programmable introduction of all four transition mutations without double-stranded DNA cleavage.
C1 [Gaudelli, Nicole M.; Komor, Alexis C.; Rees, Holly A.; Packer, Michael S.; Badran, Ahmed H.; Bryson, David I.; Liu, David R.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA.
   [Gaudelli, Nicole M.; Komor, Alexis C.; Rees, Holly A.; Packer, Michael S.; Badran, Ahmed H.; Bryson, David I.; Liu, David R.] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA.
   [Gaudelli, Nicole M.; Komor, Alexis C.; Rees, Holly A.; Packer, Michael S.; Badran, Ahmed H.; Bryson, David I.; Liu, David R.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Komor, Alexis C.] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA.
   [Packer, Michael S.; Bryson, David I.] Beam Therapeut, 675 West Kendall St, Cambridge, MA 02139 USA.
C3 Harvard University; Harvard University; Howard Hughes Medical Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of California System; University of California San Diego; Beam Therapeutics, Inc.
RP Liu, DR (corresponding author), Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA.; Liu, DR (corresponding author), Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA.; Liu, DR (corresponding author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
EM drliu@fas.harvard.edu
FU DARPA [HR0011-17-2-0049]; US NIH [RM1 HG009490, R01 EB022376, R35 GM118062]; HHMI; Ruth L. Kirchstein National Research Service Awards [F32 GM 112366, F32 GM106621];  [T32 GM008313]; National Human Genome Research Institute [RM1HG009490] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM008313, R35GM118062] Funding Source: NIH RePORTER
NR 43
TC 3019
Z9 3984
U1 41
U2 1311
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 23
PY 2017
VL 551
IS 7681
BP 464
EP +
DI 10.1038/nature24644
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FN5JO
UT WOS:000416043700037
PM 29160308
DA 2026-03-09
ER

PT J
AU Glazebrook, K
   Schreiber, C
   Labbé, I
   Nanayakkara, T
   Kacprzak, GG
   Oesch, PA
   Papovich, C
   Spitler, LR
   Straatman, CMS
   Tran, KVH
   Yuan, TT
AF Glazebrook, Karl
   Schreiber, Corentin
   Labbe, Ivo
   Nanayakkara, Themiya
   Kacprzak, Glenn G.
   Oesch, Pascal A.
   Papovich, Casey
   Spitler, Lee R.
   Straatman, Caroline M. S.
   Tran, Kim-Vy H.
   Yuan, Tiantian
TI A massive, quiescent galaxy at a redshift of 3.717
SO NATURE
LA English
DT Article
ID star-forming galaxy; similar-to 4; stellar mass; spectroscopy; zfourge
AB Finding massive galaxies that stopped forming stars in the early Universe presents an observational challenge because their rest-frame ultraviolet emission is negligible and they can only be reliably identified by extremely deep near-infrared surveys. These surveys have revealed the presence of massive, quiescent early-type galaxies(1-6) appearing as early as redshift z approximate to 2, an epoch three billion years after the Big Bang. Their age and formation processes have now been explained by an improved generation of galaxy-formation models(7-9), in which they form rapidly at z approximate to 3-4, consistent with the typical masses and ages derived from their observations. Deeper surveys have reported evidence for populations of massive, quiescent galaxies at even higher redshifts and earlier times, using coarsely sampled photometry. However, these early, massive, quiescent galaxies are not predicted by the latest generation of theoretical models(7-10). Here we report the spectroscopic confirmation of one such galaxy at redshift z = 3.717, with a stellar mass of 1.7 x 10(11) solar masses. We derive its age to be nearly half the age of the Universe at this redshift and the absorption line spectrum shows no current star formation. These observations demonstrate that the galaxy must have formed the majority of its stars quickly, within the first billion years of cosmic history in a short, extreme starburst. This ancestral starburst appears similar to those being found by submillimetre-wavelength surveys(11-14). The early formation of such massive systems implies that our picture of early galaxy assembly requires substantial revision.
C1 [Glazebrook, Karl; Nanayakkara, Themiya; Kacprzak, Glenn G.] Swinburne Univ Technol, Ctr Astrophys & Supercomp, POB 218, Hawthorn, Vic 3122, Australia.
   [Schreiber, Corentin; Labbe, Ivo] Leiden Univ, Leiden Observ, POB 9513, NL-2300 RA Leiden, Netherlands.
   [Oesch, Pascal A.] Univ Geneva, Observ Geneva, Chemin Maillettes 51, CH-1290 Chavannes Des Bois, Switzerland.
   [Papovich, Casey; Tran, Kim-Vy H.] Texas A&M Univ, Dept Phys & Astron, George P & Cynthia W Mitchell Inst Fundamental Ph, College Stn, TX 77843 USA.
   [Spitler, Lee R.] Macquarie Univ, Macquarie Res Ctr Astron Astrophys & Astrophoton, Sydney, NSW 2109, Australia.
   [Spitler, Lee R.] Australian Astron Observ, POB 915, N Ryde, NSW 1670, Australia.
   [Straatman, Caroline M. S.] Max Planck Inst Astron, Konigstuhl 17, D-69117 Heidelberg, Germany.
   [Yuan, Tiantian] Australian Natl Univ, Res Sch Astron & Astrophys, Cotter Rd, Weston, ACT 2611, Australia.
C3 Swinburne University of Technology; Leiden University; Leiden University - Excl LUMC; University of Geneva; Texas A&M University System; Texas A&M University College Station; Macquarie University; Max Planck Society; Australian National University
RP Glazebrook, K (corresponding author), Swinburne Univ Technol, Ctr Astrophys & Supercomp, POB 218, Hawthorn, Vic 3122, Australia.
EM kglazebrook@swin.edu.au
FU Australian Research Council (ARC) Discovery Program [DP130101460, DP160102235]; Australian Research Council through the award of a Future Fellowship [FT140100933]; Australian Research Council (ARC) Discovery Program [DP130101460, DP160102235]; Australian Research Council through the award of a Future Fellowship [FT140100933]; Direct For Mathematical & Physical Scien; Division Of Astronomical Sciences [1410728] Funding Source: National Science Foundation
NR 36
TC 223
Z9 242
U1 0
U2 10
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 6
PY 2017
VL 544
IS 7648
BP 71
EP +
DI 10.1038/nature21680
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EQ8GQ
UT WOS:000398323300034
PM 28382981
DA 2026-03-09
ER

PT J
AU Leach, JP
   Heallen, T
   Zhang, M
   Rahmani, M
   Morikawa, Y
   Hill, MC
   Segura, A
   Willerson, JT
   Martin, JF
AF Leach, John P.
   Heallen, Todd
   Zhang, Min
   Rahmani, Mahdis
   Morikawa, Yuka
   Hill, Matthew C. .
   Segura, Ana
   Willerson, James T.
   Martin, James F.
TI Hippo pathway deficiency reverses systolic heart failure after infarction
SO NATURE
LA English
DT Article
ID myocardial-infarction; cardiac fibrosis; transgenic mice; regeneration; injury; generation; tamoxifen; apoptosis; dynamics; survival
AB Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs, such as the heart are particularly vulnerable to organ failure. Once established, heart failure commonly results in mortality(1). The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration(2), is upregulated in human heart failure. Here we show that deletion of the Hippo pathway component Salvador (Salv) in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared with controls. Using translating ribosomal affinity purification, we isolate cardiomyocyte-specific translating messenger RNA. Hippo-deficient cardiomyocytes have increased expression of proliferative genes and stress response genes, such as the mitochondrial quality control gene, Park2. Genetic studies indicate that Park2 is essential for heart repair, suggesting a requirement for mitochondrial quality control in regenerating myocardium. Gene therapy with a virus encoding Salv short hairpin RNA improves heart function when delivered at the time of infarct or after ischaemic heart failure following myocardial infarction was established. Our findings indicate that the failing heart has a previously unrecognized reparative capacity involving more than cardiomyocyte renewal.
C1 [Leach, John P.; Zhang, Min; Martin, James F.] Baylor Coll Med, Dept Mol Physiol & Biophys, One Baylor Plaza, Houston, TX 77030 USA.
   [Heallen, Todd; Rahmani, Mahdis; Morikawa, Yuka; Segura, Ana; Willerson, James T.; Martin, James F.] Texas Heart Inst, 6770 Bertner Ave, Houston, TX 77030 USA.
   [Zhang, Min] Shanghai Childrens Med Ctr, Shanghai 200127, Peoples R China.
   [Hill, Matthew C. .; Martin, James F.] Baylor Coll Med, Program Dev Biol, One Baylor Plaza, Houston, TX 77030 USA.
   [Martin, James F.] Baylor Coll Med, Cardiovasc Res Inst, One Baylor Plaza, Houston, TX 77030 USA.
C3 Baylor College of Medicine; Texas Heart Institute; Shanghai Jiao Tong University; Baylor College of Medicine; Baylor College of Medicine
RP Martin, JF (corresponding author), Baylor Coll Med, Dept Mol Physiol & Biophys, One Baylor Plaza, Houston, TX 77030 USA.; Martin, JF (corresponding author), Texas Heart Inst, 6770 Bertner Ave, Houston, TX 77030 USA.; Martin, JF (corresponding author), Baylor Coll Med, Program Dev Biol, One Baylor Plaza, Houston, TX 77030 USA.; Martin, JF (corresponding author), Baylor Coll Med, Cardiovasc Res Inst, One Baylor Plaza, Houston, TX 77030 USA.
EM jfmartin@bcm.edu
FU National Institutes of Health [DE023177, HL127717, HL130804, HL118761, F31HL136065, 5T32HL007676-23]; Vivian L. Smith Foundation; State of Texas; LeDucq Foundation Transatlantic Networks of Excellence in Cardiovascular Research [14CVD01]; Intellectual and Developmental Disabilities Research Center from the Eunice Kennedy Shriver National Institute of Child Health & Human Development [1 U54 HD083092]; Mouse Phenotyping Core at Baylor College of Medicine [U54 HG006348]; American Heart Association Scientist Development Grant [16SDG26460001]; Neuroconnectivity core and Optical Imaging and Vital Microscopy core at Baylor College of Medicine; American Heart Association (AHA) [16SDG26460001] Funding Source: American Heart Association (AHA); National Heart Lung and Blood Institute [R01HL127717, R01HL118761] Funding Source: NIH RePORTER
NR 41
TC 351
Z9 420
U1 9
U2 124
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 12
PY 2017
VL 550
IS 7675
BP 260
EP +
DI 10.1038/nature24045
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FJ5YG
UT WOS:000412829500049
PM 28976966
DA 2026-03-09
ER

PT J
AU Chatterjee, S
   Law, CJ
   Wharton, RS
   Burke-Spolaor, S
   Hessels, JWT
   Bower, GC
   Cordes, JM
   Tendulkar, SP
   Bassa, CG
   Demorest, P
   Butler, BJ
   Seymour, A
   Scholz, P
   Abruzzo, MW
   Bogdanov, S
   Kaspi, VM
   Keimpema, A
   Lazio, TJW
   Marcote, B
   McLaughlin, MA
   Paragi, Z
   Ransom, SM
   Rupen, M
   Spitler, LG
   van Langevelde, HJ
AF Chatterjee, S.
   Law, C. J. .
   Wharton, R. S.
   Burke-Spolaor, S.
   Hessels, J. W. T.
   Bower, G. C.
   Cordes, J. M.
   Tendulkar, S. P.
   Bassa, C. G.
   Demorest, P.
   Butler, B. J.
   Seymour, A.
   Scholz, P.
   Abruzzo, M. W.
   Bogdanov, S.
   Kaspi, V. M.
   Keimpema, A.
   Lazio, T. J. . W.
   Marcote, B.
   McLaughlin, M. A.
   Paragi, Z.
   Ransom, S. M.
   Rupen, M.
   Spitler, L. G.
   van Langevelde, H. J. .
TI A direct localization of a fast radio burst and its host
SO NATURE
LA English
DT Article
ID gamma-ray bursts; photometric system; dispersion measure; alpha survey; milky-way; galaxy; pulses; stars; emission; redshift
AB Fast radio bursts(1,2) are astronomical radio flashes of unknown physical nature with durations of milliseconds. Their dispersive arrival times suggest an extragalactic origin and imply radio luminosities that are orders of magnitude larger than those of all known short-duration radio transients(3). So far all fast radio bursts have been detected with large single-dish telescopes with arcminute localizations, and attempts to identify their counterparts (source or host galaxy) have relied on the contemporaneous variability of field sources(4) or the presence of peculiar field stars(5) or galaxies(4). These attempts have not resulted in an unambiguous association(6,7) with a host or multi-wavelength counterpart. Here we report the subarcsecond localization of the fast radio burst FRB 121102, the only known repeating burst source(8-11), using high-time-resolution radio interferometric observations that directly image the bursts. Our precise localization reveals that FRB 121102 originates within 100 milliarcseconds of a faint 180-microJansky persistent radio source with a continuum spectrum that is consistent with non-thermal emission, and a faint (twenty-fifth magnitude) optical counterpart. The flux density of the persistent radio source varies by around ten per cent on day timescales, and very long baseline radio interferometry yields an angular size of less than 1.7 milliarcseconds. Our observations are inconsistent with the fast radio burst having a Galactic origin or its source being located within a prominent star-forming galaxy. Instead, the source appears to be co-located with a low-luminosity active galactic nucleus or a previously unknown type of extragalactic source. Localization and identification of a host or counterpart has been essential to understanding the origins and physics of other kinds of transient events, including gamma-ray bursts(12,13) and tidal disruption events(14). However, if other fast radio bursts have similarly faint radio and optical counterparts, our findings imply that direct subarcsecond localizations may be the only way to provide reliable associations.
C1 [Chatterjee, S.; Wharton, R. S.; Cordes, J. M.] Cornell Univ, Cornell Ctr Astrophys & Planetary Sci, Ithaca, NY 14853 USA.
   [Chatterjee, S.; Wharton, R. S.; Cordes, J. M.] Cornell Univ, Dept Astron, Ithaca, NY 14853 USA.
   [Law, C. J. .] Univ Calif Berkeley, Dept Astron, Berkeley, CA 94720 USA.
   [Law, C. J. .] Univ Calif Berkeley, Radio Astron Lab, Berkeley, CA 94720 USA.
   [Burke-Spolaor, S.; Demorest, P.; Butler, B. J.] Natl Radio Astron Observ, Socorro, NM 87801 USA.
   [Burke-Spolaor, S.; McLaughlin, M. A.] West Virginia Univ, Dept Phys & Astron, Morgantown, WV 26506 USA.
   [Burke-Spolaor, S.; McLaughlin, M. A.] West Virginia Univ, Ctr Gravitat Waves & Cosmol, Chestnut Ridge Res Bldg, Morgantown, WV 26505 USA.
   [Hessels, J. W. T.; Bassa, C. G.] Netherlands Inst Radio Astron, ASTRON, Postbus 2, NL-7990 AA Dwingeloo, Netherlands.
   [Hessels, J. W. T.] Univ Amsterdam, Anton Pannekoek Inst Astron, Sci Pk 904, NL-1098 XH Amsterdam, Netherlands.
   [Bower, G. C.] Acad Sinica, Inst Astron & Astrophys, 645 N Aohoku Pl, Hilo, HI 96720 USA.
   [Tendulkar, S. P.; Kaspi, V. M.] McGill Univ, Dept Phys, 3600 Univ St, Montreal, PQ H3A 2T8, Canada.
   [Tendulkar, S. P.; Kaspi, V. M.] McGill Univ, McGill Space Inst, 3600 Univ St, Montreal, PQ H3A 2T8, Canada.
   [Seymour, A.] Arecibo Observ, HC3 Box 53995, Arecibo, PR 00612 USA.
   [Scholz, P.; Rupen, M.] Natl Res Council Canada, Herzberg Astron & Astrophys, Domin Radio Astrophys Observ, POB 248, Penticton, BC V2A 6J9, Canada.
   [Abruzzo, M. W.] Haverford Coll, 370 Lancaster Ave, Haverford, PA 19041 USA.
   [Bogdanov, S.] Columbia Univ, Columbia Astrophys Lab, 538 W 120th St, New York, NY 10027 USA.
   [Keimpema, A.; Marcote, B.; Paragi, Z.; van Langevelde, H. J. .] Joint Inst VLBI ERIC, Postbus 2, NL-7990 AA Dwingeloo, Netherlands.
   [Lazio, T. J. . W.] CALTECH, Jet Prop Lab, 4800 Oak Grove Dr, Pasadena, CA 91109 USA.
   [Ransom, S. M.] Natl Radio Astron Observ, Edgemont Rd, Charlottesville, VA 22903 USA.
   [Spitler, L. G.] Max Planck Inst Radioastron, Hugel 69, D-53121 Bonn, Germany.
   [van Langevelde, H. J. .] Leiden Univ, Sterrewacht Leiden, Postbus 9513, NL-2300 RA Leiden, Netherlands.
C3 Cornell University; Cornell University; University of California System; University of California Berkeley; University of California System; University of California Berkeley; National Radio Astronomy Observatory (NRAO); West Virginia University; West Virginia University; University of Amsterdam; Academia Sinica - Taiwan; McGill University; McGill University; National Aeronautics & Space Administration (NASA); National Research Council Canada; Haverford College; Columbia University; National Aeronautics & Space Administration (NASA); NASA Jet Propulsion Laboratory (JPL); California Institute of Technology; National Radio Astronomy Observatory (NRAO); Max Planck Society; Leiden University - Excl LUMC; Leiden University
RP Chatterjee, S (corresponding author), Cornell Univ, Cornell Ctr Astrophys & Planetary Sci, Ithaca, NY 14853 USA.
EM shami.chatterjee@cornell.edu
FU Direct For Mathematical & Physical Scien; Division Of Astronomical Sciences [1611606] Funding Source: National Science Foundation; Direct For Mathematical & Physical Scien; Division Of Astronomical Sciences [1156780] Funding Source: National Science Foundation; Direct For Mathematical & Physical Scien; Division Of Physics [1430284] Funding Source: National Science Foundation; Office of Integrative Activities; Office Of The Director [1458952] Funding Source: National Science Foundation
NR 47
TC 723
Z9 803
U1 0
U2 37
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 5
PY 2017
VL 541
IS 7635
BP 58
EP +
DI 10.1038/nature20797
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6NA
UT WOS:000396119500028
PM 28054614
DA 2026-03-09
ER

PT J
AU Hirschi, M
   Herzik, MA
   Wie, JH
   Suo, Y
   Borschel, WF
   Ren, DJ
   Lander, GC
   Lee, SY
AF Hirschi, Marscha
   Herzik, Mark A., Jr.
   Wie, Jinhong
   Suo, Yang
   Borschel, William F.
   Ren, Dejian
   Lander, Gabriel C.
   Lee, Seok-Yong
TI Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3
SO NATURE
LA English
DT Article
ID beam-induced motion; trpv1 structures; resolution; mutation; software; program
AB The modulation of ion channel activity by lipids is increasingly recognized as a fundamental component of cellular signalling. The transient receptor potential mucolipin (TRPML) channel family belongs to the TRP superfamily1,2 and is composed of three members: TRPML1-TRPML3. TRPMLs are the major Ca2+-permeable channels on late endosomes and lysosomes (LEL). They regulate the release of Ca2+ from organelles, which is important for various physiological processes, including organelle trafficking and fusion3. Loss-of-function mutations in the MCOLN1 gene, which encodes TRPML1, cause the neurodegenerative lysosomal storage disorder mucolipidosis type IV, and a gain-of-function mutation (Ala419Pro) in TRPML3 gives rise to the varitint-waddler (Va) mouse phenotype4-6. Notably, TRPML channels are activated by the lowabundance and LEL-enriched signalling lipid phosphatidylinositol3,5- bisphosphate (PtdIns(3,5) P-2), whereas other phosphoinositides such as PtdIns(4,5) P-2, which is enriched in plasma membranes, inhibit TRPMLs(7,8). Conserved basic residues at the N terminus of the channel are important for activation by PtdIns(3,5) P2 and inhibition by PtdIns(4,5) P-2 (8). However, owing to a lack of structural information, the mechanism by which TRPML channels recognize PtdIns(3,5) P-2 and increase their Ca2+ conductance remains unclear. Here we present the cryo-electron microscopy (cryo-EM) structure of a full-length TRPML3 channel from the common marmoset (Callithrix jacchus) at an overall resolution of 2.9 angstrom. Our structure reveals not only the molecular basis of ion conduction but also the unique architecture of TRPMLs, wherein the voltage sensor-like domain is linked to the pore via a cytosolic domain that we term the mucolipin domain. Combined with functional studies, these data suggest that the mucolipin domain is responsible for PtdIns(3,5) P-2 binding and subsequent channel activation, and that it acts as a 'gating pulley' for lipid-dependent TRPML gating.
C1 [Hirschi, Marscha; Suo, Yang; Borschel, William F.; Lee, Seok-Yong] Duke Univ, Dept Biochem, Sch Med, Durham, NC 27710 USA.
   [Herzik, Mark A., Jr.; Lander, Gabriel C.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA.
   [Wie, Jinhong; Ren, Dejian] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA.
C3 Duke University; Scripps Research Institute; University of Pennsylvania
RP Lee, SY (corresponding author), Duke Univ, Dept Biochem, Sch Med, Durham, NC 27710 USA.; Lander, GC (corresponding author), Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA.
EM glander@scripps.edu; seok-yong.lee@duke.edu
FU National Institutes of Health (NIH) [R35NS097241, DP2EB020402, R01NS055293, R01NS074257]; Helen Hay Whitney Foundation; NIH [S100D021634]; National Institute of Neurological Disorders and Stroke [R35NS097241] Funding Source: NIH RePORTER
NR 52
TC 96
Z9 114
U1 0
U2 30
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 19
PY 2017
VL 550
IS 7676
BP 411
EP 414
DI 10.1038/nature24055
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK1NF
UT WOS:000413247900064
PM 29019979
DA 2026-03-09
ER

PT J
AU Frigge, T
   Hafke, B
   Witte, T
   Krenzer, B
   Streubühr, C
   Syed, AS
   Trontl, VM
   Avigo, I
   Zhou, P
   Ligges, M
   von der Linde, D
   Bovensiepen, U
   Horn-von Hoegen, M
   Wippermann, S
   Lücke, A
   Gerstmann, U
   Schmidt, WG
AF Frigge, T.
   Hafke, B.
   Witte, T.
   Krenzer, B.
   Streubuehr, C.
   Syed, A. Samad
   Trontl, V. Miksic
   Avigo, I.
   Zhou, P.
   Ligges, M.
   von der Linde, D.
   Bovensiepen, U.
   Horn-von Hoegen, M.
   Wippermann, S.
   Luecke, A.
   Gerstmann, U.
   Schmidt, W. G.
TI Optically excited structural transition in atomic wires on surfaces at the quantum limit
SO NATURE
LA English
DT Article
ID charge-density-wave; ultrafast electron crystallography; diffraction; phase; motions
AB Transient control over the atomic potential-energy landscapes of solids could lead to new states of matter and to quantum control of nuclear motion on the timescale of lattice vibrations. Recently developed ultrafast time-resolved diffraction techniques(1) combine ultrafast temporal manipulation with atomic-scale spatial resolution and femtosecond temporal resolution. These advances have enabled investigations of photo-induced structural changes in bulk solids that often occur on timescales as short as a few hundred femtoseconds(2-6). In contrast, experiments at surfaces and on single atomic layers such as graphene report timescales of structural changes that are orders of magnitude longer(7-9). This raises the question of whether the structural response of low-dimensional materials to femtosecond laser excitation is, in general, limited. Here we show that a photo-induced transition from the low-to high-symmetry state of a charge density wave in atomic indium (In) wires supported by a silicon (Si) surface takes place within 350 femtoseconds. The optical excitation breaks and creates In-In bonds, leading to the non-thermal excitation of soft phonon modes, and drives the structural transition in the limit of critically damped nuclear motion through coupling of these soft phonon modes to a manifold of surface and interface phonons that arise from the symmetry breaking at the silicon surface. This finding demonstrates that carefully tuned electronic excitations can create non-equilibrium potential energy surfaces that drive structural dynamics at interfaces in the quantum limit (that is, in a regime in which the nuclear motion is directed and deterministic)(8). This technique could potentially be used to tune the dynamic response of a solid to optical excitation, and has widespread potential application, for example in ultrafast detectors(10,11).
C1 [Frigge, T.; Hafke, B.; Witte, T.; Krenzer, B.; Streubuehr, C.; Syed, A. Samad; Trontl, V. Miksic; Avigo, I.; Zhou, P.; Ligges, M.; von der Linde, D.; Bovensiepen, U.; Horn-von Hoegen, M.] Univ Duisburg Essen, Fak Phys, Lotharstr 1, D-47057 Duisburg, Germany.
   [Frigge, T.; Hafke, B.; Witte, T.; Krenzer, B.; Streubuehr, C.; Syed, A. Samad; Trontl, V. Miksic; Avigo, I.; Zhou, P.; Ligges, M.; von der Linde, D.; Bovensiepen, U.; Horn-von Hoegen, M.] Univ Duisburg Essen, Ctr Nanointegrat CENIDE, Lotharstr 1, D-47057 Duisburg, Germany.
   [Wippermann, S.] Max Planck Inst Eisenforschung, Max Planck Str 1, D-40237 Dusseldorf, Germany.
   [Luecke, A.; Gerstmann, U.; Schmidt, W. G.] Univ Paderborn, Lehrstuhl Theoret Mat Phys, D-33095 Paderborn, Germany.
C3 University of Duisburg Essen; University of Duisburg Essen; Max Planck Society; University of Paderborn
RP Horn-von Hoegen, M (corresponding author), Univ Duisburg Essen, Fak Phys, Lotharstr 1, D-47057 Duisburg, Germany.; Horn-von Hoegen, M (corresponding author), Univ Duisburg Essen, Ctr Nanointegrat CENIDE, Lotharstr 1, D-47057 Duisburg, Germany.
EM mhvh@uni-due.de
FU Deutsche Forschungsgemeinschaft [SFB616, FOR1700, SFB1242, FOR1405]; High Performance Computing Center Stuttgart; Paderborn Center for Parallel Computing
NR 35
TC 115
Z9 121
U1 0
U2 126
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 13
PY 2017
VL 544
IS 7649
BP 207
EP +
DI 10.1038/nature21432
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ER6EK
UT WOS:000398897900032
PM 28355177
DA 2026-03-09
ER

PT J
AU Hezaveh, YD
   Levasseur, LP
   Marshall, PJ
AF Hezaveh, Yashar D.
   Levasseur, Laurence Perreault
   Marshall, Philip J.
TI Fast automated analysis of strong gravitational lenses with convolutional neural networks
SO NATURE
LA English
DT Article
AB Quantifying image distortions caused by strong gravitational lensing-the formation of multiple images of distant sources due to the deflection of their light by the gravity of intervening structures-and estimating the corresponding matter distribution of these structures (the 'gravitational lens') has primarily been performed using maximum likelihood modelling of observations. This procedure is typically time-and resource-consuming, requiring sophisticated lensing codes, several data preparation steps, and finding the maximum likelihood model parameters in a computationally expensive process with downhill optimizers(1). Accurate analysis of a single gravitational lens can take up to a few weeks and requires expert knowledge of the physical processes and methods involved. Tens of thousands of new lenses are expected to be discovered with the upcoming generation of ground and space surveys(2,3). Here we report the use of deep convolutional neural networks to estimate lensing parameters in an extremely fast and automated way, circumventing the difficulties that are faced by maximum likelihood methods. We also show that the removal of lens light can be made fast and automated using independent component analysis(4) of multi-filter imaging data. Our networks can recover the parameters of the 'singular isothermal ellipsoid' density profile(5), which is commonly used to model strong lensing systems, with an accuracy comparable to the uncertainties of sophisticated models but about ten million times faster: 100 systems in approximately one second on a single graphics processing unit. These networks can provide a way for non-experts to obtain estimates of lensing parameters for large samples of data.
C1 [Hezaveh, Yashar D.; Levasseur, Laurence Perreault; Marshall, Philip J.] Stanford Univ, Kavli Inst Particle Astrophys & Cosmol, Stanford, CA 94305 USA.
   [Hezaveh, Yashar D.; Levasseur, Laurence Perreault; Marshall, Philip J.] SLAC Natl Accelerator Lab, Menlo Pk, CA 94025 USA.
C3 Stanford University; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory
RP Hezaveh, YD; Levasseur, LP (corresponding author), Stanford Univ, Kavli Inst Particle Astrophys & Cosmol, Stanford, CA 94305 USA.; Hezaveh, YD; Levasseur, LP (corresponding author), SLAC Natl Accelerator Lab, Menlo Pk, CA 94025 USA.
EM hezaveh@stanford.edu; lplevass@stanford.edu
FU NASA through Hubble Fellowship - Space Telescope Science Institute [HST-HF2-51358.001-A]; NASA [NAS 5-26555]; US Department of Energy [DE-AC02-76SF00515]
NR 25
TC 203
Z9 237
U1 2
U2 35
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 31
PY 2017
VL 548
IS 7669
BP 555
EP +
DI 10.1038/nature23463
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FF2BO
UT WOS:000408703100032
PM 28858317
DA 2026-03-09
ER

PT J
AU Aartsen, MG
   Hill, GC
   Kyriacou, A
   Robertson, S
   Wallace, A
   Whelan, BJ
   Ackermann, M
   Bernardini, E
   Blot, S
   Bradascio, F
   Bretz, HP
   Brostean-Kaiser, J
   Franckowiak, A
   Jacobi, E
   Karg, T
   Kintscher, T
   Kunwar, S
   Nahnhauer, R
   Satalecka, K
   Spiering, C
   Stachurska, J
   Stasik, A
   Strotjohann, NL
   Terliuk, A
   Usner, M
   van Santen, J
   Adams, J
   Bagherpour, H
   Aguilar, JA
   Ansseau, I
   Heereman, D
   Meagher, K
   Meures, T
   O'Murchadha, A
   Pinat, E
   Raab, C
   Ahlers, M
   Koskinen, DJ
   Larson, MJ
   Medici, M
   Rameez, M
   Ahrens, M
   Bohm, C
   Dumm, JP
   Finley, C
   Flis, S
   Hultqvist, K
   Walck, C
   Zoll, M
   Al Samarai, I
   Bron, S
   Carver, T
   Christov, A
   Montaruli, T
   Altmann, D
   Anton, G
   Glüsenkamp, T
   Katz, U
   Kittler, T
   Tselengidou, M
   Andeen, K
   Plum, M
   Anderson, T
   DeLaunay, JJ
   Dunkman, M
   Eller, P
   Huang, F
   Keivani, A
   Lanfranchi, JL
   Pankova, DV
   Tesic, G
   Turley, CF
   Weiss, MJ
   Argüelles, C
   Axani, S
   Collin, GH
   Conrad, JM
   Moulai, M
   Auffenberg, J
   Brenzke, M
   Glauch, T
   Haack, C
   Kalaczynski, P
   Koschinsky, JP
   Leuermann, M
   Rdel, L
   Reimann, R
   Rongen, M
   Sälzer, T
   Schoenen, S
   Schumacher, L
   Stettner, J
   Vehring, M
   Vogel, E
   Wallraff, M
   Waza, A
   Wiebusch, CH
   Bai, X
   Barron, JP
   Giang, W
   Grant, D
   Kopper, C
   Moore, RW
   Nowicki, SC
   Herrera, SES
   Sarkar, S
   Wandler, FD
   Weaver, C
   Wood, TR
   Woolsey, E
   Yanez, JP
   Barwick, SW
   Yodh, G
   Baum, V
   Böser, S
   di Lorenzo, V
   Eberhardt, B
   Ehrhardt, T
   Köpke, L
   Krückl, G
   Momenté, G
   Peiffer, P
   Sandroos, J
   Steuer, A
   Wiebe, K
   Bay, R
   Filimonov, K
   Price, PB
   Woschnagg, K
   Beatty, JJ
   Tjus, JB
   Bos, F
   Eichmann, B
   Kroll, M
   Schöneberg, S
   Tenholt, F
   Becker, KH
   Bindig, D
   Helbing, K
   Hickford, S
   Hoffmann, R
   Lauber, F
   Naumann, U
   Pollmann, AO
   Soldin, D
   BenZvi, S
   Cross, R
   Berley, D
   Blaufuss, E
   Cheung, E
   Felde, J
   Friedman, E
   Hellauer, R
   Hoffman, KD
   Maunu, R
   Olivas, A
   Schmidt, T
   Song, M
   Sullivan, GW
   Besson, DZ
   Binder, G
   Klein, SR
   Miarecki, S
   Palczewski, T
   Tatar, J
   Börner, M
   Fuchs, T
   Hünnefeld, M
   Meier, M
   Menne, T
   Pieloth, D
   Rhode, W
   Ruhe, T
   Sandrock, A
   Schlunder, P
   Soedingrekso, J
   Werthebach, J
   Bose, D
   Dujmovic, H
   In, S
   Jeong, M
   Kang, W
   Kim, J
   Rott, C
   Botner, O
   Burgman, A
   Hallgren, A
   de los Heros, CP
   Unger, E
   Bourbeau, J
   Braun, J
   Casey, J
   Chirkin, D
   Day, M
   Desiati, P
   Díaz-Vélez, JC
   Fahey, S
   Ghorbani, K
   Griffith, Z
   Halzen, F
   Hanson, K
   Hokanson-Fasig, B
   Hoshina, K
   Jero, K
   Karle, A
   Kauer, M
   Kelley, JL
   Kheirandish, A
   Liu, QR
   Luszczak, W
   Mancina, S
   McNally, F
   Merino, G
   Schneider, A
   Tobin, MN
   Tosi, D
   Ty, B
   Vandenbroucke, J
   Wandkowsky, N
   Wendt, C
   Westerhoff, S
   Wille, L
   Wolf, M
   Wood, J
   Xu, DL
   Yuan, T
   Brayeur, L
   Casier, M
   De Clercq, C
   de Vries, KD
   de Wasseige, G
   Kunnen, J
   Lünemann, J
   Maggi, G
   Toscano, S
   van Eijndhoven, N
   Clark, K
   Classen, L
   Kappes, A
   Coenders, S
   Huber, M
   Krings, K
   Rea, IC
   Resconi, E
   Turcati, A
   Cowen, DF
   de André, JPAM
   DeYoung, T
   Hignight, J
   Lennarz, D
   Mahn, KBM
   Micallef, J
   Neer, G
   Rysewyk, D
   Dembinski, H
   Evenson, PA
   Gaisser, TK
   Gonzalez, JG
   Koirala, R
   Pandya, H
   Seckel, D
   Stanev, T
   Tilav, S
   De Ridder, S
   Labare, M
   Ryckbosch, D
   Van Driessche, W
   Vanheule, S
   Vraeghe, M
   de With, M
   Hebecker, D
   Kolanoski, H
   Fazely, AR
   Ter-Antonyan, S
   Xu, XW
   Gallagher, J
   Gerhardt, L
   Goldschmidt, A
   Nygren, DR
   Przybylski, GT
   Stezelberger, T
   Stokstad, RG
   Ishihara, A
   Kim, M
   Kuwabara, T
   Lu, L
   Mase, K
   Relich, M
   Stossl, A
   Yoshida, S
   Japaridze, GS
   Jones, BJP
   Kiryluk, J
   Lesiak-Bzdak, M
   Niederhausen, H
   Xu, Y
   Kohnen, G
   Kopper, S
   Nakarmi, P
   Pepper, JA
   Toale, PA
   Williams, DR
   Kowalski, M
   Kurahashi, N
   Relethford, B
   Richman, M
   Wills, L
   Madsen, J
   Seunarine, S
   Spiczak, GM
   Maruyama, R
   Rawlins, K
   Sarkar, S
   Sutherland, M
   Taboada, I
   Tung, CF
AF Aartsen, M. G.
   Hill, G. C.
   Kyriacou, A.
   Robertson, S.
   Wallace, A.
   Whelan, B. J.
   Ackermann, M.
   Bernardini, E.
   Blot, S.
   Bradascio, F.
   Bretz, H. -P.
   Brostean-Kaiser, J.
   Franckowiak, A.
   Jacobi, E.
   Karg, T.
   Kintscher, T.
   Kunwar, S.
   Nahnhauer, R.
   Satalecka, K.
   Spiering, C.
   Stachurska, J.
   Stasik, A.
   Strotjohann, N. L.
   Terliuk, A.
   Usner, M.
   van Santen, J.
   Adams, J.
   Bagherpour, H.
   Aguilar, J. A.
   Ansseau, I.
   Heereman, D.
   Meagher, K.
   Meures, T.
   O'Murchadha, A.
   Pinat, E.
   Raab, C.
   Ahlers, M.
   Koskinen, D. J.
   Larson, M. J.
   Medici, M.
   Rameez, M.
   Ahrens, M.
   Bohm, C.
   Dumm, J. P.
   Finley, C.
   Flis, S.
   Hultqvist, K.
   Walck, C.
   Zoll, M.
   Al Samarai, I.
   Bron, S.
   Carver, T.
   Christov, A.
   Montaruli, T.
   Altmann, D.
   Anton, G.
   Gluesenkamp, T.
   Katz, U.
   Kittler, T.
   Tselengidou, M.
   Andeen, K.
   Plum, M.
   Anderson, T.
   DeLaunay, J. J.
   Dunkman, M.
   Eller, P.
   Huang, F.
   Keivani, A.
   Lanfranchi, J. L.
   Pankova, D. V.
   Tesic, G.
   Turley, C. F.
   Weiss, M. J.
   Arguelles, C.
   Axani, S.
   Collin, G. H.
   Conrad, J. M.
   Moulai, M.
   Auffenberg, J.
   Brenzke, M.
   Glauch, T.
   Haack, C.
   Kalaczynski, P.
   Koschinsky, J. P.
   Leuermann, M.
   Rdel, L.
   Reimann, R.
   Rongen, M.
   Saelzer, T.
   Schoenen, S.
   Schumacher, L.
   Stettner, J.
   Vehring, M.
   Vogel, E.
   Wallraff, M.
   Waza, A.
   Wiebusch, C. H.
   Bai, X.
   Barron, J. P.
   Giang, W.
   Grant, D.
   Kopper, C.
   Moore, R. W.
   Nowicki, S. C.
   Herrera, S. E. Sanchez
   Sarkar, S.
   Wandler, F. D.
   Weaver, C.
   Wood, T. R.
   Woolsey, E.
   Yanez, J. P.
   Barwick, S. W.
   Yodh, G.
   Baum, V.
   Boeser, S.
   di Lorenzo, V.
   Eberhardt, B.
   Ehrhardt, T.
   Koepke, L.
   Krueckl, G.
   Momente, G.
   Peiffer, P.
   Sandroos, J.
   Steuer, A.
   Wiebe, K.
   Bay, R.
   Filimonov, K.
   Price, P. B.
   Woschnagg, K.
   Beatty, J. J.
   Tjus, J. Becker
   Bos, F.
   Eichmann, B.
   Kroll, M.
   Schoeneberg, S.
   Tenholt, F.
   Becker, K. -H.
   Bindig, D.
   Helbing, K.
   Hickford, S.
   Hoffmann, R.
   Lauber, F.
   Naumann, U.
   Pollmann, A. Obertacke
   Soldin, D.
   BenZvi, S.
   Cross, R.
   Berley, D.
   Blaufuss, E.
   Cheung, E.
   Felde, J.
   Friedman, E.
   Hellauer, R.
   Hoffman, K. D.
   Maunu, R.
   Olivas, A.
   Schmidt, T.
   Song, M.
   Sullivan, G. W.
   Besson, D. Z.
   Binder, G.
   Klein, S. R.
   Miarecki, S.
   Palczewski, T.
   Tatar, J.
   Boerner, M.
   Fuchs, T.
   Huennefeld, M.
   Meier, M.
   Menne, T.
   Pieloth, D.
   Rhode, W.
   Ruhe, T.
   Sandrock, A.
   Schlunder, P.
   Soedingrekso, J.
   Werthebach, J.
   Bose, D.
   Dujmovic, H.
   In, S.
   Jeong, M.
   Kang, W.
   Kim, J.
   Rott, C.
   Botner, O.
   Burgman, A.
   Hallgren, A.
   de los Heros, C. Perez
   Unger, E.
   Bourbeau, J.
   Braun, J.
   Casey, J.
   Chirkin, D.
   Day, M.
   Desiati, P.
   Diaz-Velez, J. C.
   Fahey, S.
   Ghorbani, K.
   Griffith, Z.
   Halzen, F.
   Hanson, K.
   Hokanson-Fasig, B.
   Hoshina, K.
   Jero, K.
   Karle, A.
   Kauer, M.
   Kelley, J. L.
   Kheirandish, A.
   Liu, Q. R.
   Luszczak, W.
   Mancina, S.
   McNally, F.
   Merino, G.
   Schneider, A.
   Tobin, M. N.
   Tosi, D.
   Ty, B.
   Vandenbroucke, J.
   Wandkowsky, N.
   Wendt, C.
   Westerhoff, S.
   Wille, L.
   Wolf, M.
   Wood, J.
   Xu, D. L.
   Yuan, T.
   Brayeur, L.
   Casier, M.
   De Clercq, C.
   de Vries, K. D.
   de Wasseige, G.
   Kunnen, J.
   Lunemann, J.
   Maggi, G.
   Toscano, S.
   van Eijndhoven, N.
   Clark, K.
   Classen, L.
   Kappes, A.
   Coenders, S.
   Huber, M.
   Krings, K.
   Rea, I. C.
   Resconi, E.
   Turcati, A.
   Cowen, D. F.
   de Andre, J. P. A. M.
   DeYoung, T.
   Hignight, J.
   Lennarz, D.
   Mahn, K. B. M.
   Micallef, J.
   Neer, G.
   Rysewyk, D.
   Dembinski, H.
   Evenson, P. A.
   Gaisser, T. K.
   Gonzalez, J. G.
   Koirala, R.
   Pandya, H.
   Seckel, D.
   Stanev, T.
   Tilav, S.
   De Ridder, S.
   Labare, M.
   Ryckbosch, D.
   Van Driessche, W.
   Vanheule, S.
   Vraeghe, M.
   de With, M.
   Hebecker, D.
   Kolanoski, H.
   Fazely, A. R.
   Ter-Antonyan, S.
   Xu, X. W.
   Gallagher, J.
   Gerhardt, L.
   Goldschmidt, A.
   Nygren, D. R.
   Przybylski, G. T.
   Stezelberger, T.
   Stokstad, R. G.
   Ishihara, A.
   Kim, M.
   Kuwabara, T.
   Lu, L.
   Mase, K.
   Relich, M.
   Stossl, A.
   Yoshida, S.
   Japaridze, G. S.
   Jones, B. J. P.
   Kiryluk, J.
   Lesiak-Bzdak, M.
   Niederhausen, H.
   Xu, Y.
   Kohnen, G.
   Kopper, S.
   Nakarmi, P.
   Pepper, J. A.
   Toale, P. A.
   Williams, D. R.
   Kowalski, M.
   Kurahashi, N.
   Relethford, B.
   Richman, M.
   Wills, L.
   Madsen, J.
   Seunarine, S.
   Spiczak, G. M.
   Maruyama, R.
   Rawlins, K.
   Sarkar, S.
   Sutherland, M.
   Taboada, I.
   Tung, C. F.
TI Measurement of the multi-TeV neutrino interaction cross-section with IceCube using Earth absorption
SO NATURE
LA English
DT Article
ID density
AB Neutrinos interact only very weakly, so they are extremely penetrating. The theoretical neutrino-nucleon interaction cross-section, however, increases with increasing neutrino energy, and neutrinos with energies above 40 teraelectronvolts (TeV) are expected to be absorbed as they pass through the Earth. Experimentally, the cross-section has been determined only at the relatively low energies (below 0.4 TeV) that are available at neutrino beams fromaccelerators(1,2). Here we report a measurement of neutrino absorption by the Earth using a sample of 10,784 energetic upward-going neutrino-induced muons. The flux of high-energy neutrinos transiting long paths through the Earth is attenuated compared to a reference sample that follows shorter trajectories. Using a fit to the two-dimensional distribution of muon energy and zenith angle, we determine the neutrino-nucleon interaction cross-section for neutrino energies 6.3-980 TeV, more than an order of magnitude higher than previous measurements. The measured cross-section is about 1.3 times the prediction of the standard model(3), consistent with the expectations for charged-and neutral-current interactions. We do not observe a large increase in the crosssection with neutrino energy, in contrast with the predictions of some theoretical models, including those invoking more compact spatial dimensions(4) or the production of leptoquarks(5). This cross-section measurement can be used to set limits on the existence of some hypothesized beyond-standard-model particles, including leptoquarks.
C1 [Aartsen, M. G.; Hill, G. C.; Kyriacou, A.; Robertson, S.; Wallace, A.; Whelan, B. J.] Univ Adelaide, Dept Phys, Adelaide, SA 5005, Australia.
   [Ackermann, M.; Bernardini, E.; Blot, S.; Bradascio, F.; Bretz, H. -P.; Brostean-Kaiser, J.; Franckowiak, A.; Jacobi, E.; Karg, T.; Kintscher, T.; Kunwar, S.; Nahnhauer, R.; Satalecka, K.; Spiering, C.; Stachurska, J.; Stasik, A.; Strotjohann, N. L.; Terliuk, A.; Usner, M.; van Santen, J.; Kowalski, M.] DESY, D-17738 Zeuthen, Germany.
   [Adams, J.; Bagherpour, H.] Univ Canterbury, Dept Phys & Astron, Christchurch, New Zealand.
   [Aguilar, J. A.; Ansseau, I.; Heereman, D.; Meagher, K.; Meures, T.; O'Murchadha, A.; Pinat, E.; Raab, C.] Univ Libre Bruxelles, Sci Fac, B-1050 Brussels, Belgium.
   [Ahlers, M.; Koskinen, D. J.; Larson, M. J.; Medici, M.; Rameez, M.; Sarkar, S.] Univ Copenhagen, Niels Bohr Inst, DK-2100 Copenhagen, Denmark.
   [Ahrens, M.; Bohm, C.; Dumm, J. P.; Finley, C.; Flis, S.; Hultqvist, K.; Walck, C.; Zoll, M.] Stockholm Univ, Oskar Klein Ctr, SE-10691 Stockholm, Sweden.
   [Ahrens, M.; Bohm, C.; Dumm, J. P.; Finley, C.; Flis, S.; Hultqvist, K.; Walck, C.; Zoll, M.] Stockholm Univ, Dept Phys, SE-10691 Stockholm, Sweden.
   [Al Samarai, I.; Bron, S.; Carver, T.; Christov, A.; Montaruli, T.] Univ Geneva, Dept Phys Nucl & Corpusculaire, CH-1211 Geneva, Switzerland.
   [Altmann, D.; Anton, G.; Gluesenkamp, T.; Katz, U.; Kittler, T.; Tselengidou, M.] Friedrich Alexander Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, D-91058 Erlangen, Germany.
   [Andeen, K.; Plum, M.] Marquette Univ, Dept Phys, Milwaukee, WI 53201 USA.
   [Anderson, T.; DeLaunay, J. J.; Dunkman, M.; Eller, P.; Huang, F.; Keivani, A.; Lanfranchi, J. L.; Pankova, D. V.; Tesic, G.; Turley, C. F.; Weiss, M. J.] Penn State Univ, Dept Phys, University Pk, PA 16802 USA.
   [Arguelles, C.; Axani, S.; Collin, G. H.; Conrad, J. M.; Moulai, M.] MIT, Dept Phys, Cambridge, MA 02139 USA.
   [Auffenberg, J.; Brenzke, M.; Glauch, T.; Haack, C.; Kalaczynski, P.; Koschinsky, J. P.; Leuermann, M.; Rdel, L.; Reimann, R.; Rongen, M.; Saelzer, T.; Schoenen, S.; Schumacher, L.; Stettner, J.; Vehring, M.; Vogel, E.; Wallraff, M.; Waza, A.; Wiebusch, C. H.] Rhein Westfal TH Aachen, Phys Inst 3, D-52056 Aachen, Germany.
   [Bai, X.] South Dakota Sch Mines & Technol, Phys Dept, Rapid City, SD 57701 USA.
   [Barron, J. P.; Giang, W.; Grant, D.; Kopper, C.; Moore, R. W.; Nowicki, S. C.; Herrera, S. E. Sanchez; Sarkar, S.; Wandler, F. D.; Weaver, C.; Wood, T. R.; Woolsey, E.; Yanez, J. P.] Univ Alberta, Dept Phys, Edmonton, AB T6G 2E1, Canada.
   [Barwick, S. W.; Yodh, G.] Univ Calif Irvine, Dept Phys & Astron, Irvine, CA 92697 USA.
   [Baum, V.; Boeser, S.; di Lorenzo, V.; Eberhardt, B.; Ehrhardt, T.; Koepke, L.; Krueckl, G.; Momente, G.; Peiffer, P.; Sandroos, J.; Steuer, A.; Wiebe, K.] Johannes Gutenberg Univ Mainz, Inst Phys, D-55099 Mainz, Germany.
   [Bay, R.; Filimonov, K.; Price, P. B.; Woschnagg, K.; Binder, G.; Klein, S. R.; Miarecki, S.; Palczewski, T.; Tatar, J.] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Beatty, J. J.; Sutherland, M.] Ohio State Univ, Dept Phys, Columbus, OH 43210 USA.
   [Beatty, J. J.; Sutherland, M.] Ohio State Univ, Ctr Cosmol & Astroparticle Phys, Columbus, OH 43210 USA.
   [Tjus, J. Becker; Bos, F.; Eichmann, B.; Kroll, M.; Schoeneberg, S.; Tenholt, F.] Ruhr Univ Bochum, Fak Phys & Astron, D-44780 Bochum, Germany.
   [Becker, K. -H.; Bindig, D.; Helbing, K.; Hickford, S.; Hoffmann, R.; Lauber, F.; Naumann, U.; Pollmann, A. Obertacke; Soldin, D.] Univ Wuppertal, Dept Phys, D-42119 Wuppertal, Germany.
   [BenZvi, S.; Cross, R.] Univ Rochester, Dept Phys & Astron, 601 Elmwood Ave, Rochester, NY 14627 USA.
   [Berley, D.; Blaufuss, E.; Cheung, E.; Felde, J.; Friedman, E.; Hellauer, R.; Hoffman, K. D.; Maunu, R.; Olivas, A.; Schmidt, T.; Song, M.; Sullivan, G. W.] Univ Maryland, Dept Phys, College Pk, MD 20742 USA.
   [Besson, D. Z.] Univ Kansas, Dept Phys & Astron, Lawrence, KS 66045 USA.
   [Binder, G.; Klein, S. R.; Miarecki, S.; Palczewski, T.; Tatar, J.; Gerhardt, L.; Goldschmidt, A.; Nygren, D. R.; Przybylski, G. T.; Stezelberger, T.; Stokstad, R. G.] Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA.
   [Boerner, M.; Fuchs, T.; Huennefeld, M.; Meier, M.; Menne, T.; Pieloth, D.; Rhode, W.; Ruhe, T.; Sandrock, A.; Schlunder, P.; Soedingrekso, J.; Werthebach, J.] TU Dortmund Univ, Dept Phys, D-44221 Dortmund, Germany.
   [Bose, D.; Dujmovic, H.; In, S.; Jeong, M.; Kang, W.; Kim, J.; Rott, C.] Sungkyunkwan Univ, Dept Phys, Suwon 440746, South Korea.
   [Botner, O.; Burgman, A.; Hallgren, A.; de los Heros, C. Perez; Unger, E.] Uppsala Univ, Dept Phys & Astron, S-75120 Uppsala, Sweden.
   [Bourbeau, J.; Braun, J.; Casey, J.; Chirkin, D.; Day, M.; Desiati, P.; Diaz-Velez, J. C.; Fahey, S.; Ghorbani, K.; Griffith, Z.; Halzen, F.; Hanson, K.; Hokanson-Fasig, B.; Hoshina, K.; Jero, K.; Karle, A.; Kauer, M.; Kelley, J. L.; Kheirandish, A.; Liu, Q. R.; Luszczak, W.; Mancina, S.; McNally, F.; Merino, G.; Schneider, A.; Tobin, M. N.; Tosi, D.; Ty, B.; Vandenbroucke, J.; Wandkowsky, N.; Wendt, C.; Westerhoff, S.; Wille, L.; Wolf, M.; Wood, J.; Xu, D. L.; Yuan, T.] Univ Wisconsin, Dept Phys, Madison, WI 53706 USA.
   [Bourbeau, J.; Braun, J.; Casey, J.; Chirkin, D.; Day, M.; Desiati, P.; Diaz-Velez, J. C.; Fahey, S.; Ghorbani, K.; Griffith, Z.; Halzen, F.; Hanson, K.; Hokanson-Fasig, B.; Hoshina, K.; Jero, K.; Karle, A.; Kauer, M.; Kelley, J. L.; Kheirandish, A.; Liu, Q. R.; Luszczak, W.; Mancina, S.; McNally, F.; Merino, G.; Schneider, A.; Tobin, M. N.; Tosi, D.; Ty, B.; Vandenbroucke, J.; Wandkowsky, N.; Wendt, C.; Westerhoff, S.; Wille, L.; Wolf, M.; Wood, J.; Xu, D. L.; Yuan, T.] Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA.
   [Hoshina, K.] Univ Tokyo, Earthquake Res Inst, Bunkyo Ku, Tokyo 1130032, Japan.
   [Brayeur, L.; Casier, M.; De Clercq, C.; de Vries, K. D.; de Wasseige, G.; Kunnen, J.; Lunemann, J.; Maggi, G.; Toscano, S.; van Eijndhoven, N.] Vrije Univ Brussel, Dienst ELEM, B-1050 Brussels, Belgium.
   [Clark, K.] SNOLAB, Lively P3Y 1N2, ON, Canada.
   [Classen, L.; Kappes, A.] Westfal Wilhelms Univ Munster, Inst Kernphys, D-48149 Munster, Germany.
   [Coenders, S.; Huber, M.; Krings, K.; Rea, I. C.; Resconi, E.; Turcati, A.] Tech Univ Munich, Phys Dept, D-85748 Garching, Germany.
   [Cowen, D. F.] Penn State Univ, Dept Phys, University Pk, PA 16802 USA.
   [Cowen, D. F.] Penn State Univ, Dept Phys & Astron, University Pk, PA 16802 USA.
   [de Andre, J. P. A. M.; DeYoung, T.; Hignight, J.; Lennarz, D.; Mahn, K. B. M.; Micallef, J.; Neer, G.; Rysewyk, D.] Michigan State Univ, Dept Phys & Astron, E Lansing, MI 48824 USA.
   [Dembinski, H.; Evenson, P. A.; Gaisser, T. K.; Gonzalez, J. G.; Koirala, R.; Pandya, H.; Seckel, D.; Stanev, T.; Tilav, S.] Univ Delaware, Bartol Res Inst, Newark, DE 19716 USA.
   [Dembinski, H.; Evenson, P. A.; Gaisser, T. K.; Gonzalez, J. G.; Koirala, R.; Pandya, H.; Seckel, D.; Stanev, T.; Tilav, S.] Univ Delaware, Dept Phys & Astron, Newark, DE 19716 USA.
   [De Ridder, S.] Univ Ghent, Dept Phys & Astron, B-9000 Ghent, Belgium.
   [Labare, M.; Ryckbosch, D.; Van Driessche, W.; Vanheule, S.; Vraeghe, M.; de With, M.; Hebecker, D.; Kolanoski, H.; Kowalski, M.] Humboldt Univ, Inst Ohys, D-12489 Berlin, Germany.
   [Fazely, A. R.; Ter-Antonyan, S.; Xu, X. W.] Southern Univ, Dept Phys, Baton Rouge, LA 70813 USA.
   [Gallagher, J.] Univ Wisconsin, Dept Astron, Madison, WI 53706 USA.
   [Ishihara, A.; Kim, M.; Kuwabara, T.; Lu, L.; Mase, K.; Relich, M.; Stossl, A.; Yoshida, S.] Chiba Univ, Dept Phys, Chiba 2638522, Japan.
   [Ishihara, A.; Kim, M.; Kuwabara, T.; Lu, L.; Mase, K.; Relich, M.; Stossl, A.; Yoshida, S.] Chiba Univ, Inst Global Prominent Res, Chiba 2638522, Japan.
   [Japaridze, G. S.] Clark Atlanta Univ, Ctr Theoret Studies Phys Syst, Atlanta, GA 30314 USA.
   [Jones, B. J. P.] Univ Texas Arlington, Dept Phys, Arlington, TX 76019 USA.
   [Kiryluk, J.; Lesiak-Bzdak, M.; Niederhausen, H.; Xu, Y.] SUNY Stony Brook, Dept Phys & Astron, Stony Brook, NY 11794 USA.
   [Gallagher, J.] Univ Mons, B-7000 Mons, Belgium.
   [Kopper, S.; Nakarmi, P.; Pepper, J. A.; Toale, P. A.; Williams, D. R.] Univ Alabama, Dept Phys & Astron, Tuscaloosa, AL 35487 USA.
   [Kurahashi, N.; Relethford, B.; Richman, M.; Wills, L.] Drexel Univ, Dept Phys, Philadelphia, PA 19104 USA.
   [Madsen, J.; Seunarine, S.; Spiczak, G. M.] Univ Wisconsin, Dept Phys, River Falls, WI 54022 USA.
   [Maruyama, R.] Yale Univ, Dept Phys, New Haven, CT 06520 USA.
   [Rawlins, K.] Univ Alaska Anchorage, Dept Phys & Astron, Anchorage, AK 99508 USA.
   [Sarkar, S.] Univ Oxford, Dept Phys, Oxford OX1 3NP, England.
   [Taboada, I.; Tung, C. F.] Georgia Inst Technol, Sch Phys, Atlanta, GA 30332 USA.
   [Taboada, I.; Tung, C. F.] Georgia Inst Technol, Ctr Relativist Astrophys, Atlanta, GA 30332 USA.
C3 Adelaide University; University of Adelaide; Helmholtz Association; Deutsches Elektronen-Synchrotron (DESY); University of Canterbury; Universite Libre de Bruxelles; University of Copenhagen; Niels Bohr Institute; Stockholm University; Oskar Klein Centre; Stockholm University; University of Geneva; University of Erlangen Nuremberg; Marquette University; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Massachusetts Institute of Technology (MIT); RWTH Aachen University; South Dakota School Mines & Technology; University of Alberta; University of California System; University of California Irvine; Johannes Gutenberg University of Mainz; University of California System; University of California Berkeley; University System of Ohio; Ohio State University; University System of Ohio; Ohio State University; University of Wurzburg; Ruhr University Bochum; University of Wuppertal; University of Rochester; University System of Maryland; University of Maryland College Park; University of Kansas; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; Dortmund University of Technology; Sungkyunkwan University (SKKU); Uppsala University; University of Wisconsin System; University of Wisconsin Madison; University of Wisconsin System; University of Wisconsin Madison; University of Tokyo; Vrije Universiteit Brussel; University of Munster; Technical University of Munich; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Michigan State University; University of Delaware; University of Delaware; Ghent University; Humboldt University of Berlin; Southern University System; Southern University & A&M College; University of Wisconsin System; University of Wisconsin Madison; Chiba University; Chiba University; Clark Atlanta University; University of Texas System; University of Texas Arlington; State University of New York (SUNY) System; Stony Brook University; University of Mons; University of Alabama System; University of Alabama Tuscaloosa; Drexel University; University of Wisconsin System; Yale University; University of Alaska System; University of Alaska Anchorage; University of Oxford; University System of Georgia; Georgia Institute of Technology; University System of Georgia; Georgia Institute of Technology
RP Klein, SR (corresponding author), Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.; Klein, SR (corresponding author), Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA.
EM srklein@lbl.gov
FU United States Air Force Academy; US National Science Foundation, Physics Division; University of Wisconsin Alumni Research Foundation; Grid Laboratory of Wisconsin (GLOW) grid infrastructure at the University of Wisconsin, Madison; Open Science Grid (OSG) grid infrastructure; US Department of Energy; National Energy Research Scientific Computing Center; Louisiana Optical Network Initiative (LONI) grid computing resources; Natural Sciences and Engineering Research Council of Canada; WestGrid; Swedish Research Council; Swedish Polar Research Secretariat; Swedish National Infrastructure for Computing (SNIC); Knut and Alice Wallenberg Foundation; German Ministry for Education and Research (BMBF); Deutsche Forschungsgemeinschaft (DFG); Helmholtz Alliance for Astroparticle Physics (HAP); Initiative and Networking Fund of the Helmholtz Association, Germany; Fund for Scientific Research (FNRS-FWO); FWO Odysseus programme; Marsden Fund; Australian Research Council; Japan Society for Promotion of Science (JSPS); Swiss National Science Foundation (SNSF); National Research Foundation of Korea (NRF); Villum Fonden; Danish National Research Foundation (DNRF); Flanders Institute to encourage scientific and technological research in industry (IWT); Belgian Federal Science Policy Office (BELSPO); US National Science Foundation, Office of Polar Programs; Compute/Calcul Canada; Grants-in-Aid for Scientific Research [16H02174] Funding Source: KAKEN; Direct For Mathematical & Physical Scien [1607199] Funding Source: National Science Foundation; Direct For Mathematical & Physical Scien; Division Of Physics [1403586, 1505296, 1555121] Funding Source: National Science Foundation; Division Of Physics [1607199] Funding Source: National Science Foundation; Division Of Physics; Direct For Mathematical & Physical Scien [1607644] Funding Source: National Science Foundation; Office of Advanced Cyberinfrastructure (OAC); Direct For Computer & Info Scie & Enginr [1626251] Funding Source: National Science Foundation; Science and Technology Facilities Council [ST/P000770/1, ST/J000507/1, ST/M003787/1, ST/L000474/1] Funding Source: researchfish; Villum Fonden [00013161] Funding Source: researchfish; STFC [ST/L000474/1, ST/M003787/1, ST/P000770/1, ST/J000507/1] Funding Source: UKRI
NR 37
TC 125
Z9 146
U1 0
U2 23
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 30
PY 2017
VL 551
IS 7682
BP 596
EP +
DI 10.1038/nature24459
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FO1KW
UT WOS:000416520400036
PM 29168503
DA 2026-03-09
ER

PT J
AU Wang, Y
   Xiao, J
   Zhu, HY
   Li, Y
   Alsaid, Y
   Fong, KY
   Zhou, Y
   Wang, SQ
   Shi, W
   Wang, Y
   Zettl, A
   Reed, EJ
   Zhang, X
AF Wang, Ying
   Xiao, Jun
   Zhu, Hanyu
   Li, Yao
   Alsaid, Yousif
   Fong, King Yan
   Zhou, Yao
   Wang, Siqi
   Shi, Wu
   Wang, Yuan
   Zettl, Alex
   Reed, Evan J.
   Zhang, Xiang
TI Structural phase transition in monolayer MoTe2 driven by electrostatic doping
SO NATURE
LA English
DT Article
ID fese films; superconductivity
AB Monolayers of transition-metal dichalcogenides (TMDs) exhibit numerous crystal phases with distinct structures, symmetries and physical properties(1-3). Exploring the physics of transitions between these different structural phases in two dimensions(4) may provide a means of switching material properties, with implications for potential applications. Structural phase transitions in TMDs have so far been induced by thermal or chemical means(5,6); purely electrostatic control over crystal phases through electrostatic doping was recently proposed as a theoretical possibility, but has not yet been realized(7,8). Here we report the experimental demonstration of an electrostatic-doping-driven phase transition between the hexagonal and monoclinic phases of monolayer molybdenum ditelluride (MoTe2). We find that the phase transition shows a hysteretic loop in Raman spectra, and can be reversed by increasing or decreasing the gate voltage. We also combine second-harmonic generation spectroscopy with polarization-resolved Raman spectroscopy to show that the induced monoclinic phase preserves the crystal orientation of the original hexagonal phase. Moreover, this structural phase transition occurs simultaneously across the whole sample. This electrostatic-doping control of structural phase transition opens up new possibilities for developing phase-change devices based on atomically thin membranes.
C1 [Wang, Ying; Xiao, Jun; Zhu, Hanyu; Alsaid, Yousif; Fong, King Yan; Wang, Siqi; Wang, Yuan; Zhang, Xiang] Univ Calif Berkeley, NSF Nanoscale Sci & Engn Ctr NSEC, 3112 Etcheverry Hall, Berkeley, CA 94720 USA.
   [Li, Yao; Zhou, Yao; Reed, Evan J.] Stanford Univ, Dept Mat Sci & Engn, Stanford, CA 94305 USA.
   [Shi, Wu; Zettl, Alex; Zhang, Xiang] Lawrence Berkeley Natl Lab, Mat Sci Div, 1 Cyclotron Rd, Berkeley, CA 94720 USA.
   [Shi, Wu; Zettl, Alex] Univ Calif Berkeley, Kavli Energy NanoSci Inst, Berkeley, CA 94720 USA.
   [Shi, Wu; Zettl, Alex] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Zhang, Xiang] King Abdulaziz Univ, Dept Phys, Jeddah 21589, Saudi Arabia.
C3 National Science Foundation (NSF); University of California System; University of California Berkeley; Stanford University; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; University of California System; University of California Berkeley; University of California System; University of California Berkeley; King Abdulaziz University
RP Zhang, X (corresponding author), Univ Calif Berkeley, NSF Nanoscale Sci & Engn Ctr NSEC, 3112 Etcheverry Hall, Berkeley, CA 94720 USA.; Zhang, X (corresponding author), Lawrence Berkeley Natl Lab, Mat Sci Div, 1 Cyclotron Rd, Berkeley, CA 94720 USA.; Zhang, X (corresponding author), King Abdulaziz Univ, Dept Phys, Jeddah 21589, Saudi Arabia.
EM xiang@berkeley.edu
FU Office of Science, Office of Basic Energy Sciences, Materials Sciences and Engineering Division of the US Department of Energy [DE-AC02-05CH11231]; National Science Foundation (NSF) [EFMA-154274]; Army Research Office [W911NF-15-1-0570]; Office of Naval Research [N00014-15-1-2697]; NSF [DMR-1455050, EECS-1436626]; Stanford Graduate Fellowship programme; Direct For Mathematical & Physical Scien; Division Of Materials Research [1455050] Funding Source: National Science Foundation
NR 49
TC 248
Z9 266
U1 17
U2 995
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 26
PY 2017
VL 550
IS 7677
BP 487
EP +
DI 10.1038/nature24043
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK7OW
UT WOS:000413697800036
DA 2026-03-09
ER

PT J
AU Baron, MG
   Norman, DB
   Barrett, PM
AF Baron, Matthew G.
   Norman, David B.
   Barrett, Paul M.
TI A new hypothesis of dinosaur relationships and early dinosaur evolution
SO NATURE
LA English
DT Article
ID postcranial anatomy; diversification; saurischia; argentina; africa; origin
AB For 130 years, dinosaurs have been divided into two distinct clades-Ornithischia and Saurischia. Here we present a hypothesis for the phylogenetic relationships of the major dinosaurian groups that challenges the current consensus concerning early dinosaur evolution and highlights problematic aspects of current cladistic definitions. Our study has found a sister-group relationship between Ornithischia and Theropoda (united in the new clade Ornithoscelida), with Sauropodomorpha and Herrerasauridae (as the redefined Saurischia) forming its monophyletic outgroup. This new tree topology requires redefinition and rediagnosis of Dinosauria and the subsidiary dinosaurian clades. In addition, it forces re-evaluations of early dinosaur cladogenesis and character evolution, suggests that hypercarnivory was acquired independently in herrerasaurids and theropods, and offers an explanation for many of the anatomical features previously regarded as notable convergences between theropods and early ornithischians.
C1 [Baron, Matthew G.; Norman, David B.; Barrett, Paul M.] Univ Cambridge, Dept Earth Sci, Downing St, Cambridge CB2 3EQ, England.
   [Baron, Matthew G.; Barrett, Paul M.] Natl Hist Museum, Dept Earth Sci, Cromwell Rd, London, England.
C3 University of Cambridge; Natural History Museum London
RP Baron, MG (corresponding author), Univ Cambridge, Dept Earth Sci, Downing St, Cambridge CB2 3EQ, England.
EM mgb46@cam.ac.uk
FU NERC/CASE Doctoral Studentship [NE/L501578/1]
NR 37
TC 198
Z9 227
U1 11
U2 224
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 23
PY 2017
VL 543
IS 7646
BP 501
EP +
DI 10.1038/nature21700
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EO9OM
UT WOS:000397018000041
PM 28332513
DA 2026-03-09
ER

PT J
AU Maiolino, R
   Russell, HR
   Fabian, AC
   Carniani, S
   Gallagher, R
   Cazzoli, S
   Arribas, S
   Belfiore, F
   Bellocchi, E
   Colina, L
   Cresci, G
   Ishibashi, W
   Marconi, A
   Mannucci, F
   Oliva, E
   Sturm, E
AF Maiolino, R.
   Russell, H. R.
   Fabian, A. C.
   Carniani, S.
   Gallagher, R.
   Cazzoli, S.
   Arribas, S.
   Belfiore, F.
   Bellocchi, E.
   Colina, L.
   Cresci, G.
   Ishibashi, W.
   Marconi, A.
   Mannucci, F.
   Oliva, E.
   Sturm, E.
TI Star formation inside a galactic outflow
SO NATURE
LA English
DT Article
ID integral field spectroscopy; massive molecular outflows; compact dwarf galaxy; infrared galaxy; positive feedback; seyfert-galaxy; forming galaxy; quasar feedback; host galaxy; agn feedback
AB Recent observations have revealed massive galactic molecular outflows(1-3) that may have the physical conditions (high gas densities(4-6)) required to form stars. Indeed, several recent models predict that such massive outflows may ignite star formation within the outflow itself(7-11). This star-formation mode, in which stars form with high radial velocities, could contribute to the morphological evolution of galaxies(12), to the evolution in size and velocity dispersion of the spheroidal component of galaxies(11,13), and would contribute to the population of high-velocity stars, which could even escape the galaxy(13). Such star formation could provide in situ chemical enrichment of the circumgalactic and intergalactic medium (through supernova explosions of young stars on large orbits), and some models also predict it to contribute substantially to the star-formation rate observed in distant galaxies9. Although there exists observational evidence for star formation triggered by outflows or jets into their host galaxy, as a consequence of gas compression, evidence for star formation occurring within galactic outflows is still missing. Here we report spectroscopic observations that unambiguously reveal star formation occurring in a galactic outflow at a redshift of 0.0448. The inferred star-formation rate in the outflow is larger than 15 solar masses per year. Star formation may also be occurring in other galactic outflows, but may have been missed by previous observations owing to the lack of adequate diagnostics(14,15).
C1 [Maiolino, R.; Carniani, S.; Gallagher, R.; Belfiore, F.] Univ Cambridge, Cavendish Lab, 19 JJ Thomson Ave, Cambridge CB3 0HE, England.
   [Maiolino, R.; Carniani, S.; Gallagher, R.; Belfiore, F.] Univ Cambridge, Kavli Inst Cosmol, Madingley Rd, Cambridge CB3 0HA, England.
   [Russell, H. R.; Fabian, A. C.] Inst Astron, Madingley Rd, Cambridge CB3 0HA, England.
   [Cazzoli, S.; Arribas, S.; Bellocchi, E.; Colina, L.] CSIC, Dept Astrofis, Ctr Astrobiol CSIC INTA, Madrid, Spain.
   [Cresci, G.; Marconi, A.; Mannucci, F.; Oliva, E.] INAF, Osserv Astrofis Arcetri, Largo E Fermi 5, I-20125 Florence, Italy.
   [Ishibashi, W.] Univ Zurich, Inst Phys, Winterthurerstr 190, CH-8057 Zurich, Switzerland.
   [Marconi, A.] Univ Studi Firenze, Dipartimento Fis & Astron, Via G Sansone 1, I-50019 Florence, Italy.
   [Sturm, E.] Max Planck Inst Extraterr Phys, Giessenbachstr, D-85748 Garching, Germany.
C3 University of Cambridge; University of Cambridge; University of Cambridge; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Centro de Astrobiologia (INTA); Istituto Nazionale Astrofisica (INAF); University of Zurich; University of Florence; Max Planck Society
RP Maiolino, R (corresponding author), Univ Cambridge, Cavendish Lab, 19 JJ Thomson Ave, Cambridge CB3 0HE, England.; Maiolino, R (corresponding author), Univ Cambridge, Kavli Inst Cosmol, Madingley Rd, Cambridge CB3 0HA, England.
EM r.maiolino@mrao.cam.ac.uk
FU Science and Technology Facilities Council (STFC); ERC [695671, 340442]; Spanish Ministry of Economy [AYA2012-32295, ESP2015-68964-P]; Science and Technology Facilities Council [ST/M001172/1, ST/P004636/1, ST/N000927/1] Funding Source: researchfish; STFC [ST/P004636/1, ST/M001172/1] Funding Source: UKRI
NR 47
TC 204
Z9 219
U1 0
U2 5
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 13
PY 2017
VL 544
IS 7649
BP 202
EP +
DI 10.1038/nature21677
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ER6EK
UT WOS:000398897900031
PM 28346938
DA 2026-03-09
ER

PT J
AU Shi, Y
   Yamada, K
   Liddelow, SA
   Smith, ST
   Zhao, LZ
   Luo, WJ
   Tsai, RM
   Spina, S
   Grinberg, LT
   Rojas, JC
   Gallardo, G
   Wang, K
   Oh, JR
   Robinson, G
   Finn, MB
   Jiang, H
   Sullivan, PM
   Baufeld, C
   Wood, MW
   Sutphen, C
   Mccue, L
   Xiong, CJ
   Del-Aguila, JL
   Morris, JC
   Cruchaga, C
   Fagan, AM
   Miller, BL
   Boxer, AL
   Seeley, WW
   Butovsky, O
   Barres, BA
   Paul, SM
   Holtzman, DM
AF Shi, Yang
   Yamada, Kaoru
   Liddelow, Shane Antony
   Smith, Scott T. .
   Zhao, Lingzhi
   Luo, Wenjie
   Tsai, Richard M. .
   Spina, Salvatore
   Grinberg, Lea T. .
   Rojas, Julio C.
   Gallardo, Gilbert
   Wang, Kairuo
   Roth, Joseph
   Robinson, Grace
   Finn, Mary Beth
   Jiang, Hong
   Sullivan, Patrick M. .
   Baufeld, Caroline
   Wood, Michael W.
   Sutphen, Courtney
   McCue, Lena
   Xiong, Chengjie
   Del-Aguila, Jorge L.
   Morris, John C.
   Cruchaga, Carlos
   Fagan, Anne M. .
   Miller, Bruce L.
   Boxer, Adam L.
   Seeley, William W.
   Butovsky, Oleg
   Barres, Ben A.
   Paul, Steven M. .
   Holtzman, David M. .
TI ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy
SO NATURE
LA English
DT Article
ID frontal-lobe dementia; apolipoprotein-e; alzheimers-disease; frontotemporal dementia; transgenic mice; brain atrophy; in-vivo; association; epsilon-4; microglia
AB APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-beta pathology relative to other ApoE isoforms(1). However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-alpha (TNF-alpha) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-alpha. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an epsilon 4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-beta pathology with symptomatic Alzheimer disease who usually have tau pathology, epsilon 4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-beta pathology. ApoE4 exerts a 'toxic' gain of function whereas the absence of ApoE is protective.
C1 [Shi, Yang; Gallardo, Gilbert; Wang, Kairuo; Roth, Joseph; Finn, Mary Beth; Jiang, Hong; Sutphen, Courtney; Morris, John C.; Fagan, Anne M. .; Holtzman, David M. .] Washington Univ, Sch Med, Charles F & Joanne Knight Alzheimers Dis Res Ctr, Dept Neurol,Hope Ctr Neurol Disorders, St Louis, MO 63110 USA.
   [Yamada, Kaoru] Univ Tokyo, Grad Sch Med, Dept Neuropathol, Tokyo 1130033, Japan.
   [Liddelow, Shane Antony; Barres, Ben A.] Stanford Univ, Sch Med, Dept Neurobiol, Stanford, CA 94305 USA.
   [Liddelow, Shane Antony] Univ Melbourne, Dept Pharmacol & Therapeut, Parkville, Vic 3010, Australia.
   [Smith, Scott T. .; Baufeld, Caroline; Butovsky, Oleg] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA.
   [Zhao, Lingzhi; Luo, Wenjie] Cornell Univ, Weill Cornell Med Coll, Feil Family Brain & Mind Res Inst, Appel Alzheimers Dis Res Inst, New York, NY 10021 USA.
   [Tsai, Richard M. .; Spina, Salvatore; Grinberg, Lea T. .; Rojas, Julio C.; Miller, Bruce L.; Boxer, Adam L.; Seeley, William W.] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94143 USA.
   [Grinberg, Lea T. .; Seeley, William W.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA.
   [Robinson, Grace] Univ Missouri, Sch Med, Dept Ophthalmol, Columbia, MO 65212 USA.
   [Sullivan, Patrick M. .] Duke Univ, Med Ctr, Durham Vet Hlth Adm Med Ctr, Dept Med,Geriatr Res Educ & Clin Ctr, Durham, NC 27705 USA.
   [Wood, Michael W.] AstraZeneca R&D, Wilmington, DE 19850 USA.
   [McCue, Lena; Xiong, Chengjie] Washington Univ St Louis, Div Biostat, St Louis, MO 63110 USA.
   [Del-Aguila, Jorge L.; Cruchaga, Carlos] Washington Univ, Sch Med, Dept Psychiat, 660 S Euclid Ave B8134, St Louis, MO 63110 USA.
   [Cruchaga, Carlos] Washington Univ, Sch Med, Dept Dev Biol, 660 S Euclid Ave, St Louis, MO 63110 USA.
   [Butovsky, Oleg] Harvard Med Sch, Brigham & Womens Hosp, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA.
   [Paul, Steven M. .] Voyager Therapeut, Cambridge, MA 02139 USA.
C3 Washington University (WUSTL); University of Tokyo; Stanford University; University of Melbourne; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard Medical School; Cornell University; Weill Cornell Medicine; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of Missouri System; University of Missouri Columbia; Geriatric Research Education & Clinical Center; US Department of Veterans Affairs; Veterans Health Administration (VHA); Duke University; AstraZeneca; Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital
RP Holtzman, DM (corresponding author), Washington Univ, Sch Med, Charles F & Joanne Knight Alzheimers Dis Res Ctr, Dept Neurol,Hope Ctr Neurol Disorders, St Louis, MO 63110 USA.
EM holtzman@wustl.edu
FU National Institutes of Health (NIH) [NS090934, P01-AG03991, P01-AG026276, P50 AG05681]; JPB Foundation; Cure Alzheimer's Fund; AstraZeneca; NIH [AG023501, AG019724, K08 AG052648, AG051812, NS088137, K01 NS096719-01]; Consortium for Frontotemporal Dementia Research; Tau Consortium; National Multiple Sclerosis Society [5092A1]; Nancy Davis Foundation; Amyotrophic Lateral Sclerosis Association [ALSA2087]; Alzheimer's Disease Neuroimaging Initiative (ADNI) (NIH) [U01 AG024904]; Department of Defense ADNI [W81XWH-12-2-0012]; National Institute of Neurological Disorders and Stroke [R01NS088137] Funding Source: NIH RePORTER; National Institute on Aging [P01AG019724, P01AG003991, R01AG054672, P01AG026276] Funding Source: NIH RePORTER
NR 29
TC 950
Z9 1100
U1 9
U2 290
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 28
PY 2017
VL 549
IS 7673
BP 523
EP +
DI 10.1038/nature24016
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI4GT
UT WOS:000411930000051
PM 28959956
DA 2026-03-09
ER

PT J
AU Zaremba-Niedzwiedzka, K
   Caceres, EF
   Saw, JH
   Bäckström, D
   Juzokaite, L
   Vancaester, E
   Seitz, KW
   Anantharaman, K
   Starnawski, P
   Kjeldsen, KU
   Stott, MB
   Nunoura, T
   Banfield, JF
   Schramm, A
   Baker, BJ
   Spang, A
   Ettema, TJG
AF Zaremba-Niedzwiedzka, Katarzyna
   Caceres, Eva F.
   Saw, Jimmy H.
   Backstrom, Disa
   Juzokaite, Lina
   Vancaester, Emmelien
   Seitz, Kiley W.
   Anantharaman, Karthik
   Starnawski, Piotr
   Kjeldsen, Kasper U.
   Stott, Matthew B.
   Nunoura, Takuro
   Banfield, Jillian F.
   Schramm, Andreas
   Baker, Brett J.
   Spang, Anja
   Ettema, Thijs J. G.
TI Asgard archaea illuminate the origin of eukaryotic cellular complexity
SO NATURE
LA English
DT Article
ID membrane-trafficking system; single-cell; domain; reconstruction; evolution; tree; mitochondria; performance; separation; transport
AB The origin and cellular complexity of eukaryotes represent a major enigma in biology. Current data support scenarios in which an archaeal host cell and an alphaproteobacterial (mitochondrial) endosymbiont merged together, resulting in the first eukaryotic cell. The host cell is related to Lokiarchaeota, an archaeal phylum with many eukaryotic features. The emergence of the structural complexity that characterizes eukaryotic cells remains unclear. Here we describe the 'Asgard' superphylum, a group of uncultivated archaea that, as well as Lokiarchaeota, includes Thor-, Odin- and Heimdallarchaeota. Asgard archaea affiliate with eukaryotes in phylogenomic analyses, and their genomes are enriched for proteins formerly considered specific to eukaryotes. Notably, thorarchaeal genomes encode several homologues of eukaryotic membrane-trafficking machinery components, including Sec23/24 and TRAPP domains. Furthermore, we identify thorarchaeal proteins with similar features to eukaryotic coat proteins involved in vesicle biogenesis. Our results expand the known repertoire of 'eukaryote-specific' proteins in Archaea, indicating that the archaeal host cell already contained many key components that govern eukaryotic cellular complexity.
C1 [Zaremba-Niedzwiedzka, Katarzyna; Caceres, Eva F.; Saw, Jimmy H.; Backstrom, Disa; Juzokaite, Lina; Vancaester, Emmelien; Spang, Anja; Ettema, Thijs J. G.] Uppsala Univ, Dept Cell & Mol Biol, Sci Life Lab, SE-75123 Uppsala, Sweden.
   [Seitz, Kiley W.; Baker, Brett J.] Univ Texas Austin, Inst Marine Sci, Dept Marine Sci, Port Aransas, TX 78373 USA.
   [Anantharaman, Karthik; Banfield, Jillian F.] Univ Calif Berkeley, Dept Earth & Planetary Sci, Berkeley, CA 94720 USA.
   [Anantharaman, Karthik; Banfield, Jillian F.] Univ Calif Berkeley, Dept Environm Sci Policy & Management, Berkeley, CA 94720 USA.
   [Starnawski, Piotr; Kjeldsen, Kasper U.; Schramm, Andreas] Aarhus Univ, Sect Microbiol, DK-8000 Aarhus, Denmark.
   [Starnawski, Piotr; Kjeldsen, Kasper U.; Schramm, Andreas] Aarhus Univ, Ctr Geomicrobiol, Dept Biosci, DK-8000 Aarhus, Denmark.
   [Stott, Matthew B.] Extremophile Res Grp, GNS Sci, Private Bag 2000, Taupo 3352, New Zealand.
   [Nunoura, Takuro] Japan Agcy Marine Earth Sci & Technol, Res & Dev Ctr Marine Biosci, Yokosuka, Kanagawa 2370061, Japan.
   [Vancaester, Emmelien] Univ Ghent, Dept Plant Syst Biol, VIB, Technol Pk 927, B-9052 Ghent, Belgium.
   [Vancaester, Emmelien] Univ Ghent, Dept Plant Biotechnol & Bioinformat, Technol Pk 927, B-9052 Ghent, Belgium.
C3 Uppsala University; University of Texas System; University of Texas Austin; University of California System; University of California Berkeley; University of California System; University of California Berkeley; Aarhus University; Aarhus University; Earth Sciences New Zealand; GNS Science - New Zealand; Japan Agency for Marine-Earth Science & Technology (JAMSTEC); Ghent University; Flanders Institute for Biotechnology (VIB); Ghent University
RP Ettema, TJG (corresponding author), Uppsala Univ, Dept Cell & Mol Biol, Sci Life Lab, SE-75123 Uppsala, Sweden.
EM thijs.ettema@icm.uu.se
FU Swedish Research Council (VR-RFI); Knut and Alice Wallenberg Foundation; European Research Council (ERC) [310039-PUZZLE_CELL, 294200-MICROENERGY]; Swedish Foundation for Strategic Research [SSF-FFL5]; Swedish Research Council (VR grant) [2015-04959]; Marie Curie IIF [331291]; IEF [625521]; European Union; Danish National Research Foundation [DNRF104]; US Department of Energy (Sustainable Systems Scientific Focus Area [DE-AC02-05CH11231]; Swedish Research Council [2015-04959] Funding Source: Swedish Research Council
NR 90
TC 749
Z9 871
U1 11
U2 475
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 19
PY 2017
VL 541
IS 7637
BP 353
EP +
DI 10.1038/nature21031
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6QP
UT WOS:000396128800034
PM 28077874
DA 2026-03-09
ER

PT J
AU Cannavo, E
   Koelling, N
   Harnett, D
   Garfield, D
   Casale, FP
   Ciglar, L
   Gustafson, HE
   Viales, RR
   Marco-Ferreres, R
   Degner, JF
   Zhao, BQ
   Stegle, O
   Birney, E
   Furlong, EEM
AF Cannavo, Enrico
   Koelling, Nils
   Harnett, Dermot
   Garfield, David
   Casale, Francesco P.
   Ciglar, Lucia
   Gustafson, Hilary E.
   Viales, Rebecca R.
   Marco-Ferreres, Raquel
   Degner, Jacob F.
   Zhao, Bingqing
   Stegle, Oliver
   Birney, Ewan
   Furlong, Eileen E. M.
TI Genetic variants regulating expression levels and isoform diversity during embryogenesis
SO NATURE
LA English
DT Article
ID genome-wide association; 3' untranslated regions; alternative polyadenylation; drosophila-melanogaster; correlated traits; natural variation; messenger-rnas; mechanisms; mouse
AB Embryonic development is driven by tightly regulated patterns of gene expression, despite extensive genetic variation among individuals. Studies of expression quantitative trait loci(1-4) (eQTL) indicate that genetic variation frequently alters gene expression in cell-culture models and differentiated tissues(5,6). However, the extent and types of genetic variation impacting embryonic gene expression, and their interactions with developmental programs, remain largely unknown. Here we assessed the effect of genetic variation on transcriptional (expression levels) and post-transcriptional (3' RNA processing) regulation across multiple stages of metazoan development, using 80 inbred Drosophila wild isolates(7), identifying thousands of developmental-stage-specific and shared QTL. Given the small blocks of linkage disequilibrium in Drosophila(7-9), we obtain near base-pair resolution, resolving causal mutations in developmental enhancers, validated transcription-factor-binding sites and RNA motifs. This fine-grain mapping uncovered extensive allelic interactions within enhancers that have opposite effects, thereby buffering their impact on enhancer activity. QTL affecting 3' RNA processing identify new functional motifs leading to transcript isoform diversity and changes in the lengths of 3' untranslated regions. These results highlight how developmental stage influences the effects of genetic variation and uncover multiple mechanisms that regulate and buffer expression variation during embryogenesis.
C1 [Cannavo, Enrico; Harnett, Dermot; Garfield, David; Ciglar, Lucia; Gustafson, Hilary E.; Viales, Rebecca R.; Marco-Ferreres, Raquel; Degner, Jacob F.; Zhao, Bingqing; Furlong, Eileen E. M.] EMBL, Genome Biol Unit, D-69117 Heidelberg, Germany.
   [Koelling, Nils; Casale, Francesco P.; Stegle, Oliver; Birney, Ewan] EBI, EMBL, Hinxton CB10 ISD, England.
C3 European Molecular Biology Laboratory (EMBL); European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute
RP Furlong, EEM (corresponding author), EMBL, Genome Biol Unit, D-69117 Heidelberg, Germany.; Birney, E (corresponding author), EBI, EMBL, Hinxton CB10 ISD, England.
EM birney@ebi.ac.uk; furlong@embl.de
FU European Molecular Biology Laboratory (EMBL) Genomics Core facility; European Research Council (ERC); ERC advanced grant CisRegVar; EMBL predoctoral funds
NR 32
TC 45
Z9 50
U1 0
U2 33
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 19
PY 2017
VL 541
IS 7637
BP 402
EP +
DI 10.1038/nature20802
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6QP
UT WOS:000396128800044
PM 28024300
DA 2026-03-09
ER

PT J
AU Akondy, RS
   Fitch, M
   Edupuganti, S
   Yang, S
   Kissick, HT
   Li, KW
   Youngblood, BA
   Abdelsamed, HA
   McGuire, DJ
   Cohen, KW
   Alexe, G
   Nagar, S
   McCausland, MM
   Gupta, S
   Tata, P
   Haining, WN
   McElrath, MJ
   Zhang, D
   Hu, B
   Greenleaf, WJ
   Goronzy, JJ
   Mulligan, MJ
   Hellerstein, M
   Ahmed, R
AF Akondy, Rama S.
   Fitch, Mark
   Edupuganti, Srilatha
   Yang, Shu
   Kissick, Haydn T.
   Li, Kelvin W.
   Youngblood, Ben A.
   Abdelsamed, Hossam A.
   McGuire, Donald J.
   Cohen, Kristen W.
   Alexe, Gabriela
   Nagar, Shashi
   McCausland, Megan M.
   Gupta, Satish
   Tata, Pramila
   Haining, W. Nicholas
   McElrath, M. Juliana
   Zhang, David
   Hu, Bin
   Greenleaf, William J.
   Goronzy, Jorg J.
   Mulligan, Mark J.
   Hellerstein, Marc
   Ahmed, Rafi
TI Origin and differentiation of human memory CD8 T cells after vaccination
SO NATURE
LA English
DT Article
ID viral-infection; life-span; effector; turnover; lymphocytes; exhaustion
AB The differentiation of human memory CD8 T cells is not well understood. Here we address this issue using the live yellow fever virus (YFV) vaccine, which induces long-term immunity in humans. We used in vivo deuterium labelling to mark CD8 T cells that proliferated in response to the virus and then assessed cellular turnover and longevity by quantifying deuterium dilution kinetics in YFV-specific CD8 T cells using mass spectrometry. This longitudinal analysis showed that the memory pool originates from CD8 T cells that divided extensively during the first two weeks after infection and is maintained by quiescent cells that divide less than once every year (doubling time of over 450 days). Although these long-lived YFV-specific memory CD8 T cells did not express effector molecules, their epigenetic landscape resembled that of effector CD8 T cells. This open chromatin profile at effector genes was maintained in memory CD8 T cells isolated even a decade after vaccination, indicating that these cells retain an epigenetic fingerprint of their effector history and remain poised to respond rapidly upon re-exposure to the pathogen.
C1 [Akondy, Rama S.; Yang, Shu; Youngblood, Ben A.; McGuire, Donald J.; McCausland, Megan M.; Mulligan, Mark J.; Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA.
   [Akondy, Rama S.; Yang, Shu; Youngblood, Ben A.; McCausland, Megan M.; Ahmed, Rafi] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA.
   [Fitch, Mark; Hellerstein, Marc] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA.
   [Edupuganti, Srilatha; Nagar, Shashi; Mulligan, Mark J.] Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA USA.
   [Kissick, Haydn T.] Emory Univ, Sch Med, Dept Urol, Atlanta, GA USA.
   [Li, Kelvin W.; Hellerstein, Marc] KineMed Inc, Emeryville, CA 94608 USA.
   [Youngblood, Ben A.; Abdelsamed, Hossam A.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA.
   [Cohen, Kristen W.; McElrath, M. Juliana] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA.
   [Alexe, Gabriela; Haining, W. Nicholas] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA.
   [Alexe, Gabriela; Haining, W. Nicholas] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Gupta, Satish; Tata, Pramila] Strand Lifesci, Bangalore, Karnataka, India.
   [Zhang, David; Hu, Bin; Goronzy, Jorg J.] Stanford Univ, Dept Med, Div Rheumatol & Immunol, Sch Med, Stanford, CA 94305 USA.
   [Greenleaf, William J.] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
   [Yang, Shu] Cent S Univ, Xiangya Sch Med, Changsha 410013, Hunan, Peoples R China.
   [Tata, Pramila] Syngene Int, Bangalore, Karnataka, India.
C3 Emory University; Emory University; University of California System; University of California Berkeley; Emory University; Emory University; Kinemed Inc; St Jude Children's Research Hospital; Fred Hutchinson Cancer Center; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Stanford University; Stanford University; Central South University; Syngene International Limited
RP Ahmed, R (corresponding author), Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA.; Ahmed, R (corresponding author), Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA.; Hellerstein, M (corresponding author), Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA.; Hellerstein, M (corresponding author), KineMed Inc, Emeryville, CA 94608 USA.
EM march@berkeley.edu; rahmed@emory.edu
FU NIH [U19AI057266, R01-AI43866-07]; NIAID [UM1 AI068618, UM1 AI069481]; National Institute of Allergy and Infectious Diseases [U19AI057266, UM1AI069481] Funding Source: NIH RePORTER; National Institute of Arthritis and Musculoskeletal and Skin Diseases [T32AR050942] Funding Source: NIH RePORTER; National Institute of Dental and Craniofacial Research; National Institute of Allergy and Infectious Diseases [UM1AI068618] Funding Source: NIH RePORTER
NR 31
TC 399
Z9 494
U1 6
U2 103
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 21
PY 2017
VL 552
IS 7685
BP 362
EP +
DI 10.1038/nature24633
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ7RI
UT WOS:000418559800050
PM 29236685
DA 2026-03-09
ER

PT J
AU Bassis, JN
   Petersen, SV
   Mac Cathles, L
AF Bassis, Jeremy N.
   Petersen, Sierra V.
   Mac Cathles, L.
TI Heinrich events triggered by ocean forcing and modulated by isostatic adjustment
SO NATURE
LA English
DT Article
ID north-atlantic; ice-sheet; iceberg discharges; greenland ice; sea-level; glaciers; retreat; records; climate
AB During the last glacial period, the Laurentide Ice Sheet sporadically discharged huge numbers of icebergs through the Hudson Strait into the North Atlantic Ocean, leaving behind distinct layers of ice-rafted debris in the ocean sediments(1-3). Perplexingly, these massive discharge events-Heinrich events-occurred during the cold portion of millennial-scale climate oscillations called Dansgaard-Oeschger cycles(2,4). This is in contrast to the expectation that ice sheets expand in colder climates and shrink in warmer climates. Here we use an ice sheet model to show that the magnitude and timing of Heinrich events can be explained by the same processes that drive the retreat of modern marine-terminating glaciers. In our model, subsurface ocean warming associated with variations in the overturning circulation increases underwater melt along the calving face, triggering rapid margin retreat and increased iceberg discharge. On millennial timescales, isostatic adjustment causes the bed to uplift, isolating the terminus from subsurface warming and allowing the ice sheet to advance again until, at its most advanced position, it is poised for another Heinrich event. This mechanism not only explains the timing and magnitude of observed Heinrich events, but also suggests that ice sheets in contact with warming oceans may be vulnerable to catastrophic collapse even with little atmospheric warming.
C1 [Bassis, Jeremy N.; Mac Cathles, L.] Univ Michigan, Dept Climate & Space Sci & Engn, Ann Arbor, MI 48109 USA.
   [Petersen, Sierra V.; Mac Cathles, L.] Univ Michigan, Dept Earth & Environm Sci, Ann Arbor, MI 48109 USA.
C3 University of Michigan System; University of Michigan; University of Michigan System; University of Michigan
RP Bassis, JN (corresponding author), Univ Michigan, Dept Climate & Space Sci & Engn, Ann Arbor, MI 48109 USA.
EM jbassis@umich.edu
FU NSF-ANT [114085]; Polar Programs [PLR-1341568]; NOAH [NA13OAR4310096]; NSF-OCE-PRF [1420902]; Michigan Society of Fellows; Directorate For Geosciences; Office of Polar Programs (OPP) [1341568] Funding Source: National Science Foundation
NR 30
TC 106
Z9 120
U1 1
U2 76
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 16
PY 2017
VL 542
IS 7641
BP 332
EP 334
DI 10.1038/nature21069
PG 3
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2LQ
UT WOS:000394451600033
PM 28202970
DA 2026-03-09
ER

PT J
AU Lasko, LM
   Jakob, CG
   Edalji, RP
   Qiu, W
   Montgomery, D
   Digiammarino, EL
   Hansen, TM
   Risi, RM
   Frey, R
   Manaves, V
   Shaw, B
   Algire, M
   Hessler, P
   Lam, LT
   Uziel, T
   Faivre, E
   Ferguson, D
   Buchanan, FG
   Martin, RL
   Torrent, M
   Chiang, GG
   Karukurichi, K
   Langston, JW
   Weinert, BT
   Choudhary, C
   de Vries, P
   Van Drie, JH
   McElligott, D
   Kesicki, E
   Marmorstein, R
   Sun, CH
   Cole, PA
   Rosenberg, SH
   Michaelides, MR
   Lai, A
   Bromberg, KD
AF Lasko, Loren M.
   Jakob, Clarissa G.
   Edalji, Rohinton P.
   Qiu, Wei
   Montgomery, Debra
   Digiammarino, Enrico L.
   Hansen, T. Matt
   Risi, Roberto M.
   Frey, Robin
   Manaves, Vlasios
   Shaw, Bailin
   Algire, Mikkel
   Hessler, Paul
   Lam, Lloyd T.
   Uziel, Tamar
   Faivre, Emily
   Ferguson, Debra
   Buchanan, Fritz G.
   Martin, Ruth L.
   Torrent, Maricel
   Chiang, Gary G.
   Karukurichi, Kannan
   Langston, J. William
   Weinert, Brian T.
   Choudhary, Chunaram
   de Vries, Peter
   Van Drie, John H.
   McElligott, David
   Kesicki, Ed
   Marmorstein, Ronen
   Sun, Chaohong
   Cole, Philip A.
   Rosenberg, Saul H.
   Michaelides, Michael R.
   Lai, Albert
   Bromberg, Kenneth D.
TI Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours
SO NATURE
LA English
DT Article
ID small-molecule inhibitor; androgen receptor; acetyltransferases p300; histone
AB The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription(1) and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind(2). The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer(3)). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products(4), bi-substrate analogues(5) and the widely used small molecule C646(6,7), lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like catalytic inhibitor of p300 and CBP. We present a high resolution (1.95 angstrom) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 competes with acetyl coenzyme A (acetyl-CoA). A-485 selectively inhibited proliferation in lineage-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.
C1 [Lasko, Loren M.; Jakob, Clarissa G.; Edalji, Rohinton P.; Qiu, Wei; Montgomery, Debra; Digiammarino, Enrico L.; Hansen, T. Matt; Risi, Roberto M.; Frey, Robin; Manaves, Vlasios; Shaw, Bailin; Algire, Mikkel; Hessler, Paul; Lam, Lloyd T.; Uziel, Tamar; Faivre, Emily; Ferguson, Debra; Buchanan, Fritz G.; Martin, Ruth L.; Torrent, Maricel; Chiang, Gary G.; Sun, Chaohong; Rosenberg, Saul H.; Michaelides, Michael R.; Lai, Albert; Bromberg, Kenneth D.] AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA.
   [Chiang, Gary G.] eFFECTOR Therapeut, 11180 Roselle St,Suite A, San Diego, CA 92121 USA.
   [Karukurichi, Kannan; Kesicki, Ed] Petra Pharma Corp, 430 E 29th St,Suite 435, New York, NY 10016 USA.
   [Langston, J. William] Faraday Pharmaceut, 1616 Eastlake Ave E, Seattle, WA 98102 USA.
   [Weinert, Brian T.; Choudhary, Chunaram] Univ Copenhagen, Fac Hlth & Med Sci, Nordisk Fdn Ctr Prot Res, Dept Prote, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
   [de Vries, Peter] Cascadian Therapeut Inc, 2601 Fourth Ave,Suite 500, Seattle, WA 98121 USA.
   [Van Drie, John H.] Van Drie Res, 109 Millpond, Andover, MA 01845 USA.
   [McElligott, David] Accelerator Corp, 430 East 29th St, New York, NY 10106 USA.
   [Marmorstein, Ronen] Univ Penn, Perelman Sch Med, 421 Curie Blvd, Philadelphia, PA 19104 USA.
   [Cole, Philip A.] Johns Hopkins Univ, 725 N Wolfe St, Baltimore, MD 21205 USA.
C3 AbbVie; University of Copenhagen; University of Pennsylvania; Johns Hopkins University
RP Lai, A; Bromberg, KD (corresponding author), AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA.
EM Albert.Lai@abbvie.com; kenneth.bromberg@abbvie.com
FU companies of the Industrial Macromolecular Crystallography Association; Hauptman-Woodward Medical Research Institute; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; Novo Nordisk Foundation [NNF140C0008541, NNF14CC0001]; NIH; FAMRI foundation; Novo Nordisk Fonden [NNF14OC0008541] Funding Source: researchfish; Novo Nordisk Foundation Center for Protein Research [PI Chunaram Choudhary] Funding Source: researchfish; National Institute of General Medical Sciences [R37GM062437] Funding Source: NIH RePORTER
NR 23
TC 611
Z9 709
U1 2
U2 154
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 5
PY 2017
VL 550
IS 7674
BP 128
EP +
DI 10.1038/nature24028
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI7XU
UT WOS:000412214100059
PM 28953875
DA 2026-03-09
ER

PT J
AU Dudas, G
   Carvalho, LM
   Bedford, T
   Tatem, AJ
   Baele, G
   Faria, NR
   Park, DJ
   Ladner, JT
   Arias, A
   Asogun, D
   Bielejec, F
   Caddy, SL
   Cotten, M
   D'Ambrozio, J
   Dellicour, S
   Di Caro, A
   Diclaro, JW
   Duraffour, S
   Elmore, MJ
   Fakoli, LS
   Faye, O
   Gilbert, ML
   Gevao, SM
   Gire, S
   Gladden-Young, A
   Gnirke, A
   Goba, A
   Grant, DS
   Haagmans, BL
   Hiscox, JA
   Jah, U
   Kugelman, JR
   Liu, D
   Lu, J
   Malboeuf, CM
   Mate, S
   Matthews, DA
   Matranga, CB
   Meredith, LW
   Qu, J
   Quick, J
   Pas, SD
   Phan, MVT
   Pollakis, G
   Reusken, CB
   Sanchez-Lockhart, M
   Schaffner, SF
   Schieffelin, JS
   Sealfon, RS
   Simon-Loriere, E
   Smits, SL
   Stoecker, K
   Thorne, L
   Tobin, EA
   Vandi, MA
   Watson, SJ
   West, K
   Whitmer, S
   Wiley, MR
   Winnicki, SM
   Wohl, S
   Wölfel, R
   Yozwiak, NL
   Andersen, KG
   Blyden, SO
   Bolay, F
   Carroll, MW
   Dahn, B
   Diallo, B
   Formenty, P
   Fraser, C
   Gao, GF
   Garry, RF
   Goodfellow, I
   Gnther, S
   Happi, CT
   Holmes, EC
   Kargbo, B
   Keïta, S
   Kellam, P
   Koopmans, MPG
   Kuhn, JH
   Loman, NJ
   Magassouba, N
   Naidoo, D
   Nichol, ST
   Nyenswah, T
   Palacios, G
   Pybus, OG
   Sabeti, PC
   Sall, A
   Ströher, U
   Wurie, I
   Suchard, MA
   Lemey, P
   Rambaut, A
AF Dudas, Gytis
   Carvalho, Luiz Max
   Bedford, Trevor
   Tatem, Andrew J.
   Baele, Guy
   Faria, Nuno R.
   Park, Daniel J.
   Ladner, Jason T.
   Arias, Armando
   Asogun, Danny
   Bielejec, Filip
   Caddy, Sarah L.
   Cotten, Matthew
   D'Ambrozio, Jonathan
   Dellicour, Simon
   Di Caro, Antonino
   Diclaro, Joseph W.
   Duraffour, Sophie
   Elmore, Michael J.
   Fakoli, Lawrence S.
   Faye, Ousmane
   Gilbert, Merle L.
   Gevao, Sahr M.
   Gire, Stephen
   Gladden-Young, Adrianne
   Gnirke, Andreas
   Goba, Augustine
   Grant, Donald S.
   Haagmans, Bart L.
   Hiscox, Julian A.
   Jah, Umaru
   Kugelman, Jeffrey R.
   Liu, Di
   Lu, Jia
   Malboeuf, Christine M.
   Mate, Suzanne
   Matthews, David A.
   Matranga, Christian B.
   Meredith, Luke W.
   Qu, James
   Quick, Joshua
   Pas, Suzan D.
   Phan, My V. T.
   Pollakis, Georgios
   Reusken, Chantal B.
   Sanchez-Lockhart, Mariano
   Schaffner, Stephen F.
   Schieffelin, John S.
   Sealfon, Rachel S.
   Simon-Loriere, Etienne
   Smits, Saskia L.
   Stoecker, Kilian
   Thorne, Lucy
   Tobin, Ekaete Alice
   Vandi, Mohamed A.
   Watson, Simon J.
   West, Kendra
   Whitmer, Shannon
   Wiley, Michael R.
   Winnicki, Sarah M.
   Wohl, Shirlee
   Wolfel, Roman
   Yozwiak, Nathan L.
   Andersen, Kristian G.
   Blyden, Sylvia O.
   Bolay, Fatorma
   Carroll, Miles W.
   Dahn, Bernice
   Diallo, Boubacar
   Formenty, Pierre
   Fraser, Christophe
   Gao, George F.
   Garry, Robert F.
   Goodfellow, Ian
   Gnther, Stephan
   Happi, Christian T.
   Holmes, Edward C.
   Kargbo, Brima
   Keita, Sakoba
   Kellam, Paul
   Koopmans, Marion P. G.
   Kuhn, Jens H.
   Loman, Nicholas J.
   Magassouba, N'Faly
   Naidoo, Dhamari
   Nichol, Stuart T.
   Nyenswah, Tolbert
   Palacios, Gustavo
   Pybus, Oliver G.
   Sabeti, Pardis C.
   Sall, Amadou
   Stroher, Ute
   Wurie, Isatta
   Suchard, Marc A.
   Lemey, Philippe
   Rambaut, Andrew
TI Virus genomes reveal factors that spread and sustained the Ebola epidemic
SO NATURE
LA English
DT Article
ID real-time; disease; evolution; dynamics; outbreak; transmission; measles; guinea; hypermutation; surveillance
AB The 2013-2016 West African epidemic caused by the Ebola virus was of unprecedented magnitude, duration and impact. Here we reconstruct the dispersal, proliferation and decline of Ebola virus throughout the region by analysing 1,610 Ebola virus genomes, which represent over 5% of the known cases. We test the association of geography, climate and demography with viral movement among administrative regions, inferring a classic 'gravity' model, with intense dispersal between larger and closer populations. Despite attenuation of international dispersal after border closures, cross-border transmission had already sown the seeds for an international epidemic, rendering these measures ineffective at curbing the epidemic. We address why the epidemic did not spread into neighbouring countries, showing that these countries were susceptible to substantial outbreaks but at lower risk of introductions. Finally, we reveal that this large epidemic was a heterogeneous and spatially dissociated collection of transmission clusters of varying size, duration and connectivity. These insights will help to inform interventions in future epidemics.
C1 [Dudas, Gytis; Carvalho, Luiz Max; Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Kings Bldg, Edinburgh EH9 3FL, Midlothian, Scotland.
   [Dudas, Gytis; Bedford, Trevor] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA.
   [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, WorldPop, Southampton SO17 1BJ, Hants, England.
   [Tatem, Andrew J.] Flowminder Fdn, Stockholm, Sweden.
   [Baele, Guy; Bielejec, Filip; Dellicour, Simon; Lemey, Philippe] Univ Leuven, KU Leuven, Rega Inst, Dept Microbiol & Immunol, B-3000 Leuven, Belgium.
   [Faria, Nuno R.; Pybus, Oliver G.] Univ Oxford, Dept Zool, South Parks Rd, Oxford OX1 3PS, England.
   [Park, Daniel J.; Gire, Stephen; Gladden-Young, Adrianne; Gnirke, Andreas; Malboeuf, Christine M.; Matranga, Christian B.; Qu, James; Schaffner, Stephen F.; Sealfon, Rachel S.; West, Kendra; Winnicki, Sarah M.; Wohl, Shirlee; Yozwiak, Nathan L.; Sabeti, Pardis C.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.
   [Ladner, Jason T.; D'Ambrozio, Jonathan; Gilbert, Merle L.; Kugelman, Jeffrey R.; Mate, Suzanne; Sanchez-Lockhart, Mariano; Wiley, Michael R.; Palacios, Gustavo] US Army, Med Res Inst Infect Dis, Ctr Genome Sci, Frederick, MD 21702 USA.
   [Arias, Armando; Caddy, Sarah L.; Lu, Jia; Meredith, Luke W.; Thorne, Lucy; Goodfellow, Ian] Univ Cambridge, Addenbrookes Hosp, Dept Pathol, Cambridge CB2 2QQ, England.
   [Arias, Armando] Tech Univ Denmark, Natl Vet Inst, Bulowsvej 27, DK-1870 Frederiksberg C, Denmark.
   [Asogun, Danny; Tobin, Ekaete Alice] Irrua Specialist Teaching Hosp, Inst Lassa Fever Res & Control, Irrua, Nigeria.
   [Asogun, Danny; Di Caro, Antonino; Duraffour, Sophie; Stoecker, Kilian; Tobin, Ekaete Alice; Wolfel, Roman; Carroll, Miles W.; Gnther, Stephan] European Mobile Lab Consortium, D-20359 Hamburg, Germany.
   [Cotten, Matthew; Phan, My V. T.; Watson, Simon J.; Kellam, Paul] Wellcome Trust Sanger Inst, Virus Genom, Cambridge CB10 1SA, England.
   [Cotten, Matthew; Haagmans, Bart L.; Pas, Suzan D.; Phan, My V. T.; Reusken, Chantal B.; Smits, Saskia L.; Koopmans, Marion P. G.] Erasmus Univ, Dept Virosci, Med Ctr, POB 2040, NL-300 CA Rotterdam, Netherlands.
   [Di Caro, Antonino] Natl Inst Infect Dis L Spallanzani IRCCS, Via Portuense 292, I-00149 Rome, Italy.
   [Diclaro, Joseph W.] Naval Med Res Unit 3, 3A Lmtidad Ramses St, Cairo 11517, Egypt.
   [Duraffour, Sophie; Gnther, Stephan] Bernhard Nocht Inst Trop Med, D-20359 Hamburg, Germany.
   [Elmore, Michael J.; Carroll, Miles W.] Publ Hlth England, Natl Infect Serv, Salisbury SP4 0JG, Wilts, England.
   [Fakoli, Lawrence S.; Bolay, Fatorma] Liberian Inst Biomed Res, Charlesville, Liberia.
   [Faye, Ousmane; Sall, Amadou] Inst Pasteur, Arbovirus & Viral Hemorrhag Fever Unit, 36 Ave Pasteur,BP 220, Dakar, Senegal.
   [Gevao, Sahr M.; Wurie, Isatta] Univ Sierra Leone, Freetown, Sierra Leone.
   [Gire, Stephen; Wohl, Shirlee; Yozwiak, Nathan L.; Sabeti, Pardis C.] Harvard Univ, Dept Organism & Evolutionary Biol, Ctr Syst Biol, Cambridge, MA 02138 USA.
   [Goba, Augustine; Grant, Donald S.; Vandi, Mohamed A.] Kenema Govt Hosp, Viral Hemorrhag Fever Program, 1 Combema Rd, Kenema, Sierra Leone.
   [Goba, Augustine; Grant, Donald S.; Vandi, Mohamed A.; Kargbo, Brima] Minist Hlth & Sanitat, 4th Floor Youyi Bldg, Freetown, Sierra Leone.
   [Hiscox, Julian A.; Pollakis, Georgios] Univ Liverpool, Inst Infect & Global Hlth, Liverpool L69 2BE, Merseyside, England.
   [Hiscox, Julian A.; Carroll, Miles W.] Univ Liverpool, NIHR Hlth Protect Res Unit Emerging & Zoonot Infe, Liverpool L69 3GL, Merseyside, England.
   [Jah, Umaru; Meredith, Luke W.; Goodfellow, Ian] Univ Makeni, Makeni, Sierra Leone.
   [Liu, Di; Gao, George F.] Chinese Acad Sci, Inst Microbiol, Beijing 100101, Peoples R China.
   [Matthews, David A.] Univ Bristol, Bristol BS8 1TD, Avon, England.
   [Quick, Joshua; Loman, Nicholas J.] Univ Birmingham, Inst Microbiol & Infect, Birmingham B15 2TT, W Midlands, England.
   [Sanchez-Lockhart, Mariano; Wiley, Michael R.] Univ Nebraska Med Ctr, Omaha, NE 68198 USA.
   [Schieffelin, John S.; Winnicki, Sarah M.] Infect Dis Sect, Dept Pediat, New Orleans, LA 70112 USA.
   [Sealfon, Rachel S.] Flatiron Inst, Ctr Computat Biol, New York, NY 10010 USA.
   [Sealfon, Rachel S.] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA.
   [Simon-Loriere, Etienne] Inst Pasteur, Funct Genet Infect Dis Unit, 28 Rue Docteur Roux, F-75724 Paris 15, France.
   [Simon-Loriere, Etienne] CNRS URA3012, Genet Fonct Malad Infect, F-75015 Paris, France.
   [Stoecker, Kilian; Wolfel, Roman] Bundeswehr Inst Microbiol, Neuherbergstr 11, D-80937 Munich, Germany.
   [Whitmer, Shannon; Nichol, Stuart T.; Stroher, Ute] Ctr Dis Control & Prevent, Viral Special Pathogens Branch, 1600 Clifton Rd NE, Atlanta, GA 30333 USA.
   [Andersen, Kristian G.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA.
   [Andersen, Kristian G.] Scripps Translat Sci Inst, La Jolla, CA 92037 USA.
   [Blyden, Sylvia O.] Minist Social Welf Gender & Childrens Affairs, New Englandville, Freetown, Sierra Leone.
   [Carroll, Miles W.] Univ Southampton, South Gen Hosp, Southampton SO16 6YD, Hants, England.
   [Dahn, Bernice; Nyenswah, Tolbert] Minstry Hlth Liberia, Monrovia, Liberia.
   [Diallo, Boubacar] WHO, Conakry, Guinea.
   [Formenty, Pierre; Naidoo, Dhamari] WHO, Geneva, Switzerland.
   [Fraser, Christophe] Univ Oxford, Oxford Big Data Inst, Nuffield Dept Med, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford OX3 7FZ, England.
   [Gao, George F.] Chinese Ctr Dis Control & Prevent China CDC, Beijing 102206, Peoples R China.
   [Garry, Robert F.] Dept Microbiol & Immunol, New Orleans, LA 70112 USA.
   [Happi, Christian T.] Redeemers Univ, Dept Biol Sci, Ede, Osun State, Nigeria.
   [Happi, Christian T.] Redeemers Univ, ACEGID, Ede, Osun State, Nigeria.
   [Holmes, Edward C.] Univ Sydney, Sch Life & Environm Sci, Charles Perkins Ctr, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia.
   [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia.
   [Keita, Sakoba] Minist Hlth Guinea, Conakry, Guinea.
   [Kellam, Paul] Imperial Coll London, Div Infect Dis, Fac Med, London W2 1PG, England.
   [Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, B-8200 Res Plaza, Frederick, MD 21702 USA.
   [Magassouba, N'Faly] Univ Gamal Abdel Nasser Conakry, Lab Fievres Hemorrag Guinee, Conakry, Guinea.
   [Suchard, Marc A.] Univ Calif Los Angeles, UCLA Fielding Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90095 USA.
   [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 USA.
   [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA.
   [Rambaut, Andrew] Univ Edinburgh, Ctr Immunol Infect & Evolut, Kings Bldg, Edinburgh EH9 3FL, Midlothian, Scotland.
   [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA.
C3 University of Edinburgh; Fred Hutchinson Cancer Center; University of Southampton; KU Leuven; University of Oxford; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; University of Cambridge; Technical University of Denmark; Wellcome Trust Sanger Institute; Erasmus University Rotterdam; Erasmus MC; IRCCS Lazzaro Spallanzani; Naval Medical Research Center (NMRC); Naval Medical Research Unit - No. 3 (NAMRU-3); Leibniz Association; Bernhard Nocht Institut fur Tropenmedizin; Public Health England; Pasteur Network; Institut Pasteur Dakar; Harvard University; Kenema Government Hospital; Ministry of Health & Sanitation Sierra Leone; University of Liverpool; University of Liverpool; University of Makeni; Chinese Academy of Sciences; Institute of Microbiology, CAS; University of Bristol; University of Birmingham; University of Nebraska System; University of Nebraska Medical Center; Simons Foundation; Flatiron Institute; Princeton University; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Ecology & Environment (INEE); Bundeswehr Institute of Microbiology (IMB); Centers for Disease Control & Prevention - USA; Scripps Research Institute; Scripps Research Institute; University of Southampton; World Health Organization; World Health Organization; University of Oxford; Chinese Center for Disease Control & Prevention; Redeemers University; Redeemers University; University of Sydney; University of Sydney; Imperial College London; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of Edinburgh; National Institutes of Health (NIH) - USA; NIH Fogarty International Center (FIC)
RP Dudas, G; Rambaut, A (corresponding author), Univ Edinburgh, Inst Evolutionary Biol, Kings Bldg, Edinburgh EH9 3FL, Midlothian, Scotland.; Dudas, G (corresponding author), Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA.; Lemey, P (corresponding author), Univ Leuven, KU Leuven, Rega Inst, Dept Microbiol & Immunol, B-3000 Leuven, Belgium.; Rambaut, A (corresponding author), Univ Edinburgh, Ctr Immunol Infect & Evolut, Kings Bldg, Edinburgh EH9 3FL, Midlothian, Scotland.; Rambaut, A (corresponding author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA.
EM gdudas@fredhutch.org; philippe.lemey@kuleuven.be; a.rambaut@ed.ac.uk
FU European Union [278433-PREDEMICS, 643476-COMPARE, 634650-VIROGENESIS, 666100-EVIDENT]; ERC [260864]; European Commission [IFS/2011/272-372]; National Institutes of Health [R01 AI107034, R01 AI117011, R01 HG006139]; National Science Foundation [IIS 1251151, DMS 1264153]; NIH [AI081982, AI082119, AI082805 AI088843, AI104216, AI104621, AI115754, HSN272200900049C, HHSN272201400048C, R35 GM119774-01, 1U01HG007480-01, UL1TR001114]; National Health AMP; Medical Research Council (Australia); Defense Threat Reduction Agency; Global Emerging Infections System and the Targeted Acquisition of Reference Materials Augmenting Capabilities (TARMAC) Initiative agencies from the US Department of Defense; Bill and Melinda Gates Foundation [OPP1106427, 1032350, OPP1134076, OPP1123407]; Wellcome Trust [106866/Z/15/Z]; Clinton Health Access Initiative; National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections; Ministry of Science and Technology of China [2016YFC1200800]; National Natural Science Foundation of China [81590760, 81321063]; Mahan Post-doctoral fellowship Fred Hutchinson Cancer Research Center; National Institute of Allergy and Infectious Disease [U19AI110818, 5R01AI114855-03]; United States Agency for International Development [OAA-G-15-00001]; World Bank [ACE019]; PEW Biomedical Scholarship; NIAID [HHSN272201400048C, HHSN272200700016I]; BBSRC [BB/M02542X/1, BB/N001176/1] Funding Source: UKRI; MRC [MR/L015080/1, MC_UU_12014/12, MR/M501621/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/M02542X/1, BB/N001176/1] Funding Source: researchfish; Medical Research Council [MC_UU_12014/12, MR/L015080/1, MR/M501621/1] Funding Source: researchfish; Bill and Melinda Gates Foundation [OPP1123407] Funding Source: Bill and Melinda Gates Foundation; Direct For Mathematical & Physical Scien; Division Of Mathematical Sciences [1264153] Funding Source: National Science Foundation; National Human Genome Research Institute [R01HG006139] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [U19AI110818] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R35GM119774] Funding Source: NIH RePORTER
NR 57
TC 280
Z9 337
U1 1
U2 145
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 20
PY 2017
VL 544
IS 7650
BP 309
EP +
DI 10.1038/nature22040
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ES4SG
UT WOS:000399524400029
PM 28405027
DA 2026-03-09
ER

PT J
AU Safra, M
   Sas-Chen, A
   Nir, R
   Winkler, R
   Nachshon, A
   Bar-Yaacov, D
   Erlacher, M
   Rossmanith, W
   Stern-Ginossar, N
   Schwartz, S
AF Safra, Modi
   Sas-Chen, Aldema
   Nir, Roni
   Winkler, Roni
   Nachshon, Aharon
   Bar-Yaacov, Dan
   Erlacher, Matthias
   Rossmanith, Walter
   Stern-Ginossar, Noam
   Schwartz, Schraga
TI The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution
SO NATURE
LA English
DT Article
ID hereditary optic neuropathy; mapping reveals; mouse; seq; dna; n-1-methyladenosine; methylation; expression; methyltransferase; pseudouridylation
AB Modifications on mRNA offer the potential of regulating mRNA fate post-transcriptionally. Recent studies suggested the widespread presence of N-1-methyladenosine (m(1)A), which disrupts Watson-Crick base pairing, at internal sites of mRNAs(1,2). These studies lacked the resolution of identifying individual modified bases, and did not identify specific sequence motifs undergoing the modification or an enzymatic machinery catalysing them, rendering it challenging to validate and functionally characterize putative sites. Here we develop an approach that allows the transcriptome-wide mapping of m(1)A at single-nucleotide resolution. Within the cytosol, m(1)A is present in a low number of mRNAs, typically at low stoichiometries, and almost invariably in tRNA T-loop-like structures, where it is introduced by the TRMT6/TRMT61A complex. We identify a single m(1)A site in the mitochondrial ND5 mRNA, catalysed by TRMT10C, with methylation levels that are highly tissue specific and tightly developmentally controlled. m1A leads to translational repression, probably through a mechanism involving ribosomal scanning or translation. Our findings suggest that m(1)A on mRNA, probably because of its disruptive impact on base pairing, leads to translational repression, and is generally avoided by cells, while revealing one case in mitochondria where tight spatiotemporal control over m(1)A levels was adopted as a potential means of post-transcriptional regulation.
C1 [Safra, Modi; Sas-Chen, Aldema; Nir, Roni; Winkler, Roni; Nachshon, Aharon; Bar-Yaacov, Dan; Stern-Ginossar, Noam; Schwartz, Schraga] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel.
   [Erlacher, Matthias] Med Univ Innsbruck, Bioctr Innsbruck, Div Genom & RNom, Innrain 80-82, A-6020 Innsbruck, Austria.
   [Rossmanith, Walter] Med Univ Vienna, Ctr Anat & Cell Biol, A-1090 Vienna, Austria.
C3 Weizmann Institute of Science; Medical University of Innsbruck; Medical University of Vienna
RP Schwartz, S (corresponding author), Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel.
EM schwartz@weizmann.ac.il
FU Austrian Science Fund (FWF) [P28494, P25983] Funding Source: Austrian Science Fund (FWF)
NR 41
TC 518
Z9 589
U1 5
U2 118
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 9
PY 2017
VL 551
IS 7679
BP 251
EP +
DI 10.1038/nature24456
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FM1KF
UT WOS:000414734200052
PM 29072297
DA 2026-03-09
ER

PT J
AU Felsenberg, J
   Barnstedt, O
   Cognigni, P
   Lin, SW
   Waddell, S
AF Felsenberg, Johannes
   Barnstedt, Oliver
   Cognigni, Paola
   Lin, Suewei
   Waddell, Scott
TI Re-evaluation of learned information in Drosophila
SO NATURE
LA English
DT Article
ID long-term-memory; dopamine neurons; olfactory memory; reconsolidation; extinction; prediction; reward; expression; retrieval; inhibition
AB Animals constantly assess the reliability of learned information to optimize their behaviour. On retrieval, consolidated long-term memory can be neutralized by extinction if the learned prediction was inaccurate(1). Alternatively, retrieved memory can be maintained, following a period of reconsolidation during which it is labile(2). Although extinction and reconsolidation provide opportunities to alleviate problematic human memories(3-5), we lack a detailed mechanistic understanding of memory updating. Here we identify neural operations underpinning the re-evaluation of memory in Drosophila. Reactivation of reward-reinforced olfactory memory can lead to either extinction or reconsolidation, depending on prediction accuracy. Each process recruits activity in specific parts of the mushroom body output network and distinct subsets of reinforcing dopaminergic neurons. Memory extinction requires output neurons with dendrites in the alpha and alpha' lobes of the mushroom body, which drive negatively reinforcing dopaminergic neurons that innervate neighbouring zones. The aversive valence of these new extinction memories neutralizes previously learned odour preference. Memory reconsolidation requires the gamma 2 alpha'1 mushroom body output neurons. This pathway recruits negatively reinforcing dopaminergic neurons innervating the same compartment and re-engages positively reinforcing dopaminergic neurons to reconsolidate the original reward memory. These data establish that recurrent and hierarchical connectivity between mushroom body output neurons and dopaminergic neurons enables memory re-evaluation driven by reward-prediction error.
C1 [Felsenberg, Johannes; Barnstedt, Oliver; Cognigni, Paola; Lin, Suewei; Waddell, Scott] Univ Oxford, Ctr Neural Circuits & Behav, Tinsley Bldg,Mansfield Rd, Oxford OX1 3SR, England.
   [Lin, Suewei] Acad Sinica, Inst Mol Biol, Taipei 115, Taiwan.
C3 University of Oxford; Academia Sinica - Taiwan
RP Waddell, S (corresponding author), Univ Oxford, Ctr Neural Circuits & Behav, Tinsley Bldg,Mansfield Rd, Oxford OX1 3SR, England.
EM scott.waddell@cncb.ox.ac.uk
FU Deutsche Forschungsgemeinschaft [FE 1563/1-1]; EMBO Long-Term Fellowship; Medical Research Council; University College War Memorial Studentship; Goodger and Schorstein Scholarship; Wellcome Trust Principal Research Fellowship in the Basic Biomedical Sciences; Gatsby Charitable Foundation; Oxford Martin School; Bettencourt-Schueller Foundation; Wellcome Trust [090309/Z/09/Z] Funding Source: researchfish
NR 41
TC 104
Z9 115
U1 0
U2 49
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 13
PY 2017
VL 544
IS 7649
BP 240
EP +
DI 10.1038/nature21716
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ER6EK
UT WOS:000398897900039
PM 28379939
DA 2026-03-09
ER

PT J
AU Schmitt, LI
   Wimmer, RD
   Nakajima, M
   Happ, M
   Mofakham, S
   Halassa, MM
AF Schmitt, L. Ian
   Wimmer, Ralf D.
   Nakajima, Miho
   Happ, Michael
   Mofakham, Sima
   Halassa, Michael M.
TI Thalamic amplification of cortical connectivity sustains attentional control
SO NATURE
LA English
DT Article
ID prefrontal cortex; mediodorsal thalamus; sequence generation; working-memory; dynamics; information; network; neurons; rat; projections
AB Although interactions between the thalamus and cortex are critical for cognitive function(1-3), the exact contribution of the thalamus to these interactions remains unclear. Recent studies have shown diverse connectivity patterns across the thalamus(4,5), but whether this diversity translates to thalamic functions beyond relaying information to or between cortical regions(6) is unknown. Here we show, by investigating the representation of two rules used to guide attention in the mouse prefrontal cortex (PFC), that the mediodorsal thalamus sustains these representations without relaying categorical information. Specifically, mediodorsal input amplifies local PFC connectivity, enabling rule-specific neural sequences to emerge and thereby maintain rule representations. Consistent with this notion, broadly enhancing PFC excitability diminishes rule specificity and behavioural performance, whereas enhancing mediodorsal excitability improves both. Overall, our results define a previously unknown principle in neuroscience; thalamic control of functional cortical connectivity. This function, which is dissociable from categorical information relay, indicates that the thalamus has a much broader role in cognition than previously thought.
C1 [Schmitt, L. Ian; Wimmer, Ralf D.; Nakajima, Miho; Happ, Michael; Mofakham, Sima; Halassa, Michael M.] NYU Langone Med Ctr, Dept Neurosci & Physiol, NYU Neurosci Inst, New York, NY 10016 USA.
   [Halassa, Michael M.] NYU, Ctr Neural Sci, 550 1St Ave, New York, NY 10016 USA.
C3 NYU Langone Medical Center; New York University
RP Halassa, MM (corresponding author), NYU Langone Med Ctr, Dept Neurosci & Physiol, NYU Neurosci Inst, New York, NY 10016 USA.; Halassa, MM (corresponding author), NYU, Ctr Neural Sci, 550 1St Ave, New York, NY 10016 USA.
EM michael.halassa@nyumc.org
FU NARSAD Young Investigator award; Swiss National Science Foundation; JSPS; NIMH; NINDS; Brain and Behavior Foundation; Sloan Foundation; Klingenstein Foundation; Human Frontiers Science Program
NR 43
TC 442
Z9 525
U1 4
U2 124
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 11
PY 2017
VL 545
IS 7653
BP 219
EP +
DI 10.1038/nature22073
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EU3XG
UT WOS:000400963800033
PM 28467827
DA 2026-03-09
ER

PT J
AU Moyroud, E
   Wenzel, T
   Middleton, R
   Rudall, PJ
   Banks, H
   Reed, A
   Mellers, G
   Killoran, P
   Westwood, MM
   Steiner, U
   Vignolini, S
   Glover, BJ
AF Moyroud, Edwige
   Wenzel, Tobias
   Middleton, Rox
   Rudall, Paula J.
   Banks, Hannah
   Reed, Alison
   Mellers, Greg
   Killoran, Patrick
   Westwood, M. Murphy
   Steiner, Ullrich
   Vignolini, Silvia
   Glover, Beverley J.
TI Disorder in convergent floral nanostructures enhances signalling to bees
SO NATURE
LA English
DT Article
ID cell-shape; flower; blue; bumblebees; pigment; anthocyanin; iridescence; appearance; scattering; evolution
AB Diverse forms of nanoscale architecture generate structural colour and perform signalling functions within and between species. Structural colour is the result of the interference of light from approximately regular periodic structures; some structural disorder is, however, inevitable in biological organisms. Is this disorder functional and subject to evolutionary selection, or is it simply an unavoidable outcome of biological developmental processes? Here we show that disordered nanostructures enable flowers to produce visual signals that are salient to bees. These disordered nanostructures (identified in most major lineages of angiosperms) have distinct anatomies but convergent optical properties; they all produce angle-dependent scattered light, predominantly at short wavelengths (ultraviolet and blue). We manufactured artificial flowers with nanoscale structures that possessed tailored levels of disorder in order to investigate how foraging bumblebees respond to this optical effect. We conclude that floral nanostructures have evolved, on multiple independent occasions, an effective degree of relative spatial disorder that generates a photonic signature that is highly salient to insect pollinators.
C1 [Moyroud, Edwige; Reed, Alison; Mellers, Greg; Killoran, Patrick; Westwood, M. Murphy; Glover, Beverley J.] Univ Cambridge, Dept Plant Sci, Downing St, Cambridge CB2 3EA, England.
   [Wenzel, Tobias; Steiner, Ullrich] Univ Cambridge, Dept Phys, JJ Thomson Ave, Cambridge CB3 OHE, England.
   [Middleton, Rox; Vignolini, Silvia] Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England.
   [Rudall, Paula J.; Banks, Hannah] Royal Bot Gardens, Richmond TW9 3AB, Surrey, England.
   [Steiner, Ullrich] Adolphe Merkle Inst, Chemin Verdiers 4, CH-1700 Fribourg, Switzerland.
C3 University of Cambridge; University of Cambridge; University of Cambridge; Royal Botanic Gardens, Kew
RP Glover, BJ (corresponding author), Univ Cambridge, Dept Plant Sci, Downing St, Cambridge CB2 3EA, England.; Vignolini, S (corresponding author), Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England.
EM sv319@cam.ac.uk; bjg26@cam.ac.uk
FU Leverhulme Trust [F/09741/G]; BBSRC (DTG studentship); David Phillips fellowship [BB/K014617/1, 76933]; European Research Council [ERC-2014-STG H2020 639088]; Herchel Smith fund; EU Marie Curie actions (NanoPetals); EPSRC [EP/G037221/1]; Winton Fund for the Physics of Sustainability; Cambridge Trust CHESS; Adolphe Merkle Foundation and the Swiss National Science Foundation (National Center of Competence in Research Bio-Inspired Materials) (U.S.); EU [722842]; BBSRC [BB/K014617/1, BB/P001157/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/P001157/1, BB/K014617/1] Funding Source: researchfish; Engineering and Physical Sciences Research Council [1360817] Funding Source: researchfish
NR 37
TC 147
Z9 160
U1 2
U2 171
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 26
PY 2017
VL 550
IS 7677
BP 469
EP +
DI 10.1038/nature24285
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK7OW
UT WOS:000413697800033
PM 29045384
DA 2026-03-09
ER

PT J
AU Satoh, T
   Nakagawa, K
   Sugihara, F
   Kuwahara, R
   Ashihara, M
   Yamane, F
   Minowa, Y
   Fukushima, K
   Ebina, I
   Yoshioka, Y
   Kumanogoh, A
   Akira, S
AF Satoh, Takashi
   Nakagawa, Katsuhiro
   Sugihara, Fuminori
   Kuwahara, Ryusuke
   Ashihara, Motooki
   Yamane, Fumihiro
   Minowa, Yosuke
   Fukushima, Kiyoharu
   Ebina, Isao
   Yoshioka, Yoshichika
   Kumanogoh, Atsushi
   Akira, Shizuo
TI Identification of an atypical monocyte and committed progenitor involved in fibrosis
SO NATURE
LA English
DT Article
ID transcription factor; host responses; differentiation; polarization; macrophages; homeostasis; rather; origin
AB Monocytes and macrophages comprise a variety of subsets with diverse functions(1-5). It is thought that these cells play a crucial role in homeostasis of peripheral organs, key immunological processes and development of various diseases. Among these diseases, fibrosis is a life-threatening disease of unknown aetiology. Its pathogenesis is poorly understood, and there are few effective therapies. The development of fibrosis is associated with activation of monocytes and macrophages(6-8). However, the specific subtypes of monocytes and macrophages that are involved in fibrosis have not yet been identified. Here we show that Ceacam1(+)Msr1(+)Ly6C(-)F4/80(-)Mac1(+) monocytes, which we term segregated-nucleus-containing atypical monocytes (SatM), share granulocyte characteristics, are regulated by CCAAT/enhancer binding protein beta (C/EBP beta), and are critical for fibrosis. Cebpb deficiency results in a complete lack of SatM. Furthermore, the development of bleomycin-induced fibrosis, but not inflammation, was prevented in chimaeric mice with Cebpb(-/-) haematopoietic cells. Adoptive transfer of SatM into Cebpb(-/-) mice resulted in fibrosis. Notably, SatM are derived from Ly6C(-)Fc epsilon RI+ granulocyte/macrophage progenitors, and a newly identified SatM progenitor downstream of Ly6C(-)Fc epsilon RI+ granulocyte/macrophage progenitors, but not from macrophage/dendritic-cell progenitors. Our results show that SatM are critical for fibrosis and that C/EBP beta licenses differentiation of SatM from their committed progenitor.
C1 [Satoh, Takashi; Nakagawa, Katsuhiro; Yamane, Fumihiro; Fukushima, Kiyoharu; Ebina, Isao; Akira, Shizuo] Osaka Univ, Immunol Frontier Res Ctr, World Premier Inst, Lab Host Def, Osaka 5650871, Japan.
   [Satoh, Takashi; Nakagawa, Katsuhiro; Yamane, Fumihiro; Fukushima, Kiyoharu; Ebina, Isao; Akira, Shizuo] Osaka Univ, Res Inst Microbial Dis RIMD, Dept Host Def, Osaka 5650871, Japan.
   [Sugihara, Fuminori; Yoshioka, Yoshichika] Osaka Univ, Immunol Frontier Res Ctr, World Premier Inst, Lab Biofunct Imaging, Osaka 5650871, Japan.
   [Kuwahara, Ryusuke] Osaka Univ, Res Ctr Ultra High Voltage Elect Microscopy, Osaka 5670047, Japan.
   [Ashihara, Motooki; Minowa, Yosuke; Ebina, Isao] Chugai Pharmaceut Co Ltd, Discovery Res Dept, Div Res, Kanagawa 2478530, Japan.
   [Kumanogoh, Atsushi] Japan Agcy Med Res & Dev, Core Res Evolut Sci & Technol, Tokyo 1000004, Japan.
   [Kumanogoh, Atsushi] Osaka Univ, Grad Sch Med, Dept Resp Med Allergy & Rheumat Dis, Osaka 5650871, Japan.
C3 University of Osaka; University of Osaka; University of Osaka; University of Osaka; Chugai Pharmaceutical Co., Ltd.; Roche Holding; Roche Holding Japan; Japan Science & Technology Agency (JST); University of Osaka
RP Akira, S (corresponding author), Osaka Univ, Immunol Frontier Res Ctr, World Premier Inst, Lab Host Def, Osaka 5650871, Japan.; Akira, S (corresponding author), Osaka Univ, Res Inst Microbial Dis RIMD, Dept Host Def, Osaka 5650871, Japan.
EM sakira@biken.osaka-u.ac.jp
FU Government of Japan; Japan Society for the Promotion of Science (JSPS); Japan Science and Technology Agency (JST) [16H06234, 15H05704]; US National Institutes of Health [P01-AI070167]; 'Visionary Research Fund' from Takeda Science Foundation; Nanotechnology Platform of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan [12024046]; Grants-in-Aid for Scientific Research [15H05704, 16H01849, 17K19557, 16H06234] Funding Source: KAKEN
NR 28
TC 253
Z9 282
U1 1
U2 87
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 5
PY 2017
VL 541
IS 7635
BP 96
EP +
DI 10.1038/nature20611
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6NA
UT WOS:000396119500037
PM 28002407
DA 2026-03-09
ER

PT J
AU Gross, I
   Akhtar, W
   Garcia, V
   Martínez, LJ
   Chouaieb, S
   Garcia, K
   Carrétéro, C
   Barthélémy, A
   Appel, P
   Maletinsky, P
   Kim, JV
   Chauleau, JY
   Jaouen, N
   Viret, M
   Bibes, M
   Fusil, S
   Jacques, V
AF Gross, I.
   Akhtar, W.
   Garcia, V.
   Martinez, L. J.
   Chouaieb, S.
   Garcia, K.
   Carretero, C.
   Barthelemy, A.
   Appel, P.
   Maletinsky, P.
   Kim, J. -V.
   Chauleau, J. Y.
   Jaouen, N.
   Viret, M.
   Bibes, M.
   Fusil, S.
   Jacques, V.
TI Real-space imaging of non-collinear antiferromagnetic order with a single-spin magnetometer
SO NATURE
LA English
DT Article
ID room-temperature; bifeo3 films; nanoscale
AB Although ferromagnets have many applications, their large magnetization and the resulting energy cost for switching magnetic moments bring into question their suitability for reliable low-power spintronic devices. Non-collinear antiferromagnetic systems do not suffer from this problem, and often have extra functionalities: non-collinear spin order(1) may break space-inversion symmetry(2,3) and thus allow electric-field control of magnetism(4,5), or may produce emergent spin-orbit effects(6) that enable efficient spin-charge interconversion(7). To harness these traits for next-generation spintronics, the nanoscale control and imaging capabilities that are now routine for ferromagnets must be developed for antiferromagnetic systems. Here, using a non-invasive, scanning single-spin magnetometer based on a nitrogen-vacancy defect in diamond(8-10), we demonstrate real-space visualization of non-collinear antiferromagnetic order in a magnetic thin film at room temperature. We image the spin cycloid of a multiferroic bismuth ferrite (BiFeO3) thin film and extract a period of about 70 nanometres, consistent with values determined by macroscopic diffraction(11,12). In addition, we take advantage of the magnetoelectric coupling present in BiFeO3 to manipulate the cycloid propagation direction by an electric field. Besides highlighting the potential of nitrogen-vacancy magnetometry for imaging complex antiferromagnetic orders at the nanoscale, these results demonstrate how BiFeO3 can be used in the design of reconfigurable nanoscale spin textures.
C1 [Gross, I.; Akhtar, W.; Martinez, L. J.; Chouaieb, S.; Jacques, V.] Univ Montpellier, Lab Charles Coulomb, F-34095 Montpellier, France.
   [Gross, I.; Akhtar, W.; Martinez, L. J.; Chouaieb, S.; Jacques, V.] CNRS, F-34095 Montpellier, France.
   [Gross, I.] Univ Paris Saclay, Univ Paris Sud, ENS Cachan, Lab Aime Cotton,CNRS, F-91405 Orsay, France.
   [Garcia, V.; Garcia, K.; Carretero, C.; Barthelemy, A.; Bibes, M.; Fusil, S.] Univ Paris Saclay, Univ Paris Sud, CNRS, Unite Mixte Phys,Thales, F-91767 Palaiseau, France.
   [Appel, P.; Maletinsky, P.] Univ Basel, Dept Phys, Klingelbergstr 82, CH-4056 Basel, Switzerland.
   [Kim, J. -V.] Univ Paris Saclay, Univ Paris Sud, CNRS, Ctr Nanosci & Nanotechnol, F-91405 Orsay, France.
   [Chauleau, J. Y.; Viret, M.] Univ Paris Saclay, CNRS, CEA, SPEC, F-91191 Gif Sur Yvette, France.
   [Chauleau, J. Y.; Jaouen, N.] Synchrotron SOLEIL, F-91192 Gif Sur Yvette, France.
   [Fusil, S.] Univ Paris Saclay, Univ Evry, F-91025 Evry, France.
C3 Universite de Montpellier; Centre National de la Recherche Scientifique (CNRS); Universite Paris Saclay; Centre National de la Recherche Scientifique (CNRS); Universite Paris Saclay; Centre National de la Recherche Scientifique (CNRS); Thales Group; University of Basel; Universite Paris Saclay; Universite Paris Cite; Centre National de la Recherche Scientifique (CNRS); CEA; Centre National de la Recherche Scientifique (CNRS); Universite Paris Saclay; SOLEIL Synchrotron; Universite Paris Saclay
RP Jacques, V (corresponding author), Univ Montpellier, Lab Charles Coulomb, F-34095 Montpellier, France.; Jacques, V (corresponding author), CNRS, F-34095 Montpellier, France.
EM vincent.jacques@umontpellier.fr
FU European Research Council (ERC-StG, IMAGINE); European Union Seventh Framework Program (FP7) under the project DIADEMS; French Agence Nationale de la Recherche (ANR) through project FERROMON and PIAF; French National Research Agency (ANR) as part of the 'Investissements d'Avenir' program (Labex NanoSaclay) [ANR-10-LABX-0035]
NR 41
TC 227
Z9 258
U1 10
U2 325
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 14
PY 2017
VL 549
IS 7671
BP 252
EP +
DI 10.1038/nature23656
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG7AE
UT WOS:000410555900041
PM 28905889
DA 2026-03-09
ER

PT J
AU Yao, Z
   Yaeger, R
   Rodrik-Outmezguine, VS
   Tao, A
   Torres, NM
   Chang, MT
   Drosten, M
   Zhao, HY
   Cecchi, F
   Hembrough, T
   Michels, J
   Baumert, H
   Miles, L
   Campbell, NM
   de Stanchina, E
   Solit, DB
   Barbacid, M
   Taylor, BS
   Rosen, N
AF Yao, Zhan
   Yaeger, Rona
   Rodrik-Outmezguine, Vanessa S.
   Tao, Anthony
   Torres, Neilawattie M.
   Chang, Matthew T.
   Drosten, Matthias
   Zhao, Huiyong
   Cecchi, Fabiola
   Hembrough, Todd
   Michels, Judith
   Baumert, Herve
   Miles, Linde
   Campbell, Naomi M.
   de Stanchina, Elisa
   Solit, David B.
   Barbacid, Mariano
   Taylor, Barry S.
   Rosen, Neal
TI Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS
SO NATURE
LA English
DT Article
ID wild-type; mutations; mechanisms
AB Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2)(1). Here we characterize a third class of BRAF mutants-those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.
C1 [Yao, Zhan; Rodrik-Outmezguine, Vanessa S.; Torres, Neilawattie M.; Zhao, Huiyong; Miles, Linde; de Stanchina, Elisa; Rosen, Neal] Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol, New York, NY 10065 USA.
   [Yaeger, Rona; Solit, David B.; Rosen, Neal] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA.
   [Tao, Anthony] New York Univ, Coll Arts & Sci, Ctr Neural Sci, New York, NY 10012 USA.
   [Chang, Matthew T.; Solit, David B.; Taylor, Barry S.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA.
   [Chang, Matthew T.; Taylor, Barry S.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA.
   [Chang, Matthew T.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 USA.
   [Drosten, Matthias; Barbacid, Mariano] CNIO, Mol Oncol Programme, Melchor Fernandez Almagro 3, Madrid 28029, Spain.
   [Cecchi, Fabiola; Hembrough, Todd] NantOmics LLC, Mol Oncol Grp, 9600 Med Ctr Dr,Suite 300, Rockville, MD 20854 USA.
   [Michels, Judith] Dept Med Oncol, Gustave Roussy Canc Campus, Villejuif, France.
   [Michels, Judith] Univ Paris Sud, Fac Med, Le Kremlin Bicetre, France.
   [Baumert, Herve] St Joseph Hosp, Urol Dept, Paris, France.
   [Miles, Linde] Johns Hopkins Univ, Dept Pharmacol & Mol Sci, Anti Canc Drug Dev Grad Training Program, Baltimore, MD 21205 USA.
   [Campbell, Naomi M.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA.
   [Solit, David B.; Taylor, Barry S.] Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, New York, NY 10065 USA.
   [Rosen, Neal] Mem Sloan Kettering Canc Ctr, Ctr Mech Based Therapeut, New York, NY 10065 USA.
C3 Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; New York University; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; University of California System; University of California San Francisco; Centro Nacional de Investigaciones Oncologicas (CNIO); UNICANCER; Gustave Roussy; Universite Paris Saclay; Universite Paris Cite; Hopital Paris Saint-Joseph; Johns Hopkins University; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center
RP Rosen, N (corresponding author), Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol, New York, NY 10065 USA.; Rosen, N (corresponding author), Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA.; Rosen, N (corresponding author), Mem Sloan Kettering Canc Ctr, Ctr Mech Based Therapeut, New York, NY 10065 USA.
EM rosenn@mskcc.org
FU National Institutes of Health (NIH) [P01 CA129243, R35 CA210085]; Melanoma Research Alliance [237059, 348724]; Commonwealth Foundation for Cancer Research; Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center; Stand Up To Cancer - American Cancer Society Lung Cancer Dream Team Translational Research Grant [SU2C-AACR-DT17-15]; NIH MSKCC Cancer Center Support Grant [P30 CA008748]; Conquer Cancer Foundation of the American Society of Clinical Oncology; NIH [R01 CA204749, R01 CA180037, U54 ODSS020355, T32 GM007175]; Sontag Foundation; Josie Robertson Foundation; Cycle For Survival; Arlene and Joseph Taub Foundation; European Research Council [ERC-AG/250297-RAS AHEAD]; EU [HEALTH-F2-2010-259770/LUNGTARGET, HEALTH-2010-260791/ EUROCANPLATFORM]; Spanish Ministry of Economy and Competitiveness [SAF2011-30173, SAF2014-59864-R]; AXA Research Fund; National Cancer Institute [R35CA210085, P01CA129243, R01CA204749, P30CA008748] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007175] Funding Source: NIH RePORTER; National Health and Medical Research Council (NHMRC) [237059] Funding Source: National Health and Medical Research Council (NHMRC)
NR 18
TC 437
Z9 514
U1 1
U2 48
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 10
PY 2017
VL 548
IS 7666
BP 234
EP +
DI 10.1038/nature23291
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD1GB
UT WOS:000407284300048
PM 28783719
DA 2026-03-09
ER

PT J
AU Allen, B
   Lippner, G
   Chen, YT
   Fotouhi, B
   Momeni, N
   Yau, ST
   Nowak, MA
AF Allen, Benjamin
   Lippner, Gabor
   Chen, Yu-Ting
   Fotouhi, Babak
   Momeni, Naghmeh
   Yau, Shing-Tung
   Nowak, Martin A.
TI Evolutionary dynamics on any population structure
SO NATURE
LA English
DT Article
ID cooperation; network; emergence; games; selection
AB Evolution occurs in populations of reproducing individuals. The structure of a population can affect which traits evolve(1,2). Understanding evolutionary game dynamics in structured populations remains difficult. Mathematical results are known for special structures in which all individuals have the same number of neighbours(3-8). The general case, in which the number of neighbours can vary, has remained open. For arbitrary selection intensity, the problem is in a computational complexity class that suggests there is no efficient algorithm(9). Whether a simple solution for weak selection exists has remained unanswered. Here we provide a solution for weak selection that applies to any graph or network. Our method relies on calculating the coalescence times(10,11) of random walks(12). We evaluate large numbers of diverse population structures for their propensity to favour cooperation. We study how small changes in population structure-graph surgery-affect evolutionary outcomes. We find that cooperation flourishes most in societies that are based on strong pairwise ties.
C1 [Allen, Benjamin] Emmanuel Coll, Dept Math, Boston, MA 02115 USA.
   [Allen, Benjamin; Chen, Yu-Ting; Fotouhi, Babak; Momeni, Naghmeh; Nowak, Martin A.] Harvard Univ, Program Evolutionary Dynam, Cambridge, MA 02138 USA.
   [Allen, Benjamin; Lippner, Gabor; Chen, Yu-Ting] Harvard Univ, Ctr Math Sci & Applicat, Cambridge, MA 02138 USA.
   [Lippner, Gabor] Northeastern Univ, Dept Math, Boston, MA USA.
   [Chen, Yu-Ting] Univ Tennessee, Dept Math, Knoxville, TN 37996 USA.
   [Fotouhi, Babak] Harvard Univ, Inst Quantitat Social Sci, Cambridge, MA 02138 USA.
   [Momeni, Naghmeh] McGill Univ, Dept Elect & Comp Engn, Montreal, PQ, Canada.
   [Yau, Shing-Tung; Nowak, Martin A.] Harvard Univ, Dept Math, Cambridge, MA 02138 USA.
   [Nowak, Martin A.] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA.
C3 Harvard University; Harvard University; Northeastern University; University of Tennessee System; University of Tennessee Knoxville; Harvard University; McGill University; Harvard University; Harvard University
RP Allen, B (corresponding author), Emmanuel Coll, Dept Math, Boston, MA 02115 USA.; Allen, B (corresponding author), Harvard Univ, Program Evolutionary Dynam, Cambridge, MA 02138 USA.; Allen, B (corresponding author), Harvard Univ, Ctr Math Sci & Applicat, Cambridge, MA 02138 USA.
EM allenb@emmanuel.edu
FU Office of Naval Research [N00014-16-1-2914]; John Templeton Foundation; AFOSR [FA9550-13-1-0097]; James S. McDonnell Foundation; Center for Mathematical Sciences and Applications at Harvard University; Division Of Mathematical Sciences; Direct For Mathematical & Physical Scien [1418252] Funding Source: National Science Foundation
NR 52
TC 411
Z9 454
U1 19
U2 334
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 13
PY 2017
VL 544
IS 7649
BP 227
EP +
DI 10.1038/nature21723
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ER6EK
UT WOS:000398897900036
PM 28355181
DA 2026-03-09
ER

PT J
AU Pieper, K
   Tan, J
   Piccoli, L
   Foglierini, M
   Barbieri, S
   Chen, YW
   Silacci-Fregni, C
   Wolf, T
   Jarrossay, D
   Anderle, M
   Abdi, A
   Ndungu, FM
   Doumbo, OK
   Traore, B
   Tran, TM
   Jongo, S
   Zenklusen, I
   Crompton, PD
   Daubenberger, C
   Bull, PC
   Allusto, FS
   Lanzavecchia, A
AF Pieper, Kathrin
   Tan, Joshua
   Piccoli, Luca
   Foglierini, Mathilde
   Barbieri, Sonia
   Chen, Yiwei
   Silacci-Fregni, Chiara
   Wolf, Tobias
   Jarrossay, David
   Anderle, Marica
   Abdi, Abdirahman
   Ndungu, Francis M.
   Doumbo, Ogobara K.
   Traore, Boubacar
   Tran, Tuan M.
   Jongo, Said
   Zenklusen, Isabelle
   Crompton, Peter D.
   Daubenberger, Claudia
   Bull, Peter C.
   Allusto, Federica S.
   Lanzavecchia, Antonio
TI Public antibodies to malaria antigens generated by two LAIR1 insertion modalities
SO NATURE
LA English
DT Article
ID monoclonal-antibody; rna-seq; b-cells; dna; regions; repair
AB In two previously described donors, the extracellular domain of LAIR1, a collagen-binding inhibitory receptor encoded on chromosome 19 (ref. 1), was inserted between the V and DJ segments of an antibody. This insertion generated, through somatic mutations, broadly reactive antibodies against RIFINs, a type of variant antigen expressed on the surface of Plasmodium falciparum-infected erythrocytes(2). To investigate how frequently such antibodies are produced in response to malaria infection, we screened plasma from two large cohorts of individuals living in malaria-endemic regions. Here we report that 5-10% of malaria-exposed individuals, but none of the European blood donors tested, have high levels of LAIR1-containing antibodies that dominate the response to infected erythrocytes without conferring enhanced protection against febrile malaria. By analysing the antibody-producing B cell clones at the protein, cDNA and gDNA levels, we characterized additional LAIR1 insertions between the V and DJ segments and discovered a second insertion modality whereby the LAIR1 exon encoding the extracellular domain and flanking intronic sequences are inserted into the switch region. By exon shuffling, this mechanism leads to the production of bispecific antibodies in which the LAIR1 domain is precisely positioned at the elbow between the VH and CH1 domains. Additionally, in one donor the genomic DNA encoding the VH and CH1 domains was deleted, leading to the production of a camel-like LAIR1-containing antibody. Sequencing of the switch regions of memory B cells from European blood donors revealed frequent templated inserts originating from transcribed genes that, in rare cases, comprised exons with orientations and frames compatible with expression. These results reveal different modalities of LAIR1 insertion that lead to public and dominant antibodies against infected erythrocytes and suggest that insertion of templated DNA represents an additional mechanism of antibody diversification that can be selected in the immune response against pathogens and exploited for B cell engineering.
C1 [Pieper, Kathrin; Tan, Joshua; Piccoli, Luca; Foglierini, Mathilde; Barbieri, Sonia; Chen, Yiwei; Silacci-Fregni, Chiara; Wolf, Tobias; Jarrossay, David; Anderle, Marica; Allusto, Federica S.; Lanzavecchia, Antonio] Univ Svizzera Italiana, Inst Res Biomed, Via Vincenzo Vela 6, CH-6500 Bellinzona, Switzerland.
   [Tan, Joshua] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Med, Oxford OX3 9DU, England.
   [Foglierini, Mathilde] SIB, CH-1015 Lausanne, Switzerland.
   [Chen, Yiwei; Wolf, Tobias; Allusto, Federica S.; Lanzavecchia, Antonio] Swiss Fed Inst Technol, Inst Microbiol, Wolfgang Pauli Str 10, CH-8093 Zurich, Switzerland.
   [Abdi, Abdirahman; Ndungu, Francis M.] CGMRC, KEMRI Wellcome Trust Res Programme, POB 230, Kilifi 80108, Kenya.
   [Doumbo, Ogobara K.; Traore, Boubacar] Univ Sci Tech & Technol Bamako, Malaria Res & Training Ctr, Bamako 91094, Mali.
   [Tran, Tuan M.] Indiana Univ Sch Med, Dept Med, Div Infect Dis, Indianapolis, IN 46202 USA.
   [Jongo, Said] Bagamoyo Clin, Ifakara Hlth Inst, POB 74, Bagamoyo, Tanzania.
   [Zenklusen, Isabelle; Daubenberger, Claudia] Swiss Trop & Publ Hlth Inst, Clin Immunol Unit, CH-4002 Basel, Switzerland.
   [Zenklusen, Isabelle; Daubenberger, Claudia] Univ Basel, Peterspl 1, CH-4003 Basel, Switzerland.
   [Crompton, Peter D.] NIAID, Lab Immunogenet, NIH, Rockville, MD 20852 USA.
   [Bull, Peter C.] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England.
C3 Universita della Svizzera Italiana; University of Oxford; Swiss Institute of Bioinformatics; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Science & Technology of Bamako; Indiana University System; Indiana University Bloomington; Ifakara Health Institute; Swiss School of Public Health (SSPH+); University of Basel; Swiss Tropical & Public Health Institute; University of Basel; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); University of Cambridge
RP Lanzavecchia, A (corresponding author), Univ Svizzera Italiana, Inst Res Biomed, Via Vincenzo Vela 6, CH-6500 Bellinzona, Switzerland.; Lanzavecchia, A (corresponding author), Swiss Fed Inst Technol, Inst Microbiol, Wolfgang Pauli Str 10, CH-8093 Zurich, Switzerland.
EM lanzavecchia@irb.usi.ch
FU Swiss Vaccine Research Institute; Fondazione Aldo e Cele Dacco; European Research Council [670955 BROADimmune]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Helmut Horten Foundation; National Institute of Allergy and Infectious Diseases [K08AI125682, ZIAAI001155] Funding Source: NIH RePORTER
NR 33
TC 88
Z9 102
U1 1
U2 35
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 31
PY 2017
VL 548
IS 7669
BP 597
EP +
DI 10.1038/nature23670
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FF2BO
UT WOS:000408703100041
PM 28847005
DA 2026-03-09
ER

PT J
AU Rutledge, GG
   Böhme, U
   Sanders, M
   Rrid, AJ
   Cotton, JA
   Maiga-Ascofare, O
   Djimdé, AA
   Apinjoh, TO
   Amenga-Etego, L
   Manske, M
   Barnwell, JW
   Renaud, F
   Ollomo, B
   Prugnolle, F
   Anstey, NM
   Auburn, S
   Price, RN
   McCarthy, JS
   Kwiatkowski, DP
   Newbold, CI
   Berriman, M
   Otto, TD
AF Rutledge, Gavin G.
   Bohme, Ulrike
   Sanders, Mandy
   Rrid, Adam J.
   Cotton, James A.
   Maiga-Ascofare, Oumou
   Djimde, Abdoulaye A.
   Apinjoh, Tobias O.
   Amenga-Etego, Lucas
   Manske, Magnus
   Barnwell, John W.
   Renaud, Francois
   Ollomo, Benjamin
   Prugnolle, Franck
   Anstey, Nicholas M.
   Auburn, Sarah
   Price, Ric N.
   McCarthy, James S.
   Kwiatkowski, Dominic P.
   Newbold, Chris I.
   Berriman, Matthew
   Otto, Thomas D.
TI Plasmodium malariae and P. ovale genomes provide insights into malaria parasite evolution
SO NATURE
LA English
DT Article
ID gene-expression; sequence; algorithm; alignment; family; brasilianum; phylogeny; generation; assembly; inference
AB Elucidation of the evolutionary history and interrelatedness of Plasmodium species that infect humans has been hampered by a lack of genetic information for three human-infective species: P. malariae and two P. ovale species (P. o. curtisi and P. o. wallikeri)(1). These species are prevalent across most regions in which malaria is endemic(2,3) and are often undetectable by light microscopy(4), rendering their study in human populations difficult(5). The exact evolutionary relationship of these species to the other human-infective species has been contested(6,7). Using a new reference genome for P. malariae and a manually curated draft P. o. curtisi genome, we are now able to accurately place these species within the Plasmodium phylogeny. Sequencing of a P. malariae relative that infects chimpanzees reveals similar signatures of selection in the P. malariae lineage to another Plasmodium lineage shown to be capable of colonization of both human and chimpanzee hosts. Molecular dating suggests that these host adaptations occurred over similar evolutionary timescales. In addition to the core genome that is conserved between species, differences in gene content can be linked to their specific biology. The genome suggests that P. malariae expresses a family of heterodimeric proteins on its surface that have structural similarities to a protein crucial for invasion of red blood cells. The data presented here provide insight into the evolution of the Plasmodium genus as a whole.
C1 [Rutledge, Gavin G.; Bohme, Ulrike; Sanders, Mandy; Rrid, Adam J.; Cotton, James A.; Djimde, Abdoulaye A.; Manske, Magnus; Berriman, Matthew; Otto, Thomas D.] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.
   [Maiga-Ascofare, Oumou; Amenga-Etego, Lucas; Barnwell, John W.] Univ Sci Techn & Technol Bamako, Malaria Res & Training Ctr, BP E 2528, Bamako, Mali.
   [Sanders, Mandy; Apinjoh, Tobias O.; Auburn, Sarah] German Ctr Infect Res, D-20359 Hamburg, Germany.
   [Cotton, James A.; Manske, Magnus; Auburn, Sarah; Price, Ric N.] Univ Buea, Post Off Box 63, Buea, South West Regi, Cameroon.
   [Sanders, Mandy; Apinjoh, Tobias O.; McCarthy, James S.] Navrongo Hlth Res Ctr, Post Off Box 114, Navrongo, Upper East Regi, Ghana.
   [Cotton, James A.; Amenga-Etego, Lucas; Ollomo, Benjamin; Anstey, Nicholas M.] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA.
   [Rrid, Adam J.; Barnwell, John W.; Renaud, Francois; Ollomo, Benjamin; Prugnolle, Franck; Auburn, Sarah] UM1 CNRS IRD, Lab MIVEGEC, F-34394 Montpellier, France.
   [Sanders, Mandy; Djimde, Abdoulaye A.; Manske, Magnus; Prugnolle, Franck; Price, Ric N.] Ctr Int Recherches Med Franceville, BP 709 Franceville, Franceville, Gabon.
   [Sanders, Mandy; Apinjoh, Tobias O.; Anstey, Nicholas M.] Menzies Sch Hlth Res & Charles Darwin Univ, Global & Trop Hlth Div, Darwin, NT, Australia.
   [Sanders, Mandy; Djimde, Abdoulaye A.; Barnwell, John W.; Prugnolle, Franck] Univ Oxford, Nuffield Dept Clin Med, Ctr Top Med & Global Hlth, Oxford OX3 7LJ, England.
   [Bohme, Ulrike; Berriman, Matthew] Univ Queensland, QIMR Berghofer Med Res Inst, Clin Trop Med Lab, Brisbane, Qld, Australia.
   [Rrid, Adam J.; Djimde, Abdoulaye A.; Barnwell, John W.; McCarthy, James S.; Kwiatkowski, Dominic P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.
   [Sanders, Mandy; Renaud, Francois; McCarthy, James S.; Newbold, Chris I.] Univ Oxford, Inst Mol Med, John Radcliffe Hosp, Oxford OX3 9DS, England.
C3 Wellcome Trust Sanger Institute; University of Science & Technology of Bamako; German Center for Infection Research; Navrongo Health Research Center; Centers for Disease Control & Prevention - USA; Universite de Montpellier; Institut de Recherche pour le Developpement (IRD); Charles Darwin University; Menzies School of Health Research; University of Oxford; QIMR Berghofer Medical Research Institute; University of Queensland; University of Oxford; Wellcome Centre for Human Genetics; University of Oxford
RP Berriman, M; Otto, TD (corresponding author), Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.
EM mb4@sanger.ac.uk; tdo@sanger.ac.uk
FU Medical Research Council [MR/J004111/1, MR/L008661/1]; Wellcome Trust [098051, 091625, 104792/Z/14/Z]; ANR JCJC ORIGIN; LMI Zofac; CNRS; IRD; CIRMF; NHMRC [1041802, 1042072]; National Health and Medical Research Council (NHMRC) [1042072, 1041802] Funding Source: National Health and Medical Research Council (NHMRC); Medical Research Council [G0600718, MR/L008661/1, 1500002, G0600718B, MR/M006212/1] Funding Source: researchfish; Wellcome Trust [204911/Z/16/Z, 104792/Z/14/Z] Funding Source: researchfish; MRC [G0600718, MR/L008661/1, MR/M006212/1] Funding Source: UKRI; Wellcome Trust [104792/Z/14/Z] Funding Source: Wellcome Trust
NR 77
TC 141
Z9 163
U1 0
U2 64
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 2
PY 2017
VL 542
IS 7639
BP 101
EP +
DI 10.1038/nature21038
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6MY
UT WOS:000396119300039
PM 28117441
DA 2026-03-09
ER

PT J
AU Gillon, M
   Triaud, AHMJ
   Demory, BO
   Jehin, E
   Agol, E
   Deck, KM
   Lederer, SM
   de Wit, J
   Burdanov, A
   Ingalls, JG
   Bolmont, E
   Leconte, J
   Raymond, SN
   Selsis, F
   Turbet, M
   Barkaoui, K
   Burgasser, A
   Burleigh, MR
   Carey, SJ
   Chaushev, A
   Copperwheat, CM
   Delrez, L
   Fernandes, CS
   Holdsworth, DL
   Kotze, EJ
   Van Grootel, V
   Almleaky, Y
   Benkhaldoun, Z
   Magain, P
   Queloz, D
AF Gillon, Michael
   Triaud, Amaury H. M. J.
   Demory, Brice-Olivier
   Jehin, Emmanuel
   Agol, Eric
   Deck, Katherine M.
   Lederer, Susan M.
   de Wit, Julien
   Burdanov, Artem
   Ingalls, James G.
   Bolmont, Emeline
   Leconte, Jeremy
   Raymond, Sean N.
   Selsis, Franck
   Turbet, Martin
   Barkaoui, Khalid
   Burgasser, Adam
   Burleigh, Matthew R.
   Carey, Sean J.
   Chaushev, Aleksander
   Copperwheat, Chris M.
   Delrez, Laetitia
   Fernandes, Catarina S.
   Holdsworth, Daniel L.
   Kotze, Enrico J.
   Van Grootel, Valerie
   Almleaky, Yaseen
   Benkhaldoun, Zouhair
   Magain, Pierre
   Queloz, Didier
TI Seven temperate terrestrial planets around the nearby ultracool dwarf star TRAPPIST-1
SO NATURE
LA English
DT Article
ID main-sequence stars; transiting planets; habitable zones; super-earths; systems; stellar; models; eccentricity; resonances; inversion
AB One aim of modern astronomy is to detect temperate, Earth-like exoplanets that are well suited for atmospheric characterization. Recently, three Earth-sized planets were detected that transit (that is, pass in front of) a star with a mass just eight per cent that of the Sun, located 12 parsecs away(1). The transiting configuration of these planets, combined with the Jupiter-like size of their host star-named TRAPPIST-1-makes possible in-depth studies of their atmospheric properties with present-day and future astronomical facilities(1-3). Here we report the results of a photometric monitoring campaign of that star from the ground and space. Our observations reveal that at least seven planets with sizes and masses similar to those of Earth revolve around TRAPPIST-1. The six inner planets form a near-resonant chain, such that their orbital periods (1.51, 2.42, 4.04, 6.06, 9.1 and 12.35 days) are near-ratios of small integers. This architecture suggests that the planets formed farther from the star and migrated inwards(4,5). Moreover, the seven planets have equilibrium temperatures low enough to make possible the presence of liquid water on their surfaces(6-8).
C1 [Gillon, Michael; Jehin, Emmanuel; Burdanov, Artem; Magain, Pierre] Univ Liege, Space Sci Technol & Astrophys Res STAR Inst, Allee 6 Auot 19C,Bat B5C, B-4000 Liege, Belgium.
   [Triaud, Amaury H. M. J.] Inst Astron, Madingley Rd, Cambridge CB3 0HA, England.
   [Demory, Brice-Olivier] Univ Bern, Ctr Space & Habitabil, Sidlerstr 5, CH-3012 Bern, Switzerland.
   [Demory, Brice-Olivier] Cavendish Lab, JJ Thomson Ave, Cambridge CB3 0HE, England.
   [Agol, Eric] Univ Washington, Dept Astron, Seattle, WA 98195 USA.
   [Agol, Eric] NASA, Astrobiol Inst, Virtual Planetary Lab, Seattle, WA 98195 USA.
   [Deck, Katherine M.] CALTECH, Dept Geol & Planetary Sci, Pasadena, CA 91125 USA.
   [Lederer, Susan M.] NASA, Johnson Space Ctr, 2101 NASA Pkwy, Houston, TX 77058 USA.
   [de Wit, Julien] MIT, Dept Earth Atmospher & Planetary Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Ingalls, James G.; Carey, Sean J.] CALTECH, Spitzer Sci Ctr, 1200 E Calif Blvd,Mail Code 314-6, Pasadena, CA 91125 USA.
   [Bolmont, Emeline] Univ Namur, Dept Math, NaXys, 8 Rempart La Vierge, B-5000 Namur, Belgium.
   [Bolmont, Emeline] Univ Paris Diderot, CNRS, Ctr Saclay, IRFU,SAp,DRF,CEA,Lab AIM Paris Saclay, F-91191 Gif Sur Yvette, France.
   [Leconte, Jeremy; Raymond, Sean N.; Selsis, Franck] Univ Bordeaux, CNRS, Lab Astrophys Bordeaux, B18N Allee Geoffroy St Hilaire, F-33615 Pessac, France.
   [Turbet, Martin; Delrez, Laetitia] Univ Paris 06, Sorbonne Univ, CNRS, Lab Meteorol Dynam, 4 Pl Jussieu, F-75005 Paris, France.
   [Barkaoui, Khalid; Benkhaldoun, Zouhair] Cadi Ayyad Univ, FSSM, Lab LPHEA, Oukaimeden Observ, BP 2390, Marrakech, Morocco.
   [Burgasser, Adam] Univ Calif San Diego, Ctr Astrophys & Space Sci, La Jolla, CA 92093 USA.
   [Burleigh, Matthew R.; Chaushev, Aleksander] Univ Leicester, Dept Phys & Astron, Leicester Inst Space & Earth Observ, Leicester LE1 7RH, Leics, England.
   [Copperwheat, Chris M.] Liverpool John Moores Univ, Astrophys Res Inst, Liverpool L3 5RF, Merseyside, England.
   [Holdsworth, Daniel L.] Univ Cent Lancashire, Jeremiah Horrocks Inst, Preston PR1 2HE, Lancs, England.
   [Kotze, Enrico J.] South African Astron Observ, Observ, POB 9, ZA-7935 Cape Town, South Africa.
   [Almleaky, Yaseen] King Abdulaziz Univ, Fac Sci, Space & Astron Dept, Jeddah 21589, Saudi Arabia.
   [Almleaky, Yaseen] King Abdullah Ctr Crescent Observat & Astron, Makkah Clock, Mecca 24231, Saudi Arabia.
   [Queloz, Didier] Univ Geneva, Observ Geneva, 51 Chemin Maillettes, CH-1290 Sauverny, Switzerland.
C3 University of Liege; University of Cambridge; University of Bern; University of Cambridge; University of Washington; University of Washington Seattle; National Aeronautics & Space Administration (NASA); California Institute of Technology; National Aeronautics & Space Administration (NASA); NASA Johnson Space Center; Massachusetts Institute of Technology (MIT); California Institute of Technology; University of Namur; CEA; Centre National de la Recherche Scientifique (CNRS); Universite Paris Cite; Universite Paris Saclay; Universite de Bordeaux; Centre National de la Recherche Scientifique (CNRS); Centre National de la Recherche Scientifique (CNRS); Institut Polytechnique de Paris; Ecole Polytechnique; Sorbonne Universite; Cadi Ayyad University of Marrakech; University of California System; University of California San Diego; University of Leicester; Liverpool John Moores University; University of Lancashire; National Research Foundation - South Africa; South African Astronomical Observatory; King Abdulaziz University; University of Geneva
RP Gillon, M (corresponding author), Univ Liege, Space Sci Technol & Astrophys Res STAR Inst, Allee 6 Auot 19C,Bat B5C, B-4000 Liege, Belgium.
EM michael.gillon@ulg.ac.be
FU NASA; NASA [NNX15AI75G, NNX13AF62G, NNH05ZDA001C]; Belgian Fonds (National) de la Recherche Scientifique (F.R.S.-FNRS) [FRFC 2.5.594.09.F]; University of Liege; European Research Council (ERC) [336480, 679030]; Actions de Recherche Concertee (ARC) grant - Wallonia-Brussels Federation; UK Science and Technology Facilities Council; Swiss National Science Foundation [PP00P2_163967]; National Science Foundation (NSF) [AST-1615315]; European Research Council through ERC [SPIRE 647383]; Agence Nationale pour la Recherche (ANR) [ANR-13-BS05-0003-002];  [296.C-5010(A)]; STFC [ST/P002218/1, ST/L00061X/1, ST/J001465/1, ST/N000757/1, ST/L001306/1, ST/N001524/1, ST/M003035/1, ST/P006892/1] Funding Source: UKRI; Swiss National Science Foundation (SNF) [PP00P2_163967] Funding Source: Swiss National Science Foundation (SNF); Science and Technology Facilities Council [ST/M003035/1, ST/L00061X/1, ST/N000757/1, ST/P006892/1, 1362676, ST/J001465/1, ST/N001524/1, ST/M000966/1, ST/L001306/1, ST/P002218/1] Funding Source: researchfish; Direct For Mathematical & Physical Scien; Division Of Astronomical Sciences [1615315] Funding Source: National Science Foundation; NASA [807250, NNX15AI75G] Funding Source: Federal RePORTER; European Research Council (ERC) [679030] Funding Source: European Research Council (ERC)
NR 58
TC 1151
Z9 1329
U1 9
U2 220
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 23
PY 2017
VL 542
IS 7642
BP 456
EP +
DI 10.1038/nature21360
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1RG
UT WOS:000395094100031
PM 28230125
DA 2026-03-09
ER

PT J
AU Meng, QJ
   Grossnickle, DM
   Liu, D
   Zhang, YG
   Neander, AI
   Ji, Q
   Luo, ZX
AF Meng, Qing-Jin
   Grossnickle, David M.
   Liu, Di
   Zhang, Yu-Guang
   Neander, April I.
   Ji, Qiang
   Luo, Zhe-Xi
TI New gliding mammaliaforms from the Jurassic
SO NATURE
LA English
DT Article
ID multituberculate mammals; adaptive radiation; anatomy; diversification; transformation; proportions; adaptations; evolution
AB Stem mammaliaforms are Mesozoic forerunners to mammals, and they offer critical evidence for the anatomical evolution and ecological diversification during the earliest mammalian history. Two new eleutherodonts from the Late Jurassic period have skin membranes and skeletal features that are adapted for gliding. Characteristics of their digits provide evidence of roosting behaviour, as in dermopterans and bats, and their feet have a calcaneal calcar to support the uropagatium as in bats. The new volant taxa are phylogenetically nested with arboreal eleutherodonts. Together, they show an evolutionary experimentation similar to the iterative evolutions of gliders within arboreal groups of marsupial and placental mammals. However, gliding eleutherodonts possess rigid interclavicle-clavicle structures, convergent to the avian furculum, and they retain shoulder girdle plesiomorphies of mammaliaforms and monotremes. Forelimb mobility required by gliding occurs at the acromion-clavicle and glenohumeral joints, is different from and convergent to the shoulder mobility at the pivotal clavicle-sternal joint in marsupial and placental gliders.
C1 [Meng, Qing-Jin; Liu, Di; Zhang, Yu-Guang] Beijing Museum Nat Hist, Beijing 100050, Peoples R China.
   [Grossnickle, David M.; Luo, Zhe-Xi] Univ Chicago, Comm Evolut Biol, Chicago, IL 60637 USA.
   [Neander, April I.; Luo, Zhe-Xi] Univ Chicago, Dept Organismal Biol & Anat, 1025 E 57Th St, Chicago, IL 60637 USA.
   [Ji, Qiang] Hebei GEO Univ, Shijiazhuang 050031, Hebei, Peoples R China.
C3 University of Chicago; University of Chicago; Hebei GEO University
RP Luo, ZX (corresponding author), Univ Chicago, Comm Evolut Biol, Chicago, IL 60637 USA.; Luo, ZX (corresponding author), Univ Chicago, Dept Organismal Biol & Anat, 1025 E 57Th St, Chicago, IL 60637 USA.
EM zxluo@uchicago.edu
FU Beijing Scientific Commission; UChicago-BSD; UChicago Fellowship; FMNH Fellowship
NR 50
TC 77
Z9 88
U1 1
U2 67
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 17
PY 2017
VL 548
IS 7667
BP 291
EP +
DI 10.1038/nature23476
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD8AU
UT WOS:000407748400024
PM 28792929
DA 2026-03-09
ER

PT J
AU D'Agostino, M
   Risselada, HJ
   Lürick, A
   Ungermann, C
   Mayer, A
AF D'Agostino, Massimo
   Risselada, Herre Jelger
   Luerick, Anna
   Ungermann, Christian
   Mayer, Andreas
TI A tethering complex drives the terminal stage of SNARE-dependent membrane fusion
SO NATURE
LA English
DT Article
ID vacuole fusion; homotypic fusion; hops catalyzes; protein vps33; force-field; docking; exocytosis; hemifusion; dynamics; fragmentation
AB Membrane fusion in eukaryotic cells mediates the biogenesis of organelles, vesicular traffic between them, and exo- and endocytosis of important signalling molecules, such as hormones and neurotransmitters. Distinct tasks in intracellular membrane fusion have been assigned to conserved protein systems. Tethering proteins mediate the initial recognition and attachment of membranes, whereas SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein complexes are considered as the core fusion engine. SNARE complexes provide mechanical energy to distort membranes and drive them through a hemifusion intermediate towards the formation of a fusion pore(1-3). This last step is highly energy-demanding(4,5). Here we combine the in vivo and in vitro fusion of yeast vacuoles with molecular simulations to show that tethering proteins are critical for overcoming the final energy barrier to fusion pore formation. SNAREs alone drive vacuoles only into the hemifused state. Tethering proteins greatly increase the volume of SNARE complexes and deform the site of hemifusion, which lowers the energy barrier for pore opening and provides the driving force. Thereby, tethering proteins assume a crucial mechanical role in the terminal stage of membrane fusion that is likely to be conserved at multiple steps of vesicular traffic. We therefore propose that SNAREs and tethering proteins should be considered as a single, non-dissociable device that drives fusion. The core fusion machinery may then be larger and more complex than previously thought.
C1 [D'Agostino, Massimo; Mayer, Andreas] Univ Lausanne, Dept Biochim, Chemin Boveresses 155, CH-1066 Epalinges, Switzerland.
   [Risselada, Herre Jelger] Georg August Univ, Dept Theoret Phys, Friedrich Hund Pl 1, D-37077 Gottingen, Gottingen, Germany.
   [Risselada, Herre Jelger] Leibniz Inst Surface Modificat, Chem Dept, Permoserstr 15, D-04318 Leipzig, Germany.
   [Luerick, Anna; Ungermann, Christian] Univ Osnabruck, Dept Biol Chem, Barbarastr 13, D-49076 Osnabruck, Germany.
C3 University of Lausanne; University of Gottingen; Leibniz Association; Leibniz Institut fur Oberflachenmodifizierung (IOM); University Osnabruck
RP Mayer, A (corresponding author), Univ Lausanne, Dept Biochim, Chemin Boveresses 155, CH-1066 Epalinges, Switzerland.
EM andreas.mayer@unil.ch
FU DFG [SFB 944]; State of Lower Saxony; SNF; ERC
NR 51
TC 89
Z9 99
U1 5
U2 66
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 30
PY 2017
VL 551
IS 7682
BP 634
EP +
DI 10.1038/nature24469
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FO1KW
UT WOS:000416520400044
PM 29088698
DA 2026-03-09
ER

PT J
AU Guerriero, JL
   Sotayo, A
   Ponichtera, HE
   Castrillon, JA
   Pourzia, AL
   Schad, S
   Johnson, SF
   Carrasco, RD
   Lazo, S
   Bronson, RT
   Davis, SP
   Lobera, M
   Nolan, MA
   Letai, A
AF Guerriero, Jennifer L.
   Sotayo, Alaba
   Ponichtera, Holly E.
   Castrillon, Jessica A.
   Pourzia, Alexandra L.
   Schad, Sara
   Johnson, Shawn F.
   Carrasco, Ruben D.
   Lazo, Suzan
   Bronson, Roderick T.
   Davis, Scott P.
   Lobera, Mercedes
   Nolan, Michael A.
   Letai, Anthony
TI Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages
SO NATURE
LA English
DT Article
ID progression; expression; cells; responses; efficacy; modulate; defines; protein; cancer; stroma
AB Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction and elimination. Tumour-associated macrophages often have net pro-tumour effects(1), but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition)(2,3) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies)(4,5) tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro(6). Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy.
C1 [Guerriero, Jennifer L.; Sotayo, Alaba; Ponichtera, Holly E.; Castrillon, Jessica A.; Pourzia, Alexandra L.; Schad, Sara; Johnson, Shawn F.; Lazo, Suzan; Letai, Anthony] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA.
   [Carrasco, Ruben D.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA.
   [Bronson, Roderick T.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA.
   [Davis, Scott P.; Lobera, Mercedes; Nolan, Michael A.] GlaxoSmithKline, 200 Technol Sq Suite 602, Cambridge, MA 02139 USA.
C3 Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; GlaxoSmithKline; Glaxosmithkline USA
RP Letai, A (corresponding author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA.; Nolan, MA (corresponding author), GlaxoSmithKline, 200 Technol Sq Suite 602, Cambridge, MA 02139 USA.
EM Michael.A.Nolan@gsk.com; Anthony_Letai@dfci.harvard.edu
FU NIH NCI [F32CA180733, R01CA205967]; Friends of Dana-Farber, Dancing for a Cure; GlaxoSmithKline
NR 35
TC 464
Z9 522
U1 5
U2 243
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 16
PY 2017
VL 543
IS 7645
BP 428
EP +
DI 10.1038/nature21409
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN9RN
UT WOS:000396337400052
PM 28273064
DA 2026-03-09
ER

PT J
AU Sigal, M
   Logan, CY
   Kapalczynska, M
   Mollenkopf, HJ
   Berger, H
   Wiedenmann, B
   Nusse, R
   Amieva, MR
   Meyer, TF
AF Sigal, Michael
   Logan, Catriona Y.
   Kapalczynska, Marta
   Mollenkopf, Hans-Joachim
   Berger, Hilmar
   Wiedenmann, Bertram
   Nusse, Roeland
   Amieva, Manuel R.
   Meyer, Thomas F.
TI Stromal R-spondin orchestrates gastric epithelial stem cells and gland homeostasis
SO NATURE
LA English
DT Article
ID small-intestine; wnt receptors; lgr5; stomach; mouse; cancer; identification; populations; expression; reveals
AB The constant regeneration of stomach epithelium is driven by long-lived stem cells(1-3), but the mechanism that regulates their turnover is not well understood. We have recently found that the gastric pathogen Helicobacter pylori can activate gastric stem cells and increase epithelial turnover(4), while Wnt signalling is known to be important for stem cell identity and epithelial regeneration in several tissues(5). Here we find that antral Wnt signalling, marked by the classic Wnt target gene Axin2, is limited to the base and lower isthmus of gastric glands, where the stem cells reside. Axin2 is expressed by Lgr5(+) cells, as well as adjacent, highly proliferative Lgr(5-) cells that are able to repopulate entire glands, including the base, upon depletion of the Lgr5(+) population. Expression of both Axin2 and Lgr5 requires stroma-derived R-spondin 3 produced by gastric myofibroblasts proximal to the stem cell compartment. Exogenous R-spondin administration expands and accelerates proliferation of Axin2(+)/Lgr5(-) but not Lgr5(+) cells. Consistent with these observations, H. pylori infection increases stromal R-spondin 3 expression and expands the Axin2(+) cell pool to cause hyperproliferation and gland hyperplasia. The ability of stromal niche cells to control and adapt epithelial stem cell dynamics constitutes a sophisticated mechanism that orchestrates epithelial regeneration and maintenance of tissue integrity.
C1 [Sigal, Michael; Kapalczynska, Marta; Berger, Hilmar; Meyer, Thomas F.] Max Planck Inst Infect Biol, Dept Mol Biol, D-10117 Berlin, Germany.
   [Sigal, Michael; Kapalczynska, Marta; Wiedenmann, Bertram] Charite, Dept Gastroenterol & Hepatol, D-13353 Berlin, Germany.
   [Sigal, Michael] Berlin Inst Hlth, D-10117 Berlin, Germany.
   [Logan, Catriona Y.; Nusse, Roeland] Stanford Univ, Dept Dev Biol, Howard Hughes Med Inst, Stanford Inst Stem Cell Biol & Regenerat Med,Sch, Stanford, CA 94305 USA.
   [Mollenkopf, Hans-Joachim] Max Planck Inst Infect Biol, Core Facil Microarray Genom, D-10117 Berlin, Germany.
   [Amieva, Manuel R.] Stanford Univ, Dept Microbiol & Immunol, Sch Med, Stanford, CA 94305 USA.
   [Amieva, Manuel R.] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA.
   [Meyer, Thomas F.] Ctr Syst Biomed, Steinbeis Innovat, D-14612 Falkensee, Germany.
C3 Max Planck Society; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Stanford University; Howard Hughes Medical Institute; Max Planck Society; Stanford University; Stanford University
RP Sigal, M; Meyer, TF (corresponding author), Max Planck Inst Infect Biol, Dept Mol Biol, D-10117 Berlin, Germany.; Sigal, M (corresponding author), Charite, Dept Gastroenterol & Hepatol, D-13353 Berlin, Germany.; Sigal, M (corresponding author), Berlin Inst Hlth, D-10117 Berlin, Germany.; Meyer, TF (corresponding author), Ctr Syst Biomed, Steinbeis Innovat, D-14612 Falkensee, Germany.
EM michael.sigal@charite.de; meyer@mpiib-berlin.mpg.de
FU Deutsche Forschungsgemeinschaft [SI 1983/2-1, SI 1983/3-1, ME 705/18-1]; Innovation Fund of the Max Planck Society; WILL Foundation; Charite University Medicine Berlin; Berlin Institute of Health
CR Barker N, 2007, NATURE, V449, P1003, DOI 10.1038/nature06196
   Barker N, 2010, CELL STEM CELL, V7, P656, DOI 10.1016/j.stem.2010.11.016
   Barker N, 2010, CELL STEM CELL, V6, P25, DOI 10.1016/j.stem.2009.11.013
   Churchill GA, 2002, NAT GENET, V32, P490, DOI 10.1038/ng1031
   Clevers H, 2014, SCIENCE, V346, P54, DOI 10.1126/science.1248012
   de Lau W, 2011, NATURE, V476, P293, DOI 10.1038/nature10337
   Hayakawa Y, 2015, GUT, V64, P544, DOI 10.1136/gutjnl-2014-307190
   Herring BP, 2014, VASC CELL, V6, P0, DOI 10.1186/2045-824X-6-21
   Koo BK, 2012, NATURE, V488, P665, DOI 10.1038/nature11308
   LEE ER, 1985, AM J ANAT, V172, P205, DOI 10.1002/aja.1001720304
   Leushacke M, 2013, CELL REP, V5, P349, DOI 10.1016/j.celrep.2013.09.025
   Matsuo J, 2017, GASTROENTEROLOGY, V152, P218, DOI 10.1053/j.gastro.2016.09.018
   Muñoz J, 2012, EMBO J, V31, P3079, DOI 10.1038/emboj.2012.166
   Muzumdar MD, 2007, GENESIS, V45, P593, DOI 10.1002/dvg.20335
   Neufeld S, 2012, GENESIS, V50, P741, DOI 10.1002/dvg.22040
   Schlaermann P, 2016, GUT, V65, P202, DOI 10.1136/gutjnl-2014-307949
   Seshagiri S, 2012, NATURE, V488, P660, DOI 10.1038/nature11282
   Sigal M, 2015, GASTROENTEROLOGY, V148, P1392, DOI 10.1053/j.gastro.2015.02.049
   Stange DE, 2013, CELL, V155, P357, DOI 10.1016/j.cell.2013.09.008
   Subramanian A, 2005, P NATL ACAD SCI USA, V102, P15545, DOI 10.1073/pnas.0506580102
   Tian H, 2011, NATURE, V478, P255, DOI 10.1038/nature10408
   Tomasetti C, 2015, SCIENCE, V347, P78, DOI 10.1126/science.1260825
   Ueno H, 2006, DEV CELL, V11, P519, DOI 10.1016/j.devcel.2006.08.001
   van Amerongen R, 2012, CELL STEM CELL, V11, P387, DOI 10.1016/j.stem.2012.05.023
   Wilhelm F, 2017, MOL CANCER RES, V15, P776, DOI 10.1158/1541-7786.MCR-16-0472
   Yan KS, 2012, P NATL ACAD SCI USA, V109, P466, DOI 10.1073/pnas.1118857109
NR 26
TC 171
Z9 192
U1 0
U2 46
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 24
PY 2017
VL 548
IS 7668
BP 451
EP +
DI 10.1038/nature23642
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FE5VI
UT WOS:000408279000038
PM 28813421
DA 2026-03-09
ER

PT J
AU Schmidtko, S
   Stramma, L
   Visbeck, M
AF Schmidtko, Sunke
   Stramma, Lothar
   Visbeck, Martin
TI Decline in global oceanic oxygen content during the past five decades
SO NATURE
LA English
DT Article
ID north pacific oxygen; water; zones
AB Ocean models predict a decline in the dissolved oxygen inventory of the global ocean of one to seven per cent by the year 2100, caused by a combination of a warming-induced decline in oxygen solubility and reduced ventilation of the deep ocean(1,2). It is thought that such a decline in the oceanic oxygen content could affect ocean nutrient cycles and the marine habitat, with potentially detrimental consequences for fisheries and coastal economies(3-6). Regional observational data indicate a continuous decrease in oceanic dissolved oxygen concentrations in most regions of the global ocean(1,7-10), with an increase reported in a few limited areas, varying by study(1,10). Prior work attempting to resolve variations in dissolved oxygen concentrations at the global scale reported a global oxygen loss of 550 +/- 130 teramoles (10(12) mol) per decade between 100 and 1,000 metres depth based on a comparison of data from the 1970s and 1990s(10). Here we provide a quantitative assessment of the entire ocean oxygen inventory by analysing dissolved oxygen and supporting data for the complete oceanic water column over the past 50 years. We find that the global oceanic oxygen content of 227.4 +/- 1.1 petamoles (10(15) mol) has decreased by more than two per cent (4.8 +/- 2.1 petamoles) since 1960, with large variations in oxygen loss in different ocean basins and at different depths. We suggest that changes in the upper water column are mostly due to a warming-induced decrease in solubility and biological consumption. Changes in the deeper ocean may have their origin in basin-scale multi-decadal variability, oceanic overturning slow-down and a potential increase in biological consumption(11,12).
C1 [Schmidtko, Sunke; Stramma, Lothar; Visbeck, Martin] GEOMAR Helmholtz Ctr Ocean Res Kiel, Dsternbrooker Weg 20, D-24105 Kiel, Germany.
   [Visbeck, Martin] Univ Kiel, D-24098 Kiel, Germany.
C3 Helmholtz Association; GEOMAR Helmholtz Center for Ocean Research Kiel; University of Kiel
RP Schmidtko, S (corresponding author), GEOMAR Helmholtz Ctr Ocean Res Kiel, Dsternbrooker Weg 20, D-24105 Kiel, Germany.
EM sschmidtko@geomar.de
FU German Federal Ministry of Education and Research project MIKLIP; German Research Foundation (DFG) [SFB-754]
NR 40
TC 992
Z9 1147
U1 34
U2 700
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 16
PY 2017
VL 542
IS 7641
BP 335
EP +
DI 10.1038/nature21399
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2LQ
UT WOS:000394451600034
PM 28202958
DA 2026-03-09
ER

PT J
AU Bolnick, DI
   Stutz, WE
AF Bolnick, Daniel I.
   Stutz, William E. .
TI Frequency dependence limits divergent evolution by favouring rare immigrants over residents
SO NATURE
LA English
DT Article
ID ecological speciation; sympatric speciation; immune genes; competition; selection; stickleback; mhc; metaanalysis; diversity; predation
AB Two distinct forms of natural selection promote adaptive biological diversity. Divergent selection occurs when different environments favour different phenotypes, leading to increased differences between populations(1). Negative frequency-dependent selection occurs when rare variants within a population are favoured over common ones(2), increasing diversity within populations(3). These two diversifying forces promote genetic variation at different spatial scales, and may act in opposition, but their relative effects remain unclear because they are rarely measured concurrently. Here we show that negative frequency-dependent selection within populations can favor rare immigrants over locally adapted residents. We reciprocally transplanted lake and stream ecotypes of threespine stickleback(4) into lake and stream habitats, while manipulating the relative abundance of residents versus immigrants. We found negative frequency-dependence: survival was highest for the locally rare ecotype, rather than natives. Also, individuals with locally rare major histocompatibility complex (MHC) class IIb genotypes were infected by fewer parasites. This negative frequency-dependent selection will tend to favour rare immigrants over common residents, amplifying the effect of migration and undermining the efficacy of divergent natural selection to drive population differences. The only signal of divergent selection was a tendency for foreign fish to have higher parasite loads than residents, after controlling for MHC genotype rarity. Frequency-dependent ecological interactions have long been thought to promote speciation. Our results suggest a more nuanced view in which negative frequency dependence alters the fate of migrants to promote or constrain evolutionary divergence between populations.
C1 [Bolnick, Daniel I.; Stutz, William E. .] Univ Texas Austin, Dept Integrat Biol, Austin, TX 78712 USA.
   [Stutz, William E. .] Western Michigan Univ, Off Inst Res, Kalamazoo, MI 49008 USA.
C3 University of Texas System; University of Texas Austin; Western Michigan University
RP Bolnick, DI (corresponding author), Univ Texas Austin, Dept Integrat Biol, Austin, TX 78712 USA.
EM danbolnick@austin.utexas.edu
FU Howard Hughes Medical Institute; NSF [DEB-1144773, DEB-1456462]; EEB Graduate Program at the University of Texas
NR 38
TC 53
Z9 58
U1 1
U2 90
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 8
PY 2017
VL 546
IS 7657
BP 285
EP +
DI 10.1038/nature22351
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW9FY
UT WOS:000402823400036
PM 28562593
DA 2026-03-09
ER

PT J
AU Koh, MJ
   Nguyen, TT
   Lam, JK
   Torker, S
   Hyvl, J
   Schrock, RR
   Hoveyda, AH
AF Koh, Ming Joo
   Nguyen, Thach T.
   Lam, Jonathan K.
   Torker, Sebastian
   Hyvl, Jakub
   Schrock, Richard R.
   Hoveyda, Amir H.
TI Molybdenum chloride catalysts for Z-selective olefin metathesis reactions
SO NATURE
LA English
DT Article
ID cross-metathesis; trifluoromethylation; inhibitor; complexes; metal
AB The development of catalyst-controlled stereoselective olefin metathesis processes(1) has been a pivotal recent advance in chemistry. The incorporation of appropriate ligands within complexes based on molybdenum(2), tungsten(3) and ruthenium(4) has led to reactivity and selectivity levels that were previously inaccessible. Here we show that molybdenum monoaryloxide chloride complexes furnish higher-energy (Z) isomers of trifluoromethyl-substituted alkenes through cross-metathesis reactions with the commercially available, inexpensive and typically inert Z-1,1,1,4,4,4-hexafluoro-2-butene. Furthermore, otherwise inefficient and non-stereoselective transformations with Z-1,2-dichloroethene and 1,2-dibromoethene can be effected with substantially improved efficiency and Z selectivity. The use of such molybdenum monoaryloxide chloride complexes enables the synthesis of representative biologically active molecules and trifluoromethyl analogues of medicinally relevant compounds. The origins of the activity and selectivity levels observed, which contradict previously proposed principles(5), are elucidated with the aid of density functional theory calculations.
C1 [Koh, Ming Joo; Nguyen, Thach T.; Torker, Sebastian; Hoveyda, Amir H.] Boston Coll, Dept Chem, Merkert Chem Ctr, Chestnut Hill, MA 02467 USA.
   [Lam, Jonathan K.; Hyvl, Jakub; Schrock, Richard R.] MIT, Dept Chem, Cambridge, MA 02139 USA.
C3 Boston College; Massachusetts Institute of Technology (MIT)
RP Hoveyda, AH (corresponding author), Boston Coll, Dept Chem, Merkert Chem Ctr, Chestnut Hill, MA 02467 USA.
EM amir.hoveyda@bc.edu
FU United States National Institutes of Health, Institute of General Medical Sciences [GM-59426]; LaMattina Graduate Fellowship; Bristol-Myers Squibb
NR 30
TC 128
Z9 135
U1 3
U2 173
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 2
PY 2017
VL 542
IS 7639
BP 80
EP +
DI 10.1038/nature21043
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6MY
UT WOS:000396119300035
PM 28114300
DA 2026-03-09
ER

PT J
AU Wagner, MJ
   Kim, TH
   Savall, J
   Schnitzer, MJ
   Luo, LQ
AF Wagner, Mark J.
   Kim, Tony Hyun
   Savall, Joan
   Schnitzer, Mark J.
   Luo, Liqun
TI Cerebellar granule cells encode the expectation of reward
SO NATURE
LA English
DT Article
ID ventral tegmental area; neuronal-activity; dopamine; motor; mice; transmission; projections; responses; signals; cortex
AB The human brain contains approximately 60 billion cerebellar granule cells(1), which outnumber all other brain neurons combined. Classical theories posit that a large, diverse population of granule cells allows for highly detailed representations of sensorimotor context, enabling downstream Purkinje cells to sense fine contextual changes(2-6). Although evidence suggests a role for the cerebellum in cognition(7-10), granule cells are known to encode only sensory(11-13) and motor(14) context. Here, using two-photon calcium imaging in behaving mice, we show that granule cells convey information about the expectation of reward. Mice initiated voluntary forelimb movements for delayed sugar-water reward. Some granule cells responded preferentially to reward or reward omission, whereas others selectively encoded reward anticipation. Reward responses were not restricted to forelimb movement, as a Pavlovian task evoked similar responses. Compared to predictable rewards, unexpected rewards elicited markedly different granule cell activity despite identical stimuli and licking responses. In both tasks, reward signals were widespread throughout multiple cerebellar lobules. Tracking the same granule cells over several days of learning revealed that cells with reward-anticipating responses emerged from those that responded at the start of learning to reward delivery, whereas reward-omission responses grew stronger as learning progressed. The discovery of predictive, non-sensorimotor encoding in granule cells is a major departure from the current understanding of these neurons and markedly enriches the contextual information available to postsynaptic Purkinje cells, with important implications for cognitive processing in the cerebellum.
C1 [Wagner, Mark J.; Kim, Tony Hyun; Savall, Joan; Schnitzer, Mark J.; Luo, Liqun] Stanford Univ, Dept Biol, Stanford, CA 94305 USA.
   [Wagner, Mark J.; Kim, Tony Hyun; Savall, Joan; Schnitzer, Mark J.; Luo, Liqun] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Kim, Tony Hyun] Stanford Univ, Dept Elect Engn, Stanford, CA 94305 USA.
   [Schnitzer, Mark J.] Stanford Univ, Dept Appl Phys, Stanford, CA 94305 USA.
C3 Stanford University; Howard Hughes Medical Institute; Stanford University; Stanford University; Stanford University
RP Wagner, MJ; Schnitzer, MJ; Luo, LQ (corresponding author), Stanford Univ, Dept Biol, Stanford, CA 94305 USA.; Wagner, MJ; Schnitzer, MJ; Luo, LQ (corresponding author), Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.
EM mjwagner@stanford.edu; mschnitz@stanford.edu; lluo@stanford.edu
FU Epilepsy Training Grant; NIH; Hughes Collaborative Innovation Award; National Institute of Neurological Disorders and Stroke [R01NS050835] Funding Source: NIH RePORTER
NR 48
TC 356
Z9 416
U1 2
U2 114
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 6
PY 2017
VL 544
IS 7648
BP 96
EP +
DI 10.1038/nature21726
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EQ8GQ
UT WOS:000398323300040
PM 28321129
DA 2026-03-09
ER

PT J
AU Surana, NK
   Kasper, DL
AF Surana, Neeraj K.
   Kasper, Dennis L.
TI Moving beyond microbiome-wide associations to causal microbe identification
SO NATURE
LA English
DT Article
ID escherichia-coli; crohns-disease; bacteria; organisms; lectin; host
AB Microbiome-wide association studies have established that numerous diseases are associated with changes in the microbiota(1,2). These studies typically generate a long list of commensals implicated as biomarkers of disease, with no clear relevance to disease pathogenesis(1-5). If the field is to move beyond correlations and begin to address causation, an effective system is needed for refining this catalogue of differentially abundant microbes and to allow subsequent mechanistic studies(1,4). Here we demonstrate that triangulation of microbe-phenotype relationships is an effective method for reducing the noise inherent in microbiota studies and enabling identification of causal microbes. We found that gnotobiotic mice harbouring different microbial communities exhibited differential survival in a colitis model. Co-housing of these mice generated animals that had hybrid microbiotas and displayed intermediate susceptibility to colitis. Mapping of microbe-phenotype relationships in parental mouse strains and in mice with hybrid microbiotas identified the bacterial family Lachnospiraceae as a correlate for protection from disease. Using directed microbial culture techniques, we discovered Clostridium immunis, a previously unknown bacterial species from this family, that-when administered to colitis-prone mice-protected them against colitis-associated death. To demonstrate the generalizability of our approach, we used it to identify several commensal organisms that induce intestinal expression of an antimicrobial peptide. Thus, we have used microbe-phenotype triangulation to move beyond the standard correlative microbiome study and identify causal microbes for two completely distinct phenotypes. Identification of disease-modulating commensals by microbe-phenotype triangulation may be more broadly applicable to human microbiome studies.
C1 [Surana, Neeraj K.; Kasper, Dennis L.] Harvard Med Sch, Div Immunol, Dept Microbiol & Immunobiol, Boston, MA 02115 USA.
   [Surana, Neeraj K.] Boston Childrens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA.
C3 Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital
RP Surana, NK; Kasper, DL (corresponding author), Harvard Med Sch, Div Immunol, Dept Microbiol & Immunobiol, Boston, MA 02115 USA.; Surana, NK (corresponding author), Boston Childrens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA.
EM neeraj.surana@childrens.harvard.edu; dennis_kasper@hms.harvard.edu
FU Boston Children's Hospital; National Institutes of Health [K08 AI108690, U19 AI109764]
NR 31
TC 196
Z9 238
U1 1
U2 110
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 14
PY 2017
VL 552
IS 7684
BP 244
EP +
DI 10.1038/nature25019
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ0FK
UT WOS:000418029500045
PM 29211710
DA 2026-03-09
ER

PT J
AU Desjardins, MM
   Viennot, JJ
   Dartiailh, MC
   Bruhat, LE
   Delbecq, MR
   Lee, M
   Choi, MS
   Cottet, A
   Kontos, T
AF Desjardins, M. M.
   Viennot, J. J.
   Dartiailh, M. C.
   Bruhat, L. E.
   Delbecq, M. R.
   Lee, M.
   Choi, M. -S.
   Cottet, A.
   Kontos, T.
TI Observation of the frozen charge of a Kondo resonance
SO NATURE
LA English
DT Article
ID numerical renormalization-group; carbon nanotubes; transport-coefficients; anderson model; quantum; capacitance; circuit; spin
AB The ability to control electronic states at the nanoscale has contributed to our modern understanding of condensed matter. In particular, quantum dot circuits represent model systems for the study of strong electronic correlations, epitomized by the Kondo effect(1-3). We use circuit quantum electrodynamics architectures to study the internal degrees of freedom of this many-body phenomenon. Specifically, we couple a quantum dot to a highquality- factor microwave cavity to measure with exceptional sensitivity the dot's electronic compressibility, that is, its ability to accommodate charges. Because electronic compressibility corresponds solely to the charge response of the electronic system, it is not equivalent to the conductance, which generally involves other degrees of freedom such as spin. Here, by performing dual conductance and compressibility measurements in the Kondo regime, we uncover directly the charge dynamics of this peculiar mechanism of electron transfer. The Kondo resonance, visible in transport measurements, is found to be ` transparent' to microwave photons trapped in the high-quality cavity, thereby revealing that (in such a many-body resonance) finite conduction is achieved from a charge frozen by Coulomb interaction. This freezing of charge dynamics(4-6) is in contrast to the physics of a free electron gas. We anticipate that the tools of cavity quantum electrodynamics could be used in other types of mesoscopic circuits with many-body correlations7,8, providing a model system in which to perform quantum simulation of fermion-boson problems.
C1 [Desjardins, M. M.; Dartiailh, M. C.; Bruhat, L. E.; Cottet, A.; Kontos, T.] Univ Paris 06, Sorbonne Univ, Univ Paris Diderot Sorbonne Paris Cite, PSL Res Univ,CNRS,Ecole Normal Super,Lab Pierre A, 24 Rue Lhomond, F-75231 Paris 05, France.
   [Viennot, J. J.] Univ Colorado, JILA, Boulder, CO 80309 USA.
   [Viennot, J. J.] Univ Colorado, Dept Phys, Boulder, CO 80309 USA.
   [Delbecq, M. R.] RIKEN, Ctr Emergent Matter Sci, 147 Main Bldg,2-1 Hirosawa, Wako, Saitama 3510198, Japan.
   [Lee, M.] Kyung Hee Univ, Coll Appl Sci, Dept Appl Phys, 1732 Deogyeong Daero, Yongin 17104, Gyeonggi Do, South Korea.
   [Choi, M. -S.] Korea Univ, Dept Phys, 145 Anam Ro, Seoul 02841, South Korea.
   [Delbecq, M. R.] PSL Res Univ, Coll France, USR CNRS 3573, JEIP, 11 Pl Marcelin Berthelot, F-75231 Paris 05, France.
C3 Sorbonne Universite; Universite PSL; Centre National de la Recherche Scientifique (CNRS); University of Colorado System; University of Colorado Boulder; University of Colorado System; University of Colorado Boulder; RIKEN; Kyung Hee University; Korea University; Universite PSL; College de France
RP Kontos, T (corresponding author), Univ Paris 06, Sorbonne Univ, Univ Paris Diderot Sorbonne Paris Cite, PSL Res Univ,CNRS,Ecole Normal Super,Lab Pierre A, 24 Rue Lhomond, F-75231 Paris 05, France.
EM kontos@lpa.ens.fr
FU Jeunes Equipes de l'Institut de Physique du College de France (JEIP); ERC; NRF of Korea [2009-0069554, 2011-0030046, 2015-003689]; National Research Foundation of Korea [2011-0030046] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
NR 32
TC 39
Z9 42
U1 0
U2 67
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 4
PY 2017
VL 545
IS 7652
BP 71
EP +
DI 10.1038/nature21704
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET7MK
UT WOS:000400480400032
PM 28405018
DA 2026-03-09
ER

PT J
AU Penn, AC
   Zhang, CL
   Georges, F
   Royer, L
   Reillat, CB
   Hosy, E
   Petersen, JD
   Humeau, Y
   Choquet, D
AF Penn, A. C.
   Zhang, C. L.
   Georges, F.
   Royer, L.
   Reillat, C. B.
   Hosy, E.
   Petersen, J. D.
   Humeau, Y.
   Choquet, D.
TI Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors
SO NATURE
LA English
DT Article
ID living cells; plasticity; mechanisms; proteins; binding
AB Long-term potentiation (LTP) of excitatory synaptic transmission has long been considered a cellular correlate for learning and memory(1,2). Early LTP (less than 1 h) had initially been explained either by presynaptic increases in glutamate release(3-5) or by direct modification of postsynaptic AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor function(6,7). Compelling models have more recently proposed that synaptic potentiation can occur by the recruitment of additional postsynaptic AMPA receptors (AMPARs)(8), sourced either from an intracellular reserve pool by exocytosis or from nearby extra-synaptic receptors preexisting on the neuronal surface(9-12). However, the exact mechanism through which synapses can rapidly recruit new AMPARs during early LTP remains unknown. In particular, direct evidence for a pivotal role of AMPAR surface diffusion as a trafficking mechanism in synaptic plasticity is still lacking. Here, using AMPAR immobilization approaches, we show that interfering with AMPAR surface diffusion markedly impairs synaptic potentiation of Schaffer collaterals and commissural inputs to the CA1 area of the mouse hippocampus in cultured slices, acute slices and in vivo. Our data also identify distinct contributions of various AMPAR trafficking routes to the temporal profile of synaptic potentiation. In addition, AMPAR immobilization in vivo in the dorsal hippocampus inhibited fear conditioning, indicating that AMPAR diffusion is important for the early phase of contextual learning. Therefore, our results provide a direct demonstration that the recruitment of new receptors to synapses by surface diffusion is a critical mechanism for the expression of LTP and hippocampal learning. Since AMPAR surface diffusion is dictated by weak Brownian forces that are readily perturbed by protein-protein interactions, we anticipate that this fundamental trafficking mechanism will be a key target for modulating synaptic potentiation and learning.
C1 [Penn, A. C.; Zhang, C. L.; Georges, F.; Royer, L.; Reillat, C. B.; Hosy, E.; Petersen, J. D.; Humeau, Y.; Choquet, D.] Univ Bordeaux, Interdisciplinary Inst Neurosci, UMR5297, F-33000 Bordeaux, France.
   [Penn, A. C.; Zhang, C. L.; Georges, F.; Royer, L.; Reillat, C. B.; Hosy, E.; Petersen, J. D.; Humeau, Y.; Choquet, D.] CNRS, Interdisciplinary Inst Neurosci, UMR 5297, F-33000 Bordeaux, France.
   [Penn, A. C.] Univ Sussex, Sch Life Sci, Sussex Neurosci, Brighton BN1 9QG, E Sussex, England.
   [Georges, F.] Univ Bordeaux, CNRS UMR 5293, Inst Neurodegenerat Dis, 146 Rue Leo Saignat, F-33076 Bordeaux, France.
   [Petersen, J. D.; Choquet, D.] Univ Bordeaux, UMS CNRS 3420, Bordeaux Imaging Ctr, US4,INSERM, Bordeaux, France.
   [Royer, L.] Brandeis Univ, Dept Biol, 415 South St, Waltham, MA 02254 USA.
C3 Centre National de la Recherche Scientifique (CNRS); Universite de Bordeaux; CNRS - National Institute for Biology (INSB); Universite de Bordeaux; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); University of Sussex; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite de Bordeaux; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Bordeaux; Brandeis University
RP Choquet, D (corresponding author), Univ Bordeaux, Interdisciplinary Inst Neurosci, UMR5297, F-33000 Bordeaux, France.; Choquet, D (corresponding author), CNRS, Interdisciplinary Inst Neurosci, UMR 5297, F-33000 Bordeaux, France.; Choquet, D (corresponding author), Univ Bordeaux, UMS CNRS 3420, Bordeaux Imaging Ctr, US4,INSERM, Bordeaux, France.
EM daniel.choquet@u-bordeaux.fr
FU EMBO; EMBO [ALTF 129-2009]; European Commission Marie Curie Actions [FP7-PEOPLE-2010-IEF-273567]; Medical Research Council [MR/M020746/1]; Ministere de l'Enseignement Superieur et de la Recherche; Centre National de la Recherche Scientifique; Conseil Regional d'Aquitaine; Agence Nationale pour la Recherche; ERC;  [ANR-10INBS-04-0]; Medical Research Council [MR/M020746/1] Funding Source: researchfish; MRC [MR/M020746/1] Funding Source: UKRI
NR 33
TC 234
Z9 277
U1 3
U2 78
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 21
PY 2017
VL 549
IS 7672
BP 384
EP +
DI 10.1038/nature23658
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FH7PB
UT WOS:000411381300035
PM 28902836
DA 2026-03-09
ER

PT J
AU Olival, KJ
   Hosseini, PR
   Zambrana-Torrelio, C
   Ross, N
   Bogich, TL
   Daszak, P
AF Olival, Kevin J.
   Hosseini, Parviez R.
   Zambrana-Torrelio, Carlos
   Ross, Noam
   Bogich, Tiffany L.
   Daszak, Peter
TI Host and viral traits predict zoonotic spillover from mammals
SO NATURE
LA English
DT Article
ID transmission; database; virus; specificity; phylogeny; emergence; records; bats
AB The majority of human emerging infectious diseases are zoonotic, with viruses that originate in wild mammals of particular concern (for example, HIV, Ebola and SARS)(1-3). Understanding patterns of viral diversity in wildlife and determinants of successful cross-species transmission, or spillover, are therefore key goals for pandemic surveillance programs(4). However, few analytical tools exist to identify which host species are likely to harbour the next human virus, or which viruses can cross species boundaries(5-7). Here we conduct a comprehensive analysis of mammalian host-virus relationships and show that both the total number of viruses that infect a given species and the proportion likely to be zoonotic are predictable. After controlling for research effort, the proportion of zoonotic viruses per species is predicted by phylogenetic relatedness to humans, host taxonomy and human population within a species range-which may reflect human-wildlife contact. We demonstrate that bats harbour a significantly higher proportion of zoonotic viruses than all other mammalian orders. We also identify the taxa and geographic regions with the largest estimated number of 'missing viruses' and 'missing zoonoses' and therefore of highest value for future surveillance. We then show that phylogenetic host breadth and other viral traits are significant predictors of zoonotic potential, providing a novel framework to assess if a newly discovered mammalian virus could infect people.
C1 [Olival, Kevin J.; Hosseini, Parviez R.; Zambrana-Torrelio, Carlos; Ross, Noam; Bogich, Tiffany L.; Daszak, Peter] EcoHlth Alliance, 460 West 34th St, New York, NY 10001 USA.
C3 EcoHealth Alliance
RP Olival, KJ; Daszak, P (corresponding author), EcoHlth Alliance, 460 West 34th St, New York, NY 10001 USA.
EM olival@ecohealthalliance.org; daszak@ecohealthalliance.org
FU United States Agency for International Development (USAID) Emerging Pandemic Threats PREDICT program; NIH NIAID [R01AI079231, R01AI110964]; National Institute of Allergy and Infectious Diseases [R01AI110964] Funding Source: NIH RePORTER
NR 57
TC 776
Z9 887
U1 15
U2 336
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 29
PY 2017
VL 546
IS 7660
BP 646
EP +
DI 10.1038/nature22975
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY9QB
UT WOS:000404332000046
PM 28636590
DA 2026-03-09
ER

PT J
AU Ott, PA
   Hu, ZT
   Keskin, DB
   Shukla, SA
   Sun, J
   Bozym, DJ
   Zhang, WD
   Luoma, A
   Giobbie-Hurder, A
   Peter, L
   Chen, C
   Olive, O
   Carter, TA
   Li, SQ
   Lieb, DJ
   Eisenhaure, T
   Gjini, E
   Stevens, J
   Lane, WJ
   Javeri, I
   Nellaiappan, K
   Salazar, AM
   Daley, H
   Seaman, M
   Buchbinder, EI
   Yoon, CH
   Harden, M
   Lennon, N
   Gabriel, S
   Rodig, SJ
   Barouch, DH
   Aster, JC
   Getz, G
   Wucherpfennig, K
   Neuberg, D
   Ritz, J
   Lander, ES
   Fritsch, EF
   Hacohen, N
   Wu, CJ
AF Ott, Patrick A.
   Hu, Zhuting
   Keskin, Derin B.
   Shukla, Sachet A.
   Sun, Jing
   Bozym, David J.
   Zhang, Wandi
   Luoma, Adrienne
   Giobbie-Hurder, Anita
   Peter, Lauren
   Chen, Christina
   Olive, Oriol
   Carter, Todd A.
   Li, Shuqiang
   Lieb, David J.
   Eisenhaure, Thomas
   Gjini, Evisa
   Stevens, Jonathan
   Lane, William J.
   Javeri, Indu
   Nellaiappan, Kaliappanadar
   Salazar, Andres M.
   Daley, Heather
   Seaman, Michael
   Buchbinder, Elizabeth I.
   Yoon, Charles H.
   Harden, Maegan
   Lennon, Niall
   Gabriel, Stacey
   Rodig, Scott J.
   Barouch, Dan H.
   Aster, Jon C.
   Getz, Gad
   Wucherpfennig, Kai
   Neuberg, Donna
   Ritz, Jerome
   Lander, Eric S.
   Fritsch, Edward F.
   Hacohen, Nir
   Wu, Catherine J.
TI An immunogenic personal neoantigen vaccine for patients with melanoma
SO NATURE
LA English
DT Article
ID cd4(+) t-cells; sequencing data; cancer-immunotherapy; immune-responses; expression; prediction; molecules; epitopes; antigens; peptide
AB Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens(1), a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response(2), their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4(+) and CD8(+) T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.
C1 [Ott, Patrick A.; Hu, Zhuting; Keskin, Derin B.; Shukla, Sachet A.; Sun, Jing; Bozym, David J.; Zhang, Wandi; Chen, Christina; Olive, Oriol; Daley, Heather; Buchbinder, Elizabeth I.; Ritz, Jerome; Fritsch, Edward F.; Wu, Catherine J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.
   [Ott, Patrick A.; Buchbinder, Elizabeth I.; Ritz, Jerome; Wu, Catherine J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA.
   [Ott, Patrick A.; Keskin, Derin B.; Buchbinder, Elizabeth I.; Yoon, Charles H.; Barouch, Dan H.; Aster, Jon C.; Getz, Gad; Wucherpfennig, Kai; Ritz, Jerome; Lander, Eric S.; Hacohen, Nir; Wu, Catherine J.] Harvard Med Sch, Boston, MA 02215 USA.
   [Keskin, Derin B.; Shukla, Sachet A.; Carter, Todd A.; Li, Shuqiang; Lieb, David J.; Eisenhaure, Thomas; Harden, Maegan; Lennon, Niall; Gabriel, Stacey; Getz, Gad; Lander, Eric S.; Fritsch, Edward F.; Hacohen, Nir; Wu, Catherine J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Luoma, Adrienne; Wucherpfennig, Kai] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA.
   [Giobbie-Hurder, Anita; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA.
   [Peter, Lauren; Seaman, Michael; Barouch, Dan H.] Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA.
   [Peter, Lauren; Barouch, Dan H.] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA.
   [Gjini, Evisa; Rodig, Scott J.] Dana Farber Canc Inst, CIO, Boston, MA 02215 USA.
   [Stevens, Jonathan; Lane, William J.; Rodig, Scott J.; Aster, Jon C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA.
   [Javeri, Indu; Nellaiappan, Kaliappanadar] CuriRx Inc, Wilmington, MA 01887 USA.
   [Salazar, Andres M.] Oncovir Inc, 3203 Cleveland Ave NW, Washington, DC 20008 USA.
   [Yoon, Charles H.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02215 USA.
   [Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02214 USA.
   [Hacohen, Nir] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02214 USA.
   [Fritsch, Edward F.] Neon Therapeut Inc, Cambridge, MA 02139 USA.
C3 Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard University; Massachusetts Institute of Technology (MIT); Ragon Institute; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital
RP Wu, CJ (corresponding author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Wu, CJ (corresponding author), Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA.; Wu, CJ (corresponding author), Harvard Med Sch, Boston, MA 02215 USA.; Wu, CJ (corresponding author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
EM cwu@partners.org
FU Broad Institute SPARC program; National Institutes of Health [NCI-1RO1CA155010-02, NHLBI-5R01HL103532-03, NCI-SPORE-2P50CA101942-11A1, NCI-R50 RCA211482A]; Francis and Adele Kittredge Family Immuno-Oncology and Melanoma Research Fund; Faircloth Family Research Fund; DFCI Center for Cancer Immunotherapy Research fellowship; National Cancer Institute [P50CA101942, R01CA155010] Funding Source: NIH RePORTER
NR 45
TC 2108
Z9 2512
U1 19
U2 960
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 13
PY 2017
VL 547
IS 7662
BP 217
EP +
DI 10.1038/nature22991
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FA3AX
UT WOS:000405314500039
PM 28678778
DA 2026-03-09
ER

PT J
AU Maretty, L
   Jensen, JM
   Petersen, B
   Sibbesen, JAN
   Liu, SY
   Villesen, P
   Kov, LS
   Belling, K
   Have, CTH
   Izarzugaza, JMG
   Rosjean, MG
   Bork-Jensen, J
   Rove, JG
   Ls, TDA
   Huang, SJ
   Chang, YQ
   Xu, RQ
   Ye, WJ
   Rao, JH
   Guo, XS
   Sun, JH
   Cao, HZ
   Ye, C
   van Beusekom, J
   Espeseth, T
   Flindt, E
   Friborg, RM
   Halager, AE
   Le Hellard, S
   Hultman, CM
   Lescai, F
   Li, ST
   Lund, O
   Longren, P
   Mailund, T
   Matey-Hernandez, ML
   Mors, O
   Pedersen, CNS
   Icheritz-Pontén, TS
   Sullivan, P
   Syed, A
   Westergaard, D
   Yadav, R
   Li, N
   Xu, X
   Hansen, T
   Krogh, A
   Bolund, L
   Sorensen, TIA
   Pedersen, O
   Upta, RG
   Rasmussen, S
   Besenbacher, S
   Borglum, AD
   Wang, J
   Eiberg, H
   Kristiansen, K
   Brunak, S
   Schierup, MH
AF Maretty, Lasse
   Jensen, Jacob Malte
   Petersen, Bent
   Sibbesen, Jonas A. Ndreas
   Liu, Siyang
   Villesen, Palle
   Kov, Laurits S.
   Belling, Kirstine
   Have, Christian T. Heil
   Izarzugaza, Jose M. G.
   Rosjean, Marie G.
   Bork-Jensen, Jette
   Rove, Jakob G.
   Ls, Thomas D. A.
   Huang, Shujia
   Chang, Yuqi
   Xu, Ruiqi
   Ye, Weijian
   Rao, Junhua
   Guo, Xiaosen
   Sun, Jihua
   Cao, Hongzhi
   Ye, Chen
   van Beusekom, Johan
   Espeseth, Thomas
   Flindt, Esben
   Friborg, Rune M.
   Halager, Anders E.
   Le Hellard, Stephanie
   Hultman, Christina M.
   Lescai, Francesco
   Li, Shengting
   Lund, Ole
   Longren, Peter
   Mailund, Thomas
   Matey-Hernandez, Maria Luisa
   Mors, Ole
   Pedersen, Christian N. S.
   Icheritz-Ponten, Thomas S.
   Sullivan, Patrick
   Syed, Ali
   Westergaard, David
   Yadav, Rachita
   Li, Ning
   Xu, Xun
   Hansen, Torben
   Krogh, Anders
   Bolund, Lars
   Sorensen, Thorkild I. A.
   Pedersen, Oluf
   Upta, Ramneek G.
   Rasmussen, Simon
   Besenbacher, Soren
   Borglum, Anders D.
   Wang, Jun
   Eiberg, Hans
   Kristiansen, Karsten
   Brunak, Soren
   Schierup, Mikkel Heide
TI Sequencing and de novo assembly of 150 genomes from Denmark as a population reference
SO NATURE
LA English
DT Article
ID structural variation; mutations; discovery; alignment; patterns; quality; loci; gene; age; map
AB Hundreds of thousands of human genomes are now being sequenced to characterize genetic variation and use this information to augment association mapping studies of complex disorders and other phenotypic traits(1-4). Genetic variation is identified mainly by mapping short reads to the reference genome or by performing local assembly(2,5-7). However, these approaches are biased against discovery of structural variants and variation in the more complex parts of the genome. Hence, large-scale de novo assembly is needed. Here we show that it is possible to construct excellent de novo assemblies from high-coverage sequencing with mate-pair libraries extending up to 20 kilobases. We report de novo assemblies of 150 individuals (50 trios) from the GenomeDenmark project. The quality of these assemblies is similar to those obtained using the more expensive long-read technology(4,8-13). We use the assemblies to identify a rich set of structural variants including many novel insertions and demonstrate how this variant catalogue enables further deciphering of known association mapping signals. We leverage the assemblies to provide 100 completely resolved major histocompatibility complex haplotypes and to resolve major parts of the Y chromosome. Our study provides a regional reference genome that we expect will improve the power of future association mapping studies and hence pave the way for precision medicine initiatives, which now are being launched in many countries including Denmark.
C1 [Maretty, Lasse; Sibbesen, Jonas A. Ndreas; Liu, Siyang; Krogh, Anders] Univ Copenhagen, Bioinformat Ctr, Dept Biol, DK-2200 Copenhagen, Denmark.
   [Jensen, Jacob Malte; Villesen, Palle; Kov, Laurits S.; Friborg, Rune M.; Halager, Anders E.; Mailund, Thomas; Pedersen, Christian N. S.; Besenbacher, Soren; Schierup, Mikkel Heide] Aarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus, Denmark.
   [Jensen, Jacob Malte; Villesen, Palle; Kov, Laurits S.; Rove, Jakob G.; Ls, Thomas D. A.; Lescai, Francesco; Li, Shengting; Mailund, Thomas; Mors, Ole; Pedersen, Christian N. S.; Borglum, Anders D.; Wang, Jun; Schierup, Mikkel Heide] Aarhus Univ, Ctr Integrat Sequencing, iSEQ, DK-8000 Aarhus, Denmark.
   [Petersen, Bent; Belling, Kirstine; Izarzugaza, Jose M. G.; Rosjean, Marie G.; van Beusekom, Johan; Lund, Ole; Longren, Peter; Matey-Hernandez, Maria Luisa; Icheritz-Ponten, Thomas S.; Syed, Ali; Westergaard, David; Yadav, Rachita; Upta, Ramneek G.; Rasmussen, Simon; Brunak, Soren] Tech Univ Denmark, Dept Bio & Hlth Informat, DTU Bioinformat, DK-2800 Kongens Lyngby, Denmark.
   [Liu, Siyang; Xu, Ruiqi; Ye, Weijian; Rao, Junhua; Sun, Jihua; Li, Ning] BGI Europe, Ole Maaloes Vej 3, DK-2200 Copenhagen, Denmark.
   [Villesen, Palle; Mors, Ole; Besenbacher, Soren] Aarhus Univ, Dept Clin Med, DK-8000 Aarhus, Denmark.
   [Have, Christian T. Heil; Bork-Jensen, Jette; Sun, Jihua; Hansen, Torben; Sorensen, Thorkild I. A.; Pedersen, Oluf] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, DK-2100 Copenhagen, Denmark.
   [Rove, Jakob G.; Ls, Thomas D. A.; Lescai, Francesco; Li, Shengting; Borglum, Anders D.] Aarhus Univ, Dept Biomed, DK-8000 Aarhus, Denmark.
   [Rove, Jakob G.; Ls, Thomas D. A.; Lescai, Francesco; Li, Shengting; Mors, Ole; Borglum, Anders D.] iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, DK-8000 Aarhus, Denmark.
   [Huang, Shujia; Chang, Yuqi; Guo, Xiaosen; Cao, Hongzhi; Ye, Chen; Xu, Xun; Bolund, Lars; Wang, Jun; Kristiansen, Karsten] BGI Shenzhen, Shenzhen 518083, Peoples R China.
   [Huang, Shujia] South China Univ Technol, Sch Biosci & Biotechnol, Guangzhou 510006, Guangdong, Peoples R China.
   [Guo, Xiaosen; Flindt, Esben; Wang, Jun; Kristiansen, Karsten] Univ Copenhagen, Dept Biol, Lab Genom & Mol Biomed, DK-2100 Copenhagen, Denmark.
   [Espeseth, Thomas] Univ Oslo, Dept Psychol, N-0317 Oslo, Norway.
   [Espeseth, Thomas; Le Hellard, Stephanie] Univ Bergen, KG Jebsen Ctr Psychosis Res, Dept Clin Sci, NORMENT, N-5021 Bergen, Norway.
   [Le Hellard, Stephanie] Haukeland Hosp, Ctr Med Genet & Mol Med, Dr E Martens Res Grp Biol Psychiat, N-5021 Bergen, Norway.
   [Hultman, Christina M.; Sullivan, Patrick] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden.
   [Sullivan, Patrick] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.
   [Sorensen, Thorkild I. A.] Bispebjerg & Frederiksberg Hosp, Dept Clin Epidemiol, DK-2000 Frederiksberg, Denmark.
   [Sorensen, Thorkild I. A.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Publ Hlth, DK-2200 Copenhagen, Denmark.
   [Eiberg, Hans] Univ Copenhagen, Dept Cellular & Mol Med, DK-2200 Copenhagen, Denmark.
   [Brunak, Soren] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, DK-2200 Copenhagen, Denmark.
   [Schierup, Mikkel Heide] Aarhus Univ, Dept Biosci, DK-8000 Aarhus, Denmark.
C3 University of Copenhagen; Aarhus University; Aarhus University; Technical University of Denmark; Aarhus University; Novo Nordisk Foundation; University of Copenhagen; Aarhus University; Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH); Beijing Genomics Institute (BGI); South China University of Technology; University of Copenhagen; University of Oslo; University of Bergen; University of Bergen; Haukeland University Hospital; Karolinska Institutet; University of North Carolina; University of North Carolina Chapel Hill; University of Copenhagen; Bispebjerg Hospital; University of Copenhagen; University of Copenhagen; University of Copenhagen; Aarhus University
RP Schierup, MH (corresponding author), Aarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus, Denmark.; Schierup, MH (corresponding author), Aarhus Univ, Ctr Integrat Sequencing, iSEQ, DK-8000 Aarhus, Denmark.; Brunak, S (corresponding author), Tech Univ Denmark, Dept Bio & Hlth Informat, DTU Bioinformat, DK-2800 Kongens Lyngby, Denmark.; Kristiansen, K (corresponding author), BGI Shenzhen, Shenzhen 518083, Peoples R China.; Kristiansen, K (corresponding author), Univ Copenhagen, Dept Biol, Lab Genom & Mol Biomed, DK-2100 Copenhagen, Denmark.; Brunak, S (corresponding author), Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, DK-2200 Copenhagen, Denmark.; Schierup, MH (corresponding author), Aarhus Univ, Dept Biosci, DK-8000 Aarhus, Denmark.
EM kk@bio.ku.dk; brunak@cbs.dtu.dk; mheide@birc.au.dk
FU Innovation Fund Denmark; Novo Nordisk Foundation [NNF14CC0001]; Lundbeck Foundation [R155-2014-1724] Funding Source: researchfish; NNF Center for Basic Metabolic Research [Pedersen Group, Hansen Group] Funding Source: researchfish; Novo Nordisk Foundation Center for Protein Research [PI Søren Brunak] Funding Source: researchfish; Villum Fonden [00007278] Funding Source: researchfish
NR 53
TC 100
Z9 112
U1 0
U2 57
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 3
PY 2017
VL 548
IS 7665
BP 87
EP +
DI 10.1038/nature23264
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FC4SU
UT WOS:000406831700042
PM 28746312
DA 2026-03-09
ER

PT J
AU Gong, Z
   Hueckel, T
   Yi, GR
   Sacanna, S
AF Gong, Zhe
   Hueckel, Theodore
   Yi, Gi-Ra
   Sacanna, Stefano
TI Patchy particles made by colloidal fusion
SO NATURE
LA English
DT Article
ID valence; microspheres
AB Patches on the surfaces of colloidal particles(1-5) provide directional information that enables the self-assembly of the particles into higher-order structures. Although computational tools can make quantitative predictions and can generate design rules that link the patch motif of a particle to its internal microstructure and to the emergent properties of the self-assembled materials(6-8), the experimental realization of model systems of particles with surface patches (or 'patchy' particles) remains a challenge. Synthetic patchy colloidal particles are often poor geometric approximations of the digital building blocks used in simulations(9,10) and can only rarely be manufactured in sufficiently high yields to be routinely used as experimental model systems'. Here we introduce a method, which we refer to as colloidal fusion, for fabricating functional patchy particles in a tunable and scalable manner. Using coordination dynamics and wetting forces, we engineer hybrid liquid solid clusters that evolve into particles with a range of patchy surface morphologies on addition of a plasticizer. We are able to predict and control the evolutionary pathway by considering surface-energy minimization, leading to two main branches of product: first, spherical particles with liquid surface patches, capable of forming curable bonds with neighbouring particles to assemble robust supracolloidal structures; and second, particles with a faceted liquid compartment, which can be cured and purified to yield colloidal polyhedra. These findings outline a scalable strategy for the synthesis of patchy particles, first by designing their surface patterns by computer simulation, and then by recreating them in the laboratory with high fidelity.
C1 [Gong, Zhe; Hueckel, Theodore; Sacanna, Stefano] New York Univ, Inst Mol Design, Dept Chem, 29 Washington Pl, New York, NY 10003 USA.
   [Yi, Gi-Ra] Sungkyunkwan Univ SKKU, Sch Chem Engn, Suwon 16419, South Korea.
C3 New York University; Sungkyunkwan University (SKKU)
RP Sacanna, S (corresponding author), New York Univ, Inst Mol Design, Dept Chem, 29 Washington Pl, New York, NY 10003 USA.
EM s.sacanna@nyu.edu
FU NSF CAREER [DMR-1653465]; NSF [DMR-0923251]; NRF (Korea) [2010-0029409, 2014S1A2A2028608]
NR 24
TC 199
Z9 230
U1 4
U2 194
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 12
PY 2017
VL 550
IS 7675
BP 234
EP +
DI 10.1038/nature23901
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FJ5YG
UT WOS:000412829500044
PM 28922664
DA 2026-03-09
ER

PT J
AU Chen, J
   Zhong, MC
   Guo, HJ
   Davidson, D
   Mishel, S
   Lu, Y
   Rhee, I
   Pérez-Quintero, LA
   Zhang, SH
   Cruz-Munoz, ME
   Wu, N
   Vinh, DC
   Sinha, M
   Calderon, V
   Lowell, CA
   Danska, JS
   Veillette, A
AF Chen, Jun
   Zhong, Ming-Chao
   Guo, Huaijian
   Davidson, Dominique
   Mishel, Sabrin
   Lu, Yan
   Rhee, Inmoo
   Perez-Quintero, Luis-Alberto
   Zhang, Shaohua
   Cruz-Munoz, Mario-Ernesto
   Wu, Ning
   Vinh, Donald C.
   Sinha, Meenal
   Calderon, Virginie
   Lowell, Clifford A.
   Danska, Jayne S.
   Veillette, Andre
TI SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin
SO NATURE
LA English
DT Article
ID protein-kinase p56lck; leukemia stem-cells; multiple-myeloma; therapeutic target; family receptors; sap adapters; sirp-alpha; fcr-gamma; activation; gene
AB Cancer cells elude anti-tumour immunity through multiple mechanisms, including upregulated expression of ligands for inhibitory immune checkpoint receptors(1,2). Phagocytosis by macrophages plays a critical role in cancer control(3-6). Therapeutic blockade of signal regulatory protein (SIRP)-alpha, an inhibitory receptor on macrophages, or of its ligand CD47 expressed on tumour cells, improves tumour cell elimination in vitro and in vivo(7-10), suggesting that blockade of the SIRP alpha-CD47 checkpoint could be useful in treating human cancer(11-14). However, the prophagocytic receptor(s) responsible for tumour cell phagocytosis is(are) largely unknown. Here we find that macrophages are much more efficient at phagocytosis of haematopoietic tumour cells, compared with non-haematopoietic tumour cells, in response to SIRP alpha-CD47 blockade. Using a mouse lacking the signalling lymphocytic activation molecule (SLAM) family of homotypic haematopoietic cell-specific receptors, we determined that phagocytosis of haematopoietic tumour cells during SIRP alpha-CD47 blockade was strictly dependent on SLAM family receptors in vitro and in vivo. In both mouse and human cells, this function required a single SLAM family member, SLAMF7 (also known as CRACC, CS1, CD319), expressed on macrophages and tumour cell targets. In contrast to most SLAM receptor functions(15-17), SLAMF7-mediated phagocytosis was independent of signalling lymphocyte activation molecule-associated protein (SAP) adaptors. Instead, it depended on the ability of SLAMF7 to interact with integrin Mac-1 (refs 18-20) and utilize signals involving immunoreceptor tyrosine-based activation motifs(21,22). These findings elucidate the mechanism by which macrophages engulf and destroy haematopoietic tumour cells. They also reveal a novel SAP adaptor-independent function for a SLAM receptor. Lastly, they suggest that patients with tumours expressing SLAMF7 are more likely to respond to SIRP alpha-CD47 blockade therapy.
C1 [Chen, Jun; Zhong, Ming-Chao; Guo, Huaijian; Davidson, Dominique; Lu, Yan; Rhee, Inmoo; Perez-Quintero, Luis-Alberto; Zhang, Shaohua; Cruz-Munoz, Mario-Ernesto; Wu, Ning; Veillette, Andre] Inst Rech Clin Montreal, Lab Mol Oncol, Montreal, PQ H2W 1R7, Canada.
   [Zhong, Ming-Chao; Rhee, Inmoo; Perez-Quintero, Luis-Alberto; Veillette, Andre] McGill Univ, Dept Med, Montreal, PQ H3G 1Y6, Canada.
   [Mishel, Sabrin; Danska, Jayne S.] Hosp Sick Children, Toronto, ON M5G 0A4, Canada.
   [Mishel, Sabrin; Danska, Jayne S.] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada.
   [Rhee, Inmoo] Sejong Univ, Dept Biosci & Biotechnol, Seoul 143747, South Korea.
   [Cruz-Munoz, Mario-Ernesto] Univ Morelos, Sch Med, Cuernavaca 62350, Morelos, Mexico.
   [Vinh, Donald C.] McGill Univ, Hlth Ctr MUHC, Infect Dis Susceptibil Program, Montreal, PQ H4A 3J1, Canada.
   [Vinh, Donald C.] RI MUHC, Montreal, PQ H4A 3J1, Canada.
   [Vinh, Donald C.] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada.
   [Sinha, Meenal; Lowell, Clifford A.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA.
   [Calderon, Virginie] Inst Rech Clin Montreal, Bioinformat Core Facil, Montreal, PQ H2W 1R7, Canada.
   [Veillette, Andre] Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.
C3 Universite de Montreal; Institut de Recherche Clinique de Montreal (IRCM); McGill University; University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; Sejong University; Universidad Autonoma del Estado de Morelos; McGill University; McGill University; University of California System; University of California San Francisco; Institut de Recherche Clinique de Montreal (IRCM); Universite de Montreal; Universite de Montreal
RP Veillette, A (corresponding author), Inst Rech Clin Montreal, Lab Mol Oncol, Montreal, PQ H2W 1R7, Canada.; Veillette, A (corresponding author), McGill Univ, Dept Med, Montreal, PQ H3G 1Y6, Canada.; Veillette, A (corresponding author), Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.
EM andre.veillette@ircm.qc.ca
FU Canadian Institutes of Health Research (CIHR) [MT-14429, MOP-82906, FDN-143338]; Canadian Cancer Society Research Institute (CCSRI) [018114]; National Institutes of Health [RO1AI65495, RO1AI68150, RO1AI113272]; Natural Sciences and Engineering Research Council (NSERC) [1050319]; Cole Foundation; RDV Foundation; Fonds de la recherche du Quebec - Sante (FRQ-S)
NR 47
TC 240
Z9 289
U1 0
U2 94
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 27
PY 2017
VL 544
IS 7651
BP 493
EP +
DI 10.1038/nature22076
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA ET1TN
UT WOS:000400051900046
PM 28424516
DA 2026-03-09
ER

PT J
AU Agathocleous, M
   Meacham, CE
   Burgess, RJ
   Piskounova, E
   Zhao, ZY
   Crane, GM
   Cowin, BL
   Bruner, E
   Murphy, MM
   Chen, WN
   Spangrude, GJ
   Hu, ZP
   DeBerardinis, RJ
   Morrison, SJ
AF Agathocleous, Michalis
   Meacham, Corbin E.
   Burgess, Rebecca J.
   Piskounova, Elena
   Zhao, Zhiyu
   Crane, Genevieve M.
   Cowin, Brianna L.
   Bruner, Emily
   Murphy, Malea M.
   Chen, Weina
   Spangrude, Gerald J.
   Hu, Zeping
   DeBerardinis, Ralph J.
   Morrison, Sean J.
TI Ascorbate regulates haematopoietic stem cell function and leukaemogenesis
SO NATURE
LA English
DT Article
ID vitamin-c; clonal hematopoiesis; alpha-ketoglutarate; dna demethylation; cancer-cells; tet2; 5-methylcytosine; acid; differentiation; mutations
AB Stem-cell fate can be influenced by metabolite levels in culture, but it is not known whether physiological variations in metabolite levels in normal tissues regulate stem-cell function in vivo. Here we describe a metabolomics method for the analysis of rare cell populations isolated directly from tissues and use it to compare mouse haematopoietic stem cells (HSCs) to restricted haematopoietic progenitors. Each haematopoietic cell type had a distinct metabolic signature. Human and mouse HSCs had unusually high levels of ascorbate, which decreased with differentiation. Systemic ascorbate depletion in mice increased HSC frequency and function, in part by reducing the function of Tet2, a dioxygenase tumour suppressor. Ascorbate depletion cooperated with Flt3 internal tandem duplication (Flt3(ITD)) leukaemic mutations to accelerate leukaemogenesis, through cell-autonomous and possibly non-cell-autonomous mechanisms, in a manner that was reversed by dietary ascorbate. Ascorbate acted cell-autonomously to negatively regulate HSC function and myelopoiesis through Tet2-dependent and Tet2-independent mechanisms. Ascorbate therefore accumulates within HSCs to promote Tet activity in vivo, limiting HSC frequency and suppressing leukaemogenesis.
C1 [Agathocleous, Michalis; Meacham, Corbin E.; Burgess, Rebecca J.; Piskounova, Elena; Zhao, Zhiyu; Crane, Genevieve M.; Cowin, Brianna L.; Bruner, Emily; Murphy, Malea M.; Hu, Zeping; DeBerardinis, Ralph J.; Morrison, Sean J.] Univ Texas Southwestern Med Ctr Dallas, Childrens Res Inst, Dallas, TX 75390 USA.
   [Agathocleous, Michalis; Meacham, Corbin E.; Burgess, Rebecca J.; Piskounova, Elena; Zhao, Zhiyu; Crane, Genevieve M.; Cowin, Brianna L.; Bruner, Emily; Murphy, Malea M.; Hu, Zeping; DeBerardinis, Ralph J.; Morrison, Sean J.] Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA.
   [Chen, Weina] Univ Texas Southwestern Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA.
   [Spangrude, Gerald J.] Univ Utah, Dept Med, Salt Lake City, UT 84112 USA.
   [DeBerardinis, Ralph J.; Morrison, Sean J.] Univ Texas Southwestern Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA.
C3 University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Utah System of Higher Education; University of Utah; Howard Hughes Medical Institute; University of Texas System; University of Texas Southwestern Medical Center
RP Morrison, SJ (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Childrens Res Inst, Dallas, TX 75390 USA.; Morrison, SJ (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA.; Morrison, SJ (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA.
EM Sean.Morrison@UTSouthwestern.edu
FU Cancer Prevention and Research Institute of Texas; National Institutes of Health [R37 AG024945, R01 DK100848]
NR 58
TC 456
Z9 506
U1 3
U2 190
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 28
PY 2017
VL 549
IS 7673
BP 476
EP +
DI 10.1038/nature23876
PG 27
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FI4GT
UT WOS:000411930000041
PM 28825709
DA 2026-03-09
ER

PT J
AU Miles, A
   Harding, NJ
   Bottà, G
   Clarkson, CS
   Antao, T
   Kozak, K
   Schrider, DR
   Kern, AD
   Redmond, S
   Sharakhov, I
   Pearson, RD
   Bergey, C
   Fontaine, MC
   Donnelly, MJ
   Lawniczak, MKN
   Kwiatkowski, DP
   Ayala, D
   Besensky, NJ
   Burt, A
   Caputo, B
   della Torre, A
   Fontaine, MC
   Godfray, HCJ
   Hahn, MW
   Midega, J
   Neafsey, DE
   O'Loughlin, S
   Pinto, J
   Riehle, MM
   Vernick, KD
   Weetman, D
   Wilding, CS
   White, BJ
   Troco, AD
   Diabaté, A
   Costantini, C
   Rohatgi, KR
   Besansky, NJ
   Elissa, N
   Coulibaly, B
   Dinis, J
   Midegal, J
   Mbogo, C
   Bejon, P
   Mawejje, HD
   Stalker, J
   Rockett, K
   Drury, E
   Mead, D
   Jeffreys, A
   Hubbard, C
   Rowlands, K
   Isaacs, AT
   Jyothi, D
   Malangone, C
   Vauterin, P
   Jeffery, B
   Wright, I
   Hart, L
   Kluczyriski, K
   Cornelius, V
   MacInnisn, B
   Henrichs, C
   Giacomantonio, R
AF Miles, Alistair
   Harding, Nicholas J.
   Botta, Giordano
   Clarkson, Chris S.
   Antao, Tiago
   Kozak, Krzysztof
   Schrider, Daniel R.
   Kern, Andrew D.
   Redmond, Seth
   Sharakhov, Igor
   Pearson, Richard D.
   Bergey, Christina
   Fontaine, Michael C.
   Donnelly, Martin J.
   Lawniczak, Mara K. N.
   Kwiatkowski, Dominic P.
   Ayala, Diego
   Besensky, Nora J.
   Burt, Austin
   Caputo, Beniamino
   della Torre, Alessandra
   Fontaine, Michael C.
   Godfray, H. Charles J.
   Hahn, Matthew W.
   Midega, Janet
   Neafsey, Daniel E.
   O'Loughlin, Samantha
   Pinto, Joao
   Riehle, Michelle M.
   Vernick, Kenneth D.
   Weetman, David
   Wilding, Craig S.
   White, Bradley J.
   Troco, Arlete D.
   Diabate, Abdoulaye
   Costantini, Carlo
   Rohatgi, Kyanne R.
   Besansky, Nora J.
   Elissa, Nohal
   Coulibaly, Bouhacar
   Dinis, Joao
   Midegal, Janet
   Mbogo, Charles
   Bejon, Philip
   Mawejje, Henry D.
   Stalker, Jim
   Rockett, Kirk
   Drury, Eleanor
   Mead, Daniel
   Jeffreys, Anna
   Hubbard, Christina
   Rowlands, Kate
   Isaacs, Alison T.
   Jyothi, Dushyanth
   Malangone, Cinzia
   Vauterin, Paul
   Jeffery, Ben
   Wright, Ian
   Hart, Lee
   Kluczyriski, Krzysztof
   Cornelius, Victoria
   MacInnisn, Bronwyn
   Henrichs, Christa
   Giacomantonio, Rachel
TI Genetic diversity of the African malaria vector Anopheles gambiae
SO NATURE
LA English
DT Article
ID population-structure; incipient speciation; positive selection; mosquito; flow; introgression; divergence; resistance; suggests; identity
AB The sustainability of malaria control in Africa is threatened by the rise of insecticide resistance in Anopheles mosquitoes, which transmit the disease(1). To gain a deeper understanding of how mosquito populations are evolving, here we sequenced the genomes of 765 specimens of Anopheles gambiae and Anopheles coluzzii sampled from 15 locations across Africa, and identified over 50 million single nucleotide polymorphisms within the accessible genome. These data revealed complex population structure and patterns of gene flow, with evidence of ancient expansions, recent bottlenecks, and local variation in effective population size. Strong signals of recent selection were observed in insecticide-resistance genes, with several sweeps spreading over large geographical distances and between species. The design of new tools for mosquito control using gene-drive systems will need to take account of high levels of genetic diversity in natural mosquito populations.
C1 [Miles, Alistair; Clarkson, Chris S.; Kozak, Krzysztof; Pearson, Richard D.; Donnelly, Martin J.; Lawniczak, Mara K. N.; Kwiatkowski, Dominic P.; Stalker, Jim; Drury, Eleanor; Mead, Daniel; Jyothi, Dushyanth; Malangone, Cinzia; Giacomantonio, Rachel] Wellcome Trust Sanger Inst, Malaria Programme, Cambridge CB10 1SA, England.
   [Miles, Alistair; Harding, Nicholas J.; Botta, Giordano; Antao, Tiago; Pearson, Richard D.; Kwiatkowski, Dominic P.; Rockett, Kirk; Jeffreys, Anna; Hubbard, Christina; Rowlands, Kate; Vauterin, Paul; Jeffery, Ben; Wright, Ian; Hart, Lee; Kluczyriski, Krzysztof; Cornelius, Victoria; Henrichs, Christa] Univ Oxford, MRC Ctr Genom & Global Hlth, Oxford OX3 7BN, England.
   [Botta, Giordano; Caputo, Beniamino; della Torre, Alessandra] Univ Roma SAPIENZA, Dipartimento Sanita Pubbl & Malattie Infett, Ist Pasteur Italia Fdn Cenci Bolognetti, Rome, Italy.
   [Clarkson, Chris S.; Antao, Tiago; Donnelly, Martin J.; Isaacs, Alison T.] Univ Liverpool Liverpool Sch Trop Med, Dept Vector Biol, Pembroke Pl, Liverpool L3 5QA, Merseyside, England.
   [Antao, Tiago] Univ Montana, Missoula, MT 59812 USA.
   [Schrider, Daniel R.] Rutgers State Univ, Dept Genet, 604 Alison Rd, Piscataway, NJ 08854 USA.
   [Redmond, Seth; Neafsey, Daniel E.] Broad Inst, Genome Sequencing & Anal Program, 415 Main St, Cambridge, MD 02142 USA.
   [Sharakhov, Igor] Virginia Tech, Dept Entomol, Blacksburg, VA 24061 USA.
   Tomsk State Univ, Lab Ecol Genet & Environm Protect, Tomsk 634050, Russia.
   [Bergey, Christina; Besensky, Nora J.; Rohatgi, Kyanne R.; Besansky, Nora J.] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA.
   [Fontaine, Michael C.] Univ Groningen, Groningen Inst Evolutionary Life Sci GELIFES, Nijenborgh 7, NL-9747 AG Groningen, Netherlands.
   [Ayala, Diego; Elissa, Nohal] Ctr Int Rech Med Franceville, Unite Ecol Syst Vectoriels, Franceville, Gabon.
   [Ayala, Diego; Costantini, Carlo] UM2, UM1, CNRS 5290, IRD,UMR MIVEGEC,IRD 224, Montpellier, France.
   Imperial Coll, Dept Life Sci, Silwood Pk, Ascot SL5 7PY, Berks, England.
   [Godfray, H. Charles J.] Univ Oxford, Dept Zool, Tinbergen Bldg,South Parks Rd, Oxford OX1 3PS, England.
   [Hahn, Matthew W.] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA.
   [Hahn, Matthew W.] Indiana Univ, Sch Informat & Comp, Bloomington, IN 47405 USA.
   [Midega, Janet; Midegal, Janet; Mbogo, Charles; Bejon, Philip] KEMRI Wellcome Trust Res Programme, POB 230, Kilifi, Kenya.
   Univ Nova Lisboa, IHMT, GHTM, Rua Junqueira 100, P-1349008 Lisbon, Portugal.
   Univ Minnesota, Microbial & Plant Genom Inst, Dept Microbiol & Immunol, St Paul, MN 55108 USA.
   Inst Pasteur, Unit Genet & Genom Insect Vectors, Paris, France.
   Liverpool John Moores Univ, Sch Nat Sci & Psychol, Liverpool L3 3AF, Merseyside, England.
   [White, Bradley J.] Univ Calif Riverside, Dept Entomol, Riverside, CA 92521 USA.
   [Troco, Arlete D.] Minist Saude, Direccao Nacl Sude Publ, Programa Nacl Controle Malaria, Luanda, Angola.
   [Diabate, Abdoulaye] IRSS, Bobo Dioulasso, Burkina Faso.
   [Costantini, Carlo] OCEAC, Lab Rech Paludisme, Yaounde, Cameroon.
   [Coulibaly, Bouhacar] Univ Bamako, MRTC, Bamako, Mali.
   [Dinis, Joao] Minist Saude Publ, Inst Nacl Saude Publ, Bissau, Guinea Bissau.
   [Mawejje, Henry D.] Infect Dis Res Collaborat, 2C Nakasero Hill Rd,POB 7475, Kampala, Uganda.
   [MacInnisn, Bronwyn] Broad Inst Massachusetts Inst Technol & Harvard, 415 Main St, Cambridge, MA 02142 USA.
C3 Wellcome Trust Sanger Institute; University of Oxford; Sapienza University Rome; University of Liverpool; Liverpool School of Tropical Medicine; University of Montana System; University of Montana; Rutgers University System; Rutgers University New Brunswick; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Virginia Polytechnic Institute & State University; Tomsk State University; University of Notre Dame; University of Groningen; Institut de Recherche pour le Developpement (IRD); Universite de Montpellier; Imperial College London; University of Oxford; Indiana University System; Indiana University Bloomington; Indiana University System; Indiana University Bloomington; Universidade Nova de Lisboa; Institute of Hygiene & Tropical Medicine - UNL; University of Minnesota System; University of Minnesota Twin Cities; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Liverpool John Moores University; University of California System; University of California Riverside; University of Bamako; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute
RP Miles, A; Donnelly, MJ; Lawniczak, MKN; Kwiatkowski, DP (corresponding author), Wellcome Trust Sanger Inst, Malaria Programme, Cambridge CB10 1SA, England.; Miles, A; Kwiatkowski, DP (corresponding author), Univ Oxford, MRC Ctr Genom & Global Hlth, Oxford OX3 7BN, England.; Donnelly, MJ (corresponding author), Univ Liverpool Liverpool Sch Trop Med, Dept Vector Biol, Pembroke Pl, Liverpool L3 5QA, Merseyside, England.
EM alistairmiles@bdi.ox.ac.uk; Martin.Donnelly@Istmed.ac.uk; mara@sangerac.uk; dominic@sangerac.uk
FU Wellcome Trust [090770/Z/09/Z, 090532/Z/09/Z, 098051]; Medical Research Council UK; Department for International Development (DFID) [MR/M006212/1]; MRC [G1100339]; Foundation for the National Institutes of Health through Vector-Based Control of Transmission: Discovery Research (VCTR) program of the Grand Challenges in Global Health initiative of the Bill AMP; Melinda Gates Foundation; National Institute of Allergy and Infectious Diseases (NIAID) [U19AI089674, R01AI082734]; Sir Henry Wellcome Postdoctoral Fellowship; Medical Research Council [G0600718, G1002624, G0600718B, MR/M006212/1, G1100339] Funding Source: researchfish; Wellcome Trust [204911/Z/16/Z] Funding Source: researchfish; MRC [MR/M006212/1, G1100339, G0600718, G1002624] Funding Source: UKRI; National Institute of Allergy and Infectious Diseases [U19AI089674] Funding Source: NIH RePORTER
NR 50
TC 243
Z9 271
U1 3
U2 130
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 7
PY 2017
VL 552
IS 7683
BP 96
EP +
DI 10.1038/nature24995
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FP4BA
UT WOS:000417560500050
PM 29186111
DA 2026-03-09
ER

PT J
AU Nakada, Y
   Canseco, DC
   Thet, S
   Abdisalaam, S
   Asaithamby, A
   Santos, CX
   Shah, AM
   Zhang, H
   Faber, JE
   Kinter, MT
   Szweda, LI
   Xing, C
   Hu, ZP
   Deberardinis, RJ
   Schiattarella, G
   Hill, JA
   Oz, O
   Lu, ZG
   Zhang, CC
   Kimura, W
   Sadek, HA
AF Nakada, Yuji
   Canseco, Diana C.
   Thet, SuWannee
   Abdisalaam, Salim
   Asaithamby, Aroumougame
   Santos, Celio X.
   Shah, Ajay M.
   Zhang, Hua
   Faber, James E.
   Kinter, Michael T.
   Szweda, Luke I.
   Xing, Chao
   Hu, Zeping
   Deberardinis, Ralph J. .
   Schiattarella, Gabriele
   Hill, Joseph A.
   Oz, Orhan
   Lu, Zhigang
   Zhang, Cheng Cheng
   Kimura, Wataru
   Sadek, Hesham A.
TI Hypoxia induces heart regeneration in adult mice
SO NATURE
LA English
DT Article
ID cell-cycle arrest; stem-cells; alpha-ketoglutarate; mouse heart; cardiomyocytes; zebrafish; 5-bromodeoxyuridine; proliferation; carboxylation; metabolism
AB The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the lasting and severe effects of cardiomyopathy. Recently, it has become clear that the mammalian heart is not a post-mitotic organ. For example, the neonatal heart is capable of regenerating lost myocardium(1), and the adult heart is capable of modest self-renewal(2,3). In both of these scenarios, cardiomyocyte renewal occurs via the proliferation of pre-existing cardiomyocytes, and is regulated by aerobic-respiration-mediated oxidative DNA damage(4,5). Therefore, we reasoned that inhibiting aerobic respiration by inducing systemic hypoxaemia would alleviate oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals. Here we report that, in mice, gradual exposure to severe systemic hypoxaemia, in which inspired oxygen is gradually decreased by 1% and maintained at 7% for 2 weeks, results in inhibition of oxidative metabolism, decreased reactive oxygen species production and oxidative DNA damage, and reactivation of cardiomyocyte mitosis. Notably, we find that exposure to hypoxaemia 1 week after induction of myocardial infarction induces a robust regenerative response with decreased myocardial fibrosis and improvement of left ventricular systolic function. Genetic fate-mapping analysis confirms that the newly formed myocardium is derived from pre-existing cardiomyocytes. These results demonstrate that the endogenous regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxaemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine.
C1 [Nakada, Yuji; Canseco, Diana C.; Thet, SuWannee; Schiattarella, Gabriele; Hill, Joseph A.; Kimura, Wataru; Sadek, Hesham A.] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA.
   [Abdisalaam, Salim; Asaithamby, Aroumougame] Univ Texas Southwestern Med Ctr Dallas, Dept Radiat Oncol, Dallas, TX 75390 USA.
   [Santos, Celio X.; Shah, Ajay M.] Kings Coll London, Div Cardiovasc, BHF Ctr Res Excellence, Fac Med,James Black Ctr, London SE5 9NU, England.
   [Zhang, Hua; Faber, James E.] Univ N Carolina, McAllister Heart Inst, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA.
   [Kinter, Michael T.; Szweda, Luke I.] Oklahoma Med Res Fdn, Free Radical Biol & Aging Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.
   [Xing, Chao] Univ Texas Southwestern Med Ctr Dallas, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA.
   [Hu, Zeping; Deberardinis, Ralph J. .] Univ Texas Southwestern Med Ctr Dallas, Res Inst, Childrens Med Ctr, Dallas, TX 75390 USA.
   [Oz, Orhan] Univ Texas Southwestern Med Ctr Dallas, Dept Radiol, Dallas, TX 75390 USA.
   [Lu, Zhigang; Zhang, Cheng Cheng] Univ Texas Southwestern Med Ctr Dallas, Dept Physiol & Dev Biol, Dallas, TX 75390 USA.
   [Kimura, Wataru] Univ Tsukuba, Tsukuba Adv Res Alliance, Life Sci Ctr, 1-1-1 Tennoudai, Tsukuba, Ibaraki 3058577, Japan.
   [Sadek, Hesham A.] Univ Texas Southwestern Med Ctr Dallas, Ctr Regenerat Sci & Med, Dallas, TX 75390 USA.
C3 University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of London; King's College London; University of North Carolina; University of North Carolina Chapel Hill; Oklahoma Medical Research Foundation; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Tsukuba; University of Texas System; University of Texas Southwestern Medical Center
RP Kimura, W; Sadek, HA (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA.; Kimura, W (corresponding author), Univ Tsukuba, Tsukuba Adv Res Alliance, Life Sci Ctr, 1-1-1 Tennoudai, Tsukuba, Ibaraki 3058577, Japan.; Sadek, HA (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Ctr Regenerat Sci & Med, Dallas, TX 75390 USA.
EM wataru.kimura@utsouthwestern.edu; hesham.sadek@utsouthwestern.edu
FU NIH [1R01HL115275-01, UL1TR001105]; Center for Regenerative Science and Medicine; British Heart Foundation [CH/1999001/11735]; British Heart Foundation [RG/13/11/30384] Funding Source: researchfish
NR 28
TC 570
Z9 664
U1 6
U2 231
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 12
PY 2017
VL 541
IS 7636
BP 222
EP +
DI 10.1038/nature20173
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6PI
UT WOS:000396125500042
PM 27798600
DA 2026-03-09
ER

PT J
AU Aronov, D
   Nevers, R
   Tank, DW
AF Aronov, Dmitriy
   Nevers, Rhino
   Tank, David W.
TI Mapping of a non-spatial dimension by the hippocampal-entorhinal circuit
SO NATURE
LA English
DT Article
ID unit-activity; spatial map; cells; memory; representation; navigation; sequences; place; direction; space
AB During spatial navigation, neural activity in the hippocampus and the medial entorhinal cortex (MEC) is correlated to navigational variables such as location(1,2), head direction(3), speed(4), and proximity to boundaries(5). These activity patterns are thought to provide a map-like representation of physical space. However, the hippocampal-entorhinal circuit is involved not only in spatial navigation, but also in a variety of memory-guided behaviours(6). The relationship between this general function and the specialized spatial activity patterns is unclear. A conceptual framework reconciling these views is that spatial representation is just one example of a more general mechanism for encoding continuous, task-relevant variables(7-10). Here we tested this idea by recording from hippocampal and entorhinal neurons during a task that required rats to use a joystick to manipulate sound along a continuous frequency axis. We found neural representation of the entire behavioural task, including activity that formed discrete firing fields at particular sound frequencies. Neurons involved in this representation overlapped with the known spatial cell types in the circuit, such as place cells and grid cells. These results suggest that common circuit mechanisms in the hippocampal-entorhinal system are used to represent diverse behavioural tasks, possibly supporting cognitive processes beyond spatial navigation.
C1 [Aronov, Dmitriy; Nevers, Rhino; Tank, David W.] Princeton Univ, Princeton Neurosci Inst, Princeton, NJ 08544 USA.
C3 Princeton University
RP Aronov, D; Tank, DW (corresponding author), Princeton Univ, Princeton Neurosci Inst, Princeton, NJ 08544 USA.
EM da2006@columbia.edu; dwtank@princeton.edu
FU Simons Foundation; NIH [1K99NS093071]; US Federal Work-Study program
NR 39
TC 424
Z9 581
U1 4
U2 134
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 30
PY 2017
VL 543
IS 7647
BP 719
EP +
DI 10.1038/nature21692
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EP8IS
UT WOS:000397619700056
PM 28358077
DA 2026-03-09
ER

PT J
AU Ummadisingu, A
   Steier, L
   Seo, JY
   Matsui, T
   Abate, A
   Tress, W
   Grätzel, M
AF Ummadisingu, Amita
   Steier, Ludmilla
   Seo, Ji-Youn
   Matsui, Taisuke
   Abate, Antonio
   Tress, Wolfgang
   Gratzel, Michael
TI The effect of illumination on the formation of metal halide perovskite films
SO NATURE
LA English
DT Article
ID solar-cells; photovoltaic performance; crystal-growth; thin-films; kinetics; charge; pbi2
AB Optimizing the morphology of metal halide perovskite films is an important way to improve the performance of solar cells(1) when these materials are used as light harvesters(2), because film homogeneity is correlated with photovoltaic performance(3). Many device architectures and processing techniques have been explored with the aim of achieving high-performance devices(4), including single-step deposition(5), sequential deposition(6,7) and anti-solvent methods(1,8). Earlier studies have looked at the influence of reaction conditions on film quality(3), such as the concentration of the reactants9,10 and the reaction temperature(11). However, the precise mechanism of the reaction and the main factors that govern it are poorly understood. The consequent lack of control is the main reason for the large variability observed in perovskite morphology and the related solar-cell performance(2,3). Here we show that light has a strong influence on the rate of perovskite formation and on film morphology in both of the main deposition methods currently used: sequential deposition and the anti-solvent method. We study the reaction of a metal halide (lead iodide) with an organic compound (methylammonium iodide) using confocal laser scanning fluorescence microscopy and scanning electron microscopy. The lead iodide crystallizes before the intercalation of methylammonium iodide commences, producing the methylammonium lead iodide perovskite. We find that the formation of perovskite via such a sequential deposition is much accelerated by light. The influence of light on morphology is reflected in a doubling of solar-cell efficiency. Conversely, using the anti-solvent method to form methyl ammonium lead iodide perovskite in a single step from the same starting materials, we find that the best photovoltaic performance is obtained when films are produced in the dark. The discovery of light-activated crystallization not only identifies a previously unknown source of variability in opto-electronic properties, but also opens up new ways of tuning morphology and structuring perovskites for various applications.
C1 [Ummadisingu, Amita; Steier, Ludmilla; Seo, Ji-Youn; Matsui, Taisuke; Abate, Antonio; Tress, Wolfgang; Gratzel, Michael] Ecole Polytech Fed Lausanne, LPI, Inst Chem Sci & Engn, Stn 6, CH-1015 Lausanne, Switzerland.
   [Steier, Ludmilla] Imperial Coll London, Dept Chem, London SW7 2AZ, England.
   [Matsui, Taisuke] Panasonic Corp, Adv Res Div, Adv Funct Mat Res Grp, 1006 Kadoma, Kadoma, Osaka 5718501, Japan.
   [Abate, Antonio] Mat & Energie GmbH, Helmholtz Zentrum Berlin, Kekulestr 5, D-12489 Berlin, Germany.
C3 Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Imperial College London; Panasonic; Helmholtz Association; Helmholtz-Zentrum fuer Materialien und Energie GmbH (HZB)
RP Grätzel, M (corresponding author), Ecole Polytech Fed Lausanne, LPI, Inst Chem Sci & Engn, Stn 6, CH-1015 Lausanne, Switzerland.
EM michael.graetzel@epfl.ch
FU Swiss National Science Foundation [200021-157135/1]; Panasonic Corporation
NR 30
TC 284
Z9 295
U1 8
U2 782
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 11
PY 2017
VL 545
IS 7653
BP 208
EP +
DI 10.1038/nature22072
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EU3XG
UT WOS:000400963800031
PM 28445459
DA 2026-03-09
ER

PT J
AU Zhang, J
   Hess, PW
   Kyprianidis, A
   Becker, P
   Lee, A
   Smith, J
   Pagano, G
   Potirniche, ID
   Potter, AC
   Vishwanath, A
   Yao, NY
   Monroe, C
AF Zhang, J.
   Hess, P. W.
   Kyprianidis, A.
   Becker, P.
   Lee, A.
   Smith, J.
   Pagano, G.
   Potirniche, I. -D.
   Potter, A. C.
   Vishwanath, A.
   Yao, N. Y.
   Monroe, C.
TI Observation of a discrete time crystal
SO NATURE
LA English
DT Article
ID many-body localization
AB Spontaneous symmetry breaking is a fundamental concept in many areas of physics, including cosmology, particle physics and condensed matter(1). An example is the breaking of spatial translational symmetry, which underlies the formation of crystals and the phase transition from liquid to solid. Using the analogy of crystals in space, the breaking of translational symmetry in time and the emergence of a 'time crystal' was recently proposed(2,3), but was later shown to be forbidden in thermal equilibrium(4-6). However, non-equilibrium Floquet systems, which are subject to a periodic drive, can exhibit persistent time correlations at an emergent subharmonic frequency(7-10). This new phase of matter has been dubbed a 'discrete time crystal'(10). Here we present the experimental observation of a discrete time crystal, in an interacting spin chain of trapped atomic ions. We apply a periodic Hamiltonian to the system under many-body localization conditions, and observe a subharmonic temporal response that is robust to external perturbations. The observation of such a time crystal opens the door to the study of systems with long-range spatio-temporal correlations and novel phases of matter that emerge under intrinsically nonequilibrium conditions(7).
C1 [Zhang, J.; Hess, P. W.; Kyprianidis, A.; Becker, P.; Lee, A.; Smith, J.; Pagano, G.; Monroe, C.] Univ Maryland, Dept Phys, Joint Quantum Inst, College Pk, MD 20742 USA.
   [Zhang, J.; Hess, P. W.; Kyprianidis, A.; Becker, P.; Lee, A.; Smith, J.; Pagano, G.; Monroe, C.] NIST, College Pk, MD 20742 USA.
   [Potirniche, I. -D.; Vishwanath, A.; Yao, N. Y.] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Potter, A. C.] Univ Texas Austin, Dept Phys, Austin, TX 78712 USA.
   [Vishwanath, A.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.
   [Monroe, C.] IonQ Inc, College Pk, MD 20742 USA.
C3 University System of Maryland; University of Maryland College Park; National Institute of Standards & Technology (NIST) - USA; University of California System; University of California Berkeley; University of Texas System; University of Texas Austin; Harvard University
RP Zhang, J (corresponding author), Univ Maryland, Dept Phys, Joint Quantum Inst, College Pk, MD 20742 USA.; Zhang, J (corresponding author), NIST, College Pk, MD 20742 USA.
EM jiehang.zhang@gmail.com
FU ARO Atomic and Molecular Physics Program; AFOSR MURI on Quantum Measurement and Verification; IARPA LogiQ program; IC Postdoctoral Research Fellowship Program; NSF Physics Frontier Center at JQI; Miller Institute for Basic Research in Science; AFOSR MURI grant [FA9550- 14-1-0035]; Simons Investigator Program; LDRD Program of LBNL under US DOE [DE-AC02-05CH11231]; Direct For Mathematical & Physical Scien; Division Of Physics [1430094] Funding Source: National Science Foundation
NR 33
TC 931
Z9 1048
U1 15
U2 298
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 9
PY 2017
VL 543
IS 7644
BP 217
EP +
DI 10.1038/nature21413
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0GQ
UT WOS:000395688700033
PM 28277505
DA 2026-03-09
ER

PT J
AU Farr, WM
   Tevenson, SS
   Miller, MC
   Mandel, I
   Farr, B
   Vecchio, A
AF Farr, Will M.
   Tevenson, Simon S.
   Miller, M. Coleman
   Mandel, Ilya
   Farr, Ben
   Vecchio, Alberto
TI Distinguishing spin-aligned and isotropic black hole populations with gravitational waves
SO NATURE
LA English
DT Article
ID evolution; mass; misalignment
AB The direct detection of gravitational waves(1-4) from merging binary black holes opens up a window into the environments in which binary black holes form. One signature of such environments is the angular distribution of the black hole spins. Binary systems that formed through dynamical interactions between already-compact objects are expected to have isotropic spin orientations(5-9) (that is, the spins of the black holes are randomly oriented with respect to the orbit of the binary system), whereas those that formed from pairs of stars born together are more likely to have spins that are preferentially aligned with the orbit(10-14). The best-measured combination of spin parameters(3,4) for each of the four likely binary black hole detections GW150914, LVT151012, GW151226 and GW170104 is the 'effective' spin. Here we report that, if the magnitudes of the black hole spins are allowed to extend to high values, the effective spins for these systems indicate a 0.015 odds ratio against an aligned angular distribution compared to an isotropic one. When considering the effect of ten additional detections(15), this odds ratio decreases to 2.9 x 10(-7) against alignment. The existing preference for either an isotropic spin distribution or low spin magnitudes for the observed systems will be confirmed (or overturned) confidently in the near future.
C1 [Farr, Will M.; Tevenson, Simon S.; Mandel, Ilya; Vecchio, Alberto] Univ Birmingham, Birmingham Inst Gravitat Wave Astron, Birmingham B15 2TT, W Midlands, England.
   [Farr, Will M.; Tevenson, Simon S.; Mandel, Ilya; Vecchio, Alberto] Univ Birmingham, Sch Phys & Astron, Birmingham B15 2TT, W Midlands, England.
   [Tevenson, Simon S.; Mandel, Ilya] Kavli Inst Theoret Phys, Santa Barbara, CA 93106 USA.
   [Miller, M. Coleman] Univ Maryland, Dept Astron, College Pk, MD 20742 USA.
   [Miller, M. Coleman] Univ Maryland, Joint Space Sci Inst, College Pk, MD 20742 USA.
   [Farr, Ben] Univ Chicago, Enrico Fermi Inst, 5640 S Ellis Ave, Chicago, IL 60637 USA.
   [Farr, Ben] Univ Chicago, Kavli Inst Cosmol Phys, Chicago, IL 60637 USA.
C3 University of Birmingham; University of Birmingham; University System of Maryland; University of Maryland College Park; University System of Maryland; University of Maryland College Park; University of Chicago; University of Chicago
RP Farr, WM (corresponding author), Univ Birmingham, Birmingham Inst Gravitat Wave Astron, Birmingham B15 2TT, W Midlands, England.; Farr, WM (corresponding author), Univ Birmingham, Sch Phys & Astron, Birmingham B15 2TT, W Midlands, England.
EM w.farr@bham.ac.uk
FU STFC; University of Birmingham Institute for Advanced Study Distinguished Visiting Fellows programme; National Science Foundation [NSF PHY11-25915]; STFC [ST/N000633/1, ST/N000072/1] Funding Source: UKRI; Science and Technology Facilities Council [ST/N000072/1, ST/N000633/1] Funding Source: researchfish
NR 43
TC 238
Z9 268
U1 0
U2 13
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 24
PY 2017
VL 548
IS 7668
BP 426
EP +
DI 10.1038/nature23453
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FE5VI
UT WOS:000408279000032
PM 28836595
DA 2026-03-09
ER

PT J
AU Lv, BQ
   Feng, ZL
   Xu, QN
   Gao, X
   Ma, JZ
   Kong, LY
   Richard, P
   Huang, YB
   Strocov, VN
   Fang, C
   Weng, HM
   Shi, YG
   Qian, T
   Ding, H
AF Lv, B. Q.
   Feng, Z-L.
   Xu, Q. -N.
   Gao, X.
   Ma, J. -Z.
   Kong, L. -Y.
   Richard, P.
   Huang, Y. -B.
   Strocov, V. N.
   Fang, C.
   Weng, H. -M.
   Shi, Y. -G.
   Qian, T.
   Ding, H.
TI Observation of three-component fermions in the topological semimetal molybdenum phosphide
SO NATURE
LA English
DT Article
ID majorana fermions; dirac semimetal; discovery; surface
AB In quantum field theory, Lorentz invariance leads to three types of fermion-Dirac, Weyl and Majorana. Although the existence of Weyl and Majorana fermions as elementary particles in high-energy physics is debated, all three types of fermion have been proposed to exist as low-energy, long-wavelength quasiparticle excitations in condensed-matter systems(1-12). The existence of Dirac and Weyl fermions in condensed-matter systems has been confirmed experimentally(13-18), and that of Majorana fermions is supported by various experiments(19,20). However, in condensed-matter systems, fermions in crystals are constrained by the symmetries of the 230 crystal space groups rather than by Lorentz invariance, giving rise to the possibility of finding other types of fermionic excitation that have no counterparts in high-energy physics(21-29). Here we use angle-resolved photoemission spectroscopy to demonstrate the existence of a triply degenerate point in the electronic structure of crystalline molybdenum phosphide. Quasiparticle excitations near a triply degenerate point are three-component fermions, beyond the conventional Dirac-Weyl-Majorana classification, which attributes Dirac and Weyl fermions to four-and two-fold degenerate points, respectively. We also observe pairs of Weyl points in the bulk electronic structure of the crystal that coexist with the three-component fermions. This material thus represents a platform for studying the interplay between different types of fermions. Our experimental discovery opens up a way of exploring the new physics of unconventional fermions in condensed-matter systems.
C1 [Lv, B. Q.; Feng, Z-L.; Xu, Q. -N.; Gao, X.; Ma, J. -Z.; Kong, L. -Y.; Richard, P.; Fang, C.; Weng, H. -M.; Shi, Y. -G.; Qian, T.; Ding, H.] Chinese Acad Sci, Beijing Natl Lab Condensed Matter Phys, Beijing 100190, Peoples R China.
   [Lv, B. Q.; Feng, Z-L.; Xu, Q. -N.; Gao, X.; Ma, J. -Z.; Kong, L. -Y.; Richard, P.; Fang, C.; Weng, H. -M.; Shi, Y. -G.; Qian, T.; Ding, H.] Chinese Acad Sci, Inst Phys, Beijing 100190, Peoples R China.
   [Lv, B. Q.; Feng, Z-L.; Xu, Q. -N.; Gao, X.; Ma, J. -Z.; Kong, L. -Y.; Richard, P.; Ding, H.] Univ Chinese Acad Sci, Beijing 100049, Peoples R China.
   [Richard, P.; Weng, H. -M.; Qian, T.; Ding, H.] Collaborat Innovat Ctr Quantum Matter, Beijing, Peoples R China.
   [Huang, Y. -B.] Chinese Acad Sci, Shanghai Inst Appl Phys, Shanghai Synchrotron Radiat Facil, Shanghai 201204, Peoples R China.
   [Strocov, V. N.] Paul Scherrer Inst, Swiss Light Source, CH-5232 Villigen, Switzerland.
C3 Chinese Academy of Sciences; Chinese Academy of Sciences; Institute of Physics, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Peking University; Tsinghua University; Collaborative Innovation Center of Quantum Matter; Chinese Academy of Sciences; Shanghai Institute of Applied Physics, CAS; Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute
RP Shi, YG; Qian, T; Ding, H (corresponding author), Chinese Acad Sci, Beijing Natl Lab Condensed Matter Phys, Beijing 100190, Peoples R China.; Shi, YG; Qian, T; Ding, H (corresponding author), Chinese Acad Sci, Inst Phys, Beijing 100190, Peoples R China.; Ding, H (corresponding author), Univ Chinese Acad Sci, Beijing 100049, Peoples R China.; Qian, T; Ding, H (corresponding author), Collaborat Innovat Ctr Quantum Matter, Beijing, Peoples R China.
EM ygshi@iphy.ac.cn; tqian@iphy.ac.cn; dingh@iphy.ac.cn
FU National Natural Science Foundation of China [11622435, 11474330, 11422428, 11674369, 11474340, 11674371, 11234014]; Ministry of Science and Technology of China [2016YFA0401000, 2016YFA0300600, 2015CB921300, 2013CB921700, 2016YFA0302400, 2016YFA0300300]; Chinese Academy of Sciences [XDB07000000]; CAS Pioneer 'Hundred Talents Program'
NR 34
TC 318
Z9 356
U1 5
U2 382
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 29
PY 2017
VL 546
IS 7660
BP 627
EP +
DI 10.1038/nature22390
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EY9QB
UT WOS:000404332000042
PM 28628922
DA 2026-03-09
ER

PT J
AU Jih, G
   Iglesias, N
   Currie, MA
   Bhanu, NV
   Paulo, JA
   Gygi, SP
   Garcia, BA
   Moazed, D
AF Jih, Gloria
   Iglesias, Nahid
   Currie, Mark A.
   Bhanu, Natarajan V.
   Paulo, Joao A.
   Gygi, Steven P.
   Garcia, Benjamin A.
   Moazed, Danesh
TI Unique roles for histone H3K9me states in RNAi and heritable silencing of transcription
SO NATURE
LA English
DT Article
ID decoy search strategy; protein-phosphorylation; epigenetic inheritance; product specificity; heterochromatin; chromatin; complex; rits; h3; interference
AB Heterochromatic DNA domains have important roles in the regulation of gene expression and maintenance of genome stability by silencing repetitive DNA elements and transposons. From fission yeast to mammals, heterochromatin assembly at DNA repeats involves the activity of small noncoding RNAs (sRNAs) associated with the RNA interference (RNAi) pathway(1-9). Typically, sRNAs, originating from long noncoding RNAs, guide Argonaute-containing effector complexes to complementary nascent RNAs to initiate histone H3 lysine 9 di- and trimethylation (H3K9me2 and H3K9me3, respectively) and the formation of heterochromatin(10-17). H3K9me is in turn required for the recruitment of RNAi to chromatin to promote the amplification of sRNA(11,15,18). Yet, how heterochromatin formation, which silences transcription, can proceed by a co-transcriptional mechanism that also promotes sRNA generation remains paradoxical. Here, using Clr4, the fission yeast Schizosaccharomyces pombe homologue of mammalian SUV39H H3K9 methyltransferases, we design active-site mutations that block H3K9me3, but allow H3K9me2 catalysis. We show that H3K9me2 defines a functionally distinct heterochromatin state that is sufficient for RNAi-dependent co-transcriptional gene silencing at pericentromeric DNA repeats. Unlike H3K9me3 domains, which are transcriptionally silent, H3K9me2 domains are transcriptionally active, contain modifications associated with euchromatic transcription, and couple RNAi-mediated transcript degradation to the establishment of H3K9me domains. The two H3K9me states recruit reader proteins with different efficiencies, explaining their different downstream silencing functions. Furthermore, the transition from H3K9me2 to H3K9me3 is required for RNAi-independent epigenetic inheritance of H3K9me domains. Our findings demonstrate that H3K9me2 and H3K9me3 define functionally distinct chromatin states and uncover a mechanism for the formation of transcriptionally permissive heterochromatin that is compatible with its broadly conserved role in sRNA-mediated genome defence.
C1 [Jih, Gloria; Iglesias, Nahid; Currie, Mark A.; Paulo, Joao A.; Gygi, Steven P.; Moazed, Danesh] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
   [Jih, Gloria; Iglesias, Nahid; Currie, Mark A.; Moazed, Danesh] Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA.
   [Bhanu, Natarajan V.; Garcia, Benjamin A.] Univ Penn, Dept Biochem & Biophys, Epigenet Program, Perelman Sch Med, Philadelphia, PA 19104 USA.
C3 Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Harvard University; Harvard Medical School; University of Pennsylvania
RP Moazed, D (corresponding author), Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.; Moazed, D (corresponding author), Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA.
EM danesh@hms.harvard.edu
FU NIH [T32 GM007226, RO1 GM072805, K01 DK098285, RO1 GM110174]; EMBO long-term fellowship; Swiss National Science Foundation; National Cancer Institute [P01CA196539] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM072805, T32GM007226] Funding Source: NIH RePORTER
NR 44
TC 92
Z9 126
U1 1
U2 54
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 27
PY 2017
VL 547
IS 7664
BP 463
EP +
DI 10.1038/nature23267
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB7ZK
UT WOS:000406358300038
PM 28682306
DA 2026-03-09
ER

PT J
AU Sengupta, A
   Carrara, F
   Stocker, R
AF Sengupta, Anupam
   Carrara, Francesco
   Stocker, Roman
TI Phytoplankton can actively diversify their migration strategy in response to turbulent cues
SO NATURE
LA English
DT Article
ID vertical migration; nitric-oxide; harmful; morphology; selection; motility
AB Marine phytoplankton inhabit a dynamic environment where turbulence, together with nutrient and light availability, shapes species fitness, succession and selection(1,2). Many species of phytoplankton are motile and undertake diel vertical migrations to gain access to nutrient-rich deeper layers at night and well-lit surface waters during the day(3,4). Disruption of this migratory strategy by turbulence is considered to be an important cause of the succession between motile and non-motile species when conditions turn turbulent(1,5,)6. However, this classical view neglects the possibility that motile species may actively respond to turbulent cues to avoid layers of strong turbulence(7). Here we report that phytoplankton, including raphidophytes and dinoflagellates, can actively diversify their migratory strategy in response to hydrodynamic cues characteristic of overturning by Kolmogorov-scale eddies. Upon experiencing repeated overturning with timescales and statistics representative of ocean turbulence, an upward-swimming population rapidly (5-60 min) splits into two subpopulations, one swimming upward and one swimming downward. Quantitative morphological analysis of the harmful-algal-bloom-forming raphidophyte Heterosigma akashiwo together with a model of cell mechanics revealed that this behaviour was accompanied by a modulation of the cells' fore-aft asymmetry. The minute magnitude of the required modulation, sufficient to invert the preferential swimming direction of the cells, highlights the advanced level of control that phytoplankton can exert on their migratory behaviour. Together with observations of enhanced cellular stress after overturning and the typically deleterious effects of strong turbulence on motile phytoplankton(5,8), these results point to an active adaptation of H. akashiwo to increase the chance of evading turbulent layers by diversifying the direction of migration within the population, in a manner suggestive of evolutionary bet-hedging. This migratory behaviour relaxes the boundaries between the fluid dynamic niches of motile and non-motile phytoplankton, and highlights that rapid responses to hydrodynamic cues are important survival strategies for phytoplankton in the ocean.
C1 [Sengupta, Anupam; Carrara, Francesco; Stocker, Roman] Swiss Fed Inst Technol, Inst Environm Engn, Dept Civil Environm & Geomat Engn, CH-8093 Zurich, Switzerland.
   [Sengupta, Anupam; Carrara, Francesco; Stocker, Roman] MIT, Dept Civil & Environm Engn, Ralph M Parsons Lab, Cambridge, MA 02139 USA.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich; Massachusetts Institute of Technology (MIT)
RP Stocker, R (corresponding author), Swiss Fed Inst Technol, Inst Environm Engn, Dept Civil Environm & Geomat Engn, CH-8093 Zurich, Switzerland.; Stocker, R (corresponding author), MIT, Dept Civil & Environm Engn, Ralph M Parsons Lab, Cambridge, MA 02139 USA.
EM romanstocker@ethz.ch
FU Human Frontier Science Program Cross Disciplinary Fellowship [LT000993/2014-C]; Swiss National Science Foundation; Gordon and Betty Moore Marine Microbial Initiative [GBMF 3783]
NR 39
TC 131
Z9 149
U1 4
U2 219
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 23
PY 2017
VL 543
IS 7646
BP 555
EP +
DI 10.1038/nature21415
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EO9OM
UT WOS:000397018000052
PM 28297706
DA 2026-03-09
ER

PT J
AU Runyan, CA
   Piasini, E
   Panzeri, S
   Harvey, CD
AF Runyan, Caroline A.
   Piasini, Eugenio
   Panzeri, Stefano
   Harvey, Christopher D.
TI Distinct timescales of population coding across cortex
SO NATURE
LA English
DT Article
ID parietal cortex; spatial navigation; auditory-cortex; neural basis; decision; dynamics; information; neurons; motion; code
AB The cortex represents information across widely varying timescales(1-5). For instance, sensory cortex encodes stimuli that fluctuate over few tens of milliseconds(6,7), whereas in association cortex behavioural choices can require the maintenance of information over seconds(8,9). However, it remains poorly understood whether diverse timescales result mostly from features intrinsic to individual neurons or from neuronal population activity. This question remains unanswered, because the timescales of coding in populations of neurons have not been studied extensively, and population codes have not been compared systematically across cortical regions. Here we show that population codes can be essential to achieve long coding timescales. Furthermore, we find that the properties of population codes differ between sensory and association cortices. We compared coding for sensory stimuli and behavioural choices in auditory cortex and posterior parietal cortex as mice performed a sound localization task. Auditory stimulus information was stronger in auditory cortex than in posterior parietal cortex, and both regions contained choice information. Although auditory cortex and posterior parietal cortex coded information by tiling in time neurons that were transiently informative for approximately 200 milliseconds, the areas had major differences in functional coupling between neurons, measured as activity correlations that could not be explained by task events. Coupling among posterior parietal cortex neurons was strong and extended over long time lags, whereas coupling among auditory cortex neurons was weak and short-lived. Stronger coupling in posterior parietal cortex led to a population code with long timescales and a representation of choice that remained consistent for approximately 1 second. In contrast, auditory cortex had a code with rapid fluctuations in stimulus and choice information over hundreds of milliseconds. Our results reveal that population codes differ across cortex and that coupling is a variable property of cortical populations that affects the timescale of information coding and the accuracy of behaviour.
C1 [Runyan, Caroline A.; Harvey, Christopher D.] Harvard Med Sch, Dept Neurobiol, Boston, MA 02115 USA.
   [Piasini, Eugenio; Panzeri, Stefano] Ist Italiano Tecnol, Neural Computat Lab, I-38068 Rovereto, Italy.
C3 Harvard University; Harvard Medical School; Istituto Italiano di Tecnologia - IIT
RP Harvey, CD (corresponding author), Harvard Med Sch, Dept Neurobiol, Boston, MA 02115 USA.; Panzeri, S (corresponding author), Ist Italiano Tecnol, Neural Computat Lab, I-38068 Rovereto, Italy.
EM stefano.panzeri@iit.it; harvey@hms.harvard.edu
FU Burroughs-Wellcome Fund Career Award at the Scientific Interface; Searle Scholars Program; New York Stem Cell Foundation; Armenise-Harvard Foundation; Alfred P. Sloan Research Foundation; NARSAD; National Institutes of Health from National Institute of Mental Health BRAINS program [R01-MH107620]; National Institute of Neurological Disorders and Stroke [R01-NS089521]; Autonomous Province of Trento (Grandi Progetti ATTEND); Fondation Bertarelli; National Eye Institute [P30EY012196] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [R01NS089521] Funding Source: NIH RePORTER
NR 44
TC 240
Z9 290
U1 0
U2 39
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 3
PY 2017
VL 548
IS 7665
BP 92
EP +
DI 10.1038/nature23020
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FC4SU
UT WOS:000406831700043
PM 28723889
DA 2026-03-09
ER

PT J
AU Kabe, R
   Adachi, C
AF Kabe, Ryota
   Adachi, Chihaya
TI Organic long persistent luminescence
SO NATURE
LA English
DT Article
ID charge-transfer states; dopant chromophore; polymer solids; recombination; photoionization; ionization; molecules; lifetime
AB Long persistent luminescence (LPL) materials-widely commercialized as 'glow-in-the-dark' paints-store excitation energy in excited states that slowly release this energy as light(1). At present, most LPL materials are based on an inorganic system of strontium aluminium oxide (SrAl2O4) doped with europium and dysprosium, and exhibit emission for more than ten hours(2). However, this system requires rare elements and temperatures higher than 1,000 degrees Celsius during fabrication, and light scattering by SrAl2O4 powders limits the transparency of LPL paints(1). Here we show that an organic LPL (OLPL) system of two simple organic molecules that is free from rare elements and easy to fabricate can generate emission that lasts for more than one hour at room temperature. Previous organic systems, which were based on two-photon ionization, required high excitation intensities and low temperatures(3). By contrast, our OLPL system-which is based on emission from excited complexes (exciplexes) upon the recombination of long-lived charge-separated states-can be excited by a standard white LED light source and generate long emission even at temperatures above 100 degrees Celsius. This OLPL system is transparent, soluble, and potentially flexible and colour-tunable, opening new applications for LPL in large-area and flexible paints, biomarkers, fabrics, and windows. Moreover, the study of long-lived charge separation in this system should advance understanding of a wide variety of organic semiconductor devices(4).
C1 [Kabe, Ryota; Adachi, Chihaya] Kyushu Univ, Ctr Organ Photon & Elect Res OPERA, Nishi Ku, 744 Motooka, Fukuoka 8190395, Japan.
   [Kabe, Ryota; Adachi, Chihaya] Kyushu Univ, Adachi Mol Exciton Engn Project, ERATO, JST,Nishi Ku, Fukuoka 8190395, Japan.
   [Adachi, Chihaya] Kyushu Univ, Int Inst Carbon Neutral Energy Res WPI I2CNER, Nishi Ku, 744 Motooka, Fukuoka 8190395, Japan.
C3 Kyushu University; Japan Science & Technology Agency (JST); Kyushu University; Kyushu University
RP Kabe, R; Adachi, C (corresponding author), Kyushu Univ, Ctr Organ Photon & Elect Res OPERA, Nishi Ku, 744 Motooka, Fukuoka 8190395, Japan.; Kabe, R; Adachi, C (corresponding author), Kyushu Univ, Adachi Mol Exciton Engn Project, ERATO, JST,Nishi Ku, Fukuoka 8190395, Japan.; Adachi, C (corresponding author), Kyushu Univ, Int Inst Carbon Neutral Energy Res WPI I2CNER, Nishi Ku, 744 Motooka, Fukuoka 8190395, Japan.
EM kabe@opera.kyushu-u.ac.jp; adachi@cstf.kyushu-u.ac.jp
FU Japan Science and Technology Agency (JST); Exploratory Research for Advanced Technology (ERATO) program; Adachi Molecular Exciton Engineering Project, under JST ERATO grant [JPMJER1305]; International Institute for Carbon Neutral Energy Research (WPI-I2CNER) - Ministry of Education, Culture, Sports, Science and Technology (MEXT); MEXT/Japan Society for the Promotion of Science (JSPS) KAKENHI grant [JP 15K21220]
NR 21
TC 1020
Z9 1083
U1 33
U2 918
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 19
PY 2017
VL 550
IS 7676
BP 384
EP 387
DI 10.1038/nature24010
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK1NF
UT WOS:000413247900058
PM 28967911
DA 2026-03-09
ER

PT J
AU Naik, S
   Larsen, SB
   Gomez, NC
   Alaverdyan, K
   Sendoel, A
   Yuan, SP
   Polak, L
   Kulukian, A
   Hai, SC
   Fuchs, E
AF Naik, Shruti
   Larsen, Samantha B.
   Gomez, Nicholas C.
   Alaverdyan, Kirill
   Sendoel, Ataman
   Yuan, Shaopeng
   Polak, Lisa
   Kulukian, Anita
   Chai, Sophia
   Fuchs, Elaine
TI Inflammatory memory sensitizes skin epithelial stem cells to tissue damage
SO NATURE
LA English
DT Article
ID aim2 inflammasome; wound repair; cancer; model; rna
AB The skin barrier is the body's first line of defence against environmental assaults, and is maintained by epithelial stem cells (EpSCs). Despite the vulnerability of EpSCs to inflammatory pressures, neither the primary response to inflammation nor its enduring consequences are well understood. Here we report a prolonged memory to acute inflammation that enables mouse EpSCs to hasten barrier restoration after subsequent tissue damage. This functional adaptation does not require skin-resident macrophages or T cells. Instead, EpSCs maintain chromosomal accessibility at key stress response genes that are activated by the primary stimulus. Upon a secondary challenge, genes governed by these domains are transcribed rapidly. Fuelling this memory is Aim2, which encodes an activator of the inflammasome. The absence of AIM2 or its downstream effectors, caspase-1 and interleukin-1 beta, erases the ability of EpSCs to recollect inflammation. Although EpSCs benefit from inflammatory tuning by heightening their responsiveness to subsequent stressors, this enhanced sensitivity probably increases their susceptibility to autoimmune and hyperproliferative disorders, including cancer.
C1 [Naik, Shruti; Larsen, Samantha B.; Gomez, Nicholas C.; Alaverdyan, Kirill; Sendoel, Ataman; Yuan, Shaopeng; Polak, Lisa; Kulukian, Anita; Chai, Sophia; Fuchs, Elaine] Rockefeller Univ, Howard Hughes Med Inst, Robin Chemers Neustein Lab Mammalian Cell Biol &, New York, NY 10065 USA.
C3 Rockefeller University; Howard Hughes Medical Institute
RP Naik, S; Fuchs, E (corresponding author), Rockefeller Univ, Howard Hughes Med Inst, Robin Chemers Neustein Lab Mammalian Cell Biol &, New York, NY 10065 USA.
EM snaik@rockefeller.edu; fuchslb@rockefeller.edu
FU Damon Runyon Cancer Research Foundation [DRG-2183-14]; L'Oreal USA For Women in Science; National Institutes of Health (NIH) [F31-AR068920-01A1]; People Programme Marie Curie Actions [629861]; Robertson Foundation; National Psoriasis Foundation [CEN5402062]; Pfizer [WI206828]; NIH [R01-AR31737, R01-AR050452]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR050452, R01AR031737] Funding Source: NIH RePORTER
NR 47
TC 532
Z9 633
U1 5
U2 182
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 26
PY 2017
VL 550
IS 7677
BP 475
EP +
DI 10.1038/nature24271
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FK7OW
UT WOS:000413697800034
PM 29045388
DA 2026-03-09
ER

PT J
AU Lim, JY
   Marshall, CR
AF Lim, Jun Y.
   Marshall, Charles R.
TI The true tempo of evolutionary radiation and decline revealed on the Hawaiian archipelago
SO NATURE
LA English
DT Article
ID oceanic island biogeography; species-area relationship; sp n. coleoptera; adaptive radiation; molecular phylogeny; volcano growth; fossil record; conveyor belt; carabidae; diversification
AB Establishing the relationship between rates of change in species richness and biotic and abiotic environmental change is a major goal of evolutionary biology. Although exquisite fossil and geological records provide insight in rare cases(1), most groups lack high-quality fossil records. Consequently, biologists typically rely on molecular phylogenies to study the diversity dynamics of clades, usually by correlating changes in diversification rate with environmental or trait shifts(2-6). However, inferences drawn from molecular phylogenies can be limited owing to the challenge of accounting for extinct species, making it difficult(7-9) to accurately determine the underlying diversity dynamics that produce them. Here, using a geologically informed model of the relationship between changing island area and species richness for the Hawaiian archipelago, we infer the rates of species richness change for 14 endemic groups over their entire evolutionary histories without the need for fossil data, or molecular phylogenies. We find that these endemic clades underwent evolutionary radiations characterized by initially increasing rates of species accumulation, followed by slow-downs. In fact, for most groups on most islands, their time of evolutionary expansion has long past, and they are now undergoing previously unrecognized long-term evolutionary decline. Our results show how landscape dynamism can drive evolutionary dynamics over broad timescales(10), including driving species loss that is not readily detected using molecular phylogenies, or without a rich fossil record(11). We anticipate that examination of other clades where the relationship between environmental change and species richness change can be quantified will reveal that many other living groups have also experienced similarly complex evolutionary trajectories, including long-term and ongoing evolutionary decline.
C1 [Lim, Jun Y.; Marshall, Charles R.] Univ Calif Berkeley, Dept Integrat Biol, 3040 Valley Life Sci Bldg, Berkeley, CA 94720 USA.
   [Lim, Jun Y.; Marshall, Charles R.] Univ Calif Berkeley, Univ Calif Museum Paleontol, 1101 Valley Life Sci Bldg, Berkeley, CA 94720 USA.
C3 University of California System; University of California Berkeley; University of California System; University of California Berkeley
RP Lim, JY; Marshall, CR (corresponding author), Univ Calif Berkeley, Dept Integrat Biol, 3040 Valley Life Sci Bldg, Berkeley, CA 94720 USA.; Lim, JY; Marshall, CR (corresponding author), Univ Calif Berkeley, Univ Calif Museum Paleontol, 1101 Valley Life Sci Bldg, Berkeley, CA 94720 USA.
EM junyinglim@berkeley.edu; crmarshall@berkeley.edu
NR 71
TC 59
Z9 71
U1 0
U2 68
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 30
PY 2017
VL 543
IS 7647
BP 710
EP +
DI 10.1038/nature21675
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EP8IS
UT WOS:000397619700054
PM 28297717
DA 2026-03-09
ER

PT J
AU Kim, J
   Bowlby, R
   Mungall, AJ
   Robertson, AG
   Odze, RD
   Cherniack, AD
   Shih, J
   Pedamallu, CS
   Cibulskis, C
   Dunford, A
   Meier, SR
   Kim, J
   Raphael, BJ
   Wu, HT
   Wong, AM
   Willis, JE
   Bass, AJ
   Derks, S
   Garman, K
   McCall, SJ
   Wiznerowicz, M
   Pantazi, A
   Parfenov, M
   Thorsson, V
   Shmulevich, I
   Dhankani, V
   Miller, M
   Sakai, R
   Wang, K
   Schultz, N
   Shen, R
   Arora, A
   Weinhold, N
   Sanchez-Vega, F
   Kelsen, DP
   Zhang, J
   Felau, I
   Demchok, J
   Rabkin, CS
   Camargo, MC
   Zenklusen, JC
   Bowen, J
   Leraas, K
   Lichtenberg, TM
   Curtis, C
   Seoane, JA
   Ojesina, AI
   Beer, DG
   Gulley, ML
   Pennathur, A
   Luketich, JD
   Zhou, ZR
   Weisenberger, DJ
   Akbani, R
   Lee, JS
   Liu, W
   Mills, GB
   Zhang, W
   Reid, BJ
   Hinoue, T
   Laird, PW
   Shen, H
   Piazuelo, MB
   Schneider, BG
   McLellan, M
   Taylor-Weiner, A
   Cibulskis, C
   Lawrence, M
   Cibulskis, K
   Stewart, C
   Getz, G
   Lander, E
   Gabriel, SB
   Ding, L
   McLellan, MD
   Miller, CA
   Appelbaum, EL
   Cordes, MG
   Fronick, CC
   Fulton, LA
   Mardis, ER
   Wilson, RK
   Schmidt, HK
   Fulton, RS
   Ally, A
   Balasundaram, M
   Bowlby, R
   Carlsen, R
   Chuah, E
   Dhalla, N
   Holt, RA
   Jones, SJM
   Kasaian, K
   Brooks, D
   Li, HI
   Ma, Y
   Marra, MA
   Mayo, M
   Moore, RA
   Mungall, AJ
   Mungall, KL
   Robertson, AG
   Schein, JE
   Sipahimalani, P
   Tam, A
   Thiessen, N
   Wong, T
   Cherniack, AD
   Shih, J
   Pedamallu, CS
   Beroukhim, R
   Bullman, S
   Cibulskis, C
   Murray, BA
   Saksena, G
   Schumacher, SE
   Gabriel, S
   Meyerson, M
   Hadjipanayis, A
   Kucherlapati, R
   Pantazi, A
   Parfenov, M
   Ren, X
   Park, PJ
   Lee, S
   Kucherlapati, M
   Yang, LX
   Baylin, SB
   Hoadley, KA
   Weisenberger, DJ
   Bootwalla, MS
   Lai, PH
   Van den Berg, DJ
   Berrios, M
   Holbrook, A
   Akbani, R
   Hwang, JE
   Jang, HJ
   Liu, WB
   Weinstein, JN
   Lee, JS
   Lu, YL
   Sohn, BH
   Mills, G
   Seth, S
   Protopopov, A
   Bristow, CA
   Mahadeshwar, HS
   Tang, JB
   Song, XZ
   Zhang, JH
   Laird, PW
   Hinoue, T
   Shen, H
   Cho, J
   Defrietas, T
   Frazer, S
   Gehlenborg, N
   Heiman, DI
   Lawrence, MS
   Lin, P
   Meier, SR
   Noble, MS
   Voet, D
   Zhang, HL
   Kim, J
   Polak, P
   Saksena, G
   Chin, L
   Getz, G
   Wong, AM
   Raphael, BJ
   Wu, HT
   Lee, S
   Park, PJ
   Yang, LX
   Thorsson, V
   Bernard, B
   Iype, L
   Miller, M
   Reynolds, SM
   Shmulevich, I
   Dhankani, V
   Abeshouse, A
   Arora, A
   Armenia, J
   Kundra, R
   Ladanyi, M
   Kjong-Van Lehmann
   Gao, J
   Sander, C
   Schultz, N
   Sánchez-Vega, F
   Shen, RL
   Weinhold, N
   Chakravarty, D
   Zhang, HX
   Radenbaugh, A
   Hegde, A
   Akbani, R
   Liu, WB
   Weinstein, JN
   Chin, L
   Bristow, CA
   Lu, YL
   Penny, R
   Crain, D
   Gardner, J
   Curley, E
   Mallery, D
   Morris, S
   Paulauskis, J
   Shelton, T
   Shelton, C
   Bowen, J
   Frick, J
   Gastier-Foster, JM
   Gerken, M
   Leraas, KM
   Lichtenberg, TM
   Ramirez, NC
   Wise, L
   Zmuda, E
   Tarvin, K
   Saller, C
   Park, YS
   Button, M
   Carvalho, AL
   Reis, RM
   Matsushita, MM
   Lucchesi, F
   de Oliveira, AT
   Le, X
   Paklina, O
   Setdikova, G
   Lee, JH
   Bennett, J
   Iacocca, M
   Huelsenbeck-Dill, L
   Potapova, CO
   Voronina, O
   Liu, O
   Fulidou, V
   Cates, C
   Sharp, A
   Behera, M
   Force, S
   Khuri, F
   Owonikoko, T
   Pickens, A
   Ramalingam, S
   Sica, G
   Dinjens, W
   van Nistelrooij, A
   Wijnhoven, B
   Sandusky, G
   Stepa, S
   Crain, D
   Paulauskis, J
   Penny, R
   Gardner, J
   Mallery, D
   Morris, S
   Shelton, T
   Shelton, C
   Curley, E
   Juhl, IH
   Zornig, C
   Kwon, SY
   Kelsen, D
   Kim, GHK
   Bartlett, J
   Parfitt, J
   Chetty, R
   Darling, G
   Knox, J
   Wong, R
   El-Zimaity, H
   Liu, G
   Boussioutas, A
   Park, DY
   Kemp, R
   Carlotti, CG
   Tirapelli, DPD
   Saggioro, FP
   Sankarankutty, AK
   Noushmehr, H
   dos Santos, JS
   Trevisan, FA
   Eschbacher, J
   Eschbacher, J
   Dubina, M
   Mozgovoy, E
   Carey, F
   Chalmers, S
   Forgie, I
   Godwin, A
   Reilly, C
   Madan, R
   Naima, Z
   Ferrer-Torres, D
   Vinco, M
   Dhir, R
   Luketich, J
   Pennathur, A
   Ajani, JA
   McCall, SJ
   Janjigian, Y
   Kelsen, D
   Ladanyi, M
   Tang, L
   Camargo, MC
   Ajani, JA
   Cheong, JH
   Chudamani, S
   Liu, J
   Lolla, L
   Naresh, R
   Pihl, T
   Sun, Q
   Wan, YH
   Wu, Y
   Demchok, JA
   Felau, I
   Ferguson, ML
   Shaw, KRM
   Sheth, M
   Tarnuzzer, R
   Wang, ZN
   Yang, LM
   Zenklusen, JC
   Hutter, CM
   Sofia, HJ
   Zhang, JS
AF Kim, Jihun
   Bowlby, Reanne
   Mungall, Andrew J.
   Robertson, A. Gordon
   Odze, Robert D.
   Cherniack, Andrew D.
   Shih, Juliann
   Pedamallu, Chandra Sekhar
   Cibulskis, Carrie
   Dunford, Andrew
   Meier, Samuel R.
   Kim, Jaegil
   Raphael, Benjamin J.
   Wu, Hsin-Ta
   Wong, Alexandra M.
   Willis, Joseph E.
   Bass, Adam J.
   Derks, Sarah
   Garman, Katherine
   McCall, Shannon J.
   Wiznerowicz, Maciej
   Pantazi, Angeliki
   Parfenov, Michael
   Thorsson, Vesteinn
   Shmulevich, Ilya
   Dhankani, Varsha
   Miller, Michael
   Sakai, Ryo
   Wang, Kenneth
   Schultz, Nikolaus
   Shen, Ronglai
   Arora, Arshi
   Weinhold, Nils
   Sanchez-Vega, Francisco
   Kelsen, David P.
   Zhang, Julia
   Felau, Ina
   Demchok, John
   Rabkin, Charles S.
   Camargo, M. Constanza
   Zenklusen, Jean Claude
   Bowen, Jay
   Leraas, Kristen
   Lichtenberg, Tara M.
   Curtis, Christina
   Seoane, Jose A.
   Ojesina, Akinyemi I.
   Beer, David G.
   Gulley, Margaret L.
   Pennathur, Arjun
   Luketich, James D.
   Zhou, Zhongren
   Weisenberger, Daniel J.
   Akbani, Rehan
   Lee, Ju-Seog
   Liu, Wenbin
   Mills, Gordon B.
   Zhang, Wei
   Reid, Brian J.
   Hinoue, Toshinori
   Laird, Peter W.
   Shen, Hui
   Piazuelo, M. Blanca
   Schneider, Barbara G.
   McLellan, Michael
   Taylor-Weiner, Amaro
   Cibulskis, Carrie
   Lawrence, Michael
   Cibulskis, Kristian
   Stewart, Chip
   Getz, Gad
   Lander, Eric
   Gabriel, Stacey B.
   Ding, Li
   McLellan, Michael D.
   Miller, Christopher A.
   Appelbaum, Elizabeth L.
   Cordes, Matthew G.
   Fronick, Catrina C.
   Fulton, Lucinda A.
   Mardis, Elaine R.
   Wilson, Richard K.
   Schmidt, Heather K.
   Fulton, Robert S.
   Ally, Adrian
   Balasundaram, Miruna
   Bowlby, Reanne
   Carlsen, Rebecca
   Chuah, Eric
   Dhalla, Noreen
   Holt, Robert A.
   Jones, Steven J. M.
   Kasaian, Katayoon
   Brooks, Denise
   Li, Haiyan I.
   Ma, Yussanne
   Marra, Marco A.
   Mayo, Michael
   Moore, Richard A.
   Mungall, Andrew J.
   Mungall, Karen L.
   Robertson, A. Gordon
   Schein, Jacqueline E.
   Sipahimalani, Payal
   Tam, Angela
   Thiessen, Nina
   Wong, Tina
   Cherniack, Andrew D.
   Shih, Juliann
   Pedamallu, Chandra Sekhar
   Beroukhim, Rameen
   Bullman, Susan
   Cibulskis, Carrie
   Murray, Bradley A.
   Saksena, Gordon
   Schumacher, Steven E.
   Gabriel, Stacey
   Meyerson, Matthew
   Hadjipanayis, Angela
   Kucherlapati, Raju
   Pantazi, Angeliki
   Parfenov, Michael
   Ren, Xiaojia
   Park, Peter J.
   Lee, Semin
   Kucherlapati, Melanie
   Yang, Lixing
   Baylin, Stephen B.
   Hoadley, Katherine A.
   Weisenberger, Daniel J.
   Bootwalla, Moiz S.
   Lai, Phillip H.
   Van den Berg, David J.
   Berrios, Mario
   Holbrook, Andrea
   Akbani, Rehan
   Hwang, Jun-Eul
   Jang, Hee-Jin
   Liu, Wenbin
   Weinstein, John N.
   Lee, Ju-Seog
   Lu, Yiling
   Sohn, Bo Hwa
   Mills, Gordon
   Seth, Sahil
   Protopopov, Alexei
   Bristow, Christopher A.
   Mahadeshwar, Harshad S.
   Tang, Jiabin
   Song, Xingzhi
   Zhang, Jianhua
   Laird, Peter W.
   Hinoue, Toshinori
   Shen, Hui
   Cho, Juok
   Defrietas, Timothy
   Frazer, Scott
   Gehlenborg, Nils
   Heiman, David I.
   Lawrence, Michael S.
   Lin, Pei
   Meier, Samuel R.
   Noble, Michael S.
   Doug Voet
   Zhang, Hailei
   Kim, Jaegil
   Polak, Paz
   Saksena, Gordon
   Chin, Lynda
   Getz, Gad
   Wong, Alexandra M.
   Raphael, Benjamin J.
   Wu, Hsin-Ta
   Lee, Semin
   Park, Peter J.
   Yang, Lixing
   Thorsson, Vesteinn
   Bernard, Brady
   Iype, Lisa
   Miller, Michael
   Reynolds, Sheila M.
   Shmulevich, Ilya
   Dhankani, Varsha
   Abeshouse, Adam
   Arora, Arshi
   Armenia, Joshua
   Kundra, Ritika
   Ladanyi, Marc
   Kjong-Van Lehmann
   Gao, Jianjiong
   Sander, Chris
   Schultz, Nikolaus
   Sanchez-Vega, Francisco
   Shen, Ronglai
   Weinhold, Nils
   Chakravarty, Debyani
   Zhang, Hongxin
   Radenbaugh, Amie
   Hegde, Apruva
   Akbani, Rehan
   Liu, Wenbin
   Weinstein, John N.
   Chin, Lynda
   Bristow, Christopher A.
   Lu, Yiling
   Penny, Robert
   Crain, Daniel
   Gardner, Johanna
   Curley, Erin
   Mallery, David
   Morris, Scott
   Paulauskis, Joseph
   Shelton, Troy
   Shelton, Candace
   Bowen, Jay
   Frick, Jessica
   Gastier-Foster, Julie M.
   Gerken, Mark
   Leraas, Kristen M.
   Lichtenberg, Tara M.
   Ramirez, Nilsa C.
   Wise, Lisa
   Zmuda, Erik
   Tarvin, Katherine
   Saller, Charles
   Park, Young Soo
   Button, Michael
   Carvalho, Andre L.
   Reis, Rui Manuel
   Matsushita, Marcus Medeiros
   Lucchesi, Fabiano
   de Oliveira, Antonio Talvane
   Le, Xuan
   Paklina, Oxana
   Setdikova, Galiya
   Lee, Jae-Hyuck
   Bennett, Joseph
   Iacocca, Mary
   Huelsenbeck-Dill, Lori
   Potapova, Cureline Olga
   Voronina, Olga
   Liu, Ouida
   Fulidou, Victoria
   Cates, Crystal
   Sharp, Alexis
   Behera, Madhusmitara
   Force, Seth
   Khuri, Fadio
   Owonikoko, Taofeek
   Pickens, Allan
   Ramalingam, Suresh
   Sica, Gabriel
   Dinjens, Winand
   van Nistelrooij, Anna
   Wijnhoven, Bas
   Sandusky, George
   Stepa, Serghei
   Crain, Daniel
   Paulauskis, Joseph
   Penny, Robert
   Gardner, Johanna
   Mallery, David
   Morris, Scott
   Shelton, Troy
   Shelton, Candace
   Curley, Erin
   Juhl, Invidumed Hartmut
   Zornig, Carsten
   Kwon, Sun Young
   Kelsen, David
   Kim, Goyang Hark Kyun
   Bartlett, John
   Parfitt, Jeremy
   Chetty, Runjan
   Darling, Gail
   Knox, Jennifer
   Wong, Rebecca
   El-Zimaity, Haila
   Liu, Geoffrey
   Boussioutas, Alex
   Park, Do Young
   Kemp, Rafael
   Carlotti, Carlos Gilberto, Jr.
   da Cunha Tirapelli, Daniela Pretti
   Saggioro, Fabiano Pinto
   Sankarankutty, Ajith Kumar
   Noushmehr, Houtan
   dos Santos, Jose Sebastiao
   Trevisan, Felipe Amstalden
   Eschbacher, Jennifer
   Eschbacher, Jennifer
   Dubina, Michael
   Mozgovoy, Eugene
   Carey, Frank
   Chalmers, Sally
   Forgie, Ian
   Godwin, Andrew
   Reilly, Colleen
   Madan, Rashna
   Naima, Zaid
   Ferrer-Torres, Daysha
   Rathmell, W. Kimryn
   Dhir, Rajiv
   Luketich, James
   Pennathur, Arjun
   Ajani, Jaffer A.
   McCall, Shannon J.
   Janjigian, Yelena
   Kelsen, David
   Ladanyi, Marc
   Tang, Laura
   Camargo, M. Constanza
   Ajani, Jaffer A.
   Cheong, Jae-Ho
   Chudamani, Sudha
   Liu, Jai
   Lolla, Laxmi
   Naresh, Rashi
   Pihl, Todd
   Sun, Qiang
   Wan, Yunhu
   Wu, Ye
   Demchok, John A.
   Felau, Ina
   Ferguson, Martin L.
   Shaw, Kenna R. Mills
   sheth, Margi
   Tarnuzzer, Roy
   Wang, Zhining
   Yang, Liming
   Zenklusen, Jean Claude
   Hutter, Carolyn M.
   Sofia, Heidi J.
   Zhang, Jiashan
TI Integrated genomic characterization of oesophageal carcinoma
SO NATURE
LA English
DT Article
ID squamous-cell carcinoma; structural variations; cancer statistics; lineage-survival; adenocarcinoma; genes; lung; identification; signatures; landscape
AB Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies.
C1 [Kim, Jihun; Park, Young Soo] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul 05505, South Korea.
   [Ally, Adrian; Balasundaram, Miruna; Carlsen, Rebecca; Chuah, Eric; Dhalla, Noreen; Holt, Robert A.; Jones, Steven J. M.; Kasaian, Katayoon; Brooks, Denise; Li, Haiyan I.; Ma, Yussanne; Marra, Marco A.; Mayo, Michael; Moore, Richard A.; Mungall, Karen L.; Schein, Jacqueline E.; Sipahimalani, Payal; Tam, Angela; Thiessen, Nina; Wong, Tina] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada.
   [Odze, Robert D.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA.
   [Odze, Robert D.; Meyerson, Matthew] Harvard Med Sch, Dept Pathol, Boston, MA 02215 USA.
   [Cherniack, Andrew D.; Pedamallu, Chandra Sekhar; Dunford, Andrew; Taylor-Weiner, Amaro; Lawrence, Michael; Cibulskis, Kristian; Stewart, Chip; Lander, Eric; Gabriel, Stacey B.; Cherniack, Andrew D.; Pedamallu, Chandra Sekhar; Beroukhim, Rameen; Bullman, Susan; Murray, Bradley A.; Schumacher, Steven E.; Gabriel, Stacey; Cho, Juok; Defrietas, Timothy; Frazer, Scott; Gehlenborg, Nils; Heiman, David I.; Lawrence, Michael S.; Lin, Pei; Noble, Michael S.; Doug Voet; Zhang, Hailei; Polak, Paz] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA.
   [Pedamallu, Chandra Sekhar; Bass, Adam J.; Derks, Sarah; Cherniack, Andrew D.; Beroukhim, Rameen; Bullman, Susan; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.
   [Raphael, Benjamin J.; Wu, Hsin-Ta; Wong, Alexandra M.] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA.
   [Raphael, Benjamin J.; Wu, Hsin-Ta; Wong, Alexandra M.] Brown Univ, Ctr Computat Mol Biol, Providence, RI 02912 USA.
   [Willis, Joseph E.] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA.
   [Willis, Joseph E.] Case Med Ctr, Dept Pathol, Cleveland, OH 44106 USA.
   [Bass, Adam J.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA.
   [Derks, Sarah] Vrije Univ Amsterdam, Med Ctr, Dept Med Oncol, Amsterdam, Netherlands.
   [Garman, Katherine; Cates, Crystal; Sharp, Alexis] Duke Univ, Dept Pathol, Durham, NC 27710 USA.
   [Wiznerowicz, Maciej] Int Inst Mol Oncol, PL-60203 Poznan, Poland.
   [Wiznerowicz, Maciej] Greater Poland Canc Ctr, PL-61866 Poznan, Poland.
   [Wiznerowicz, Maciej] Poznan Univ Med Sci, PL-61866 Poznan, Poland.
   [Hadjipanayis, Angela; Kucherlapati, Raju; Ren, Xiaojia; Kucherlapati, Melanie] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.
   [Ren, Xiaojia; Protopopov, Alexei] KEW Grp Inc, Cambridge, MA 02139 USA.
   [Thorsson, Vesteinn; Bernard, Brady; Iype, Lisa; Reynolds, Sheila M.] Inst Syst Biol, Seattle, WA 98109 USA.
   [Sakai, Ryo] Katholieke Univ Leuven, Dept Elect Engn ESAT STADIUS, Leuven, Belgium.
   [Sakai, Ryo] Katholieke Univ Leuven, iMinds Med IT, B-3001 Leuven, Belgium.
   [Wang, Kenneth] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA.
   [Schultz, Nikolaus; Armenia, Joshua; Kundra, Ritika; Gao, Jianjiong; Chakravarty, Debyani; Zhang, Hongxin] Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, New York, NY 10065 USA.
   [Shen, Ronglai] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA.
   [Abeshouse, Adam; Kjong-Van Lehmann; Sander, Chris] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA.
   [Kelsen, David P.; Janjigian, Yelena] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA.
   [Zhang, Julia; Demchok, John; Demchok, John A.; Ferguson, Martin L.; Shaw, Kenna R. Mills; sheth, Margi; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zhang, Jiashan] NCI, Bethesda, MD 20892 USA.
   [Rabkin, Charles S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
   [Leraas, Kristen; Frick, Jessica; Gastier-Foster, Julie M.; Gerken, Mark; Leraas, Kristen M.; Ramirez, Nilsa C.; Wise, Lisa; Zmuda, Erik] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA.
   [Curtis, Christina; Seoane, Jose A.] Stanford Univ, Sch Med, Div Oncol, Dept Med, Stanford, CA 94305 USA.
   [Curtis, Christina; Seoane, Jose A.] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA.
   [Ojesina, Akinyemi I.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA.
   [Ojesina, Akinyemi I.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA.
   [Beer, David G.; Ferrer-Torres, Daysha] Univ Michigan, Ctr Comprehens Canc, Dept Thorac Surg, Ann Arbor, MI 48109 USA.
   [Gulley, Margaret L.] Univ North Carolina Chapel Hill, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA.
   [Luketich, James D.; Luketich, James] Univ Pittsburgh, Med Ctr, Sch Med, Dept Cardiothorac Surg, Pittsburgh, PA 15213 USA.
   [Zhou, Zhongren] Univ Rochester, Dept Pathol & Lab Med, Rochester, NY 14642 USA.
   [Weisenberger, Daniel J.] Univ Southern Calif, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA.
   [Liu, Wenbin; Weinstein, John N.; Hegde, Apruva] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA.
   [Lee, Ju-Seog; Mills, Gordon B.; Mills, Gordon] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA.
   [Zhang, Wei] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA.
   [Reid, Brian J.] Fred Hutchinson Canc Res Ctr, North Seattle, WA 98109 USA.
   [Hinoue, Toshinori] Van Andel Res Inst, Ctr Epigenet, Grand Rapids, MI 49503 USA.
   [Piazuelo, M. Blanca; Schneider, Barbara G.] Vanderbilt Univ, Med Ctr, Div Gastroenterol, Dept Med, Nashville, TN 37232 USA.
   [McLellan, Michael; Ding, Li; McLellan, Michael D.; Miller, Christopher A.; Appelbaum, Elizabeth L.; Cordes, Matthew G.; Fronick, Catrina C.; Fulton, Lucinda A.; Mardis, Elaine R.; Wilson, Richard K.; Schmidt, Heather K.; Fulton, Robert S.] Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA.
   [Taylor-Weiner, Amaro; Lee, Semin; Gehlenborg, Nils] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA.
   [Polak, Paz] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.
   [Ding, Li] Washington Univ, Sch Med, Dept Med, St Louis, MO 63108 USA.
   [Beroukhim, Rameen] Harvard Med Sch, Dept Med, Boston, MA 02215 USA.
   [Schumacher, Steven E.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.
   [Hadjipanayis, Angela; Kucherlapati, Raju; Kucherlapati, Melanie] Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA.
   [Baylin, Stephen B.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Canc Biol Div, Baltimore, MD 21231 USA.
   [Hoadley, Katherine A.] Univ North Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27514 USA.
   [Bootwalla, Moiz S.; Lai, Phillip H.; Berrios, Mario; Holbrook, Andrea] USC, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA.
   [Van den Berg, David J.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90033 USA.
   [Hwang, Jun-Eul; Jang, Hee-Jin; Lee, Ju-Seog; Sohn, Bo Hwa] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Inst Personalized Canc Treatment, Houston, TX 77030 USA.
   [Hwang, Jun-Eul] Chonnam Natl Univ, Sch Med, Dept Hematooncol, Kwangju, South Korea.
   [Seth, Sahil; Protopopov, Alexei; Mahadeshwar, Harshad S.; Tang, Jiabin; Song, Xingzhi; Zhang, Jianhua] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Inst Appl Canc Sci, Houston, TX 77054 USA.
   [Weinstein, John N.; Le, Xuan; Tang, Laura] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA.
   [Radenbaugh, Amie] Univ Calif Santa Cruz, Genom Inst, Santa Cruz, CA 95064 USA.
   [Gardner, Johanna; Morris, Scott; Paulauskis, Joseph; Shelton, Troy] Int Genom Consortium, Phoenix, AZ 85004 USA.
   [Tarvin, Katherine; Saller, Charles] Analyt Biol Serv Inc, Wilmington, DE 19801 USA.
   [Button, Michael] Asterand Biosci, Detroit, MI 48202 USA.
   [Carvalho, Andre L.; Reis, Rui Manuel] Barretos Canc Hosp, Mol Oncol Res Ctr, Sao Paulo, Brazil.
   [Reis, Rui Manuel] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, Braga, Portugal.
   [Matsushita, Marcus Medeiros] Barretos Canc Hosp, Dept Pathol, Sao Paulo, Brazil.
   [Lucchesi, Fabiano] Barretos Canc Hosp, Dept Radiol, Sao Paulo, Brazil.
   [de Oliveira, Antonio Talvane] Barretos Canc Hosp, Dept Surg, Sao Paulo, Brazil.
   [Le, Xuan] BioreclamationIVT, Dept Res Pathol, Chestertown, MD 21620 USA.
   [Paklina, Oxana; Setdikova, Galiya] Botkin Municipal Clin, Moscow 125284, Russia.
   [Lee, Jae-Hyuck] Chonnam Natl Univ, Sch Med, Dept Pathol, Hwasun, South Korea.
   [Bennett, Joseph; Iacocca, Mary; Huelsenbeck-Dill, Lori] Christiana Care Hlth Syst, Helen F Graham Canc Ctr & Res Inst, Newark, DE 19713 USA.
   [Potapova, Cureline Olga; Voronina, Olga; Liu, Ouida; Fulidou, Victoria] Cureline Inc, San Francisco, CA 94080 USA.
   [Behera, Madhusmitara; Force, Seth; Khuri, Fadio; Owonikoko, Taofeek; Pickens, Allan; Ramalingam, Suresh; Sica, Gabriel] Emory Univ, Atlanta, GA 30322 USA.
   [Behera, Madhusmitara; Force, Seth; Khuri, Fadio; Owonikoko, Taofeek; Pickens, Allan; Ramalingam, Suresh; Sica, Gabriel] Winship Canc Inst, Atlanta, GA 30322 USA.
   [Dinjens, Winand] Univ Med Ctr, Erasmus MC Canc Inst, Dept Pathol, NL-3000 CA Rotterdam, Netherlands.
   [van Nistelrooij, Anna; Wijnhoven, Bas] Univ Med Ctr Rotterdam, Erasmus MC Canc Inst, Dept Surg, NL-3000 CA Rotterdam, Netherlands.
   [van Nistelrooij, Anna] Univ Med Ctr Rotterdam, Erasmus MC Canc Inst, Dept Pathol, NL-3000 CA Rotterdam, Netherlands.
   [Sandusky, George] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA.
   [Stepa, Serghei] Inst Oncol Moldova, Kishinev, Moldova.
   [Juhl, Invidumed Hartmut] Indivumed GmbH, D-20251 Hamburg, Germany.
   [Zornig, Carsten] Israelit Krankenhaus Hamburg, D-22297 Hamburg, Germany.
   [Kwon, Sun Young] Keimyung Univ, Sch Med, Dept Pathol, Daegu, South Korea.
   [Kim, Goyang Hark Kyun] Natl Canc Ctr, Ctr Gastr Canc, Goyang, South Korea.
   [Bartlett, John] Ontario Inst Canc Res, Ontario Tumour Bank, Toronto, ON M5G 0A3, Canada.
   [Parfitt, Jeremy] London Hlth Sci Ctr, Ontario Tumour Bank, London, ON N6A 5A5, Canada.
   [Chetty, Runjan; Darling, Gail; Knox, Jennifer; Wong, Rebecca; El-Zimaity, Haila; Liu, Geoffrey] Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada.
   [Boussioutas, Alex] Univ Melbourne, Sir Peter MacCallum Canc Dept Oncol, Melbourne, Vic 3002, Australia.
   [Park, Do Young] Pusan Natl Univ, Sch Med, Dept Pathol, Pusan, South Korea.
   [Kemp, Rafael; Carlotti, Carlos Gilberto, Jr.; da Cunha Tirapelli, Daniela Pretti; Sankarankutty, Ajith Kumar; dos Santos, Jose Sebastiao; Trevisan, Felipe Amstalden] Univ Sao Paulo, Ribeirao Preto Med School FMRP, Dept Surg & Anat, BR-14049900 Sao Paulo, Brazil.
   [Saggioro, Fabiano Pinto] Univ Sao Paulo, Ribeirao Preto Med School FMRP, Dept Pathol, BR-14049900 Sao Paulo, Brazil.
   [Noushmehr, Houtan] Univ Sao Paulo, Ribeirao Preto Med School FMRP, Dept Genet, BR-14049900 Sao Paulo, Brazil.
   [Eschbacher, Jennifer] St Josephs Hosp, Dept Pathol, Phoenix, AZ 85013 USA.
   [Dubina, Michael; Mozgovoy, Eugene] St Petersburg Acad Univ, RAS, St Petersburg 194021, Russia.
   [Carey, Frank; Chalmers, Sally; Forgie, Ian] Univ Dundee, Ninewells Hosp & Med Sch, Tayside Tissue Bank, Dundee DD1 9SY, Scotland.
   [Godwin, Andrew; Reilly, Colleen; Madan, Rashna; Naima, Zaid] Univ Kansas, Med Ctr, Kansas City, KS 66160 USA.
   [Ferrer-Torres, Daysha] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA.
   [Rathmell, W. Kimryn] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Dept Med, Chapel Hill, NC 27599 USA.
   [Dhir, Rajiv] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA.
   [Ajani, Jaffer A.] Univ Texas MD Anderson Canc Ctr, Dept GI Med Oncol, Houston, TX 77030 USA.
   [Cheong, Jae-Ho] Yonsei Univ, Coll Med, Dept Surg, Seoul 120752, South Korea.
   [Chudamani, Sudha; Liu, Jai; Lolla, Laxmi; Wu, Ye] Leidos Biomed, Rockville, MD 20850 USA.
   [Naresh, Rashi; Pihl, Todd; Sun, Qiang; Wan, Yunhu] CSRA Inc, Falls Church, VA 22042 USA.
   [Hutter, Carolyn M.] NHGRI, NIH, Bethesda, MD 20892 USA.
C3 University of Ulsan; Asan Medical Center; British Columbia Cancer Agency; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Brown University; Brown University; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Vrije Universiteit Amsterdam; Duke University; Miedzynarodowy Instytut Biologii Molekularnej i Komorkowej; Wielkopolskie Centrum Onkologii; Poznan University of Medical Sciences; Harvard University; Harvard Medical School; Institute for Systems Biology (ISB); KU Leuven; Interuniversity Microelectronics Centre; KU Leuven; Mayo Clinic; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); NIH National Cancer Institute- Division of Cancer Epidemiology & Genetics; University System of Ohio; Ohio State University; Nationwide Childrens Hospital; Research Institute at Nationwide Children's Hospital; Stanford University; Stanford University; University of Alabama System; University of Alabama Birmingham; HudsonAlpha Institute for Biotechnology; University of Michigan System; University of Michigan; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Rochester; University of Southern California; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; Fred Hutchinson Cancer Center; Van Andel Institute; Van Andel Research Institute; Vanderbilt University; Washington University (WUSTL); Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Washington University (WUSTL); Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Johns Hopkins University; Johns Hopkins Medicine; University of North Carolina; University of North Carolina Chapel Hill; University of Southern California; University of Southern California; University of Texas System; UTMD Anderson Cancer Center; Chonnam National University; University of Texas System; UTMD Anderson Cancer Center; Memorial Sloan Kettering Cancer Center; University of California System; University of California Santa Cruz; International Genomics Consortium; Hospital de Cancer de Barretos; Universidade do Minho; Hospital de Cancer de Barretos; Hospital de Cancer de Barretos; Hospital de Cancer de Barretos; Chonnam National University; Helen F. Graham Cancer Center & Research Institute; Christiana Care Health System; Emory University; Erasmus University Rotterdam; Erasmus MC; Erasmus MC Cancer Institute; Erasmus University Rotterdam; Erasmus MC; Erasmus MC Cancer Institute; Erasmus University Rotterdam; Erasmus MC; Erasmus MC Cancer Institute; Indiana University System; Indiana University Bloomington; Oncological Institute of the Republic of Moldova; Keimyung University; National Cancer Center - Korea (NCC); University of Toronto; Ontario Institute for Cancer Research; London Health Sciences Centre; University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; Peter Maccallum Cancer Center; University of Melbourne; Pusan National University; Pusan National University Hospital; Universidade de Sao Paulo; Universidade de Sao Paulo; Universidade de Sao Paulo; St. Joseph's Hospital and Medical Center; Russian Academy of Sciences; St. Petersburg Scientific Centre of the Russian Academy of Sciences; St Petersburg Academic University; University of Dundee; University of Kansas; University of Kansas Medical Center; University of Michigan System; University of Michigan; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Texas System; UTMD Anderson Cancer Center; Yonsei University; Yonsei University Health System; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI)
RP Bass, AJ (corresponding author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Bass, AJ (corresponding author), Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA.; Thorsson, V (corresponding author), Inst Syst Biol, Seattle, WA 98109 USA.
EM adam_bass@dfci.harvard.edu; Vesteinn.Thorsson@systemsbiology.org
FU Intramural Research Program; United States National Institutes of Health [5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, U54HG003273, P30CA16672]; National Cancer Institute [P30CA008748, T32CA009676, P30CA016672] Funding Source: NIH RePORTER; National Institute of Environmental Health Sciences [P30ES010126] Funding Source: NIH RePORTER
NR 58
TC 1270
Z9 1377
U1 5
U2 252
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 12
PY 2017
VL 541
IS 7636
BP 169
EP +
DI 10.1038/nature20805
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6PI
UT WOS:000396125500030
PM 28052061
DA 2026-03-09
ER

PT J
AU Wolfson, RL
   Chantranupong, L
   Wyant, GA
   Gu, X
   Orozco, JM
   Shen, K
   Condon, KJ
   Petri, S
   Kedir, J
   Scaria, SM
   Abu-Remaileh, M
   Frankel, WN
   Sabatini, DM
AF Wolfson, Rachel L.
   Chantranupong, Lynne
   Wyant, Gregory A.
   Gu, Xin
   Orozco, Jose M.
   Shen, Kuang
   Condon, Kendall J.
   Petri, Sabrina
   Kedir, Jibril
   Scaria, Sonia M.
   Abu-Remaileh, Monther
   Frankel, Wayne N.
   Sabatini, David M.
TI KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1
SO NATURE
LA English
DT Article
ID rag gtpases; signaling pathway; focal epilepsy; tumor-suppressor; amino-acids; complex; mutations; gene; szt2; encephalopathy
AB The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth that responds to diverse environmental signals and is deregulated in many human diseases, including cancer and epilepsy(1-3). Amino acids are a key input to this system, and act through the Rag GTPases to promote the translocation of mTORC1 to the lysosomal surface, its site of activation(4). Multiple protein complexes regulate the Rag GTPases in response to amino acids, including GATOR1, a GTPase activating protein for RAGA, and GATOR2, a positive regulator of unknown molecular function. Here we identify a protein complex (KICSTOR) that is composed of four proteins, KPTN, ITFG2, C12orf66 and SZT2, and that is required for amino acid or glucose deprivation to inhibit mTORC1 in cultured human cells. In mice that lack SZT2, mTORC1 signalling is increased in several tissues, including in neurons in the brain. KICSTOR localizes to lysosomes; binds and recruits GATOR1, but not GATOR2, to the lysosomal surface; and is necessary for the interaction of GATOR1 with its substrates, the Rag GTPases, and with GATOR2. Notably, several KICSTOR components are mutated in neurological diseases associated with mutations that lead to hyperactive mTORC1 signalling(5-10). Thus, KICSTOR is a lysosome-associated negative regulator of mTORC1 signalling, which, like GATOR1, is mutated in human disease11,12.
C1 [Wolfson, Rachel L.; Chantranupong, Lynne; Wyant, Gregory A.; Gu, Xin; Orozco, Jose M.; Shen, Kuang; Condon, Kendall J.; Kedir, Jibril; Scaria, Sonia M.; Abu-Remaileh, Monther; Sabatini, David M.] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA.
   [Wolfson, Rachel L.; Chantranupong, Lynne; Wyant, Gregory A.; Gu, Xin; Orozco, Jose M.; Shen, Kuang; Condon, Kendall J.; Kedir, Jibril; Scaria, Sonia M.; Abu-Remaileh, Monther; Sabatini, David M.] MIT, Dept Biol, 9 Cambridge Ctr, Cambridge, MA 02142 USA.
   [Wolfson, Rachel L.; Chantranupong, Lynne; Wyant, Gregory A.; Gu, Xin; Orozco, Jose M.; Shen, Kuang; Condon, Kendall J.; Kedir, Jibril; Scaria, Sonia M.; Abu-Remaileh, Monther; Sabatini, David M.] MIT, Dept Biol, Howard Hughes Med Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Wolfson, Rachel L.; Chantranupong, Lynne; Wyant, Gregory A.; Gu, Xin; Orozco, Jose M.; Shen, Kuang; Condon, Kendall J.; Kedir, Jibril; Scaria, Sonia M.; Abu-Remaileh, Monther; Sabatini, David M.] Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Wolfson, Rachel L.; Chantranupong, Lynne; Wyant, Gregory A.; Gu, Xin; Orozco, Jose M.; Shen, Kuang; Condon, Kendall J.; Kedir, Jibril; Scaria, Sonia M.; Abu-Remaileh, Monther; Sabatini, David M.] Broad Inst Harvard & Massachusetts Inst Technol, 7 Cambridge Ctr, Cambridge, MA 02142 USA.
   [Petri, Sabrina; Frankel, Wayne N.] Columbia Univ, Med Ctr, Dept Genet & Dev, New York, NY 10032 USA.
   [Petri, Sabrina; Frankel, Wayne N.] Columbia Univ, Med Ctr, Inst Genom Med, New York, NY 10032 USA.
C3 Massachusetts Institute of Technology (MIT); Whitehead Institute; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Howard Hughes Medical Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Columbia University; Columbia University
RP Sabatini, DM (corresponding author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA.; Sabatini, DM (corresponding author), MIT, Dept Biol, 9 Cambridge Ctr, Cambridge, MA 02142 USA.; Sabatini, DM (corresponding author), MIT, Dept Biol, Howard Hughes Med Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Sabatini, DM (corresponding author), Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Sabatini, DM (corresponding author), Broad Inst Harvard & Massachusetts Inst Technol, 7 Cambridge Ctr, Cambridge, MA 02142 USA.
EM sabatini@wi.mit.edu
FU NIH [R01 CA103866, R37 AI47389, R37 NS031348, T32 GM007753, F30 CA189333, F31 CA180271, F30 CA210373]; Department of Defense [W81XWH-07-0448]; NSF [2016197106]; National Defense Science & Engineering Graduate Fellowship (NDSEG) Program; Life Sciences Research Foundation; EMBO Long-Term Fellowship; Paul Gray UROP Fund [3143900]; National Cancer Institute [R01CA103866] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007753] Funding Source: NIH RePORTER
NR 28
TC 255
Z9 338
U1 1
U2 54
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 16
PY 2017
VL 543
IS 7645
BP 438
EP +
DI 10.1038/nature21423
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN9RN
UT WOS:000396337400054
PM 28199306
DA 2026-03-09
ER

PT J
AU Nagano, T
   Lubling, Y
   Váarnai, C
   Dudley, C
   Leung, W
   Baran, Y
   Cohen, NM
   Wingett, S
   Fraser, P
   Tanay, A
AF Nagano, Takashi
   Lubling, Yaniv
   Varnai, Csilla
   Dudley, Carmel
   Leung, Wing
   Baran, Yael
   Cohen, Netta Mendelson
   Wingett, Steven
   Fraser, Peter
   Tanay, Amos
TI Cell-cycle dynamics of chromosomal organization at single-cell resolution
SO NATURE
LA English
DT Article
ID topologically associating domains; chromatin; principles; reorganization; cohesin; genome
AB Chromosomes in proliferating metazoan cells undergo marked structural metamorphoses every cell cycle, alternating between highly condensed mitotic structures that facilitate chromosome segregation, and decondensed interphase structures that accommodate transcription, gene silencing and DNA replication. Here we use single-cell Hi-C (high-resolution chromosome conformation capture) analysis to study chromosome conformations in thousands of individual cells, and discover a continuum of cis-interaction profiles that finely position individual cells along the cell cycle. We show that chromosomal compartments, topological-associated domains (TADs), contact insulation and long-range loops, all defined by bulk Hi-C maps, are governed by distinct cell-cycle dynamics. In particular, DNA replication correlates with a build-up of compartments and a reduction in TAD insulation, while loops are generally stable from G1 to S and G2 phase. Whole-genome three-dimensional structural models reveal a radial architecture of chromosomal compartments with distinct epigenomic signatures. Our single-cell data therefore allow re-interpretation of chromosome conformation maps through the prism of the cell cycle.
C1 [Nagano, Takashi; Varnai, Csilla; Leung, Wing; Wingett, Steven; Fraser, Peter] Babraham Inst, Nucl Dynam Programme, Cambridge CB22 3AT, England.
   [Lubling, Yaniv; Dudley, Carmel; Baran, Yael; Cohen, Netta Mendelson; Tanay, Amos] Weizmann Inst Sci, Dept Comp Sci & Appl Math, Rehovot, Israel.
   [Lubling, Yaniv; Dudley, Carmel; Baran, Yael; Cohen, Netta Mendelson; Tanay, Amos] Weizmann Inst Sci, Dept Biol Regulat, Rehovot, Israel.
   [Fraser, Peter] Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA.
C3 UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); Babraham Institute; Weizmann Institute of Science; Weizmann Institute of Science; State University System of Florida; Florida State University
RP Váarnai, C; Fraser, P (corresponding author), Babraham Inst, Nucl Dynam Programme, Cambridge CB22 3AT, England.; Tanay, A (corresponding author), Weizmann Inst Sci, Dept Comp Sci & Appl Math, Rehovot, Israel.; Tanay, A (corresponding author), Weizmann Inst Sci, Dept Biol Regulat, Rehovot, Israel.; Fraser, P (corresponding author), Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA.
EM csilla.varnai@babraham.ac.uk; peter.fraser@babraham.ac.uk; amos.tanay@weizmann.ac.il
FU National Institutes of Health [1U01HL129971-01]; European Research Council [340152, 309706]; Flight Attendant Medical Research Institute; European Research Council (ERC) [340152, 309706] Funding Source: European Research Council (ERC)
NR 23
TC 573
Z9 684
U1 0
U2 185
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 6
PY 2017
VL 547
IS 7661
BP 61
EP +
DI 10.1038/nature23001
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EZ6PM
UT WOS:000404839900031
PM 28682332
DA 2026-03-09
ER

PT J
AU Kang, K
   Lee, KH
   Han, YM
   Gao, H
   Xie, SE
   Muller, DA
   Park, J
AF Kang, Kibum
   Lee, Kan-Heng
   Han, Yimo
   Gao, Hui
   Xie, Saien
   Muller, David A.
   Park, Jiwoong
TI Layer-by-layer assembly of two-dimensional materials into wafer-scale heterostructures
SO NATURE
LA English
DT Article
ID graphene; films
AB High-performance semiconductor films with vertical compositions that are designed to atomic-scale precision provide the foundation for modern integrated circuitry and novel materials discovery(1-3). One approach to realizing such films is sequential layer-by-layer assembly, whereby atomically thin two-dimensional building blocks are vertically stacked, and held together by van der Waals interactions'. With this approach, graphene and transition-metal dichalcogenides-which represent one- and three -atom-thick two-dimensional building blocks, respectively have been used to realize previously inaccessible heterostructures with interesting physical properties(7-11). However, no large-scale assembly method exists at present that maintains the intrinsic properties of these two-dimensional building blocks while producing pristine interlayer interfaces(12-15), thus limiting the layer-by-layer assembly method to small-scale proof-of-concept demonstrations. Here we report the generation of wafer-scale semiconductor films with a very high level of spatial uniformity and pristine interfaces. The vertical composition and properties of these films are designed at the atomic scale using layer-by-layer assembly of two-dimensional building blocks under vacuum. We fabricate several large-scale, high-quality heterostructure films and devices, including superlattice films with vertical compositions designed layer-by-layer, batch-fabricated tunnel device arrays with resistances that can be tuned over four orders of magnitude, band-engineered heterostructure tunnel diodes, and millimetre-scale ultrathin membranes and windows. The stacked films are detachable, suspendable and compatible with water or plastic surfaces, which will enable their integration with advanced optical and mechanical systems.
C1 [Kang, Kibum; Gao, Hui; Park, Jiwoong] Cornell Univ, Dept Chem & Chem Biol, Ithaca, NY 14853 USA.
   [Kang, Kibum; Gao, Hui; Park, Jiwoong] Univ Chicago, Dept Chem, 5735 S Ellis Ave, Chicago, IL 60637 USA.
   [Kang, Kibum; Park, Jiwoong] Univ Chicago, James Franck Inst, 5640 S Ellis Ave, Chicago, IL 60637 USA.
   [Lee, Kan-Heng; Han, Yimo; Xie, Saien; Muller, David A.] Cornell Univ, Sch Appl & Engn Phys, Ithaca, NY 14853 USA.
   [Lee, Kan-Heng; Xie, Saien; Park, Jiwoong] Univ Chicago, Inst Mol Engn, Chicago, IL 60637 USA.
   [Muller, David A.; Park, Jiwoong] Cornell Univ, Kavli Inst Cornell Nanoscale Sci, Ithaca, NY 14853 USA.
C3 Cornell University; University of Chicago; University of Chicago; Cornell University; University of Chicago; Cornell University
RP Park, J (corresponding author), Cornell Univ, Dept Chem & Chem Biol, Ithaca, NY 14853 USA.; Park, J (corresponding author), Univ Chicago, Dept Chem, 5735 S Ellis Ave, Chicago, IL 60637 USA.; Park, J (corresponding author), Univ Chicago, James Franck Inst, 5640 S Ellis Ave, Chicago, IL 60637 USA.; Park, J (corresponding author), Univ Chicago, Inst Mol Engn, Chicago, IL 60637 USA.; Park, J (corresponding author), Cornell Univ, Kavli Inst Cornell Nanoscale Sci, Ithaca, NY 14853 USA.
EM jwpark@uchicago.edu
FU Air Force Office of Scientific Research [FA9550-16-1-0031, FA2386-13-1-4118]; Nano Material Technology Development Program through the National Research Foundation of Korea - Ministry of Science, ICT, and Future Planning [2012M3A7B4049887]; National Science Foundation (NSF) through the Platform for the Accelerated Realization, Analysis, and Discovery of Interface Materials (PARADIM) [DMR-1539918]; Cornell Center for Materials Research (CCMR) [NSF DMR-1120296]; CCMR [NSF DMR-1120296]; MRSEC Shared User Facilities at the University of Chicago [NSF DMR-1420709]; Direct For Mathematical & Physical Scien; Division Of Materials Research [1539918] Funding Source: National Science Foundation
NR 30
TC 541
Z9 630
U1 16
U2 902
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 12
PY 2017
VL 550
IS 7675
BP 229
EP 233
DI 10.1038/nature23905
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FJ5YG
UT WOS:000412829500043
PM 28953885
DA 2026-03-09
ER

PT J
AU Lee, JR
   Raymond, B
   Bracegirdle, TJ
   Chadès, I
   Fuller, RA
   Shaw, JD
   Terauds, A
AF Lee, Jasmine R.
   Raymond, Ben
   Bracegirdle, Thomas J.
   Chades, Iadine
   Fuller, Richard A.
   Shaw, Justine D.
   Terauds, Aleks
TI Climate change drives expansion of Antarctic ice-free habitat
SO NATURE
LA English
DT Article
ID biological invasions; peninsula; sea; surface; model; shelf; sheet; snow; risk; melt
AB Antarctic terrestrial biodiversity occurs almost exclusively in ice-free areas that cover less than 1% of the continent. Climate change will alter the extent and configuration of ice-free areas, yet the distribution and severity of these effects remain unclear. Here we quantify the impact of twenty-first century climate change on ice-free areas under two Intergovernmental Panel on Climate Change (IPCC) climate forcing scenarios using temperature-index melt modelling. Under the strongest forcing scenario, ice-free areas could expand by over 17,000 km(2) by the end of the century, close to a 25% increase. Most of this expansion will occur in the Antarctic Peninsula, where a threefold increase in ice-free area could drastically change the availability and connectivity of biodiversity habitat. Isolated ice-free areas will coalesce, and while the effects on biodiversity are uncertain, we hypothesize that they could eventually lead to increasing regional-scale biotic homogenization, the extinction of less-competitive species and the spread of invasive species.
C1 [Lee, Jasmine R.; Fuller, Richard A.; Shaw, Justine D.] Univ Queensland, Sch Biol Sci, Ctr Biodivers & Conservat Sci, Brisbane, Qld 4072, Australia.
   [Lee, Jasmine R.; Chades, Iadine] CSIRO, Dutton Pk, Qld 4102, Australia.
   [Raymond, Ben; Terauds, Aleks] Dept Environm & Energy, Australian Antarctic Div, 203 Channel Highway, Kingston, Tas 7050, Australia.
   [Raymond, Ben] Univ Tasmania, Antarctic Climate & Ecosyst Cooperat Res Ctr, Private Bag 80, Hobart, Tas 7001, Australia.
   [Raymond, Ben] Univ Tasmania, Inst Marine & Antarctic, Private Bag 129, Hobart, Tas 7000, Australia.
   [Bracegirdle, Thomas J.] British Antarctic Survey, Madingley Rd, Cambridge CB3 0ET, England.
   [Chades, Iadine; Shaw, Justine D.] Univ Queensland, ARC Ctr Excellence Environm Decis, Brisbane, Qld 4072, Australia.
C3 University of Queensland; Commonwealth Scientific & Industrial Research Organisation (CSIRO); Australian Antarctic Division; Antarctic Climate & Ecosystems Cooperative Research Centre (ACE CRC); University of Tasmania; University of Tasmania; UK Research & Innovation (UKRI); Natural Environment Research Council (NERC); NERC British Antarctic Survey; University of Queensland
RP Lee, JR (corresponding author), Univ Queensland, Sch Biol Sci, Ctr Biodivers & Conservat Sci, Brisbane, Qld 4072, Australia.; Lee, JR (corresponding author), CSIRO, Dutton Pk, Qld 4102, Australia.
EM jasmine.lee1@uqconnect.edu.au
FU Holsworth Wildlife Research Endowment - Equity Trustees Charitable Foundation; Australian Antarctic Science Program [4296, 4297]; Ecological Society of Australia; CSIRO; Australian Research Council Future Fellowship; Polar Science for Planet Earth programme of the British Antarctic Survey; SCAR (Scientific Committee for Antarctic Research) AntClim21 (Antarctic Climate in the 21st Century) SRP (Scientific Research Programme); Natural Environment Research Council [bas0100032] Funding Source: researchfish; NERC [bas0100032] Funding Source: UKRI
NR 69
TC 333
Z9 366
U1 6
U2 222
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 6
PY 2017
VL 547
IS 7661
BP 49
EP +
DI 10.1038/nature22996
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EZ6PM
UT WOS:000404839900029
PM 28658207
DA 2026-03-09
ER

PT J
AU Stupakiewicz, A
   Szerenos, K
   Afanasiev, D
   Kirilyuk, A
   Kimel, AV
AF Stupakiewicz, A.
   Szerenos, K.
   Afanasiev, D.
   Kirilyuk, A.
   Kimel, A. V.
TI Ultrafast nonthermal photo-magnetic recording in a transparent medium
SO NATURE
LA English
DT Article
ID anisotropy; films
AB Discovering ways to control the magnetic state of media with the lowest possible production of heat and at the fastest possible speeds is important in the study of fundamental magnetism(1-5), with clear practical potential. In metals, it is possible to switch the magnetization between two stable states (and thus to record magnetic bits) using femtosecond circularly polarized laser pulses(6-8). However, the switching mechanisms in these materials are directly related to laser-induced heating close to the Curie temperature(9-12). Although several possible routes for achieving alloptical switching in magnetic dielectrics have been discussed(13,14), no recording has hitherto been demonstrated. Here we describe ultrafast all-optical photo-magnetic recording in transparent films of the dielectric cobalt-substituted garnet. A single linearly polarized femtosecond laser pulse resonantly pumps specific d-d transitions in the cobalt ions, breaking the degeneracy between metastable magnetic states. By changing the polarization of the laser pulse, we deterministically steer the net magnetization in the garnet, thus writing '0' and '1' magnetic bits at will. This mechanism outperforms existing alternatives in terms of the speed of the write-read magnetic recording event (less than 20 picoseconds) and the unprecedentedly low heat load (less than 6 joules per cubic centimetre).
C1 [Stupakiewicz, A.; Szerenos, K.] Univ Bialystok, Magnetism Lab, Fac Phys, 1L Ciolkowskiego, PL-15245 Bialystok, Poland.
   [Afanasiev, D.; Kirilyuk, A.; Kimel, A. V.] Radboud Univ Nijmegen, Inst Mol & Mat, 135 Heyendaalseweg, NL-6525 AJ Nijmegen, Netherlands.
C3 University of Bialystok; Radboud University Nijmegen
RP Stupakiewicz, A (corresponding author), Univ Bialystok, Magnetism Lab, Fac Phys, 1L Ciolkowskiego, PL-15245 Bialystok, Poland.; Kimel, AV (corresponding author), Radboud Univ Nijmegen, Inst Mol & Mat, 135 Heyendaalseweg, NL-6525 AJ Nijmegen, Netherlands.
EM and@uwb.edu.pl; a.kimel@science.ru.nl
FU National Science Centre Poland [DEC-2013/09/B/ST3/02669]; European Research Council under the European Union/ERC [257280]; Foundation for Fundamental Research on Matter
NR 31
TC 265
Z9 279
U1 3
U2 261
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 2
PY 2017
VL 542
IS 7639
BP 71
EP +
DI 10.1038/nature20807
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6MY
UT WOS:000396119300033
PM 28099412
DA 2026-03-09
ER

PT J
AU Tukiainen, T
   Villani, AC
   Yen, A
   Rivas, MA
   Marshall, JL
   Satija, R
   Aguirre, M
   Gauthier, L
   Fleharty, M
   Kirby, A
   Ummings, BBC
   Astel, SEC
   Karczewski, KJ
   Aguet, F
   Byrnes, A
   Lappalainen, T
   Regev, A
   Ardlie, KG
   Hacohen, N
   MacArthur, DG
AF Tukiainen, Taru
   Villani, Alexandra-Chloe
   Yen, Angela
   Rivas, Manuel A.
   Marshall, Jamie L.
   Satija, Rahul
   Aguirre, Matt
   Gauthier, Laura
   Fleharty, Mark
   Kirby, Andrew
   Ummings, Beryl B. . C.
   Astel, Stephane E. C.
   Karczewski, Konrad J.
   Aguet, Francois
   Byrnes, Andrea
   Lappalainen, Tuuli
   Regev, Aviv
   Ardlie, Kristin G.
   Hacohen, Nir
   MacArthur, Daniel G.
TI Landscape of X chromosome inactivation across human tissues
SO NATURE
LA English
DT Article
ID single-cell; gene-expression; allelic expression; dna methylation; patterns; transcriptome
AB X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals(1,2). The extent to which XCI is shared between cells and tissues remains poorly characterized(3,4), as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression(5) and phenotypic traits(6). Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity(6,7). Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.
C1 [Tukiainen, Taru; Rivas, Manuel A.; Marshall, Jamie L.; Aguirre, Matt; Gauthier, Laura; Kirby, Andrew; Ummings, Beryl B. . C.; Karczewski, Konrad J.; Byrnes, Andrea; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
   [Tukiainen, Taru; Villani, Alexandra-Chloe; Yen, Angela; Rivas, Manuel A.; Marshall, Jamie L.; Satija, Rahul; Aguirre, Matt; Gauthier, Laura; Fleharty, Mark; Kirby, Andrew; Ummings, Beryl B. . C.; Karczewski, Konrad J.; Aguet, Francois; Byrnes, Andrea; Regev, Aviv; Ardlie, Kristin G.; Hacohen, Nir; MacArthur, Daniel G.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Villani, Alexandra-Chloe; Hacohen, Nir] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA.
   [Yen, Angela] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Rivas, Manuel A.] Stanford Univ, Dept Biomed Data Sci, Stanford, CA 94305 USA.
   [Satija, Rahul; Astel, Stephane E. C.; Lappalainen, Tuuli] New York Genome Ctr, New York, NY 10013 USA.
   [Satija, Rahul] NYU, Dept Biol, Ctr Genom & Syst Biol, New York, NY 10003 USA.
   [Astel, Stephane E. C.; Lappalainen, Tuuli] Columbia Univ, Dept Syst Biol, New York, NY 10032 USA.
   [Regev, Aviv] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
C3 Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Massachusetts Institute of Technology (MIT); Stanford University; New York University; Columbia University; Massachusetts Institute of Technology (MIT)
RP Tukiainen, T; MacArthur, DG (corresponding author), Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.; Tukiainen, T; MacArthur, DG (corresponding author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
EM ttuk@broadinstitute.org; danmac@broadinstitute.org
FU Academy of Finland [285725]; Finnish Cultural Foundation; Orion-Farmos Research Foundation; Emil Aaltonen Foundation; NIGMS Fellowship [F32GM115208]; NIH [U54DK105566, R01MH101820, R01GM104371]; Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS; NCI\SAIC-Frederick, Inc. (SAIC-F) subcontracts [10XS170, 10XS171, X10S172]; Laboratory, Data Analysis, and Coordinating Center (LDACC) [HHSN268201000029C]; SAIC-F subcontract [10ST1035];  [DA006227];  [DA033684];  [N01MH000028];  [MH090941];  [MH101814];  [MH090951];  [MH090937];  [MH101820];  [MH101825];  [MH090936];  [MH101819];  [MH090948];  [MH101782];  [MH101810];  [MH101822]; National Human Genome Research Institute [T32HG000044] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK043351] Funding Source: NIH RePORTER; Academy of Finland (AKA) [285725] Funding Source: Academy of Finland (AKA)
NR 50
TC 752
Z9 845
U1 3
U2 59
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 12
PY 2017
VL 550
IS 7675
BP 244
EP +
DI 10.1038/nature24265
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FJ5YG
UT WOS:000412829500046
PM 29022598
DA 2026-03-09
ER

PT J
AU Wang, YG
   Guo, YR
   Liu, K
   Yin, Z
   Liu, R
   Xia, Y
   Tan, L
   Yang, PY
   Lee, JH
   Li, XJ
   Hawke, D
   Zheng, YH
   Qian, X
   Lyu, JX
   He, J
   Xing, DM
   Tao, YJ
   Lu, ZM
AF Wang, Yugang
   Guo, Yusong R.
   Liu, Ke
   Yin, Zheng
   Liu, Rui
   Xia, Yan
   Tan, Lin
   Yang, Peiying
   Lee, Jong-Ho
   Li, Xin-jian
   Hawke, David
   Zheng, Yanhua
   Qian, Xu
   Lyu, Jianxin
   He, Jie
   Xing, Dongming
   Tao, Yizhi Jane
   Lu, Zhimin
TI KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase
SO NATURE
LA English
DT Article
ID lysine succinylation; structural basis; gcn5; generation; domain; saga; coa
AB Histone modifications, such as the frequently occurring lysine succinylation(1,2), are central to the regulation of chromatin-based processes. However, the mechanism and functional consequences of histone succinylation are unknown. Here we show that the alpha-ketoglutarate dehydrogenase (alpha-KGDH) complex is localized in the nucleus in human cell lines and binds to lysine acetyltransferase 2A (KAT2A, also known as GCN5) in the promoter regions of genes. We show that succinyl-coenzyme A (succinyl-CoA) binds to KAT2A. The crystal structure of the catalytic domain of KAT2A in complex with succinyl-CoA at 2.3 angstrom resolution shows that succinyl-CoA binds to a deep cleft of KAT2A with the succinyl moiety pointing towards the end of a flexible loop 3, which adopts different structural conformations in succinyl-CoA-bound and acetyl-CoA-bound forms. Site-directed mutagenesis indicates that tyrosine 645 in this loop has an important role in the selective binding of succinylCoA over acetyl-CoA. KAT2A acts as a succinyltransferase and succinylates histone H3 on lysine 79, with a maximum frequency around the transcription start sites of genes. Preventing the alpha-KGDH complex from entering the nucleus, or expression of KAT2A(Tyr645Ala), reduces gene expression and inhibits tumour cell proliferation and tumour growth. These findings reveal an important mechanism of histone modification and demonstrate that local generation of succinyl-CoA by the nuclear alpha-KGDH complex coupled with the succinyltransferase activity of KAT2A is instrumental in histone succinylation, tumour cell proliferation, and tumour development.
C1 [Wang, Yugang; Liu, Rui; Xia, Yan; Lee, Jong-Ho; Li, Xin-jian; Zheng, Yanhua; Lu, Zhimin] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Brain Tumor Ctr, Houston, TX 77030 USA.
   [Guo, Yusong R.; Tao, Yizhi Jane] Rice Univ, Dept Biosci, Houston, TX 77005 USA.
   [Liu, Ke] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA.
   [Yin, Zheng] Houston Methodist Res Inst, Dept Syst Med & Bioengn, Houston, TX 77030 USA.
   [Tan, Lin; Yang, Peiying] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Gen Oncol, Houston, TX 77054 USA.
   [Hawke, David] Univ Texas MD Anderson Canc Ctr, Dept Mol Pathol, Houston, TX 77030 USA.
   [Qian, Xu; Lyu, Jianxin] Hangzhou Med Coll, Peoples Hosp, Hangzhou 310014, Zhejiang, Peoples R China.
   [Lyu, Jianxin] Wenzhou Med Univ, Sch Lab Med & Life Sci, Key Lab Lab Med, Minist Educ China, Wenzhou 325035, Zhejiang, Peoples R China.
   [He, Jie] Chinese Acad Med Sci, Canc Inst & Hosp, Peking Union Med Coll, Lab Thorac Surg, Beijing 100021, Peoples R China.
   [Xing, Dongming] Qingdao Univ, Canc Inst, Affiliated Hosp, Qingdao 266061, Shandong, Peoples R China.
   [Xing, Dongming] Qingdao Canc Inst, Qingdao 266061, Shandong, Peoples R China.
   [Xing, Dongming] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China.
   [Lu, Zhimin] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA.
   [Lu, Zhimin] Univ Texas Houston, MD Anderson Canc Ctr UTHlth, Grad Sch Biomed Sci, Houston, TX 77030 USA.
C3 University of Texas System; UTMD Anderson Cancer Center; Rice University; University of California System; University of California Berkeley; Houston Methodist; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; Hangzhou Medical College; Wenzhou Medical University; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Cancer Institute & Hospital - CAMS; Qingdao University; Tsinghua University; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas Health Science Center Houston
RP Lu, ZM (corresponding author), Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Brain Tumor Ctr, Houston, TX 77030 USA.; Tao, YJ (corresponding author), Rice Univ, Dept Biosci, Houston, TX 77005 USA.; Xing, DM (corresponding author), Qingdao Univ, Canc Inst, Affiliated Hosp, Qingdao 266061, Shandong, Peoples R China.; Xing, DM (corresponding author), Qingdao Canc Inst, Qingdao 266061, Shandong, Peoples R China.; Xing, DM (corresponding author), Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China.; Lu, ZM (corresponding author), Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA.; Lu, ZM (corresponding author), Univ Texas Houston, MD Anderson Canc Ctr UTHlth, Grad Sch Biomed Sci, Houston, TX 77030 USA.
EM pharm@mail.tsinghua.edu.cn; ytao@rice.edu; zhiminlu@mdanderson.org
FU National Institute of Neurological Disorders and Stroke [R01 NS089754]; National Cancer Institute [2R01 CA109035, R01 CA169603]; MD Anderson Support Grant [P30CA016672]; Welch Foundation [C-1565]; National Institutes of Health Brain Cancer Specialized Program of Research Excellence [2P50 CA127001]; National Cancer Institute [P50CA127001, P30CA016672] Funding Source: NIH RePORTER
NR 19
TC 419
Z9 478
U1 5
U2 130
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 14
PY 2017
VL 552
IS 7684
BP 273
EP +
DI 10.1038/nature25003
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FQ0FK
UT WOS:000418029500051
PM 29211711
DA 2026-03-09
ER

PT J
AU Berger, JB
   Wadley, HNG
   Mcmeeking, RM
AF Berger, J. B.
   Wadley, H. N. G.
   Mcmeeking, R. M.
TI Mechanical metamaterials at the theoretical limit of isotropic elastic stiffness
SO NATURE
LA English
DT Article
ID strength; behavior; design
AB A wide variety of high-performance applications(1) require materials for which shape control is maintained under substantial stress, and that have minimal density. Bio-inspired hexagonal and square honeycomb structures and lattice materials based on repeating unit cells composed of webs or trusses(2), when made from materials of high elastic stiffness and low density(3), represent some of the lightest, stiffest and strongest materials available today(4). Recent advances in 3D printing and automated assembly have enabled such complicated material geometries to be fabricated at low (and declining) cost. These mechanical metamaterials have properties that are a function of their mesoscale geometry as well as their constituents(3,5-12), leading to combinations of properties that are unobtainable in solid materials; however, a material geometry that achieves the theoretical upper bounds for isotropic elasticity and strain energy storage (the Hashin-Shtrikman upper bounds) has yet to be identified. Here we evaluate the manner in which strain energy distributes under load in a representative selection of material geometries, to identify the morphological features associated with high elastic performance. Using finite-element models, supported by analytical methods, and a heuristic optimization scheme, we identify a material geometry that achieves the Hashin-Shtrikman upper bounds on isotropic elastic stiffness. Previous work has focused on truss networks and anisotropic honeycombs, neither of which can achieve this theoretical limit(13). We find that stiff but well distributed networks of plates are required to transfer loads efficiently between neighbouring members. The resulting low-density mechanical metamaterials have many advantageous properties: their mesoscale geometry can facilitate large crushing strains with high energy absorption(2,14,15), optical bandgaps(16-19) and mechanically tunable acoustic bandgaps(20), high thermal insulation(21), buoyancy, and fluid storage and transport. Our relatively simple design can be manufactured using origami-like sheet folding(22) and bonding methods.
C1 [Berger, J. B.; Mcmeeking, R. M.] Univ Calif, Dept Mat, Santa Barbara, CA 93106 USA.
   [Berger, J. B.; Mcmeeking, R. M.] Univ Calif, Dept Mech Engn, Santa Barbara, CA 93106 USA.
   [Wadley, H. N. G.] Univ Virginia, Sch Engn & Appl Sci, Dept Mat Sci & Engn, Charlottesville, VA 22904 USA.
   [Mcmeeking, R. M.] Univ Aberdeen, Kings Coll, Sch Engn, Aberdeen AB24 3UE, Scotland.
   [Mcmeeking, R. M.] INM Leibniz Inst New Mat, Campus D22, D-66123 Saarbrucken, Germany.
C3 University of California System; University of California Santa Barbara; University of California System; University of California Santa Barbara; University of Virginia; University of Aberdeen; Leibniz Association; Leibniz Institut fur Neue Materialien (INM)
RP Berger, JB (corresponding author), Univ Calif, Dept Mat, Santa Barbara, CA 93106 USA.; Berger, JB (corresponding author), Univ Calif, Dept Mech Engn, Santa Barbara, CA 93106 USA.
EM berger@engineering.ucsb.edu
FU ONR [N00014-15-1-2933]; DARPA MCMA programme [W91CRB-10-1-005]
NR 31
TC 739
Z9 764
U1 57
U2 916
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 23
PY 2017
VL 543
IS 7646
BP 533
EP +
DI 10.1038/nature21075
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EO9OM
UT WOS:000397018000047
PM 28219078
DA 2026-03-09
ER

PT J
AU Kong, XJ
   Kuilman, T
   Shahrabi, A
   Oshuizen, JB
   Kemper, K
   Song, JY
   Niessen, HWM
   Rozeman, EA
   Foppen, MHG
   Lank, CUB
   Peeper, DS
AF Kong, Xiangjun
   Kuilman, Thomas
   Shahrabi, Aida
   Oshuizen, Julia B.
   Kemper, Kristel
   Song, Ji-Ying
   Niessen, Hans W. M.
   Rozeman, Elisa A.
   Foppen, Marnix H. Geukes
   Lank, Christian U. B.
   Peeper, Daniel S.
TI Cancer drug addiction is relayed by an ERK2-dependent phenotype switch
SO NATURE
LA English
DT Article
ID braf v600e-mutant melanoma; malignant-melanoma; vemurafenib; inhibition; resistance; patient; cells; xenografts; activation; efficacy
AB Observations from cultured cells(1-3), animal models(4) and patients(5-7) raise the possibility that the dependency of tumours on the therapeutic drugs to which they have acquired resistance represents a vulnerability with potential applications in cancer treatment. However, for this drug addiction trait to become of clinical interest, we must first define the mechanism that underlies it. We performed an unbiased CRISPR-Cas9 knockout screen on melanoma cells that were both resistant and addicted to inhibition of the serine/ threonine-protein kinase BRAF, in order to functionally mine their genome for 'addiction genes. Here we describe a signalling pathway comprising ERK2 kinase and JUNB and FRA1 transcription factors, disruption of which allowed addicted tumour cells to survive on treatment discontinuation. This occurred in both cultured cells and mice and was irrespective of the acquired drug resistance mechanism. In melanoma and lung cancer cells, death induced by drug withdrawal was preceded by a specific ERK2-dependent phenotype switch, alongside transcriptional reprogramming reminiscent of the epithelial-mesenchymal transition. In melanoma cells, this reprogramming caused the shutdown of microphthalmia-associated transcription factor (MITF), a lineage survival oncoprotein; restoring this protein reversed phenotype switching and prevented the lethality associated with drug addiction. In patients with melanoma that had progressed during treatment with a BRAF inhibitor, treatment cessation was followed by increased expression of the receptor tyrosine kinase AXL, which is associated with the phenotype switch. Drug discontinuation synergized with the melanoma chemotherapeutic agent dacarbazine by further suppressing MITF and its prosurvival target, B-cell lymphoma 2 (BCL-2), and by inducing DNA damage in cancer cells. Our results uncover a pathway that underpins drug addiction in cancer cells, which may help to guide the use of alternating therapeutic strategies for enhanced clinical responses in drug-resistant cancers.
C1 [Kong, Xiangjun; Kuilman, Thomas; Shahrabi, Aida; Oshuizen, Julia B.; Kemper, Kristel; Rozeman, Elisa A.; Foppen, Marnix H. Geukes; Lank, Christian U. B.; Peeper, Daniel S.] Netherlands Canc Inst, Div Mol Oncol & Immunol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands.
   [Song, Ji-Ying] Netherlands Canc Inst, Div Expt Anim Pathol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands.
   [Niessen, Hans W. M.] Vrije Univ Amsterdam, Dept Pathol & Cardiac Surg, ACS, Med Ctr, NL-1007 MB Amsterdam, Netherlands.
C3 Netherlands Cancer Institute; Netherlands Cancer Institute; Vrije Universiteit Amsterdam
RP Peeper, DS (corresponding author), Netherlands Canc Inst, Div Mol Oncol & Immunol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands.
EM d.peeper@nki.nl
FU European Research Council under the European Union's Seventh Framework Programme (FP7)/ERC synergy grant [319661 COMBATCANCER]; Queen Wilhelmina Award; Dutch Cancer Society/Koningin Wilhelmina Fonds [10304]
NR 30
TC 115
Z9 141
U1 2
U2 64
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 12
PY 2017
VL 550
IS 7675
BP 270
EP +
DI 10.1038/nature24037
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FJ5YG
UT WOS:000412829500051
PM 28976960
DA 2026-03-09
ER

PT J
AU Rao, H
   Chmidt, LCS
   Bonin, J
   Robert, M
AF Rao, Heng
   Chmidt, Luciana C. S.
   Bonin, Julien
   Robert, Marc
TI Visible-light-driven methane formation from CO2 with a molecular iron catalyst
SO NATURE
LA English
DT Article
ID carbon-dioxide; electrochemical conversion; photochemical reduction; efficient; electroreduction; complexes; chemicals; ch4; fe
AB Converting CO2 into fuel or chemical feedstock compounds could in principle reduce fossil fuel consumption and climate-changing CO2 emissions(1,2). One strategy aims for electrochemical conversions powered by electricity from renewable sources(3-5), but photochemical approaches driven by sunlight are also conceivable(6). A considerable challenge in both approaches is the development of efficient and selective catalysts, ideally based on cheap and Earth-abundant elements rather than expensive precious metals(7). Of the molecular photo-and electrocatalysts reported, only a few catalysts are stable and selective for CO2 reduction; moreover, these catalysts produce primarily CO or HCOOH, and catalysts capable of generating even low to moderate yields of highly reduced hydrocarbons remain rare(8-17). Here we show that an iron tetraphenylporphyrin complex functionalized with trimethylammonio groups, which is the most efficient and selective molecular electro-catalyst for converting CO2 to CO known(18-20), can also catalyse the eight-electron reduction of CO2 to methane upon visible light irradiation at ambient temperature and pressure. We find that the catalytic system, operated in an acetonitrile solution containing a photosensitizer and sacrificial electron donor, operates stably over several days. CO is the main product of the direct CO2 photoreduction reaction, but a two-pot procedure that first reduces CO2 and then reduces CO generates methane with a selectivity of up to 82 per cent and a quantum yield (light-to-product efficiency) of 0.18 per cent. However, we anticipate that the operating principles of our system may aid the development of other molecular catalysts for the production of solar fuels from CO2 under mild conditions.
C1 [Rao, Heng; Chmidt, Luciana C. S.; Bonin, Julien; Robert, Marc] Univ Paris Diderot, Sorbonne Paris Cite, Lab Electrochim Mol, UMR CNRS 7591, 15 Rue Jean Antoine de Baif, F-75205 Paris 13, France.
   [Chmidt, Luciana C. S.] Univ Nacl Cordoba, Fac Ciencias Quim, Dept Quim Organ, INFIQC CONICET, RA-5000 Cordoba, Argentina.
C3 Universite Paris Cite; National University of Cordoba; Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET)
RP Bonin, J; Robert, M (corresponding author), Univ Paris Diderot, Sorbonne Paris Cite, Lab Electrochim Mol, UMR CNRS 7591, 15 Rue Jean Antoine de Baif, F-75205 Paris 13, France.
EM julien.bonin@univ-paris-diderot.fr; robert@univ-paris-diderot.fr
FU CNRS; Defi Transition energetique "Emergence CO2" (the PERIODIC project); China Scholarship Council [201507040033]
NR 33
TC 872
Z9 928
U1 22
U2 1465
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 3
PY 2017
VL 548
IS 7665
BP 74
EP +
DI 10.1038/nature23016
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FC4SU
UT WOS:000406831700039
PM 28723895
DA 2026-03-09
ER

PT J
AU Papa, I
   Saliba, D
   Ponzoni, M
   Bustamante, S
   Canete, PF
   Gonzalez-Figueroa, P
   McNamara, HA
   Valvo, S
   Grimbaldeston, M
   Sweet, RA
   Vohra, H
   Cockburn, IA
   Meyer-Hermann, M
   Dustin, ML
   Doglioni, C
   Vinuesa, CG
AF Papa, Ilenia
   Saliba, David
   Ponzoni, Maurilio
   Bustamante, Sonia
   Canete, Pablo F.
   Gonzalez-Figueroa, Paula
   McNamara, Hayley A.
   Valvo, Salvatore
   Grimbaldeston, Michele
   Sweet, Rebecca A.
   Vohra, Harpreet
   Cockburn, Ian A.
   Meyer-Hermann, Michael
   Dustin, Michael L.
   Doglioni, Claudio
   Vinuesa, Carola G.
TI TFH-derived dopamine accelerates productive synapses in germinal centres
SO NATURE
LA English
DT Article
ID follicular helper-cells; catecholamine synthesis; tyrosine-hydroxylase; dense-core; b-cells; selection; norepinephrine; lymphocyte; expression; mechanism
AB Protective high-affinity antibody responses depend on competitive selection of B cells carrying somatically mutated B-cell receptors by follicular helper T (T-FH) cells in germinal centres. The rapid T-B-cell interactions that occur during this process are reminiscent of neural synaptic transmission pathways. Here we show that a proportion of human T-FH cells contain dense-core granules marked by chromogranin B, which are normally found in neuronal presynaptic terminals storing catecholamines such as dopamine. T-FH cells produce high amounts of dopamine and release it upon cognate interaction with B cells. Dopamine causes rapid translocation of intracellular ICOSL (inducible T-cell co-stimulator ligand, also known as ICOSLG) to the B-cell surface, which enhances accumulation of CD40L and chromogranin B granules at the human T-FH cell synapse and increases the synapse area. Mathematical modelling suggests that faster dopamine-induced T-B-cell interactions increase total germinal centre output and accelerate it by days. Delivery of neurotransmitters across the T-B-cell synapse may be advantageous in the face of infection.
C1 [Papa, Ilenia; Canete, Pablo F.; Gonzalez-Figueroa, Paula; McNamara, Hayley A.; Sweet, Rebecca A.; Cockburn, Ian A.; Vinuesa, Carola G.] Australian Natl Univ, John Curtin Sch Med Res, Dept Immunol & Infect Dis, Canberra, ACT 2601, Australia.
   [Saliba, David; Valvo, Salvatore; Dustin, Michael L.] Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Kennedy Inst Rheumatol, Oxford OX3 7LD, England.
   [Ponzoni, Maurilio; Doglioni, Claudio] IRCCS Sci Inst San Raffaele, Dept Pathol, Ateneo Vita Salute, I-20132 Milan, Italy.
   [Bustamante, Sonia] Univ New South Wales, Mark Wainwright Analyt Ctr, Bioanalyt Mass Spectrometry Facil, Sydney, NSW 2052, Australia.
   [Grimbaldeston, Michele] Univ South Australia, Ctr Canc Biol, Adelaide, SA 5000, Australia.
   [Grimbaldeston, Michele] SA Pathol, Adelaide, SA 5000, Australia.
   [Grimbaldeston, Michele] Genentech Inc, OMNI Biomarker Dev, San Francisco, CA 94080 USA.
   [Vohra, Harpreet] Australian Natl Univ, John Curtin Sch Med Res, Imaging & Cytometry Facil, Canberra, ACT 2601, Australia.
   [Meyer-Hermann, Michael] Helmholtz Ctr Infect Res, Dept Syst Immunol, D-38124 Braunschweig, Germany.
   [Meyer-Hermann, Michael] Helmholtz Ctr Infect Res, Braunschweig Integrated Ctr Syst Biol, D-38124 Braunschweig, Germany.
   [Vinuesa, Carola G.] Shanghai Jiao Tong Univ, Sch Med, Shanghai Renji Hosp, China Australia Ctr Personalised Immunol, Shanghai 200085, Peoples R China.
C3 Australian National University; John Curtin School of Medical Research; University of Oxford; Kennedy Institute for Rheumatology; Vita-Salute San Raffaele University; IRCCS Ospedale San Raffaele; University of New South Wales Sydney; Centre for Cancer Biology; Adelaide University; University of South Australia; SA Pathology; Roche Holding; Genentech; Roche Holding USA; Australian National University; John Curtin School of Medical Research; Helmholtz Association; Helmholtz-Center for Infection Research; Helmholtz Association; Helmholtz-Center for Infection Research; Shanghai Jiao Tong University
RP Vinuesa, CG (corresponding author), Australian Natl Univ, John Curtin Sch Med Res, Dept Immunol & Infect Dis, Canberra, ACT 2601, Australia.; Vinuesa, CG (corresponding author), Shanghai Jiao Tong Univ, Sch Med, Shanghai Renji Hosp, China Australia Ctr Personalised Immunol, Shanghai 200085, Peoples R China.
EM carola.vinuesa@anu.edu.au
FU NIHR Oxford Biomedical Research Centre; Australian National Health and Medical Research Council; Wellcome Trust; European Research Council [AdG670930]; Human Frontier Science Program [RGP0033/2015]; Kennedy Trust [KENN161702] Funding Source: researchfish; Wellcome Trust [100262/Z/12/Z] Funding Source: researchfish; Wellcome Trust [100262/Z/12/Z] Funding Source: Wellcome Trust
NR 43
TC 119
Z9 134
U1 0
U2 46
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 20
PY 2017
VL 547
IS 7663
BP 318
EP +
DI 10.1038/nature23013
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB0OR
UT WOS:000405844900027
PM 28700579
DA 2026-03-09
ER

PT J
AU Zhang, GQ
   Liu, KW
   Li, Z
   Lohaus, R
   Hsiao, YY
   Niu, SC
   Wang, JY
   Lin, YC
   Xu, Q
   Chen, LJ
   Yoshida, K
   Fujiwara, S
   Wang, ZW
   Zhang, YQ
   Mitsuda, N
   Wang, MN
   Liu, GH
   Pecoraro, L
   Huang, HX
   Xiao, XJ
   Lin, M
   Wu, XY
   Wu, WL
   Chen, YY
   Chang, SB
   Sakamoto, S
   Ohme-Takagi, M
   Yagi, M
   Zeng, SJ
   Shen, CY
   Yeh, CM
   Luo, YB
   Tsai, WC
   Van de Peer, Y
   Liu, ZJ
AF Zhang, Guo-Qiang
   Liu, Ke-Wei
   Li, Zhen
   Lohaus, Rolf
   Hsiao, Yu-Yun
   Niu, Shan-Ce
   Wang, Jie-Yu
   Lin, Yao-Cheng
   Xu, Qing
   Chen, Li-Jun
   Yoshida, Kouki
   Fujiwara, Sumire
   Wang, Zhi-Wen
   Zhang, Yong-Qiang
   Mitsuda, Nobutaka
   Wang, Meina
   Liu, Guo-Hui
   Pecoraro, Lorenzo
   Huang, Hui-Xia
   Xiao, Xin-Ju
   Lin, Min
   Wu, Xin-Yi
   Wu, Wan-Lin
   Chen, You-Yi
   Chang, Song-Bin
   Sakamoto, Shingo
   Ohme-Takagi, Masaru
   Yagi, Masafumi
   Zeng, Si-Jin
   Shen, Ching-Yu
   Yeh, Chuan-Ming
   Luo, Yi-Bo
   Tsai, Wen-Chieh
   Van de Peer, Yves
   Liu, Zhong-Jian
TI The Apostasia genome and the evolution of orchids
SO NATURE
LA English
DT Article
ID mads-box genes; multiple sequence alignment; phylogenetic analysis; maximum-likelihood; supplement trembl; new-jersey; arabidopsis; inference; origin; scale
AB Constituting approximately 10% of flowering plant species, orchids (Orchidaceae) display unique flower morphologies, possess an extraordinary diversity in lifestyle, and have successfully colonized almost every habitat on Earth(1-3). Here we report the draft genome sequence of Apostasia shenzhenica(4), a representative of one of two genera that form a sister lineage to the rest of the Orchidaceae, providing a reference for inferring the genome content and structure of the most recent common ancestor of all extant orchids and improving our understanding of their origins and evolution. In addition, we present transcriptome data for representatives of Vanilloideae, Cypripedioideae and Orchidoideae, and novel third-generation genome data for two species of Epidendroideae, covering all five orchid subfamilies. A. shenzhenica shows clear evidence of a whole-genome duplication, which is shared by all orchids and occurred shortly before their divergence. Comparisons between A. shenzhenica and other orchids and angiosperms also permitted the reconstruction of an ancestral orchid gene toolkit. We identify new gene families, gene family expansions and contractions, and changes within MADS-box gene classes, which control a diverse suite of developmental processes, during orchid evolution. This study sheds new light on the genetic mechanisms underpinning key orchid innovations, including the development of the labellum and gynostemium, pollinia, and seeds without endosperm, as well as the evolution of epiphytism; reveals relationships between the Orchidaceae subfamilies; and helps clarify the evolutionary history of orchids within the angiosperms.
C1 [Zhang, Guo-Qiang; Liu, Ke-Wei; Niu, Shan-Ce; Wang, Jie-Yu; Xu, Qing; Chen, Li-Jun; Zhang, Yong-Qiang; Wang, Meina; Liu, Guo-Hui; Pecoraro, Lorenzo; Huang, Hui-Xia; Xiao, Xin-Ju; Lin, Min; Wu, Xin-Yi; Wu, Wan-Lin; Zeng, Si-Jin; Liu, Zhong-Jian] Natl Orchid Conservat Ctr China, Shenzhen Key Lab Orchid Conservat & Utilizat, Shenzhen 518114, Peoples R China.
   [Zhang, Guo-Qiang; Liu, Ke-Wei; Niu, Shan-Ce; Wang, Jie-Yu; Xu, Qing; Chen, Li-Jun; Zhang, Yong-Qiang; Wang, Meina; Liu, Guo-Hui; Pecoraro, Lorenzo; Huang, Hui-Xia; Xiao, Xin-Ju; Lin, Min; Wu, Xin-Yi; Wu, Wan-Lin; Zeng, Si-Jin; Liu, Zhong-Jian] Orchid Conservat & Res Ctr Shenzhen, Shenzhen 518114, Peoples R China.
   [Li, Zhen; Lohaus, Rolf; Lin, Yao-Cheng; Van de Peer, Yves] Univ Ghent, Dept Plant Biotechnol & Bioinformat, B-9052 Ghent, Belgium.
   [Li, Zhen; Lohaus, Rolf; Lin, Yao-Cheng; Van de Peer, Yves] VIB Ctr Plant Syst Biol, B-9052 Ghent, Belgium.
   [Hsiao, Yu-Yun; Wu, Wan-Lin; Chen, You-Yi; Chang, Song-Bin; Tsai, Wen-Chieh] Natl Cheng Kung Univ, Orchid Res & Dev Ctr, Tainan 701, Taiwan.
   [Hsiao, Yu-Yun; Chen, You-Yi; Chang, Song-Bin; Tsai, Wen-Chieh] Natl Cheng Kung Univ, Dept Life Sci, Tainan 701, Taiwan.
   [Niu, Shan-Ce; Luo, Yi-Bo] Chinese Acad Sci, Inst Bot, State Key Lab Systemat & Evolutionary Bot, Beijing 100093, Peoples R China.
   [Wang, Jie-Yu; Liu, Zhong-Jian] South China Agr Univ, Coll Forestry, Guangzhou 510640, Guangdong, Peoples R China.
   [Yoshida, Kouki] Taisei Corp, Technol Ctr, Totsuka Ku, Nase Cho 344-1, Yokohama, Kanagawa 2450051, Japan.
   [Fujiwara, Sumire; Mitsuda, Nobutaka; Sakamoto, Shingo; Ohme-Takagi, Masaru] Natl Inst Adv Ind Sci & Technol, Bioprod Res Inst, Cent 6,Higashi 1-1-1, Tsukuba, Ibaraki 3058562, Japan.
   [Wang, Zhi-Wen] PubBiotech Serv Corp, Wuhan 430070, Hubei, Peoples R China.
   [Ohme-Takagi, Masaru; Yeh, Chuan-Ming] Saitama Univ, Grad Sch Sci & Engn, Sakura Ku, 255 Shimo Okubo, Saitama 3388570, Japan.
   [Yagi, Masafumi] NIFS, 2-1 Fujimoto, Tsukuba, Ibaraki 3058519, Japan.
   [Shen, Ching-Yu; Tsai, Wen-Chieh] Natl Cheng Kung Univ, Inst Trop Plant Sci, Tainan 701, Taiwan.
   [Van de Peer, Yves] Genom Res Inst, Dept Genet, ZA-0028 Pretoria, South Africa.
   [Liu, Zhong-Jian] Fujian Agr & Forestry Univ, Coll Landscape Architecture, Fuzhou 350002, Fujian, Peoples R China.
   [Liu, Zhong-Jian] Tsinghua Univ, Grad Sch Shenzhen, Ctr Biotechnol & BioMed, Shenzhen 518055, Peoples R China.
   [Lin, Yao-Cheng] Acad Sinica, Biotechnol Ctr Southern Taiwan, Agr Biotechnol Res Ctr, Tainan 741, Taiwan.
C3 Ghent University; Ghent University; Flanders Institute for Biotechnology (VIB); National Cheng Kung University; National Cheng Kung University; Chinese Academy of Sciences; Institute of Botany, CAS; South China Agricultural University; Taisei Corporation; National Institute of Advanced Industrial Science & Technology (AIST); Saitama University; National Cheng Kung University; Fujian Agriculture & Forestry University; Tsinghua Shenzhen International Graduate School; Tsinghua University; Academia Sinica - Taiwan
RP Liu, ZJ (corresponding author), Natl Orchid Conservat Ctr China, Shenzhen Key Lab Orchid Conservat & Utilizat, Shenzhen 518114, Peoples R China.; Liu, ZJ (corresponding author), Orchid Conservat & Res Ctr Shenzhen, Shenzhen 518114, Peoples R China.; Van de Peer, Y (corresponding author), Univ Ghent, Dept Plant Biotechnol & Bioinformat, B-9052 Ghent, Belgium.; Van de Peer, Y (corresponding author), VIB Ctr Plant Syst Biol, B-9052 Ghent, Belgium.; Tsai, WC (corresponding author), Natl Cheng Kung Univ, Orchid Res & Dev Ctr, Tainan 701, Taiwan.; Tsai, WC (corresponding author), Natl Cheng Kung Univ, Dept Life Sci, Tainan 701, Taiwan.; Luo, YB (corresponding author), Chinese Acad Sci, Inst Bot, State Key Lab Systemat & Evolutionary Bot, Beijing 100093, Peoples R China.; Liu, ZJ (corresponding author), South China Agr Univ, Coll Forestry, Guangzhou 510640, Guangdong, Peoples R China.; Yeh, CM (corresponding author), Saitama Univ, Grad Sch Sci & Engn, Sakura Ku, 255 Shimo Okubo, Saitama 3388570, Japan.; Tsai, WC (corresponding author), Natl Cheng Kung Univ, Inst Trop Plant Sci, Tainan 701, Taiwan.; Van de Peer, Y (corresponding author), Genom Res Inst, Dept Genet, ZA-0028 Pretoria, South Africa.; Liu, ZJ (corresponding author), Fujian Agr & Forestry Univ, Coll Landscape Architecture, Fuzhou 350002, Fujian, Peoples R China.; Liu, ZJ (corresponding author), Tsinghua Univ, Grad Sch Shenzhen, Ctr Biotechnol & BioMed, Shenzhen 518055, Peoples R China.
EM cmyeh@mail.saitama-u.ac.jp; luoyb@ibcas.ac.cn; tsaiwc@mail.ncku.edu.tw; yves.vandepeer@psb.vib-ugent.be; liuzj@sinicaorchid.org
FU Funds for Environmental Project of Shenzhen, China [2013-02]; State Forestry Administration P. R. China [2011-4-53]; Funds for Forestry Science and Technology Innovation Project of Guangdong, China [2016KJCX025, 2013KJCX014-05]; Fundamental Research Project of Shenzhen, China [JCYJ20170307170746099, JCYJ20150403150235943]; Guangdong Natural Science Foundation [2017A030312004]; Multidisciplinary Research Partnership 'Bioinformatics: from nucleotides to networks' Project of Ghent University [01MR0310W]; European Union under European Research Council [322739-DOUBLEUP]
NR 96
TC 306
Z9 356
U1 17
U2 325
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 21
PY 2017
VL 549
IS 7672
BP 379
EP +
DI 10.1038/nature23897
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FH7PB
UT WOS:000411381300034
PM 28902843
DA 2026-03-09
ER

PT J
AU Schoebel, S
   Mi, W
   Stein, A
   Ovchinnikov, S
   Pavlovicz, R
   DiMaio, F
   Baker, D
   Chambers, MG
   Su, HY
   Li, DS
   Rapoport, TA
   Liao, MF
AF Schoebel, Stefan
   Mi, Wei
   Stein, Alexander
   Ovchinnikov, Sergey
   Pavlovicz, Ryan
   DiMaio, Frank
   Baker, David
   Chambers, Melissa G.
   Su, Huayou
   Li, Dongsheng
   Rapoport, Tom A.
   Liao, Maofu
TI Cryo-EM structure of the protein-conducting ERAD channel Hrd1 in complex with Hrd3
SO NATURE
LA English
DT Article
ID endoplasmic-reticulum degradation; x-ray-structure; ubiquitin-ligase; web server; membrane-proteins; quality-control; prediction; alignment; translocation; microscopy
AB Misfolded endoplasmic reticulum proteins are retro-translocated through the membrane into the cytosol, where they are poly-ubiquitinated, extracted from the membrane, and degraded by the proteasome(1-4)-a pathway termed endoplasmic reticulum-associated protein degradation (ERAD). Proteins with misfolded domains in the endoplasmic reticulum lumen or membrane are discarded through the ERAD-L and ERAD-M pathways, respectively. In Saccharomyces cerevisiae, both pathways require the ubiquitin ligase Hrd1, a multi-spanning membrane protein with a cytosolic RING finger domain(5,6). Hrd1 is the crucial membrane component for retro-translocation(7,8), but it is unclear whether it forms a protein-conducting channel. Here we present a cryo-electron microscopy structure of S. cerevisiae Hrd1 in complex with its endoplasmic reticulum luminal binding partner, Hrd3. Hrd1 forms a dimer within the membrane with one or two Hrd3 molecules associated at its luminal side. Each Hrd1 molecule has eight transmembrane segments, five of which form an aqueous cavity extending from the cytosol almost to the endoplasmic reticulum lumen, while a segment of the neighbouring Hrd1 molecule forms a lateral seal. The aqueous cavity and lateral gate are reminiscent of features of protein-conducting conduits that facilitate polypeptide movement in the opposite direction-from the cytosol into or across membranes(9-11). Our results suggest that Hrd1 forms a retro-translocation channel for the movement of misfolded polypeptides through the endoplasmic reticulum membrane.
C1 [Schoebel, Stefan; Rapoport, Tom A.] Harvard Med Sch, Howard Hughes Med Inst, 240 Longwood Ave, Boston, MA 02115 USA.
   [Schoebel, Stefan; Mi, Wei; Chambers, Melissa G.; Rapoport, Tom A.; Liao, Maofu] Harvard Med Sch, Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 USA.
   [Stein, Alexander] Max Planck Inst Biophys Chem, D-37077 Gottingen, Germany.
   [Ovchinnikov, Sergey; Pavlovicz, Ryan; DiMaio, Frank; Baker, David] Univ Washington, Inst Prot Design, Seattle, WA 98195 USA.
   [Su, Huayou; Li, Dongsheng] Natl Univ Def Technol, Sch Comp Sci, Natl Lab Parallel & Distributed Proc PDL, Changsha, Hunan, Peoples R China.
   [Schoebel, Stefan] Univ Gothenburg, Dept Chem & Mol Biol, S-40530 Gothenburg, Sweden.
C3 Howard Hughes Medical Institute; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Max Planck Society; University of Washington; University of Washington Seattle; National University of Defense Technology - China; University of Gothenburg
RP Rapoport, TA (corresponding author), Harvard Med Sch, Howard Hughes Med Inst, 240 Longwood Ave, Boston, MA 02115 USA.; Rapoport, TA; Liao, MF (corresponding author), Harvard Med Sch, Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 USA.
EM tom_rapoport@hms.harvard.edu; maofu_liao@hms.harvard.edu
FU European Molecular Biology Organization (EMBO LTF) [1437-2012]; European Research Council (ERC) under the Horizon 2020 research and innovation program [677770]; National Key Research and Development Program of China [2016YFB1000101]; NIGMS Award [R01GM052586]; National Institute of General Medical Sciences [R01GM052586] Funding Source: NIH RePORTER; European Research Council (ERC) [677770] Funding Source: European Research Council (ERC)
NR 51
TC 152
Z9 179
U1 1
U2 58
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 17
PY 2017
VL 548
IS 7667
BP 352
EP +
DI 10.1038/nature23314
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FD8AU
UT WOS:000407748400037
PM 28682307
DA 2026-03-09
ER

PT J
AU Torrejon, J
   Riou, M
   Araujo, FA
   Tsunegi, S
   Khalsa, G
   Querlioz, D
   Bortolotti, P
   Cros, V
   Yakushiji, K
   Fukushima, A
   Kubota, H
   Uasa, SY
   Stiles, MD
   Grollier, J
AF Torrejon, Jacob
   Riou, Mathieu
   Araujo, Flavio Abreu
   Tsunegi, Sumito
   Khalsa, Guru
   Querlioz, Damien
   Bortolotti, Paolo
   Cros, Vincent
   Yakushiji, Kay
   Fukushima, Akio
   Kubota, Hitoshi
   Uasa, Shinji Y.
   Stiles, Mark D.
   Grollier, Julie
TI Neuromorphic computing with nanoscale spintronic oscillators
SO NATURE
LA English
DT Article
ID driven
AB Neurons in the brain behave as nonlinear oscillators, which develop rhythmic activity and interact to process information(1). Taking inspiration from this behaviour to realize high-density, low-power neuromorphic computing will require very large numbers of nanoscale nonlinear oscillators. A simple estimation indicates that to fit 10(8) oscillators organized in a two-dimensional array inside a chip the size of a thumb, the lateral dimension of each oscillator must be smaller than one micrometre. However, nanoscale devices tend to be noisy and to lack the stability that is required to process data in a reliable way. For this reason, despite multiple theoretical proposals(2-5) and several candidates, including memristive(6) and superconducting(7) oscillators, a proof of concept of neuromorphic computing using nanoscale oscillators has yet to be demonstrated. Here we show experimentally that a nanoscale spintronic oscillator (a magnetic tunnel junction)(8,9) can be used to achieve spoken-digit recognition with an accuracy similar to that of state-of-the-art neural networks. We also determine the regime of magnetization dynamics that leads to the greatest performance. These results, combined with the ability of the spintronic oscillators to interact with each other, and their long lifetime and low energy consumption, open up a path to fast, parallel, on-chip computation based on networks of oscillators.
C1 [Torrejon, Jacob; Riou, Mathieu; Araujo, Flavio Abreu; Bortolotti, Paolo; Cros, Vincent; Grollier, Julie] Univ Paris Saclay, Univ Paris Sud, Thales, CNRS,Unite Mixte Phys, F-91767 Palaiseau, France.
   [Tsunegi, Sumito; Yakushiji, Kay; Fukushima, Akio; Kubota, Hitoshi; Uasa, Shinji Y.; Stiles, Mark D.] Natl Inst Adv Ind Sci & Technol, Spintron Res Ctr, Tsukuba, Ibaraki 3058568, Japan.
   [Khalsa, Guru; Stiles, Mark D.] NIST, Ctr Nanoscale Sci & Technol, Gaithersburg, MD 20899 USA.
   [Querlioz, Damien] Univ Paris Saclay, Univ Paris Sud, CNRS, Ctr Nanosci & Nanotechnol, F-91405 Orsay, France.
   [Khalsa, Guru] Cornell Univ, Dept Mat Sci & Engn, Ithaca, NY 14853 USA.
C3 Centre National de la Recherche Scientifique (CNRS); Universite Paris Saclay; Institut Polytechnique de Paris; Ecole Polytechnique; Thales Group; National Institute of Advanced Industrial Science & Technology (AIST); National Institute of Standards & Technology (NIST) - USA; Centre National de la Recherche Scientifique (CNRS); Universite Paris Cite; Universite Paris Saclay; Cornell University
RP Grollier, J (corresponding author), Univ Paris Saclay, Univ Paris Sud, Thales, CNRS,Unite Mixte Phys, F-91767 Palaiseau, France.
EM julie.grollier@cnrs-thales.fr
FU European Research Council (ERC) [bioSPINspired 682955]
NR 30
TC 1114
Z9 1215
U1 22
U2 496
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 27
PY 2017
VL 547
IS 7664
BP 428
EP +
DI 10.1038/nature23011
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FB7ZK
UT WOS:000406358300030
PM 28748930
DA 2026-03-09
ER

PT J
AU Dominici, C
   Moreno-Bravo, JA
   Puiggros, SR
   Rappeneau, Q
   Rama, N
   Vieugue, P
   Bernet, A
   Mehlen, P
   Chédotal, A
AF Dominici, Chloe
   Moreno-Bravo, Juan Antonio
   Puiggros, Sergi Roig
   Rappeneau, Quentin
   Rama, Nicolas
   Vieugue, Pauline
   Bernet, Agnes
   Mehlen, Patrick
   Chedotal, Alain
TI Floor-plate-derived netrin-1 is dispensable for commissural axon guidance
SO NATURE
LA English
DT Article
ID expression pattern; cell; protein; rig-1/robo3; regulator; hindbrain; gradient; family; mice
AB Netrin-1 is an evolutionarily conserved, secreted extracellular matrix protein involved in axon guidance at the central nervous system midline(1,2). Netrin-1 is expressed by cells localized at the central nervous system midline, such as those of the floor plate in vertebrate embryos(1,3). Growth cone turning assays and three-dimensional gel diffusion assays have shown that netrin-1 can attract commissural axons(2,4-6). Loss-of-function experiments further demonstrated that commissural axon extension to the midline is severely impaired in the absence of netrin-1 (refs 3, 7-9). Together, these data have long supported a model in which commissural axons are attracted by a netrin-1 gradient diffusing from the midline. Here we selectively ablate netrin-1 expression in floor-plate cells using a Ntn1 conditional knockout mouse line. We find that hindbrain and spinal cord commissural axons develop normally in the absence of floor-plate-derived netrin-1. Furthermore, we show that netrin-1 is highly expressed by cells in the ventricular zone, which can release netrin-1 at the pial surface where it binds to commissural axons. Notably, Ntn1 deletion from the ventricular zone phenocopies commissural axon guidance defects previously described in Ntn1-knockout mice. These results show that the classical view that attraction of commissural axons is mediated by a gradient of floor-plate-derived netrin-1 is inaccurate and that netrin-1 primarily acts locally by promoting growth cone adhesion.
C1 [Dominici, Chloe; Moreno-Bravo, Juan Antonio; Puiggros, Sergi Roig; Rappeneau, Quentin; Chedotal, Alain] UPMC Paris 06, Sorbonne Univ, INSERM, CNRS,Inst Vis, 17 Rue Moreau, F-75012 Paris, France.
   [Puiggros, Sergi Roig; Rama, Nicolas; Vieugue, Pauline; Bernet, Agnes; Mehlen, Patrick] Univ Lyon, Ctr Rech Cancerol Lyon, INSERM CNRS UMR5286 U1052,LabEx DEVweCAN, Apoptosis,Canc & Dev Lab,Ctr Leon Berard,Equipe L, F-69008 Lyon, France.
C3 Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); Sorbonne Universite; UNICANCER; Centre Leon Berard; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite Lyon 1
RP Chédotal, A (corresponding author), UPMC Paris 06, Sorbonne Univ, INSERM, CNRS,Inst Vis, 17 Rue Moreau, F-75012 Paris, France.; Mehlen, P (corresponding author), Univ Lyon, Ctr Rech Cancerol Lyon, INSERM CNRS UMR5286 U1052,LabEx DEVweCAN, Apoptosis,Canc & Dev Lab,Ctr Leon Berard,Equipe L, F-69008 Lyon, France.
EM patrick.mehlen@lyon.unicancer.fr; alain.chedotal@inserm.fr
FU Agence Nationale de la Recherche [ANR-14-CE13-0004-01]; French state funds [ANR-10-LABX-65, ANR-11-IDEX-0004-02]; INCA; ERC; ANR; Fondation Bettencourt; Fondation pour la recherche medicale; Agence Nationale de la Recherche (ANR) [ANR-14-CE13-0004] Funding Source: Agence Nationale de la Recherche (ANR)
NR 32
TC 144
Z9 184
U1 0
U2 46
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 18
PY 2017
VL 545
IS 7654
BP 350
EP +
DI 10.1038/nature22331
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV0WF
UT WOS:000401466500063
PM 28445456
DA 2026-03-09
ER

PT J
AU Berlow, RB
   Dyson, HJ
   Wright, PE
AF Berlow, Rebecca B.
   Dyson, H. Jane
   Wright, Peter E.
TI Hypersensitive termination of the hypoxic response by a disordered protein switch
SO NATURE
LA English
DT Article
ID creb-binding protein; intrinsic disorder; structural basis; inducible factor-1-alpha; taz1 domain; allostery; cited2; transactivation; hydroxylation; hif-1-alpha
AB The cellular response to hypoxia is critical for cell survival and is fine-tuned to allow cells to recover from hypoxic stress and adapt to heterogeneous or fluctuating oxygen levels(1,2). The hypoxic response is mediated by the a-subunit of the transcription factor HIF-1 (HIF-1 alpha)(3), which interacts through its intrinsically disordered C-terminal transactivation domain with the TAZ1 (also known as CH1) domain of the general transcriptional coactivators CBP and p300 to control the transcription of critical adaptive genes(4-6). One such gene encodes CITED2, a negative feedback regulator that attenuates HIF-1 transcriptional activity by competing for TAZ1 binding through its own disordered transactivation domain(7-9). Little is known about the molecular mechanism by which CITED2 displaces the tightly bound HIF-1 alpha from their common cellular target. The HIF-1 alpha and CITED2 transactivation domains bind to TAZ1 through helical motifs that flank a conserved LP(Q/ E) L sequence that is essential for negative feedback regulation(5,6,8,9). Here we show that human CITED2 displaces HIF-1 alpha by forming a transient ternary complex with TAZ1 and HIF-1 alpha and competing for a shared binding site through its LPEL motif, thus promoting a conformational change in TAZ1 that increases the rate of HIF-1 alpha dissociation. Through allosteric enhancement of HIF-1 alpha release, CITED2 activates a highly responsive negative feedback circuit that rapidly and efficiently attenuates the hypoxic response, even at modest CITED2 concentrations. This hypersensitive regulatory switch is entirely dependent on the unique flexibility and binding properties of these intrinsically disordered proteins and probably exemplifies a common strategy used by the cell to respond rapidly to environmental signals.
C1 [Berlow, Rebecca B.; Dyson, H. Jane; Wright, Peter E.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA.
   [Berlow, Rebecca B.; Dyson, H. Jane; Wright, Peter E.] Scripps Res Inst, Skaggs Inst Chem Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA.
C3 Scripps Research Institute; Scripps Research Institute
RP Wright, PE (corresponding author), Scripps Res Inst, Dept Integrat Struct & Computat Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA.; Wright, PE (corresponding author), Scripps Res Inst, Skaggs Inst Chem Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA.
EM wright@scripps.edu
FU National Institutes of Health [CA096865]; Skaggs Institute for Chemical Biology; American Cancer Society [125343-PF-13-202-01-DMC]
NR 30
TC 142
Z9 163
U1 0
U2 65
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 16
PY 2017
VL 543
IS 7645
BP 447
EP +
DI 10.1038/nature21705
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN9RN
UT WOS:000396337400056
PM 28273070
DA 2026-03-09
ER

PT J
AU Ortiz-Ramírez, C
   Michard, E
   Simon, AA
   Damineli, DSC
   Hernández-Coronado, M
   Becker, JD
   Feijó, JA
AF Ortiz-Ramirez, Carlos
   Michard, Erwan
   Simon, Alexander A.
   Damineli, Daniel S. C.
   Hernandez-Coronado, Marcela
   Becker, Jorg D.
   Feijo, Jose A.
TI GLUTAMATE RECEPTOR-LIKE channels are essential for chemotaxis and reproduction in mosses
SO NATURE
LA English
DT Article
ID physcomitrella-patens; expression; arabidopsis; evolution; gene; calcium; sperm; identification; family; plants
AB Glutamate receptors are well characterized channels that mediate cell-to-cell communication during neurotransmission in animals, but their functional role in organisms without a nervous system remains unclear. In plants, genes of the GLUTAMATE RECEPTOR-LIKE (GLR) family have been implicated in defence against pathogens, reproduction, control of stomata aperture and light signal transduction(1-5). However, the large number of GLR genes present in angiosperm genomes (20 to 70)(6) has prevented the observation of strong phenotypes in loss-of-function mutants. Here we show that in the basal land plant Physcomitrella patens, mutation of the GLR genes GLR1 and GLR2 causes failure of sperm cells to target the female reproductive organs. In addition, we show that GLR genes encode non-selective Ca2+-permeable channels that can regulate cytoplasmic Ca2+ and are needed to induce the expression of a BELL1-like transcription factor essential for zygote development. Our work reveals functions for GLR channels in sperm chemotaxis and transcriptional regulation. Sperm chemotaxis is essential for fertilization in both animals and early land plants such as bryophytes and pteridophytes. Therefore, our results suggest that ionotropic glutamate receptors may have been conserved throughout plant evolution to mediate cell-to-cell communication during sexual reproduction.
C1 [Ortiz-Ramirez, Carlos; Michard, Erwan; Hernandez-Coronado, Marcela; Becker, Jorg D.; Feijo, Jose A.] Inst Gulbenkian Ciencias, P-2780156 Oeiras, Portugal.
   [Michard, Erwan; Simon, Alexander A.; Damineli, Daniel S. C.; Feijo, Jose A.] Univ Maryland, Dept Cell Biol & Mol Genet, 0118 BioSci Res Bldg, College Pk, MD 20742 USA.
   [Ortiz-Ramirez, Carlos; Hernandez-Coronado, Marcela] NYU, Dept Biol, Ctr Genom & Syst Biol, 12 Waverly Pl, New York, NY 10003 USA.
C3 Instituto Gulbenkian de Ciencia; University System of Maryland; University of Maryland College Park; New York University
RP Feijó, JA (corresponding author), Inst Gulbenkian Ciencias, P-2780156 Oeiras, Portugal.; Feijó, JA (corresponding author), Univ Maryland, Dept Cell Biol & Mol Genet, 0118 BioSci Res Bldg, College Pk, MD 20742 USA.
EM jfeijo@umd.edu
FU MarieCurie ITN-Plant Origins (FP7-PEOPLE-ITN); Fundacao para a Ciencua e Tecnologia (FCT)-Portugal [BEX-BCM/0376/2012, PTDC/BIA-PLA/4018/2012]; National Science Foundation (NSF)-US [MCB 1616437/2016]; Div Of Molecular and Cellular Bioscience; Direct For Biological Sciences [1616437] Funding Source: National Science Foundation; Fundação para a Ciência e a Tecnologia [PTDC/BIA-PLA/4018/2012, PTDC/BEX-BCM/0376/2012] Funding Source: FCT
NR 30
TC 101
Z9 112
U1 6
U2 123
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 7
PY 2017
VL 549
IS 7670
BP 91
EP +
DI 10.1038/nature23478
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG0DH
UT WOS:000409388700039
PM 28737761
DA 2026-03-09
ER

PT J
AU Kossin, JP
AF Kossin, James P.
TI Hurricane intensification along United States coast suppressed during active hurricane periods
SO NATURE
LA English
DT Article
ID tropical cyclone intensity; extreme storms state; understanding trends; atlantic hurricanes; variability; landfall; shear
AB The North Atlantic ocean/atmosphere environment exhibits pronounced interdecadal variability that is known to strongly modulate Atlantic hurricane activity(1-6). Variability in sea surface temperature (SST) is correlated with hurricane variability through its relationship with the genesis and thermodynamic potential intensity of hurricanes(7). Another key factor that governs the genesis and intensity of hurricanes is ambient environmental vertical wind shear(8-10) (VWS). Warmer SSTs generally correlate with more frequent genesis and greater potential intensity, while VWS inhibits genesis and prevents any hurricanes that do form from reaching their potential intensity. When averaged over the main hurricane-development region in the Atlantic, SST and VWS co-vary inversely(11,12), so that the two factors act in concert to either enhance or inhibit basin-wide hurricane activity. Here I show, however, that conditions conducive to greater basin-wide Atlantic hurricane activity occur together with conditions for more probable weakening of hurricanes near the United States coast. Thus, the VWS and SST form a protective barrier along the United States coast during periods of heightened basin-wide hurricane activity. Conversely, during the most-recent period of basin-wide quiescence, hurricanes (and particularly major hurricanes) near the United States coast, although substantially less frequent, exhibited much greater variability in their rate of intensification, and were much more likely to intensify rapidly. Such heightened variability poses greater challenges to operational forecasting and, consequently, greater coastal risk during hurricane events.
C1 [Kossin, James P.] NOAA, Natl Ctr Environm Informat, Ctr Weather & Climate, 1225 W Dayton St, Madison, WI 53706 USA.
C3 National Oceanic Atmospheric Admin (NOAA) - USA
RP Kossin, JP (corresponding author), NOAA, Natl Ctr Environm Informat, Ctr Weather & Climate, 1225 W Dayton St, Madison, WI 53706 USA.
EM james.kossin@noaa.gov
NR 30
TC 67
Z9 76
U1 4
U2 52
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 19
PY 2017
VL 541
IS 7637
BP 390
EP +
DI 10.1038/nature20783
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6QP
UT WOS:000396128800041
PM 28052058
DA 2026-03-09
ER

PT J
AU Shlush, LI
   Mitchell, A
   Heisler, L
   Abelson, S
   Ng, SWK
   Trotman-Grant, A
   Medeiros, JJF
   Rao-Bhatia, A
   Jaciw-Zurakowsky, I
   Marke, R
   McLeod, JL
   Doedens, M
   Bader, G
   Voisin, V
   Xu, CJ
   McPherson, JD
   Hudson, TJ
   Wang, JCY
   Minden, MD
   Dick, JE
AF Shlush, Liran I.
   Mitchell, Amanda
   Heisler, Lawrence
   Abelson, Sagi
   Ng, Stanley W. K.
   Trotman-Grant, Aaron
   Medeiros, Jessie J. F.
   Rao-Bhatia, Abilasha
   Jaciw-Zurakowsky, Ivana
   Marke, Rene
   McLeod, Jessica L.
   Doedens, Monica
   Bader, Gary
   Voisin, Veronique
   Xu, ChangJiang
   McPherson, John D.
   Hudson, Thomas J.
   Wang, Jean C. Y.
   Minden, Mark D.
   Dick, John E.
TI Tracing the origins of relapse in acute myeloid leukaemia to stem cells
SO NATURE
LA English
DT Article
ID clonal evolution; somatic mutations; chemotherapy; mice; transplantation; sensitivity; resistance; diagnosis
AB In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission(1). Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs(2). However, other lines of evidence have pointed to the pre-existence of drug-resistant cells(3). For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy(3-5), suggesting that resistant cells are generated by evolutionary processes before treatment(3) and are selected by therapy(6-8). Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells(9,10) have been linked to relapse owing to their dormancy and self-renewal properties(11-13), and leukaemia stem cell gene expression signatures are highly predictive of therapy failure(14,15), experimental studies have been primarily correlative(7) and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse.
C1 [Shlush, Liran I.; Mitchell, Amanda; Abelson, Sagi; Ng, Stanley W. K.; Trotman-Grant, Aaron; Medeiros, Jessie J. F.; Rao-Bhatia, Abilasha; Jaciw-Zurakowsky, Ivana; McLeod, Jessica L.; Doedens, Monica; Wang, Jean C. Y.; Minden, Mark D.; Dick, John E.] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada.
   [Shlush, Liran I.] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel.
   [Shlush, Liran I.] Div Hematol, Rambam Healthcare Campus, IL-31096 Haifa, Israel.
   [Heisler, Lawrence; McPherson, John D.; Hudson, Thomas J.] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada.
   [Marke, Rene] Radboud Univ Nijmegen, Lab Pediat Oncol, Med Ctr, NL-6525 GA Nijmegen, Netherlands.
   [Bader, Gary; Dick, John E.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada.
   [Bader, Gary; Voisin, Veronique; Xu, ChangJiang] Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada.
   [Hudson, Thomas J.; Minden, Mark D.] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada.
   [Wang, Jean C. Y.; Minden, Mark D.] Univ Toronto, Dept Med, Toronto, ON M5S 1A8, Canada.
   [Wang, Jean C. Y.; Minden, Mark D.] Univ Hlth Network, Div Med Oncol & Hematol, Toronto, ON M5G 2M9, Canada.
C3 University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; Weizmann Institute of Science; Technion Israel Institute of Technology; Rambam Health Care Campus; University of Toronto; Ontario Institute for Cancer Research; Radboud University Nijmegen; University of Toronto; University of Toronto; University of Toronto; University of Toronto; University of Toronto; University Health Network Toronto
RP Dick, JE (corresponding author), Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada.; Dick, JE (corresponding author), Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada.
EM jdick@uhnresearch.ca
FU Ontario Institute for Cancer Research; province of Ontario; Cancer Stem Cell Consortium; Government of Canada through Genome Canada; Ontario Genomics Institute [OGI-047]; Canadian Institutes of Health Research [CSC-105367]; Canadian Cancer Society; Terry Fox Foundation; Canada Research Chair; Benjamin Pearl fellowship from McEwen Centre for Regenerative Medicine; American Society of Hematology; Ontario Ministry of Health and Long Term Care
NR 32
TC 454
Z9 535
U1 3
U2 112
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 6
PY 2017
VL 547
IS 7661
BP 104
EP +
DI 10.1038/nature22993
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EZ6PM
UT WOS:000404839900039
PM 28658204
DA 2026-03-09
ER

PT J
AU Zhao, WY
   Liu, ZY
   Sun, ZG
   Zhang, QJ
   Wei, P
   Mu, X
   Zhou, HY
   Li, CC
   Ma, SF
   He, DQ
   Ji, PX
   Zhu, WT
   Nie, XL
   Su, XL
   Tang, XF
   Shen, BG
   Dong, XL
   Yang, JH
   Liu, Y
   Shi, J
AF Zhao, Wenyu
   Liu, Zhiyuan
   Sun, Zhigang
   Zhang, Qingjie
   Wei, Ping
   Mu, Xin
   Zhou, Hongyu
   Li, Cuncheng
   Ma, Shifang
   He, Danqi
   Ji, Pengxia
   Zhu, Wanting
   Nie, Xiaolei
   Su, Xianli
   Tang, Xinfeng
   Shen, Baogen
   Dong, Xiaoli
   Yang, Jihui
   Liu, Yong
   Shi, Jing
TI Superparamagnetic enhancement of thermoelectric performance
SO NATURE
LA English
DT Article
ID bulk materials; work function; size; temperature; transition; dependence; transport; barium; power; glass
AB The ability to control chemical and physical structuring at the nanometre scale is important for developing high-performance thermoelectric materials(1). Progress in this area has been achieved mainly by enhancing phonon scattering and consequently decreasing the thermal conductivity of the lattice through the design of either interface structures at nanometre or mesoscopic length scales(2-6) or multiscale hierarchical architectures(7,8). A nanostructuring approach that enables electron transport as well as phonon transport to be manipulated could potentially lead to further enhancements in thermoelectric performance. Here we show that by embedding nanoparticles of a soft magnetic material in a thermoelectric matrix we achieve dual control of phonon-and electron-transport properties. The properties of the nanoparticles-in particular, their superparamagnetic behaviour (in which the nanoparticles can be magnetized similarly to a paramagnet under an external magnetic field)-lead to three kinds of thermoelectromagnetic effect: charge transfer from the magnetic inclusions to the matrix; multiple scattering of electrons by superparamagnetic fluctuations; and enhanced phonon scattering as a result of both the magnetic fluctuations and the nanostructures themselves. We show that together these effects can effectively manipulate electron and phonon transport at nanometre and mesoscopic length scales and thereby improve the thermoelectric performance of the resulting nanocomposites.
C1 [Zhao, Wenyu; Liu, Zhiyuan; Sun, Zhigang; Zhang, Qingjie; Wei, Ping; Mu, Xin; Zhou, Hongyu; Li, Cuncheng; Ma, Shifang; He, Danqi; Ji, Pengxia; Zhu, Wanting; Nie, Xiaolei; Su, Xianli; Tang, Xinfeng] Wuhan Univ Technol, State Key Lab Adv Technol Mat Synth & Proc, Wuhan 430070, Hubei, Peoples R China.
   [Shen, Baogen; Dong, Xiaoli] Chinese Acad Sci, Inst Phys, Beijing Natl Lab Condensed Matter Phys, Beijing 100190, Peoples R China.
   [Yang, Jihui] Univ Washington, Dept Mat Sci & Engn, Seattle, WA 98195 USA.
   [Liu, Yong; Shi, Jing] Wuhan Univ, Sch Phys & Technol, Wuhan 430072, Hubei, Peoples R China.
C3 Wuhan University of Technology; Chinese Academy of Sciences; Institute of Physics, CAS; University of Washington; University of Washington Seattle; Wuhan University
RP Zhang, QJ (corresponding author), Wuhan Univ Technol, State Key Lab Adv Technol Mat Synth & Proc, Wuhan 430070, Hubei, Peoples R China.; Yang, JH (corresponding author), Univ Washington, Dept Mat Sci & Engn, Seattle, WA 98195 USA.
EM zhangqj@whut.edu.cn; jihuiy@uw.edu
FU National Natural Science Foundation of China [51620105014, 11274248, 51572210, 51521001]; National Basic Research Program of China (973-program) [2013CB632505]
NR 45
TC 584
Z9 626
U1 18
U2 1018
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 14
PY 2017
VL 549
IS 7671
BP 247
EP +
DI 10.1038/nature23667
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FG7AE
UT WOS:000410555900040
PM 28905895
DA 2026-03-09
ER

PT J
AU Gazibegovic, S
   Car, D
   Zhang, H
   Balk, SC
   Logan, JA
   de Moor, MWA
   Cassidy, MC
   Schmits, R
   Xu, D
   Wang, GZ
   Krogstrup, P
   Veld, RLMOH
   Zuo, K
   Vos, Y
   Shen, J
   Bouman, D
   Hojaei, BS
   Pennachio, D
   Lee, JS
   van Veldhoven, PJ
   Koelling, S
   Verheijen, MA
   Kouwenhoven, LP
   Palmstrom, CJ
   Bakkers, EPAM
AF Gazibegovic, Sasa
   Car, Diana
   Zhang, Hao
   Balk, Stijn C.
   Logan, John A.
   de Moor, Michiel W. A.
   Cassidy, Maja C.
   Schmits, Rudi
   Xu, Di
   Wang, Guanzhong
   Krogstrup, Peter
   Veld, Roy L. M. Op het
   Zuo, Kun
   Vos, Yoram
   Shen, Jie
   Bouman, Daniel
   Hojaei, Borzoyeh S.
   Pennachio, Daniel
   Lee, Joon Sue
   van Veldhoven, Petrus J.
   Koelling, Sebastian
   Verheijen, Marcel A.
   Kouwenhoven, Leo P.
   Palmstrom, Chris J.
   Bakkers, Erik P. A. M.
TI RETRACTED: Epitaxy of advanced nanowire quantum devices (Retracted article. See vol. 604, pg. 786, 2022)
SO NATURE
LA English
DT Article; Retracted Publication
ID inas; transport; field
AB Semiconductor nanowires are ideal for realizing various low-dimensional quantum devices. In particular, topological phases of matter hosting non-Abelian quasiparticles (such as anyons) can emerge when a semiconductor nanowire with strong spin-orbit coupling is brought into contact with a superconductor(1,2). To exploit the potential of non-Abelian anyons-which are key elements of topological quantum computing-fully, they need to be exchanged in a well-controlled braiding operation(3-8). Essential hardware for braiding is a network of crystalline nanowires coupled to superconducting islands. Here we demonstrate a technique for generic bottom-up synthesis of complex quantum devices with a special focus on nanowire networks with a predefined number of superconducting islands. Structural analysis confirms the high crystalline quality of the nanowire junctions, as well as an epitaxial superconductor-semiconductor interface. Quantum transport measurements of nanowire 'hashtags' reveal Aharonov-Bohm and weak-antilocalization effects, indicating a phase-coherent system with strong spin-orbit coupling. In addition, a proximity-induced hard superconducting gap (with vanishing sub-gap conductance) is demonstrated in these hybrid superconductor-semiconductor nanowires, highlighting the successful materials development necessary for a first braiding experiment. Our approach opens up new avenues for the realization of epitaxial three-dimensional quantum architectures which have the potential to become key components of various quantum devices.
C1 [Gazibegovic, Sasa; Car, Diana; Zhang, Hao; Balk, Stijn C.; de Moor, Michiel W. A.; Cassidy, Maja C.; Xu, Di; Wang, Guanzhong; Veld, Roy L. M. Op het; Zuo, Kun; Vos, Yoram; Shen, Jie; Bouman, Daniel; Kouwenhoven, Leo P.; Bakkers, Erik P. A. M.] Delft Univ Technol, QuTech, NL-2600 GA Delft, Netherlands.
   [Gazibegovic, Sasa; Car, Diana; Zhang, Hao; Balk, Stijn C.; de Moor, Michiel W. A.; Cassidy, Maja C.; Xu, Di; Wang, Guanzhong; Veld, Roy L. M. Op het; Zuo, Kun; Vos, Yoram; Shen, Jie; Bouman, Daniel; Kouwenhoven, Leo P.; Bakkers, Erik P. A. M.] Delft Univ Technol, Kavli Inst NanoSci, NL-2600 GA Delft, Netherlands.
   [Gazibegovic, Sasa; Car, Diana; Veld, Roy L. M. Op het; van Veldhoven, Petrus J.; Koelling, Sebastian; Verheijen, Marcel A.; Bakkers, Erik P. A. M.] Eindhoven Univ Technol, Dept Appl Phys, NL-5600 MB Eindhoven, Netherlands.
   [Logan, John A.; Hojaei, Borzoyeh S.; Pennachio, Daniel; Palmstrom, Chris J.] Univ Calif Santa Barbara, Dept Mat, Santa Barbara, CA 93106 USA.
   [Schmits, Rudi] TNO Tech Sci, Nanoinstrumentat Dept, NL-2600 AD Delft, Netherlands.
   [Krogstrup, Peter] Univ Copenhagen, Ctr Quantum Devices, Niels Bohr Inst, DK-2100 Copenhagen, Denmark.
   [Krogstrup, Peter] Univ Copenhagen, Stn Q Copenhagen, Niels Bohr Inst, DK-2100 Copenhagen, Denmark.
   [Lee, Joon Sue; Palmstrom, Chris J.] Univ Calif Santa Barbara, Calif NanoSyst Inst, Santa Barbara, CA 93106 USA.
   [Verheijen, Marcel A.] Philips Innovat Serv Eindhoven, High Tech Campus 11, NL-5656 AE Eindhoven, Netherlands.
   [Kouwenhoven, Leo P.] Delft Univ Technol, Microsoft Stn Q, NL-2600 GA Delft, Netherlands.
   [Palmstrom, Chris J.] Univ Calif Santa Barbara, Elect & Comp Engn, Santa Barbara, CA 93106 USA.
C3 Delft University of Technology; Delft University of Technology; Eindhoven University of Technology; University of California System; University of California Santa Barbara; Netherlands Organization Applied Science Research; University of Copenhagen; Niels Bohr Institute; University of Copenhagen; Niels Bohr Institute; University of California System; University of California Santa Barbara; Philips; Delft University of Technology; University of California System; University of California Santa Barbara
RP Bakkers, EPAM (corresponding author), Delft Univ Technol, QuTech, NL-2600 GA Delft, Netherlands.; Bakkers, EPAM (corresponding author), Delft Univ Technol, Kavli Inst NanoSci, NL-2600 GA Delft, Netherlands.; Bakkers, EPAM (corresponding author), Eindhoven Univ Technol, Dept Appl Phys, NL-5600 MB Eindhoven, Netherlands.
EM e.p.a.m.bakkers@tue.nl
FU European Research Council [ERC HELENA 617256]; Dutch Organization for Scientific Research [NWO-VICI 700.10.441]; Foundation for Fundamental Research on Matter (FOM); Microsoft Corporation Station-Q; Solliance, a solar energy R&D initiative of ECN; TNO; Holst; TU/e; imec; Forschungszentrum Julich; Dutch province of Noord-Brabant; Office of Naval Research (ONR); Microsoft Research
NR 33
TC 221
Z9 237
U1 5
U2 245
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 24
PY 2017
VL 548
IS 7668
BP 434
EP +
DI 10.1038/nature23468
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FE5VI
UT WOS:000408279000034
PM 28836603
DA 2026-03-09
ER

PT J
AU Nonomura, K
   Woo, SH
   Chang, RB
   Gillich, A
   Qiu, Z
   Francisco, AG
   Ranade, SS
   Liberles, SD
   Patapoutian, A
AF Nonomura, Keiko
   Woo, Seung-Hyun
   Chang, Rui B.
   Gillich, Astrid
   Qiu, Zhaozhu
   Francisco, Allain G.
   Ranade, Sanjeev S.
   Liberles, Stephen D.
   Patapoutian, Ardem
TI Piezo2 senses airway stretch and mediates lung inflation-induced apnoea
SO NATURE
LA English
DT Article
ID hering-breuer reflex; distal arthrogryposis; respiratory-distress; vagal innervation; neural crest; dorsal-root; mouse lung; mice; neurons; channel
AB Respiratory dysfunction is a notorious cause of perinatal mortality in infants and sleep apnoea in adults, but the mechanisms of respiratory control are not clearly understood. Mechanical signals transduced by airway-innervating sensory neurons control respiration; however, the physiological significance and molecular mechanisms of these signals remain obscured. Here we show that global and sensory neuron-specific ablation of the mechanically activated ion channel Piezo2 causes respiratory distress and death in newborn mice. Optogenetic activation of Piezo2(+) vagal sensory neurons causes apnoea in adult mice. Moreover, induced ablation of Piezo2 in sensory neurons of adult mice causes decreased neuronal responses to lung inflation, an impaired Hering-Breuer mechanoreflex, and increased tidal volume under normal conditions. These phenotypes are reproduced in mice lacking Piezo2 in the nodose ganglion. Our data suggest that Piezo2 is an airway stretch sensor and that Piezo2-mediated mechanotransduction within various airway-innervating sensory neurons is critical for establishing efficient respiration at birth and maintaining normal breathing in adults.
C1 [Nonomura, Keiko; Woo, Seung-Hyun; Qiu, Zhaozhu; Francisco, Allain G.; Ranade, Sanjeev S.; Patapoutian, Ardem] Scripps Res Inst, Dorris Neurosci Ctr, Howard Hughes Med Inst, Mol & Cellular Neurosci, La Jolla, CA 92037 USA.
   [Chang, Rui B.; Liberles, Stephen D.] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
   [Gillich, Astrid] Stanford Univ, Sch Med, Howard Hughes Med Inst, Dept Biochem, Stanford, CA 94305 USA.
   [Qiu, Zhaozhu] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA.
   [Qiu, Zhaozhu] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA.
   [Qiu, Zhaozhu] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA.
   [Ranade, Sanjeev S.] Gladstone Inst, San Francisco, CA 94158 USA.
C3 Scripps Research Institute; Howard Hughes Medical Institute; Harvard University; Harvard Medical School; Stanford University; Howard Hughes Medical Institute; Novartis; Novartis USA; Johns Hopkins University; Johns Hopkins University; University of California System; University of California San Francisco; The J David Gladstone Institutes
RP Patapoutian, A (corresponding author), Scripps Res Inst, Dorris Neurosci Ctr, Howard Hughes Med Inst, Mol & Cellular Neurosci, La Jolla, CA 92037 USA.; Liberles, SD (corresponding author), Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
EM Stephen_Liberles@hms.harvard.edu; ardem@scripps.edu
FU NIH [R01DE022358, R01HL132255]; Giovanni Armenise-Harvard Foundation
NR 58
TC 331
Z9 398
U1 3
U2 128
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 12
PY 2017
VL 541
IS 7636
BP 176
EP +
DI 10.1038/nature20793
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN6PI
UT WOS:000396125500031
PM 28002412
DA 2026-03-09
ER

PT J
AU Smartt, SJ
   Chen, TW
   Jerkstrand, A
   Coughlin, M
   Kankare, E
   Sim, SA
   Fraser, M
   Inserra, C
   Maguire, K
   Chambers, KC
   Huber, ME
   Krühler, T
   Leloudas, G
   Magee, M
   Shingles, LJ
   Smith, KW
   Young, DR
   Tonry, J
   Kotak, R
   Gal-Yam, A
   Lyman, JD
   Homan, DS
   Agliozzo, C
   Anderson, JP
   Angus, CR
   Ashall, C
   Barbarino, C
   Bauer, FE
   Berton, M
   Botticella, MT
   Bulla, M
   Bulger, J
   Cannizzaro, G
   Cano, Z
   Cartier, R
   Cikota, A
   Clark, P
   De Cia, A
   Della Valle, M
   Denneau, L
   Dennefeld, M
   Dessart, L
   Dimitriadis, G
   Elias-Rosa, N
   Firth, RE
   Flewelling, H
   Flörs, A
   Franckowiak, A
   Frohmaier, C
   Galbany, L
   González-Gaitán, S
   Greiner, J
   Gromadzki, M
   Guelbenzu, AN
   Gutiérrez, CP
   Hamanowicz, A
   Hanlon, L
   Harmanen, J
   Heintz, KE
   Heinze, A
   Hernandez, MS
   Hodgkin, ST
   Hook, IM
   Izzo, L
   James, PA
   Jonker, PG
   Kerzendorf, WE
   Klose, S
   Kostrzewa-Rutkowska, Z
   Kowalski, M
   Kromer, M
   Kuncarayakti, H
   Lawrence, A
   Lowe, TB
   Magnier, EA
   Manulis, I
   Martin-Carrillo, A
   Mattila, S
   McBrien, O
   Müller, A
   Nordin, J
   O'Neill, D
   Onori, F
   Palmerio, JT
   Pastorello, A
   Patat, F
   Pignata, G
   Podsiadlowski, P
   Pumo, ML
   Prentice, SJ
   Rau, A
   Razza, A
   Rest, A
   Reynolds, T
   Roy, R
   Ruiter, AJ
   Rybicki, KA
   Salmon, L
   Schady, P
   Schultz, ASB
   Schweyer, T
   Seitenzahl, IR
   Smith, M
   Sollerman, J
   Stalder, B
   Stubbs, CW
   Sullivan, M
   Szegedi, H
   Taddia, F
   Taubenberger, S
   Terreran, G
   van Soelen, B
   Vos, J
   Wainscoat, RJ
   Walton, NA
   Waters, C
   Weiland, H
   Willman, M
   Wiseman, P
   Wright, DE
   Wyrzykowski, L
   Yaron, O
AF Smartt, S. J.
   Chen, T. -W.
   Jerkstrand, A.
   Coughlin, M.
   Kankare, E.
   Sim, S. A.
   Fraser, M.
   Inserra, C.
   Maguire, K.
   Chambers, K. C.
   Huber, M. E.
   Kruhler, T.
   Leloudas, G.
   Magee, M.
   Shingles, L. J.
   Smith, K. W.
   Young, D. R.
   Tonry, J.
   Kotak, R.
   Gal-Yam, A.
   Lyman, J. D.
   Homan, D. S.
   Agliozzo, C.
   Anderson, J. P.
   Angus, C. R.
   Ashall, C.
   Barbarino, C.
   Bauer, F. E.
   Berton, M.
   Botticella, M. T.
   Bulla, M.
   Bulger, J.
   Cannizzaro, G.
   Cano, Z.
   Cartier, R.
   Cikota, A.
   Clark, P.
   De Cia, A.
   Della Valle, M.
   Denneau, L.
   Dennefeld, M.
   Dessart, L.
   Dimitriadis, G.
   Elias-Rosa, N.
   Firth, R. E.
   Flewelling, H.
   Floers, A.
   Franckowiak, A.
   Frohmaier, C.
   Galbany, L.
   Gonzalez-Gaitan, S.
   Greiner, J.
   Gromadzki, M.
   Guelbenzu, A. Nicuesa
   Gutierrez, C. P.
   Hamanowicz, A.
   Hanlon, L.
   Harmanen, J.
   Heintz, K. E.
   Heinze, A.
   Hernandez, M. -S.
   Hodgkin, S. T.
   Hook, I. M.
   Izzo, L.
   James, P. A.
   Jonker, P. G.
   Kerzendorf, W. E.
   Klose, S.
   Kostrzewa-Rutkowska, Z.
   Kowalski, M.
   Kromer, M.
   Kuncarayakti, H.
   Lawrence, A.
   Lowe, T. B.
   Magnier, E. A.
   Manulis, I.
   Martin-Carrillo, A.
   Mattila, S.
   McBrien, O.
   Mueller, A.
   Nordin, J.
   O'Neill, D.
   Onori, F.
   Palmerio, J. T.
   Pastorello, A.
   Patat, F.
   Pignata, G.
   Podsiadlowski, Ph.
   Pumo, M. L.
   Prentice, S. J.
   Rau, A.
   Razza, A.
   Rest, A.
   Reynolds, T.
   Roy, R.
   Ruiter, A. J.
   Rybicki, K. A.
   Salmon, L.
   Schady, P.
   Schultz, A. S. B.
   Schweyer, T.
   Seitenzahl, I. R.
   Smith, M.
   Sollerman, J.
   Stalder, B.
   Stubbs, C. W.
   Sullivan, M.
   Szegedi, H.
   Taddia, F.
   Taubenberger, S.
   Terreran, G.
   van Soelen, B.
   Vos, J.
   Wainscoat, R. J.
   Walton, N. A.
   Waters, C.
   Weiland, H.
   Willman, M.
   Wiseman, P.
   Wright, D. E.
   Wyrzykowski, L.
   Yaron, O.
TI A kilonova as the electromagnetic counterpart to a gravitational-wave source
SO NATURE
LA English
DT Article
ID observatory supernova search; neutron-star; light curves; faint type; galaxy; rates; outflows; distance; elements; spectra
AB Gravitational waves were discovered with the detection of binary black-hole mergers(1) and they should also be detectable from lower-mass neutron-star mergers. These are predicted to eject material rich in heavy radioactive isotopes that can power an electromagnetic signal. This signal is luminous at optical and infrared wavelengths and is called a kilonova(2-5). The gravitational-wave source GW170817 arose from a binary neutron-star merger in the nearby Universe with a relatively well confined sky position and distance estimate(6). Here we report observations and physical modelling of a rapidly fading electromagnetic transient in the galaxy NGC 4993, which is spatially coincident with GW170817 and with a weak, short.-ray burst(7,8). The transient has physical parameters that broadly match the theoretical predictions of blue kilonovae from neutron-star mergers. The emitted electromagnetic radiation can be explained with an ejected mass of 0.04 +/- 0.01 solar masses, with an opacity of less than 0.5 square centimetres per gram, at a velocity of 0.2 +/- 0.1 times light speed. The power source is constrained to have a power-law slope of -1.2 +/- 0.3, consistent with radioactive powering from r-process nuclides. (The r-process is a series of neutron capture reactions that synthesise many of the elements heavier than iron.) We identify line features in the spectra that are consistent with light r-process elements (atomic masses of 90-140). As it fades, the transient rapidly becomes red, and a higher-opacity, lanthanide-rich ejecta component may contribute to the emission. This indicates that neutron-star mergers produce gravitational waves and radioactively powered kilonovae, and are a nucleosynthetic source of the r-process elements.
C1 [Smartt, S. J.; Kankare, E.; Sim, S. A.; Maguire, K.; Magee, M.; Shingles, L. J.; Smith, K. W.; Young, D. R.; Kotak, R.; Clark, P.; McBrien, O.; O'Neill, D.] Queens Univ Belfast, Sch Math & Phys, Astrophys Res Ctr, Belfast BT7 1NN, Antrim, North Ireland.
   [Chen, T. -W.; Kruhler, T.; Greiner, J.; Rau, A.; Schady, P.; Schweyer, T.; Wiseman, P.] Max Planck Inst Extraterr Phys, Giessenbach Str 1, D-85748 Munich, Germany.
   [Jerkstrand, A.; Floers, A.; Taubenberger, S.] Max Planck Inst Astrophys, Karl Schwarzschild Str 1, D-85748 Munich, Germany.
   [Coughlin, M.] LIGC Lab West Bridge, Room 257 Calif Inst Technol,MC 100-36, Pasadena, CA 91125 USA.
   [Fraser, M.; Hanlon, L.; Martin-Carrillo, A.; Salmon, L.] Univ Coll Dublin, Sch Phys OBrien Ctr Sci North, Dublin 4, Ireland.
   [Inserra, C.; Angus, C. R.; Cartier, R.; Dimitriadis, G.; Firth, R. E.; Gutierrez, C. P.; Smith, M.; Sullivan, M.] Univ Southampton, Dept Phys & Astron, Southampton SO17 1BJ, Hants, England.
   [Chambers, K. C.; Huber, M. E.; Tonry, J.; Bulger, J.; Denneau, L.; Flewelling, H.; Heinze, A.; Lowe, T. B.; Magnier, E. A.; Schultz, A. S. B.; Wainscoat, R. J.; Waters, C.; Weiland, H.; Willman, M.] Univ Hawaii, Inst Astron, 2680 Woodlawn Dr, Honolulu, HI 96322 USA.
   [Leloudas, G.; Heintz, K. E.] Univ Copenhagen, Niels Bohr Inst, Dark Cosmol Ctr, Juliane Maries Vej 30, DK-2100 Copenhagen O, Denmark.
   [Gal-Yam, A.; Manulis, I.; Yaron, O.] Weizmann Inst Sci, Dept Particle Phys & Astrophys, IL-76100 Rehovot, Israel.
   [Lyman, J. D.] Univ Warwick, Dept Phys, Coventry CV4 7AL, W Midlands, England.
   [Homan, D. S.; Lawrence, A.] Univ Edinburgh, Royal Observ, SUPA, Inst Astron, Blackford Hill, Edinburgh EH9 3HJ, Midlothian, Scotland.
   [Agliozzo, C.; Pignata, G.] Univ Andres Bello, Dept Ciencias Fis, Ave Republ 252, Santiago, Chile.
   [Agliozzo, C.; Bauer, F. E.; Pignata, G.] Millennium Inst Astrophys MAS, Nuncio Monseiior Sotero Sanz 100, Santiago, Chile.
   [Anderson, J. P.; Razza, A.] European Southern Observ, Alonso Cordova 3107,Casilla 19, Santiago, Chile.
   [Ashall, C.; James, P. A.; Prentice, S. J.] Liverpool John Moores Univ, Astrophys Res Inst, IC2,Liverpool Sci Pk,146 Brownlow Hill, Liverpool L3 5RF, Merseyside, England.
   [Barbarino, C.; Roy, R.; Sollerman, J.; Taddia, F.] Stockholm Univ, Dept Astron, Oskar Klein Ctr, S-10691 Stockholm, Sweden.
   [Bauer, F. E.] Pontificia Univ Catolica Chile, Inst Astrofis, Casilla 306, Santiago 22, Chile.
   [Bauer, F. E.] Pontificia Univ Catolica Chile, Ctr Astroingn, Fac Fis, Casilla 306, Santiago 22, Chile.
   [Bauer, F. E.] Space Sci Inst, 4750 Walnut St Suite 205, Boulder, CO 80301 USA.
   [Berton, M.] Univ Padua, Dipartimento Fis Astron G Galilei, Vicolo Osservatorio 3, I-35122 Padua, Italy.
   [Berton, M.] INAF, Osservatorio Astronom Brera, Via E Bianchi 46, I-23807 Merate, Italy.
   [Botticella, M. T.; Della Valle, M.] INAF, Osservatorio Astron Capodimonte, Via Salita Moiariello 16, I-30131 Naples, Italy.
   [Bulla, M.] Stockholm Univ, Oskar Klein Ctr, Dept Phys, S-10691 Stockholm, Sweden.
   [Cannizzaro, G.; Jonker, P. G.; Kostrzewa-Rutkowska, Z.; Onori, F.] SRON Netherlands Inst Space Res, SRON, Sorbonnelaan 2, NL-3584 CA Utrecht, Netherlands.
   [Cannizzaro, G.; Jonker, P. G.; Kostrzewa-Rutkowska, Z.; Onori, F.] Raclboud Univ, Dept Astrophys MAPP, POB 9010, NL-6500 GL Nijmegen, Netherlands.
   [Cano, Z.; Izzo, L.] Inst Astrofis Andalucia IAA CSIC, E-18008 Granada, Spain.
   [Cikota, A.; De Cia, A.; Floers, A.; Hamanowicz, A.; Kerzendorf, W. E.; Patat, F.; Taubenberger, S.] European Southern Observ, Karl Schwarzschild Str 2, D-85748 Garching, Germany.
   [Della Valle, M.] ICRANet Pescara, Piazza Repubbl 10, I-65122 Pescara, Italy.
   [Dennefeld, M.] IAP CNRS, Paris, France.
   [Dennefeld, M.] Univ Paris 06, Paris, France.
   [Dessart, L.] Univ Chile, Unidad Mixta Int FrancoChilena Astron CNRS UMI 33, Dept Astron, Camino El Observ 1515, Santiago, Chile.
   [Elias-Rosa, N.] Ist Nazl Astrofis, Viale Parco Mellini 84, I-00136 Rome, Italy.
   [Floers, A.] Tech Univ Munich, Phys Dept, James Franck Str 1, D-85748 Garching, Germany.
   [Franckowiak, A.; Kowalski, M.] Deutsches Elektronen Synchrotron DESY, D-I5738 Zeuthen, Germany.
   [Frohmaier, C.] Univ Portsmouth, Inst Cosmol & Gravitat, Dennis Sciama Bldg,Burnaby Rd, Portsmouth PO1 3FX, Hants, England.
   [Galbany, L.] Univ Pittsburgh, Dept Phys & Astron, PITT PACC, Pittsburgh, PA 15260 USA.
   [Gonzalez-Gaitan, S.] Univ Lisbon, Inst Super Tecn, CENTRA, Lisbon, Portugal.
   [Gromadzki, M.; Hamanowicz, A.; Rybicki, K. A.; Wyrzykowski, L.] Warsaw Univ Astron Observ, Aleje Ujazdowskie 4, PL-00478 Warsaw, Poland.
   [Guelbenzu, A. Nicuesa; Klose, S.] Thuringer Landessternwarte Tautenburg, Sternwarte 5, D-07778 Tautenburg, Germany.
   [Harmanen, J.; Kuncarayakti, H.; Mattila, S.; Reynolds, T.] Univ Turku, Dept Phys & Astron, Tuorla Observ, Vaisalantie 20, Piikkio, Finland.
   [Heintz, K. E.] Univ Iceland, Inst Sci, Ctr Astrophys & Cosmol, Dunhagi 5, IS-107 Reykjavik, Iceland.
   [Hernandez, M. -S.; Vos, J.] Univ Valparaiso, Inst Fis Astron, Gran Bretana 1111, Valparaiso 2360102, Chile.
   [Hodgkin, S. T.; Walton, N. A.] Univ Cambridge, Inst Astron, Rvlaclingley Rd, Cambridge CB3 OHA, England.
   [Hook, I. M.] Univ Lancaster, Dept Phys, Lancaster LA1 4YB, England.
   [Kowalski, M.; Nordin, J.] Humboldt Univ, Inst Phys, Ncwtonstr 15, D-12489 Berlin, Germany.
   [Kromer, M.] Heidelberg Univ, Zentrum Astron, Inst Theoret Astrophys, Philosophenweg 12, D-69120 Heidelberg, Germany.
   [Kromer, M.] Heidelberger Inst Theoret Studien, Schloss Wolfsbrunnenweg 35, D-69118 Heidelberg, Germany.
   [Kuncarayakti, H.] Univ Turku, Finnish Ctr Astron ESO FINCA, Vaisalantie 20, Piikkio 21500, Finland.
   [Mueller, A.] Max Planck Inst Astron, Konigstuhl 17, D-69117 Heidelberg, Germany.
   [Palmerio, J. T.] UPMC Univ Paris 6, Sorbonne Univ, F-75014 Paris, France.
   [Palmerio, J. T.] CNRS, UMR 7095, Inst Astrophys Paris, 98 Bis Blvd Arago, F-75014 Paris, France.
   [Pastorello, A.; Pumo, M. L.; Terreran, G.] INAF, Osservatorio Astron Padova, Vicolo Osservatorio 5, I-35122 Padua, Italy.
   [Podsiadlowski, Ph.] Univ Oxford, Dept Astrophys, Oxford OX1 3RH, England.
   [Pumo, M. L.] Univ Catania, DFA DIEEI, Via Santa Sofia 64, I-95123 Catania, Italy.
   [Pumo, M. L.] INFN, Lab Nazl Sud, Via Santa Sofia 62, I-95123 Catania, Italy.
   [Razza, A.] Univ Chile, Dept Astron, Camino El Observ 1515, Santiago, Chile.
   [Rest, A.] Space Telescope Sci Inst, 3700 San Martin Dr, Baltimore, MD 21218 USA.
   [Rest, A.] Johns Hopkins Univ, Dept Phys & Astron, 3400 North Charles St, Baltimore, MD 21213 USA.
   [Roy, R.] IUCAA, Pune 411007, Maharashtra, India.
   [Ruiter, A. J.; Seitenzahl, I. R.] Univ New South Wales, Sch Phys Environm & Math Sci, Australian Def Force Acad, Canberra, ACT 2600, Australia.
   [Ruiter, A. J.] Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT 2611, Australia.
   [Ruiter, A. J.] ARC Ctr Excellence All sky Astrophys CAASTRO, Tucson, AZ 85719 USA.
   [Stalder, B.] LSST, 950 North Cherry Ave, Tucson, AZ 85719 USA.
   [Stubbs, C. W.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.
   [Szegedi, H.; van Soelen, B.] Univ Free State, Dept Phys, ZA-9300 Bloemfontein, South Africa.
   [Terreran, G.] Northwestern Univ, CIERA, Evanston, IL 60203 USA.
   [Terreran, G.] Northwestern Univ, Dept Phys & Astron, Evanston, IL 60203 USA.
   [Wright, D. E.] Univ Minnesota, Sch Phys & Astron, 116 Church St SE, Minneapolis, MN 55455 USA.
C3 Queens University Belfast; Max Planck Society; Max Planck Society; University College Dublin; University of Southampton; University of Hawaii System; University of Copenhagen; Niels Bohr Institute; Weizmann Institute of Science; University of Warwick; University of Edinburgh; Universidad Andres Bello; European Southern Observatory; Liverpool John Moores University; Stockholm University; Oskar Klein Centre; Pontificia Universidad Catolica de Chile; Pontificia Universidad Catolica de Chile; University of Padua; Istituto Nazionale Astrofisica (INAF); Istituto Nazionale Astrofisica (INAF); Stockholm University; Oskar Klein Centre; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Astrofisica de Andalucia (IAA); European Southern Observatory; Sorbonne Universite; Universidad de Chile; Istituto Nazionale Astrofisica (INAF); Technical University of Munich; Helmholtz Association; Deutsches Elektronen-Synchrotron (DESY); University of Portsmouth; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Universidade de Lisboa; University of Warsaw; University of Turku; University of Iceland; Universidad de Valparaiso; University of Cambridge; Lancaster University; Humboldt University of Berlin; Ruprecht Karls University Heidelberg; University of Turku; Max Planck Society; Sorbonne Universite; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Istituto Nazionale Astrofisica (INAF); University of Padua; University of Oxford; University of Catania; Istituto Nazionale di Fisica Nucleare (INFN); Universidad de Chile; Space Telescope Science Institute; Johns Hopkins University; Inter-University Centre for Astronomy & Astrophysics; Australian Defense Force Academy; University of New South Wales Sydney; Australian National University; Harvard University; University of the Free State; Northwestern University; Northwestern University; University of Minnesota System; University of Minnesota Twin Cities
RP Smartt, SJ (corresponding author), Queens Univ Belfast, Sch Math & Phys, Astrophys Res Ctr, Belfast BT7 1NN, Antrim, North Ireland.
EM s.smartt@qub.ac.uk
FU ePESSTO (the extended Public ESO Spectroscopic Survey for Transient Objects Survey) ESO programme [199.D-0143, 099.D-0376]; DFG [HA 1850/28-1]; NASA [NNX08AR22G, NNX12AR65G, NNX14AM74G, NNX12AR55G]; National Science Foundation [AST-1238877]; EU/FP7-ERC [291222, 615929]; STFC [ST/P000312/1, ERF ST/M005348/1, ST/P000495/1]; Marie Sklodowska-Curie [702533]; Polish NCN grant [OPUS 2015/17/B/ST9/03167]; Knut and Alice Wallenberg Foundation; PRIN-INAF; David and Ellen Lee Prize Postdoctoral Fellowship at the California Institute of Technology; Royal Society Science Foundation Ireland University Research Fellowship; ERC [647208]; V.R; Alexander von Humboldt Sofja Kovalevskaja Award; Vilho, Yrjo and Kalle Vaisala Foundation; FONDECYT [3160504]; US National Science Foundation [AST-1311862]; Swedish Research Council; Swedish Space Board; EU via ERC [725161]; Quantum Universe I-Core programme; ISF; BSF; Kimmel award; IRC [GOIPG/2017/1525]; Australian Research Council Centre of Excellence for All-sky Astrophysics (CAASTRO) [CE110001020]; Australian Research Council [FT160100028]; Millennium Science Initiative grant [IC120009]; Irish Research Council (IRC) [GOIPG/2017/1525] Funding Source: Irish Research Council (IRC); European Research Council (ERC) [647208] Funding Source: European Research Council (ERC); STFC [ST/P000495/1, ST/M005348/1, ST/P000312/1, ST/P00038X/1, ST/N002520/1] Funding Source: UKRI; Science and Technology Facilities Council [ST/P000495/1, ST/N002520/1, 1507817, ST/M005348/1, ST/M001229/1, ST/P000312/1, 1372992, ST/N000927/1] Funding Source: researchfish
NR 70
TC 691
Z9 751
U1 2
U2 90
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 2
PY 2017
VL 551
IS 7678
BP 75
EP +
DI 10.1038/nature24303
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA FL4SY
UT WOS:000414222900047
PM 29094693
DA 2026-03-09
ER

PT J
AU Turgay, Y
   Eibauer, M
   Goldman, AE
   Shimi, T
   Khayat, M
   Ben-Harush, K
   Dubrovsky-Gaupp, A
   Sapra, KT
   Goldman, RD
   Medalia, O
AF Turgay, Yagmur
   Eibauer, Matthias
   Goldman, Anne E.
   Shimi, Takeshi
   Khayat, Maayan
   Ben-Harush, Kfir
   Dubrovsky-Gaupp, Anna
   Sapra, K. Tanuj
   Goldman, Robert D.
   Medalia, Ohad
TI The molecular architecture of lamins in somatic cells
SO NATURE
LA English
DT Article
ID nuclear lamins; supramolecular organization; intermediate-filaments; escherichia-coli; expression; envelope; tail
AB The nuclear lamina is a fundamental constituent of metazoan nuclei. It is composed mainly of lamins, which are intermediate filament proteins that assemble into a filamentous meshwork, bridging the nuclear envelope and chromatin(1-4). Besides providing structural stability to the nucleus(5,6), the lamina is involved in many nuclear activities, including chromatin organization, transcription and replication(7-10). However, the structural organization of the nuclear lamina is poorly understood. Here we use cryo-electron tomography to obtain a detailed view of the organization of the lamin meshwork within the lamina. Data analysis of individual lamin filaments resolves a globular-decorated fibre appearance and shows that A-and B-type lamins assemble into tetrameric filaments of 3.5 nm thickness. Thus, lamins exhibit a structure that is remarkably different from the other canonical cytoskeletal elements. Our findings define the architecture of the nuclear lamin meshworks at molecular resolution, providing insights into their role in scaffolding the nuclear lamina.
C1 [Turgay, Yagmur; Eibauer, Matthias; Dubrovsky-Gaupp, Anna; Sapra, K. Tanuj; Medalia, Ohad] Univ Zurich, Dept Biochem, Winterthurerstr 190, CH-8057 Zurich, Switzerland.
   [Goldman, Anne E.; Shimi, Takeshi; Goldman, Robert D.] Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, 303 E Chicago Ave, Chicago, IL 60611 USA.
   [Khayat, Maayan; Medalia, Ohad] Ben Gurion Univ Negev, Dept Life Sci, IL-84105 Beer Sheva, Israel.
   [Khayat, Maayan; Medalia, Ohad] Ben Gurion Univ Negev, Natl Inst Biotechnol Negev, IL-84105 Beer Sheva, Israel.
   [Ben-Harush, Kfir] Coll Engn, Dept Chem Engn, Jabotinsky 84, IL-77245 Ashdod, Israel.
C3 University of Zurich; Northwestern University; Feinberg School of Medicine; Ben-Gurion University of the Negev; Ben-Gurion University of the Negev
RP Medalia, O (corresponding author), Univ Zurich, Dept Biochem, Winterthurerstr 190, CH-8057 Zurich, Switzerland.; Medalia, O (corresponding author), Ben Gurion Univ Negev, Dept Life Sci, IL-84105 Beer Sheva, Israel.; Medalia, O (corresponding author), Ben Gurion Univ Negev, Natl Inst Biotechnol Negev, IL-84105 Beer Sheva, Israel.
EM omedalia@bioc.uzh.ch
FU Swiss National Science Foundation [SNSF 31003A 159706/1]; Maxi Foundation; Forschungskredit of the University of Zurich; National Institutes of Health [GM106023]; Progeria Research Foundation;  [GIF I-1289-412.13/2015]
NR 41
TC 327
Z9 369
U1 1
U2 77
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 9
PY 2017
VL 543
IS 7644
BP 261
EP +
DI 10.1038/nature21382
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN0GQ
UT WOS:000395688700043
PM 28241138
DA 2026-03-09
ER

PT J
AU Collins, C
   Dyer, MS
   Pitcher, MJ
   Whitehead, GFS
   Zanella, M
   Mandal, P
   Claridge, JB
   Darling, GR
   Rosseinsky, MJ
AF Collins, C.
   Dyer, M. S.
   Pitcher, M. J.
   Whitehead, G. F. S.
   Zanella, M.
   Mandal, P.
   Claridge, J. B.
   Darling, G. R.
   Rosseinsky, M. J.
TI Accelerated discovery of two crystal structure types in a complex inorganic phase field
SO NATURE
LA English
DT Article
ID structure prediction; atomistic simulation; powder-diffraction; strontium gallate; solid-solutions; oxide; refinement; algorithm; la; identification
AB The discovery of new materials is hampered by the lack of efficient approaches to the exploration of both the large number of possible elemental compositions for such materials, and of the candidate structures at each composition(1). For example, the discovery of inorganic extended solid structures has relied on knowledge of crystal chemistry coupled with time-consuming materials synthesis with systematically varied elemental ratios(2,3). Computational methods have been developed to guide synthesis by predicting structures at specific compositions(4-6) and predicting compositions for known crystal structures(7,8), with notable successes(9,10). However, the challenge of finding qualitatively new, experimentally realizable compounds, with crystal structures where the unit cell and the atom positions within it differ from known structures, remains for compositionally complex systems. Many valuable properties arise from substitution into known crystal structures, but materials discovery using this approach alone risks both missing best-in-class performance and attempting design with incomplete knowledge(8,11). Here we report the experimental discovery of two structure types by computational identification of the region of a complex inorganic phase field that contains them. This is achieved by computing probe structures that capture the chemical and structural diversity of the system and whose energies can be ranked against combinations of currently known materials. Subsequent experimental exploration of the lowest-energy regions of the computed phase diagram affords two materials with previously unreported crystal structures featuring unusual structural motifs. This approach will accelerate the systematic discovery of new materials in complex compositional spaces by efficiently guiding synthesis and enhancing the predictive power of the computational tools through expansion of the knowledge base underpinning them.
C1 [Collins, C.; Dyer, M. S.; Pitcher, M. J.; Whitehead, G. F. S.; Zanella, M.; Mandal, P.; Claridge, J. B.; Darling, G. R.; Rosseinsky, M. J.] Univ Liverpool, Dept Chem, Liverpool L69 7ZD, Merseyside, England.
C3 University of Liverpool
RP Rosseinsky, MJ (corresponding author), Univ Liverpool, Dept Chem, Liverpool L69 7ZD, Merseyside, England.
EM rossein@liverpool.ac.uk
FU EPSRC [EP/N004884]; Materials Chemistry Consortium [EPSRC: EP/L000202]; PRACE-3IP project [FP7 RI-312763]; UK's investment in e-infrastructure; EPSRC [EP/N004884/1, EP/L000202/1] Funding Source: UKRI; Engineering and Physical Sciences Research Council [EP/L000202/1, EP/N004884/1, EP/K000225/1] Funding Source: researchfish
NR 76
TC 71
Z9 87
U1 2
U2 183
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 8
PY 2017
VL 546
IS 7657
BP 280
EP +
DI 10.1038/nature22374
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EW9FY
UT WOS:000402823400035
PM 28593963
DA 2026-03-09
ER

PT J
AU Rheinbay, E
   Parasuraman, P
   Grimsby, J
   Tiao, G
   Engreitz, JM
   Kim, J
   Lawrence, MS
   Taylor-Weiner, A
   Rodriguez-Cuevas, S
   Rosenberg, M
   Hess, J
   Stewart, C
   Maruvka, YE
   Stojanov, P
   Cortes, ML
   Seepo, S
   Cibulskis, C
   Tracy, A
   Pugh, TJ
   Lee, J
   Zheng, ZL
   Ellisen, LW
   Iafrate, AJ
   Boehm, JS
   Gabriel, SB
   Meyerson, M
   Golub, TR
   Baselga, J
   Hidalgo-Miranda, A
   Shioda, T
   Bernards, A
   Lander, ES
   Getz, G
AF Rheinbay, Esther
   Parasuraman, Prasanna
   Grimsby, Jonna
   Tiao, Grace
   Engreitz, Jesse M.
   Kim, Jaegil
   Lawrence, Michael S.
   Taylor-Weiner, Amaro
   Rodriguez-Cuevas, Sergio
   Rosenberg, Mara
   Hess, Julian
   Stewart, Chip
   Maruvka, Yosef E.
   Stojanov, Petar
   Cortes, Maria L.
   Seepo, Sara
   Cibulskis, Carrie
   Tracy, Adam
   Pugh, Trevor J.
   Lee, Jesse
   Zheng, Zongli
   Ellisen, Leif W.
   Iafrate, A. John
   Boehm, Jesse S.
   Gabriel, Stacey B.
   Meyerson, Matthew
   Golub, Todd R.
   Baselga, Jose
   Hidalgo-Miranda, Alfredo
   Shioda, Toshi
   Bernards, Andre
   Lander, Eric S.
   Getz, Gad
TI Recurrent and functional regulatory mutations in breast cancer
SO NATURE
LA English
DT Article
ID estrogen-receptor binding; tert promoter mutations; genome-wide analysis; somatic mutations; luminal subtype; expression; foxa1; landscape; discovery; protein
AB Genomic analysis of tumours has led to the identification of hundreds of cancer genes on the basis of the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here we perform deep sequencing in 360 primary breast cancers and develop computational methods to identify significantly mutated promoters. Clear signals are found in the promoters of three genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbours a mutational hotspot in its promoter leading to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that affect protein binding to their promoters and alter expression levels. Our study shows that promoter regions harbour recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions. Power analyses indicate that more such regions remain to be discovered through deep sequencing of adequately sized cohorts of patients.
C1 [Rheinbay, Esther; Grimsby, Jonna; Tiao, Grace; Engreitz, Jesse M.; Kim, Jaegil; Lawrence, Michael S.; Taylor-Weiner, Amaro; Rosenberg, Mara; Hess, Julian; Stewart, Chip; Maruvka, Yosef E.; Stojanov, Petar; Cortes, Maria L.; Seepo, Sara; Cibulskis, Carrie; Tracy, Adam; Boehm, Jesse S.; Gabriel, Stacey B.; Meyerson, Matthew; Golub, Todd R.; Lander, Eric S.; Getz, Gad] Broad Inst MIT & Harvard, Cambridge, MA 02124 USA.
   [Rheinbay, Esther; Parasuraman, Prasanna; Lawrence, Michael S.; Maruvka, Yosef E.; Lee, Jesse; Zheng, Zongli; Ellisen, Leif W.; Iafrate, A. John; Shioda, Toshi; Bernards, Andre; Getz, Gad] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA.
   [Engreitz, Jesse M.] MIT, Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Rodriguez-Cuevas, Sergio] Inst Enfermedades Mama FUCAM AC, Mexico City 04980, DF, Mexico.
   [Pugh, Trevor J.] Univ Toronto, Princess Margaret Canc Ctr, Univ Hlth Network, Toronto, ON M5G 1L7, Canada.
   [Pugh, Trevor J.] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada.
   [Ellisen, Leif W.; Meyerson, Matthew; Golub, Todd R.; Getz, Gad] Harvard Med Sch, Boston, MA 02115 USA.
   [Meyerson, Matthew; Golub, Todd R.] Dana Farber Canc Inst, Boston, MA 02115 USA.
   [Baselga, Jose] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA.
   [Hidalgo-Miranda, Alfredo] Inst Nacl Med Genom, Mexico City 14610, DF, Mexico.
   [Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.
C3 Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Massachusetts Institute of Technology (MIT); University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; University of Toronto; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Memorial Sloan Kettering Cancer Center; Instituto Nacional de Medicina Genomica; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital
RP Getz, G (corresponding author), Broad Inst MIT & Harvard, Cambridge, MA 02124 USA.; Getz, G (corresponding author), Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA.; Getz, G (corresponding author), Harvard Med Sch, Boston, MA 02115 USA.; Getz, G (corresponding author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.
EM gadgetz@broadinstitute.org
FU Carlos Slim Foundation in Mexico; Fannie and John Hertz Foundation; Massachusetts General Hospital; National Cancer Institute [P30CA008748] Funding Source: NIH RePORTER
NR 69
TC 230
Z9 279
U1 0
U2 47
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 6
PY 2017
VL 547
IS 7661
BP 55
EP +
DI 10.1038/nature22992
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EZ6PM
UT WOS:000404839900030
PM 28658208
DA 2026-03-09
ER

PT J
AU Holler, M
   Guizar-Sicairos, M
   Tsai, EHR
   Dinapoli, R
   Müller, E
   Bunk, O
   Raabe, J
   Aeppli, G
AF Holler, Mirko
   Guizar-Sicairos, Manuel
   Tsai, Esther H. R.
   Dinapoli, Roberto
   Muller, Elisabeth
   Bunk, Oliver
   Raabe, Jorg
   Aeppli, Gabriel
TI High-resolution non-destructive three-dimensional imaging of integrated circuits
SO NATURE
LA English
DT Article
ID computed-tomography
AB Modern nanoelectronics(1,2) has advanced to a point at which it is impossible to image entire devices and their interconnections non-destructively because of their small feature sizes and the complex three-dimensional structures resulting from their integration on a chip. This metrology gap implies a lack of direct feedback between design and manufacturing processes, and hampers quality control during production, shipment and use. Here we demonstrate that X-ray ptychography(3,4)-a high-resolution coherent diffractive imaging technique-can create three-dimensional images of integrated circuits of known and unknown designs with a lateral resolution in all directions down to 14.6 nanometres. We obtained detailed device geometries and corresponding elemental maps, and show how the devices are integrated with each other to form the chip. Our experiments represent a major advance in chip inspection and reverse engineering over the traditional destructive electron microscopy and ion milling techniques(5-7). Foreseeable developments in X-ray sources(8), optics(9) and detectors(10), as well as adoption of an instrument geometry(11) optimized for planar rather than cylindrical samples, could lead to a thousand-fold increase in efficiency, with concomitant reductions in scan times and voxel sizes.
C1 [Holler, Mirko; Guizar-Sicairos, Manuel; Tsai, Esther H. R.; Dinapoli, Roberto; Muller, Elisabeth; Bunk, Oliver; Raabe, Jorg; Aeppli, Gabriel] Paul Scherrer Inst, CH-5232 Villigen, Switzerland.
   [Aeppli, Gabriel] ETH, Dept Phys, CH-8093 Zurich, Switzerland.
   [Aeppli, Gabriel] Ecole Polytech Fed Lausanne, Inst Phys, CH-1015 Lausanne, Switzerland.
C3 Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute; Swiss Federal Institutes of Technology Domain; ETH Zurich; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne
RP Holler, M (corresponding author), Paul Scherrer Inst, CH-5232 Villigen, Switzerland.
EM mirko.holler@psi.ch
FU Swiss National Science Foundation [200021_152554]; R'EQUIP [145056]; Swiss National Science Foundation (SNF) [200021_152554] Funding Source: Swiss National Science Foundation (SNF)
NR 36
TC 367
Z9 429
U1 20
U2 364
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 16
PY 2017
VL 543
IS 7645
BP 402
EP +
DI 10.1038/nature21698
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EN9RN
UT WOS:000396337400046
PM 28300088
DA 2026-03-09
ER

PT J
AU Yamamoto, M
   Ohsawa, S
   Kunimasa, K
   Igaki, T
AF Yamamoto, Masatoshi
   Ohsawa, Shizue
   Kunimasa, Kei
   Igaki, Tatsushi
TI The ligand Sas and its receptor PTP1OD drive tumour-suppressive cell competition
SO NATURE
LA English
DT Article
ID tyrosine-phosphatase; signaling pathway; drosophila; ras; overgrowth; neighbors; mutants; cd148
AB Normal epithelial cells often exert anti-tumour effects against nearby oncogenic cells. In the Drosophila imaginal epithelium, clones of oncogenic cells with loss-of-function mutations in the apico-basal polarity genes scribble or discs large are actively eliminated by cell competition when surrounded by wild-type cells'. Although c-Jun N-terminal kinase (JNK) signalling plays a crucial role in this cell elimination(1-5), the initial event, which occurs at the interface between normal cells and polarity-deficient cells, has not previously been identified. Here, through a genetic screen in Drosophila, we identify the ligand Sas and the receptor-type tyrosine phosphatase PTP10D as the cell-surface ligand-receptor system that drives tumour-suppressive cell competition. At the interface between the wild-type 'winner' and the polarity-deficient 'loser' clones, winner cells relocalize Sas to the lateral cell surface, whereas loser cells relocalize PTP10D there. This leads to the trans activation of Sas-PTP10D signalling in loser cells, which restrains EGFR signalling and thereby enables elevated JNK signalling in loser cells, triggering cell elimination. In the absence of Sas-PTP10D, elevated EGFR signalling in loser cells switches the role of JNK from pro-apoptotic to pro-proliferative by inactivating the Hippo pathway, thereby driving the overgrowth of polarity-deficient cells. These findings uncover the mechanism by which normal epithelial cells recognize oncogenic polarity-deficient neighbours to drive cell competition.
C1 [Yamamoto, Masatoshi; Ohsawa, Shizue; Kunimasa, Kei; Igaki, Tatsushi] Kyoto Univ, Grad Sch Biostudies, Genet Lab, Sakyo Ku, Yoshida Konoe Cho, Kyoto 6068501, Japan.
   [Igaki, Tatsushi] Japan Sci & Technol Agcy JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 3320012, Japan.
C3 Kyoto University; Japan Science & Technology Agency (JST)
RP Igaki, T (corresponding author), Kyoto Univ, Grad Sch Biostudies, Genet Lab, Sakyo Ku, Yoshida Konoe Cho, Kyoto 6068501, Japan.; Igaki, T (corresponding author), Japan Sci & Technol Agcy JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 3320012, Japan.
EM igaki@lif.kyoto-u.ac.jp
FU MEXT/JSPS KAKENHI [26114002, 25112710, 15H05862, 23127508]; Nakajima Foundation; Inoue Science Research Award; Naito Foundation; Takeda Science Foundation; JST; Platform for Dynamic Approaches to Living System from AMED; Grants-in-Aid for Scientific Research [15H05862, 25112710, 23127508, 26114002, 15K21726, 26711013] Funding Source: KAKEN
NR 30
TC 120
Z9 139
U1 0
U2 19
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 9
PY 2017
VL 542
IS 7640
BP 246
EP 250
DI 10.1038/nature21033
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK2DJ
UT WOS:000393737500044
PM 28092921
DA 2026-03-09
ER

PT J
AU Chung, S
   Weber, F
   Zhong, P
   Tan, CL
   Nguyen, TN
   Beier, KT
   Hormann, N
   Chang, WC
   Zhang, Z
   Do, JP
   Ao, SY
   Krashes, MJ
   Tasic, B
   Cetin, A
   Zeng, H
   Knight, ZA
   Luo, L
   Dan, Y
AF Chung, Shinjae
   Weber, Franz
   Zhong, Peng
   Tan, Chan Lek
   Nguyen, Thuc Nghi
   Beier, Kevin T.
   Hormann, Nikolai
   Chang, Wei-Cheng
   Zhang, Zhe
   Do, Johnny Phong
   Ao, Shenqin Y.
   Krashes, Michael J.
   Tasic, Bosiljka
   Cetin, Ali
   Zeng, Hongkui
   Knight, Zachary A. .
   Luo, Liqun
   Dan, Yang
TI Identification of preoptic sleep neurons using retrograde labelling and gene profiling
SO NATURE
LA English
DT Article
ID gabaergic neurons; rem-sleep; basal forebrain; galaninergic neurons; recovery sleep; nucleus; circuit; hypothalamus; deprivation; activation
AB In humans and other mammalian species, lesions in the preoptic area of the hypothalamus cause profound sleep impairment(1-5), indicating a crucial role of the preoptic area in sleep generation. However, the underlying circuit mechanism remains poorly understood. Electrophysiological recordings and c-Fos immunohistochemistry have shown the existence of sleep-active neurons in the preoptic area, especially in the ventrolateral preoptic area and median preoptic nucleus(6-9). Pharmacogenetic activation of c-Fos-labelled sleep-active neurons has been shown to induce sleep(10). However, the sleep-active neurons are spatially intermingled with wake-active neurons(6,7), making it difficult to target the sleep neurons specifically for circuit analysis. Here we identify a population of preoptic area sleep neurons on the basis of their projection target and discover their molecular markers. Using a lentivirus expressing channelrhodopsin-2 or a light-activated chloride channel for retrograde labelling, bidirectional optogenetic manipulation, and optrode recording, we show that the preoptic area GABAergic neurons projecting to the tuberomammillary nucleus are both sleep active and sleep promoting. Furthermore, translating ribosome affinity purification and single-cell RNA sequencing identify candidate markers for these neurons, and optogenetic and pharmacogenetic manipulations demonstrate that several peptide markers (cholecystokinin, corticotropin-releasing hormone, and tachykinin 1) label sleep-promoting neurons. Together, these findings provide easy genetic access to sleep-promoting preoptic area neurons and a valuable entry point for dissecting the sleep control circuit.
C1 [Chung, Shinjae; Weber, Franz; Zhong, Peng; Hormann, Nikolai; Chang, Wei-Cheng; Zhang, Zhe; Do, Johnny Phong; Dan, Yang] Univ Calif Berkeley, Howard Hughes Med Inst, Dept Mol & Cell Biol, Div Neurobiol,Helen Wills Neurosci Inst, Berkeley, CA 94720 USA.
   [Tan, Chan Lek; Knight, Zachary A. .] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA.
   [Nguyen, Thuc Nghi; Ao, Shenqin Y.; Tasic, Bosiljka; Cetin, Ali; Zeng, Hongkui] Allen Inst Brain Sci, Seattle, WA 98103 USA.
   [Beier, Kevin T.; Luo, Liqun] Stanford Univ, Howard Hughes Med Inst, Dept Biol, Stanford, CA 94305 USA.
   [Krashes, Michael J.] NIDDKD, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA.
   [Krashes, Michael J.] NIDA, NIH, Baltimore, MD 21224 USA.
C3 University of California System; University of California Berkeley; Howard Hughes Medical Institute; University of California System; University of California San Francisco; Allen Institute for Brain Science; Stanford University; Howard Hughes Medical Institute; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); NIH National Institute on Drug Abuse (NIDA)
RP Dan, Y (corresponding author), Univ Calif Berkeley, Howard Hughes Med Inst, Dept Mol & Cell Biol, Div Neurobiol,Helen Wills Neurosci Inst, Berkeley, CA 94720 USA.
EM ydan@berkeley.edu
FU Davis Postdoctoral Fellowship; Tourette Syndrome Association; EMBO Long-term Fellowship; Human Frontier Science Program Fellowship; Howard Hughes Medical Institute; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK106399] Funding Source: NIH RePORTER
NR 45
TC 226
Z9 261
U1 5
U2 87
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 25
PY 2017
VL 545
IS 7655
BP 477
EP +
DI 10.1038/nature22350
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EV6TH
UT WOS:000401906500051
PM 28514446
DA 2026-03-09
ER

PT J
AU Thompson, LR
   Sanders, JG
   McDonald, D
   Amir, A
   Ladau, J
   Locey, KJ
   Prill, RJ
   Tripathi, A
   Gibbons, SM
   Ackermann, G
   Navas-Molina, JA
   Janssen, S
   Kopylova, E
   Vázquez-Baeza, Y
   González, A
   Morton, JT
   Mirarab, S
   Xu, ZZ
   Jiang, LJ
   Haroon, MF
   Kanbar, J
   Zhu, QJ
   Song, SJ
   Kosciolek, T
   Bokulich, NA
   Lefler, J
   Brislawn, CJ
   Humphrey, G
   Owens, SM
   Hampton-Marcell, J
   Berg-Lyons, D
   McKenzie, V
   Fierer, N
   Fuhrman, JA
   Clauset, A
   Stevens, RL
   Shade, A
   Pollard, KS
   Goodwin, KD
   Jansson, JK
   Gilbert, JA
   Knight, R
   Rivera, JLA
   Al-Moosawi, L
   Alverdy, J
   Amato, KR
   Andras, J
   Angenent, LT
   Antonopoulos, DA
   Apprill, A
   Armitage, D
   Ballantine, K
   Bárta, J
   Baum, JK
   Berry, A
   Bhatnagar, A
   Bhatnagar, M
   Biddle, JF
   Bittner, L
   Boldgiv, B
   Bottos, E
   Boyer, DM
   Braun, J
   Brazelton, W
   Brearley, FQ
   Campbell, AH
   Caporaso, JG
   Cardona, C
   Carroll, J
   Cary, SC
   Casper, BB
   Charles, TC
   Chu, HY
   Claar, DC
   Clark, RG
   Clayton, JB
   Clemente, JC
   Cochran, A
   Coleman, ML
   Collins, G
   Colwell, RR
   Contreras, M
   Crary, BB
   Creer, S
   Cristol, DA
   Crump, BC
   Cui, DY
   Daly, SE
   Davalos, L
   Dawson, RD
   Defazio, J
   Delsuc, F
   Dionisi, HM
   Dominguez-Bello, MG
   Dowell, R
   Dubinsky, EA
   Dunn, PO
   Ercolini, D
   Espinoza, RE
   Ezenwa, V
   Fenner, N
   Findlay, HS
   Fleming, ID
   Vincenzo, F
   Forsman, A
   Freeman, C
   Friedman, ES
   Galindo, G
   Garcia, L
   Garcia-Amado, MA
   Garshelis, D
   Gasser, RB
   Gerdts, G
   Gibson, MK
   Gifford, I
   Gill, RT
   Giray, T
   Gittel, A
   Golyshin, P
   Gong, DL
   Grossart, HP
   Guyton, K
   Haig, SJ
   Hale, V
   Hall, RS
   Hallam, SJ
   Handley, KM
   Hasan, NA
   Haydon, SR
   Hickman, JE
   Hidalgo, G
   Hofmockel, KS
   Hooker, J
   Hulth, S
   Hultman, J
   Hyde, E
   Ibáñez-Alamo, JD
   Jastrow, JD
   Jex, AR
   Johnson, LS
   Johnston, ER
   Joseph, S
   Jurburg, SD
   Jurelevicius, D
   Karlsson, A
   Karlsson, R
   Kauppinen, S
   Kellogg, CTE
   Kennedy, SJ
   Kerkhof, LJ
   King, GM
   Kling, GW
   Koehler, AV
   Krezalek, M
   Kueneman, J
   Lamendella, R
   Landon, EM
   Lane-deGraaf, K
   LaRoche, J
   Larsen, P
   Laverock, B
   Lax, S
   Lentino, M
   Levin, II
   Liancourt, P
   Liang, WJ
   Linz, AM
   Lipson, DA
   Liu, YQ
   Lladser, ME
   Lozada, M
   Spirito, CM
   MacCormack, WP
   MacRae-Crerar, A
   Magris, M
   Martín-Platero, AM
   Martín-Vivaldi, M
   Martínez, LM
   Martínez-Bueno, M
   Marzinelli, EM
   Mason, OU
   Mayer, GD
   McDevitt-Irwin, JM
   McDonald, JE
   McGuire, KL
   McMahon, KD
   McMinds, R
   Medina, M
   Mendelson, JR
   Metcalf, JL
   Meyer, F
   Michelangeli, F
   Miller, K
   Mills, DA
   Minich, J
   Mocali, S
   Moitinho-Silva, L
   Moore, A
   Morgan-Kiss, RM
   Munroe, P
   Myrold, D
   Neufeld, JD
   Ni, YY
   Nicol, GW
   Nielsen, S
   Nissimov, JI
   Niu, KF
   Nolan, MJ
   Noyce, K
   O'Brien, SL
   Okamoto, N
   Orlando, L
   Castellano, YO
   Osuolale, O
   Oswald, W
   Parnell, J
   Peralta-Sánchez, JM
   Petraitis, P
   Pfister, C
   Pilon-Smits, E
   Piombino, P
   Pointing, SB
   Pollock, FJ
   Potter, C
   Prithiviraj, B
   Quince, C
   Rani, A
   Ranjan, R
   Rao, S
   Rees, AP
   Richardson, M
   Riebesell, U
   Robinson, C
   Rockne, KJ
   Rodriguezl, SM
   Rohwer, F
   Roundstone, W
   Safran, RJ
   Sangwan, N
   Sanz, V
   Schrenk, M
   Schrenzel, MD
   Scott, NM
   Seger, RL
   Seguin-Orlando, A
   Seldin, L
   Seyler, LM
   Shakhsheer, B
   Sheets, GM
   Shen, CC
   Shi, Y
   Shin, HD
   Shogan, BD
   Shutler, D
   Siegel, J
   Simmons, S
   Sjöling, S
   Smith, DP
   Soler, JJ
   Sperling, M
   Steinberg, PD
   Stephens, B
   Stevens, MA
   Taghavi, S
   Tai, V
   Tait, K
   Tan, CL
   Tas, N
   Taylor, DL
   Thomas, T
   Timling, I
   Turner, BL
   Urich, T
   Ursell, LK
   van der Lelie, D
   Van Treuren, W
   van Zwieten, L
   Vargas-Robles, D
   Thurber, RV
   Vitaglione, P
   Walker, DA
   Walters, WA
   Wang, S
   Wang, T
   Weaver, T
   Webster, NS
   Wehrle, B
   Weisenhorn, P
   Weiss, S
   Werner, JJ
   West, K
   Whitehead, A
   Whitehead, SR
   Whittingham, LA
   Willerslev, E
   Williams, AE
   Wood, SA
   Woodhams, DC
   Yang, YQ
   Zaneveld, J
   Zarraonaindia, I
   Zhang, QK
   Zhao, HX
AF Thompson, Luke R.
   Sanders, Jon G.
   McDonald, Daniel
   Amir, Amnon
   Ladau, Joshua
   Locey, Kenneth J.
   Prill, Robert J.
   Tripathi, Anupriya
   Gibbons, Sean M.
   Ackermann, Gail
   Navas-Molina, Jose A.
   Janssen, Stefan
   Kopylova, Evguenia
   Vazquez-Baeza, Yoshiki
   Gonzalez, Antonio
   Morton, James T.
   Mirarab, Siavash
   Xu, Zhenjiang Zech
   Jiang, Lingjing
   Haroon, Mohamed F.
   Kanbar, Jad
   Zhu, Qiyun
   Song, Se Jin
   Kosciolek, Tomasz
   Bokulich, Nicholas A.
   Lefler, Joshua
   Brislawn, Colin J.
   Humphrey, Gregory
   Owens, Sarah M.
   Hampton-Marcell, Jarrad
   Berg-Lyons, Donna
   McKenzie, Valerie
   Fierer, Noah
   Fuhrman, Jed A.
   Clauset, Aaron
   Stevens, Rick L.
   Shade, Ashley
   Pollard, Katherine S.
   Goodwin, Kelly D.
   Jansson, Janet K.
   Gilbert, Jack A.
   Knight, Rob
   Rivera, Jose L. Agosto
   Al-Moosawi, Lisa
   Alverdy, John
   Amato, Katherine R.
   Andras, Jason
   Angenent, Largus T.
   Antonopoulos, Dionysios A.
   Apprill, Amy
   Armitage, David
   Ballantine, Kate
   Barta, Jiri
   Baum, Julia K.
   Berry, Allison
   Bhatnagar, Ashish
   Bhatnagar, Monica
   Biddle, Jennifer F.
   Bittner, Lucie
   Boldgiv, Bazartseren
   Bottos, Eric
   Boyer, Donal M.
   Braun, Josephine
   Brazelton, William
   Brearley, Francis Q.
   Campbell, Alexandra H.
   Caporaso, J. Gregory
   Cardona, Cesar
   Carroll, JoLynn
   Cary, S. Craig
   Casper, Brenda B.
   Charles, Trevor C.
   Chu, Haiyan
   Claar, Danielle C.
   Clark, Robert G.
   Clayton, Jonathan B.
   Clemente, Jose C.
   Cochran, Alyssa
   Coleman, Maureen L.
   Collins, Gavin
   Colwell, Rita R.
   Contreras, Monica
   Crary, Benjamin B.
   Creer, Simon
   Cristol, Daniel A.
   Crump, Byron C.
   Cui, Duoying
   Daly, Sarah E.
   Davalos, Liliana
   Dawson, Russell D.
   Defazio, Jennifer
   Delsuc, Frederic
   Dionisi, Hebe M.
   Dominguez-Bello, Maria Gloria
   Dowell, Robin
   Dubinsky, Eric A.
   Dunn, Peter O.
   Ercolini, Danilo
   Espinoza, Robert E.
   Ezenwa, Vanessa
   Fenner, Nathalie
   Findlay, Helen S.
   Fleming, Irma D.
   Fogliano, Vincenzo
   Forsman, Anna
   Freeman, Chris
   Friedman, Elliot S.
   Galindo, Giancarlo
   Garcia, Liza
   Alexandra Garcia-Amado, Maria
   Garshelis, David
   Gasser, Robin B.
   Gerdts, Gunnar
   Gibson, Molly K.
   Gifford, Isaac
   Gill, Ryan T.
   Giray, Tugrul
   Gittel, Antje
   Golyshin, Peter
   Gong, Donglai
   Grossart, Hans-Peter
   Guyton, Kristina
   Haig, Sarah-Jane
   Hale, Vanessa
   Hall, Ross Stephen
   Hallam, Steven J.
   Handley, Kim M.
   Hasan, Nur A.
   Haydon, Shane R.
   Hickman, Jonathan E.
   Hidalgo, Glida
   Hofmockel, Kirsten S.
   Hooker, Jeff
   Hulth, Stefan
   Hultman, Jenni
   Hyde, Embriette
   Ibanez-Alamo, Juan Diego
   Jastrow, Julie D.
   Jex, Aaron R.
   Johnson, L. Scott
   Johnston, Eric R.
   Joseph, Stephen
   Jurburg, Stephanie D.
   Jurelevicius, Diogo
   Karlsson, Anders
   Karlsson, Roger
   Kauppinen, Seth
   Kellogg, Colleen T. E.
   Kennedy, Suzanne J.
   Kerkhof, Lee J.
   King, Gary M.
   Kling, George W.
   Koehler, Anson V.
   Krezalek, Monika
   Kueneman, Jordan
   Lamendella, Regina
   Landon, Emily M.
   Lane-deGraaf, Kelly
   LaRoche, Julie
   Larsen, Peter
   Laverock, Bonnie
   Lax, Simon
   Lentino, Miguel
   Levin, Iris I.
   Liancourt, Pierre
   Liang, Wenju
   Linz, Alexandra M.
   Lipson, David A.
   Liu, Yongqin
   Lladser, Manuel E.
   Lozada, Mariana
   Spirito, Catherine M.
   MacCormack, Walter P.
   MacRae-Crerar, Aurora
   Magris, Magda
   Martin-Platero, Antonio M.
   Martin-Vivaldi, Manuel
   Margarita Martinez, L.
   Martinez-Bueno, Manuel
   Marzinelli, Ezequiel M.
   Mason, Olivia U.
   Mayer, Gregory D.
   McDevitt-Irwin, Jamie M.
   McDonald, James E.
   McGuire, Krista L.
   McMahon, Katherine D.
   McMinds, Ryan
   Medina, Monica
   Mendelson, Joseph R., III
   Metcalf, Jessica L.
   Meyer, Folker
   Michelangeli, Fabian
   Miller, Kim
   Mills, David A.
   Minich, Jeremiah
   Mocali, Stefano
   Moitinho-Silva, Lucas
   Moore, Anni
   Morgan-Kiss, Rachael M.
   Munroe, Paul
   Myrold, David
   Neufeld, Josh D.
   Ni, Yingying
   Nicol, Graeme W.
   Nielsen, Shaun
   Nissimov, Jozef I.
   Niu, Kefeng
   Nolan, Matthew J.
   Noyce, Karen
   O'Brien, Sarah L.
   Okamoto, Noriko
   Orlando, Ludovic
   Castellano, Yadira Ortiz
   Osuolale, Olayinka
   Oswald, Wyatt
   Parnell, Jacob
   Peralta-Sanchez, Juan M.
   Petraitis, Peter
   Pfister, Catherine
   Pilon-Smits, Elizabeth
   Piombino, Paola
   Pointing, Stephen B.
   Pollock, F. Joseph
   Potter, Caitlin
   Prithiviraj, Bharath
   Quince, Christopher
   Rani, Asha
   Ranjan, Ravi
   Rao, Subramanya
   Rees, Andrew P.
   Richardson, Miles
   Riebesell, Ulf
   Robinson, Carol
   Rockne, Karl J.
   Rodriguezl, Selena Marie
   Rohwer, Forest
   Roundstone, Wayne
   Safran, Rebecca J.
   Sangwan, Naseer
   Sanz, Virginia
   Schrenk, Matthew
   Schrenzel, Mark D.
   Scott, Nicole M.
   Seger, Rita L.
   Seguin-Orlando, Andaine
   Seldin, Lucy
   Seyler, Lauren M.
   Shakhsheer, Baddr
   Sheets, Gabriela M.
   Shen, Congcong
   Shi, Yu
   Shin, Hak                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   