PT J
AU Capak, PL
   Carilli, C
   Jones, G
   Casey, CM
   Riechers, D
   Sheth, K
   Carollo, CM
   Ilbert, O
   Karim, A
   LeFevre, O
   Lilly, S
   Scoville, N
   Smolcic, V
   Yan, L
AF Capak, P. L.
   Carilli, C.
   Jones, G.
   Casey, C. M.
   Riechers, D.
   Sheth, K.
   Carollo, C. M.
   Ilbert, O.
   Karim, A.
   LeFevre, O.
   Lilly, S.
   Scoville, N.
   Smolcic, V.
   Yan, L.
TI Galaxies at redshifts 5 to 6 with systematically low dust content and high [C II] emission
SO NATURE
LA English
DT Article
ID star-forming galaxy; similar-to 7; uv attenuation; ultraviolet; alma; gas; starbursts; absorption; evolution; continuum
AB The rest-frame ultraviolet properties of galaxies during the first three billion years of cosmic time (redshift z > 4) indicate a rapid evolution in the dust obscuration of such galaxies(1-3). This evolution implies a change in the average properties of the interstellar medium, but the measurements are systematically uncertain owing to untested assumptions(4,5) and the inability to detect heavily obscured regions of the galaxies. Previous attempts to measure the interstellar medium directly in normal galaxies at these red-shifts have failed for a number of reasons(6-9), with two notable exceptions(10,11). Here we report measurements of the forbidden C II emission (that is, [C II]) from gas, and the far-infrared emission from dust, in nine typical star-forming galaxies about one billion years after the Big Bang (z approximate to 5-6). We find that these galaxies have thermal emission that is less than 1/12 that of similar systems about two billion years later, and enhanced [C II] emission relative to the far-infrared continuum, confirming a strong evolution in the properties of the interstellar medium in the early Universe. The gas is distributed over scales of one to eight kiloparsecs, and shows diverse dynamics within the sample. These results are consistent with early galaxies having significantly less dust than typical galaxies seen at z < 3 and being comparable in dust content to local low-metallicity systems(12).
C1 [Capak, P. L.; Yan, L.] CALTECH, Ctr Infrared Proc & Anal, Pasadena, CA 91125 USA.
   [Capak, P. L.; Scoville, N.; Yan, L.] CALTECH, Pasadena, CA 91125 USA.
   [Carilli, C.] Natl Radio Astron Observ, Socorro, NM 87801 USA.
   [Carilli, C.] Univ Cambridge, Cavendish Lab, Astrophys Grp, Cambridge CB3 0HE, England.
   [Jones, G.] New Mexico Inst Min & Technol, Socorro, NM 87801 USA.
   [Casey, C. M.] Univ Texas Austin, Dept Astron, Austin, TX 78712 USA.
   [Riechers, D.] Cornell Univ, Dept Astron, Ithaca, NY 14853 USA.
   [Sheth, K.; Lilly, S.] Natl Radio Astron Observ, Charlottesville, VA 22903 USA.
   [Carollo, C. M.] ETH, Inst Astron, CH-8093 Zurich, Switzerland.
   [Ilbert, O.; LeFevre, O.] Aix Marseille Univ, CNRS, LAM, UMR 7326, F-13388 Marseille, France.
   [Karim, A.] Argelander Inst Astron, D-53121 Bonn, Germany.
   [Smolcic, V.] Univ Zagreb, Dept Phys, Zagreb 10002, Croatia.
C3 California Institute of Technology; California Institute of Technology; National Radio Astronomy Observatory (NRAO); University of Cambridge; New Mexico Institute of Mining Technology; University of Texas System; University of Texas Austin; Cornell University; National Radio Astronomy Observatory (NRAO); Swiss Federal Institutes of Technology Domain; ETH Zurich; Aix-Marseille Universite; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); University of Bonn; University of Zagreb
RP Capak, PL (corresponding author), CALTECH, Ctr Infrared Proc & Anal, 1200 East Calif Blvd, Pasadena, CA 91125 USA.
EM capak@astro.caltech.edu
FU NASA; European Union [337595]
NR 44
TC 410
Z9 439
U1 0
U2 13
PU NATURE PUBLISHING 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 25
PY 2015
VL 522
IS 7557
BP 455
EP +
DI 10.1038/nature14500
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL2OC
UT WOS:000356782900044
PM 26108853
DA 2026-03-09
ER

PT J
AU Turner, JL
   Beck, SC
   Benford, DJ
   Consiglio, SM
   Ho, PTP
   Kovács, A
   Meier, DS
   Zhao, JH
AF Turner, J. L.
   Beck, S. C.
   Benford, D. J.
   Consiglio, S. M.
   Ho, P. T. P.
   Kovacs, A.
   Meier, D. S.
   Zhao, J-H.
TI Highly efficient star formation in NGC 5253 possibly from stream-fed accretion
SO NATURE
LA English
DT Article
ID small-magellanic-cloud; galaxy ngc-5253; dwarf galaxy; central region; cold streams; gas; cluster; starburst; dust; spectroscopy
AB Gas clouds in present-day galaxies are inefficient at forming stars. Low star-formation efficiency is a critical parameter in galaxy evolution: it is why stars are still forming nearly 14 billion years after the Big Bang(1) and why star clusters generally do not survive their births, instead dispersing to form galactic disks or bulges'. Yet the existence of ancient massive bound star clusters (globular clusters) in the Milky Way suggests that efficiencies were higher when they formed ten billion years ago. A local dwarf galaxy, NGC 5253, has a young star cluster that provides an example of highly efficient star formation(3). Here we report the detection of the J = 3 -> 2 rotational transition of CO at the location of the massive cluster. The gas cloud is hot, dense, quiescent and extremely dusty. Its gas-to-dust ratio is lower than the Galactic value, which we attribute to dust enrichment by the embedded star cluster. Its star-formation efficiency exceeds 50 percent, tenfold that of clouds in the Milky Way. We suggest that high efficiency results from the force-feeding of star formation by a streamer of gas falling into the galaxy.
C1 [Turner, J. L.; Consiglio, S. M.] Univ Calif Los Angeles, Dept Phys & Astron, Los Angeles, CA 90095 USA.
   [Beck, S. C.] Tel Aviv Univ, Dept Phys & Astron, IL-69978 Ramat Aviv, Israel.
   [Benford, D. J.] NASA, Goddard Space Flight Ctr, Observat Cosmol Lab, Greenbelt, MD 20771 USA.
   [Ho, P. T. P.] Acad Sinica, Astron & Astrophys, Taipei 10617, Taiwan.
   [Kovacs, A.] CALTECH, Dept Phys, Pasadena, CA 91125 USA.
   [Kovacs, A.] Univ Minnesota, Inst Astrophys, Minneapolis, MN 55405 USA.
   [Meier, D. S.] New Mexico Inst Min & Technol, Dept Phys, Socorro, NM USA.
   [Meier, D. S.] Natl Radio Astron Observ, Socorro, NM USA.
   [Zhao, J-H.] Harvard Smithsonian Ctr Astrophys, Cambridge, MA 02138 USA.
C3 University of California System; University of California Los Angeles; Tel Aviv University; National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center; Academia Sinica - Taiwan; California Institute of Technology; University of Minnesota System; University of Minnesota Twin Cities; New Mexico Institute of Mining Technology; National Radio Astronomy Observatory (NRAO); Harvard University; Smithsonian Institution; Smithsonian Astrophysical Observatory
RP Turner, JL (corresponding author), Univ Calif Los Angeles, Dept Phys & Astron, Los Angeles, CA 90095 USA.
EM turner@astro.ucla.edu
FU Smithsonian Institution; Academica Sinica
NR 36
TC 69
Z9 79
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 MAR 19
PY 2015
VL 519
IS 7543
BP 331
EP +
DI 10.1038/nature14218
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD6AY
UT WOS:000351171900036
PM 25788096
DA 2026-03-09
ER

PT J
AU Su, J
   Hu, C
   Yan, X
   Jin, Y
   Chen, Z
   Guan, Q
   Wang, Y
   Zhong, D
   Jansson, C
   Wang, F
   Schnürer, A
   Sun, C
AF Su, J.
   Hu, C.
   Yan, X.
   Jin, Y.
   Chen, Z.
   Guan, Q.
   Wang, Y.
   Zhong, D.
   Jansson, C.
   Wang, F.
   Schnurer, A.
   Sun, C.
TI Expression of barley SUSIBA2 transcription factor yields high-starch low-methane rice
SO NATURE
LA English
DT Article
ID gene-expression; community; emissions; fluxes; field
AB Atmospheric methane is the second most important greenhouse gas after carbon dioxide, and is responsible for about 20% of the global warming effect since pre-industrial times(1,2). Rice paddies are the largest anthropogenic methane source and produce 7-17% of atmospheric methane(2,3). Warm waterlogged soil and exuded nutrients from rice roots provide ideal conditions for methanogenesis in paddies with annual methane emissions of 25-100-million tonnes(3,4). This scenario will be exacerbated by an expansion in rice cultivation needed to meet the escalating demand for food in the coming decades(4). There is an urgent need to establish sustainable technologies for increasing rice production while reducing methane fluxes from rice paddies. However, ongoing efforts for methane mitigation in rice paddies are mainly based on farming practices and measures that are difficult to implement(5). Despite proposed strategies to increase rice productivity and reduce methane emissions(4,6), no high-starch low-methane-emission rice has been developed. Here we show that the addition of a single transcription factor gene, barley SUSIBA2 (refs 7, 8), conferred a shift of carbon flux to SUSIBA2 rice, favouring the allocation of photo-synthates to aboveground biomass over allocation to roots. The altered allocation resulted in an increased biomass and starch content in the seeds and stems, and suppressed methanogenesis, possibly through a reduction in root exudates. Three-year field trials in China demonstrated that the cultivation of SUSIBA2 rice was associated with a significant reduction in methane emissions and a decrease in rhizospheric methanogen levels. SUSIBA2 rice offers a sustainable means of providing increased starch content for food production while reducing greenhouse gas emissions from rice cultivation. Approaches to increase rice productivity and reduce methane emissions as seen in SUSIBA2 rice may be particularly beneficial in a future climate with rising temperatures resulting in increased methane emissions from paddies(9,10).
C1 [Su, J.; Hu, C.; Chen, Z.; Guan, Q.; Wang, Y.; Zhong, D.; Wang, F.] Fujian Acad Agr Sci, Inst Biotechnol, Fuzhou 350003, Peoples R China.
   [Su, J.; Hu, C.; Yan, X.; Jin, Y.; Sun, C.] Swedish Univ Agr Sci, Linnean Ctr Plant Biol, Uppsala BioCtr, Dept Plant Biol, SE-75007 Uppsala, Sweden.
   [Jin, Y.] Hunan Agr Univ, Hunan Prov Key Lab Crop Germplasm Innovat & Utili, Changsha 410128, Hunan, Peoples R China.
   [Jansson, C.] Pacific NW Natl Lab, Environm Mol Sci Lab EMSL, Richland, WA 99352 USA.
   [Schnurer, A.] Swedish Univ Agr Sci, Dept Microbiol, Uppsala BioCtr, SE-75007 Uppsala, Sweden.
C3 Fujian Academy of Agricultural Sciences; Swedish University of Agricultural Sciences; Hunan Agricultural University; United States Department of Energy (DOE); Pacific Northwest National Laboratory; Swedish University of Agricultural Sciences
RP Sun, C (corresponding author), Swedish Univ Agr Sci, Linnean Ctr Plant Biol, Uppsala BioCtr, Dept Plant Biol, POB 7080, SE-75007 Uppsala, Sweden.
EM wf@fjage.org; Chuanxin.Sun@slu.se
FU Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas) [219-2014-1172]; Formas/Sida [220-2009-2069]; SLU Larosatesansokan Programme (TC4F) for Team 4 - Vinnova; Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas) under the Strategic Research Area for the TCBB Programme; National Natural Science Foundation of China [30771298, 31370389]; SLU programme BarleyFunFood; Carl Trygger Foundation [CTS 11: 450]; US Department of Energy [DE-AC05-76RL01830]; Pacific Northwest National Laboratory
NR 29
TC 171
Z9 211
U1 15
U2 376
PU NATURE PUBLISHING 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 30
PY 2015
VL 523
IS 7562
BP 602
EP +
DI 10.1038/nature14673
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN7ZL
UT WOS:000358655200047
PM 26200336
DA 2026-03-09
ER

PT J
AU Tan, J
   Jakob, C
   Rossow, WB
   Tselioudis, G
AF Tan, Jackson
   Jakob, Christian
   Rossow, William B.
   Tselioudis, George
TI Increases in tropical rainfall driven by changes in frequency of organized deep convection
SO NATURE
LA English
DT Article
ID pacific cloud regimes; western pacific; weather states; global precipitation; hydrological cycle; isccp; identification; patterns; richer
AB Increasing global precipitation has been associated with a warming climate resulting from a strengthening of the hydrological cycle(1). This increase, however, is not spatially uniform. Observations and models have found that changes in rainfall show patterns characterized as 'wet-gets-wetter'(1-7) and 'warmer-gets-wetter'(5,8,9). These changes in precipitation are largely located in the tropics and hence are probably associated with convection. However, the underlying physical processes for the observed changes are not entirely clear. Here we show from observations that most of the regional increase in tropical precipitation is associated with changes in the frequency of organized deep convection. By assessing the contributions of various convective regimes to precipitation, we find that the spatial patterns of change in the frequency of organized deep convection are strongly correlated with observed change in rainfall, both positive and negative (correlation of 0.69), and can explain most of the patterns of increase in rainfall. In contrast, changes in less organized forms of deep convection or changes in precipitation within organized deep convection contribute less to changes in precipitation. Our results identify organized deep convection as the link between changes in rainfall and in the dynamics of the tropical atmosphere, thus providing a framework for obtaining a better understanding of changes in rainfall. Given the lack of a distinction between the different degrees of organization of convection in climate models(10), our results highlight an area of priority for future climate model development in order to achieve accurate rainfall projections in a warming climate.
C1 [Tan, Jackson; Jakob, Christian] Monash Univ, Sch Earth Atmosphere & Environm, ARC Ctr Excellence Climate Syst Sci, Clayton, Vic 3800, Australia.
   [Rossow, William B.] CUNY City Coll, CREST Inst, New York, NY 10031 USA.
   [Tselioudis, George] NASA, Goddard Inst Space Studies, New York, NY 10027 USA.
C3 Monash University; City University of New York (CUNY) System; City College of New York (CUNY); National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center; Goddard Institute for Space Studies
RP Tan, J (corresponding author), Monash Univ, Sch Earth Atmosphere & Environm, ARC Ctr Excellence Climate Syst Sci, Clayton, Vic 3800, Australia.
EM jackson.tan@nasa.gov
FU Australian Research Council Centre of Excellence for Climate System Science [CE110001028]; NASA [NNX13AO39G]; NASA; Monash University
NR 30
TC 151
Z9 166
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 MAR 26
PY 2015
VL 519
IS 7544
BP 451
EP +
DI 10.1038/nature14339
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE1WF
UT WOS:000351602800052
PM 25810207
DA 2026-03-09
ER

PT J
AU Martínez-Botí, MA
   Marino, G
   Foster, GL
   Ziveri, P
   Henehan, MJ
   Rae, JWB
   Mortyn, PG
   Vance, D
AF Martinez-Boti, M. A.
   Marino, G.
   Foster, G. L.
   Ziveri, P.
   Henehan, M. J.
   Rae, J. W. B.
   Mortyn, P. G.
   Vance, D.
TI Boron isotope evidence for oceanic carbon dioxide leakage during the last deglaciation
SO NATURE
LA English
DT Article
ID western equatorial pacific; planktonic-foraminifera; southern-ocean; atmospheric co2; deep-ocean; globigerinoides-sacculifer; seasonal-changes; atlantic sector; surface waters; north pacific
AB Atmospheric CO2 fluctuations over glacial-interglacial cycles remain a major challenge to our understanding of the carbon cycle and the climate system. Leading hypotheses put forward to explain glacial-interglacial atmospheric CO2 variations invoke changes in deep-ocean carbon storage(1,2), probably modulated by processes in the Southern Ocean, where much of the deep ocean is ventilated(3). A central aspect of such models is that, during deglaciations, an isolated glacial deep-ocean carbon reservoir is reconnected with the atmosphere, driving the atmospheric CO2 rise observed in ice-core records(4-6). However, direct documentation of changes in surface ocean carbon content and the associated transfer of carbon to the atmosphere during deglaciations has been hindered by the lack of proxy reconstructions that unambiguously reflect the oceanic carbonate system. Radiocarbon activity tracks changes in ocean ventilation(6), but not in ocean carbon content, whereas proxies that record increased deglacial upwelling(4,7) do not constrain the proportion of upwelled carbon that is degassed relative to that which is taken up by the biological pump. Here we apply the boron isotope pH proxy in planktic foraminifera to two sediment cores from the sub-Antarctic Atlantic and the eastern equatorial Pacific as a more direct tracer of oceanic CO2 outgassing. We show that surface waters at both locations, which partly derive from deep water upwelled in the Southern Ocean(8,9), became a significant source of carbon to the atmosphere during the last deglaciation, when the concentration of atmospheric CO2 was increasing. This oceanic CO2 outgassing supports the view that the ventilation of a deep-ocean carbon reservoir in the Southern Ocean had a key role in the deglacial CO2 rise, although our results allow for the possibility that processes operating in other regions may also have been important for the glacial-interglacial ocean-atmosphere exchange of carbon.
C1 [Martinez-Boti, M. A.; Foster, G. L.; Henehan, M. J.] Univ Southampton, Natl Oceanog Ctr Southampton, Southampton SO14 3ZH, Hants, England.
   [Marino, G.; Ziveri, P.; Mortyn, P. G.] Univ Autonoma Barcelona, Inst Environm Sci & Technol ICTA, Bellaterra 08193, Catalonia, Spain.
   [Marino, G.] Australian Natl Univ, Res Sch Earth Sci, Canberra, ACT 2601, Australia.
   [Ziveri, P.] ICREA, Barcelona 08010, Catalonia, Spain.
   [Ziveri, P.] Vrije Univ Amsterdam, Fac Earth & Life Sci, Dept Earth Sci, Earth & Climate Cluster, NL-1081 HV Amsterdam, Netherlands.
   [Henehan, M. J.] Yale Univ, Dept Geol & Geophys, New Haven, CT 06511 USA.
   [Rae, J. W. B.] CALTECH, Div Geol & Planetary Sci, Pasadena, CA 91125 USA.
   [Rae, J. W. B.] Univ St Andrews, Dept Earth & Environm Sci, St Andrews KY16 9AL, Fife, Scotland.
   [Mortyn, P. G.] Univ Autonoma Barcelona, Dept Geog, Bellaterra 08193, Catalonia, Spain.
   [Vance, D.] ETH, Dept Earth Sci, Inst Geochem & Petrol, CH-8092 Zurich, Switzerland.
C3 NERC National Oceanography Centre; University of Southampton; Autonomous University of Barcelona; Australian National University; ICREA; Vrije Universiteit Amsterdam; Yale University; California Institute of Technology; University of St Andrews; Autonomous University of Barcelona; Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Martínez-Botí, MA (corresponding author), Univ Southampton, Natl Oceanog Ctr Southampton, Waterfront Campus, Southampton SO14 3ZH, Hants, England.
EM m.a.martinez-boti@noc.soton.ac.uk; gianluca.marino@anu.edu.au
FU European Community; Universitat Autonoma de Barcelona; Spanish Ministry of Science and Innovation (PROCARSO) [CGL2009-10806]; NERC [NE/D00876/X2]; NOAA/UCAR Climate and Global Change Postdoctoral Fellowship; Australian Laureate Fellowship [FL120100050]; ICREA Funding Source: Custom
NR 101
TC 170
Z9 185
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 FEB 12
PY 2015
VL 518
IS 7538
BP 219
EP U154
DI 10.1038/nature14155
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300035
PM 25673416
DA 2026-03-09
ER

PT J
AU Stensola, T
   Stensola, H
   Moser, MB
   Moser, EI
AF Stensola, Tor
   Stensola, Hanne
   Moser, May-Britt
   Moser, Edvard I.
TI Shearing-induced asymmetry in entorhinal grid cells
SO NATURE
LA English
DT Article
ID spatial representation; path-integration; cortex; map; fields; model
AB Grid cells are neurons with periodic spatial receptive fields (grids) that tile two-dimensional space in a hexagonal pattern. To provide useful information about location, grids must be stably anchored to an external reference frame. The mechanisms underlying this anchoring process have remained elusive. Here we show in differently sized familiar square enclosures that the axes of the grids are offset from the walls by an angle that minimizes symmetry with the borders of the environment. This rotational offset is invariably accompanied by an elliptic distortion of the grid pattern. Reversing the ellipticity analytically by a shearing transformation removes the angular offset. This, together with the near-absence of rotation in novel environments, suggests that the rotation emerges through non-coaxial strain as a function of experience. The systematic relationship between rotation and distortion of the grid pattern points to shear forces arising from anchoring to specific geometric reference points as key elements of the mechanism for alignment of grid patterns to the external world.
C1 [Stensola, Tor; Stensola, Hanne; Moser, May-Britt; Moser, Edvard I.] Norwegian Univ Sci & Technol, Kavli Inst Syst Neurosci, N-7491 Trondheim, Norway.
   [Stensola, Tor; Stensola, Hanne; Moser, May-Britt; Moser, Edvard I.] Norwegian Univ Sci & Technol, Ctr Neural Computat, N-7491 Trondheim, Norway.
C3 Norwegian University of Science & Technology (NTNU); Norwegian University of Science & Technology (NTNU)
RP Stensola, T (corresponding author), Norwegian Univ Sci & Technol, Kavli Inst Syst Neurosci, Olav Kyrres Gate 9, N-7491 Trondheim, Norway.
EM tor.stensola@ntnu.no; edvard.moser@ntnu.no
FU European Research Council [232608, 338865]; European Commission [600725]; Kavli Foundation; Louis-Jeantet Prize for Medicine; Centre of Excellence funding scheme of the Research Council of Norway (Centre for the Biology of Memory) [145993]; Centre of Excellence funding scheme of the Research Council of Norway (Centre for Neural Computation) [223262]; European Research Council (ERC) [232608, 338865] Funding Source: European Research Council (ERC)
NR 24
TC 145
Z9 180
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 FEB 12
PY 2015
VL 518
IS 7538
BP 207
EP U425
DI 10.1038/nature14151
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300032
PM 25673414
DA 2026-03-09
ER

PT J
AU Kommineni, S
   Bretl, DJ
   Lam, V
   Chakraborty, R
   Hayward, M
   Simpson, P
   Cao, YM
   Bousounis, P
   Kristich, CJ
   Salzman, NH
AF Kommineni, Sushma
   Bretl, Daniel J.
   Lam, Vy
   Chakraborty, Rajrupa
   Hayward, Michael
   Simpson, Pippa
   Cao, Yumei
   Bousounis, Pavlos
   Kristich, Christopher J.
   Salzman, Nita H.
TI Bacteriocin production augments niche competition by enterococci in the mammalian gastrointestinal tract
SO NATURE
LA English
DT Article
ID resistant enterococci; infections; microbiota; faecalis; health; as-48
AB Enterococcus faecalis is both a common commensal of the human gastrointestinal tract and a leading cause of hospital-acquired infections(1). Systemic infections with multidrug-resistant enterococci occur subsequent to gastrointestinal colonization(2). Preventing colonization by multidrug-resistant E. faecalis could therefore be a valuable approach towards limiting infection. However, little is known about the mechanisms E. faecalis uses to colonize and compete for stable gastrointestinal niches. Pheromone-responsive conjugative plasmids encoding bacteriocins are common among enterococcal strains(3) and could modulate niche competition among enterococci or between enterococci and the intestinal microbiota. We developed a model of colonization of the mouse gut with E. faecalis, without disrupting the microbiota, to evaluate the role of the conjugative plasmid pPD1 expressing baderiocin 21 (ref. 4) in enterococcal colonization. Here we show that E. faecalis harbouring pPD1 replaces indigenous enterococci and outcompetes E. faecalis lacking pPD1. Furthermore, in the intestine, pPD1 is transferred to other E. faecalis strains by conjugation, enhancing their survival. Colonization with an E. faecalis strain carrying a conjugation-defective pPD1 mutant subsequently resulted in clearance of vancomycin-resistant enterococci, without plasmid transfer. Therefore, bacteriocin expression by commensal bacteria can influence niche competition in the gastrointestinal tract, and bacteriocins, delivered by commensals that occupy a precise intestinal bacterial niche, may be an effective therapeutic approach to specifically eliminate intestinal colonization by multidrug-resistant bacteria, without profound disruption of the indigenous microbiota.
C1 [Kommineni, Sushma; Lam, Vy; Chakraborty, Rajrupa; Hayward, Michael; Bousounis, Pavlos; Salzman, Nita H.] Med Coll Wisconsin, Div Gastroenterol, Dept Pediat, Milwaukee, WI 53226 USA.
   [Simpson, Pippa; Cao, Yumei] Med Coll Wisconsin, Div Quantitat Hlth Sci, Dept Pediat, Milwaukee, WI 53226 USA.
   [Kommineni, Sushma; Bretl, Daniel J.; Chakraborty, Rajrupa; Kristich, Christopher J.; Salzman, Nita H.] Med Coll Wisconsin, Dept Microbiol & Mol Genet, Milwaukee, WI 53226 USA.
C3 Medical College of Wisconsin; Medical College of Wisconsin; Medical College of Wisconsin
RP Salzman, NH (corresponding author), Med Coll Wisconsin, Div Gastroenterol, Dept Pediat, Milwaukee, WI 53226 USA.
EM ckristich@mcw.edu; nsalzman@mcw.edu
FU National Institutes of Health [AI057757, AI097619, GM099526, AI081692, 0D006447]
NR 20
TC 344
Z9 409
U1 2
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 OCT 29
PY 2015
VL 526
IS 7575
BP 719
EP 722
DI 10.1038/nature15524
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CU8ZH
UT WOS:000363832100052
PM 26479034
DA 2026-03-09
ER

PT J
AU Tajitsu, A
   Sadakane, K
   Naito, H
   Arai, A
   Aoki, W
AF Tajitsu, Akito
   Sadakane, Kozo
   Naito, Hiroyuki
   Arai, Akira
   Aoki, Wako
TI Explosive lithium production in the classical nova V339 Del (Nova Delphini 2013)
SO NATURE
LA English
DT Article
ID thermonuclear formation; agb stars; li-7; evolution; lines; discovery; creation; be-7
AB The origin of lithium (Li) and its production process have long been uncertain. Li could be produced by Big Bang nucleosynthesis, interactions of energetic cosmic rays with interstellar matter, evolved low-mass stars, novae, and supernova explosions. Chemical evolution models and observed stellar Li abundances suggest that at least half the Li may have been produced in red giants, asymptotic giant branch (AGB) stars, and novae(1-3). No direct evidence, however, for the supply of Li from evolved stellar objects to the Galactic medium has hitherto been found. Here we report the detection of highly blue-shifted resonance lines of the singly ionized radioactive isotope of beryllium, Be-7, in the near-ultraviolet spectra of the classical nova V339 Del (Nova Delphini 2013) 38 to 48 days after the explosion. Be-7 decays to form Li-7 within a short time (half-life of 53.22 days(4)). The Be-7 was created during the nova explosion via the alpha-capture reaction He-3(alpha,gamma)Be-7 (ref. 5). This result supports the theoretical prediction that a significant amount of 7Li is produced in classical nova explosions.
C1 [Tajitsu, Akito] Subaru Telescope, Natl Astron Observ Japan, Hilo, HI 96720 USA.
   [Sadakane, Kozo] Osaka Kyoiku Univ, Astron Inst, Osaka 5828582, Japan.
   [Naito, Hiroyuki] Nagoya Univ, Grad Sch Sci, Chikusa Ku, Nagoya, Aichi 4648602, Japan.
   [Naito, Hiroyuki] Nayoro Observ, Nayoro, Hokkaido 0960066, Japan.
   [Arai, Akira] Univ Hyogo, Ctr Astron, Sayo, Hyogo 6795313, Japan.
   [Arai, Akira] Kyoto Sangyo Univ, Koyama Astron Observ, Kita Ku, Kyoto 6038555, Japan.
   [Aoki, Wako] Natl Astron Observ Japan, Mitaka, Tokyo 1818588, Japan.
C3 National Institutes of Natural Sciences (NINS) - Japan; National Astronomical Observatory of Japan (NAOJ); Osaka University of Education; Nagoya University; University of Hyogo; Kyoto Sangyo University; National Institutes of Natural Sciences (NINS) - Japan; National Astronomical Observatory of Japan (NAOJ)
RP Tajitsu, A (corresponding author), Subaru Telescope, Natl Astron Observ Japan, 650 North Aohoku Pl, Hilo, HI 96720 USA.
EM tajitsu@naoj.org
NR 41
TC 109
Z9 121
U1 0
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 FEB 19
PY 2015
VL 518
IS 7539
BP 381
EP 384
DI 10.1038/nature14161
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400038
PM 25693569
DA 2026-03-09
ER

PT J
AU Najm, FJ
   Madhavan, M
   Zaremba, A
   Shick, E
   Karl, RT
   Factor, DC
   Miller, TE
   Nevin, ZS
   Kantor, C
   Sargent, A
   Quick, KL
   Schlatzer, DM
   Tang, H
   Papoian, R
   Brimacombe, KR
   Shen, M
   Boxer, MB
   Jadhav, A
   Robinson, AP
   Podojil, JR
   Miller, SD
   Miller, RH
   Tesar, PJ
AF Najm, Fadi J.
   Madhavan, Mayur
   Zaremba, Anita
   Shick, Elizabeth
   Karl, Robert T.
   Factor, Daniel C.
   Miller, Tyler E.
   Nevin, Zachary S.
   Kantor, Christopher
   Sargent, Alex
   Quick, Kevin L.
   Schlatzer, Daniela M.
   Tang, Hong
   Papoian, Ruben
   Brimacombe, Kyle R.
   Shen, Min
   Boxer, Matthew B.
   Jadhav, Ajit
   Robinson, Andrew P.
   Podojil, Joseph R.
   Miller, Stephen D.
   Miller, Robert H.
   Tesar, Paul J.
TI Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo
SO NATURE
LA English
DT Article
ID oligodendrocyte progenitor cells; central-nervous-system; myelin basic-protein; multiple-sclerosis; spinal-cord; rna-seq; differentiation; glucocorticoids; lysolecithin; transcripts
AB Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes(1). These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention(2). To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells(3-5). Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.
C1 [Najm, Fadi J.; Madhavan, Mayur; Shick, Elizabeth; Karl, Robert T.; Factor, Daniel C.; Miller, Tyler E.; Nevin, Zachary S.; Tesar, Paul J.] Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA.
   [Zaremba, Anita; Kantor, Christopher; Sargent, Alex; Miller, Robert H.; Tesar, Paul J.] Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA.
   [Miller, Tyler E.] Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH 44106 USA.
   [Miller, Tyler E.] Cleveland Clin, Dept Stem Cell Biol & Regenerat Med, Lerner Res Inst, Cleveland, OH 44195 USA.
   [Quick, Kevin L.] PerkinElmer, Waltham, MA 02451 USA.
   [Schlatzer, Daniela M.] Case Western Reserve Univ, Sch Med, Ctr Prote & Bioinformat, Cleveland, OH 44106 USA.
   [Tang, Hong; Papoian, Ruben] Univ Cincinnati, Coll Med, Ctr Drug Discovery, Cincinnati, OH 45237 USA.
   [Brimacombe, Kyle R.; Shen, Min; Boxer, Matthew B.; Jadhav, Ajit] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20852 USA.
   [Robinson, Andrew P.; Podojil, Joseph R.; Miller, Stephen D.] Northwestern Univ, Feinberg Sch Med, Dept Microbiol & Immunol, Chicago, IL 60611 USA.
   [Robinson, Andrew P.; Podojil, Joseph R.; Miller, Stephen D.] Northwestern Univ, Feinberg Sch Med, Interdept Immunobiol Ctr, Chicago, IL 60611 USA.
C3 University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; Cleveland Clinic Foundation; PerkinElmer, Inc.; University System of Ohio; Case Western Reserve University; University System of Ohio; University of Cincinnati; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS); Northwestern University; Feinberg School of Medicine; Northwestern University; Feinberg School of Medicine
RP Tesar, PJ (corresponding author), Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA.
EM rhm3@gwu.edu; paul.tesar@case.edu
FU US NIH [NS085246, NS030800, NS026543]; NewYork Stem Cell Foundation; Myelin Repair Foundation; Mt. Sinai Health Care Foundation; NIH [T32GM008056, F30CA183510]; Cytometry & Imaging Microscopy, Proteomics, and Genomics core facilities of the Case Comprehensive Cancer Center [P30CA043703]; CWRU Council; National Cancer Institute [P30CA043703] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007250] Funding Source: NIH RePORTER
NR 30
TC 363
Z9 429
U1 1
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 11
PY 2015
VL 522
IS 7555
BP 216
EP +
DI 10.1038/nature14335
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700039
PM 25896324
DA 2026-03-09
ER

PT J
AU Lin, MC
   Gong, M
   Lu, BG
   Wu, YP
   Wang, DY
   Guan, MY
   Angell, M
   Chen, CX
   Yang, J
   Hwang, BJ
   Dai, HJ
AF Lin, Meng-Chang
   Gong, Ming
   Lu, Bingan
   Wu, Yingpeng
   Wang, Di-Yan
   Guan, Mingyun
   Angell, Michael
   Chen, Changxin
   Yang, Jiang
   Hwang, Bing-Joe
   Dai, Hongjie
TI An ultrafast rechargeable aluminium-ion battery
SO NATURE
LA English
DT Article
ID graphite-intercalation; electrolyte; chloride; liquids; electrodeposition; deposition; anions; alloy
AB The development of new rechargeable battery systems could fuel various energy applications, from personal electronics to grid storage(1,2). Rechargeable aluminium-based batteries offer the possibilities of low cost and low flammability, together with three-electron-redox properties leading to high capacity'. However, research efforts over the past 30 years have encountered numerous problems, such as cathode material disintegration'', low cell discharge voltage (about 0.55 volts; ref. 5), capacitive behaviour without discharge voltage plateaus (1.1-0.2 volts(6) or 1.8-0.8 volts(7)) and insufficient cycle life (less than 100 cycles) with rapid capacity decay (by 26-85 per cent over 100 cydes)(4-7). Here we present a rechargeable aluminium battery with high-rate capability that uses an aluminium metal anode and a three-dimensional graphitic-foam cathode. The battery operates through the electrochemical deposition and dissolution of aluminium at the anode, and intercalation/de-intercalation of chloroaluminate anions in the graphite, using a non-flammable ionic liquid electrolyte. The cell exhibits well-defined discharge voltage plateaus near 2 volts, a specific capacity of about 70 mA h g(-1) and a Coulombic efficiency of approximately 98 per cent. The cathode was found to enable fast anion diffusion and intercalation, affording charging times of around one minute with a current density of similar to 4,000 mA g(-1) (equivalent to similar to 3,000 W kg(-1)) and to withstand more than 7,500 cycles without capacity decay.
C1 [Lin, Meng-Chang; Gong, Ming; Lu, Bingan; Wu, Yingpeng; Wang, Di-Yan; Guan, Mingyun; Angell, Michael; Chen, Changxin; Yang, Jiang; Dai, Hongjie] Stanford Univ, Dept Chem, Stanford, CA 94305 USA.
   [Lin, Meng-Chang] Ind Technol Res Inst, Green Energy & Environm Res Labs, Hsinchu 31040, Taiwan.
   [Lu, Bingan] Hunan Univ, Sch Phys & Elect, Changsha 410082, Hunan, Peoples R China.
   [Wang, Di-Yan] Natl Taiwan Normal Univ, Dept Chem, Taipei 11677, Taiwan.
   [Wang, Di-Yan] Acad Sinica, Inst Atom & Mol Sci, Taipei 10617, Taiwan.
   [Hwang, Bing-Joe] Natl Taiwan Univ Sci & Technol, Dept Chem Engn, Taipei 10607, Taiwan.
C3 Stanford University; Industrial Technology Research Institute - Taiwan; Hunan University; National Taiwan Normal University; Academia Sinica - Taiwan; National Taiwan University of Science & Technology
RP Dai, HJ (corresponding author), Stanford Univ, Dept Chem, Stanford, CA 94305 USA.
EM hdai@stanford.edu
FU Bureau of Energy, Ministry of Economic Affairs, Taiwan; National Natural Science Foundation of China [21303046]; China Scholarship Council [201308430178]; Hunan University Fund for Multidisciplinary Developing [531107040762]; US Department of Energy for novel carbon materials development and electrical characterization work [DOE DE-SC0008684]; Stanford GCEP; Precourt Institute of Energy; Global Networking Talent 3.0 plan from the Ministry of Education of Taiwan [NTUST 104DI005]; U.S. Department of Energy (DOE) [DE-SC0008684] Funding Source: U.S. Department of Energy (DOE)
NR 29
TC 2188
Z9 2395
U1 49
U2 2793
PU NATURE PUBLISHING 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 16
PY 2015
VL 520
IS 7547
BP 325
EP +
DI 10.1038/nature14340
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG0RI
UT WOS:000352974200033
PM 25849777
DA 2026-03-09
ER

PT J
AU Cho, HS
   Deng, HX
   Miyasaka, K
   Dong, ZY
   Cho, M
   Neimark, AV
   Kang, JK
   Yaghi, OM
   Terasaki, O
AF Cho, Hae Sung
   Deng, Hexiang
   Miyasaka, Keiichi
   Dong, Zhiyue
   Cho, Minhyung
   Neimark, Alexander V.
   Kang, Jeung Ku
   Yaghi, Omar M.
   Terasaki, Osamu
TI Extra adsorption and adsorbate superlattice formation in metal-organic frameworks
SO NATURE
LA English
DT Article
ID porous coordination polymers; ultrahigh surface-area; x-ray-diffraction; mesoporous silica; hydrogen storage; argon adsorption; crystal; sites; visualization; sorption
AB Metal-organic frameworks (MOFs) have a high internal surface area and widely tunable composition(1,2), which make them useful for applications involving adsorption, such as hydrogen, methane or carbon dioxide storage(3-9). The selectivity and uptake capacity of the adsorption process are determined by interactions involving the adsorbates and their porous host materials. But, although the interactions of adsorbate molecules with the internal MOF surface(10-17) and also amongst themselves within individual pores(18-22) have been extensively studied, adsorbate-adsorbate interactions across pore walls have not been explored. Here we show that local strain in the MOF, induced by pore filling, can give rise to collective and long-range adsorbate-adsorbate interactions and the formation of adsorbate superlattices that extend beyond an original MOF unit cell. Specifically, we use in situ small-angle X-ray scattering to track and map the distribution and ordering of adsorbate molecules in five members of the mesoporous MOF-74 series along entire adsorption-desorption isotherms. We find in all cases that the capillary condensation that fills the pores gives rise to the formation of 'extra adsorption domains'-that is, domains spanning several neighbouring pores, which have a higher adsorbate density than non-domain pores. In the case of one MOF, IRMOF-74-V-hex, these domains form a superlattice structure that is difficult to reconcile with the prevailing view of pore-filling as a stochastic process. The visualization of the adsorption process provided by our data, with clear evidence for initial adsorbate aggregation in distinct domains and ordering before an even distribution is finally reached, should help to improve our understanding of this process and may thereby improve our ability to exploit it practically.
C1 [Cho, Hae Sung; Miyasaka, Keiichi; Cho, Minhyung; Kang, Jeung Ku; Yaghi, Omar M.; Terasaki, Osamu] Korea Adv Inst Sci & Technol, Grad Sch Energy Environm Water & Sustainabil, WCU BK21Plus, Taejon 305701, South Korea.
   [Deng, Hexiang; Dong, Zhiyue] Wuhan Univ, Coll Chem & Mol Sci, Key Lab Biomed Polymers Minist Educ, Wuhan 430072, Peoples R China.
   [Deng, Hexiang] Wuhan Univ, Inst Adv Studies, Wuhan 430072, Peoples R China.
   [Neimark, Alexander V.] Rutgers State Univ, Dept Chem & Biochem Engn, Piscataway, NJ 08854 USA.
   [Yaghi, Omar M.] Univ Calif Berkeley, Dept Chem, Div Mat Sci, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA.
   [Yaghi, Omar M.] Kavli Energy NanoSci Inst, Berkeley, CA 94720 USA.
   [Yaghi, Omar M.] King Fahd Univ Petr & Minerals, Dhahran 31261, Saudi Arabia.
   [Terasaki, Osamu] Stockholm Univ, Berzelii Ctr EXSELENT Porous Mat, Dept Mat & Environm Chem, SE-10691 Stockholm, Sweden.
C3 Korea Advanced Institute of Science & Technology (KAIST); Wuhan University; Wuhan University; Rutgers University System; Rutgers University New Brunswick; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; University of California System; University of California Berkeley; King Fahd University of Petroleum & Minerals; Stockholm University
RP Yaghi, OM (corresponding author), Korea Adv Inst Sci & Technol, Grad Sch Energy Environm Water & Sustainabil, WCU BK21Plus, Taejon 305701, South Korea.
EM yaghi@berkeley.edu; terasaki@kaist.ac.kr
FU WCU/BK21+; HIMC of Global Frontier Project - Ministry of Science, ICT and Future Planning [2013M3A6B1078884]; Korea Center for Artificial Photosynthesis; Berzelii Centre EXSELENT on Porous Materials; BASF (Ludwigshafen, Germany); 1000 Talent Plan of China; National Natural Science Foundation of China [21471118]; National Key Basic Research Program of China [2014CB239203]; NSF ERC 'Structured Organic Particulate Systems'; National Research Foundation of Korea [2009-0093881] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
NR 30
TC 224
Z9 238
U1 24
U2 997
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 503
EP U193
DI 10.1038/nature15734
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500045
PM 26550825
DA 2026-03-09
ER

PT J
AU Yan, WP
   Song, H
   Song, FH
   Guo, YS
   Wu, CH
   Her, AS
   Pu, Y
   Wang, S
   Naowarojna, N
   Weitz, A
   Hendrich, MP
   Costello, CE
   Zhang, LX
   Liu, PH
   Zhang, YJ
AF Yan, Wupeng
   Song, Heng
   Song, Fuhang
   Guo, Yisong
   Wu, Cheng-Hsuan
   Her, Ampon Sae
   Pu, Yi
   Wang, Shu
   Naowarojna, Nathchar
   Weitz, Andrew
   Hendrich, Michael P.
   Costello, Catherine E.
   Zhang, Lixin
   Liu, Pinghua
   Zhang, Yan Jessie
TI RETRACTED: RETRACTED ARTICLE: Endoperoxide formation by an α-ketoglutarate-dependent mononuclear non-haem iron enzyme (Retracted article. See vol. 593, pg. 612, 2021)
SO NATURE
LA English
DT Article; Retracted Publication
ID cofactor-independent dioxygenation; crystal-structure; oxygen activation; phase refinement; structural basis; model; biosynthesis; purification; improvement; validation
AB Many peroxy-containing secondary metabolites(1,2) have been isolated and shown to provide beneficial effects to human health(3-5). Yet, the mechanisms of most endoperoxide biosyntheses are not well understood. Although endoperoxides have been suggested as key reaction intermediates in several cases(6-8), the only well-characterized endoperoxide biosynthetic enzyme is prostaglandin H synthase, a haem-containing enzyme(9). Fumitremorgin B endoperoxidase (FtmOx1) from Aspergillus fumigatus is the first reported alpha-ketoglutarate-dependent mononuclear non-haem iron enzyme that can catalyse an endoperoxide formation reaction(10-12). To elucidate the mechanistic details for this unique chemical transformation, we report the X-ray crystal structures of FtmOx1 and the binary complexes it forms with either the co-substrate (alpha-ketoglutarate) or the substrate (fumitremorgin B). Uniquely, after alpha-ketoglutarate has bound to the mononuclear iron centre in a bidentate fashion, the remaining open site for oxygen binding and activation is shielded from the substrate or the solvent by a tyrosine residue (Y224). Upon replacing Y224 with alanine or phenylalanine, the FtmOx1 catalysis diverts from endoperoxide formation to the more commonly observed hydroxylation. Subsequent characterizations by a combination of stopped-flow optical absorption spectroscopy and freeze-quench electron paramagnetic resonance spectroscopy support the presence of transient radical species in FtmOx1 catalysis. Our results help to unravel the novel mechanism for this endoperoxide formation reaction.
C1 [Yan, Wupeng; Zhang, Yan Jessie] Univ Texas Austin, Dept Mol Biosci, Austin, TX 78712 USA.
   [Song, Heng; Wu, Cheng-Hsuan; Her, Ampon Sae; Pu, Yi; Wang, Shu; Naowarojna, Nathchar; Costello, Catherine E.; Liu, Pinghua] Boston Univ, Dept Chem, 590 Commonwealth Ave, Boston, MA 02215 USA.
   [Song, Fuhang; Zhang, Lixin] Chinese Acad Sci, Inst Microbiol, Key Lab Pathogen Microbiol & Immunol, Beijing 100101, Peoples R China.
   [Pu, Yi; Costello, Catherine E.] Boston Univ, Sch Med, Ctr Biomed Mass Spectrometry, Boston, MA 02118 USA.
   [Zhang, Yan Jessie] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA.
   [Guo, Yisong; Weitz, Andrew; Hendrich, Michael P.] Carnegie Mellon Univ, Dept Chem, Pittsburgh, PA 15213 USA.
C3 University of Texas System; University of Texas Austin; Boston University; Chinese Academy of Sciences; Institute of Microbiology, CAS; Boston University; University of Texas System; University of Texas Austin; Carnegie Mellon University
RP Liu, PH (corresponding author), Boston Univ, Dept Chem, 590 Commonwealth Ave, Boston, MA 02215 USA.
EM lzhang03@gmail.com; pinghua@bu.edu; jzhang@cm.utexas.edu
FU National Institutes of Health [R01 GM093903, P41 GM104603, R01 GM104896, R01 GM077387]; National Science Foundation [CHE-1309148, CHE-1126268]; Welch Foundation [F-1778]; 973 program [2013CB734000]; Carnegie Mellon University; National Distinguished Young Scholar Program in China [31125002]; National Institute of General Medical Sciences [R01GM104896] Funding Source: NIH RePORTER; Direct For Mathematical & Physical Scien; Division Of Chemistry [1309148] Funding Source: National Science Foundation
NR 62
TC 82
Z9 99
U1 1
U2 173
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 539
EP +
DI 10.1038/nature15519
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500053
PM 26524521
DA 2026-03-09
ER

PT J
AU Weiss, Y
   McNeill, J
   Pearson, DG
   Nowell, GM
   Ottley, CJ
AF Weiss, Yaakov
   McNeill, John
   Pearson, D. Graham
   Nowell, Geoff M.
   Ottley, Chris J.
TI Highly saline fluids from a subducting slab as the source for fluid-rich diamonds
SO NATURE
LA English
DT Article
ID trace-element; infrared-absorption; quantitative-determination; silicate inclusions; coexisting fluid; forming fluids; mantle; evolution; nitrogen; metasomatism
AB The infiltration of fluids into continental lithospheric mantle is a key mechanism for controlling abrupt changes in the chemical and physical properties of the lithospheric root(1,2), as well as diamond formation(3), yet the origin and composition of the fluids involved are still poorly constrained. Such fluids are trapped within diamonds when they form(4-7) and so diamonds provide a unique means of directly characterizing the fluids that percolate through the deep continental lithospheric mantle. Here we show a clear chemical evolutionary trend, identifying saline fluids as parental to silicic and carbonatitic deep mantle melts, in diamonds from the Northwest Territories, Canada. Fluid-rock interaction along with in situ melting cause compositional transitions, as the saline fluids traverse mixed peridotite-eclogite lithosphere. Moreover, the chemistry of the parental saline fluids-especially their strontium isotopic compositions-and the timing of host diamond formation suggest that a subducting Mesozoic plate under western North America is the source of the fluids. Our results imply a strong association between subduction, mantle metasomatism and fluid-rich diamond formation, emphasizing the importance of subduction-derived fluids in affecting the composition of the deep lithospheric mantle.
C1 [Weiss, Yaakov] Columbia Univ, Lamont Doherty Earth Observ, New York, NY 10964 USA.
   [McNeill, John; Nowell, Geoff M.; Ottley, Chris J.] Univ Durham, Dept Earth Sci, Durham DH1 3LE, England.
   [Pearson, D. Graham] Univ Alberta, Dept Earth & Atmospher Sci, Edmonton, AB T6G 2E3, Canada.
C3 Columbia University; Durham University; University of Alberta
RP Weiss, Y (corresponding author), Columbia Univ, Lamont Doherty Earth Observ, New York, NY 10964 USA.
EM yweiss@ldeo.columbia.edu
FU National Science Foundation [1348045]; Diamond Trading Company at Durham University; Deep Carbon Observatory (Sloan Foundation); Israel Science Foundation [435/12]; Division Of Earth Sciences; Directorate For Geosciences [1348045] Funding Source: National Science Foundation
NR 46
TC 159
Z9 168
U1 0
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 AUG 20
PY 2015
VL 524
IS 7565
BP 339
EP +
DI 10.1038/nature14857
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP2NN
UT WOS:000359714000033
PM 26289205
DA 2026-03-09
ER

PT J
AU Supek, F
   Lehner, B
AF Supek, Fran
   Lehner, Ben
TI Differential DNA mismatch repair underlies mutation rate variation across the human genome
SO NATURE
LA English
DT Article
ID rna-seq data; somatic mutations; excision-repair; cancer; replication; organization; signatures; landscape; damage
AB Cancer genome sequencing has revealed considerable variation in somatic mutation rates across the human genome, with mutation rates elevated inheterochromatic late replicating regionsand reduced in early replicating euchromatin(1-5). Multiple mechanisms have been suggested to underlie this(2,6-10), but the actual cause is unknown. Here we identify variable DNA mismatch repair (MMR) as the basis of this variation. Analysing similar to 17 million single-nucleotide variants from the genomes of 652 tumours, we show that regional autosomal mutation rates at megabase resolution are largely stable across cancer types, with differences related to changes in replication timing and gene expression. However, mutations arising after the inactivation of MMR are no longer enriched in late replicating heterochromatin relative to early replicating euchromatin. Thus, differential DNA repair and not differential mutation supply is the primary cause of the large-scale regional mutation rate variation across the human genome.
C1 [Supek, Fran; Lehner, Ben] CRG, EMBL CRG Syst Biol Unit, Barcelona 08003, Spain.
   [Supek, Fran; Lehner, Ben] UPF, Barcelona 08003, Spain.
   [Supek, Fran] Rudjer Boskovic Inst, Div Elect, Zagreb 10000, Croatia.
   [Lehner, Ben] ICREA, Barcelona 08010, Spain.
C3 Barcelona Institute of Science & Technology; Pompeu Fabra University; Centre de Regulacio Genomica (CRG); Pompeu Fabra University; Rudjer Boskovic Institute; ICREA
RP Lehner, B (corresponding author), CRG, EMBL CRG Syst Biol Unit, Barcelona 08003, Spain.
EM ben.lehner@crg.eu
FU Spanish Ministry of Economy and Competitiveness [BFU2011-26206]; Spanish Ministry of Economy and Competitiveness (Centro de Excelencia Severo Ochoa) [SEV-2012-0208]; European Research Council Consolidator grant IR-DC [616434]; Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR); EMBO Young Investigator Program; EMBL-CRG Systems Biology Program; FP7 project 4DCellFate [277899]; FP7 project MAESTRA [ICT-2013-612944]; Marie Curie Actions; European Research Council (ERC) [616434] Funding Source: European Research Council (ERC); ICREA Funding Source: Custom
CR Alexandrov LB, 2013, NATURE, V500, P415, DOI 10.1038/nature12477
   Amouroux R, 2010, NUCLEIC ACIDS RES, V38, P2878, DOI 10.1093/nar/gkp1247
   Unknown -, 2010, J STAT SOFTW, V0, P0
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NR 40
TC 263
Z9 332
U1 0
U2 76
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 7
PY 2015
VL 521
IS 7550
BP 81
EP U173
DI 10.1038/nature14173
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH4YS
UT WOS:000354040900037
PM 25707793
DA 2026-03-09
ER

PT J
AU Monier, B
   Gettings, M
   Gay, G
   Mangeat, T
   Schott, S
   Guarner, A
   Suzanne, M
AF Monier, Bruno
   Gettings, Melanie
   Gay, Guillaume
   Mangeat, Thomas
   Schott, Sonia
   Guarner, Ana
   Suzanne, Magali
TI Apico-basal forces exerted by apoptotic cells drive epithelium folding
SO NATURE
LA English
DT Article
ID neural-tube closure; drosophila embryogenesis; mesoderm invagination; adherens junctions; myosin-ii; constriction; shape; morphogenesis; contractions; mechanism
AB Epithelium folding is a basic morphogenetic event that is essential in transforming simple two-dimensional epithelial sheets into three-dimensional structures in both vertebrates and invertebrates(1). Folding has been shown to rely on apical constriction(2-7). The resulting cell-shape changes depend either on adherens junction basal shift(2) or on a redistribution of myosin II3-5,7, which could be driven by mechanical signals(8). Yet the initial cellular mechanisms that trigger and coordinate cell remodelling remain largely unknown. Here we unravel the active role of apoptotic cells in initiating morphogenesis, thus revealing a novel mechanism of epithelium folding. We show that, in a live developing tissue, apoptotic cells exert a transient pulling force upon the apical surface of the epithelium through a highly dynamic apico-basal myosin II cable. The apoptotic cells then induce a non-autonomous increase in tissue tension together with cortical myosin II apical stabilization in the surrounding tissue, eventually resulting in epithelium folding. Together our results, supported by a theoretical biophysical three-dimensional model, identify an apoptotic myosin-II-dependent signal as the initial signal leading to cell reorganization and tissue folding. This work further reveals that, far from being passively eliminated as generally assumed ( for example, during digit individualization(9)), apoptotic cells actively influence their surroundings and trigger tissue remodelling through regulation of tissue tension.
C1 [Monier, Bruno; Gettings, Melanie; Mangeat, Thomas; Schott, Sonia; Suzanne, Magali] Univ Toulouse, UPS, LBCMCP, F-31062 Toulouse, France.
   [Monier, Bruno; Gettings, Melanie; Mangeat, Thomas; Schott, Sonia; Suzanne, Magali] CNRS, LBCMCP, F-31062 Toulouse, France.
   [Gay, Guillaume] DamCB, Data Anal & Modelling Cell Biol, F-13005 Marseille, France.
   [Guarner, Ana] Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa CSIC UAM, E-28049 Madrid, Spain.
C3 Universite de Toulouse; Universite Toulouse III - Paul Sabatier; Centre National de la Recherche Scientifique (CNRS); Universite de Toulouse; Universite Toulouse III - Paul Sabatier; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Centro de Biologia Molecular Severo Ochoa (CBM); Autonomous University of Madrid
RP Suzanne, M (corresponding author), Univ Toulouse, UPS, LBCMCP, F-31062 Toulouse, France.
EM guillaume@damcb.com; magali.suzanne@univ-tlse3.fr
FU Agence Nationale de la Recherche (ANR); Fondation de la Recherche et de l'Innovation Therapeutique en Cancerologie (RITC); University of Toulouse
NR 29
TC 196
Z9 229
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 12
PY 2015
VL 518
IS 7538
BP 245
EP U252
DI 10.1038/nature14152
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300041
PM 25607361
DA 2026-03-09
ER

PT J
AU Storkey, J
   Macdonald, AJ
   Poulton, PR
   Scott, T
   Köhler, IH
   Schnyder, H
   Goulding, KWT
   Crawley, MJ
AF Storkey, J.
   Macdonald, A. J.
   Poulton, P. R.
   Scott, T.
   Koehler, I. H.
   Schnyder, H.
   Goulding, K. W. T.
   Crawley, M. J.
TI Grassland biodiversity bounces back from long-term nitrogen addition
SO NATURE
LA English
DT Article
ID rothamsted-experimental-station; species richness; deposition; uk; cessation; recovery
AB The negative effect of increasing atmospheric nitrogen (N) pollution on grassland biodiversity is now incontrovertible(1-3). However, the recent introduction of cleaner technologies in the UK has led to reductions in the emissions of nitrogen oxides, with concomitant decreases in N deposition(4). The degree to which grassland biodiversity can be expected to 'bounce back' in response to these improvements in air quality is uncertain, with a suggestion that long-term chronic N addition may lead to an alternative low biodiversity state5. Here we present evidence from the 160-year-old Park Grass Experiment at Rothamsted Research, UK6, that shows a positive response of biodiversity to reducing N addition from either atmospheric pollution or fertilizers. The proportion of legumes, species richness and diversity increased across the experiment between 1991 and 2012 as both wet and dry N deposition declined. Plots that stopped receiving inorganic N fertilizer in 1989 recovered much of the diversity that had been lost, especially if limed. There was no evidence that chronic N addition has resulted in an alternative low biodiversity state on the Park Grass plots, except where there has been extreme acidification, although it is likely that the recovery of plant communities has been facilitated by the twice-yearly mowing and removal of biomass. This may also explain why a comparable response of plant communities to reduced N inputs has yet to be observed in the wider landscape.
C1 [Storkey, J.; Macdonald, A. J.; Poulton, P. R.; Scott, T.; Goulding, K. W. T.] Rothamsted Res, Harpenden AL5 2JQ, Herts, England.
   [Koehler, I. H.; Schnyder, H.] Tech Univ Munich, Lehrstuhl Grunlandlehre, D-85354 Freising Weihenstephan, Germany.
   [Crawley, M. J.] Univ London Imperial Coll Sci Technol & Med, Dept Biol Sci, Ascot SL5 7PY, Berks, England.
C3 UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); Rothamsted Research; Technical University of Munich; Imperial College London
RP Storkey, J (corresponding author), Rothamsted Res, Harpenden AL5 2JQ, Herts, England.
EM jonathan.storkey@rothamsted.ac.uk
FU UK Biotechnology and Biological Sciences Research Council (BBSRC); Lawes Agricultural Trust; Deutsche Forschungsgemeinschaft (DFG) [SCHN 557/5-1]; BBSRC [BBS/E/C/00004962, BBS/E/C/00005189, BBS/E/C/00005999, BBS/E/C/00005198, BBS/E/C/00004980, BBS/E/C/00005196] Funding Source: UKRI; NERC [NE/J011568/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BBS/E/C/00006004, BBS/E/C/00004980, BBS/E/C/00005999, BBS/E/C/00005196, BBS/E/C/00005198, BBS/E/C/00004962, BBS/E/C/00005189] Funding Source: researchfish; Natural Environment Research Council [NE/J011568/1] Funding Source: researchfish
NR 26
TC 154
Z9 185
U1 12
U2 490
PU NATURE PUBLISHING 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 17
PY 2015
VL 528
IS 7582
BP 401
EP +
DI 10.1038/nature16444
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CY8SM
UT WOS:000366678600053
PM 26633635
DA 2026-03-09
ER

PT J
AU Sarkar, D
   Xie, XJ
   Liu, W
   Cao, W
   Kang, JH
   Gong, YJ
   Kraemer, S
   Ajayan, PM
   Banerjee, K
AF Sarkar, Deblina
   Xie, Xuejun
   Liu, Wei
   Cao, Wei
   Kang, Jiahao
   Gong, Yongji
   Kraemer, Stephan
   Ajayan, Pulickel M.
   Banerjee, Kaustav
TI A subthermionic tunnel field-effect transistor with an atomically thin channel
SO NATURE
LA English
DT Article
AB The fast growth of information technology has been sustained by continuous scaling down of the silicon-based metal-oxide field-effect transistor. However, such technology faces two major challenges to further scaling. First, the device electrostatics (the ability of the transistor's gate electrode to control its channel potential) are degraded when the channel length is decreased, using conventional bulk materials such as silicon as the channel. Recently, two-dimensional semiconducting materials(1-7) have emerged as promising candidates to replace silicon, as they can maintain excellent device electrostatics even at much reduced channel lengths. The second, more severe, challenge is that the supply voltage can no longer be scaled down by the same factor as the transistor dimensions because of the fundamental thermionic limitation of the steepness of turn-on characteristics, or subthreshold swing(8,9). To enable scaling to continue without a power penalty, a different transistor mechanism is required to obtain subthermionic subthreshold swing, such as band-to-band tunnelling(10-16). Here we demonstrate band-to-band tunnel field-effect transistors (tunnelFETs), based on a two-dimensional semiconductor, that exhibit steep turn-on; subthreshold swing is a minimum of 3.9 millivolts per decade and an average of 31.1 millivolts per decade for four decades of drain current at room temperature. By using highly doped germanium as the source and atomically thin molybdenum disulfide as the channel, a vertical heterostructure is built with excellent electrostatics, a strain-free heterointerface, a lowtunnelling barrier, and a large tunnelling area. Our atomically thin and layered semiconducting-channel tunnel-FET(ATLAS-TFET) is the only planar architecture tunnel-FET to achieve subthermionic subthreshold swing over four decades of drain current, as recommended in ref. 17, and is also the only tunnel-FET(inany architecture) to achieve this at a low power-supply voltage of 0.1 volts. Our device is at present the thinnest-channel subthermionic transistor, and has the potential to open up new avenues for ultra-dense and low-power integrated circuits, as well as for ultra-sensitive biosensors and gas sensors(18-21).
C1 [Sarkar, Deblina; Xie, Xuejun; Liu, Wei; Cao, Wei; Kang, Jiahao; Banerjee, Kaustav] Univ Calif Santa Barbara, Dept Elect & Comp Engn, Santa Barbara, CA 93106 USA.
   [Gong, Yongji; Ajayan, Pulickel M.] Rice Univ, Dept Mat Sci & Nanoengn, Houston, TX 77005 USA.
   [Kraemer, Stephan] Univ Calif Santa Barbara, Dept Mat, Santa Barbara, CA 93106 USA.
C3 University of California System; University of California Santa Barbara; Rice University; University of California System; University of California Santa Barbara
RP Banerjee, K (corresponding author), Univ Calif Santa Barbara, Dept Elect & Comp Engn, Santa Barbara, CA 93106 USA.
EM kaustav@ece.ucsb.edu
FU Air Force Office of Scientific Research [FA9550-14-1-0268]; US NSF [CCF-1162633]; Army Research Office (MURI) [W911NF-11-1-0362]; MRSEC Program of the NSF [DMR1121053]; NSF-funded Materials Research Facilities Network; Direct For Computer & Info Scie & Enginr; Division of Computing and Communication Foundations [1162633] Funding Source: National Science Foundation
NR 29
TC 882
Z9 997
U1 18
U2 862
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 1
PY 2015
VL 526
IS 7571
BP 91
EP 95
DI 10.1038/nature15387
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS5CY
UT WOS:000362095100039
PM 26432247
DA 2026-03-09
ER

PT J
AU Durand, E
   Nguyen, VS
   Zoued, A
   Logger, L
   Péhau-Arnaudet, G
   Aschtgen, MS
   Spinelli, S
   Desmyter, A
   Bardiaux, B
   Dujeancourt, A
   Roussel, A
   Cambillau, C
   Cascales, E
   Fronzes, R
AF Durand, Eric
   Van Son Nguyen
   Zoued, Abdelrahim
   Logger, Laureen
   Pehau-Arnaudet, Gerard
   Aschtgen, Marie-Stephanie
   Spinelli, Silvia
   Desmyter, Aline
   Bardiaux, Benjamin
   Dujeancourt, Annick
   Roussel, Alain
   Cambillau, Christian
   Cascales, Eric
   Fronzes, Remi
TI Biogenesis and structure of a type VI secretion membrane core complex
SO NATURE
LA English
DT Article
ID bacterial type vi; icmf family protein; high-resolution; system; lipoprotein; refinement; effectors; requires; tssl; replacement
AB Bacteria share their ecological niches with other microbes. The bacterial type VI secretion system is one of the key players in microbial competition, as well as being an important virulence determinant during bacterial infections. It assembles a nano-crossbow-like structure in the cytoplasm of the attacker cell that propels an arrow made of a haemolysin co-regulated protein (Hcp) tube and a valine-glycine repeat protein G (VgrG) spike and punctures the prey's cell wall. The nano-crossbow is stably anchored to the cell envelope of the attacker by a membrane core complex. Here we show that this complex is assembled by the sequential addition of three type VI subunits (Tss) - TssJ, TssM and TssL-and present a structure of the fully assembled complex at 11.6 angstrom resolution, determined by negative-stain electron microscopy. With overall C-5 symmetry, this 1.7-megadalton complex comprises a large base in the cytoplasm. It extends in the periplasm via ten arches to form a double-ring structure containing the carboxy-terminal domain of TssM (TssM(ct)) and TssJ that is anchored in the outer membrane. The crystal structure of the TssM(ct)-TssJ complex coupled to whole-cell accessibility studies suggest that large conformational changes induce transient pore formation in the outer membrane, allowing passage of the attacking Hcp tube/VgrG spike.
C1 [Durand, Eric; Zoued, Abdelrahim; Logger, Laureen; Aschtgen, Marie-Stephanie] Aix Marseille Univ, CNRS, UMR 7255, Lab Ingn Syst Macromol, F-13402 Marseille 20, France.
   [Durand, Eric; Van Son Nguyen; Spinelli, Silvia; Desmyter, Aline; Roussel, Alain; Cambillau, Christian] CNRS, UMR 7257, Architecture & Fonct Macromol Biol, F-13288 Marseille 09, France.
   [Durand, Eric; Dujeancourt, Annick; Fronzes, Remi] Inst Pasteur, Biol Struct Secret Bacterienne G5, F-75015 Paris, France.
   [Durand, Eric] CNRS, UMR3528, Inst Pasteur, F-75015 Paris, France.
   [Durand, Eric; Van Son Nguyen; Spinelli, Silvia; Desmyter, Aline; Roussel, Alain; Cambillau, Christian] Aix Marseille Univ, AFMB, IHU Mediterrane Infect, F-13288 Marseille 09, France.
   [Bardiaux, Benjamin] Inst Pasteur, Unite Bioinformat Struct, F-75015 Paris, France.
C3 Aix-Marseille Universite; Centre National de la Recherche Scientifique (CNRS); Centre National de la Recherche Scientifique (CNRS); Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Aix-Marseille Universite; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris
RP Cambillau, C (corresponding author), CNRS, UMR 7257, Architecture & Fonct Macromol Biol, Campus Luminy,Case 932, F-13288 Marseille 09, France.
EM cambillau@afmb.univ-mrs.fr; cascales@imm.cnrs.fr; remi.fronzes@pasteur.fr
FU Agence Nationale de la Recherche (ANR) [ANR-10-JCJC-1303-03, ANR-14-CE14-0006-02]; French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INSB-05-01]; Fondation pour la Recherche Medicale [SPF20101221116]; ANR [ANR-10-JCJC-1303-03, Bip:Bip]; French Embassy in Vietnam [792803C]; French Ministere de la Recherche; Fondation pour la Recherche Medicale fellowship [FDT20140931060]
NR 74
TC 224
Z9 260
U1 0
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 JUL 30
PY 2015
VL 523
IS 7562
BP 555
EP +
DI 10.1038/nature14667
PG 25
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN7ZL
UT WOS:000358655200037
PM 26200339
DA 2026-03-09
ER

PT J
AU Marotzke, J
   Forster, PM
AF Marotzke, Jochem
   Forster, Piers M.
TI Forcing, feedback and internal variability in global temperature trends
SO NATURE
LA English
DT Article
ID climate sensitivity; model; pacific
AB Most present-generation climate models simulate an increase in global-mean surface temperature (GMST) since 1998, whereas observations suggest a warming hiatus. It is unclear to what extent this mismatch is caused by incorrect model forcing, by incorrect model response to forcing or by random factors. Here we analyse simulations and observations of GMST from 1900 to 2012, and show that the distribution of simulated 15-year trends shows no systematic bias against the observations. Using a multiple regression approach that is physically motivated by surface energy balance, we isolate the impact of radiative forcing, climate feedback and ocean heat uptake on GMST-with the regression residual interpreted as internal variability-and assess all possible 15- and 62-year trends. The differences between simulated and observed trends are dominated by random internal variability over the shorter timescale and by variations in the radiative forcings used to drive models over the longer timescale. For either trend length, spread in simulated climate feedback leaves no traceable imprint on GMST trends or, consequently, on the difference between simulations and observations. The claim that climate models systematically overestimate the response to radiative forcing from increasing greenhouse gas concentrations therefore seems to be unfounded.
C1 [Marotzke, Jochem] Max Planck Inst Meteorol, D-20146 Hamburg, Germany.
   [Forster, Piers M.] Univ Leeds, Sch Earth & Environm, Leeds LS2 9JT, W Yorkshire, England.
C3 Max Planck Society; University of Leeds
RP Marotzke, J (corresponding author), Max Planck Inst Meteorol, Bundesstr 53, D-20146 Hamburg, Germany.
EM jochem.marotzke@mpimet.mpg.de
FU Max Planck Society for the Advancement of Science; Royal Society Wolfson Merit Award; EPSRC [EP/1014721/1]; EPSRC [EP/I014721/1] Funding Source: UKRI; Engineering and Physical Sciences Research Council [EP/I014721/1] Funding Source: researchfish
NR 48
TC 162
Z9 178
U1 0
U2 178
PU NATURE PUBLISHING 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 29
PY 2015
VL 517
IS 7536
BP 565
EP U291
DI 10.1038/nature14117
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA2ZL
UT WOS:000348775000033
PM 25631444
DA 2026-03-09
ER

PT J
AU Kim, D
   Fiske, BP
   Birsoy, K
   Freinkman, E
   Kami, K
   Possemato, RL
   Chudnovsky, Y
   Pacold, ME
   Chen, WW
   Cantor, JR
   Shelton, LM
   Gui, DY
   Kwon, M
   Ramkissoon, SH
   Ligon, KL
   Kang, SW
   Snuderl, M
   Vander Heiden, MG
   Sabatini, DM
AF Kim, Dohoon
   Fiske, Brian P.
   Birsoy, Kivanc
   Freinkman, Elizaveta
   Kami, Kenjiro
   Possemato, Richard L.
   Chudnovsky, Yakov
   Pacold, Michael E.
   Chen, Walter W.
   Cantor, Jason R.
   Shelton, Laura M.
   Gui, Dan Y.
   Kwon, Manjae
   Ramkissoon, Shakti H.
   Ligon, Keith L.
   Kang, Seong Woo
   Snuderl, Matija
   Vander Heiden, Matthew G.
   Sabatini, David M.
TI SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance
SO NATURE
LA English
DT Article
ID pyruvate-kinase m2; tumor hypoxia; stem-cells; cancer; metabolism; serine; methylglyoxal; aminoacetone; catabolism; threonine
AB Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumour microenvironment(1-3). Here we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischaemic zones of gliomas. Inhuman glioblastoma multiforme, mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumour regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition.
C1 [Kim, Dohoon; Birsoy, Kivanc; Freinkman, Elizaveta; Possemato, Richard L.; Chudnovsky, Yakov; Pacold, Michael E.; Chen, Walter W.; Cantor, Jason R.; Kwon, Manjae; Kang, Seong Woo; Sabatini, David M.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA.
   [Kim, Dohoon; Birsoy, Kivanc; Freinkman, Elizaveta; Possemato, Richard L.; Chudnovsky, Yakov; Pacold, Michael E.; Chen, Walter W.; Cantor, Jason R.; Kang, Seong Woo; Sabatini, David M.] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA.
   [Kim, Dohoon; Birsoy, Kivanc; Freinkman, Elizaveta; Possemato, Richard L.; Chudnovsky, Yakov; Pacold, Michael E.; Chen, Walter W.; Cantor, Jason R.; Kwon, Manjae; Kang, Seong Woo; Sabatini, David M.] MIT, Dept Biol, Cambridge, MA 02139 USA.
   [Kim, Dohoon; Fiske, Brian P.; Birsoy, Kivanc; Freinkman, Elizaveta; Possemato, Richard L.; Chudnovsky, Yakov; Pacold, Michael E.; Chen, Walter W.; Cantor, Jason R.; Gui, Dan Y.; Kang, Seong Woo; Vander Heiden, Matthew G.; Sabatini, David M.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA.
   [Kim, Dohoon; Fiske, Brian P.; Birsoy, Kivanc; Freinkman, Elizaveta; Possemato, Richard L.; Chudnovsky, Yakov; Pacold, Michael E.; Chen, Walter W.; Cantor, Jason R.; Gui, Dan Y.; Kang, Seong Woo; Vander Heiden, Matthew G.; Sabatini, David M.] Broad Inst Harvard & MIT, Seven Cambridge Ctr, Cambridge, MA 02142 USA.
   [Kami, Kenjiro] Human Metabolome Technol Inc, Tsuruoka, Yamagata 9970052, Japan.
   [Pacold, Michael E.; Ramkissoon, Shakti H.; Ligon, Keith L.; Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02215 USA.
   [Shelton, Laura M.] Human Metabolome Technol Ameri Inc, Boston, MA 02134 USA.
   [Ramkissoon, Shakti H.; Ligon, Keith L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA.
   [Ramkissoon, Shakti H.; Ligon, Keith L.] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA.
   [Snuderl, Matija] NYU, Langone Med Ctr, Dept Pathol, New York, NY 10016 USA.
   [Snuderl, Matija] NYU, Sch Med, New York, NY 10016 USA.
C3 Massachusetts Institute of Technology (MIT); Whitehead Institute; Massachusetts Institute of Technology (MIT); Howard Hughes Medical Institute; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); 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; Brigham & Women's Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; NYU Langone Medical Center; New York University; New York University
RP Sabatini, DM (corresponding author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA.
EM sabatini@wi.mit.edu
FU Basic Research Fellowship from the American Brain Tumor Association; MIT School of Science Fellowship in Cancer Research; National Institutes of Health (NIH) [T32GM007287, K99 CA168940, K08-NS087118, R01CA168653, 5P30CA14051]; Jane Coffin Childs Memorial Fund; Leukemia and Lymphoma Society; American Cancer Society; American Brain Tumor Association Discovery Grant; US National Institute of Aging; Smith Family Foundation; Burroughs Wellcome Fund; Damon Runyon Cancer Research Foundation; Stern family; DOD CDMRP Discovery Award; David H. Koch Institute for Integrative Cancer Research at MIT; Alexander and Margaret Stewart Trust Fund; NIH [CA103866, CA129105, AI07389]; National Cancer Institute [R01CA129105, P30CA014051, R01CA103866] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007753] Funding Source: NIH RePORTER
NR 39
TC 299
Z9 351
U1 1
U2 83
PU NATURE PUBLISHING 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 16
PY 2015
VL 520
IS 7547
BP 363
EP +
DI 10.1038/nature14363
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG0RI
UT WOS:000352974200042
PM 25855294
DA 2026-03-09
ER

PT J
AU Kreiter, S
   Vormehr, M
   van de Roemer, N
   Diken, M
   Löwer, M
   Diekmann, J
   Boegel, S
   Schrörs, B
   Vascotto, F
   Castle, JC
   Tadmor, AD
   Schoenberger, SP
   Huber, C
   Türeci, Ö
   Sahin, U
AF Kreiter, Sebastian
   Vormehr, Mathias
   van de Roemer, Niels
   Diken, Mustafa
   Loewer, Martin
   Diekmann, Jan
   Boegel, Sebastian
   Schroers, Barbara
   Vascotto, Fulvia
   Castle, John C.
   Tadmor, Arbel D.
   Schoenberger, Stephen P.
   Huber, Christoph
   Tuereci, Oezlem
   Sahin, Ugur
TI Mutant MHC class II epitopes drive therapeutic immune responses to cancer
SO NATURE
LA English
DT Article
ID exome analysis reveals; cd4(+) t-cells; pd-1 blockade; antigens; lymphocytes; efficiency; landscape; stability; patient
AB Tumour-specific mutations are ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognized as neo-antigens by the mature T-cell repertoire. Their systematic targeting by vaccine approaches, however, has been hampered by the fact that every patient's tumour possesses a unique set of mutations (the mutanome') that must first be identified. Recently, we proposed a personalized immunotherapy approach to target the full spectrum of a patient's individual tumour-specific mutationsl. Here we show in three independent murine tumour models that a considerable fraction of non-synonymous cancer mutations is immunogenic and that, unexpectedly, the majority of the immunogenic mutanome is recognized by Cal+ T cells. Vaccination with such Cal+ immunogenic mutations confers strong antitumour activity. Encouraged by these findings, we established a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of their expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines. We show that vaccination with such polytope mRNA vaccines induces potent tumour control and complete rejection of established aggressively growing tumours in mice. Moreover, we demonstrate that Cal+ T cell neo-epitope vaccination reshapes the tumour microenvironment and induces cytotoxic T lymphocyte responses against an independent immunodominant antigen in mice, indicating orchestration of antigen spread. Finally, we demonstrate an abundance of mutations predicted to bind to MHC class II in human cancers as well by employing the same predictive algorithm on corresponding human cancer types. Thus, the tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo-epitope target repertoire of cancers, enabling the effective targeting of every patient's tumour with vaccines produced 'just in time'.
C1 [Kreiter, Sebastian; Diken, Mustafa; Loewer, Martin; Diekmann, Jan; Boegel, Sebastian; Schroers, Barbara; Vascotto, Fulvia; Castle, John C.; Tadmor, Arbel D.; Tuereci, Oezlem; Sahin, Ugur] Johannes Gutenberg Univ Mainz, Univ Med Ctr, TRON Translat Oncol, D-55131 Mainz, Germany.
   [Vormehr, Mathias; van de Roemer, Niels; Huber, Christoph; Sahin, Ugur] Res Ctr Immunotherapy FZI, D-55131 Mainz, Germany.
   [Diekmann, Jan; Sahin, Ugur] Biopharmaceut New Technol BioNTech Corp, D-55131 Mainz, Germany.
   [Schoenberger, Stephen P.] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA.
C3 Johannes Gutenberg University of Mainz; BioNTech SE; La Jolla Institute for Immunology
RP Sahin, U (corresponding author), Johannes Gutenberg Univ Mainz, Univ Med Ctr, TRON Translat Oncol, Freiligrathstr 12, D-55131 Mainz, Germany.
EM sahin@uni-mainz.de
FU CI3 excellence cluster program of the Federal Ministry of Education and Research (BMBF)
NR 30
TC 913
Z9 1071
U1 3
U2 293
PU NATURE PUBLISHING 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 30
PY 2015
VL 520
IS 7549
BP 692
EP U269
DI 10.1038/nature14426
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700053
PM 25901682
DA 2026-03-09
ER

PT J
AU Ulaganathan, VK
   Sperl, B
   Rapp, UR
   Ullrich, A
AF Ulaganathan, Vijay K.
   Sperl, Bianca
   Rapp, Ulf R.
   Ullrich, Axel
TI Germline variant FGFR4 p.G388R exposes a membrane-proximal STAT3 binding site
SO NATURE
LA English
DT Article
ID gly388arg polymorphism; arg388 allele; cancer; growth; metaanalysis; progression; sufficient; prognosis; receptor; domains
AB Variant rs351855-G/A is a commonly occurring single-nucleotide polymorphism of coding regions in exon 9 of the fibroblast growth factor receptor FGFR4 (CD334) gene (c.1162G>A). It results in an amino-acid change at codon 388 from glycine to arginine (p.Gly388Arg) in the transmembrane domain of the receptor. Despite compelling genetic evidence for the association of this common variant with cancers of the bone(1), breast(2), colon(3), prostate(4,5), skin(6), lung(7,8), head and neck(9), as well as soft-tissue sarcomas and non-Hodgkin lymphoma, the underlying biological mechanism has remained elusive. Here we show that substitution of the conserved glycine 388 residue to a charged arginine residue alters the transmembrane spanning segment and exposes a membrane-proximal cytoplasmic signal transducer and activator of transcription 3 (STAT3) binding site Y-390-(P) XXQ(393). We demonstrate that such membrane-proximal STAT3 binding motifs in the germline of type I membrane receptors enhance STAT3 tyrosine phosphorylation by recruiting STAT3 proteins to the inner cell membrane. Remarkably, such germline variants frequently co-localize with somatic mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Using Fgfr4 single nucleotide polymorphism knock-in mice and transgenic mouse models for breast and lung cancers, we validate the enhanced STAT3 signalling induced by the FGFR4 Arg388-variant in vivo. Thus, our findings elucidate the molecular mechanism behind the genetic association of rs351855 with accelerated cancer progression and suggest that germline variants of cell-surface molecules that recruit STAT3 to the inner cell membrane are a significant risk for cancer prognosis and disease progression.
C1 [Ulaganathan, Vijay K.; Sperl, Bianca; Ullrich, Axel] Max Planck Inst Biochem, Dept Mol Biol, D-82152 Martinsried, Germany.
   [Rapp, Ulf R.] Max Planck Inst Heart & Lung Res, Mol Mech Lung Canc, D-61231 Bad Nauheim, Germany.
C3 Max Planck Society; Max Planck Society
RP Ullrich, A (corresponding author), Max Planck Inst Biochem, Dept Mol Biol, Klopferspitz 18, D-82152 Martinsried, Germany.
EM ulaganat@biochem.mpg.de; ullrich@biochem.mpg.de
FU NHLBI [HL-102923, HL-102924, HL-102925, HL-102926, HL-103010]
NR 20
TC 54
Z9 63
U1 0
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 DEC 24
PY 2015
VL 528
IS 7583
BP 570
EP +
DI 10.1038/nature16449
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900056
PM 26675719
DA 2026-03-09
ER

PT J
AU Li, XC
   Roberti, R
   Blobel, G
AF Li, Xiaochun
   Roberti, Rita
   Blobel, Guenter
TI Structure of an integral membrane sterol reductase from Methylomicrobium alcaliphilum
SO NATURE
LA English
DT Article
ID lamin-b-receptor; 3-beta-hydroxysterol delta(14)-reductase; crystal-structure; mutations; protein; steroidogenesis; expression; disorders; dysplasia; topology
AB Sterols are essential biological molecules in the majority of life forms. Sterol reductases(1) including Delta(14)-sterol reductase (C14SR, also known as TM7SF2), 7-dehydrocholesterol reductase (DHCR7) and 24-dehydrocholesterol reductase (DHCR24) reduce specific carbon-carbon double bonds of the sterol moiety using a reducing cofactor during sterol biosynthesis. Lamin B receptor(2) (LBR), an integral inner nuclear membrane protein, also contains a functional C14SR domain. Here we report the crystal structure of a Delta(14)-sterol reductase (MaSR1) from the methanotrophic bacterium Methylomicro-bium alcaliphilum 20Z (a homologue of human C14SR, LBR and DHCR7) with the cofactor NADPH. The enzyme contains ten transmembrane segments (TM1-10). Its catalytic domain comprises the carboxy-terminal half (containing TM6-10) and envelops two interconnected pockets, one of which faces the cytoplasm and houses NADPH, while the other one is accessible from the lipid bilayer. Comparison with a soluble steroid 5 beta-reductase structure(3) suggests that the reducing end of NADPH meets the sterol substrate at the juncture of the two pockets. A sterol reductase activity assay proves that MaSR1 can reduce the double bond of a cholesterol biosynthetic intermediate, demonstrating functional conservation to human C14SR. Therefore, our structure as a prototype of integral membrane sterol reductases provides molecular insight into mutations in DHCR7 and LBR for inborn human diseases.
C1 [Li, Xiaochun; Blobel, Guenter] Rockefeller Univ, Howard Hughes Med Inst, Lab Cell Biol, New York, NY 10065 USA.
   [Roberti, Rita] Univ Perugia, Dept Expt Med, I-06132 Perugia, Italy.
C3 Rockefeller University; Howard Hughes Medical Institute; University of Perugia
RP Li, XC (corresponding author), Rockefeller Univ, Howard Hughes Med Inst, Lab Cell Biol, New York, NY 10065 USA.
EM xli05@rockefeller.edu; blobel@rockefeller.edu
FU Howard Hughes Medical Institute Funding Source: Medline; NIGMS NIH HHS [P41 GM111244] Funding Source: Medline
NR 36
TC 55
Z9 70
U1 4
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 JAN 1
PY 2015
VL 517
IS 7532
BP 104
EP U280
DI 10.1038/nature13797
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AX8SI
UT WOS:000347178400044
PM 25307054
DA 2026-03-09
ER

PT J
AU DeAngelis, AM
   Qu, X
   Zelinka, MD
   Hall, A
AF DeAngelis, Anthony M.
   Qu, Xin
   Zelinka, Mark D.
   Hall, Alex
TI An observational radiative constraint on hydrologic cycle intensification
SO NATURE
LA English
DT Article
ID earth system model; k-distribution; part i; climate sensitivity; gaseous absorption; solar-radiation; coupled model; water-vapor; circulation; parameterization
AB Intensification of the hydrologic cycle is a key dimension of climate change, with substantial impacts on human and natural systems(1,2). A basic measure of hydrologic cycle intensification is the increase in global-mean precipitation per unit surface warming, which varies by a factor of three in current-generation climate models (about 1-3 per cent per kelvin)(3-5). Part of the uncertainty may originate from atmosphere-radiation interactions. As the climate warms, increases in shortwave absorption from atmospheric moistening will suppress the precipitation increase. This occurs through a reduction of the latent heating increase required to maintain a balanced atmospheric energy budget(6,7). Using an ensemble of climate models, here we show that such models tend to underestimate the sensitivity of solar absorption to variations in atmospheric water vapour, leading to an underestimation in the shortwave absorption increase and an overestimation in the precipitation increase. This sensitivity also varies considerably among models due to differences in radiative transfer parameterizations, explaining a substantial portion of model spread in the precipitation response. Consequently, attaining accurate shortwave absorption responses through improvements to the radiative transfer schemes could reduce the spread in the predicted global precipitation increase per degree warming for the end of the twenty-first century by about 35 per cent, and reduce the estimated ensemble-mean increase in this quantity by almost 40 per cent.
C1 [DeAngelis, Anthony M.; Qu, Xin; Hall, Alex] Univ Calif Los Angeles, Dept Atmospher & Ocean Sci, Los Angeles, CA 90095 USA.
   [Zelinka, Mark D.] Lawrence Livermore Natl Lab, Program Climate Model Diag & Intercomparison, Livermore, CA 94550 USA.
C3 University of California System; University of California Los Angeles; United States Department of Energy (DOE); Lawrence Livermore National Laboratory
RP DeAngelis, AM (corresponding author), Univ Calif Los Angeles, Dept Atmospher & Ocean Sci, Los Angeles, CA 90095 USA.
EM adeangelis@ucla.edu
FU Regional and Global Climate Modeling Program of the Office of Science of the US Department of Energy; US Department of Energy [DE-AC52-07NA27344]
NR 80
TC 137
Z9 150
U1 4
U2 111
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 10
PY 2015
VL 528
IS 7581
BP 249
EP +
DI 10.1038/nature15770
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX9VH
UT WOS:000366053300038
PM 26659186
DA 2026-03-09
ER

PT J
AU Leung, D
   Jung, I
   Rajagopal, N
   Schmitt, A
   Selvaraj, S
   Lee, AY
   Yen, CA
   Lin, S
   Lin, YI
   Qiu, YJ
   Xie, W
   Yue, F
   Hariharan, M
   Ray, P
   Kuan, S
   Edsall, L
   Yang, HB
   Chi, NC
   Zhang, MQ
   Ecker, JR
   Ren, B
AF Leung, Danny
   Jung, Inkyung
   Rajagopal, Nisha
   Schmitt, Anthony
   Selvaraj, Siddarth
   Lee, Ah Young
   Yen, Chia-An
   Lin, Shin
   Lin, Yiing
   Qiu, Yunjiang
   Xie, Wei
   Yue, Feng
   Hariharan, Manoj
   Ray, Pradipta
   Kuan, Samantha
   Edsall, Lee
   Yang, Hongbo
   Chi, Neil C.
   Zhang, Michael Q.
   Ecker, Joseph R.
   Ren, Bing
TI Integrative analysis of haplotype-resolved epigenomes across human tissues
SO NATURE
LA English
DT Article
ID embryonic stem-cells; gene-expression; enhancers; genome; transcription; promoters; landscape; brain; atlas; state
AB Allelic differences between the two homologous chromosomes can affect the propensity of inheritance in humans; however, the extent of such differences in the human genome has yet to be fully explored. Here we delineate allelic chromatin modifications and transcriptomes among a broad set of human tissues, enabled by a chromosome-spanning haplotype reconstruction strategy(1). The resulting large collection of haplotype-resolved epigenomic maps reveals extensive allelic biases in both chromatin state and transcription, which show considerable variation across tissues and between individuals, and allow us to investigate cis-regulatory relationships between genes and their control sequences. Analyses of histone modification maps also uncover intriguing characteristics of cis-regulatory elements and tissue-restricted activities of repetitive elements. The rich data sets described here will enhance our understanding of the mechanisms by which cis-regulatory elements control gene expression programs.
C1 [Leung, Danny; Jung, Inkyung; Rajagopal, Nisha; Schmitt, Anthony; Selvaraj, Siddarth; Lee, Ah Young; Yen, Chia-An; Qiu, Yunjiang; Kuan, Samantha; Edsall, Lee; Ren, Bing] Ludwig Inst Canc Res, La Jolla, CA 92093 USA.
   [Lin, Shin; Lin, Yiing] Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
   [Lin, Shin] Stanford Univ, Dept Cardiovasc Med, Stanford, CA 94304 USA.
   [Lin, Yiing] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA.
   [Xie, Wei] Tsinghua Univ, Tsinghua Univ Peking Univ Ctr Life Sci, Sch Life Sci, Beijing 100084, Peoples R China.
   [Yue, Feng] Penn State Univ, Dept Biochem & Mol Biol, Coll Med, Hershey, PA 17033 USA.
   [Hariharan, Manoj; Ecker, Joseph R.] Salk Inst Biol Studies, Genom Anal Lab, Howard Hughes Med Inst, La Jolla, CA 92093 USA.
   [Ray, Pradipta; Zhang, Michael Q.] Univ Texas Dallas, Ctr Syst Biol, Richardson, TX 75080 USA.
   [Yang, Hongbo; Chi, Neil C.] Univ Calif San Diego, Dept Med, Div Cardiol, La Jolla, CA 92093 USA.
   [Chi, Neil C.; Ren, Bing] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA.
   [Zhang, Michael Q.] Tsinghua Univ, TNLIST Tsinghua Natl Lab Informat Sci & Technol, Bioinformat Div, Ctr Synthet & Syst Biol, Beijing 100084, Peoples R China.
   [Ren, Bing] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA.
   [Ren, Bing] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA.
C3 Ludwig Institute for Cancer Research; Stanford University; Stanford University; Washington University (WUSTL); Tsinghua University; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Penn State Health; Howard Hughes Medical Institute; Salk Institute; University of Texas System; University of Texas Dallas; University of California System; University of California San Diego; University of California System; University of California San Diego; Tsinghua University; University of California System; University of California San Diego; University of California System; University of California San Diego
RP Ren, B (corresponding author), Ludwig Inst Canc Res, La Jolla, CA 92093 USA.
EM biren@ucsd.edu
FU NIH Epigenome Roadmap Project [U01 ES017166]; CIRM [RN2-00905-1]; NIH [ES017166, F32HL110473, K99HL119617]; NSFC [91019016]; NBRPC [2012CB316503]; National Institute of General Medical Sciences [T32GM008666] Funding Source: NIH RePORTER
NR 30
TC 149
Z9 192
U1 0
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 FEB 19
PY 2015
VL 518
IS 7539
BP 350
EP 354
DI 10.1038/nature14217
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400032
PM 25693566
DA 2026-03-09
ER

PT J
AU Bryson, JFJ
   Nichols, CIO
   Herrero-Albillos, J
   Kronast, F
   Kasama, T
   Alimadadi, H
   van der Laan, G
   Nimmo, F
   Harrison, RJ
AF Bryson, James F. J.
   Nichols, Claire I. O.
   Herrero-Albillos, Julia
   Kronast, Florian
   Kasama, Takeshi
   Alimadadi, Hossein
   van der Laan, Gerrit
   Nimmo, Francis
   Harrison, Richard J.
TI Long-lived magnetism from solidification-driven convection on the pallasite parent body
SO NATURE
LA English
DT Article
ID fe-ni; dynamo; planetesimals; differentiation; chondrites; records; origin; metal; al-26
AB Palaeomagnetic measurements of meteorites(1-5) suggest that, shortly after the birth of the Solar System, the molten metallic cores of many small planetary bodies convected vigorously and were capable of generating magnetic fields(6). Convection on these bodies is currently thought to have been thermally driven(7,8), implying that magnetic activity would have been short-lived(9). Here we report a time-series palaeomagnetic record derived from nanomagnetic imaging(10) of the Imilac and Esquel pallasite meteorites, a group of meteorites consisting of centimetre-sized metallic and silicate phases. We find a history of long-lived magnetic activity on the pallasite parent body, capturing the decay and eventual shutdown of the magnetic field as core solidification completed. We demonstrate that magnetic activity driven by progressive solidification of an inner core(11-13) is consistent with our measured magnetic field characteristics and cooling rates(14). Solidification-driven convection was probably common among small body cores(15), and, in contrast to thermally driven convection, will have led to a relatively late (hundreds of millions of years after accretion), long-lasting, intense and widespread epoch of magnetic activity among these bodies in the early Solar System.
C1 [Bryson, James F. J.; Nichols, Claire I. O.; Harrison, Richard J.] Univ Cambridge, Dept Earth Sci, Cambridge CB2 3EQ, England.
   [Herrero-Albillos, Julia] Ctr Univ Def, E-50090 Zaragoza, Spain.
   [Herrero-Albillos, Julia] Univ Zaragoza, CSIC, Inst Ciencia Mat Aragon, E-50009 Zaragoza, Spain.
   [Kronast, Florian] Helmholtz Zentrum Berlin Mat & Energie, D-12489 Berlin, Germany.
   [Kasama, Takeshi; Alimadadi, Hossein] Tech Univ Denmark, Ctr Electron Nanoscopy, DK-2800 Kongens Lyngby, Denmark.
   [van der Laan, Gerrit] Diamond Light Source, Didcot OX11 0DE, Oxon, England.
   [Nimmo, Francis] Univ Calif Santa Cruz, Dept Earth & Planetary Sci, Santa Cruz, CA 95064 USA.
C3 University of Cambridge; University of Zaragoza; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Centro de Quimica y Materiales de Aragon (CEQMA); CSIC - Instituto de Ciencia de Materiales de Aragon (ICMA); Helmholtz Association; Helmholtz-Zentrum fuer Materialien und Energie GmbH (HZB); Technical University of Denmark; Diamond Light Source; University of California System; University of California Santa Cruz
RP Bryson, JFJ (corresponding author), Univ Cambridge, Dept Earth Sci, Downing St, Cambridge CB2 3EQ, England.
EM jfjb2@cam.ac.uk
FU European Research Council under the European Union [320750, 312284]; Natural Environment Research Council; Fundacion ARAID; Spanish MINECO [MAT2011-23791]; Natural Environment Research Council [1089641] Funding Source: researchfish
NR 35
TC 73
Z9 83
U1 4
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 JAN 22
PY 2015
VL 517
IS 7535
BP 472
EP +
DI 10.1038/nature14114
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AZ4MU
UT WOS:000348196500031
PM 25612050
DA 2026-03-09
ER

PT J
AU Giri, N
   Del Pópolo, MG
   Melaugh, G
   Greenaway, RL
   Rätzke, K
   Koschine, T
   Pison, L
   Gomes, MFC
   Cooper, AI
   James, SL
AF Giri, Nicola
   Del Popolo, Mario G.
   Melaugh, Gavin
   Greenaway, Rebecca L.
   Raetzke, Klaus
   Koschine, Toenjes
   Pison, Laure
   Gomes, Margarida F. Costa
   Cooper, Andrew I.
   James, Stuart L.
TI Liquids with permanent porosity
SO NATURE
LA English
DT Article
ID porous organic cages; methane; solubility; binding; separation; frameworks; crystals; solvents; gases
AB Porous solids such as zeolites(1) and metal-organic frameworks(2,3) are useful in molecular separation and in catalysis, but their solid nature can impose limitations. For example, liquid solvents, rather than porous solids, are the most mature technology for post-combustion capture of carbon dioxide because liquid circulation systems are more easily retrofitted to existing plants. Solid porous adsorbents offer major benefits, such as lower energy penalties in adsorption-desorption cycles(4), but they are difficult to implement in conventional flow processes. Materials that combine the properties of fluidity and permanent porosity could therefore offer technological advantages, but permanent porosity is not associated with conventional liquids(5). Here we report free-flowing liquids whose bulk properties are determined by their permanent porosity. To achieve this, we designed cage molecules(6,7) that provide a well-defined pore space and that are highly soluble in solvents whose molecules are too large to enter the pores. The concentration of unoccupied cages can thus be around 500 times greater than in other molecular solutions that contain cavities(8-10), resulting in a marked change in bulk properties, such as an eightfold increase in the solubility of methane gas. Our results provide the basis for development of a new class of functional porous materials for chemical processes, and we present a one-step, multigram scale-up route for highly soluble 'scrambled' porous cages prepared from a mixture of commercially available reagents. The unifying design principle for these materials is the avoidance of functional groups that can penetrate into the molecular cage cavities.
C1 [Giri, Nicola; James, Stuart L.] Queens Univ Belfast, Sch Chem & Chem Engn, Belfast BT9 5AG, Antrim, North Ireland.
   [Del Popolo, Mario G.; Melaugh, Gavin] Queens Univ Belfast, Sch Math & Phys, Belfast BT7 1NN, Antrim, North Ireland.
   [Del Popolo, Mario G.] Univ Nacl Cuyo, CONICET, RA-5500 Mendoza, Argentina.
   [Del Popolo, Mario G.] Univ Nacl Cuyo, Fac Ciencias Exactas & Nat, RA-5500 Mendoza, Argentina.
   [Greenaway, Rebecca L.; Cooper, Andrew I.] Univ Liverpool, Dept Chem, Liverpool L69 7ZD, Merseyside, England.
   [Greenaway, Rebecca L.; Cooper, Andrew I.] Univ Liverpool, Ctr Mat Discovery, Liverpool L69 7ZD, Merseyside, England.
   [Raetzke, Klaus; Koschine, Toenjes] Univ Kiel, Tech Fak, D-24143 Kiel, Germany.
   [Pison, Laure; Gomes, Margarida F. Costa] Univ Clermont Ferrand, Inst Chim Clermont Ferrand, CNRS, UMR 6296, F-63178 Aubiere, France.
C3 Queens University Belfast; Queens University Belfast; University Nacional Cuyo Mendoza; University Nacional Cuyo Mendoza; University of Liverpool; University of Liverpool; University of Kiel; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Chemistry (INC)
RP James, SL (corresponding author), Queens Univ Belfast, Sch Chem & Chem Engn, David Keir Bldg,Stranmillis Rd, Belfast BT9 5AG, Antrim, North Ireland.
EM S.James@qub.ac.uk
FU Leverhulme Trust [F/00 203/T]; EPSRC [EP/C511794/1]; ANPCyT [PICT-2011-2128]; EC-H2020. MSCRISE programme [643998 ENACT]; CNRS; Blaise Pascal University; Auvergne Regional Government, France; European Research Council under the European Union's Seventh Framework Programme/ERC [321156]; Engineering and Physical Sciences Research Council [EP/C511794/1, EP/K039687/1] Funding Source: researchfish; EPSRC [EP/K039687/1] Funding Source: UKRI
NR 24
TC 483
Z9 545
U1 30
U2 804
PU NATURE PUBLISHING 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 12
PY 2015
VL 527
IS 7577
BP 216
EP +
DI 10.1038/nature16072
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700041
PM 26560299
DA 2026-03-09
ER

PT J
AU Peng, Y
   Maiolino, R
   Cochrane, R
AF Peng, Y.
   Maiolino, R.
   Cochrane, R.
TI Strangulation as the primary mechanism for shutting down star formation in galaxies
SO NATURE
LA English
DT Article
ID mass-metallicity relation; agn feedback; black-holes; evolution; origin; stellar; gas; outflows; model; ii.
AB Local galaxies are broadly divided into two main classes, star-forming (gas-rich) and quiescent (passive and gas-poor). The primary mechanism responsible for quenching star formation in galaxies and transforming them into quiescent and passive systems is still unclear. Sudden removal of gas through outflows(1-6) or stripping(7-9) is one of the mechanisms often proposed. An alternative mechanism is so-called "strangulation''(10-14), in which the supply of cold gas to the galaxy is halted. Here we report an analysis of the stellar metallicity (the fraction of elements heavier than helium in stellar atmospheres) in local galaxies, from 26,000 spectra, that clearly reveals that strangulation is the primary mechanism responsible for quenching star formation, with a typical timescale of four billion years, at least for local galaxies with a stellar mass less than 10(11) solar masses. This result is further supported independently by the stellar age difference between quiescent and star-forming galaxies, which indicates that quiescent galaxies of less than 10(11) solar masses are on average observed four billion years after quenching due to strangulation.
C1 [Peng, Y.; Maiolino, R.; Cochrane, R.] Univ Cambridge, Cavendish Lab, Cambridge CB3 0HE, England.
   [Peng, Y.; Maiolino, R.] Univ Cambridge, Kavli Inst Cosmol, Cambridge CB3 0HA, England.
   [Cochrane, R.] Royal Observ, Inst Astron, Edinburgh EH9 3HJ, Midlothian, Scotland.
C3 University of Cambridge; University of Cambridge; University of Edinburgh
RP Peng, Y (corresponding author), Univ Cambridge, Cavendish Lab, 19 JJ Thomson Ave, Cambridge CB3 0HE, England.
EM yp244@mrao.cam.ac.uk
FU Science and Technology Facilities Council [ST/M001172/1, ST/K003119/1] Funding Source: researchfish; STFC [ST/M001172/1, ST/K003119/1] Funding Source: UKRI
NR 40
TC 506
Z9 551
U1 3
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 MAY 14
PY 2015
VL 521
IS 7551
BP 192
EP +
DI 10.1038/nature14439
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH9SY
UT WOS:000354377800052
PM 25971510
DA 2026-03-09
ER

PT J
AU Clark, CW
   Barankov, R
   Huber, MG
   Arif, M
   Cory, DG
   Pushin, DA
AF Clark, Charles W.
   Barankov, Roman
   Huber, Michael G.
   Arif, Muhammad
   Cory, David G.
   Pushin, Dmitry A.
TI Controlling neutron orbital angular momentum
SO NATURE
LA English
DT Article
ID beams
AB The quantized orbital angular momentum (OAM) of photons1 offers an additional degree of freedom and topological protection from noise. Photonic OAM states have therefore been exploited in various applications(2,3) ranging from studies of quantum entanglement and quantuminformation science(4-7) to imaging(8-12). TheOAM states of electron beams(13-15) have been shown to be similarly useful, for example in rotating nanoparticles and determining the chirality of crystals(16-19). However, although neutrons-as massive, penetrating and neutral particles-are important in materials characterization, quantum information and studies of the foundations of quantum mechanics, OAM control of neutrons has yet to be achieved. Here, we demonstrate OAM control of neutrons using macroscopic spiral phase plates that apply a ` twist' to an input neutron beam. The twisted neutron beams are analysed with neutron interferometry. Our techniques, applied to spatially incoherent beams, demonstrate both the addition of quantum angular momenta along the direction of propagation, effected by multiple spiral phase plates, and the conservation of topological charge with respect to uniform phase fluctuations. Neutron-based studies of quantum information science(20,21), the foundations of quantum mechanics(22,23), and scattering and imaging(24) of magnetic, superconducting and chiral materials have until now been limited to three degrees of freedom: spin, path and energy. The optimization of OAMcontrol, leading to well defined values ofOAM, would provide an additional quantized degree of freedom for such studies.
C1 [Clark, Charles W.] NIST, Joint Quantum Inst, Gaithersburg, MD 20899 USA.
   [Clark, Charles W.] Univ Maryland, Gaithersburg, MD 20899 USA.
   [Barankov, Roman] Boston Univ, Photon Ctr, Boston, MA 02215 USA.
   [Barankov, Roman] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA.
   [Huber, Michael G.; Arif, Muhammad] NIST, Gaithersburg, MD 20899 USA.
   [Cory, David G.] Univ Waterloo, Dept Chem, Waterloo, ON N2L 3G1, Canada.
   [Cory, David G.] Perimeter Inst Theoret Phys, Waterloo, ON N2L 2Y5, Canada.
   [Cory, David G.; Pushin, Dmitry A.] Univ Waterloo, Inst Quantum Comp, Waterloo, ON N2L 3G1, Canada.
   [Cory, David G.] Canadian Inst Adv Res, Toronto, ON M5G 1Z8, Canada.
   [Pushin, Dmitry A.] Univ Waterloo, Dept Phys & Astron, Waterloo, ON N2L 3G1, Canada.
C3 National Institute of Standards & Technology (NIST) - USA; University System of Maryland; University of Maryland College Park; Boston University; Boston University; National Institute of Standards & Technology (NIST) - USA; University of Waterloo; Perimeter Institute for Theoretical Physics; University of Waterloo; Canadian Institute for Advanced Research (CIFAR); University of Waterloo
RP Pushin, DA (corresponding author), Univ Waterloo, Inst Quantum Comp, Waterloo, ON N2L 3G1, Canada.
EM dmitry.pushin@uwaterloo.ca
FU NSERC; CERC; NIST
NR 49
TC 181
Z9 207
U1 0
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 SEP 24
PY 2015
VL 525
IS 7570
BP 504
EP +
DI 10.1038/nature15265
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR8KI
UT WOS:000361599900047
PM 26399831
DA 2026-03-09
ER

PT J
AU Jiang, JS
   Pentelute, BL
   Collier, RJ
   Zhou, ZH
AF Jiang, Jiansen
   Pentelute, Bradley L.
   Collier, R. John
   Zhou, Z. Hong
TI Atomic structure of anthrax protective antigen pore elucidates toxin translocation
SO NATURE
LA English
DT Article
ID protein translocation; phenylalanine clamp; crystal-structure; receptor; binding; system; visualization; mutations; software; driven
AB Anthrax toxin, comprising protective antigen, lethal factor, and oedema factor, is the major virulence factor of Bacillus anthracis, an agent that causes high mortality in humans and animals. Protective antigen forms oligomeric prepores that undergo conversion to membrane-spanning pores by endosomal acidification, and these pores translocate the enzymes lethal factor and oedema factor into the cytosol of target cells(1). Protective antigen is not only a vaccine component and therapeutic target for anthrax infections but also an excellent model system for understanding the mechanism of protein translocation. On the basis of biochemical and electrophysiological results, researchers have proposed that a phi (Phi)-clamp composed of phenylalanine (Phe)427 residues of protective antigen catalyses protein translocation via a charge-state-dependent Brownian ratchet(2-9). Although atomic structures of protective antigen prepores are available(10-14), how protective antigen senses low pH, converts to active pore, and translocates lethal factor and oedema factor are not well defined without an atomic model of its pore. Here, by cryoelectron microscopy with direct electron counting, we determine the protective antigen pore structure at 2.9-angstrom resolution. The structure reveals the long-sought-after catalytic Phi-clamp and the membrane-spanning translocation channel, and supports the Brownian ratchet model for protein translocation. Comparisons of four structures reveal conformational changes in prepore to pore conversion that support a multi-step mechanism by which low pH is sensed and the membrane-spanning channel is formed.
C1 [Jiang, Jiansen; Zhou, Z. Hong] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA.
   [Jiang, Jiansen; Zhou, Z. Hong] Univ Calif Los Angeles, Calif NanoSyst Inst, Los Angeles, CA 90095 USA.
   [Pentelute, Bradley L.] MIT, Dept Chem, Cambridge, MA 02139 USA.
   [Collier, R. John] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA.
C3 University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; Massachusetts Institute of Technology (MIT); Harvard University; Harvard Medical School
RP Zhou, ZH (corresponding author), Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA.
EM Hong.Zhou@ucla.edu
FU National Institutes of Health [AI094386/AI046420, GM071940, AI022021, AI057159, 1S10RR23057, 1S10OD018111]; American Heart Association [14POST18870059]; Damon Runyon Cancer Research Foundation; National Science Foundation (CAREER) [CHE-1351807]; National Science Foundation [DBI-1338135]; American Heart Association (AHA) [14POST18870059] Funding Source: American Heart Association (AHA); National Institute of Allergy and Infectious Diseases [R01AI094386] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM071940] Funding Source: NIH RePORTER; Direct For Biological Sciences [1338135] Funding Source: National Science Foundation; Div Of Biological Infrastructure [1338135] Funding Source: National Science Foundation
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NR 49
TC 196
Z9 232
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 MAY 28
PY 2015
VL 521
IS 7553
BP 545
EP U323
DI 10.1038/nature14247
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ2AN
UT WOS:000355286600049
PM 25778700
DA 2026-03-09
ER

PT J
AU Huang, XP
   Karpiak, J
   Kroeze, WK
   Zhu, H
   Chen, X
   Moy, SS
   Saddoris, KA
   Nikolova, VD
   Farrell, MS
   Wang, S
   Mangano, TJ
   Deshpande, DA
   Jiang, A
   Penn, RB
   Jin, J
   Koller, BH
   Kenakin, T
   Shoichet, BK
   Roth, BL
AF Huang, Xi-Ping
   Karpiak, Joel
   Kroeze, Wesley K.
   Zhu, Hu
   Chen, Xin
   Moy, Sheryl S.
   Saddoris, Kara A.
   Nikolova, Viktoriya D.
   Farrell, Martilias S.
   Wang, Sheng
   Mangano, Thomas J.
   Deshpande, Deepak A.
   Jiang, Alice
   Penn, Raymond B.
   Jin, Jian
   Koller, Beverly H.
   Kenakin, Terry
   Shoichet, Brian K.
   Roth, Bryan L.
TI Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65
SO NATURE
LA English
DT Article
ID protein-coupled receptor; airway smooth-muscle; extracellular acidification; ogr1; expression; ph; activation; hippocampus; lorazepam; acidosis
AB At least 120 non-olfactory G-protein-coupled receptors in the human genome are 'orphans' for which endogenous ligands are unknown, and many have no selective ligands, hindering the determination of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Using yeast-based screens against GPR68, here we identify the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. More than 3,000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators, many of which were confirmed in functional assays. One potent GPR68 modulator, ogerin, suppressed recall in fear conditioning in wild-type but not in GPR68-knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs.
C1 [Huang, Xi-Ping; Kroeze, Wesley K.; Zhu, Hu; Farrell, Martilias S.; Wang, Sheng; Mangano, Thomas J.; Jiang, Alice; Kenakin, Terry; Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA.
   [Huang, Xi-Ping; Mangano, Thomas J.; Jiang, Alice; Roth, Bryan L.] Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA.
   [Karpiak, Joel; Shoichet, Brian K.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA.
   [Chen, Xin; Jin, Jian] Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery CICBDD, Chapel Hill, NC 27599 USA.
   [Chen, Xin; Jin, Jian; Roth, Bryan L.] Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA.
   [Moy, Sheryl S.; Saddoris, Kara A.; Nikolova, Viktoriya D.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA.
   [Moy, Sheryl S.; Saddoris, Kara A.; Nikolova, Viktoriya D.] Univ N Carolina, Carolina Inst Dev Disabil CIDD, Chapel Hill, NC 27599 USA.
   [Deshpande, Deepak A.; Penn, Raymond B.] Thomas Jefferson Univ, Ctr Translat Med, Philadelphia, PA 19107 USA.
   [Deshpande, Deepak A.; Penn, Raymond B.] Thomas Jefferson Univ, Dept Med, Philadelphia, PA 19107 USA.
   [Koller, Beverly H.] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27599 USA.
C3 University of North Carolina; University of North Carolina Chapel Hill; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH); University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of California System; University of California San Francisco; 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; Thomas Jefferson University; Thomas Jefferson University; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine
RP Roth, BL (corresponding author), Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA.
EM bshoichet@gmail.com; bryan_roth@med.unc.edu
FU National Institutes of Health (NIH) [U01104974, R01 DA017204]; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP); Michael Hooker Chair for Protein Therapeutics and Translational Proteomics; Genentech Foundation Predoctoral Fellowship; NIH [GM59957, GM71896, U19MH082441]; Structural Genomics Consortium; NICHD [U54 HD079124];  [P01 HL114471]; National Heart Lung and Blood Institute [P01HL114471] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM071896] Funding Source: NIH RePORTER
NR 44
TC 227
Z9 275
U1 1
U2 79
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 477
EP +
DI 10.1038/nature15699
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500039
PM 26550826
DA 2026-03-09
ER

PT J
AU Toyoda, K
   Hiji, R
   Noguchi, A
   Urabe, S
AF Toyoda, Kenji
   Hiji, Ryoto
   Noguchi, Atsushi
   Urabe, Shinji
TI Hong-Ou-Mandel interference of two phonons in trapped ions
SO NATURE
LA English
DT Article
ID entanglement
AB The quantum statistics of bosons and fermions manifest themselves in the manner in which two indistinguishable particles interfere quantum mechanically. When two photons, which are bosonic particles, enter a beam-splitter with one photon in each input port, they bunch together at either of the two output ports. The corresponding disappearance of the coincidence count is the Hong-Ou-Mandel effect(1). Here we show the phonon counterpart of this effect in a system of trapped-ion phonons, which are collective excitations derived by quantizing vibrational motions that obey Bose-Einstein statistics. We realize a beam-splitter transformation of the phonons by employing the mutual Coulomb repulsion between ions, and perform a two-phonon quantum interference experiment using that transformation. We observe an almost perfect disappearance of the phonon coincidence between two ion sites, confirming that phonons can be considered indistinguishable bosonic particles. The two-particle interference demonstrated here is purely a quantum effect, without a classical counterpart, hence it should be possible to demonstrate the existence of entanglement on this basis. We attempt to generate an entangled state of phonons at the centre of the Hong-Ou-Mandel dip in the coincidence temporal profile, under the assumption that the entangled phonon state is successfully generated if the fidelity of the analysis pulses is taken into account adequately. Two-phonon interference, as demonstrated here, proves the bosonic nature of phonons in a trapped-ion system. It opens the way to establishing phonon modes as carriers of quantum information in their own right(2-4), and could have implications for the quantum simulation of bosonic particles(5,6) and analogue quantum computation via boson sampling(7).
C1 [Toyoda, Kenji; Hiji, Ryoto; Noguchi, Atsushi; Urabe, Shinji] Osaka Univ, Grad Sch Engn Sci, 1-3 Machikaneyama, Toyonaka, Osaka 5608531, Japan.
C3 University of Osaka
RP Toyoda, K (corresponding author), Osaka Univ, Grad Sch Engn Sci, 1-3 Machikaneyama, Toyonaka, Osaka 5608531, Japan.
EM toyoda@ee.es.osaka-u.ac.jp
FU JSPS KAKENHI [26400418]; Grants-in-Aid for Scientific Research [15J11058, 26400418] Funding Source: KAKEN
NR 11
TC 89
Z9 97
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 NOV 5
PY 2015
VL 527
IS 7576
BP 74
EP 77
DI 10.1038/nature15735
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV4XV
UT WOS:000364270700045
PM 26536958
DA 2026-03-09
ER

PT J
AU Lin, DYW
   Huang, S
   Chen, J
AF Lin, David Yin-wei
   Huang, Shuo
   Chen, Jue
TI Crystal structures of a polypeptide processing and secretion transporter
SO NATURE
LA English
DT Article
ID nucleotide-binding domain; maltose transporter; abc transporters; atp hydrolysis; streptococcus coma; peptidase domain; protein; translocation; complex; crystallization
AB Bacteria secrete peptides and proteins to communicate, to poison competitors, and to manipulate host cells. Among the various protein-translocation machineries, the peptidase-containing ATP-binding cassette transporters (PCATs) are appealingly simple. Each PCAT contains two peptidase domains that cleave the secretion signal from the substrate, two transmembrane domains that form a translocation pathway, and two nucleotide-binding domains that hydrolyse ATP. In Gram-positive bacteria, PCATs function both as maturation proteases and exporters for quorum-sensing or antimicrobial polypeptides. In Gram-negative bacteria, PCATs interact with two other membrane proteins to form the type 1 secretion system. Here we present crystal structures of PCAT1 from Clostridium thermocellum in two different conformations. These structures, accompanied by biochemical data, show that the translocation pathway is a large a-helical barrel sufficient to accommodate small folded proteins. ATP binding alternates access to the transmembrane pathway and also regulates the protease activity, thereby coupling substrate processing to translocation.
C1 [Lin, David Yin-wei; Chen, Jue] Rockefeller Univ, Lab Membrane Biol & Biophys, New York, NY 10065 USA.
   [Lin, David Yin-wei; Huang, Shuo; Chen, Jue] Howard Hughes Med Inst, New York, NY 10065 USA.
C3 Rockefeller University; Howard Hughes Medical Institute
RP Chen, J (corresponding author), Rockefeller Univ, Lab Membrane Biol & Biophys, 1230 York Ave, New York, NY 10065 USA.
EM juechen@rockefeller.edu
FU Howard Hughes Medical Institute
NR 54
TC 96
Z9 113
U1 0
U2 71
PU NATURE PUBLISHING 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 23
PY 2015
VL 523
IS 7561
BP 425
EP U92
DI 10.1038/nature14623
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN4DD
UT WOS:000358378900029
PM 26201595
DA 2026-03-09
ER

PT J
AU Abitua, PB
   Gainous, TB
   Kaczmarczyk, AN
   Winchell, CJ
   Hudson, C
   Kamata, K
   Nakagawa, M
   Tsuda, M
   Kusakabe, TG
   Levine, M
AF Abitua, Philip Barron
   Gainous, T. Blair
   Kaczmarczyk, Angela N.
   Winchell, Christopher J.
   Hudson, Clare
   Kamata, Kaori
   Nakagawa, Masashi
   Tsuda, Motoyuki
   Kusakabe, Takehiro G.
   Levine, Michael
TI The pre-vertebrate origins of neurogenic placodes
SO NATURE
LA English
DT Article
ID gonadotropin-releasing-hormone; neural crest; ciona-intestinalis; messenger-rna; expression; evolution; system; generation; induction; relaxin-3
AB The sudden appearance of the neural crest and neurogenic placodes in early branching vertebrates has puzzled biologists for over a century(1). These embryonic tissues contribute to the development of the cranium and associated sensory organs, which were crucial for the evolution of the vertebrate "new head"(2,3). Aprevious study suggests that rudimentary neural crest cells existed in ancestral chordates(4). However, the evolutionary origins of neurogenic placodes have remained obscure owing to a paucity of embryonic data from tunicates, the closest living relatives to those early vertebrates(5). Here we show that the tunicate Ciona intestinalis exhibits a proto-placodal ectoderm (PPE) that requires inhibition of bone morphogenetic protein (BMP) and expresses the key regulatory determinant Six1/ 2 and its co-factor Eya, a developmental process conserved across vertebrates. The Ciona PPE is shown to produce ciliated neurons that express genes for gonadotropin releasing hormone (GnRH), a G-protein-coupled receptor for relaxin-3 (RXFP3) and a functional cyclic nucleotide-gated channel (CNGA), which suggests dual chemosensory and neurosecretory activities. These observations provide evidence that Ciona has a neurogenic proto-placode, which forms neurons that appear to be related to those derived from the olfactory placode and hypothalamic neurons of vertebrates. We discuss the possibility that the PPE-derived GnRH neurons of Ciona resemble an ancestral cell type, a progenitor to the complex neuronal circuit that integrates sensory information and neuroendocrine functions in vertebrates.
C1 [Abitua, Philip Barron; Gainous, T. Blair; Kaczmarczyk, Angela N.; Winchell, Christopher J.; Levine, Michael] Univ Calif Berkeley, Dept Mol & Cell Biol, Div Genet Genom & Dev, Ctr Integrat Genom, Berkeley, CA 94720 USA.
   [Hudson, Clare] Univ Paris 06, Sorbonne Univ, CNRS, Lab Biol Dev Villefranche Sur Mer,Observ Oceanol, F-06230 Villefranche Sur Mer, France.
   [Kamata, Kaori; Nakagawa, Masashi; Tsuda, Motoyuki] Univ Hyogo, Grad Sch Life Sci, Kamigori, Hyogo 6781297, Japan.
   [Kusakabe, Takehiro G.] Konan Univ, Fac Sci & Engn, Inst Integrat Neurobiol, Kobe, Hyogo 6588501, Japan.
   [Kusakabe, Takehiro G.] Konan Univ, Fac Sci & Engn, Dept Biol, Kobe, Hyogo 6588501, Japan.
C3 University of California System; University of California Berkeley; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); University of Hyogo; Konan University; Konan University
RP Levine, M (corresponding author), Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA.
EM msl2@princeton.edu
FU National Institutes of Health [NS076542]; Japan Society for the Promotion of Science [25650118, 25290067]; Japan Space Forum [h160179]; Agence Nationale de la Recherche [ANR-09-BLAN-0013-01]; National Science Foundation; California Institute for Regenerative Medicine; National Institute of Neurological Disorders and Stroke [R01NS076542] Funding Source: NIH RePORTER; Agence Nationale de la Recherche (ANR) [ANR-09-BLAN-0013] Funding Source: Agence Nationale de la Recherche (ANR); Grants-in-Aid for Scientific Research [25650118] Funding Source: KAKEN
NR 44
TC 92
Z9 103
U1 0
U2 38
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 27
PY 2015
VL 524
IS 7566
BP 462
EP +
DI 10.1038/nature14657
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP7LN
UT WOS:000360069300037
PM 26258298
DA 2026-03-09
ER

PT J
AU Lee, ASY
   Kranzusch, PJ
   Cate, JHD
AF Lee, Amy S. Y.
   Kranzusch, Philip J.
   Cate, Jamie H. D.
TI eIF3 targets cell-proliferation messenger RNAs for translational activation or repression
SO NATURE
LA English
DT Article
ID c-jun; preinitiation complex; viral translation; binding protein; par-clip; initiation; sites; identification; transformation; specificity
AB Regulation of protein synthesis is fundamental for all aspects of eukaryotic biology by controlling development, homeostasis and stress responses(1,2). The 13-subunit, 800-kilodalton eukaryotic initiation factor 3 (eIF3) organizes initiation factor and ribosome interactions required for productive translation(3). However, current understanding of eIF3 function does not explain genetic evidence correlating eIF3 deregulation with tissue-specific cancers and developmental defects(4). Here we report the genome-wide discovery of human transcripts that interact with eIF3 using photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation (PAR-CLIP)(5). eIF3 binds to a highly specific program of messenger RNAs involved in cell growth control processes, including cell cycling, differentiation and apoptosis, via them RNA 5' untranslated region. Surprisingly, functional analysis of the interaction between eIF3 and two mRNAs encoding the cell proliferation regulators c-JUN and BTG1 reveals that eIF3 uses different modes of RNA stem-loop binding to exert either translational activation or repression. Our findings illuminate a new role for eIF3 in governing a specialized repertoire of gene expression and suggest that binding of eIF3 to specific mRNAs could be targeted to control carcinogenesis.
C1 [Lee, Amy S. Y.; Kranzusch, Philip J.; Cate, Jamie H. D.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
   [Lee, Amy S. Y.; Cate, Jamie H. D.] Univ Calif Berkeley, Ctr RNA Syst Biol, Berkeley, CA 94720 USA.
   [Kranzusch, Philip J.] Univ Calif Berkeley, HHMI, Berkeley, CA 94720 USA.
   [Cate, Jamie H. D.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
   [Cate, Jamie H. D.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA.
C3 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 Cate, JHD (corresponding author), Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
EM jcate@lbl.gov
FU National Institutes of Health (NIH) [S10RR029668, S10RR027303]; NIH [S10RR025622]; National Institute of General Medical Sciences Center for RNA Systems Biology; American Cancer Society [PF-14-108-01-RMC]; Howard Hughes Medical Institute
NR 42
TC 328
Z9 407
U1 3
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 JUN 4
PY 2015
VL 522
IS 7554
BP 111
EP U292
DI 10.1038/nature14267
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ5QP
UT WOS:000355543400040
PM 25849773
DA 2026-03-09
ER

PT J
AU Al Ma'Mari, F
   Moorsom, T
   Teobaldi, G
   Deacon, W
   Prokscha, T
   Luetkens, H
   Lee, S
   Sterbinsky, GE
   Arena, DA
   MacLaren, DA
   Flokstra, M
   Ali, M
   Wheeler, MC
   Burnell, G
   Hickey, BJ
   Cespedes, O
AF Al Ma'Mari, Fatma
   Moorsom, Timothy
   Teobaldi, Gilberto
   Deacon, William
   Prokscha, Thomas
   Luetkens, Hubertus
   Lee, Steve
   Sterbinsky, George E.
   Arena, Dario A.
   MacLaren, Donald A.
   Flokstra, Machiel
   Ali, Mannan
   Wheeler, May C.
   Burnell, Gavin
   Hickey, Bryan J.
   Cespedes, Oscar
TI Beating the Stoner criterion using molecular interfaces
SO NATURE
LA English
DT Article
ID generation; energy; length
AB Only three elements are ferromagnetic at room temperature: the transition metals iron, cobalt and nickel. The Stoner criterion explains why iron is ferromagnetic but manganese, for example, is not, even though both elements have an unfilled 3d shell and are adjacent in the periodic table: according to this criterion, the product of the density of states and the exchange integral must be greater than unity for spontaneous spin ordering to emerge(1,2). Here we demonstrate that it is possible to alter the electronic states of non-ferromagnetic materials, such as diamagnetic copper and paramagnetic manganese, to overcome the Stoner criterion and make them ferromagnetic at room temperature. This effect is achieved via interfaces between metallic thin films and C-60 molecular layers. The emergent ferromagnetic state exists over several layers of the metal before being quenched at large sample thicknesses by the material's bulk properties. Although the induced magnetization is easily measurable by magnetometry, low-energy muon spin spectroscopy(3) provides insight into its distribution by studying the depolarization process of low-energy muons implanted in the sample. This technique indicates localized spin-ordered states at, and close to, the metal-molecule interface. Density functional theory simulations suggest a mechanism based on magnetic hardening of the metal atoms, owing to electron transfer(4,5). This mechanism might allow for the exploitation of molecular coupling to design magnetic metamaterials using abundant, non-toxic components such as organic semiconductors. Charge transfer at molecular interfaces may thus be used to control spin polarization or magnetization, with consequences for the design of devices for electronic, power or computing applications (see, for example, refs 6 and 7).
C1 [Al Ma'Mari, Fatma; Moorsom, Timothy; Deacon, William; Ali, Mannan; Wheeler, May C.; Burnell, Gavin; Hickey, Bryan J.; Cespedes, Oscar] Univ Leeds, Sch Phys & Astron, Leeds LS2 9JT, W Yorkshire, England.
   [Teobaldi, Gilberto] Univ Liverpool, Stephenson Inst Renewable Energy, Dept Chem, Liverpool L69 3BX, Merseyside, England.
   [Prokscha, Thomas; Luetkens, Hubertus] Paul Scherrer Inst, Lab Muon Spin Spect, CH-5232 Villigen, Switzerland.
   [Lee, Steve; Flokstra, Machiel] Univ St Andrews, Sch Phys & Astron, SUPA, St Andrews KY16 9SS, Fife, Scotland.
   [Sterbinsky, George E.; Arena, Dario A.] Brookhaven Natl Lab, Photon Sci Directorate, Upton, NY 11973 USA.
   [MacLaren, Donald A.] Univ Glasgow, Sch Phys & Astron, SUPA, Glasgow G12 8QQ, Lanark, Scotland.
C3 University of Leeds; University of Liverpool; Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute; University of St Andrews; United States Department of Energy (DOE); Brookhaven National Laboratory; University of Glasgow
RP Cespedes, O (corresponding author), Univ Leeds, Sch Phys & Astron, Leeds LS2 9JT, W Yorkshire, England.
EM o.cespedes@leeds.ac.uk
FU Engineering and Physical Sciences Research Council [EP/K00512X/1, EP/K036408/1, EP/J01060X/1, EP/I004483/1]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-98CH10886]; Engineering and Physical Sciences Research Council [EP/K000225/1, EP/J01060X/1, EP/J021156/1, EP/K036408/1, EP/I00419X/1, EP/I004483/1, EP/K013610/1, EP/K00512X/1, EP/M000923/1, 1231114] Funding Source: researchfish; EPSRC [EP/K036408/1, EP/M000923/1, EP/I00419X/1, EP/J021156/1, EP/K013610/1, EP/K000225/1, EP/I004483/1, EP/J01060X/1, EP/K00512X/1] Funding Source: UKRI
NR 37
TC 171
Z9 182
U1 4
U2 2252
PU NATURE PUBLISHING 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 6
PY 2015
VL 524
IS 7563
BP 69
EP U128
DI 10.1038/nature14621
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO2QS
UT WOS:000359002300033
PM 26245580
DA 2026-03-09
ER

PT J
AU Harmansa, S
   Hamaratoglu, F
   Affolter, M
   Aussinus, EC
AF Harmansa, Stefan
   Hamaratoglu, Fisun
   Affolter, Markus
   Aussinus, Emmanuel C.
TI Dpp spreading is required for medial but not for lateral wing disc growth
SO NATURE
LA English
DT Article
ID morphogen gradient; cell-proliferation; gene-function; size control; i receptors; drosophila; expression; pattern; brinker; target
AB Drosophila Decapentaplegic (Dpp) has served as a paradigm to study morphogen-dependent growth control. However, the role of a Dpp gradient in tissue growth remains highly controversial. Two fundamentally different models have been proposed: the 'temporal rule' model suggests that all cells of the wing imaginal disc divide upon a 50% increase in Dpp signalling, whereas the 'growth equalization model' suggests that Dpp is only essential for proliferation control of the central cells. Here, to discriminate between these two models, we generated and used morphotrap, a membrane-tethered anti-green fluorescent protein (GFP) nanobody, which enables immobilization of enhanced (e)GFP:: Dpp on the cell surface, thereby abolishing Dpp gradient formation. We find that in the absence of Dpp spreading, wing disc patterning is lost; however, lateral cells still divide at normal rates. These data are consistent with the growth equalization model, but do not fit a global temporal rule model in the wing imaginal disc.
C1 [Harmansa, Stefan; Affolter, Markus; Aussinus, Emmanuel C.] Univ Basel, Biozentrum, Growth & Dev, Klingelbergstr 50-70, CH-4056 Basel, Switzerland.
   [Hamaratoglu, Fisun] Univ Lausanne, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland.
   [Aussinus, Emmanuel C.] Univ Zurich, IMLS, CH-8057 Zurich, Switzerland.
C3 University of Basel; University of Lausanne; University of Zurich
RP Affolter, M (corresponding author), Univ Basel, Biozentrum, Growth & Dev, Klingelbergstr 50-70, CH-4056 Basel, Switzerland.
EM Markus.Affolter@unibas.ch
FU 'Fellowships for Excellence' International PhD Program in Molecular Life Sciences of the Biozentrum, University of Basel; SystemsX.ch initiative; MorphogenetiX projects; Swiss National Science Foundation (SNSF) Professorship grant [PP00P3_150682]; Canton Basel-Stadt; Canton BaselLand; SNSF; SystemsX.ch; Swiss National Science Foundation (SNF) [PP00P3_150682] Funding Source: Swiss National Science Foundation (SNF)
NR 59
TC 98
Z9 109
U1 0
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 NOV 19
PY 2015
VL 527
IS 7578
BP 317
EP +
DI 10.1038/nature15712
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9ZN
UT WOS:000365356800044
PM 26550827
DA 2026-03-09
ER

PT J
AU Masui, K
   Lin, HH
   Sievers, J
   Anderson, CJ
   Chang, TC
   Chen, XL
   Ganguly, A
   Jarvis, M
   Kuo, CY
   Li, YC
   Liao, YW
   McLaughlin, M
   Pen, UL
   Peterson, JB
   Roman, A
   Timbie, PT
   Voytek, T
   Yadav, JK
AF Masui, Kiyoshi
   Lin, Hsiu-Hsien
   Sievers, Jonathan
   Anderson, Christopher J.
   Chang, Tzu-Ching
   Chen, Xuelei
   Ganguly, Apratim
   Jarvis, Miranda
   Kuo, Cheng-Yu
   Li, Yi-Chao
   Liao, Yu-Wei
   McLaughlin, Maura
   Pen, Ue-Li
   Peterson, Jeffrey B.
   Roman, Alexander
   Timbie, Peter T.
   Voytek, Tabitha
   Yadav, Jaswant K.
TI Dense magnetized plasma associated with a fast radio burst
SO NATURE
LA English
DT Article
ID cosmological distances; reionization history; faraday-rotation; neutron-stars; to 0.8; dispersion; origin; environment; galaxy
AB Fast radio bursts are bright, unresolved, non-repeating, broadband, millisecond flashes, found primarily at high Galactic latitudes, with dispersion measures much larger than expected for a Galactic source(1-7). The inferred all-sky burst rate(8) is comparable to the core-collapse supernova rate(9) out to redshift 0.5. If the observed dispersion measures are assumed to be dominated by the intergalactic medium, the sources are at cosmological distances with redshifts of 0.2 to 1 (refs 10 and 11). These parameters are consistent with a wide range of source models(12-17). One fast burst(6) revealed circular polarization of the radio emission, but no linear polarization was detected, and hence no Faraday rotation measure could be determined. Here we report the examination of archival data revealing Faraday rotation in the fast radio burst FRB 110523. Its radio flux and dispersion measure are consistent with values from previously reported bursts and, accounting for a Galactic contribution to the dispersion and using a model of intergalactic electron density(10), we place the source at a maximum redshift of 0.5. The burst has a much higher rotation measure than expected for this line of sight through the Milky Way and the intergalactic medium, indicating magnetization in the vicinity of the source itself or within a host galaxy. The pulse was scattered by two distinct plasma screens during propagation, which requires either a dense nebula associated with the source or a location within the central region of its host galaxy. The detection in this instance of magnetization and scattering that are both local to the source favours models involving young stellar populations such as magnetars over models involving the mergers of older neutron stars, which are more likely to be located in low-density regions of the host galaxy.
C1 [Masui, Kiyoshi] Univ British Columbia, Dept Phys & Astron, Vancouver, BC V6T 1Z1, Canada.
   [Masui, Kiyoshi; Pen, Ue-Li] Canadian Inst Adv Res, CIFAR Program Cosmol & Grav, Toronto, ON M5G 1Z8, Canada.
   [Lin, Hsiu-Hsien; Peterson, Jeffrey B.; Roman, Alexander; Voytek, Tabitha] Carnegie Mellon Univ, Dept Phys, McWilliams Ctr Cosmol, Pittsburgh, PA 15213 USA.
   [Sievers, Jonathan; Voytek, Tabitha] Univ KwaZulu Natal, Sch Chem & Phys, Astrophys & Cosmol Res Unit, ZA-4001 Durban, South Africa.
   [Sievers, Jonathan] Natl Inst Theoret Phys NITheP, KZN Node, ZA-4001 Durban, South Africa.
   [Anderson, Christopher J.; Timbie, Peter T.] Univ Wisconsin, Dept Phys, Madison, WI 53706 USA.
   [Chang, Tzu-Ching; Kuo, Cheng-Yu; Liao, Yu-Wei] Acad Sinica, Inst Astron & Astrophys, Taipei 10617, Taiwan.
   [Chen, Xuelei; Li, Yi-Chao] Chinese Acad Sci, Natl Astron Observ, Beijing 100012, Peoples R China.
   [Chen, Xuelei] Peking Univ, Ctr High Energy Phys, Beijing 100871, Peoples R China.
   [Ganguly, Apratim] Univ KwaZulu Natal, Astrophys & Cosmol Res Unit, Sch Math Stat & Comp Sci, ZA-4001 Durban, South Africa.
   [Jarvis, Miranda] Univ Toronto, Dept Astron & Astrophys, Toronto, ON M5S 3H4, Canada.
   [Kuo, Cheng-Yu] Natl Sun Yat Sen Univ, Dept Phys, Kaohsiung 804, Taiwan.
   [McLaughlin, Maura] W Virginia Univ, Dept Phys & Astron, Morgantown, WV 26506 USA.
   [Pen, Ue-Li] Canadian Inst Theoret Astrophys, Toronto, ON M5S 3H8, Canada.
   [Pen, Ue-Li] Perimeter Inst, Waterloo, ON N2L 2Y5, Canada.
   [Yadav, Jaswant K.] Indian Inst Sci Educ & Res Mohali, Sas Nagar, Manauli, India.
C3 University of British Columbia; Canadian Institute for Advanced Research (CIFAR); Carnegie Mellon University; University of Kwazulu Natal; University of Wisconsin System; University of Wisconsin Madison; Academia Sinica - Taiwan; Chinese Academy of Sciences; National Astronomical Observatory, CAS; Peking University; University of Kwazulu Natal; University of Toronto; National Sun Yat Sen University; West Virginia University; Perimeter Institute for Theoretical Physics; Indian Institute of Science Education & Research (IISER) - Mohali
RP Masui, K (corresponding author), Univ British Columbia, Dept Phys & Astron, 6224 Agr Rd, Vancouver, BC V6T 1Z1, Canada.
EM kiyo@physics.ubc.ca
FU CIFAR Global Scholars Program; MoST [103-2112-M-001-002-MY3]; MOST 863 programme [2012AA121701]; CAS [XDB09000000]; NSFC [11373030]; NSF [1211781, 1211777]; Direct For Mathematical & Physical Scien; Division Of Astronomical Sciences [1211781] Funding Source: National Science Foundation; Division Of Astronomical Sciences; Direct For Mathematical & Physical Scien [1211777] Funding Source: National Science Foundation; Office of Integrative Activities; Office Of The Director [1458952] Funding Source: National Science Foundation
NR 36
TC 335
Z9 394
U1 0
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 DEC 24
PY 2015
VL 528
IS 7583
BP 523
EP +
DI 10.1038/nature15769
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900045
PM 26633633
DA 2026-03-09
ER

PT J
AU Hilton, RG
   Galy, V
   Gaillardet, J
   Dellinger, M
   Bryant, C
   O'Regan, M
   Gröcke, DR
   Coxall, H
   Bouchez, J
   Calmels, D
AF Hilton, Robert G.
   Galy, Valier
   Gaillardet, Jerome
   Dellinger, Mathieu
   Bryant, Charlotte
   O'Regan, Matt
   Groecke, Darren R.
   Coxall, Helen
   Bouchez, Julien
   Calmels, Damien
TI Erosion of organic carbon in the Arctic as a geological carbon dioxide sink
SO NATURE
LA English
DT Article
ID permafrost-carbon; isotopic composition; climate-change; sediment; vulnerability; peatlands; coastal; burial; matter; rivers
AB Soils of the northern high latitudes store carbon over millennial timescales (thousands of years) and contain approximately double the carbon stock of the atmosphere(1-3). Warming and associated permafrost thaw can expose soil organic carbon and result in mineralization and carbon dioxide (CO2) release(4-6). However, some of this soil organic carbon may be eroded and transferred to rivers(7-9). If it escapes degradation during river transport and is buried in marine sediments, then it can contribute to a longer-term (more than ten thousand years), geological CO2 sink(8-10). Despite this recognition, the erosional flux and fate of particulate organic carbon (POC) in large rivers at high latitudes remains poorly constrained. Here, we quantify the source of POC in the Mackenzie River, the main sediment supplier to the Arctic Ocean(11,12), and assess its flux and fate. We combine measurements of radiocarbon, stable carbon isotopes and element ratios to correct for rock-derived POC10,13,14. Our samples reveal that the eroded biospheric POC has resided in the basin for millennia, with a mean radiocarbon age of 5,800 +/- 800 years, much older than the POC in large tropical rivers(13,14). From the measured biospheric POC content and variability in annual sediment yield(15), we calculate a biospheric POC flux of 2.2(-0.9)(+1.3) teragrams of carbon per year from the Mackenzie River, which is three times the CO2 drawdown by silicate weathering in this basin(16). Offshore, we find evidence for efficient terrestrial organic carbon burial over the Holocene period, suggesting that erosion of organic carbon-rich, high-latitude soils may result in an important geological CO2 sink.
C1 [Hilton, Robert G.] Univ Durham, Dept Geog, South Rd, Durham DH1 3LE, England.
   [Galy, Valier] Woods Hole Oceanog Inst, Dept Marine Chem & Geochem, Woods Hole, MA 02543 USA.
   [Gaillardet, Jerome; Dellinger, Mathieu; Bouchez, Julien] Univ Paris Diderot, Inst Phys Globe Paris, Sorbonne Paris Cite, UMR CNRS 7154, F-75005 Paris, France.
   [Bryant, Charlotte] NERC Radiocarbon Facil, E Kilbride G75 OQF, Lanark, Scotland.
   [O'Regan, Matt; Coxall, Helen] Stockholm Univ, Dept Geol Sci, SE-10691 Stockholm, Sweden.
   [Groecke, Darren R.] Univ Durham, Dept Earth Sci, Durham DH1 3LE, England.
   [Calmels, Damien] Univ Paris Sud, Lab GEOPS, UMR CNRS 8148, F-91405 Orsay, France.
C3 Durham University; Woods Hole Oceanographic Institution; Universite Paris Cite; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Stockholm University; Durham University; Universite Paris Saclay
RP Hilton, RG (corresponding author), Univ Durham, Dept Geog, South Rd, Durham DH1 3LE, England.
EM r.g.hilton@durham.ac.uk
FU Natural Environment Research Council (NERC), UK [1611.0312]; CNRS (OXYMORE); CNRS (CANNIBALT); Woods Hole Oceanographic Institution Arctic Research Initiative; Early Career Research Grant by the British Society for Geomorphology; US National Science Foundation [OCE-0928582]; Royal Society University Fellowship; NERC [NRCF010001] Funding Source: UKRI; Natural Environment Research Council [NRCF010001] Funding Source: researchfish
NR 42
TC 168
Z9 190
U1 6
U2 360
PU NATURE PUBLISHING 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 6
PY 2015
VL 524
IS 7563
BP 84
EP +
DI 10.1038/nature14653
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO2QS
UT WOS:000359002300036
PM 26245581
DA 2026-03-09
ER

PT J
AU Lehmann, J
   Kleber, M
AF Lehmann, Johannes
   Kleber, Markus
TI The contentious nature of soil organic matter
SO NATURE
LA English
DT Article
ID earth system models; humic substances; black carbon; litter decomposition; molecular-structure; temperature sensitivity; electron-acceptors; glass-transition; conceptual-model; plant
AB The exchange of nutrients, energy and carbon between soil organic matter, the soil environment, aquatic systems and the atmosphere is important for agricultural productivity, water quality and climate. Long-standing theory suggests that soil organic matter is composed of inherently stable and chemically unique compounds. Here we argue that the available evidence does not support the formation of large-molecular-size and persistent 'humic substances' in soils. Instead, soil organic matter is a continuum of progressively decomposing organic compounds. We discuss implications of this view of the nature of soil organic matter for aquatic health, soil carbon-climate interactions and land management.
C1 [Lehmann, Johannes] Cornell Univ, Coll Agr & Life Sci, Soil & Crop Sci, Sch Integrated Plant Sci, Ithaca, NY 14853 USA.
   [Lehmann, Johannes] Cornell Univ, Atkinson Ctr Sustainable Future, Ithaca, NY USA.
   [Kleber, Markus] Oregon State Univ, Dept Crop & Soil Sci, Corvallis, OR 97331 USA.
   [Kleber, Markus] Leibniz Zentrum Agrarlandschaftsforsch ZALF, Inst Bodenlandschaftsforsch, Muncheberg, Germany.
C3 Cornell University; Cornell University; Oregon State University; Leibniz Association; Leibniz Zentrum fur Agrarlandschaftsforschung (ZALF)
RP Lehmann, J (corresponding author), Cornell Univ, Coll Agr & Life Sci, Soil & Crop Sci, Sch Integrated Plant Sci, Ithaca, NY 14853 USA.
EM CL273@cornell.edu
NR 125
TC 3223
Z9 3848
U1 300
U2 4592
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 3
PY 2015
VL 528
IS 7580
BP 60
EP 68
DI 10.1038/nature16069
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000049
PM 26595271
DA 2026-03-09
ER

PT J
AU Liu, Z
   Guan, DB
   Wei, W
   Davis, SJ
   Ciais, P
   Bai, J
   Peng, SS
   Zhang, Q
   Hubacek, K
   Marland, G
   Andres, RJ
   Crawford-Brown, D
   Lin, JT
   Zhao, HY
   Hong, CP
   Boden, TA
   Feng, KS
   Peters, GP
   Xi, FM
   Liu, JG
   Li, Y
   Zhao, Y
   Zeng, N
   He, KB
AF Liu, Zhu
   Guan, Dabo
   Wei, Wei
   Davis, Steven J.
   Ciais, Philippe
   Bai, Jin
   Peng, Shushi
   Zhang, Qiang
   Hubacek, Klaus
   Marland, Gregg
   Andres, Robert J.
   Crawford-Brown, Douglas
   Lin, Jintai
   Zhao, Hongyan
   Hong, Chaopeng
   Boden, Thomas A.
   Feng, Kuishuang
   Peters, Glen P.
   Xi, Fengming
   Liu, Junguo
   Li, Yuan
   Zhao, Yu
   Zeng, Ning
   He, Kebin
TI Reduced carbon emission estimates from fossil fuel combustion and cement production in China
SO NATURE
LA English
DT Article
ID co2 emissions; pollutants
AB Nearly three-quarters of the growth in global carbon emissions from the burning of fossil fuels and cement production between 2010 and 2012 occurred in China(1,2). Yet estimates of Chinese emissions remain subject to large uncertainty; inventories of China's total fossil fuel carbon emissions in 2008 differ by 0.3 gigatonnes of carbon, or 15 per cent(1,3-5). The primary sources of this uncertainty are conflicting estimates of energy consumption and emission factors, the latter being uncertain because of very few actual measurements representative of the mix of Chinese fuels. Here we re-evaluate China's carbon emissions using updated and harmonized energy consumption and clinker production data and two new and comprehensive sets of measured emission factors for Chinese coal. We find that total energy consumption in China was 10 per cent higher in 2000-2012 than the value reported by China's national statistics(6), that emission factors for Chinese coal are on average 40 per cent lower than the default values recommended by the Intergovernmental Panel on Climate Change(7), and that emissions from China's cement production are 45 per cent less than recent estimates(1,4). Altogether, our revised estimate of China's CO2 emissions from fossil fuel combustion and cement production is 2.49 gigatonnes of carbon (2 standard deviations = +/-7.3 per cent) in 2013, which is 14 per cent lower than the emissions reported by other prominent inventories(1,4,8). Over the full period 2000 to 2013, our revised estimates are 2.9 gigatonnes of carbon less than previous estimates of China's cumulative carbon emissions(1,4). Our findings suggest that overestimation of China's emissions in 2000-2013 may be larger than China's estimated total forest sink in 1990-2007 (2.66 gigatonnes of carbon)(9) or China's land carbon sink in 2000-2009 (2.6 gigatonnes of carbon)(10).
C1 [Liu, Zhu] Harvard Univ, John F Kennedy Sch Govt, Cambridge, MA 02138 USA.
   [Guan, Dabo; Davis, Steven J.; Xi, Fengming] Chinese Acad Sci, Inst Appl Ecol, Shenyang 110016, Peoples R China.
   [Liu, Zhu] CALTECH, Resnick Sustainabil Inst, Pasadena, CA 91125 USA.
   [Guan, Dabo; Zhang, Qiang; Zhao, Hongyan; Hong, Chaopeng] Tsinghua Univ, Ctr Earth Syst Sci, Key Lab Earth Syst Modeling, Minist Educ, Beijing 100084, Peoples R China.
   [Guan, Dabo; Li, Yuan] Univ E Anglia, Sch Int Dev, Norwich NR4 7TJ, Norfolk, England.
   [Wei, Wei] Chinese Acad Sci, Shanghai Adv Res Inst, CAS Key Lab Lowcarbon Convers Sci & Engn, Shanghai 201203, Peoples R China.
   [Davis, Steven J.] Univ Calif Irvine, Dept Earth Syst Sci, Irvine, CA 92697 USA.
   [Ciais, Philippe; Peng, Shushi] UVSQ, CEA CNRS, CE Orme Merisiers, Lab Sci Climat & Environm, F-91191 Gif Sur Yvette, France.
   [Bai, Jin] Chinese Acad Sci, Inst Coal Chem, State Key Lab Coal Convers, Taiyuan 030001, Peoples R China.
   [Peng, Shushi] CNRS, F-38041 Grenoble, France.
   [Peng, Shushi] UJF Grenoble 1, LGGE, UMR5183, F-38041 Grenoble, France.
   [Hubacek, Klaus; Feng, Kuishuang] Univ Maryland, Dept Geog Sci, College Pk, MD 20742 USA.
   [Marland, Gregg] Appalachian State Univ, Res Inst Environm Energy & Econ, Boone, NC 28608 USA.
   [Andres, Robert J.; Boden, Thomas A.] Oak Ridge Natl Lab, Carbon Dioxide Informat Anal Ctr, Oak Ridge, TN 37831 USA.
   [Crawford-Brown, Douglas] Univ Cambridge, Dept Land Econ, Cambridge Ctr Climate Change Mitigat Res, Cambridge CB3 9EP, England.
   [Lin, Jintai] Peking Univ, Sch Phys, Dept Atmospher & Ocean Sci, Lab Climate & Ocean Atmosphere Studies, Beijing 100871, Peoples R China.
   [Hong, Chaopeng; He, Kebin] Tsinghua Univ, Sch Environm, State Key Joint Lab Environm Simulat & Pollut C, Beijing 100084, Peoples R China.
   [Peters, Glen P.] CICERO, N-0318 Oslo, Norway.
   [Xi, Fengming] Chinese Acad Sci, CAS Key Lab Pollut Ecol & Environm Engn, Shenyang 110016, Peoples R China.
   [Liu, Junguo] Beijing Forestry Univ, Sch Nat Conservat, Beijing 10083, Peoples R China.
   [Liu, Junguo] Int Inst Appl Syst Anal, Ecosyst Serv & Management Program, A-2361 Laxenburg, Austria.
   [Liu, Junguo] South Univ Sci & Technol China, Sch Environm Sci & Engn, Shenzhen 518055, Peoples R China.
   [Zhao, Yu] Nanjing Univ, State Key Lab Pollut Control& Resource Reuse, Nanjing 210023, Jiangsu, Peoples R China.
   [Zhao, Yu] Nanjing Univ, Sch Environm, Nanjing 210023, Jiangsu, Peoples R China.
   [Zeng, Ning] Univ Maryland, Dept Atmospher & Ocean Sci, College Pk, MD 20742 USA.
   [Zeng, Ning] Univ Maryland, Earth Syst Sci Interdisciplinary Ctr, College Pk, MD 20742 USA.
   [Zeng, Ning] Chinese Acad Sci, Inst Atmospher Phys, Beijing 100029, Peoples R China.
C3 Harvard University; Chinese Academy of Sciences; Shenyang Institute of Applied Ecology, CAS; California Institute of Technology; Tsinghua University; University of East Anglia; Chinese Academy of Sciences; Shanghai Advanced Research Institute, CAS; University of California System; University of California Irvine; CEA; Universite Paris Saclay; Chinese Academy of Sciences; Institute of Coal Chemistry, CAS; Centre National de la Recherche Scientifique (CNRS); Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); University System of Maryland; University of Maryland College Park; University of North Carolina; Appalachian State University; United States Department of Energy (DOE); Oak Ridge National Laboratory; University of Cambridge; Peking University; Tsinghua University; Chinese Academy of Sciences; Beijing Forestry University; International Institute for Applied Systems Analysis (IIASA); Southern University of Science & Technology; Nanjing University; Nanjing University; University System of Maryland; University of Maryland College Park; University System of Maryland; University of Maryland College Park; Chinese Academy of Sciences; Institute of Atmospheric Physics, CAS
RP Liu, Z (corresponding author), Harvard Univ, John F Kennedy Sch Govt, Cambridge, MA 02138 USA.
EM liuzhu@iae.ac.cn; dabo.guan@uea.ac.uk; weiwei@sari.ac.cn; hekb@tsinghua.edu.cn
FU Chinese Academy of Sciences; China's National Basic Research Program; National Natural Science Foundation of China (NSFC) [XDA05010109, 2014CB441301, XDA05010110, XDA05010103, XDA05010101, 41328008, 41222036]; Italy's Ministry for Environment, Land and Sea; Economic and Social Research Council [ES/L016028]; Institute of Applied Ecology, Chinese Academy of Sciences; European Research Council [ERC-2013-SyG 610028-IMBALANCE-P]; US Department of Energy, Office of Science, Biological and Environmental Research under US Department of Energy [DE-AC05-00OR22725]; NSFC [41422502, 41175127, 41161140353, 91425303, 41473076]; International Science AMP; Technology Cooperation Program of China [2012DFA91530]; Natural Science Foundation of Beijing, China [8151002]; National Program for Support of Top-notch Young Professionals; Fundamental Research Funds for the Central Universities [TD-JC-2013-2]; China CDM Fund [2013051, 2013124]; Shenyang Science and Technology Planning [F14-232-6-01, F14-134-9-00]; Norwegian Research Council [235523]; Economic and Social Research Council [ES/L016028/1] Funding Source: researchfish; ESRC [ES/L016028/1] Funding Source: UKRI
NR 43
TC 1352
Z9 1574
U1 119
U2 2973
PU NATURE PUBLISHING 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 20
PY 2015
VL 524
IS 7565
BP 335
EP +
DI 10.1038/nature14677
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP2NN
UT WOS:000359714000032
PM 26289204
DA 2026-03-09
ER

PT J
AU Cheng, GL
   Tomczyk, M
   Lu, SC
   Veazey, JP
   Huang, MC
   Irvin, P
   Ryu, S
   Lee, H
   Eom, CB
   Hellberg, CS
   Levy, J
AF Cheng, Guanglei
   Tomczyk, Michelle
   Lu, Shicheng
   Veazey, Joshua P.
   Huang, Mengchen
   Irvin, Patrick
   Ryu, Sangwoo
   Lee, Hyungwoo
   Eom, Chang-Beom
   Hellberg, C. Stephen
   Levy, Jeremy
TI Electron pairing without superconductivity
SO NATURE
LA English
DT Article
ID field; gas; transition; polarons; systems; model; state
AB Strontium titanate (SrTiO3) is the first and best known superconducting semiconductor(1). It exhibits an extremely low carrier density threshold for superconductivity(2), and possesses a phase diagram similar to that of high-temperature superconductors(3,4)-two factors that suggest an unconventional pairing mechanism. Despite sustained interest for 50 years, direct experimental insight into the nature of electron pairing in SrTiO3 has remained elusive. Here we perform transport experiments with nanowire-based single-electron transistors at the interface between SrTiO3 and a thin layer of lanthanum aluminate, LaAlO3. Electrostatic gating reveals a series of two-electron conductance resonances-paired electron states-that bifurcate above a critical pairing field B-p of about 1-4 tesla, an order of magnitude larger than the superconducting critical magnetic field. For magnetic fields below B-p, these resonances are insensitive to the applied magnetic field; for fields in excess of B-p, the resonances exhibit a linear Zeeman-like energy splitting. Electron pairing is stable at temperatures as high as 900 millikelvin, well above the superconducting transition temperature (about 300 millikelvin). These experiments demonstrate the existence of a robust electronic phase in which electrons pair without forming a superconducting state. Key experimental signatures are captured by a model involving an attractive Hubbard interaction that describes real-space electron pairing as a precursor to superconductivity.
C1 [Cheng, Guanglei; Tomczyk, Michelle; Lu, Shicheng; Veazey, Joshua P.; Huang, Mengchen; Irvin, Patrick; Levy, Jeremy] Univ Pittsburgh, Dept Phys & Astron, Pittsburgh, PA 15260 USA.
   [Cheng, Guanglei; Tomczyk, Michelle; Lu, Shicheng; Huang, Mengchen; Irvin, Patrick; Levy, Jeremy] Pittsburgh Quantum Inst, Pittsburgh, PA 15260 USA.
   [Ryu, Sangwoo; Lee, Hyungwoo; Eom, Chang-Beom] Univ Wisconsin, Dept Mat Sci & Engn, Madison, WI 53706 USA.
   [Hellberg, C. Stephen] Naval Res Lab, Ctr Computat Mat Sci, Washington, DC 20375 USA.
C3 Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Wisconsin System; University of Wisconsin Madison; United States Department of Defense; United States Navy; United States Naval Research Laboratory
RP Levy, J (corresponding author), Univ Pittsburgh, Dept Phys & Astron, Pittsburgh, PA 15260 USA.
EM jlevy@pitt.edu
FU ARO MURI [W911NF-08-1-0317]; AFOSR MURI [FA9550-10-1-0524, FA9550-12-1-0342]; National Science Foundation [DMR-1104191, DMR-1124131, DMR-1234096]; Office of Naval Research through the Naval Research Laboratory's Basic Research Program; Division Of Materials Research; Direct For Mathematical & Physical Scien [1234096, 1124131] Funding Source: National Science Foundation
NR 56
TC 163
Z9 194
U1 1
U2 204
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 14
PY 2015
VL 521
IS 7551
BP 196
EP +
DI 10.1038/nature14398
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH9SY
UT WOS:000354377800053
PM 25971511
DA 2026-03-09
ER

PT J
AU Forslund, K
   Hildebrand, F
   Nielsen, T
   Falony, G
   Le Chatelier, E
   Sunagawa, S
   Prifti, E
   Vieira-Silva, S
   Gudmundsdottir, V
   Pedersen, HK
   Arumugam, M
   Kristiansen, K
   Voigt, AY
   Vestergaard, H
   Hercog, R
   Costea, PI
   Kultima, JR
   Li, JH
   Jorgensen, T
   Levenez, F
   Dore, J
   Nielsen, HB
   Brunak, S
   Raes, J
   Hansen, T
   Wang, J
   Ehrlich, SD
   Bork, P
   Pedersen, O
AF Forslund, Kristoffer
   Hildebrand, Falk
   Nielsen, Trine
   Falony, Gwen
   Le Chatelier, Emmanuelle
   Sunagawa, Shinichi
   Prifti, Edi
   Vieira-Silva, Sara
   Gudmundsdottir, Valborg
   Pedersen, Helle Krogh
   Arumugam, Manimozhiyan
   Kristiansen, Karsten
   Voigt, Anita Yvonne
   Vestergaard, Henrik
   Hercog, Rajna
   Costea, Paul Igor
   Kultima, Jens Roat
   Li, Junhua
   Jorgensen, Torben
   Levenez, Florence
   Dore, Joel
   Nielsen, H. Bjorn
   Brunak, Soren
   Raes, Jeroen
   Hansen, Torben
   Wang, Jun
   Ehrlich, S. Dusko
   Bork, Peer
   Pedersen, Oluf
TI Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota
SO NATURE
LA English
DT Article
ID sp-nov.; identification; clostridium; metagenome; genm; health; coli; life; rat
AB In recent years, several associations between common chronic human disorders and altered gut microbiome composition and function have been reported(1,2). In most of these reports, treatment regimens were not controlled for and conclusions could thus be confounded by the effects of various drugs on the microbiota, which may obscure microbial causes, protective factors or diagnostically relevant signals. Our study addresses disease and drug signatures in the human gut microbiome of type 2 diabetes mellitus (T2D). Two previous quantitative gut metagenomics studies of T2D patients that were unstratified for treatment yielded divergent conclusions regarding its associated gut microbial dysbiosis(3,4). Here we show, using 784 available human gut metagenomes, how antidiabetic medication confounds these results, and analyse in detail the effects of the most widely used antidiabetic drug metformin. We provide support for microbial mediation of the therapeutic effects of metformin through short-chain fatty acid production, as well as for potential microbiota-mediated mechanisms behind known intestinal adverse effects in the form of a relative increase in abundance of Escherichia species. Controlling for metformin treatment, we report a unified signature of gut microbiome shifts in T2D with a depletion of butyrate-producing taxa(3,4). These in turn cause functional microbiome shifts, in part alleviated by metformin-induced changes. Overall, the present study emphasizes the need to disentangle gut microbiota signatures of specific human diseases from those of medication.
C1 [Forslund, Kristoffer; Hildebrand, Falk; Sunagawa, Shinichi; Voigt, Anita Yvonne; Hercog, Rajna; Costea, Paul Igor; Kultima, Jens Roat; Bork, Peer] European Mol Biol Lab, Struct & Computat Biol Unit, D-69117 Heidelberg, Germany.
   [Hildebrand, Falk; Falony, Gwen; Vieira-Silva, Sara; Raes, Jeroen] Katholieke Univ Leuven, VIB Ctr Biol Dis, B-3000 Leuven, Belgium.
   [Hildebrand, Falk; Raes, Jeroen] Vrije Univ Brussel, Dept Biosci Engn, B-1040 Brussels, Belgium.
   [Nielsen, Trine; Arumugam, Manimozhiyan; Vestergaard, Henrik; Hansen, Torben; Pedersen, Oluf] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, DK-2200 Copenhagen, Denmark.
   [Falony, Gwen; Vieira-Silva, Sara; Raes, Jeroen] Katholieke Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, Lab Mol Bacteriol, B-3000 Leuven, Belgium.
   [Le Chatelier, Emmanuelle; Prifti, Edi; Levenez, Florence; Dore, Joel; Ehrlich, S. Dusko] INRA, MICALIS, F-78352 Jouy En Josas, France.
   [Le Chatelier, Emmanuelle; Prifti, Edi; Levenez, Florence; Dore, Joel; Ehrlich, S. Dusko] INRA, Metagenopolis, F-78352 Jouy En Josas, France.
   [Prifti, Edi] Inst Cardiometab & Nutr, F-75013 Paris, France.
   [Gudmundsdottir, Valborg; Pedersen, Helle Krogh; Nielsen, H. Bjorn; Brunak, Soren] Tech Univ Denmark, Ctr Biol Sequence Anal, Dept Syst Biol, DK-2800 Lyngby, Denmark.
   [Kristiansen, Karsten; Wang, Jun] Univ Copenhagen, Dept Biol, DK-2100 Copenhagen, Denmark.
   [Voigt, Anita Yvonne] Univ Heidelberg Hosp, Inst Pathol, Dept Appl Tumor Biol, D-69120 Heidelberg, Germany.
   [Voigt, Anita Yvonne; Bork, Peer] Heidelberg Univ, Mol Med Partnership Unit, D-69120 Heidelberg, Germany.
   [Voigt, Anita Yvonne; Bork, Peer] European Mol Biol Lab, D-69120 Heidelberg, Germany.
   [Li, Junhua; Wang, Jun] Bejing Genom Inst BGI Shenzhen, Shenzhen 518083, Peoples R China.
   [Jorgensen, Torben] Capital Reg Denmark, Res Ctr Prevent & Hlth, DK-2600 Glostrup, Denmark.
   [Jorgensen, Torben] Univ Copenhagen, Fac Hlth & Med Sci, Dept Publ Hlth, DK-2600 Copenhagen, Denmark.
   [Jorgensen, Torben] Aalborg Univ, Fac Med, DK-9100 Aalborg, Denmark.
   [Brunak, Soren] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Prot Res,Dis Syst Biol, DK-2200 Copenhagen, Denmark.
   [Hansen, Torben] Univ Southern Denmark, Fac Hlth Sci, DK-5000 Odense, Denmark.
   [Wang, Jun] King Abdulaziz Univ, Princess Al Jawhara Albrahim Ctr Excellence Res H, Jeddah 80205, Saudi Arabia.
   [Wang, Jun] Macau Univ Sci & Technol, Taipa, Macau, Peoples R China.
   [Wang, Jun] Univ Hong Kong, Dept Med, Hong Kong, Hong Kong, Peoples R China.
   [Wang, Jun] Univ Hong Kong, State Key Lab Pharmaceut Biotechnol, Hong Kong, Hong Kong, Peoples R China.
   [Ehrlich, S. Dusko] Kings Coll London, Guys Hosp, Dent Inst Cent Off, Ctr Host Microbiome Interact, London SE1 9RT, England.
   [Bork, Peer] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany.
   [Bork, Peer] Univ Wurzburg, Dept Bioinformat, D-97074 Wurzburg, Germany.
C3 European Molecular Biology Laboratory (EMBL); KU Leuven; Flanders Institute for Biotechnology (VIB); Vrije Universiteit Brussel; Novo Nordisk Foundation; University of Copenhagen; KU Leuven; Universite Paris Saclay; INRAE; AgroParisTech; INRAE; Universite Paris Saclay; Sorbonne Universite; Technical University of Denmark; University of Copenhagen; Ruprecht Karls University Heidelberg; Ruprecht Karls University Heidelberg; European Molecular Biology Laboratory (EMBL); Beijing Genomics Institute (BGI); University of Copenhagen; Aalborg University; University of Copenhagen; Novo Nordisk Foundation; University of Southern Denmark; King Abdulaziz University; Macau University of Science & Technology; University of Hong Kong; University of Hong Kong; University of London; King's College London; Guy's & St Thomas' NHS Foundation Trust; Helmholtz Association; Max Delbruck Center for Molecular Medicine; University of Wurzburg
RP Ehrlich, SD (corresponding author), INRA, MICALIS, F-78352 Jouy En Josas, France.
EM dusko.ehrlich@jouy.inra.fr; bork@embl.de; oluf@sund.ku.dk
FU European Community [HEALTH-F4-2007-201052, HEALTH-2012-305312, HEALTH-2010-261376]; Metagenopolis grant [ANR-11-DPBS-0001]; European Research Council [268985]; European Union [600375]; Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (LuCamp); Novo Nordisk Foundation [NNF14CC0001]; European Molecular Biology Laboratory (EMBL); Novo Nordisk Foundation; Innovation Fund Denmark through the MicrobDiab project; European Research Council (ERC) [268985] Funding Source: European Research Council (ERC); NNF Center for Basic Metabolic Research [Arumugam Group, Hansen Group] Funding Source: researchfish
NR 52
TC 1658
Z9 1910
U1 9
U2 706
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 10
PY 2015
VL 528
IS 7581
BP 262
EP +
DI 10.1038/nature15766
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX9VH
UT WOS:000366053300041
PM 26633628
DA 2026-03-09
ER

PT J
AU Lelieveld, J
   Evans, JS
   Fnais, M
   Giannadaki, D
   Pozzer, A
AF Lelieveld, J.
   Evans, J. S.
   Fnais, M.
   Giannadaki, D.
   Pozzer, A.
TI The contribution of outdoor air pollution sources to premature mortality on a global scale
SO NATURE
LA English
DT Article
ID fine particulate matter; circulation model echam5/messy1; atmospheric chemistry; technical note; climate-change; human health; burden; emissions; submodel; disease
AB Assessment of the global burden of disease is based on epidemiological cohort studies that connect premature mortality to a wide range of causes(1-5), including the long-term health impacts of ozone and fine particulate matter with a diameter smaller than 2.5 micrometres (PM2.5)(3-9). It has proved difficult to quantify premature mortality related to air pollution, notably in regions where air quality is not monitored, and also because the toxicity of particles from various sources may vary(10). Here we use a global atmospheric chemistry model to investigate the link between prematuremortality and seven emission source categories in urban and rural environments. In accord with the global burden of disease for 2010 (ref. 5), we calculate that outdoor air pollution, mostly by PM2.5, leads to 3.3 (95 per cent confidence interval 1.61-4.81) million premature deaths per year worldwide, predominantly in Asia. We primarily assume that all particles are equally toxic(5), but also include a sensitivity study that accounts for differential toxicity. We find that emissions from residential energy use such as heating and cooking, prevalent in India and China, have the largest impact on premature mortality globally, being even more dominant if carbonaceous particles are assumed to be most toxic. Whereas in much of the USA and in a few other countries emissions from traffic and power generation are important, in eastern USA, Europe, Russia and East Asia agricultural emissions make the largest relative contribution to PM2.5, with the estimate of overall health impact depending on assumptions regarding particle toxicity. Model projections based on a business-as-usual emission scenario indicate that the contribution of outdoor air pollution to premature mortality could double by 2050.
C1 [Lelieveld, J.; Pozzer, A.] Max Planck Inst Chem, Atmospher Chem Dept, D-55128 Mainz, Germany.
   [Lelieveld, J.; Giannadaki, D.] Cyprus Inst, Energy Environm & Water Res Ctr, CY-1645 Nicosia, Cyprus.
   [Evans, J. S.] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA.
   [Evans, J. S.] Cyprus Univ Technol, Cyprus Int Inst Environm & Publ Hlth, CY-3041 Limassol, Cyprus.
   [Fnais, M.] King Saud Univ, Coll Sci, Riyadh 11451, Saudi Arabia.
C3 Max Planck Society; Harvard University; Harvard T.H. Chan School of Public Health; Cyprus University of Technology; Cyprus International Institute for Environmental & Public Health; King Saud University
RP Lelieveld, J (corresponding author), Max Planck Inst Chem, Atmospher Chem Dept, D-55128 Mainz, Germany.
EM jos.lelieveld@mpic.de
FU Distinguished Scientist Fellowship Program at the King Saud University, Riyadh; European Research Council under European Union/ERC [226144]
NR 73
TC 4431
Z9 5102
U1 92
U2 3633
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 17
PY 2015
VL 525
IS 7569
BP 367
EP +
DI 10.1038/nature15371
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900041
PM 26381985
DA 2026-03-09
ER

PT J
AU Ohto, U
   Shibata, T
   Tanji, H
   Ishida, H
   Krayukhina, E
   Uchiyama, S
   Miyake, K
   Shimizu, T
AF Ohto, Umeharu
   Shibata, Takuma
   Tanji, Hiromi
   Ishida, Hanako
   Krayukhina, Elena
   Uchiyama, Susumu
   Miyake, Kensuke
   Shimizu, Toshiyuki
TI Structural basis of CpG and inhibitory DNA recognition by Toll-like receptor 9
SO NATURE
LA English
DT Article
ID hemi-methylated dna; bacterial-dna; sra domain; human tlr9; binding; activation; protein; uhrf1
AB Innate immunity serves as the first line of defence against invading pathogens such as bacteria and viruses'. Toll-like receptors (TLRs) are examples of innate immune receptors, which sense specific molecular patterns from pathogens and activate immune responses'. TLR9 recognizes bacterial and viral DNA containing the cytosinephosphate-guanine (CpG) dideoxynucleotide moth". The molecular basis by which CpG-containing DNA (CpG-DNA) elicits immunostimulatory activity via TLR9 remains to be elucidated. Here we show the crystal structures of three forms of TLR9: unliganded, bound to agonistic CpG-DNA, and bound to inhibitory DNA (iDNA). AgonisticCpG-DNA-bound TLR9 formed a symmetric TLR9-CpG-DNA complex with 2:2 stoichiometry, whereas iDNA-bound TLR9 was a monomer. CpG-DNA was recognized by both protomers in the dimer, in particular by the amino-terminal fragment (LRRNT-LRR10) from one protomer and the carboxy-terminal fragment (LRR2O-LRR22) from the other. The iDNA, which formed a stem-loop structure suitable for binding by intramolecular base pairing, bound to the concave surface from LRR2-LRR 1 O. This structure serves as an important basis for improving our understanding of the functional mechanisms of TLR9.
C1 [Ohto, Umeharu; Tanji, Hiromi; Ishida, Hanako; Shimizu, Toshiyuki] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan.
   [Shibata, Takuma; Miyake, Kensuke] Univ Tokyo, Dept Microbiol & Immunol, Ctr Expt Med & Syst Biol, Div Innate Immun,Lab Innate Immun,Inst Med Sci,Mi, Tokyo 1088639, Japan.
   [Shibata, Takuma; Shimizu, Toshiyuki] Japan Sci & Technol Agcy JST, CREST, Kawaguchi, Saitama 3320012, Japan.
   [Krayukhina, Elena; Uchiyama, Susumu] Osaka Univ, Grad Sch Engn, Suita, Osaka 5650871, Japan.
   [Krayukhina, Elena] U Med Corp, Suita, Osaka 5650871, Japan.
C3 University of Tokyo; University of Tokyo; Japan Science & Technology Agency (JST); University of Osaka
RP Shimizu, T (corresponding author), Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan.
EM shimizu@mol.f.u-tokyo.ac.jp
FU Japanese Ministry of Education, Culture, Sports, Science, and Technology; JSPS Japanese-German Graduate Externship; Senri-Life Science Foundation; Takeda Science Foundation; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Grants-in-Aid for Scientific Research [26102530, 25253032] Funding Source: KAKEN
NR 34
TC 316
Z9 368
U1 1
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 APR 30
PY 2015
VL 520
IS 7549
BP 702
EP U303
DI 10.1038/nature14138
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700055
PM 25686612
DA 2026-03-09
ER

PT J
AU Kaina, N
   Lemoult, F
   Fink, M
   Lerosey, G
AF Kaina, Nadege
   Lemoult, Fabrice
   Fink, Mathias
   Lerosey, Geoffroy
TI Negative refractive index and acoustic superlens from multiple scattering in single negative metamaterials
SO NATURE
LA English
DT Article
ID symmetry-breaking; waves
AB Metamaterials, man-made composite media structured on a scale much smaller than a wavelength, offer surprising possibilities for engineering the propagation of waves(1-6). One of the most interesting of these is the ability to achieve superlensing-that is, to focus or image beyond the diffraction limit(7). This originates from the left-handed behaviour-the property of refracting waves negatively-that is typical of negative index metamaterials(8-10). Yet reaching this goal requires the design of 'double negative' metamaterials, which act simultaneously on the permittivity and permeability in electromagnetics(11,12), or on the density and compressibility in acoustics; this generally implies the use of two different kinds of building blocks(13,14) or specific particles presenting multiple overlapping resonances(15-17). Such a requirement limits the applicability of double negative metamaterials, and has, for example, hampered any demonstration of subwavelength focusing using left-handed acoustic metamaterials(18). Here we show that these strict conditions can be largely relaxed by relying on media that consist of only one type of single resonant unit cell. Specifically, we show with a simple yet general semi-analytical model that judiciously breaking the symmetry of a single negative metamaterial is sufficient to turn it into a double negative one. We then demonstrate that this occurs solely because of multiple scattering of waves off the metamaterial resonant elements, a phenomenon often disregarded in these media owing to their subwavelength patterning. We apply our approach to acoustics and verify through numerical simulations that it allows the realization of negative index acoustic metamaterials based on Helmholtz resonators only. Finally, we demonstrate the operation of a negative index acoustic superlens, achieving subwavelength focusing and imaging with spot width and resolution 7 and 3.5 times better than the diffraction limit, respectively. Our findings have profound implications for the physics of metamaterials, highlighting the role of their subwavelength crystalline structure, and hence entering the realm of metamaterial crystals. This widens the scope of possibilities for designing composite media with novel properties in a much simpler way than has been possible so far.
C1 [Kaina, Nadege; Lemoult, Fabrice; Fink, Mathias; Lerosey, Geoffroy] ESPCI ParisTech, Inst Langevin, F-75005 Paris, France.
   [Kaina, Nadege; Lemoult, Fabrice; Fink, Mathias; Lerosey, Geoffroy] CNRS, UMR 7587, F-75005 Paris, France.
C3 Universite PSL; Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI); Universite Paris Cite; Universite Paris Cite; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute for Engineering & Systems Sciences (INSIS)
RP Lerosey, G (corresponding author), ESPCI ParisTech, Inst Langevin, 1 Rue Jussieu, F-75005 Paris, France.
EM geoffroy.lerosey@espci.fr
FU LABEX WIFI (Laboratory of Excellence within the French Program "Investments for the Future") [ANR-10-LABX-24, ANR-10-IDEX-0001-02 PSL*]; Agence Nationale de la Recherche [ANR-13-JS09-0001-01]; French "Direction Generale de l'Armement"; Agence Nationale de la Recherche (ANR) [ANR-13-JS09-0001] Funding Source: Agence Nationale de la Recherche (ANR)
NR 34
TC 577
Z9 637
U1 23
U2 711
PU NATURE PUBLISHING 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 3
PY 2015
VL 525
IS 7567
BP 77
EP +
DI 10.1038/nature14678
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100028
PM 26333466
DA 2026-03-09
ER

PT J
AU Louveau, A
   Smirnov, I
   Keyes, TJ
   Eccles, JD
   Rouhani, SJ
   Peske, JD
   Derecki, NC
   Castle, D
   Mandell, JW
   Lee, KS
   Harris, TH
   Kipnis, J
AF Louveau, Antoine
   Smirnov, Igor
   Keyes, Timothy J.
   Eccles, Jacob D.
   Rouhani, Sherin J.
   Peske, J. David
   Derecki, Noel C.
   Castle, David
   Mandell, James W.
   Lee, Kevin S.
   Harris, Tajie H.
   Kipnis, Jonathan
TI Structural and functional features of central nervous system lymphatic vessels
SO NATURE
LA English
DT Article
ID cerebrospinal-fluid; cervical lymph; vasculature; drainage; brain; trafficking; health; sites; cells; cns
AB One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment(1-3), the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood(4-6). In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
C1 [Louveau, Antoine; Smirnov, Igor; Keyes, Timothy J.; Derecki, Noel C.; Lee, Kevin S.; Harris, Tajie H.; Kipnis, Jonathan] Univ Virginia, Sch Med, Ctr Brain Immunol & Glia, Charlottesville, VA 22908 USA.
   [Louveau, Antoine; Smirnov, Igor; Keyes, Timothy J.; Derecki, Noel C.; Lee, Kevin S.; Harris, Tajie H.; Kipnis, Jonathan] Univ Virginia, Sch Med, Dept Neurosci, Charlottesville, VA 22908 USA.
   [Eccles, Jacob D.; Rouhani, Sherin J.; Peske, J. David; Kipnis, Jonathan] Univ Virginia, Sch Med, Med Scientist Training Program, Charlottesville, VA 22908 USA.
   [Eccles, Jacob D.; Rouhani, Sherin J.; Peske, J. David] Univ Virginia, Sch Med, Beirne B Carter Ctr Immunol Res, Charlottesville, VA 22908 USA.
   [Eccles, Jacob D.] Univ Virginia, Sch Med, Dept Med, Div Allergy, Charlottesville, VA 22908 USA.
   [Rouhani, Sherin J.; Peske, J. David] Univ Virginia, Sch Med, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA 22908 USA.
   [Castle, David] Univ Virginia, Sch Med, Dept Cell Biol, Charlottesville, VA 22908 USA.
   [Mandell, James W.] Univ Virginia, Sch Med, Dept Pathol Neuropathol, Charlottesville, VA 22908 USA.
   [Lee, Kevin S.] Univ Virginia, Sch Med, Dept Neurosurg, Charlottesville, VA 22908 USA.
C3 University of Virginia; University of Virginia; University of Virginia; University of Virginia; University of Virginia; University of Virginia; University of Virginia; University of Virginia; University of Virginia
RP Louveau, A (corresponding author), Univ Virginia, Sch Med, Ctr Brain Immunol & Glia, Charlottesville, VA 22908 USA.
EM al2hk@virginia.edu; kipnis@virginia.edu
FU Fondation pour la Recherche Medicale; National Institutes of Health [R01AG034113, R01NS061973]; National Cancer Institute [P30CA044579] Funding Source: NIH RePORTER
NR 30
TC 3298
Z9 3946
U1 25
U2 623
PU NATURE PUBLISHING 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 16
PY 2015
VL 523
IS 7560
BP 337
EP +
DI 10.1038/nature14432
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM8KY
UT WOS:000357950900040
PM 26030524
DA 2026-03-09
ER

PT J
AU Obenauf, AC
   Zou, YL
   Ji, AL
   Vanharanta, S
   Shu, WP
   Shi, HB
   Kong, XJ
   Bosenberg, MC
   Wiesner, T
   Rosen, N
   Lo, RS
   Massague, J
AF Obenauf, Anna C.
   Zou, Yilong
   Ji, Andrew L.
   Vanharanta, Sakari
   Shu, Weiping
   Shi, Hubing
   Kong, Xiangju
   Bosenberg, Marcus C.
   Wiesner, Thomas
   Rosen, Neal
   Lo, Roger S.
   Massague, Joan
TI Therapy-induced tumour secretomes promote resistance and tumour progression
SO NATURE
LA English
DT Article
ID translational profiling approach; acquired-resistance; drug-resistance; raf inhibitors; melanoma; survival; evolution
AB Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer(1,2). Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafenib is driven by down-regulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and the PI(3) K/AKT/mTOR intracellular signalling pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant human melanoma, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy.
C1 [Obenauf, Anna C.; Zou, Yilong; Ji, Andrew L.; Vanharanta, Sakari; Shu, Weiping; Massague, Joan] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA.
   [Zou, Yilong] Mem Sloan Kettering Canc Ctr, Gerstner Sloan Kettering Sch Biomed Sci, New York, NY 10065 USA.
   [Vanharanta, Sakari] Univ Cambridge, MRC Canc Unit, Cambridge CB2 0XZ, England.
   [Shi, Hubing; Kong, Xiangju; Lo, Roger S.] Univ Calif Los Angeles, Dept Med, Div Dermatol, Los Angeles, CA 90095 USA.
   [Shi, Hubing; Kong, Xiangju; Lo, Roger S.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA.
   [Bosenberg, Marcus C.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA.
   [Bosenberg, Marcus C.] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06520 USA.
   [Wiesner, Thomas] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA.
   [Rosen, Neal] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA.
C3 Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; University of Cambridge; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; UCLA Jonsson Comprehensive Cancer Center; Yale University; Yale University; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center
RP Massague, J (corresponding author), Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA.
EM j-massague@ski.mskcc.org
FU AACR [SU2C]; MSK Metastasis Research Center; NIH [CA163167, CA129243]; Congressionally Directed Medical Research Program of the Department of Defense; Howard Hughes Medical Institute; Cancer Center [P30 CA008748]; Erwin Schroedinger Fellowship (FWF, Austrian Science Fund) [J3013]; Medical Research Council; National Cancer Institute [R01CA176111, P30CA008748, P01CA129243, P30CA016042] Funding Source: NIH RePORTER; Austrian Science Fund (FWF) [J3013] Funding Source: Austrian Science Fund (FWF); Medical Research Council [MC_UP_1101/4, MC_UU_12022/7] Funding Source: researchfish; MRC [MC_UU_12022/7] Funding Source: UKRI
NR 38
TC 397
Z9 466
U1 0
U2 152
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 16
PY 2015
VL 520
IS 7547
BP 368
EP +
DI 10.1038/nature14336
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG0RI
UT WOS:000352974200043
PM 25807485
DA 2026-03-09
ER

PT J
AU Plaschka, C
   Larivière, L
   Wenzeck, L
   Seizl, M
   Hemann, M
   Tegunov, D
   Petrotchenko, EV
   Borchers, CH
   Baumeister, W
   Herzog, F
   Villa, E
   Cramer, P
AF Plaschka, C.
   Lariviere, L.
   Wenzeck, L.
   Seizl, M.
   Hemann, M.
   Tegunov, D.
   Petrotchenko, E. V.
   Borchers, C. H.
   Baumeister, W.
   Herzog, F.
   Villa, E.
   Cramer, P.
TI Architecture of the RNA polymerase II-Mediator core initiation complex
SO NATURE
LA English
DT Article
ID chemical cross-linking; transcription initiation; structural basis; preinitiation complex; head module; tata-box; protein; recruitment; subcomplex; reveals
AB The conserved co-activator complex Mediator enables regulated transcription irntiation by RNA polymerase (Pol) II. Here we reconstitute an active 15-subunit core Mediator (cMed) comprising all essential Mediator subunits from Saccharomyces erevisiae. The cryo-electron microscopic structure of cMed bound to a core initiation complex was determined at 9.7 A resolution. cMed binds Pol II around the Rpb4-Rpb7 stalk near the carboxy-terminal domain (CTD). The Mediator head module binds the Pol II dock and the TFIIB ribbon and stabilizes the initiation complex. The Mediator middle module extends to the Fol II foot with a 'plank' that may influence polymerase conformation. The Mediator subunit Medl4 forms a 'beam' between the head and middle modules and connects to the tail module that is predicted to bind transcription activators located on upstream DNA. The Mediator 'arm' and 'hook' domains contribute to a 'cradle' that may position the CTD and TFIIH kinase to stimulate Pol II phosphorylation.
C1 [Plaschka, C.; Cramer, P.] Max Planck Inst Biophys Chem, Dept Mol Biol, D-37077 Gottingen, Germany.
   [Lariviere, L.; Wenzeck, L.; Seizl, M.; Hemann, M.; Herzog, F.] Univ Munich, Gene Ctr, D-81377 Munich, Germany.
   [Lariviere, L.; Wenzeck, L.; Seizl, M.; Hemann, M.; Herzog, F.] Univ Munich, Dept Biochem, D-81377 Munich, Germany.
   [Tegunov, D.; Baumeister, W.; Villa, E.] Max Planck Inst Biochem, D-82152 Martinsried, Germany.
   [Petrotchenko, E. V.; Borchers, C. H.] Univ Victoria, Dept Biochem & Microbiol, Genome British Columbia Prot Ctr, Victoria, BC V8Z7X8, Canada.
   [Villa, E.] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA.
C3 Max Planck Society; University of Munich; University of Munich; Max Planck Society; University of Victoria; University of California System; University of California San Diego
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 Boehringer Ingelheim fellowship; Elite Network of Bavaria; Genome Canada; Genome British Columbia Science and Technology Innovation Centre; Natural Sciences and Engineering Research Council of Canada; LMUexcellent initiative; Bavarian Research Center of Molecular Biosystems; Deutsche Forschungsgemeinschaft [GRK1721, SFB646]; European Research Council Advanced Grant TRANSIT; Jung-Stiftung; Volkswagen Foundation
NR 87
TC 245
Z9 289
U1 2
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 FEB 19
PY 2015
VL 518
IS 7539
BP 376
EP 380
DI 10.1038/nature14229
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400037
PM 25652824
DA 2026-03-09
ER

PT J
AU Sammut, M
   Cook, SJ
   Nguyen, KCQ
   Felton, T
   Hall, DH
   Emmons, SW
   Poole, RJ
   Barrios, A
AF Sammut, Michele
   Cook, Steven J.
   Nguyen, Ken C. Q.
   Felton, Terry
   Hall, David H.
   Emmons, Scott W.
   Poole, Richard J.
   Barrios, Arantza
TI Glia-derived neurons are required for sex-specific learning in C. elegans
SO NATURE
LA English
DT Article
ID nematode caenorhabditis-elegans; mate-searching behavior; gene-expression; nervous-system; fate specification; cells; drosophila; transdifferentiation; reconstruction; circuit
AB Sex differences in behaviour extend to cognitive-like processes such as learning, but the underlying dimorphisms in neural circuit development and organization that generate these behavioural differences are largely unknown. Here we define at the single-cell level-from development, through neural circuit connectivity, to function-the neural basis of a sex-specific learning in the nematode Caenorhabditis elegans. We show that sexual conditioning, a form of associative learning, requires a pair of male-specific interneurons whose progenitors are fully differentiated glia. These neurons are generated during sexual maturation and incorporated into pre-exisiting sex-shared circuits to couple chemotactic responses to reproductive priorities. Our findings reveal a general role for glia as neural progenitors across metazoan taxa and demonstrate that the addition of sex-specific neuron types to brain circuits during sexual maturation is an important mechanism for the generation of sexually dimorphic plasticity in learning.
C1 [Sammut, Michele; Felton, Terry; Poole, Richard J.; Barrios, Arantza] UCL, Dept Cell & Dev Biol, London WC1E 6BT, England.
   [Cook, Steven J.; Nguyen, Ken C. Q.; Hall, David H.; Emmons, Scott W.] Yeshiva Univ Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Bronx, NY 10461 USA.
   [Emmons, Scott W.] Yeshiva Univ Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA.
C3 University of London; University College London; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine
RP Barrios, A (corresponding author), UCL, Dept Cell & Dev Biol, Mortimer St, London WC1E 6BT, England.
EM r.poole@ucl.ac.uk; a.barrios@ucl.ac.uk
FU NIH [P40 OD010440, OD010943, 5T32GM007491]; Master it! Scholarship (Malta); Master it! Scholarship (EU); Marie Curie CIG grant [618779]; G. Harold and Leila Y. Mathers Charitable Foundation; Wellcome Trust [097815/Z/11/A]; National Institute of General Medical Sciences [T32GM007491] 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; Wellcome Trust [097815/Z/11/A] Funding Source: Wellcome Trust
NR 70
TC 103
Z9 128
U1 0
U2 63
PU NATURE PUBLISHING 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 15
PY 2015
VL 526
IS 7573
BP 385
EP +
DI 10.1038/nature15700
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200042
PM 26469050
DA 2026-03-09
ER

PT J
AU Feinberg, EH
   Meister, M
AF Feinberg, Evan H.
   Meister, Markus
TI Orientation columns in the mouse superior colliculus
SO NATURE
LA English
DT Article
ID monkey striate cortex; visual-cortex; functional architecture; additional observations; electrical-stimulation; cellular resolution; receptive-fields; neural activity; mice lacking; organization
AB More than twenty types of retinal ganglion cells conduct visual information from the eye to the rest of the brain(1,2). Each retinal ganglion cell type tessellates the retina in a regular mosaic, so that every point in visual space is processed for visual primitives such as contrast and motion(3). This information flows to two principal brain centres: the visual cortex and the superior colliculus. The superior colliculus plays an evolutionarily conserved role in visual behaviours(4), but its functional architecture is poorly understood. Here we report on population recordings of visual responses from neurons in the mouse superior colliculus. Many neurons respond preferentially to lines of a certain orientation or movement axis. We show that cells with similar orientation preferences form large patches that span the vertical thickness of the retinorecipient layers. This organization is strikingly different from the randomly interspersed orientation preferences in the mouse's visual cortex(5); instead, it resembles the orientation columns observed in the visual cortices of large mammals(6-8). Notably, adjacent superior colliculus orientation columns have only limited receptive field overlap. This is in contrast to the organization of visual cortex, where each point in the visual field activates neurons with all preferred orientations(9). Instead, the superior colliculus favours specific contour orientations within similar to 30 degrees regions of the visual field, a finding with implications for behavioural responses mediated by this brain centre.
C1 [Feinberg, Evan H.; Meister, Markus] Harvard Univ, Dept Mol & Cellular Biol, Ctr Brain Sci, Cambridge, MA 02138 USA.
   [Meister, Markus] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
C3 Harvard University; California Institute of Technology
RP Meister, M (corresponding author), Harvard Univ, Dept Mol & Cellular Biol, Ctr Brain Sci, 52 Oxford St, Cambridge, MA 02138 USA.
EM evan_feinberg@post.harvard.edu; meister@caltech.edu
FU NIH [T32 NS007484]; Howard Hughes Medical Institute-Helen Hay Whitney Foundation fellowship; NIH
NR 40
TC 98
Z9 111
U1 0
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 MAR 12
PY 2015
VL 519
IS 7542
BP 229
EP +
DI 10.1038/nature14103
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500038
PM 25517100
DA 2026-03-09
ER

PT J
AU Berkovits, BD
   Mayr, C
AF Berkovits, Binyamin D.
   Mayr, Christine
TI Alternative 3′ UTRs act as scaffolds to regulate membrane protein localization
SO NATURE
LA English
DT Article
ID rna-binding proteins; messenger-rna; in-vivo; gtp-binding; set protein; cell; hur; cd47; sites; immunoprecipitation
AB About half of human genes use alternative cleavage and polyadenylation (ApA) to generate messenger RNA transcripts that differ in the length of their 3' untranslated regions (3' UTRs) while producing the same protein(1-3). Here we show in human cell lines that alternative 3' UTRs differentially regulate the localization of membrane proteins. The long 3' UTR of CD47 enables efficient cell surface expression of CD47 protein, whereas the short 3' UTR primarily localizes CD47 protein to the endoplasmic reticulum. CD47 protein localization occurs post-translationally and independently of RNA localization. In our model of 3' UTR-dependent protein localization, the long 3' UTR of CD47 acts as a scaffold to recruit a protein complex containing the RNA-binding protein HuR (also known as ELAVL1) and SET4 to the site of translation. This facilitates interaction of SET with the newly translated cytoplasmic domains of CD47 and results in subsequent translocation of CD47 to the plasma membrane via activated RAC1 (ref. 5). We also show that CD47 protein has different functions depending on whether it was generated by the short or long 3' UTR isoforms. Thus, ApA contributes to the functional diversity of the proteome without changing the amino acid sequence. 3' UTR-dependent protein localization has the potential to be a widespread trafficking mechanism for membrane proteins because HuR binds to thousands of mRNAs(6-9), and we show that the long 3' UTRs of CD44, ITGA1 and TNFRSF13C, which are bound by HuR, increase surface protein expression compared to their corresponding short 3' UTRs. We propose that during translation the scaffold function of 3' UTRs facilitates binding of proteins to nascent proteins to direct their transport or function-and this role of 3' UTRs can be regulated by ApA.
C1 [Berkovits, Binyamin D.; Mayr, Christine] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA.
C3 Memorial Sloan Kettering Cancer Center
RP Mayr, C (corresponding author), Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, 1275 York Ave, New York, NY 10065 USA.
EM mayrc@mskcc.org
FU Damon Runyon-Rachleff Cancer Foundation; Island Outreach Foundation [DRR-24-13]; National Institutes of Health [U01-CA164190];  [P30 CA008748]; National Cancer Institute [P30CA008748] Funding Source: NIH RePORTER
NR 40
TC 371
Z9 479
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 JUN 18
PY 2015
VL 522
IS 7556
BP 363
EP +
DI 10.1038/nature14321
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK7PU
UT WOS:000356425400058
PM 25896326
DA 2026-03-09
ER

PT J
AU Granger, DE
   Gibbon, RJ
   Kuman, K
   Clarke, RJ
   Bruxelles, L
   Caffee, MW
AF Granger, Darryl E.
   Gibbon, Ryan J.
   Kuman, Kathleen
   Clarke, Ronald J.
   Bruxelles, Laurent
   Caffee, Marc W.
TI New cosmogenic burial ages for Sterkfontein Member 2 Australopithecus and Member 5 Oldowan
SO NATURE
LA English
DT Article
ID south-africa; hominid; skeleton; stratigraphy
AB The cave infills at Sterkfontein contain one of the richest assemblages of Australopithecus fossils in the world, including the nearly complete skeleton StW 573 ('Little Foot')(1-4) in its lower section, as well as early stone tools(5-7) in higher sections. However, the chronology of the site remains controversial(8-14) owing to the complex history of cave infilling. Much of the existing chronology based on uranium-lead dating(10,11) and palaeomagnetic stratigraphy(8,12) has recently been called into question by the recognition that dated flowstones fill cavities formed within previously cemented breccias and therefore do not form a stratigraphic sequence(4,14). Earlier dating with cosmogenic nuclides(9) suffered a high degree of uncertainty and has been questioned on grounds of sediment reworking(10,11,13). Here we use isochron burial dating with cosmogenic aluminium-26 and beryllium-10 to show that the breccia containing StW 573 did not undergo significant reworking, and that it was deposited 3.67 +/- 0.16 million years ago, far earlier than the 2.2 million year flowstones found within it(10,11). The skeleton is thus coeval with early Australopithecus afar-ensis in eastern Africa(15,16). We also date the earliest stone tools at Sterkfontein to 2.18 +/- 0.21 million years ago, placing them in the Oldowan at a time similar to that found elsewhere in South Africa at Swartkans(17) and Wonderwerk(18).
C1 [Granger, Darryl E.; Caffee, Marc W.] Purdue Univ, Dept Earth Atmospher & Planetary Sci, W Lafayette, IN 47907 USA.
   [Gibbon, Ryan J.] Univ New Brunswick, Dept Anthropol, Fredericton, NB E3B 5A3, Canada.
   [Kuman, Kathleen; Clarke, Ronald J.] Univ Witwatersrand, Evolutionary Studies Inst, ZA-2050 Johannesburg, South Africa.
   [Kuman, Kathleen; Bruxelles, Laurent] Univ Witwatersrand, Sch Geog Archaeol & Environm Studies, ZA-2050 Johannesburg, South Africa.
   [Bruxelles, Laurent] French Natl Inst Prevent Archaeol Res Inrap, F-30900 Nimes, France.
   [Bruxelles, Laurent] Univ Toulouse Jean Jaures, UMR 5608, CNRS, TRACES,Maison Rech, F-31058 Toulouse, France.
   [Caffee, Marc W.] Purdue Univ, Dept Phys & Astron, W Lafayette, IN 47907 USA.
C3 Purdue University System; Purdue University; University of New Brunswick; University of Witwatersrand; University of Witwatersrand; Universite de Toulouse; Universite de Toulouse - Jean Jaures; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Ecology & Environment (INEE); Purdue University System; Purdue University
RP Granger, DE (corresponding author), Purdue Univ, Dept Earth Atmospher & Planetary Sci, W Lafayette, IN 47907 USA.
EM dgranger@purdue.edu
FU National Science Foundation [EAR1153689, EAR0844151]; Palaeontological Scientific Trust (PAST); National Research Foundation (NRF) of South Africa; NRF (SA) [AOP1207112551-82611, AOP1207173196-82591]; Directorate For Geosciences; Division Of Earth Sciences [1153689] Funding Source: National Science Foundation
CR Balco G, 2013, QUAT GEOCHRONOL, V18, P149, DOI 10.1016/j.quageo.2013.02.002
   Balco G, 2008, AM J SCI, V308, P1083, DOI 10.2475/10.2008.02
   Bruxelles L, 2014, J HUM EVOL, V70, P36, DOI 10.1016/j.jhevol.2014.02.014
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   Walker J, 2006, SCIENCE, V314, P1592, DOI 10.1126/science.1132916
NR 30
TC 190
Z9 235
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 JUN 4
PY 2015
VL 522
IS 7554
BP 85
EP U200
DI 10.1038/nature14268
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ5QP
UT WOS:000355543400034
PM 25830884
DA 2026-03-09
ER

PT J
AU Barson, NJ
   Aykanat, T
   Hindar, K
   Baranski, M
   Bolstad, GH
   Fiske, P
   Jacq, C
   Jensen, AJ
   Johnston, SE
   Karlsson, S
   Kent, M
   Oen, TM
   Niemelä, E
   Nome, T
   Næsje, TF
   Orell, P
   Romakkaniemi, A
   Sægrov, H
   Urdal, K
   Erkinaro, J
   Lien, S
   Primmer, CR
AF Barson, Nicola J.
   Aykanat, Tutku
   Hindar, Kjetil
   Baranski, Matthew
   Bolstad, Geir H.
   Fiske, Peder
   Jacq, Celeste
   Jensen, Arne J.
   Johnston, Susan E.
   Karlsson, Sten
   Kent, Matthew
   Oen, Thomas M.
   Niemelae, Eero
   Nome, Torfinn
   Naesje, Tor F.
   Orell, Panu
   Romakkaniemi, Atso
   Saegrov, Harald
   Urdal, Kurt
   Erkinaro, Jaakko
   Lien, Sigbjorn
   Primmer, Craig R.
TI Sex-dependent dominance at a single locus maintains variation in age at maturity in salmon
SO NATURE
LA English
DT Article
ID life-history variation; atlantic salmon; balancing selection; growth-rate; genome; population; adaptation; divergence; evolution; reveals
AB Males and females share many traits that have a common genetic basis; however, selection on these traits often differs between the sexes, leading to sexual conflict(1,2). Under such sexual antagonism, theory predicts the evolution of genetic architectures that resolve this sexual conflict(2-5). Yet, despite intense theoretical and empirical interest, the specific loci underlying sexually antagonistic phenotypes have rarely been identified, limiting our understanding of how sexual conflict impacts genome evolution(3,6) and the maintenance of genetic diversity(6,7). Here we identify a large effect locus controlling age at maturity in Atlantic salmon (Salmo salar), an important fitness trait in which selection favours earlier maturation in males than females(8), and show it is a clear example of sex-dependent dominance that reduces intralocus sexual conflict and maintains adaptive variation in wild populations. Using high-density single nucleotide polymorphism data across 57 wild populations and whole genome re-sequencing, we find that the vestigial-like family member 3 gene (VGLL3) exhibits sex-dependent dominance in salmon, promoting earlier and later maturation in males and females, respectively. VGLL3, an adiposity regulator associated with size and age at maturity in humans, explained 39% of phenotypic variation, an unexpectedly large proportion for what is usually considered a highly polygenic trait. Such large effects are predicted under balancing selection from either sexually antagonistic or spatially varying selection(9,10). Our results provide the first empirical example of dominance reversal allowing greater optimization of phenotypes within each sex, contributing to the resolution of sexual conflict in a major and widespread evolutionary trade-off between age and size at maturity. They also provide key empirical evidence for how variation in reproductive strategies can be maintained over large geographical scales. We anticipate these findings will have a substantial impact on population management in a range of harvested species where trends towards earlier maturation have been observed.
C1 [Barson, Nicola J.; Kent, Matthew; Nome, Torfinn; Lien, Sigbjorn] Norwegian Univ Life Sci, Dept Anim & Aquacultural Sci, Ctr Integrat Genet CIGENE, NO-1432 As, Norway.
   [Aykanat, Tutku; Primmer, Craig R.] Univ Turku, Dept Biol, FI-20014 Turku, Finland.
   [Hindar, Kjetil; Bolstad, Geir H.; Fiske, Peder; Jensen, Arne J.; Karlsson, Sten; Naesje, Tor F.] Norwegian Inst Nat Res NINA, NO-7485 Trondheim, Norway.
   [Baranski, Matthew; Jacq, Celeste] Nofima Norwegian Inst Food Fisheries & Aquacultur, NO-1431 As, Norway.
   [Johnston, Susan E.] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH9 3FL, Midlothian, Scotland.
   [Oen, Thomas M.] AquaGen, NO-7462 Trondheim, Norway.
   [Niemelae, Eero; Orell, Panu; Romakkaniemi, Atso; Erkinaro, Jaakko] Nat Resources Inst Finland, FI-90014 Oulu, Finland.
   [Saegrov, Harald; Urdal, Kurt] Radgivende Biologer, NO-5003 Bergen, Norway.
C3 Norwegian University of Life Sciences; University of Turku; Norwegian Institute Nature Research; Nofima; University of Edinburgh; Natural Resources Institute Finland (Luke)
RP Lien, S (corresponding author), Norwegian Univ Life Sci, Dept Anim & Aquacultural Sci, Ctr Integrat Genet CIGENE, NO-1432 As, Norway.
EM sigbjorn.lien@nmbu.no; Craig.primmer@utu.fi
FU Finnish Academy [137710, 141231, 272836, 284941]; Research Council of Norway [216105, 221734/O30]; AquaGen; Academy of Finland (AKA) [137710, 272836] Funding Source: Academy of Finland (AKA)
NR 60
TC 482
Z9 513
U1 2
U2 250
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 17
PY 2015
VL 528
IS 7582
BP 405
EP +
DI 10.1038/nature16062
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CY8SM
UT WOS:000366678600054
PM 26536110
DA 2026-03-09
ER

PT J
AU Dunn, KE
   Dannenberg, F
   Ouldridge, TE
   Kwiatkowska, M
   Turberfield, AJ
   Bath, J
AF Dunn, Katherine E.
   Dannenberg, Frits
   Ouldridge, Thomas E.
   Kwiatkowska, Marta
   Turberfield, Andrew J.
   Bath, Jonathan
TI Guiding the folding pathway of DNA origami
SO NATURE
LA English
DT Article
ID single-stranded-dna; nanoscale shapes; persistence lengths; flexibility; thermodynamics; nanostructures; hybridization; stability; molecules; magnesium
AB DNA origami is a robust assembly technique that folds a single-stranded DNA template into a target structure by annealing it with hundreds of short 'staple' strands(1-4.) Its guiding design principle is that the target structure is the single most stable configuration(5). The folding transition is cooperative(4,6,7) and, as in the case of proteins, is governed by information encoded in the polymer sequence(8-11). A typical origami folds primarily into the desired shape, but misfolded structures can kinetically trap the system and reduce the yield(2). Although adjusting assembly conditions(2,12) or following empirical design rules(12,13) can improve yield, well-folded origami often need to be separated from misfolded structures(2,3,14-16). The problem could in principle be avoided if assembly pathway and kinetics were fully understood and then rationally optimized. To this end, here we present a DNA origami system with the unusual property of being able to form a small set of distinguishable and well-folded shapes that represent discrete and approximately degenerate energy minima in a vast folding landscape, thus allowing us to probe the assembly process. The obtained high yield of well-folded origami structures confirms the existence of efficient folding pathways, while the shape distribution provides information about individual trajectories through the folding landscape. We find that, similarly to protein folding, the assembly of DNA origami is highly cooperative; that reversible bond formation is important in recovering from transient misfoldings; and that the early formation of long-range connections can very effectively enforce particular folds. We use these insights to inform the design of the system so as to steer assembly towards desired structures. Expanding the rational design process to include the assembly pathway should thus enable more reproducible synthesis, particularly when targeting more complex structures. We anticipate that this expansion will be essential if DNA origami is to continue its rapid development(1-3,17-19) and become a reliable manufacturing technology(20).
C1 [Dunn, Katherine E.; Dannenberg, Frits; Turberfield, Andrew J.; Bath, Jonathan] Univ Oxford, Dept Phys, Clarendon Lab, Oxford OX1 3PU, England.
   [Dannenberg, Frits; Kwiatkowska, Marta] Univ Oxford, Dept Comp Sci, Oxford OX1 3QD, England.
   [Ouldridge, Thomas E.] Univ Oxford, Dept Phys, Rudolf Peierls Ctr Theoret Phys, Oxford OX1 3NP, England.
C3 University of Oxford; University of Oxford; University of Oxford
RP Bath, J (corresponding author), Univ Oxford, Dept Phys, Clarendon Lab, Parks Rd, Oxford OX1 3PU, England.
EM a.turberfield@physics.ox.ac.uk; j.bath@physics.ox.ac.uk
FU Engineering and Physical Sciences Research Council [EP/G037930/1, EP/P504287/1]; Human Frontier Science Program [RGP0030/2013]; Microsoft Research PhD Scholarship; ERC Advanced Grant VERIWARE; Royal Society-Wolfson Research Merit Award; BBSRC [BB/M005739/1] Funding Source: UKRI; EPSRC [EP/G037930/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/M005739/1] Funding Source: researchfish; Engineering and Physical Sciences Research Council [EP/G037930/1, GR/A10274/01] Funding Source: researchfish
NR 47
TC 152
Z9 194
U1 4
U2 247
PU NATURE PUBLISHING 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 3
PY 2015
VL 525
IS 7567
BP 82
EP +
DI 10.1038/nature14860
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100029
PM 26287459
DA 2026-03-09
ER

PT J
AU Gewin, V
AF Gewin, Virginia
TI Turning point: Martin Jinek
SO NATURE
LA English
DT Article
NR 0
TC 0
Z9 0
U1 0
U2 3
PU NATURE PUBLISHING 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 17
PY 2015
VL 525
IS 7569
BP 415
EP 415
DI 10.1038/nj7569-415a
PG 1
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900054
DA 2026-03-09
ER

PT J
AU Haslinger, K
   Peschke, M
   Brieke, C
   Maximowitsch, E
   Cryle, MJ
AF Haslinger, Kristina
   Peschke, Madeleine
   Brieke, Clara
   Maximowitsch, Egle
   Cryle, Max J.
TI X-domain of peptide synthetases recruits oxygenases crucial for glycopeptide biosynthesis
SO NATURE
LA English
DT Article
ID phenol coupling reaction; vancomycin-type; crystal-structure; gene-cluster; antibiotics; cytochrome-p450; teicoplanin; insights; condensation; cyclization
AB Non-ribosomal peptide synthetase (NRPS) mega-enzyme complexes are modular assembly lines that are involved in the biosynthesis of numerous peptide metabolites independently of the ribosome(1). The multiple interactions between catalytic domains within the NRPS machinery are further complemented by additional interactions with external enzymes, particularly focused on the final peptide maturation process. An important class of NRPS metabolites that require extensive external modification of the NRPS-bound peptide are the glycopeptide antibiotics (GPAs), which include vancomycin and teicoplanin(2,3). These clinically relevant peptide antibiotics undergo cytochrome P450-catalysed oxidative crosslinking of aromatic side chains to achieve their final, active conformation(4-12). However, the mechanism underlying the recruitment of the cytochrome P450 oxygenases to the NRPS-bound peptide was previously unknown. Here we show, through in vitro studies, that the X-domain(13,14), a conserved domain of unknown function present in the final module of all GPA NRPS machineries, is responsible for the recruitment of oxygenases to theN RPS-bound peptide to perform the essential side-chain crosslinking. X-ray crystallography shows that the X-domain is structurally related to condensation domains, but that its amino acid substitutions render it catalytically inactive. We found that the X-domain recruits cytochrome P450 oxygenases to the NRPS and determined the interface by solving the structure of a P450-X-domain complex. Additionally, we demonstrated that the modification of peptide precursors by oxygenases in vitro-in particular the installation of the second crosslink in GPA biosynthesis-occurs only in the presence of the X-domain. Our results indicate that the presentation of peptidyl carrier protein (PCP)-bound substrates for oxidation in GPA biosynthesis requires the presence of the NRPS X-domain to ensure conversion of the precursor peptide into a mature aglycone, and that the carrier protein domain alone is not always sufficient to generate a competent substrate for external cytochrome P450 oxygenases.
C1 [Haslinger, Kristina; Peschke, Madeleine; Brieke, Clara; Maximowitsch, Egle; Cryle, Max J.] Max Planck Inst Med Res, D-69120 Heidelberg, Germany.
C3 Max Planck Society
RP Cryle, MJ (corresponding author), Max Planck Inst Med Res, Jahnstr 29, D-69120 Heidelberg, Germany.
EM Max.Cryle@mpimf-heidelberg.mpg.de
FU Deutsche Forschungsgemeinschaft (Emmy-Noether Program) [CR 392/1-1]
NR 47
TC 165
Z9 193
U1 0
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 MAY 7
PY 2015
VL 521
IS 7550
BP 105
EP U271
DI 10.1038/nature14141
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH4YS
UT WOS:000354040900042
PM 25686610
DA 2026-03-09
ER

PT J
AU Drost, J
   van Jaarsveld, RH
   Ponsioen, B
   Zimberlin, C
   van Boxtel, R
   Buijs, A
   Sachs, N
   Overmeer, RM
   Offerhaus, GJ
   Begthel, H
   Korving, J
   van de Wetering, M
   Schwank, G
   Logtenberg, M
   Cuppen, E
   Snippert, HJ
   Medema, JP
   Kops, GJPL
   Clevers, H
AF Drost, Jarno
   van Jaarsveld, Richard H.
   Ponsioen, Bas
   Zimberlin, Cheryl
   van Boxtel, Ruben
   Buijs, Arjan
   Sachs, Norman
   Overmeer, Rene M.
   Offerhaus, G. Johan
   Begthel, Harry
   Korving, Jeroen
   van de Wetering, Marc
   Schwank, Gerald
   Logtenberg, Meike
   Cuppen, Edwin
   Snippert, Hugo J.
   Medema, Jan Paul
   Kops, Geert J. P. L.
   Clevers, Hans
TI Sequential cancer mutations in cultured human intestinal stem cells
SO NATURE
LA English
DT Article
ID in-vitro expansion; structural basis; organoids; adenomas; reveals; colon
AB Crypt stem cells represent the cells of origin for intestinal neoplasia. Both mouse and human intestinal stem cells can be cultured in medium containing the stem-cell-niche factors WNT, R-spondin, epidermal growth factor (EGF) and noggin over long time periods as epithelial organoids that remain genetically and phenotypically stable. Here we utilize CRISPR/Cas9 technology for targeted gene modification of four of the most commonly mutated colorectal cancer genes (APC, P53 (also known as TP53), KRAS and SMAD4) in cultured human intestinal stem cells. Mutant organoids can be selected by removing individual growth factors from the culture medium. Quadruple mutants grow independently of all stem-cell-niche factors and tolerate the presence of the P53 stabilizer nutlin-3. Upon xenotransplantation into mice, quadruple mutants grow as tumours with features of invasive carcinoma. Finally, combined loss of APC and P53 is sufficient for the appearance of extensive aneuploidy, a hallmark of tumour progression.
C1 [Drost, Jarno; van Boxtel, Ruben; Sachs, Norman; Begthel, Harry; Korving, Jeroen; van de Wetering, Marc; Schwank, Gerald; Logtenberg, Meike; Cuppen, Edwin; Clevers, Hans] Royal Netherlands Acad Arts & Sci KNAW, Hubrecht Inst, NL-3584 CT Utrecht, Netherlands.
   [Drost, Jarno; van Boxtel, Ruben; Sachs, Norman; Begthel, Harry; Korving, Jeroen; van de Wetering, Marc; Schwank, Gerald; Logtenberg, Meike; Cuppen, Edwin; Clevers, Hans] UMC Utrecht, NL-3584 CT Utrecht, Netherlands.
   [Drost, Jarno; van Jaarsveld, Richard H.; Ponsioen, Bas; Zimberlin, Cheryl; van Boxtel, Ruben; Sachs, Norman; Overmeer, Rene M.; Begthel, Harry; Korving, Jeroen; van de Wetering, Marc; Schwank, Gerald; Logtenberg, Meike; Cuppen, Edwin; Snippert, Hugo J.; Medema, Jan Paul; Kops, Geert J. P. L.; Clevers, Hans] UMC Utrecht, Canc Genom Netherlands, NL-3584 CG Utrecht, Netherlands.
   [van Jaarsveld, Richard H.; Ponsioen, Bas; Overmeer, Rene M.; Snippert, Hugo J.; Kops, Geert J. P. L.] UMC Utrecht, Ctr Mol Med, Mol Canc Res, NL-3584 CG Utrecht, Netherlands.
   [Zimberlin, Cheryl; Medema, Jan Paul] AMC, Ctr Expt Mol Med, Lab Expt Oncol & Radiobiol, NL-1105 AZ Amsterdam, Netherlands.
   [Buijs, Arjan] UMC Utrecht, Dept Med Genet, NL-3508 AB Utrecht, Netherlands.
   [Offerhaus, G. Johan] UMC Utrecht, Dept Pathol, NL-3584 CX Utrecht, Netherlands.
   [van de Wetering, Marc] Fdn Hubrecht Organoid Technol HUB, NL-3584 CT Utrecht, Netherlands.
C3 Royal Netherlands Academy of Arts & Sciences; Hubrecht Institute (KNAW); Utrecht University; Utrecht University Medical Center; Utrecht University; Utrecht University Medical Center; University of Amsterdam; Academic Medical Center Amsterdam; Utrecht University; Utrecht University Medical Center; Utrecht University; Utrecht University Medical Center
RP Clevers, H (corresponding author), Royal Netherlands Acad Arts & Sci KNAW, Hubrecht Inst, NL-3584 CT Utrecht, Netherlands.
EM h.clevers@hubrecht.eu
FU Netherlands Organisation for Scientific Research (NWO-ZonMw) VENI grant [91614138]; University of Amsterdam [2012-5735]; Dutch Digestive Diseases Foundation (MLDS) [FP13-07]; Netherlands Institute of Regenerative Medicine; Dutch Cancer Society (KWF) [KWF/PF-HUBR 2007-3956, UU2013-6070]; Stand Up to Cancer/Stichting Vrienden van het Hubrecht; NWO-ZonMw [116.005.002]; CancerGenomics.nl (NWO Gravitation) program
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NR 32
TC 854
Z9 1002
U1 5
U2 258
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 7
PY 2015
VL 521
IS 7550
BP 43
EP U329
DI 10.1038/nature14415
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH4YS
UT WOS:000354040900028
PM 25924068
DA 2026-03-09
ER

PT J
AU Kessler, SC
   Tiedeken, EJ
   Simcock, KL
   Derveau, S
   Mitchell, J
   Softley, S
   Stout, JC
   Wright, GA
AF Kessler, Sebastien C.
   Tiedeken, Erin Jo
   Simcock, Kerry L.
   Derveau, Sophie
   Mitchell, Jessica
   Softley, Samantha
   Stout, Jane C.
   Wright, Geraldine A.
TI Bees prefer foods containing neonicotinoid pesticides
SO NATURE
LA English
DT Article
ID bitter taste; exposure; insecticides; honeybees; residues; pollen; nectar; memory
AB The impact of neonicotinoid insecticides on insect pollinators is highly controversial. Sublethal concentrations alter the behaviour of social bees and reduce survival of entire colonies(1-3). However, critics argue that the reported negative effects only arise from neonicotinoid concentrations that are greater than those found in the nectar and pollen of pesticide-treated plants(4). Furthermore, it has been suggested that bees could choose to forage on other available flowers and hence avoid or dilute exposure(4,5). Here, using a two-choice feeding assay, we show that the honeybee, Apis mellifera, and the buff-tailed bumblebee, Bombus terrestris, do not avoid nectar-relevant concentrations of three of the most commonly used neonicotinoids, imidacloprid (IMD), thiamethoxam (TMX), and clothianidin (CLO), in food. Moreover, bees of both species prefer to eat more of sucrose solutions laced with IMD or TMX than sucrose alone. Stimulation with IMD, TMX and CLO neither elicited spiking responses from gustatory neurons in the bees' mouthparts, nor inhibited the responses of sucrose-sensitive neurons. Our data indicate that bees cannot taste neonicotinoids and are not repelled by them. Instead, bees preferred solutions containing IMD or TMX, even though the consumption of these pesticides caused them to eat less food overall. This work shows that bees cannot control their exposure to neonicotinoids in food and implies that treating flowering crops with IMD and TMX presents a sizeable hazard to foraging bees.
C1 [Kessler, Sebastien C.; Simcock, Kerry L.; Softley, Samantha; Wright, Geraldine A.] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
   [Tiedeken, Erin Jo; Stout, Jane C.] Trinity Coll Dublin, Dept Bot, Dublin 2, Ireland.
   [Derveau, Sophie] Newcastle Univ, Sch Biol, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England.
   [Mitchell, Jessica] Univ Oxford, Ctr Neural Circuits & Behav, Oxford OX1 3SR, England.
C3 Newcastle University - UK; Trinity College Dublin; Newcastle University - UK; University of Oxford
RP Wright, GA (corresponding author), Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
EM jeri.wright@ncl.ac.uk
FU BBSRC; NERC; Wellcome Trust; Defra; Scottish Government under the Insect Pollinators Initiative [BB/I000143/1]; Leverhulme Trust [RPG-2012-708]; Science Foundation Ireland [10/RFP/EOB2842]; US National Science Foundation [2010097514]; Irish Research Council's EMBARK Postgraduate Scholarship Scheme grant [RS/2010/2147]; BBSRC [BB/I000143/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/I000143/1] Funding Source: researchfish; Science Foundation Ireland (SFI) [10/RFP/EOB2842] Funding Source: Science Foundation Ireland (SFI)
NR 43
TC 372
Z9 460
U1 14
U2 872
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 7
PY 2015
VL 521
IS 7550
BP 74
EP U145
DI 10.1038/nature14414
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH4YS
UT WOS:000354040900035
PM 25901684
DA 2026-03-09
ER

PT J
AU Zhou, QJ
   Lai, Y
   Bacaj, T
   Zhao, ML
   Lyubimov, AY
   Uervirojnangkoorn, M
   Zeldin, OB
   Brewster, AS
   Sauter, NK
   Cohen, AE
   Soltis, SM
   Alonso-Mori, R
   Chollet, M
   Lemke, HT
   Pfuetzner, RA
   Choi, UB
   Weis, WI
   Diao, JJ
   Südhof, TC
   Brunger, AT
AF Zhou, Qiangjun
   Lai, Ying
   Bacaj, Taulant
   Zhao, Minglei
   Lyubimov, Artem Y.
   Uervirojnangkoorn, Monarin
   Zeldin, Oliver B.
   Brewster, Aaron S.
   Sauter, Nicholas K.
   Cohen, Aina E.
   Soltis, S. Michael
   Alonso-Mori, Roberto
   Chollet, Matthieu
   Lemke, Henrik T.
   Pfuetzner, Richard A.
   Choi, Ucheor B.
   Weis, William I.
   Diao, Jiajie
   Suedhof, Thomas C.
   Brunger, Axel T.
TI Architecture of the synaptotagmin-SNARE machinery for neuronal exocytosis
SO NATURE
LA English
DT Article
ID membrane-fusion; c2b domain; neurotransmitter release; 3-dimensional structure; synaptic-transmission; phospholipid-binding; transmitter release; synchronous release; vesicle docking; calcium sensor
AB Synaptotagmin-1 and neuronal SNARE proteins have central roles in evoked synchronous neurotransmitter release; however, it is unknown how they cooperate to trigger synaptic vesicle fusion. Here we report atomic-resolution crystal structures of Ca2+- and Mg2+-bound complexes between synaptotagmin-1 and the neuronal SNARE complex, one of which was determined with diffraction data froman X-ray free-electron laser, leading to an atomic-resolution structure with accurate rotamer assignments for many side chains. The structures reveal several interfaces, including a large, specific, Ca2+-independent and conserved interface. Tests of this interface by mutagenesis suggest that it is essential for Ca2+-triggered neurotransmitter release in mouse hippocampal neuronal synapses and for Ca2+-triggered vesicle fusion in a reconstituted system. We propose that this interface forms before Ca2+ triggering, moves en bloc as Ca2+ influx promotes the interactions between synaptotagmin-1 and the plasma membrane, and consequently remodels the membrane to promote fusion, possibly in conjunction with other interfaces.
C1 [Zhou, Qiangjun; Lai, Ying; Bacaj, Taulant; Zhao, Minglei; Lyubimov, Artem Y.; Uervirojnangkoorn, Monarin; Zeldin, Oliver B.; Pfuetzner, Richard A.; Choi, Ucheor B.; Diao, Jiajie; Suedhof, Thomas C.; Brunger, Axel T.] Stanford Univ, Howard Hughes Med Inst, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
   [Zhou, Qiangjun; Lai, Ying; Zhao, Minglei; Lyubimov, Artem Y.; Uervirojnangkoorn, Monarin; Zeldin, Oliver B.; Pfuetzner, Richard A.; Choi, Ucheor B.; Diao, Jiajie; Brunger, Axel T.] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA.
   [Zhou, Qiangjun; Lai, Ying; Zhao, Minglei; Lyubimov, Artem Y.; Uervirojnangkoorn, Monarin; Zeldin, Oliver B.; Pfuetzner, Richard A.; Choi, Ucheor B.; Weis, William I.; Diao, Jiajie; Brunger, Axel T.] Stanford Univ, Dept Photon Sci, Stanford, CA 94305 USA.
   [Zhou, Qiangjun; Lai, Ying; Zhao, Minglei; Lyubimov, Artem Y.; Uervirojnangkoorn, Monarin; Zeldin, Oliver B.; Pfuetzner, Richard A.; Choi, Ucheor B.; Weis, William I.; Diao, Jiajie; Brunger, Axel T.] Stanford Univ, Dept Struct Biol, Stanford, CA 94305 USA.
   [Brewster, Aaron S.; Sauter, Nicholas K.] Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA.
   [Cohen, Aina E.; Soltis, S. Michael; Alonso-Mori, Roberto; Chollet, Matthieu; Lemke, Henrik T.] SLAC Natl Accelerator Lab, Stanford, CA 94305 USA.
   [Weis, William I.] Stanford Univ, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
C3 Howard Hughes Medical Institute; Stanford University; Stanford University; Stanford University; Stanford University; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; Stanford University
RP Brunger, AT (corresponding author), Stanford Univ, Howard Hughes Med Inst, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
EM tcs1@stanford.edu; brunger@stanford.edu
FU NIH [P41 GM103403]; 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]; National Institutes of Health [R37MH63105, MH086403, GM095887, GM102520]; HHMI Collaborative Innovation Award (HCIA)
NR 87
TC 258
Z9 300
U1 0
U2 116
PU NATURE PUBLISHING 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 3
PY 2015
VL 525
IS 7567
BP 62
EP +
DI 10.1038/nature14975
PG 25
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100025
PM 26280336
DA 2026-03-09
ER

PT J
AU Ewald, CY
   Landis, JN
   Abate, JP
   Murphy, CT
   Blackwell, TK
AF Ewald, Collin Y.
   Landis, Jess N.
   Abate, Jess Porter
   Murphy, Coleen T.
   Blackwell, T. Keith
TI Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity
SO NATURE
LA English
DT Article
ID life-span extension; caenorhabditis-elegans; c-elegans; gene-expression; proline catabolism; stress-response; daf-2; skn-1; complex; mutations
AB Interventions that delay ageing mobilize mechanisms that protect and repair cellular components(1-3), but it is unknown how these interventions might slow the functional decline of extracellular matrices(4,5), which are also damaged during ageing(6,7). Reduced insulin/I GF-1 signalling (HIS) extends lifespan across the evolutionary spectrum, and in juvenile Caenorhabditis elegans also allows the transcription factor DAF-16/FOX0 to induce development into dauer, a diapause that withstands harsh conditions(1,2). It has been suggested that rIIS delays C. elegans ageing through activation of dauer-related processes during adulthood(2,8,9), but some HIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits(1,10,11). Here we show that HIS can promote C. elegans longevity through a program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) orthologue SKN-1 acting in parallel to DAF-16. SKN-1 is inhibited by IIS and has been broadly implicated in longevity(12-14), but is rendered dispensable for HIS lifespan extension by even mild activity of dauer-related processes. When IIS is decreased under conditions that do not induce dauer traits, SKN-1 most prominently increases expression of collagens and other extracellular matrix genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood extracellular matrix remodelling, and are needed for ageing to be delayed by interventions that do not involve dauer traits. By genetically delineating a dauer-independent HIS ageing pathway, our results show that IIS controls a broad set of protective mechanisms during C. elegans adulthood, and may facilitate elucidation of processes of general importance for longevity. The importance of collagen production in diverse anti-ageing interventions implies that extracellular matrix remodelling is a generally essential signature of longevity assurance, and that agents promoting extracellular matrix youthfulness may have systemic benefit.
C1 [Ewald, Collin Y.; Abate, Jess Porter; Blackwell, T. Keith] Joslin Diabet Ctr, Boston, MA 02215 USA.
   [Ewald, Collin Y.; Abate, Jess Porter; Blackwell, T. Keith] Harvard Stem Cell Inst, Cambridge, MA 02138 USA.
   [Ewald, Collin Y.; Abate, Jess Porter; Blackwell, T. Keith] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA.
   [Landis, Jess N.; Murphy, Coleen T.] Princeton Univ, Dept Mol Biol, Lewis Sigler Inst Integrat Genom, Carl Icahn Lab 148, Princeton, NJ 08544 USA.
C3 Harvard University; Harvard University Medical Affiliates; Joslin Diabetes Center, Inc.; Harvard University; Harvard University; Harvard Medical School; Princeton University
RP Blackwell, TK (corresponding author), Joslin Diabet Ctr, One Joslin Pl, Boston, MA 02215 USA.
EM ctmurphy@princeton.edu; keith.blackwell@joslin.harvard.edu
FU National Institutes of Health Office of Research Infrastructure Programs [P40 OD010440]; National Institutes of Health [GM062891, 5T32DK007260]; Diabetes Research Center award [P30DK036836]; National Science Foundation; Swiss National Science Foundation [PBSKP3_140135]; Swiss National Science Foundation (SNF) [PBSKP3_140135] Funding Source: Swiss National Science Foundation (SNF); National Institute of Diabetes and Digestive and Kidney Diseases [T32DK007260, P30DK036836] Funding Source: NIH RePORTER
NR 93
TC 238
Z9 296
U1 2
U2 109
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 5
PY 2015
VL 519
IS 7541
BP 97
EP U212
DI 10.1038/nature14021
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC4EQ
UT WOS:000350304000043
PM 25517099
DA 2026-03-09
ER

PT J
AU Pelish, HE
   Liau, BB
   Nitulescu, II
   Tangpeerachaikul, A
   Poss, ZC
   Da Silva, DH
   Caruso, BT
   Arefolov, A
   Fadeyi, O
   Christie, AL
   Du, K
   Banka, D
   Schneider, EV
   Jestel, A
   Zou, G
   Si, C
   Ebmeier, CC
   Bronson, RT
   Krivtsov, AV
   Myers, AG
   Kohl, NE
   Kung, AL
   Armstrong, SA
   Lemieux, ME
   Taatjes, DJ
   Shair, MD
AF Pelish, Henry E.
   Liau, Brian B.
   Nitulescu, Ioana I.
   Tangpeerachaikul, Anupong
   Poss, Zachary C.
   Da Silva, Diogo H.
   Caruso, Brittany T.
   Arefolov, Alexander
   Fadeyi, Olugbeminiyi
   Christie, Amanda L.
   Du, Karrie
   Banka, Deepti
   Schneider, Elisabeth V.
   Jestel, Anja
   Zou, Ge
   Si, Chong
   Ebmeier, Christopher C.
   Bronson, Roderick T.
   Krivtsov, Andrei V.
   Myers, Andrew G.
   Kohl, Nancy E.
   Kung, Andrew L.
   Armstrong, Scott A.
   Lemieux, Madeleine E.
   Taatjes, Dylan J.
   Shair, Matthew D.
TI Mediator kinase inhibition further activates super-enhancer-associated genes in AML
SO NATURE
LA English
DT Article
ID transcription factors; cell identity; cdk8; ligand; guidelines; ultrafast; knowledge; alignment; cancer; tools
AB Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes(1,2). BRD4 and CDK7 are positive regulators of SE-mediated transcription(3-5). By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces upregulation of SE-associated genes in CA-sensitiveAML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA, IRF8, IRF1 and ETV6 (refs 6-8). The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML.
C1 [Pelish, Henry E.; Liau, Brian B.; Nitulescu, Ioana I.; Tangpeerachaikul, Anupong; Da Silva, Diogo H.; Caruso, Brittany T.; Arefolov, Alexander; Fadeyi, Olugbeminiyi; Du, Karrie; Zou, Ge; Si, Chong; Myers, Andrew G.; Shair, Matthew D.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA.
   [Poss, Zachary C.; Ebmeier, Christopher C.; Taatjes, Dylan J.] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80303 USA.
   [Christie, Amanda L.; Kohl, Nancy E.] Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02215 USA.
   [Banka, Deepti] Childrens Hosp, Div Hematol Oncol, Boston, MA 02215 USA.
   [Schneider, Elisabeth V.; Jestel, Anja] Proteros Biostruct GmbH, D-82152 Martinsried, Germany.
   [Schneider, Elisabeth V.] Max Planck Inst Biochem, D-82152 Martinsried, Germany.
   [Bronson, Roderick T.] Dana Farber Canc Inst, Boston, MA 02215 USA.
   [Krivtsov, Andrei V.; Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA.
   [Krivtsov, Andrei V.; Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA.
   [Kung, Andrew L.] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA.
   [Lemieux, Madeleine E.] Bioinfo, Plantagenet, ON K0B 1L0, Canada.
C3 Harvard University; University of Colorado System; University of Colorado Boulder; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Max Planck Society; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Columbia University
RP Shair, MD (corresponding author), Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA.
EM shair@chemistry.harvard.edu
FU NIH [CA66996, T32 GM08759]; NCI [R01 CA170741, F31 CA180419]; Leukemia and Lymphoma Society Translational Research Program; Blavatnik Biomedical Accelerator Programat Harvard; Starr Cancer Consortium;  [P30-CA046934]; National Cancer Institute [P01CA066996, P30CA008748, P30CA046934, R01CA176745] Funding Source: NIH RePORTER
NR 53
TC 308
Z9 379
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 8
PY 2015
VL 526
IS 7572
BP 273
EP +
DI 10.1038/nature14904
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS9GV
UT WOS:000362399000051
PM 26416749
DA 2026-03-09
ER

PT J
AU Martínez-Botí, MA
   Foster, GL
   Chalk, TB
   Rohling, EJ
   Sexton, PF
   Lunt, DJ
   Pancost, RD
   Badger, MPS
   Schmidt, DN
AF Martinez-Boti, M. A.
   Foster, G. L.
   Chalk, T. B.
   Rohling, E. J.
   Sexton, P. F.
   Lunt, D. J.
   Pancost, R. D.
   Badger, M. P. S.
   Schmidt, D. N.
TI Plio-Pleistocene climate sensitivity evaluated using high-resolution CO2 records
SO NATURE
LA English
DT Article
ID carbon-dioxide concentration; sea-level fluctuations; boron isotope; pliocene warmth; ice volume; temperature; evolution; atlantic; constraints; sediment
AB Theory and climate modelling suggest that the sensitivity of Earth's climate to changes in radiative forcing could depend on the background climate. However, palaeoclimate data have thus far been insufficient to provide a conclusive test of this prediction. Here we present atmospheric carbon dioxide (CO2) reconstructions based on multi-site boron-isotope records from the late Pliocene epoch (3.3 to 2.3 million years ago). We find that Earth's climate sensitivity to CO2-based radiative forcing (Earth system sensitivity) was half as strong during the warm Pliocene as during the cold late Pleistocene epoch (0.8 to 0.01 million years ago). Weattribute this difference to the radiative impacts of continental ice-volume changes (the ice-albedo feedback) during the late Pleistocene, because equilibrium climate sensitivity is identical for the two intervals when we account for such impacts using sea-level reconstructions. We conclude that, on a global scale, no unexpected climate feedbacks operated during the warm Pliocene, and that predictions of equilibrium climate sensitivity (excludinglong-termice-albedo feedbacks) forour Pliocene-like future(with CO2 levels up to maximum Pliocene levels of 450 parts per million) are well described by the currently accepted range of an increase of 1.5 K to 4.5 K per doubling of CO2.
C1 [Martinez-Boti, M. A.; Foster, G. L.; Chalk, T. B.; Rohling, E. J.] Univ Southampton, Natl Oceanog Ctr Southampton, Southampton SO14 3ZH, Hants, England.
   [Rohling, E. J.] Australian Natl Univ, Res Sch Earth Sci, Canberra, ACT 2601, Australia.
   [Sexton, P. F.] Open Univ, Ctr Earth Planetary Space & Astron Res, Milton Keynes MK7 6AA, Bucks, England.
   [Lunt, D. J.] Univ Bristol, Sch Geog Sci, Bristol BS8 1SS, Avon, England.
   [Lunt, D. J.; Pancost, R. D.; Badger, M. P. S.; Schmidt, D. N.] Univ Bristol, Cabot Inst, Bristol BS8 1UJ, Avon, England.
   [Pancost, R. D.; Badger, M. P. S.] Univ Bristol, Sch Chem, Organ Geochem Unit, Bristol BS8 1TS, Avon, England.
   [Schmidt, D. N.] Univ Bristol, Sch Earth Sci, Bristol BS8 1RJ, Avon, England.
C3 University of Southampton; NERC National Oceanography Centre; Australian National University; Open University - UK; University of Bristol; University of Bristol; University of Bristol; University of Bristol
RP Foster, GL (corresponding author), Univ Southampton, Natl Oceanog Ctr Southampton, Southampton SO14 3ZH, Hants, England.
EM gavin.foster@noc.soton.ac.uk
FU NERC [NE/H006273/1, NE/I006346/1]; European Community; Australian Laureate Fellowship [FL120100050]; Yale University; Natural Environment Research Council [NE/I005714/1, NE/I006346/1, NE/H006273/1] Funding Source: researchfish; NERC [NE/I005714/1, NE/I006346/1, NE/H006273/1] Funding Source: UKRI
NR 93
TC 308
Z9 347
U1 8
U2 300
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 5
PY 2015
VL 518
IS 7537
BP 49
EP +
DI 10.1038/nature14145
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7LE
UT WOS:000349098000029
PM 25652996
DA 2026-03-09
ER

PT J
AU Buenostro, JD
   Wu, BJ
   Litzenburger, UM
   Ruff, D
   Gonzales, ML
   Snyder, MP
   Chang, HY
   Greenleaf, WJ
AF Buenostro, Jason D.
   Wu, Beijing
   Litzenburger, Ulrike M.
   Ruff, Dave
   Gonzales, Michael L.
   Snyder, Michael P.
   Chang, Howard Y.
   Greenleaf, William J.
TI Single-cell chromatin accessibility reveals principles of regulatory variation
SO NATURE
LA English
DT Article
ID rna-seq; dynamics; heterogeneity
AB Cell-to-cell variation is a universal feature of life that affects a wide range of biological phenomena, from developmental plasticity(1,2) to tumour heterogeneity(3). Although recent advances have improved our ability to document cellular phenotypic variation(4-8), the fundamental mechanisms that generate variability from identical DNA sequences remain elusive. Here we reveal the landscape and principles of mammalian DNA regulatory variation by developing a robust method for mapping the accessible genome of individual cells by assay for transposase-accessible chromatin using sequencing (ATAC-seq)(9) integrated into a programmable microfluidics platform. Single-cell ATAC-seq (scATAC-seq) maps from hundreds of single cells in aggregate closely resemble accessibility profiles from tens of millions of cells and provide insights into cell-to-cell variation. Accessibility variance is systematically associated with specific trans-factors and cis-elements, and we discover combinations of trans-factors associated with either induction or suppression of cell-to-cell variability. We further identify sets of trans-factors associated with cell-type-specific accessibility variance across eight cell types. Targeted perturbations of cell cycle or transcription factor signalling evoke stimulus-specific changes in this observed variability. The pattern of accessibility variation in cis across the genome recapitulates chromosome compartments(10) de novo, linking single-cell accessibility variation to three-dimensional genome organization. Single-cell analysis of DNA accessibility provides new insight into cellular variation of the 'regulome'.
C1 [Buenostro, Jason D.; Wu, Beijing; Snyder, Michael P.; Greenleaf, William J.] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
   [Buenostro, Jason D.; Litzenburger, Ulrike M.; Chang, Howard Y.] Stanford Univ, Sch Med, Program Epithelial Biol, Stanford, CA 94305 USA.
   [Buenostro, Jason D.; Litzenburger, Ulrike M.; Chang, Howard Y.] Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Ruff, Dave; Gonzales, Michael L.] Fluidigm Corp, San Francisco, CA 94080 USA.
   [Greenleaf, William J.] Stanford Univ, Dept Appl Phys, Stanford, CA 94025 USA.
C3 Stanford University; Stanford University; Stanford University; Howard Hughes Medical Institute; Standard BioTools Inc.; Stanford University
RP Greenleaf, WJ (corresponding author), Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
EM howchang@stanford.edu; wjg@stanford.edu
FU National Institutes of Health (NIH) [P50HG007735]; Lifespan Extension Foundation; Rita Allen Foundation; Baxter Foundation Faculty Scholar Grant; National Science Foundation; NIH [T32HG000044]; National Human Genome Research Institute (NHGRI) [5U54HG00455805];  [UH2 AR067676];  [U19AI057266]; National Human Genome Research Institute [T32HG000044] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [U19AI057266] Funding Source: NIH RePORTER
NR 28
TC 1615
Z9 2170
U1 16
U2 495
PU NATURE PUBLISHING 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 23
PY 2015
VL 523
IS 7561
BP 486
EP U264
DI 10.1038/nature14590
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN4DD
UT WOS:000358378900042
PM 26083756
DA 2026-03-09
ER

PT J
AU Stolfi, A
   Ryan, K
   Meinertzhagen, IA
   Christiaen, L
AF Stolfi, Alberto
   Ryan, Kerrianne
   Meinertzhagen, Ian A.
   Christiaen, Lionel
TI Migratory neuronal progenitors arise from the neural plate borders in tunicates
SO NATURE
LA English
DT Article
ID central-nervous-system; chordate ciona-intestinalis; primary sensory neurons; sensing ion channels; halocynthia-roretzi; merkel cells; ci-msxb; crest; origin; expression
AB The neural crest is an evolutionary novelty that fostered the emergence of vertebrate anatomical innovations such as the cranium and jaws(1). During embryonic development, multipotent neural crest cells are specified at the lateral borders of the neural plate before delaminating, migrating and differentiating into various cell types. In invertebrate chordates (cephalochordates and tunicates), neural plate border cells express conserved factors such as Msx, Snail and Pax3/7 and generate melanin-containing pigment cells(2-4), a derivative of the neural crest in vertebrates. However, invertebrate neural plate border cells have not been shown to generate homologues of other neural crest derivatives. Thus, proposed models of neural crest evolution postulate vertebrate-specific elaborations on an ancestral neural plate border program, through acquisition of migratory capabilities and the potential to generate several cell types(5-7). Here we show that a particular neuronal cell type in the tadpole larva of the tunicate Ciona intestinalis, the bipolar tail neuron, shares a set of features with neural-crest-derived spinal ganglia neurons in vertebrates. Bipolar tail neuron precursors derive from caudal neural plate border cells, delaminate and migrate along the paraxial mesoderm on either side of the neural tube, eventually differentiating into afferent neurons that form synaptic contacts with both epidermal sensory cells and motor neurons. We propose that the neural plate borders of the chordate ancestor already produced migratory peripheral neurons and pigment cells, and that the neural crest evolved through the acquisition of a multipotent progenitor regulatory state upstream of multiple, pre-existing neural plate border cell differentiation programs.
C1 [Stolfi, Alberto; Christiaen, Lionel] NYU, Dept Biol, Ctr Dev Genet, New York, NY 10003 USA.
   [Ryan, Kerrianne; Meinertzhagen, Ian A.] Dalhousie Univ, Dept Psychol & Neurosci, Life Sci Ctr, Halifax, NS B3H 4R2, Canada.
C3 New York University; Dalhousie University
RP Christiaen, L (corresponding author), NYU, Dept Biol, Ctr Dev Genet, New York, NY 10003 USA.
EM lc121@nyu.edu
FU National Science Foundation [NSF-1161835]; National Institutes of Health [GM096032]; NSERC (Ottawa) [DIS0000065]; Direct For Biological Sciences; Div Of Biological Infrastructure [1161835] Funding Source: National Science Foundation
NR 50
TC 120
Z9 141
U1 0
U2 24
PU NATURE PUBLISHING 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 19
PY 2015
VL 527
IS 7578
BP 371
EP +
DI 10.1038/nature15758
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9ZN
UT WOS:000365356800055
PM 26524532
DA 2026-03-09
ER

PT J
AU Sajish, M
   Schimmel, P
AF Sajish, Mathew
   Schimmel, Paul
TI A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol
SO NATURE
LA English
DT Article
ID small-molecule activators; histone acetyltransferase; crystal-structure; tumor-suppressor; dna-damage; heat-shock; life-span; kappa-b; stress; poly(adp-ribose)
AB Resveratrol is reported to extend lifespan(1,2) and provide cardioneuro-protective(3), anti-diabetic(4), and anti-cancer effects(3,5) by initiating a stress response(2) that induces survival genes. Because human tyrosyl transfer-RNA(tRNA) synthetase (TyrRS) translocates to the nucleus under stress conditions(6), we considered the possibility that the tyrosine-like phenolic ring of resveratrol might fit into the active site pocket to effect a nuclear role. Here we present a 2.1 angstrom co-crystal structure of resveratrol bound to the active site of TyrRS. Resveratrol nullifies the catalytic activity and redirects TyrRS to a nuclear function, stimulating NAD(+)-dependent auto-poly-ADP-ribosylation of poly(ADP-ribose) polymerase 1 (PARP1). Downstream activation of key stress signalling pathways are causally connected to TyrRS-PARP1-NAD(+) collaboration. This collaborationis also demonstrated in the mouse, and is specifically blocked in vivo by a resveratrol-displacing tyrosyl adenylate analogue. In contrast to functionally diverse tRNA synthetase catalytic nulls created by alternative splicing events that ablate active sites(7), here a non-spliced TyrRS catalytic null reveals a new PARP1- and NAD(+)-dependent dimension to the physiological mechanism of resveratrol.
C1 [Sajish, Mathew; Schimmel, Paul] Scripps Res Inst, Dept Mol & Cell Biol, Scripps Labs TRNA Synthetase Res, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA.
   [Schimmel, Paul] Scripps Florida Res Inst, Jupiter, FL 33458 USA.
C3 Scripps Research Institute; State University System of Florida; University of Florida; Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
RP Schimmel, P (corresponding author), Scripps Res Inst, Dept Mol & Cell Biol, Scripps Labs TRNA Synthetase Res, Skaggs Inst Chem Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA.
EM schimmel@scripps.edu
FU National Cancer Institute [CA92577]; National Foundation for Cancer Research; aTyr Pharma; Scripps Research Institute
NR 54
TC 127
Z9 155
U1 0
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 MAR 19
PY 2015
VL 519
IS 7543
BP 370
EP +
DI 10.1038/nature14028
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD6AY
UT WOS:000351171900045
PM 25533949
DA 2026-03-09
ER

PT J
AU Plunkett, AL
   Arce, HG
   Mardones, D
   van Dokkum, P
   Dunham, MM
   Fernández-López, M
   Gallardo, J
   Corder, SA
AF Plunkett, Adele L.
   Arce, Hector G.
   Mardones, Diego
   van Dokkum, Pieter
   Dunham, Michael M.
   Fernandez-Lopez, Manuel
   Gallardo, Jose
   Corder, Stuartt A.
TI Episodic molecular outflow in the very young protostellar cluster Serpens South
SO NATURE
LA English
DT Article
ID jets; clouds; simulations
AB The loss of mass from protostars, in the form of a jet or outflow, is a necessary counterpart to protostellar mass accretion(1,2). Outflow ejection events probably vary in their velocity and/or in the rate of mass loss. Such 'episodic' ejection events(3) have been observed during the class 0 protostellar phase (the early accretion stage)(4-10), and continue during the subsequent class I phase that marks the first one million years of star formation(11-14). Previously observed episodic-ejection sources were relatively isolated; however, the most common sites of star formation are clusters(15). Outflows link protostars with their environment and provide a viable source of the turbulence that is necessary for regulating star formation in clusters(3), but it is not known how an accretion-driven jet or outflow in a clustered environment manifests itself in its earliest stage. This early stage is important in establishing the initial conditions for momentum and energy transfer to the environment as the protostar and cluster evolve. Here we report that an outflow from a young, class 0 protostar, at the hub of the very active and filamentary Serpens South protostellar cluster(16-18), shows unambiguous episodic events. The (CO)-C-12-O-16 (J = 2-1) emission from the protostar reveals 22 distinct features of outflow ejecta, the most recent having the highest velocity. The outflow forms bipolar lobes one of the first detectable signs of star formation which originate from the peak of 1-mm continuum emission. Emission from the surrounding (CO)-O-18 envelope shows kinematics consistent with rotation and an infall of material onto the protostar. The data suggest that episodic, accretion-driven outflow begins in the earliest phase of protostellar evolution, and that the outflow remains intact in a very clustered environment, probably providing efficient momentum transfer for driving turbulence.
C1 [Plunkett, Adele L.; Arce, Hector G.; van Dokkum, Pieter] Yale Univ, Dept Astron, New Haven, CT 06511 USA.
   [Mardones, Diego] Univ Chile, Dept Astron, Santiago, Chile.
   [Dunham, Michael M.] Harvard Smithsonian Ctr Astrophys, Cambridge, MA 02138 USA.
   [Fernandez-Lopez, Manuel] CCT La Plata CONICET, Inst Argentino Radioastron, RA-1894 Villa Elisa, Argentina.
   [Gallardo, Jose; Corder, Stuartt A.] Joint ALMA Observ, Santiago, Chile.
C3 Yale University; Universidad de Chile; Smithsonian Astrophysical Observatory; Harvard University; Smithsonian Institution; Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); Instituto Argentino de Radioastronomia
RP Plunkett, AL (corresponding author), Yale Univ, Dept Astron, New Haven, CT 06511 USA.
EM adele.plunkett@yale.edu; hectorarce@yale.edu
FU National Science Foundation (NSF) [DGE-1122492]; NSF [AST-0845619]; CONICYT [PFB-06]; Submillimeter Array
NR 29
TC 87
Z9 92
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 NOV 5
PY 2015
VL 527
IS 7576
BP 70
EP 73
DI 10.1038/nature15702
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV4XV
UT WOS:000364270700044
PM 26536957
DA 2026-03-09
ER

PT J
AU Derivery, E
   Seum, C
   Daeden, A
   Loubéry, S
   Holtzer, L
   Jülicher, F
   Gonzalez-Gaitan, M
AF Derivery, Emmanuel
   Seum, Carole
   Daeden, Alicia
   Loubery, Sylvain
   Holtzer, Laurent
   Juelicher, Frank
   Gonzalez-Gaitan, Marcos
TI Polarized endosome dynamics by spindle asymmetry during asymmetric cell division
SO NATURE
LA English
DT Article
ID sara endosm; drosophila-neuroblasts; notch trafficking; rab proteins; microtubules; patronin; domains; pathway; fate; numb
AB During asymmetric division, fate determinants at the cell cortex segregate unequally into the two daughter cells. It has recently been shown that Sara (Smad anchor for receptor activation) signalling endosomes in the cytoplasm also segregate asymmetrically during asymmetric division(1,2). Biased dispatch of Sara endosomes mediates asymmetric Notch/Delta signalling during the asymmetric division of sensory organ precursors in Drosophila(1). In flies, this has been generalized to stem cells in the gut(3) and the central nervous system(1), and, in zebrafish, to neural precursors of the spinal cord(4). However, the mechanism of asymmetric endosome segregation is not understood. Here we show that the plus-end kinesin motor Klp98A targets Sara endosomes to the central spindle, where they move bidirectionally on an antiparallel array of microtubules. The microtubule depolymerizing kinesin Klp10A and its antagonist Patronin generate central spindle asymmetry. This asymmetric spindle, in turn, polarizes endosome motility, ultimately causing asymmetric endosome dispatch into one daughter cell. We demonstrate this mechanism by inverting the polarity of the central spindle by polar targeting of Patronin using nanobodies (single-domain antibodies). This spindle inversion targets the endosomes to the wrong cell. Our data uncover the molecular and physical mechanism by which organelles localized away from the cellular cortex can be dispatched asymmetrically during asymmetric division.
C1 [Derivery, Emmanuel; Seum, Carole; Daeden, Alicia; Loubery, Sylvain; Holtzer, Laurent; Gonzalez-Gaitan, Marcos] Univ Geneva, Fac Sci, Dept Biochem, CH-1211 Geneva, Switzerland.
   [Juelicher, Frank] Max Planck Inst Phys Komplexer Syst, D-01187 Dresden, Germany.
C3 University of Geneva; Max Planck Society
RP Gonzalez-Gaitan, M (corresponding author), Univ Geneva, Fac Sci, Dept Biochem, 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
EM emmanuel.derivery@unige.ch; julicher@pks.mpg.de; marcos.gonzalez@unige.ch
FU Human Frontier Science Program; Marie-Curie Intra-European Fellowship; Departement de l'Instruction Publique of the Canton of Geneva; SNF; SystemsX epiPhysX program; NCCR Chemical Biology program; ERC; Polish-Swiss research programs
NR 65
TC 110
Z9 125
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 DEC 10
PY 2015
VL 528
IS 7581
BP 280
EP +
DI 10.1038/nature16443
PG 36
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX9VH
UT WOS:000366053300045
PM 26659188
DA 2026-03-09
ER

PT J
AU Willem, M
   Tahirovic, S
   Busche, MA
   Ovsepian, SV
   Chafai, M
   Kootar, S
   Hornburg, D
   Evans, LDB
   Moore, S
   Daria, A
   Hampel, H
   Müller, V
   Giudici, C
   Nuscher, B
   Wenninger-Weinzierl, A
   Kremmer, E
   Heneka, MT
   Thal, DR
   Giedraitis, V
   Lannfelt, L
   Müller, U
   Livesey, FJ
   Meissner, F
   Herms, J
   Konnerth, A
   Marie, H
   Haass, C
AF Willem, Michael
   Tahirovic, Sabina
   Busche, Marc Aurel
   Ovsepian, Saak V.
   Chafai, Magda
   Kootar, Scherazad
   Hornburg, Daniel
   Evans, Lewis D. B.
   Moore, Steven
   Daria, Anna
   Hampel, Heike
   Mueller, Veronika
   Giudici, Camilla
   Nuscher, Brigitte
   Wenninger-Weinzierl, Andrea
   Kremmer, Elisabeth
   Heneka, Michael T.
   Thal, Dietmar R.
   Giedraitis, Vilmantas
   Lannfelt, Lars
   Mueller, Ulrike
   Livesey, Frederick J.
   Meissner, Felix
   Herms, Jochen
   Konnerth, Arthur
   Marie, Helene
   Haass, Christian
TI η-Secretase processing of APP inhibits neuronal activity in the hippocampus
SO NATURE
LA English
DT Article
ID amyloid precursor protein; pluripotent stem-cells; alzheimers-disease; beta-protein; transgenic mice; synaptic plasticity; mouse model; oligomers; peptide; identification
AB Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-beta peptide(1). Two principal physiological pathways either prevent or promote amyloid-beta generation from its precursor, beta-amyloid precursor protein (APP), in a competitive manne(r)1. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo(2). Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-eta, in addition to the long-known CTF-alpha and CTF-beta fragments generated by the alpha- and beta-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (beta-site APP cleaving enzyme 1), respectively. CTF-eta generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as g-secretase activity. g-Secretase cleavage occurs primarily at amino acids 504-505 of APP(695), releasing a truncated ectodomain. After shedding of this ectodomain, CTF-eta is further processed by ADAM10 and BACE1 to release long and short A eta peptides (termed A eta-alpha and A eta-beta). CTFs produced by g-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-eta and A eta-alpha. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic A eta-alpha was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by A eta-alpha. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.
C1 [Willem, Michael; Daria, Anna; Hampel, Heike; Mueller, Veronika; Giudici, Camilla; Nuscher, Brigitte; Haass, Christian] Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany.
   [Tahirovic, Sabina; Ovsepian, Saak V.; Wenninger-Weinzierl, Andrea; Kremmer, Elisabeth; Herms, Jochen; Haass, Christian] German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany.
   [Busche, Marc Aurel] Tech Univ Munich, Dept Psychiat & Psychotherapy, D-81675 Munich, Germany.
   [Busche, Marc Aurel; Konnerth, Arthur] Tech Univ Munich, Inst Neurosci, D-80802 Munich, Germany.
   [Busche, Marc Aurel; Kremmer, Elisabeth; Konnerth, Arthur; Haass, Christian] Univ Munich, Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany.
   [Chafai, Magda; Kootar, Scherazad; Marie, Helene] Univ Nice Sophia Antipolis, UMR 7275, CNRS, IPMC, F-06560 Valbonne, France.
   [Hornburg, Daniel; Meissner, Felix] Max Planck Inst Biochem, D-82152 Martinsried, Germany.
   [Evans, Lewis D. B.; Moore, Steven; Livesey, Frederick J.] Univ Cambridge, Gurdon Inst, Cambridge Stem Cell Inst, Cambridge CB2 1QN, England.
   [Evans, Lewis D. B.; Moore, Steven; Livesey, Frederick J.] Univ Cambridge, Dept Biochem, Cambridge CB2 1QN, England.
   [Kremmer, Elisabeth] German Res Ctr Environm Hlth, Inst Mol Immunol, D-81377 Munich, Germany.
   [Heneka, Michael T.] Univ Bonn, Clin Neurosci Unit, Dept Neurol, D-53127 Bonn, Germany.
   [Heneka, Michael T.] German Ctr Neurodegenerat Dis DZNE Bonn, D-53175 Bonn, Germany.
   [Thal, Dietmar R.] Univ Ulm, Inst Pathol, Neuropathol Lab, D-89081 Ulm, Germany.
   [Giedraitis, Vilmantas; Lannfelt, Lars] Uppsala Univ, Dept Publ Hlth Geriatr, S-75185 Uppsala, Sweden.
   [Mueller, Ulrike] Heidelberg Univ, Funct Genom, Inst Pharm & Mol Biotechnol IPMB, D-69120 Heidelberg, Germany.
C3 University of Munich; Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE); University of Munich; Technical University of Munich; Technical University of Munich; University of Munich; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite Cote d'Azur; Max Planck Society; University of Cambridge; University of Cambridge; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; University of Bonn; Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE); Ulm University; Uppsala University; Ruprecht Karls University Heidelberg
RP Willem, M (corresponding author), Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany.
EM michael.willem@mail03.med.uni-muenchen.de; christian.haass@mail03.med.uni-muenchen.de
FU European Research Council under European Union/ERC [321366-Amyloid, 318987]; AFI [13803]; Deutsche Forschungsgemeinschaft [MU 1457/9-1, MU 1457/9-2]; ERA-Net Neuron [01EW1305A]; ATIP/AVENIR program (Centre national de la recherche scientifique, CNRS); French Fondation pour la Cooperation Scientifique - Plan Alzheimer; French Government (National Research Agency, ANR) through the "Investments for the Future" LABEX SIGNALIFE: program [ANR-11-LABX-0028-01]; Langmatz Stiftung; Medical Research Council [MR/L023784/1, MR/L023784/2] Funding Source: researchfish; Wellcome Trust [101052/Z/13/Z] Funding Source: researchfish; MRC [MR/L023784/1, MR/L023784/2] Funding Source: UKRI
NR 53
TC 307
Z9 359
U1 0
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 OCT 15
PY 2015
VL 526
IS 7573
BP 443
EP +
DI 10.1038/nature14864
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200054
PM 26322584
DA 2026-03-09
ER

PT J
AU Inaba, M
   Buszczak, M
   Yamashita, YM
AF Inaba, Mayu
   Buszczak, Michael
   Yamashita, Yukiko M.
TI Nanotubes mediate niche-stem-cell signalling in the Drosophila testis
SO NATURE
LA English
DT Article
ID intraflagellar transport; mitotic kinesins; self-renewal; maintenance; division; cilia; spermatogenesis; ciliogenesis; activation; lineage
AB Stem cell niches provide resident stem cells with signals that specify their identity. Niche signals act over a short range such that only stem cells but not their differentiating progeny receive the self-renewing signals(1). However, the cellular mechanisms that limit niche signalling to stem cells remain poorly understood. Here we show that the Drosophila male germline stem cells form previously unrecognized structures, microtubule-based nanotubes, which extend into the hub, a major niche component. Microtubule-based nanotubes are observed specifically within germline stem cell populations, and require intraflagellar transport proteins for their formation. The bone morphogenetic protein (BMP) receptor Tkv localizes to microtubule-based nanotubes. Perturbation of microtubule-based nanotubes compromises activation of Dpp signalling within germline stem cells, leading to germline stem cell loss. Moreover, Dpp ligand and Tkv receptor interaction is necessary and sufficient for microtubule-based nanotube formation. We propose that microtubule-based nanotubes provide a novel mechanism for selective receptor-ligand interaction, contributing to the short-range nature of niche-stem-cell signalling.
C1 [Inaba, Mayu; Yamashita, Yukiko M.] Univ Michigan, Life Sci Inst, Dept Cell & Dev Biol, Sch Med, Ann Arbor, MI 48109 USA.
   [Inaba, Mayu; Yamashita, Yukiko M.] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA.
   [Inaba, Mayu; Buszczak, Michael] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA.
C3 University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Howard Hughes Medical Institute; University of Texas System; University of Texas Southwestern Medical Center
RP Buszczak, M (corresponding author), Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA.
EM michael.buszczak@utsouthwestern.edu; yukikomy@umich.edu
FU Howard Hughes Medical Institute; MacArthur Foundation; National Cancer Institute [P30CA142543] Funding Source: NIH RePORTER
NR 36
TC 151
Z9 183
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 JUL 16
PY 2015
VL 523
IS 7560
BP 329
EP +
DI 10.1038/nature14602
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM8KY
UT WOS:000357950900038
PM 26131929
DA 2026-03-09
ER

PT J
AU Sun, C
   Wade, MT
   Lee, Y
   Orcutt, JS
   Alloatti, L
   Georgas, MS
   Waterman, AS
   Shainline, JM
   Avizienis, RR
   Lin, S
   Moss, BR
   Kumar, R
   Pavanello, F
   Atabaki, AH
   Cook, HM
   Ou, AJ
   Leu, JC
   Chen, YH
   Asanovic, K
   Ram, RJ
   Popovic, MA
   Stojanovic, VM
AF Sun, Chen
   Wade, Mark T.
   Lee, Yunsup
   Orcutt, Jason S.
   Alloatti, Luca
   Georgas, Michael S.
   Waterman, Andrew S.
   Shainline, Jeffrey M.
   Avizienis, Rimas R.
   Lin, Sen
   Moss, Benjamin R.
   Kumar, Rajesh
   Pavanello, Fabio
   Atabaki, Amir H.
   Cook, Henry M.
   Ou, Albert J.
   Leu, Jonathan C.
   Chen, Yu-Hsin
   Asanovic, Krste
   Ram, Rajeev J.
   Popovic, Milos A.
   Stojanovic, Vladimir M.
TI Single-chip microprocessor that communicates directly using light
SO NATURE
LA English
DT Article
ID performance; modulator; networks
AB Data transport across short electrical wires is limited by both bandwidth and power density, which creates a performance bottleneck for semiconductor microchips in modern computer systems-from mobile phones to large-scale data centres. These limitations can be overcome(1-3) by using optical communications based on chip-scale electronic-photonic systems(4-7) enabled by silicon-based nanophotonic devices(8). However, combining electronics and photonics on the same chip has proved challenging, owing to microchip manufacturing conflicts between electronics and photonics. Consequently, current electronic-photonic chips(9-11) are limited to niche manufacturing processes and include only a few optical devices alongside simple circuits. Here we report an electronic-photonic system on a single chip integrating over 70 million transistors and 850 photonic components that work together to provide logic, memory, and interconnect functions. This system is a realization of a microprocessor that uses on-chip photonic devices to directly communicate with other chips using light. To integrate electronics and photonics at the scale of a microprocessor chip, we adopt a 'zero-change' approach to the integration of photonics. Instead of developing a custom process to enable the fabrication of photonics(12), which would complicate or eliminate the possibility of integration with state-of-the-art transistors at large scale and at high yield, we design optical devices using a standard microelectronics foundry process that is used for modern microprocessors(13-16). This demonstration could represent the beginning of an era of chip-scale electronic-photonic systems with the potential to transform computing system architectures, enabling more powerful computers, from network infrastructure to data centres and supercomputers.
C1 [Sun, Chen; Lee, Yunsup; Waterman, Andrew S.; Avizienis, Rimas R.; Lin, Sen; Cook, Henry M.; Ou, Albert J.; Asanovic, Krste; Stojanovic, Vladimir M.] Univ Calif Berkeley, Berkeley, CA 94720 USA.
   [Sun, Chen; Orcutt, Jason S.; Alloatti, Luca; Georgas, Michael S.; Moss, Benjamin R.; Atabaki, Amir H.; Leu, Jonathan C.; Chen, Yu-Hsin; Ram, Rajeev J.] MIT, Cambridge, MA 02139 USA.
   [Wade, Mark T.; Shainline, Jeffrey M.; Kumar, Rajesh; Pavanello, Fabio; Popovic, Milos A.] Univ Colorado, Boulder, CO 80309 USA.
C3 University of California System; University of California Berkeley; Massachusetts Institute of Technology (MIT); University of Colorado System; University of Colorado Boulder
RP Stojanovic, VM (corresponding author), Univ Calif Berkeley, Berkeley, CA 94720 USA.
EM krste@berkeley.edu; rajeev@mit.edu; milos.popovic@colorado.edu; vlada@berkeley.edu
FU DARPA POEM [HR0011-11-C-0100]; DARPA PERFECT [HR0011-12-2-0016]; Berkeley Wireless Research Center; UC Berkeley ASPIRE Lab; MIT CICS; National Science Foundation; FCRP IFC; Trusted Foundry; Intel; Santec; NSERC
NR 36
TC 1064
Z9 1321
U1 22
U2 758
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 24
PY 2015
VL 528
IS 7583
BP 534
EP +
DI 10.1038/nature16454
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900048
PM 26701054
DA 2026-03-09
ER

PT J
AU Mannige, RV
   Haxton, TK
   Proulx, C
   Robertson, EJ
   Battigelli, A
   Butterfoss, GL
   Zuckermann, RN
   Whitelam, S
AF Mannige, Ranjan V.
   Haxton, Thomas K.
   Proulx, Caroline
   Robertson, Ellen J.
   Battigelli, Alessia
   Butterfoss, Glenn L.
   Zuckermann, Ronald N.
   Whitelam, Stephen
TI Peptoid nanosheets exhibit a new secondary-structure motif
SO NATURE
LA English
DT Article
ID energy landscape; dynamics; binding; funnels; charmm
AB A promising route to the synthesis of protein-mimetic materials that are capable of complex functions, such as molecular recognition and catalysis, is provided by sequence-defined peptoid polymers(1,2)-structural relatives of biologically occurring polypeptides. Peptoids, which are relatively non-toxic and resistant to degradation3, can fold into defined structures through a combination of sequence-dependent interactions(3-8). However, the range of possible structures that are accessible to peptoids and other biological mimetics is unknown, and our ability to design protein-like architectures from these polymer classes is limited(9). Here we use molecular-dynamics simulations, together with scattering and microscopy data, to determine the atomic-resolution structure of the recently discovered peptoid nanosheet, an ordered supramolecular assembly that extends macroscopically in only two dimensions. Our simulations show that nanosheets are structurally and dynamically heterogeneous, can be formed only from peptoids of certain lengths, and are potentially porous to water and ions. Moreover, their formation is enabled by the peptoids' adoption of a secondary structure that is not seen in the natural world. This structure, a zigzag pattern that we call a Sigma('sigma')-strand, results from the ability of adjacent backbone monomers to adopt opposed rotational states, thereby allowing the backbone to remain linear and untwisted. Linear backbones tiled in a brick-like way form an extended two-dimensional nanostructure, the Sigma-sheet. The binary rotational-statemotif of the Sigma-strand is not seen in regular protein structures, which are usually built from one type of rotational state. We also show that the concept of building regular structures from multiple rotational states can be generalized beyond the peptoid nanosheet system.
C1 [Mannige, Ranjan V.; Haxton, Thomas K.; Proulx, Caroline; Robertson, Ellen J.; Battigelli, Alessia; Zuckermann, Ronald N.; Whitelam, Stephen] Lawrence Berkeley Natl Lab, Mol Foundry, Berkeley, CA 94709 USA.
   [Butterfoss, Glenn L.] New York Univ Abu Dhabi, Ctr Genom & Syst Biol, Abu Dhabi, U Arab Emirates.
C3 United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; New York University; New York University Abu Dhabi
RP Mannige, RV (corresponding author), Lawrence Berkeley Natl Lab, Mol Foundry, Berkeley, CA 94709 USA.
EM rvmannige@lbl.gov; swhitelam@lbl.gov
FU Office of Science, Office of Basic Energy Sciences of the US Department of Energy [DE-AC02-05CH11231]; Defense Threat Reduction Agency [IACRO-B0845281]; Natural Sciences and Engineering Research Council of Canada (NSERC PDF); Office of Science of the US Department of Energy [DE-AC02-05CH11231]
NR 36
TC 175
Z9 209
U1 1
U2 201
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 15
PY 2015
VL 526
IS 7573
BP 415
EP +
DI 10.1038/nature15363
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200048
PM 26444241
DA 2026-03-09
ER

PT J
AU Peelaerts, W
   Bousset, L
   Van der Perren, A
   Moskalyuk, A
   Pulizzi, R
   Giugliano, M
   Van den Haute, C
   Melki, R
   Baekelandt, V
AF Peelaerts, W.
   Bousset, L.
   Van der Perren, A.
   Moskalyuk, A.
   Pulizzi, R.
   Giugliano, M.
   Van den Haute, C.
   Melki, R.
   Baekelandt, V.
TI α-Synuclein strains cause distinct synucleinopathies after local and systemic administration
SO NATURE
LA English
DT Article
ID parkinsons-disease; lewy body; substantia-nigra; pathology; neurons; transmission; neurodegeneration; overexpression; fibrillar; brain
AB Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases, but differences in protein components and affected brain regions(1). The molecular hallmark of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are megadalton alpha-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial alpha-synuclein (alpha-SYN) filamentous deposits are prominent in multiple system atrophy and neuronal alpha-SYN inclusions are found in Parkinson's disease and dementia with Lewy bodies(2). The discovery of alpha-SYN assemblies with different structural characteristics or 'strains' has led to the hypothesis that strains could account for the different clinicopathological traits within synucleinopathies(3,4). In this study we show that alpha-SYN strain conformation and seeding propensity lead to distinct histopathological and behavioural phenotypes. We assess the properties of structurally well-defined alpha-SYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that alpha-SYN strains amplify in vivo. Fibrils seem to be the major toxic strain, resulting in progressive motor impairment and cell death, whereas ribbons cause a distinct histopathological phenotype displaying Parkinson's disease and multiple system atrophy traits. Additionally, we show that alpha-SYN assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct alpha-SYN strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes.
C1 [Peelaerts, W.; Van der Perren, A.; Van den Haute, C.; Baekelandt, V.] Katholieke Univ Leuven, Lab Neurobiol & Gene Therapy, Dept Neurosci, B-3000 Leuven, Belgium.
   [Bousset, L.; Melki, R.] CNRS, Paris Saclay Inst Neurosci, F-91198 Gif Sur Yvette, France.
   [Moskalyuk, A.; Pulizzi, R.; Giugliano, M.] Univ Antwerp, Dept Biomed Sci, Theoret Neurobiol & Neuroengn Lab, B-2610 Antwerp, Belgium.
   [Giugliano, M.] Univ Sheffield, Dept Comp Sci, Sheffield S1 4DP, S Yorkshire, England.
   [Giugliano, M.] Swiss Fed Inst Technol Lausanne, Brain Mind Inst, CH-1015 Lausanne, Switzerland.
   [Giugliano, M.] Neuroelect Res Flanders NERF, B-3001 Leuven, Belgium.
   [Van den Haute, C.] Katholieke Univ Leuven, Viral Vector Core, B-3000 Leuven, Belgium.
C3 KU Leuven; Centre National de la Recherche Scientifique (CNRS); Universite Paris Saclay; University of Antwerp; University of Sheffield; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; KU Leuven
RP Baekelandt, V (corresponding author), Katholieke Univ Leuven, Lab Neurobiol & Gene Therapy, Dept Neurosci, B-3000 Leuven, Belgium.
EM ronald.melki@lebs.cnrs-gif.fr; veerle.baekelandt@med.kuleuven.be
FU FWO-Vlaanderen [G.0768.10, G.0927.14]; IWT-Vlaanderen [IWT SBO/80020 Neuro-TARGET, SBO/110068 OPTOBRAIN, SBO/130065 MIRIAD]; FP7 RTD project MEFOPA [HEALTH-2009-241791]; FP7 RTD project INMiND [HEALTH-F2-2011-278850]; KU Leuven [OT/08/052A, OT/14/120, IMIR PF/10/017]; Agence Nationale de la Recherche [ANR-09-MNPS-013-01, ANR-11-BSV8-021-01]; Centre National de la Recherche Scientifique; 'Coup d'Elan a la Recherche Francaise' award from Fondation Bettencourt Schueller; EC-FP7 (Marie Curie Initial Training Network "NAMASEN") [264872]; ICT-FET project "ENLIGHTENMENT"; ICT-FET project "BRAINLEAP" [284801, 306502]; Belgian Science Policy Office [IUAP-VII/20]
NR 36
TC 933
Z9 1040
U1 3
U2 162
PU NATURE PUBLISHING 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 18
PY 2015
VL 522
IS 7556
BP 340
EP +
DI 10.1038/nature14547
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK7PU
UT WOS:000356425400053
PM 26061766
DA 2026-03-09
ER

PT J
AU Doyle, L
   Hallinan, J
   Bolduc, J
   Parmeggiani, F
   Baker, D
   Stoddard, BL
   Bradley, P
AF Doyle, Lindsey
   Hallinan, Jazmine
   Bolduc, Jill
   Parmeggiani, Fabio
   Baker, David
   Stoddard, Barry L.
   Bradley, Philip
TI Rational design of α-helical tandem repeat proteins with closed architectures
SO NATURE
LA English
DT Article
ID computational design; peptide-binding; dna; classification; recognition; scaffolds; sequence; binders; suite
AB Tandem repeat proteins, which are formed by repetition of modular units of protein sequence and structure, play important biological roles as macromolecular binding and scaffolding domains, enzymes, and building blocks for the assembly of fibrous materials(1,2). The modular nature of repeat proteins enables the rapid construction and diversification of extended binding surfaces by duplication and recombination of simple building blocks(3,4). The overall architecture of tandem repeat protein structures-which is dictated by the internal geometry and local packing of the repeat building blocks-is highly diverse, ranging from extended, super-helical folds that bind peptide, DNA, and RNA partners(5-9), to closed and compact conformations with internal cavities suitable for small molecule binding and catalysis(10). Here we report the development and validation of computational methods for de novo design of tandem repeat protein architectures driven purely by geometric criteria defining the inter-repeat geometry, without reference to the sequences and structures of existing repeat protein families. We have applied these methods to design a series of closed alpha-solenoid(11) repeat structures (alpha-toroids) in which the inter-repeat packing geometry is constrained so as to juxtapose the amino (N) and carboxy (C) termini; several of these designed structures have been validated by X-ray crystallography. Unlike previous approaches to tandem repeat protein engineering(12-20), our design procedure does not rely on template sequence or structural information taken from natural repeat proteins and hence can produce structures unlike those seen in nature. As an example, we have successfully designed and validated closed alpha-solenoid repeats with a left-handed helical architecture that-to our knowledge-is not yet present in the protein structure database(21).
C1 [Doyle, Lindsey; Hallinan, Jazmine; Bolduc, Jill; Stoddard, Barry L.; Bradley, Philip] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA.
   [Parmeggiani, Fabio; Baker, David] Univ Washington, Dept Biochem, Seattle, WA 98195 USA.
   [Parmeggiani, Fabio; Baker, David; Bradley, Philip] Univ Washington, Inst Prot Design, Seattle, WA 98195 USA.
   [Baker, David] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA.
   [Bradley, Philip] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98019 USA.
C3 Fred Hutchinson Cancer Center; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Howard Hughes Medical Institute; Fred Hutchinson Cancer Center
RP Bradley, P (corresponding author), Fred Hutchinson Canc Res Ctr, Div Basic Sci, 1100 Fairview Ave N, Seattle, WA 98109 USA.
EM pbradley@fredhutch.org
FU National Institutes of Health [R21GM106117, R01GM49857]; Swiss National Science Foundation Postdoc Fellowship [PBZHP3-125470]; Human Frontier Science Program Long-Term Fellowship [LT000070/2009-L]; Swiss National Science Foundation (SNF) [PBZHP3-125470] Funding Source: Swiss National Science Foundation (SNF)
NR 46
TC 102
Z9 131
U1 2
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 DEC 24
PY 2015
VL 528
IS 7583
BP 585
EP +
DI 10.1038/nature16191
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900059
PM 26675735
DA 2026-03-09
ER

PT J
AU Mathieson, I
   Lazaridis, I
   Rohland, N
   Mallick, S
   Patterson, N
   Roodenberg, SA
   Harney, E
   Stewardson, K
   Fernandes, D
   Novak, M
   Sirak, K
   Gamba, C
   Jones, ER
   Llamas, B
   Dryomov, S
   Pickrell, J
   Arsuaga, JL
   de Castro, JMB
   Carbonell, E
   Gerritsen, F
   Khokhlov, A
   Kuznetsov, P
   Lozano, M
   Meller, H
   Mochalov, O
   Moiseyev, V
   Guerra, MAR
   Roodenberg, J
   Vergès, JM
   Krause, J
   Cooper, A
   Alt, KW
   Brown, D
   Anthony, D
   Lalueza-Fox, C
   Haak, W
   Pinhasi, R
   Reich, D
AF Mathieson, Iain
   Lazaridis, Iosif
   Rohland, Nadin
   Mallick, Swapan
   Patterson, Nick
   Roodenberg, Songul Alpaslan
   Harney, Eadaoin
   Stewardson, Kristin
   Fernandes, Daniel
   Novak, Mario
   Sirak, Kendra
   Gamba, Cristina
   Jones, Eppie R.
   Llamas, Bastien
   Dryomov, Stanislav
   Pickrell, Joseph
   Luis Arsuaga, Juan
   Bermudez de Castro, Jose Maria
   Carbonell, Eudald
   Gerritsen, Fokke
   Khokhlov, Aleksandr
   Kuznetsov, Pavel
   Lozano, Marina
   Meller, Harald
   Mochalov, Oleg
   Moiseyev, Vyacheslav
   Rojo Guerra, Manuel A.
   Roodenberg, Jacob
   Maria Verges, Josep
   Krause, Johannes
   Cooper, Alan
   Alt, Kurt W.
   Brown, Dorcas
   Anthony, David
   Lalueza-Fox, Carles
   Haak, Wolfgang
   Pinhasi, Ron
   Reich, David
TI Genome-wide patterns of selection in 230 ancient Eurasians
SO NATURE
LA English
DT Article
ID genetic-determinants; positive selection; association; loci; edar; identification; polymorphisms; pigmentation; architecture; populations
AB Ancient DNA makes it possible to observe natural selection directly by analysing samples from populations before, during and after adaptation events. Here we report a genome-wide scan for selection using ancient DNA, capitalizing on the largest ancient DNA data set yet assembled: 230 West Eurasians who lived between 6500 and 300 BC, including 163 with newly reported data. The new samples include, to our knowledge, the first genome-wide ancient DNA from Anatolian Neolithic farmers, whose genetic material we obtained by extracting from petrous bones, and who we show were members of the population that was the source of Europe's first farmers. We also report a transect of the steppe region in Samara between 5600 and 300 BC, which allows us to identify admixture into the steppe from at least two external sources. We detect selection at loci associated with diet, pigmentation and immunity, and two independent episodes of selection on height.
C1 [Mathieson, Iain; Lazaridis, Iosif; Rohland, Nadin; Mallick, Swapan; Harney, Eadaoin; Stewardson, Kristin; Pickrell, Joseph; Reich, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
   [Lazaridis, Iosif; Rohland, Nadin; Mallick, Swapan; Patterson, Nick; Reich, David] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Mallick, Swapan; Harney, Eadaoin; Stewardson, Kristin; Reich, David] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA.
   [Fernandes, Daniel; Novak, Mario; Sirak, Kendra; Gamba, Cristina; Pinhasi, Ron] Univ Coll Dublin, Sch Archaeol, Dublin 4, Ireland.
   [Fernandes, Daniel; Novak, Mario; Sirak, Kendra; Gamba, Cristina; Pinhasi, Ron] Univ Coll Dublin, Earth Inst, Dublin 4, Ireland.
   [Novak, Mario] Inst Anthropol Res, Zagreb 10000, Croatia.
   [Sirak, Kendra] Emory Univ, Dept Anthropol, Atlanta, GA 30322 USA.
   [Gamba, Cristina; Jones, Eppie R.] Univ Dublin Trinity Coll, Smurfit Inst Genet, Dublin 2, Ireland.
   [Llamas, Bastien; Cooper, Alan; Haak, Wolfgang] Univ Adelaide, Sch Biol Sci, Australian Ctr Ancient DNA, Adelaide, SA 5005, Australia.
   [Llamas, Bastien; Haak, Wolfgang] Univ Adelaide, Sch Environm Inst, Australian Ctr Ancient DNA, Adelaide, SA 5005, Australia.
   [Dryomov, Stanislav] Russian Acad Sci, Inst Mol & Cellular Biol, Siberian Branch, Lab Human Mol Genet, Novosibirsk 630090, Russia.
   [Dryomov, Stanislav] Russian Acad Sci, Inst Archaeol & Ethnog, Siberian Branch, Dept Paleolith Archaeol, Novosibirsk 630090, Russia.
   [Luis Arsuaga, Juan] Ctr Mixto UCM ISCIII Evoluc & Comportamiento Huma, Madrid 28040, Spain.
   [Luis Arsuaga, Juan] Univ Complutense Madrid, Fac Ciencias Geol, Dept Paleontol, E-28040 Madrid, Spain.
   [Bermudez de Castro, Jose Maria] Ctr Nacl Invest Evoluc Humana CENIEH, Burgos 09002, Spain.
   [Carbonell, Eudald; Lozano, Marina; Maria Verges, Josep] IPHES Inst Catala Paleoecol Humana & Evolucio Soc, Tarragona 43007, Spain.
   [Carbonell, Eudald; Lozano, Marina; Maria Verges, Josep] Univ Rovira & Virgili, Area Prehist, Tarragona 43002, Spain.
   [Gerritsen, Fokke] Netherlands Inst Turkey, TR-34433 Istanbul, Turkey.
   [Khokhlov, Aleksandr; Kuznetsov, Pavel; Mochalov, Oleg] Volga State Acad Social Sci & Humanities, Samara 443099, Russia.
   [Meller, Harald; Alt, Kurt W.] State Off Heritage Management & Archaeol, D-06114 Halle, Germany.
   [Meller, Harald; Alt, Kurt W.] Archaeol Saxony Anhalt & State Museum Prehist, D-06114 Halle, Germany.
   [Moiseyev, Vyacheslav] RAS, Peter Great Museum Anthropol & Ethnog Kunstkamera, St Petersburg 199034, Russia.
   [Rojo Guerra, Manuel A.] Univ Valladolid, Dept Prehist & Archaeol, E-47002 Valladolid, Spain.
   [Roodenberg, Jacob] Netherlands Inst Near East, NL-2300 RA Leiden, Netherlands.
   [Krause, Johannes; Haak, Wolfgang] Max Planck Inst Sci Human Hist, D-07745 Jena, Germany.
   [Krause, Johannes] Univ Tubingen, Inst Archaeol Sci, D-72070 Tubingen, Germany.
   [Alt, Kurt W.] Danube Private Univ, A-3500 Krems, Austria.
   [Alt, Kurt W.] Univ Basel, Inst Prehist & Archaeol Sci, CH-4003 Basel, Switzerland.
   [Brown, Dorcas; Anthony, David] Hartwick Coll, Dept Anthropol, Oneonta, NY 13820 USA.
   [Lalueza-Fox, Carles] CSIC Univ Pompeu Fabra, Inst Evolutionary Biol, Barcelona 08003, Spain.
C3 Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Howard Hughes Medical Institute; University College Dublin; University College Dublin; Institute for Anthropological Research Zagreb; Emory University; Trinity College Dublin; Adelaide University; University of Adelaide; Adelaide University; University of Adelaide; Russian Academy of Sciences; Siberian Branch of the Russian Academy of Sciences; Russian Academy of Sciences; Institute of Archaeology & Ethnography, Siberian Branch of Russian Academy of Sciences; Siberian Branch of the Russian Academy of Sciences; Complutense University of Madrid; UCM-ISCIII Center for Human Evolution & Behavior; Complutense University of Madrid; Centro Nacional de Investigacion de La Evolucion Humana (CENIEH); Universitat Rovira i Virgili; Catalan Institute of Human Paleo-Ecology & Social Evolution (IPHES); Universitat Rovira i Virgili; Netherlands Institute in Turkey; Samara State University of Social Sciences & Education; Russian Academy of Sciences; The Kunstkamera; Universidad de Valladolid; Eberhard Karls University of Tubingen; University of Basel; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC-UPF - Institut de Biologia Evolutiva (IBE); Pompeu Fabra University
RP Mathieson, I (corresponding author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
EM iain_mathieson@hms.harvard.edu; haak@shh.mpg.de; ron.pinhasi@ucd.ie; reich@genetics.med.harvard.edu
FU Human Frontier Science Program [LT001095/2014-L]; Irish Research Council for Humanities and Social Sciences (IRCHSS); Netherlands Organization for Scientific Research [380-62-005]; RFBR [15-06-01916]; RFH [15-11-63008]; Ministry of Education and Science of the Russia Federation [33.1195.2014/k]; ERC starting grant APGREID; DFG [KR 4015/1-1, AL 287/14-1]; Spanish government [BFU2015-64699-P]; Australian Research Council [DP130102158]; ERC starting grant ADNABIOARC [263441]; Irish Research Council ERC support grant; US National Science Foundation HOMINID grant [BCS-1032255]; US National Institutes of Health [GM100233]; Howard Hughes Medical Institute; European Research Council (ERC) [263441] Funding Source: European Research Council (ERC); Division Of Behavioral and Cognitive Sci; Direct For Social, Behav & Economic Scie [1032255] Funding Source: National Science Foundation
NR 60
TC 975
Z9 1119
U1 3
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 DEC 24
PY 2015
VL 528
IS 7583
BP 499
EP +
DI 10.1038/nature16152
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900041
PM 26595274
DA 2026-03-09
ER

PT J
AU Aplin, LM
   Farine, DR
   Morand-Ferron, J
   Cockburn, A
   Thornton, A
   Sheldon, BC
AF Aplin, Lucy M.
   Farine, Damien R.
   Morand-Ferron, Julie
   Cockburn, Andrew
   Thornton, Alex
   Sheldon, Ben C.
TI Experimentally induced innovations lead to persistent culture via conformity in wild birds
SO NATURE
LA English
DT Article
ID transmission; dynamics
AB In human societies, cultural norms arise when behaviours are transmitted through social networks via high-fidelity social learning'. However, a paucity of experimental studies has meant that there is no comparable understanding of the process by which socially transmitted behaviours might spread and persist in animal populations'''. Here we show experimental evidence of the establishment of foraging traditions in a wild bird population. We introduced alternative novel foraging techniques into replicated wild sub-populations of great tits (Parus major) and used automated tracking to map the diffusion, establishment and long-term persistence of the seeded innovations. Furthermore, we used social network analysis to examine the social factors that influenced diffusion dynamics. From only two trained birds in each sub-population, the information spread rapidly through social network ties, to reach an average of 75% of individuals, with a total of 414 knowledgeable individuals performing 57,909 solutions over all replicates. The sub-populations were heavily biased towards using the technique that was originally introduced, resulting in established local traditions that were stable over two generations, despite a high population turnover. Finally, we demonstrate a strong effect of social conformity, with individuals disproportionately adopting the most frequent local variant when first acquiring an innovation, and continuing to favour social information over personal information. Cultural conformity is thought to be a key factor in the evolution of complex culture in humans''. In providing the first experimental demonstration of conformity in a wild non-primate, and of cultural norms in foraging techniques in any wild animal, our results suggest a much broader taxonomic occurrence of such an apparently complex cultural behaviour.
C1 [Aplin, Lucy M.; Farine, Damien R.; Sheldon, Ben C.] Univ Oxford, Dept Zool, Edward Grey Inst, Oxford OX1 3PS, England.
   [Aplin, Lucy M.; Cockburn, Andrew] Australian Natl Univ, Res Sch Biol, Dept Evolut Ecol & Genet, Canberra, ACT 2600, Australia.
   [Farine, Damien R.] Univ Calif Davis, Dept Anthropol, Davis, CA 95616 USA.
   [Farine, Damien R.] Smithsonian Trop Res Inst, Ancon 9100, Panama.
   [Morand-Ferron, Julie] Univ Ottawa, Dept Biol, Ottawa, ON K1N 9B2, Canada.
   [Thornton, Alex] Univ Exeter, Ctr Ecol & Conservat, Dept Biosci, Penryn TR10 9EZ, England.
   [Sheldon, Ben C.] Uppsala Univ, Dept Ecol & Genet, S-75236 Uppsala, Sweden.
C3 University of Oxford; Australian National University; University of California System; University of California Davis; Smithsonian Institution; Smithsonian Tropical Research Institute; University of Ottawa; University of Exeter; Uppsala University
RP Aplin, LM (corresponding author), Univ Oxford, Dept Zool, Edward Grey Inst, Oxford OX1 3PS, England.
EM lucy.aplin@zoo.ox.ac.uk
FU BBSRC [BB/L006081/1, BB/H021817/1]; ERC [AdG 250164]; Australian Postgraduate Award; BBSRC [BB/L006081/1, BB/H021817/2, BB/H021817/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/H021817/2, BB/L006081/1, BB/H021817/1] Funding Source: researchfish
NR 30
TC 517
Z9 578
U1 9
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 FEB 26
PY 2015
VL 518
IS 7540
BP 538
EP 541
DI 10.1038/nature13998
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC1JP
UT WOS:000350097300047
PM 25470065
DA 2026-03-09
ER

PT J
AU Busch, K
   Klapproth, K
   Barile, M
   Flossdorf, M
   Holland-Letz, T
   Schlenner, SM
   Reth, M
   Höfer, T
   Rodewald, HR
AF Busch, Katrin
   Klapproth, Kay
   Barile, Melania
   Flossdorf, Michael
   Holland-Letz, Tim
   Schlenner, Susan M.
   Reth, Michael
   Hoefer, Thomas
   Rodewald, Hans-Reimer
TI Fundamental properties of unperturbed haematopoiesis from stem cells in vivo
SO NATURE
LA English
DT Article
ID clonal analysis; reconstitution; expression; receptor; marrow; mouse; gene
AB Haematopoietic stem cells (HSCs) are widely studied by HSC transplantation into immune- and blood-cell-depleted recipients. Single HSCs can rebuild the system after transplantation(1-5). Chromosomal marking', viral integration(7-9) and barcoding' of transplanted HSCs suggest that very low numbers of HSCs perpetuate a continuous stream of differentiating cells. However, the numbers of productive HSCs during normal haematopoiesis, and the flux of differentiating progeny remain unknown. Here we devise a mouse model allowing inducible genetic labelling of the most primitive Tie(2+) HSCs in bone marrow, and quantify label progression along haematopoietic development by limiting dilution analysis and data-driven modelling. During maintenance of the haematopoietic system, at least 30% or 5,000 HSCs are productive in the adult mouse after label induction. However, the time to approach equilibrium between labelled HSCs and their progeny is surprisingly long, a time scale that would exceed the mouse's life. Indeed, we find that adult haematopoiesis is largely 'sustained by previously designated 'short-term' stem cells downstream of HSCs that nearly fully self-renew, and receive rare but polydonal HSC input. By contrast, in fetal and early postnatal life, HSCs are rapidly used to establish the immune and blood system. In the adult mouse, 5-fluoruracil-induced leukopenia enhances the output of HSCs and of downstream compartments, thus accelerating haematopoietic flux. Label tracing also identifies a strong lineage bias in adult mice, with several-hundred-fold larger myeloid than lymphoid output, which is only marginally accentuated with age. Finally, we show that transplantation imposes severe constraints on HSC engraftment, consistent with the previously observed oligodonal HSC activity under these conditions. Thus, we uncover fundamental differences between the normal maintenance of the haematopoietic system, its regulation by challenge, and its re-establishment after transplantation. HSC fate mapping and its linked modelling provide a quantitative framework for studying in situ the regulation of haematopoiesis in health and disease.
C1 [Busch, Katrin; Klapproth, Kay; Rodewald, Hans-Reimer] German Canc Res Ctr, Div Cellular Immunol, D-69120 Heidelberg, Germany.
   [Barile, Melania; Flossdorf, Michael; Hoefer, Thomas] German Canc Res Ctr, Div Theoret Syst Biol, D-69120 Heidelberg, Germany.
   [Holland-Letz, Tim] German Canc Res Ctr, Div Biostat, D-69120 Heidelberg, Germany.
   [Schlenner, Susan M.] Univ Leuven, Dept Microbiol & Immunol, B-3000 Leuven, Belgium.
   [Schlenner, Susan M.] VIB, Autoimmune Genet Lab, B-3000 Leuven, Belgium.
   [Reth, Michael] Univ Freiburg, Ctr Biol Signaling Studies, BIOSS, D-79104 Freiburg, Germany.
   [Reth, Michael] Univ Freiburg, Fac Biol, Dept Mol Immunol, D-79108 Freiburg, Germany.
   [Reth, Michael] Max Planck Inst Immunobiol & Epigenet, D-79108 Freiburg, Germany.
C3 Helmholtz Association; German Cancer Research Center (DKFZ); Helmholtz Association; German Cancer Research Center (DKFZ); Helmholtz Association; German Cancer Research Center (DKFZ); KU Leuven; Flanders Institute for Biotechnology (VIB); University of Freiburg; University of Freiburg; Max Planck Society
RP Rodewald, HR (corresponding author), German Canc Res Ctr, Div Cellular Immunol, Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
EM thoefer@dkfz.de; hr.rodewald@dkfz.de
FU International Graduate School in Molecular Medicine, Ulm; DFG [EXC294, TRR130, SFB746, SFB 873, SFB 938]; BMBF [Fkz 031614]; EU-FP7 Marie Curie ITN Quantitative T cell immunology (QuanTI); ERC [233074]; Helmholtz Alliance on preclinical cancer models (PCCC); European Research Council (ERC) [233074] Funding Source: European Research Council (ERC)
NR 24
TC 567
Z9 679
U1 0
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 FEB 26
PY 2015
VL 518
IS 7540
BP 542
EP 546
DI 10.1038/nature14242
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC1JP
UT WOS:000350097300048
PM 25686605
DA 2026-03-09
ER

PT J
AU Tresini, M
   Warmerdam, DO
   Kolovos, P
   Snijder, L
   Vrouwe, MG
   Demmers, JAA
   van IJcken, WFJ
   Grosveld, FG
   Medema, RH
   Hoeijmakers, JHJ
   Mullenders, LHF
   Vermeulen, W
   Marteijn, JA
AF Tresini, Maria
   Warmerdam, Daniel O.
   Kolovos, Petros
   Snijder, Loes
   Vrouwe, Mischa G.
   Demmers, Jeroen A. A.
   van IJcken, Wilfred F. J.
   Grosveld, Frank G.
   Medema, Rene H.
   Hoeijmakers, Jan H. J.
   Mullenders, Leon H. F.
   Vermeulen, Wim
   Marteijn, Jurgen A.
TI The core spliceosome as target and effector of non-canonical ATM signalling
SO NATURE
LA English
DT Article
ID dna-damage response; rna-polymerase-ii; ataxia-telangiectasia; transcription; activation; phosphorylation; chromatin; proteome
AB In response to DNA damage, tissue homoeostasis is ensured by protein networks promoting DNA repair, cell cycle arrest or apoptosis. DNA damage response signalling pathways coordinate these processes, partly by propagating gene-expression-modulating signals. DNA damage influences not only the abundance of messenger RNAs, but also their coding information through alternative splicing. Here we show that transcription-blocking DNA lesions promote chromatin displacement of late-stage spliceosomes and initiate a positive feedback loop centred on the signalling kinase ATM. We propose that initial spliceosome displacement and subsequent R-loop formation is triggered by pausing of RNA polymerase at DNA lesions. In turn, R-loops activate ATM, which signals to impede spliceosome organization further and augment ultraviolet-irradiation-triggered alternative splicing at the genome-wide level. Our findings define R-loop-dependent ATM activation by transcription-blocking lesions as an important event in the DNA damage response of non-replicating cells, and highlight a key role for spliceosome displacement in this process.
C1 [Tresini, Maria; Snijder, Loes; Hoeijmakers, Jan H. J.; Vermeulen, Wim; Marteijn, Jurgen A.] Erasmus Univ, Med Ctr, Dept Genet, Canc Genom Netherlands, NL-3015 CN Rotterdam, Netherlands.
   [Warmerdam, Daniel O.; Medema, Rene H.] Netherlands Canc Inst, Div Cell Biol, NL-1066 CX Amsterdam, Netherlands.
   [Kolovos, Petros; Grosveld, Frank G.] Erasmus Univ, Med Ctr, Dept Cell Biol, NL-3015 CN Rotterdam, Netherlands.
   [Vrouwe, Mischa G.; Mullenders, Leon H. F.] Leiden Univ, Dept Human Genet, Med Ctr, NL-2333 ZC Leiden, Netherlands.
   [Demmers, Jeroen A. A.] Erasmus Univ, Med Ctr, Erasmus MC Prote Ctr, NL-3015 CN Rotterdam, Netherlands.
   [van IJcken, Wilfred F. J.] Erasmus Univ, Med Ctr, Erasmus Ctr Biom, NL-3015 CN Rotterdam, Netherlands.
C3 Erasmus University Rotterdam; Erasmus MC; Netherlands Cancer Institute; Erasmus University Rotterdam; Erasmus MC; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Erasmus University Rotterdam; Erasmus MC; Erasmus University Rotterdam; Erasmus MC
RP Tresini, M (corresponding author), Erasmus Univ, Med Ctr, Dept Genet, Canc Genom Netherlands, NL-3015 CN Rotterdam, Netherlands.
EM m.tresini@erasmusmc.nl; w.vermeulen@erasmusmc.nl; j.marteijn@erasmsumc.nl
FU Netherlands Organization for Scientific Research (NWO) ZonMW TOP Grant [912.08.031, 912.12.132]; Netherlands Organization for Scientific Research (NWO) ZonMW Horizon Zenith Grant [935.11.042]; Netherlands Organization for Scientific Research (NWO) ZonMW ALW Grant [854.11.002, 823.02.013]; Association for International Cancer Research [10-594]; European Research Council [233424, 340988]; ErasmusMC fellowship; National Institute on Aging [P01AG017242] Funding Source: NIH RePORTER; European Research Council (ERC) [233424, 340988] Funding Source: European Research Council (ERC)
NR 45
TC 208
Z9 238
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 JUL 2
PY 2015
VL 523
IS 7558
BP 53
EP +
DI 10.1038/nature14512
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL7RN
UT WOS:000357169500029
PM 26106861
DA 2026-03-09
ER

PT J
AU Alarcón, CR
   Lee, H
   Goodarzi, H
   Halberg, N
   Tavazoie, SF
AF Alarcon, Claudio R.
   Lee, Hyeseung
   Goodarzi, Hani
   Halberg, Nils
   Tavazoie, Sohail F.
TI N6-methyladenosine marks primary microRNAs for processing
SO NATURE
LA English
DT Article
ID rna; platform; subunit; complex; region
AB The first step in the biogenesis of microRNAs is the processing of primary microRNAs (pri-miRNAs) by the microprocessor complex, composed of the RNA-binding protein DGCR8 and the type III RNase DROSHA(1-4). This initial event requires recognition of the junction between the stem and the flanking single-stranded RNA of the pri-miRNA hairpin by DGCR8 followed by recruitment of DROSHA, which cleaves the RNA duplex to yield the pre-miRNA product(5). While the mechanisms underlying pri-miRNA processing have been determined, the mechanism by which DGCR8 recognizes and binds pri-miRNAs, as opposed to other secondary structures present in transcripts, is not understood. Here we find in mammalian cells that methyltransferase-like 3(METTL3) methylates pri-miRNAs, marking them for recognition and processing by DGCR8. Consistent with this, METTL3 depletion reduced the binding of DGCR8 to pri-miRNAs and resulted in the global reduction of mature miRNAs and concomitant accumulation of unprocessed pri-miRNAs. In vitro processing reactions confirmed the sufficiency of the N6-methyladenosine (m(6)A) mark in promoting pri-miRNA processing. Finally, gain-of-function experiments revealed that METTL3 is sufficient to enhance miRNA maturation in a global and non-cell-type-specific manner. Our findings reveal that the m(6)A mark acts as a key post-transcriptional modification that promotes the initiation of miRNA biogenesis.
C1 [Alarcon, Claudio R.; Lee, Hyeseung; Goodarzi, Hani; Halberg, Nils; Tavazoie, Sohail F.] Rockefeller Univ, Lab Syst Canc Biol, New York, NY 10065 USA.
C3 Rockefeller University
RP Tavazoie, SF (corresponding author), Rockefeller Univ, Lab Syst Canc Biol, 1230 York Ave, New York, NY 10065 USA.
EM stavazoie@rockefeller.edu
FU Era of Hope Department of Defense Award; Department of Defense
NR 26
TC 1169
Z9 1337
U1 5
U2 263
PU NATURE PUBLISHING 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 26
PY 2015
VL 519
IS 7544
BP 482
EP +
DI 10.1038/nature14281
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE1WF
UT WOS:000351602800058
PM 25799998
DA 2026-03-09
ER

PT J
AU Deng, HS
   Gerencser, AA
   Jasper, H
AF Deng, Hansong
   Gerencser, Akos A.
   Jasper, Heinrich
TI Signal integration by Ca2+ regulates intestinal stem-cell activity
SO NATURE
LA English
DT Article
ID tissue homeostasis; neural activity; life-span; drosophila; glutamate; proliferation; calcineurin; ca2+-atpase; metabolism; insights
AB Somatic stem cells maintain tissue homeostasis by dynamically adjusting proliferation and differentiation in response to stress and metabolic cues. Here we identify Ca2+ signalling as a central regulator of intestinal stem cell (ISC) activity in Drosophila. We show that dietary l-glutamate stimulates ISC division and gut growth. The metabotropic glutamate receptor (mGluR) is required in ISCs for this response, and for an associated modulation of cytosolic Ca2+ oscillations that results in sustained high cytosolic Ca2+ concentrations. High cytosolic Ca2+ concentrations induce ISC proliferation by regulating Calcineurin and CREB-regulated transcriptional co-activator (Crtc). In response to a wide range of dietary and stress stimuli, ISCs reversibly transition between Ca2+ oscillation states that represent poised or activated modes of proliferation, respectively. We propose that the dynamic regulation of intracellular Ca2+ levels allows effective integration of diverse mitogenic signals in ISCs to adapt their proliferative activity to the needs of the tissue.
C1 [Deng, Hansong; Gerencser, Akos A.; Jasper, Heinrich] Buck Inst Res Aging, Novato, CA 94945 USA.
C3 Buck Institute for Research on Aging
RP Jasper, H (corresponding author), Buck Inst Res Aging, 8001 Redwood Blvd, Novato, CA 94945 USA.
EM hjasper@buckinstitute.org
FU National Institute on Aging [R01 AG028127]; National Institute on General Medical Sciences [R01 GM100196]; Glenn Foundation for Medical Research postdoctoral fellowship; National Institutes of Health (NIH) [S10OD010414]
NR 53
TC 148
Z9 181
U1 1
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 DEC 10
PY 2015
VL 528
IS 7581
BP 212
EP +
DI 10.1038/nature16170
PG 26
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX9VH
UT WOS:000366053300031
PM 26633624
DA 2026-03-09
ER

PT J
AU Hart, RA
   Duarte, PM
   Yang, TL
   Liu, XX
   Paiva, T
   Khatami, E
   Scalettar, RT
   Trivedi, N
   Huse, DA
   Hulet, RG
AF Hart, Russell A.
   Duarte, Pedro M.
   Yang, Tsung-Lin
   Liu, Xinxing
   Paiva, Thereza
   Khatami, Ehsan
   Scalettar, Richard T.
   Trivedi, Nandini
   Huse, David A.
   Hulet, Randall G.
TI Observation of antiferromagnetic correlations in the Hubbard model with ultracold atoms
SO NATURE
LA English
DT Article
ID optical lattice; quantum simulation; fermions; insulator; gases; spins
AB Ultracold atoms in optical lattices have great potential to contribute to a better understanding of some of the most important issues in many-body physics, such as high-temperature superconductivity(1). The Hubbard model-a simplified representation of fermions moving on a periodic lattice-is thought to describe the essential details of copper oxide superconductivity(2). This model describes many of the features shared by the copper oxides, including an interaction-driven Mott insulating state and an antiferromagnetic (AFM) state. Optical lattices filled with a two-spin-component Fermi gas of ultracold atoms can faithfully realize the Hubbard model with readily tunable parameters, and thus provide a platform for the systematic exploration of its phase diagram(3,4). Realization of strongly correlated phases, however, has been hindered by the need to cool the atoms to temperatures as low as the magnetic exchange energy, and also by the lack of reliable thermometry(5). Here we demonstrate spin-sensitive Bragg scattering of light to measure AFM spin correlations in a realization of the three-dimensional Hubbard model at temperatures down to 1.4 times that of the AFM phase transition. This temperature regime is beyond the range of validity of a simple high-temperature series expansion, which brings our experiment close to the limit of the capabilities of current numerical techniques, particularly at metallic densities. We reach these low temperatures using a compensated optical lattice technique(6), in which the confinement of each lattice beam is compensated by a blue-detuned laser beam. The temperature of the atoms in the lattice is deduced by comparing the light scattering to determinant quantum Monte Carlo simulations(7) and numerical linked-cluster expansion(8) calculations. Further refinement of the compensated lattice may produce even lower temperatures which, along with light scattering thermometry, would open avenues for producing and characterizing other novel quantum states of matter, such as the pseudogap regime and correlated metallic states of the two-dimensional Hubbard model.
C1 [Hart, Russell A.; Duarte, Pedro M.; Yang, Tsung-Lin; Liu, Xinxing; Hulet, Randall G.] Rice Univ, Dept Phys & Astron, Houston, TX 77005 USA.
   [Hart, Russell A.; Duarte, Pedro M.; Yang, Tsung-Lin; Liu, Xinxing; Hulet, Randall G.] Rice Univ, Rice Quantum Inst, Houston, TX 77005 USA.
   [Paiva, Thereza] Univ Fed Rio de Janeiro, Inst Fis, BR-21941972 Rio De Janeiro, RJ, Brazil.
   [Khatami, Ehsan] San Jose State Univ, Dept Phys & Astron, San Jose, CA 95192 USA.
   [Scalettar, Richard T.] Univ Calif Davis, Dept Phys, Davis, CA 95616 USA.
   [Trivedi, Nandini] Ohio State Univ, Dept Phys, Columbus, OH 43210 USA.
   [Huse, David A.] Princeton Univ, Dept Phys, Princeton, NJ 08544 USA.
C3 Rice University; Rice University; Universidade Federal do Rio de Janeiro; California State University System; San Jose State University; University of California System; University of California Davis; University System of Ohio; Ohio State University; Princeton University
RP Hulet, RG (corresponding author), Rice Univ, Dept Phys & Astron, 6100 Main St, Houston, TX 77005 USA.
EM randy@rice.edu
FU ARO [W911NF-13-1-0018]; DARPA OLE; NSF; ONR; Welch Foundation [C-1133]; ARO-MURI [W911NF-14-1-003]; CNPq; FAPERJ; INCT on Quantum Information; Office of the President of the University of California; Direct For Mathematical & Physical Scien; Division Of Physics [1102515] Funding Source: National Science Foundation; Division Of Physics; Direct For Mathematical & Physical Scien [1408309] Funding Source: National Science Foundation
NR 35
TC 367
Z9 432
U1 2
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 12
PY 2015
VL 519
IS 7542
BP 211
EP +
DI 10.1038/nature14223
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500034
PM 25707803
DA 2026-03-09
ER

PT J
AU Elhatisari, S
   Lee, D
   Rupak, G
   Epelbaum, E
   Krebs, H
   Lähde, TA
   Luu, T
   Meissner, UG
AF Elhatisari, Serdar
   Lee, Dean
   Rupak, Gautam
   Epelbaum, Evgeny
   Krebs, Hermann
   Laehde, Timo A.
   Luu, Thomas
   Meissner, Ulf-G.
TI Ab initio alpha-alpha scattering
SO NATURE
LA English
DT Article
ID numerical-simulation; nuclear; lattice; energy; symmetry; capture; states; stars
AB Processes such as the scattering of alpha particles (He-4), the triple-alpha reaction, and alpha capture play a major role in stellar nucleosynthesis. In particular, alpha capture on carbon determines the ratio of carbon to oxygen during helium burning, and affects subsequent carbon, neon, oxygen, and silicon burning stages. It also substantially affects models of thermonuclear type Ia supernovae, owing to carbon detonation in accreting carbon-oxygen white-dwarf stars(1-3). In these reactions, the accurate calculation of the elastic scattering of alpha particles and alpha-like nuclei-nuclei with even and equal numbers of protons and neutrons-is important for understanding background and resonant scattering contributions. First-principles calculations of processes involving alpha particles and alpha-like nuclei have so far been impractical, owing to the exponential growth of the number of computational operations with the number of particles. Here we describe an ab initio calculation of alpha-alpha scattering that uses lattice Monte Carlo simulations. We use lattice effective field theory to describe the low-energy interactions of protons and neutrons, and apply a technique called the 'adiabatic projection method' to reduce the eight-body system to a two-cluster system. We take advantage of the computational efficiency and the more favourable scaling with system size of auxiliary-field Monte Carlo simulations to compute an ab initio effective Hamiltonian for the two clusters. We find promising agreement between lattice results and experimental phase shifts for s-wave and d-wave scattering. The approximately quadratic scaling of computational operations with particle number suggests that it should be possible to compute alpha scattering and capture on carbon and oxygen in the near future. The methods described here can be applied to ultracold atomic few-body systems as well as to hadronic systems using lattice quantum chromodynamics to describe the interactions of quarks and gluons.
C1 [Elhatisari, Serdar; Luu, Thomas; Meissner, Ulf-G.] Univ Bonn, Helmholtz Inst Strahlen & Kernphys, D-53115 Bonn, Germany.
   [Elhatisari, Serdar; Luu, Thomas; Meissner, Ulf-G.] Univ Bonn, Bethe Ctr Theoret Phys, D-53115 Bonn, Germany.
   [Lee, Dean] N Carolina State Univ, Dept Phys, Raleigh, NC 27695 USA.
   [Rupak, Gautam] Mississippi State Univ, Dept Phys & Astron, Mississippi State, MS 39762 USA.
   [Rupak, Gautam] Mississippi State Univ, Ctr Computat Sci HPC2, Mississippi State, MS 39762 USA.
   [Epelbaum, Evgeny; Krebs, Hermann] Ruhr Univ Bochum, Inst Theoret Phys 2, D-44870 Bochum, Germany.
   [Laehde, Timo A.; Luu, Thomas; Meissner, Ulf-G.] Forschungszentrum Julich, Inst Adv Simulat, Inst Kernphys, D-52425 Julich, Germany.
   [Laehde, Timo A.; Luu, Thomas; Meissner, Ulf-G.] Forschungszentrum Julich, Julich Ctr Hadron Phys, D-52425 Julich, Germany.
   [Meissner, Ulf-G.] Forschungszentrum Julich, JARA High Performance Comp, D-52425 Julich, Germany.
C3 Helmholtz Association; University of Bonn; University of Bonn; North Carolina State University; Mississippi State University; Mississippi State University; Ruhr University Bochum; Helmholtz Association; Julich Research Centre; Helmholtz Association; Julich Research Centre; Helmholtz Association; Julich Research Centre
RP Lee, D (corresponding author), N Carolina State Univ, Dept Phys, Raleigh, NC 27695 USA.
EM dean_lee@ncsu.edu
FU Deutsche Forschungsgemeinschaft (Sino-German) [CRC 110]; Helmholtz Association [VH-VI-417]; BMBF [05P12PDFTE]; US Department of Energy [DE-FG02-03ER41260]; US National Science Foundation [PHY-1307453]; EU HadronPhysics3 project; ERC [259218 NUCLEAREFT]; Magnus Ehrnrooth Foundation of the Finnish Society of Sciences and Letters; Direct For Mathematical & Physical Scien; Division Of Physics [1307453] Funding Source: National Science Foundation
NR 70
TC 148
Z9 167
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 DEC 3
PY 2015
VL 528
IS 7580
BP 111
EP +
DI 10.1038/nature16067
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000058
PM 26632590
DA 2026-03-09
ER

PT J
AU Wei, SS
   Wiens, DA
   Zha, Y
   Plank, T
   Webb, SC
   Blackman, DK
   Dunn, RA
   Conder, JA
AF Wei, S. Shawn
   Wiens, Douglas A.
   Zha, Yang
   Plank, Terry
   Webb, Spahr C.
   Blackman, Donna K.
   Dunn, Robert A.
   Conder, James A.
TI Seismic evidence of effects of water on melt transport in the Lau back-arc mantle
SO NATURE
LA English
DT Article
ID spreading centers; beneath; basin; constraints; olivine; ridge; deformation; seismology; noise; zone
AB Processes of melt generation and transport beneath back-arc spreading centres are controlled by two endmember mechanisms: decompression melting similar to that at mid-ocean ridges and flux melting resembling that beneath arcs'. The Lau Basin, with an abundance of spreading ridges at different distances from the subduction zone, provides an opportunity to distinguish the effects of these two different melting processes on magma production and crust formation. Here we present constraints on the three-dimensional distribution of partial melt inferred from seismic velocities obtained from Rayleigh wave tomography using land and ocean-bottom seismographs. Low seismic velocities beneath the Central Lau Spreading Centre and the northern Eastern Lau Spreading Centre extend deeper and westwards into the back-arc, suggesting that these spreading centres are fed by melting along upwelling zones from the west, and helping to explain geochemical differences with the Valu Fa Ridge to the south(2), which has no distinct deep low-seismic-velocity anomalies. A region of low S-wave velocity, interpreted as resulting from high melt content, is imaged in the mantle wedge beneath the Central Lau Spreading Centre and the northeastern Lau Basin, even where no active spreading centre currently exists. This low-seismic-velocity anomaly becomes weaker with distance southward along the Eastern Lau Spreading Centre and the Valu Fa Ridge, in contrast to the inferred increase in magmatic productivity(1). We propose that the anomaly variations result from changes in the efficiency of melt extraction, with the decrease in melt to the south correlating with increased fractional melting and higher water content in the magma. Water released from the slab may greatly reduce the melt viscosity(3) or increase grain size(4), or both, thereby facilitating melt transport.
C1 [Wei, S. Shawn; Wiens, Douglas A.] Washington Univ, Dept Earth & Planetary Sci, St Louis, MO 63130 USA.
   [Zha, Yang; Plank, Terry; Webb, Spahr C.] Columbia Univ, Lamont Doherty Earth Observ, Palisades, NY 10964 USA.
   [Blackman, Donna K.] Univ Calif San Diego, Scripps Inst Oceanog, La Jolla, CA 92093 USA.
   [Dunn, Robert A.] Univ Hawaii, Dept Geol & Geophys, Honolulu, HI 96822 USA.
   [Conder, James A.] So Illinois Univ, Dept Geol, Carbondale, IL 62901 USA.
C3 Washington University (WUSTL); Columbia University; University of California System; University of California San Diego; Scripps Institution of Oceanography; University of Hawaii System; Southern Illinois University System; Southern Illinois University
RP Wei, SS (corresponding author), Washington Univ, Dept Earth & Planetary Sci, St Louis, MO 63130 USA.
EM songqiaowei@wustl.edu
FU Ridge 2000 Program under NSF [OCE-0426408, EAR-0911137, OCE-0426369, OCE-0430463, OCE-0426428]
NR 57
TC 44
Z9 51
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 FEB 19
PY 2015
VL 518
IS 7539
BP 395
EP 398
DI 10.1038/nature14113
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400041
PM 25642964
DA 2026-03-09
ER

PT J
AU Lazarou, M
   Sliter, DA
   Kane, LA
   Sarraf, SA
   Wang, CX
   Burman, JL
   Sideris, DP
   Fogel, AI
   Youle, RJ
AF Lazarou, Michael
   Sliter, Danielle A.
   Kane, Lesley A.
   Sarraf, Shireen A.
   Wang, Chunxin
   Burman, Jonathon L.
   Sideris, Dionisia P.
   Fogel, Adam I.
   Youle, Richard J.
TI The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy
SO NATURE
LA English
DT Article
ID parkin; phosphorylation; optineurin; mitochondria; binding; ndp52; chain; association; p62/sqstm1; activation
AB Protein aggregates and damaged organelles are tagged with ubiquitin chains to trigger selective autophagy. To initiate mitophagy, the ubiquitin kinase PINK1 phosphorylates ubiquitin to activate the ubiquitin ligase parkin, which builds ubiquitin chains on mitochondrial outer membrane proteins, where they act to recruit autophagy receptors. Using genome editing to knockout five autophagy receptors in HeLa cells, here we show that two receptors previously linked to xenophagy, NDP52 and optineurin, are the primary receptors for PINK1- and parkin-mediated mitophagy. PINK1 recruits NDP52 and optineurin, but not p62, to mitochondria to activate mitophagy directly, independently of parkin. Once recruited to mitochondria, NDP52 and optineurin recruit the autophagy factors ULK1, DFCP1 and WIPI1 to focal spots proximal to mitochondria, revealing a function for these autophagy receptors upstream of LC3. This supports a new model in which PINK1-generated phospho-ubiquitin serves as the autophagy signal on mitochondria, and parkin then acts to amplify this signal. This work also suggests direct and broader roles for ubiquitin phosphorylation in other autophagy pathways.
C1 [Lazarou, Michael; Sliter, Danielle A.; Kane, Lesley A.; Sarraf, Shireen A.; Wang, Chunxin; Burman, Jonathon L.; Sideris, Dionisia P.; Fogel, Adam I.; Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS)
RP Youle, RJ (corresponding author), NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.
EM youler@ninds.nih.gov
FU NIH, NINDS; National Health and Medical Research Council [GNT1063781]; National Institute of Neurological Disorders and Stroke [ZIANS003127, ZIANS002859, ZIANS003123] Funding Source: NIH RePORTER
NR 42
TC 2249
Z9 2571
U1 20
U2 597
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 20
PY 2015
VL 524
IS 7565
BP 309
EP +
DI 10.1038/nature14893
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP2NN
UT WOS:000359714000027
PM 26266977
DA 2026-03-09
ER

PT J
AU Wang, X
   Yamamoto, Y
   Wilson, LH
   Zhang, T
   Howitt, BE
   Farrow, MA
   Kern, F
   Ning, G
   Hong, Y
   Khor, CC
   Chevalier, B
   Bertrand, D
   Wu, LY
   Nagarajan, N
   Sylvester, FA
   Hyams, JS
   Devers, T
   Bronson, R
   Lacy, DB
   Ho, KY
   Crum, CP
   McKeon, F
   Xian, W
AF Wang, Xia
   Yamamoto, Yusuke
   Wilson, Lane H.
   Zhang, Ting
   Howitt, Brooke E.
   Farrow, Melissa A.
   Kern, Florian
   Ning, Gang
   Hong, Yue
   Khor, Chiea Chuen
   Chevalier, Benoit
   Bertrand, Denis
   Wu, Lingyan
   Nagarajan, Niranjan
   Sylvester, Francisco A.
   Hyams, Jeffrey S.
   Devers, Thomas
   Bronson, Roderick
   Lacy, D. Borden
   Ho, Khek Yu
   Crum, Christopher P.
   McKeon, Frank
   Xian, Wa
TI Cloning and variation of ground state intestinal stem cells
SO NATURE
LA English
DT Article
ID in-vitro; toxin-b; regeneration; marker; colon; vivo; generation; virulence; pathways; renewal
AB Stem cells of the gastrointestinal tract, pancreas, liver and other columnar epithelia collectively resist cloning in their elemental states. Here we demonstrate the cloning and propagation of highly clonogenic, 'ground state' stem cells of the human intestine and colon. We show that derived stem-cell pedigrees sustain limited copy number and sequence variation despite extensive serial passaging and display exquisitely precise, cell-autonomous commitment to epithelial differentiation consistent with their origins along the intestinal tract. This developmentally patterned and epigenetically maintained commitment of stem cells is likely to enforce the functional specificity of the adult intestinal tract. Using clonally derived colonic epithelia, we show that toxins A or B of the enteric pathogen Clostridium difficile recapitulate the salient features of pseudomembranous colitis. The stability of the epigenetic commitment programs of these stem cells, coupled with their unlimited replicative expansion and maintained clonogenicity, suggests certain advantages for their use in disease modelling and regenerative medicine.
C1 [Wang, Xia; Yamamoto, Yusuke; Wilson, Lane H.; Ning, Gang; Hong, Yue; Chevalier, Benoit; McKeon, Frank; Xian, Wa] Jackson Lab Genom Med, Farmington, CT 06032 USA.
   [Wilson, Lane H.; Xian, Wa] Univ Connecticut, Ctr Hlth, Dept Genet & Dev Biol, Farmington, CT 06032 USA.
   [Zhang, Ting; Kern, Florian; Khor, Chiea Chuen; Bertrand, Denis; Wu, Lingyan; Nagarajan, Niranjan; McKeon, Frank] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore 138672, Singapore.
   [Howitt, Brooke E.; Crum, Christopher P.; Xian, Wa] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02118 USA.
   [Farrow, Melissa A.; Lacy, D. Borden] Vanderbilt Univ, Sch Med, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA.
   [Khor, Chiea Chuen] Natl Univ Singapore, Dept Ophthalmol, Yong Loo Lin Sch Med, Singapore 119228, Singapore.
   [Sylvester, Francisco A.] Univ N Carolina, Dept Pediat, Div Gastroenterol, Chapel Hill, NC 27599 USA.
   [Hyams, Jeffrey S.] Connecticut Childrens Med Ctr, Div Digest Dis Hepatol & Nutr, Hartford, CT 06106 USA.
   [Devers, Thomas] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT 06032 USA.
   [Bronson, Roderick] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA.
   [Ho, Khek Yu; McKeon, Frank; Xian, Wa] Natl Univ Singapore, Dept Med, Singapore 119228, Singapore.
   [McKeon, Frank; Xian, Wa] Multiclonal Therapeut Inc, Farmington, CT 06032 USA.
C3 Jackson Laboratory; University of Connecticut; Agency for Science Technology & Research (A*STAR); A*STAR - Genome Institute of Singapore (GIS); Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Vanderbilt University; National University of Singapore; University of North Carolina; University of North Carolina Chapel Hill; Connecticut Children's Medical Center; University of Connecticut; Harvard University; Harvard Medical School; National University of Singapore
RP Xian, W (corresponding author), Jackson Lab Genom Med, Farmington, CT 06032 USA.
EM mckeon.xian@gmail.com; xianmckeon2014@gmail.com
FU Connecticut Innovations; Joint Council Office of the Agency for Science Technology Research Agency (A*STAR), Singapore; National Medical Research Council, Singapore [BNB101677A, BnB11dec063]; Department of Defense [W81XWH-10-1-0289]; National Institute of Health [AI09575504]
NR 50
TC 148
Z9 190
U1 0
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 JUN 11
PY 2015
VL 522
IS 7555
BP 173
EP +
DI 10.1038/nature14484
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700030
PM 26040716
DA 2026-03-09
ER

PT J
AU Xu, X
   Zheng, XT
   Sullivan, C
   Wang, XL
   Xing, LD
   Wang, Y
   Zhang, XM
   O'Connor, JK
   Zhang, FC
   Pan, YH
AF Xu, Xing
   Zheng, Xiaoting
   Sullivan, Corwin
   Wang, Xiaoli
   Xing, Lida
   Wang, Yan
   Zhang, Xiaomei
   O'Connor, Jingmai K.
   Zhang, Fucheng
   Pan, Yanhong
TI A bizarre Jurassic maniraptoran theropod with preserved evidence of membranous wings
SO NATURE
LA English
DT Article
ID evolution; china; dinosaurs
AB The wings of birds and their closest theropod relatives share a uniform fundamental architecture, with pinnate flight feathers as the key component(1-3). Here we report a new scansoriopterygid theropod, Yi qi gen. et sp. nov., based on a new specimen from the Middle-Upper Jurassic period Tiaojishan Formation of Hebei Province, China(4). Yi is nested phylogenetically among winged theropods but has large stiff filamentous feathers of an unusual type on both the forelimb and hindlimb. However, the filamentous feathers of Yi resemble pinnate feathers in bearing morphologically diverse melanosomes(5). Most surprisingly, Yi has a long rod-like bone extending from each wrist, and patches of membranous tissue preserved between the rod-like bones and the manual digits. Analogous features are unknown in any dinosaur but occur in various flying and gliding tetrapods(6-10), suggesting the intriguing possibility that Yi had membranous aerodynamic surfaces totally different from the archetypal feathered wings of birds and their closest relatives. Documentation of the unique forelimbs of Yi greatly increases the morphological disparity known to exist among dinosaurs, and highlights the extraordinary breadth and richness of the evolutionary experimentation that took place close to the origin of birds.
C1 [Xu, Xing; Zheng, Xiaoting; Wang, Xiaoli; Wang, Yan] Linyi Univ, Inst Geol & Paleontol, Linyi 276005, Shandong, Peoples R China.
   [Xu, Xing; Sullivan, Corwin; O'Connor, Jingmai K.; Zhang, Fucheng] Chinese Acad Sci, Inst Vertebrate Paleontol & Paleoanthropol, Key Lab Vertebrate Evolut & Human Origins, Beijing 100044, Peoples R China.
   [Zheng, Xiaoting; Zhang, Xiaomei] Shandong Tianyu Museum Nat, Pingyi 273300, Shandong, Peoples R China.
   [Xing, Lida] China Univ Geosci, Sch Earth Sci & Resources, Beijing 100083, Peoples R China.
   [Pan, Yanhong] Chinese Acad Sci, Nanjing Inst Geol & Palaeontol, Key Lab Econ Stratig & Palaeogeog, Nanjing 210008, Jiangsu, Peoples R China.
C3 Linyi University; Chinese Academy of Sciences; Institute of Vertebrate Paleontology & Paleoanthropology, CAS; China University of Geosciences; Chinese Academy of Sciences
RP Xu, X (corresponding author), Linyi Univ, Inst Geol & Paleontol, Linyi 276005, Shandong, Peoples R China.
EM xingxu@vip.sina.com; ty4291666@163.com
FU National Natural Science Foundation of China [41372014, 41472023, 41120124002, 41125008]; Major Basic Research Projects of the Ministry of Science and Technology, China [2012CB821900]
NR 24
TC 129
Z9 150
U1 10
U2 201
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 7
PY 2015
VL 521
IS 7550
BP 70
EP U131
DI 10.1038/nature14423
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH4YS
UT WOS:000354040900034
PM 25924069
DA 2026-03-09
ER

PT J
AU Evaristo, J
   Jasechko, S
   McDonnell, JJ
AF Evaristo, Jaivime
   Jasechko, Scott
   McDonnell, Jeffrey J.
TI Global separation of plant transpiration from groundwater and streamflow
SO NATURE
LA English
DT Article
ID water-use strategy; stable-isotopes; summer precipitation; uptake patterns; trees; soil; land; riparian; rainfall; drought
AB Current land surface models assume that groundwater, streamflow and plant transpiration are all sourced and mediated by the same well mixed water reservoir-the soil. However, recent work in Oregon(1) and Mexico(2) has shown evidence of ecohydrological separation, whereby different subsurface compartmentalized pools of water supply either plant transpiration fluxes or the combined fluxes of groundwater and streamflow. These findings have not yet been widely tested. Here we use hydrogen and oxygen isotopic data (H-2/H-1 (delta H-2) and O-18/O-16 (delta O-18)) from 47 globally distributed sites to show that ecohydrological separation is widespread across different biomes. Precipitation, stream water and groundwater from each site plot approximately along the delta H-2/delta O-18 slope of local precipitation inputs. But soil and plant xylem waters extracted from the 47 sites all plot below the local stream water and groundwater on the meteoric water line, suggesting that plants use soil water that does not itself contribute to groundwater recharge or streamflow. Our results further show that, at 80% of the sites, the precipitation that supplies groundwater recharge and streamflow is different from the water that supplies parts of soil water recharge and plant transpiration. The ubiquity of subsurface water compartmentalization found here, and the segregation of storm types relative to hydrological and ecological fluxes, may be used to improve numerical simulations of runoff generation, stream water transit time and evaporation-transpiration partitioning. Future land surface model parameterizations should be closely examined for how vegetation, groundwater recharge and streamflow are assumed to be coupled.
C1 [Evaristo, Jaivime; McDonnell, Jeffrey J.] Univ Saskatchewan, Global Inst Water Secur, Saskatoon, SK S7N 3H5, Canada.
   [Evaristo, Jaivime; McDonnell, Jeffrey J.] Univ Saskatchewan, Sch Environm & Sustainabil, Saskatoon, SK S7N 3H5, Canada.
   [Jasechko, Scott] Univ Calgary, Dept Geog, Calgary, AB T2N 1N4, Canada.
   [McDonnell, Jeffrey J.] Univ Aberdeen, Sch Geosci, Aberdeen AB34 3FX, Scotland.
   [McDonnell, Jeffrey J.] Oregon State Univ, Dept Forest Engn Resources & Management, Corvallis, OR 97331 USA.
C3 University of Saskatchewan; Global Institute for Water Security; University of Saskatchewan; University of Calgary; University of Aberdeen; Oregon State University
RP Evaristo, J (corresponding author), Univ Saskatchewan, Global Inst Water Secur, Saskatoon, SK S7N 3H5, Canada.
EM jaivime.evaristo@usask.ca
FU Saskatchewan Innovation and Opportunity Scholarship; Global Institute for Water Security; School of Environment and Sustainability (University of Saskatchewan); Saskatchewan Innovation and Opportunity Scholarship, Global Institute for Water Security, and School of Environment and Sustainability (University of Saskatchewan); Division Of Environmental Biology; Direct For Biological Sciences [1440409] Funding Source: National Science Foundation
NR 89
TC 422
Z9 487
U1 26
U2 934
PU NATURE PUBLISHING 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 3
PY 2015
VL 525
IS 7567
BP 91
EP +
DI 10.1038/nature14983
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100031
PM 26333467
DA 2026-03-09
ER

PT J
AU Sun, JH
   O'Boyle, DR
   Fridell, RA
   Langley, DR
   Wang, CF
   Roberts, SB
   Nower, P
   Johnson, BM
   Moulin, F
   Nophsker, MJ
   Wang, YK
   Liu, MP
   Rigat, K
   Tu, Y
   Hewawasam, P
   Kadow, J
   Meanwell, NA
   Cockett, M
   Lemm, JA
   Kramer, M
   Belema, M
   Gao, M
AF Sun, Jin-Hua
   O'Boyle, Donald R., II
   Fridell, Robert A.
   Langley, David R.
   Wang, Chunfu
   Roberts, Susan B.
   Nower, Peter
   Johnson, Benjamin M.
   Moulin, Frederic
   Nophsker, Michelle J.
   Wang, Ying-Kai
   Liu, Mengping
   Rigat, Karen
   Tu, Yong
   Hewawasam, Piyasena
   Kadow, John
   Meanwell, Nicholas A.
   Cockett, Mark
   Lemm, Julie A.
   Kramer, Melissa
   Belema, Makonen
   Gao, Min
TI Resensitizing daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5A
SO NATURE
LA English
DT Article
ID inhibitor daclatasvir; replication complex; virus-replication; crystal-structure; domain; protein; potent; acids
AB It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide(1,2). Clinical trials have demonstrated that, for the first time in human history, the potential exists to eradicate a chronic viral disease using combination therapies that contain only direct-acting antiviral agents(3). HCV nonstructural protein 5A (NS5A) is a multifunctional protein required for several stages of the virus replication cycle(4). NS5A replication complex inhibitors, exemplified by daclatasvir (DCV; also known as BMS-790052 and Daklinza), belong to the most potent class of direct-acting anti-HCV agents described so far, with in vitro activity in the picomolar (pM) to low nanomolar (nM) range. The potency observed in vitro has translated into clinical efficacy, with HCV RNA declining by similar to 3-4 log(10) in infected patients after administration of single oral doses of DCV. Understanding the exceptional potency of DCV was a key objective of this study. Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhance DCV potency by >1,000-fold, restoring activity to the pM range. This synergistic effect was validated in vivo using an HCV-infected chimaeric mouse model. The cooperative interaction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one inhibitor binds to resistant NS5A, causing a conformational change that is transmitted to adjacent NS5As, resensitizing resistant NS5A so that the second inhibitor can act to restore inhibition. This unprecedented synergistic anti-HCV activity also enhances the resistance barrier of DCV, providing additional options for HCV combination therapy and new insight into the role of NS5A in the HCV replication cycle.
C1 [Sun, Jin-Hua; O'Boyle, Donald R., II; Fridell, Robert A.; Wang, Chunfu; Roberts, Susan B.; Nower, Peter; Liu, Mengping; Rigat, Karen; Cockett, Mark; Lemm, Julie A.; Gao, Min] Bristol Myers Squibb Res & Dev, Dept Virol, Wallingford, CT 06492 USA.
   [Langley, David R.] Bristol Myers Squibb Res & Dev, Comp Assisted Drug Design, Wallingford, CT 06492 USA.
   [Johnson, Benjamin M.; Moulin, Frederic; Nophsker, Michelle J.; Kramer, Melissa] Bristol Myers Squibb Res & Dev, Pharmaceut Candidate Optimizat, Wallingford, CT 06492 USA.
   [Wang, Ying-Kai] Bristol Myers Squibb Res & Dev, Leads Discovery & Optimizat, Wallingford, CT 06492 USA.
   [Tu, Yong; Hewawasam, Piyasena; Kadow, John; Meanwell, Nicholas A.; Belema, Makonen] Bristol Myers Squibb Res & Dev, Discovery Chem, Wallingford, CT 06492 USA.
C3 Bristol-Myers Squibb; Bristol-Myers Squibb; Bristol-Myers Squibb; Bristol-Myers Squibb; Bristol-Myers Squibb
RP Gao, M (corresponding author), Bristol Myers Squibb Res & Dev, Dept Virol, 5 Res Pkwy, Wallingford, CT 06492 USA.
EM Min.Gao@bms.com
NR 28
TC 44
Z9 47
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 12
PY 2015
VL 527
IS 7577
BP 245
EP +
DI 10.1038/nature15711
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700047
PM 26536115
DA 2026-03-09
ER

PT J
AU Coffelt, SB
   Kersten, K
   Doornebal, CW
   Weiden, J
   Vrijland, K
   Hau, CS
   Verstegen, NJM
   Ciampricotti, M
   Hawinkels, LJAC
   Jonkers, J
   de Visser, KE
AF Coffelt, Seth B.
   Kersten, Kelly
   Doornebal, Chris W.
   Weiden, Jorieke
   Vrijland, Kim
   Hau, Cheei-Sing
   Verstegen, Niels J. M.
   Ciampricotti, Metamia
   Hawinkels, Lukas J. A. C.
   Jonkers, Jos
   de Visser, Karin E.
TI IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis
SO NATURE
LA English
DT Article
ID colony-stimulating factor; mammary-carcinoma; mouse model; tumor; progression; beta; inflammation; recruitment; suppression; induction
AB Metastatic disease remains the primary cause of death for patients with breast cancer. The different steps of the metastatic cascade rely on reciprocal interactions between cancer cells and their microenvironment. Within this local microenvironment and in distant organs, immune cells and their mediators are known to facilitate metastasis formation(1,2). However, theprecisecontributionof tumour-induced systemic inflammation to metastasis and the mechanisms regulating systemic inflammation are poorly understood. Here we show that tumours maximize their chance of metastasizing by evoking a systemic inflammatory cascade in mouse models of spontaneous breast cancer metastasis. We mechanistically demonstrate that interleukin (IL)-1 beta elicits IL-17 expression from gamma delta (gamma delta) T cells, resulting in systemic, granulocyte colony-stimulating factor (G-CSF)-dependent expansion and polarization of neutrophils in mice bearing mammary tumours. Tumour-induced neutrophils acquire the ability to suppress cytotoxic T lymphocytes carrying the CD8 antigen, which limit the establishment of metastases. Neutralization of IL-17 or G-CSF and absence of gamma delta T cells prevents neutrophil accumulation and downregulates the T-cell-suppressive phenotype of neutrophils. Moreover, the absence of gamma delta T cells or neutrophils profoundly reduces pulmonary and lymph node metastases without influencing primary tumour progression. Our data indicate that targeting this novel cancer-cell-initiated domino effect within the immune system-the gamma delta T cell/IL-17/neutrophil axis-represents a new strategy to inhibit metastatic disease.
C1 [Coffelt, Seth B.; Kersten, Kelly; Doornebal, Chris W.; Weiden, Jorieke; Vrijland, Kim; Hau, Cheei-Sing; Verstegen, Niels J. M.; Ciampricotti, Metamia; de Visser, Karin E.] Netherlands Canc Inst, Div Immunol, NL-1066 CX Amsterdam, Netherlands.
   [Hawinkels, Lukas J. A. C.] Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands.
   [Hawinkels, Lukas J. A. C.] Leiden Univ, Med Ctr, Ctr Biomed Genet, NL-2300 RC Leiden, Netherlands.
   [Jonkers, Jos] Netherlands Canc Inst, Div Mol Pathol, NL-1066 CX Amsterdam, Netherlands.
C3 Netherlands Cancer Institute; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Netherlands Cancer Institute
RP de Visser, KE (corresponding author), Netherlands Canc Inst, Div Immunol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands.
EM k.d.visser@nki.nl
FU Marie Curie Intra-European Fellowship [BMDCMET 275610]; European Research Council [INFLAMET 615300]; Dutch Cancer Society [2011-5004]; Worldwide Cancer Research [AICR 11-0677]; Netherlands Organization for Scientific Research NWO VIDI [917.96.307]; Dutch Cancer Society/Bas Mulder Award [UL2011-5051]
NR 34
TC 1419
Z9 1623
U1 10
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 JUN 18
PY 2015
VL 522
IS 7556
BP 345
EP +
DI 10.1038/nature14282
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK7PU
UT WOS:000356425400054
PM 25822788
DA 2026-03-09
ER

PT J
AU Zecevic, J
   Vanbutsele, G
   de Jong, KP
   Martens, JA
AF Zecevic, Jovana
   Vanbutsele, Gina
   de Jong, Krijn P.
   Martens, Johan A.
TI Nanoscale intimacy in bifunctional catalysts for selective conversion of hydrocarbons
SO NATURE
LA English
DT Article
ID hydrocracking catalysts; zeolites; nanoparticles; hydroisomerization; acid; isomerization; paraffins; platinum; crystals; olefins
AB The ability to control nanoscale features precisely is increasingly being exploited to develop and improve monofunctional catalysts(1-4). Striking effects might also be expected in the case of bifunctional catalysts, which are important in the hydrocracking of fossil and renewable hydrocarbon sources to provide high-quality diesel fuel(5-7). Such bifunctional hydrocracking catalysts contain metal sites and acid sites, and for more than 50 years the so-called intimacy criterion(8) has dictated the maximum distance between the two types of site, beyond which catalytic activity decreases. A lack of synthesis and material-characterization methods with nanometre precision has long prevented in-depth exploration of the intimacy criterion, which has often been interpreted simply as 'the closer the better' for positioning metal and acid sites(8-11). Here we show for a bifunctional catalyst-comprising an intimate mixture of zeolite Y and alumina binder, and with platinum metal controllably deposited on either the zeolite or the binder-that closest proximity between metal and zeolite acid sites can be detrimental. Specifically, the selectivity when cracking large hydrocarbon feedstock molecules for high-quality diesel production is optimized with the catalyst that contains platinum on the binder, that is, with a nanoscale rather than closest intimacy of the metal and acid sites. Thus, cracking of the large and complex hydrocarbon molecules that are typically derived from alternative sources, such as gas-to-liquid technology, vegetable oil or algal oil(6,7), should benefit especially from bifunctional catalysts that avoid locating platinum on the zeolite (the traditionally assumed optimal location). More generally, we anticipate that the ability demonstrated here to spatially organize different active sites at the nanoscale will benefit the further development and optimization of the emerging generation of multifunctional catalysts(12-15).
C1 [Zecevic, Jovana; de Jong, Krijn P.] Univ Utrecht, Debye Inst Nanomat Sci, Inorgan Chem & Catalysis, NL-3584 CG Utrecht, Netherlands.
   [Vanbutsele, Gina; Martens, Johan A.] Katholieke Univ Leuven, Ctr Surface Chem & Catalysis, B-3001 Leuven, Belgium.
C3 Utrecht University; KU Leuven
RP Martens, JA (corresponding author), Katholieke Univ Leuven, Ctr Surface Chem & Catalysis, Celestijnenlaan 200F Postbus 2461, B-3001 Leuven, Belgium.
EM k.p.dejong@uu.nl; johan.martens@biw.kuleuven.be
FU NRSC-C; European Research Council, EU FP7 ERC Advanced [338846]; Flemish government via the Methusalem program
NR 33
TC 529
Z9 589
U1 18
U2 905
PU NATURE PUBLISHING 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 10
PY 2015
VL 528
IS 7581
BP 245
EP +
DI 10.1038/nature16173
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX9VH
UT WOS:000366053300037
PM 26659185
DA 2026-03-09
ER

PT J
AU Alexandrova, EM
   Yallowitz, AR
   Li, D
   Xu, S
   Schulz, R
   Proia, DA
   Lozano, G
   Dobbelstein, M
   Moll, UM
AF Alexandrova, E. M.
   Yallowitz, A. R.
   Li, D.
   Xu, S.
   Schulz, R.
   Proia, D. A.
   Lozano, G.
   Dobbelstein, M.
   Moll, U. M.
TI Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment
SO NATURE
LA English
DT Article
ID mouse model; hsp90 complex; cancer-cells; in-vitro; gain; ganetespib; inhibitor; geldanamycin; metastasis; spectrum
AB Missense mutations in p53 generate aberrant proteins with abrogated tumour suppressor functions that can also acquire oncogenic gain-of-function activities that promote malignant progression, invasion, metastasis and chemoresistance(1-5). Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumours, which is the key requisite for the acquisition of gain-of-functions activities(6-8). Although currently 11 million patients worldwide live with tumours expressing highly stabilized mutp53, it is unknown whether mutp53 is a therapeutic target in vivo. Here we use a novel mutp53 mouse model expressing an inactivatable R248Q hotspot mutation (floxQ) to show that tumours depend on sustained mutp53 expression. Upon tamoxifen-induced mutp53 ablation, allotransplanted and autochthonous tumours curb their growth, thus extending animal survival by 37%, and advanced tumours undergo apoptosis and tumour regression or stagnation. The HSP90/HDAC6 chaperone machinery, which is significantly upregulated in cancer compared with normal tissues, is a major determinant of mutp53 stabilization(9-12). We show that long-term HSP90 inhibition significantly extends the survival of mutp53 Q/- (R248Q allele(2)) and H/H (R172H allele(3)) mice by 59% and 48%, respectively, but not their corresponding p53(-/-) (also known as Trp53(-/-)) littermates. This mutp53-dependent drug effect occurs in H/H mice treated with 17DMAG+SAHA and in H/H and Q/- mice treated with the potent Hsp90 inhibitor ganetespib. Notably, drug activity correlates with induction of mutp53 degradation, tumour apoptosis and prevention of T-cell lymphomagenesis. These proof-of-principle data identify mutp53 as an actionable cancer-specific drug target.
C1 [Alexandrova, E. M.; Yallowitz, A. R.; Li, D.; Xu, S.; Moll, U. M.] SUNY Stony Brook, Dept Pathol, Stony Brook, NY 11794 USA.
   [Schulz, R.; Dobbelstein, M.; Moll, U. M.] Univ Gottingen, Inst Mol Oncol, D-37077 Gottingen, Germany.
   [Proia, D. A.] Synta Pharmaceut Corp, Lexington, MA 02421 USA.
   [Lozano, G.] Univ Texas MD Anderson Canc Ctr, Dept Canc Genet, Houston, TX 77030 USA.
C3 State University of New York (SUNY) System; Stony Brook University; University of Gottingen; Synta Pharmaceuticals; University of Texas System; UTMD Anderson Cancer Center
RP Moll, UM (corresponding author), SUNY Stony Brook, Dept Pathol, Stony Brook, NY 11794 USA.
EM Ute.Moll@stonybrookmedicine.edu
FU National Cancer Institute [1RO1CA176647]; Deutsche Forschungsgemeinschaft [MO 1998/2-1]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [T32HD007505] Funding Source: NIH RePORTER; National Cancer Institute [R01CA176647] Funding Source: NIH RePORTER
NR 36
TC 303
Z9 334
U1 2
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 JUL 16
PY 2015
VL 523
IS 7560
BP 352
EP +
DI 10.1038/nature14430
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM8KY
UT WOS:000357950900043
PM 26009011
DA 2026-03-09
ER

PT J
AU Feldman, DR
   Collins, WD
   Gero, PJ
   Torn, MS
   Mlawer, EJ
   Shippert, TR
AF Feldman, D. R.
   Collins, W. D.
   Gero, P. J.
   Torn, M. S.
   Mlawer, E. J.
   Shippert, T. R.
TI Observational determination of surface radiative forcing by CO2 from 2000 to 2010
SO NATURE
LA English
DT Article
ID emitted radiance interferometer; carbon-dioxide; water-vapor; longwave radiation; spectra; temperature; trends; record; cloud; model
AB The climatic impact of CO2 and other greenhouse gases is usually quantified in terms of radiative forcing', calculated as the difference between estimates of the Earth's radiation field from pre-industrial and presentday concentrations of these gases. Radiative transfer models calculate that the increase in CO2 since 1750 corresponds to a global annualmean radiative forcing at the tropopause of 1.82 +/- 0.19W m(-2) (ref. 2). However, despite widespread scientific discussion and modelling of the climate impacts of well-mixed greenhouse gases, there is little direct observational evidence of the radiative impact of increasing atmospheric CO2. Here we present observationally based evidence of clear-sky CO2 surface radiative forcing that is directly attributable to the increase, between 2000 and 2010, of 22 parts per million atmospheric CO2. The time series of this forcing at the two locations the Southern Great Plains and the North Slope of Alaska are derived from Atmospheric Emitted Radiance Interferometer spectra' together with ancillary measurements and thoroughly corroborated radiative transfer calculations'. The time series both show statistically significant trends of 0.2 W m(-2) per decade (with respective uncertainties of +/- 0.06 W m(-2) per decade and 0.07 W m(-2) per decade) and have seasonal ranges of 0.1-0.2W m(-2). This is approximately ten per cent of the trend in downwelling longwave radiation'''. These results confirm theoretical predictions of the atmospheric greenhouse effect due to anthropogenic emissions, and provide empirical evidence of how rising CO2 levels, mediated by temporal variations due to photosynthesis and respiration, are affecting the surface energy balance.
C1 [Feldman, D. R.; Collins, W. D.; Torn, M. S.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Earth Sci, Berkeley, CA 94720 USA.
   [Collins, W. D.] Univ Calif Berkeley, Dept Earth & Planetary Sci, Berkeley, CA 94720 USA.
   [Gero, P. J.] Univ Wisconsin, Space Sci & Engn Ctr, Madison, WI 53706 USA.
   [Torn, M. S.] Univ Calif Berkeley, Energy & Resources Grp, Berkeley, CA 94720 USA.
   [Mlawer, E. J.] Atmospher & Environm Res Inc, Lexington, MA 02141 USA.
   [Shippert, T. R.] Pacific NW Natl Lab, Fundamental & Computat Sci, Richland, WA 99354 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 Wisconsin System; University of Wisconsin Madison; University of California System; University of California Berkeley; Atmospheric & Environmental Research; United States Department of Energy (DOE); Pacific Northwest National Laboratory
RP Feldman, DR (corresponding author), Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Earth Sci, 1 Cyclotron Rd,MS 74R-316C, Berkeley, CA 94720 USA.
EM drfeldman@lbl.gov
FU US Department of Energy, Office of Science, Office of Biological and Environmental Research, Climate and Environmental Science Division, of the US Department of Energy as part of the Atmospheric System Research Program [DE-AC02-05CH11231]; Atmospheric Radiation Measurement (ARM) Climate Research Facility Southern Great Plains; National Energy Research Scientific Computing Center (NERSC) [DE-AC02-05CH11231]
NR 46
TC 185
Z9 223
U1 1
U2 226
PU NATURE PUBLISHING 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 19
PY 2015
VL 519
IS 7543
BP 339
EP +
DI 10.1038/nature14240
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD6AY
UT WOS:000351171900038
PM 25731165
DA 2026-03-09
ER

PT J
AU Wertz, IE
   Newton, K
   Seshasayee, D
   Kusam, S
   Lam, C
   Zhang, J
   Popovych, N
   Helgason, E
   Schoeffler, A
   Jeet, S
   Ramamoorthi, N
   Kategaya, L
   Newman, RJ
   Horikawa, K
   Ugger, DD
   Sandoval, W
   Ukund, SM
   Zindal, A
   Martin, F
   Quan, C
   Tom, J
   Fairbrother, WJ
   Townsend, M
   Warming, S
   DeVoss, J
   Liu, JF
   Dueber, E
   Caplazi, P
   Lee, WP
   Goodnow, CC
   Balazs, M
   Yu, KB
   Kolumam, G
   Dixit, VM
AF Wertz, Ingrid E.
   Newton, Kim
   Seshasayee, Dhaya
   Kusam, Saritha
   Lam, Cynthia
   Zhang, Juan
   Popovych, Nataliya
   Helgason, Elizabeth
   Schoeffler, Allyn
   Jeet, Surinder
   Ramamoorthi, Nandhini
   Kategaya, Lorna
   Newman, Robert J.
   Horikawa, Keisuke
   Ugger, Debra D.
   Sandoval, Wendy
   Ukund, Susmith M.
   Zindal, Anuradha
   Martin, Flavius
   Quan, Clifford
   Tom, Jeffrey
   Fairbrother, Wayne J.
   Townsend, Michael
   Warming, Soren
   DeVoss, Jason
   Liu, Jinfeng
   Dueber, Erin
   Caplazi, Patrick
   Lee, Wyne P.
   Goodnow, Christopher C.
   Balazs, Mercedesz
   Yu, Kebing
   Kolumam, Ganesh
   Dixit, Vishva M.
TI Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation
SO NATURE
LA English
DT Article
ID nf-kappa-b; chain assembly complex; zinc-finger 7; cell-death; polyubiquitin chains; binding proteins; activation; enzyme; recognition; apoptosis
AB Inactivation of the TNFAIP3 gene, encoding the A20 protein, is associated with critical inflammatory diseases including multiple sclerosis, rheumatoid arthritis and Crohn's disease. However, the role of A20 in attenuating inflammatory signalling is unclear owing to paradoxical in vitro and in vivo findings. Here we utilize genetically engineered mice bearing mutations in the A20 ovarian tumour (OTU)-type deubiquitinase domain or in the zinc finger-4 (ZnF4) ubiquitin-binding motif to investigate these discrepancies. We find that phosphorylation of A20 promotes cleavage of Lys63-linked polyubiquitin chains by the OTU domain and enhances ZnF4-mediated substrate ubiquitination. Additionally, levels of linear ubiquitination dictate whether A20-deficient cells die in response to tumour necrosis factor. Mechanistically, linear ubiquitin chains preserve the architecture of the TNFR1 signalling complex by blocking A20-mediated disassembly of Lys63-linked polyubiquitin scaffolds. Collectively, our studies reveal molecular mechanisms whereby A20 deubiquitinase activity and ubiquitin binding, linear ubiquitination, and cellular kinases cooperate to regulate inflammation and cell death.
C1 [Wertz, Ingrid E.; Kategaya, Lorna] Genentech Inc, Discovery Oncol, San Francisco, CA 94080 USA.
   [Wertz, Ingrid E.; Kusam, Saritha; Lam, Cynthia; Popovych, Nataliya; Helgason, Elizabeth; Schoeffler, Allyn; Kategaya, Lorna; Zindal, Anuradha; Quan, Clifford; Tom, Jeffrey; Fairbrother, Wayne J.; Dueber, Erin] Genentech Inc, Early Discovery Biochem, San Francisco, CA 94080 USA.
   [Newton, Kim; Ugger, Debra D.; Dixit, Vishva M.] Genentech Inc, Physiol Chem, San Francisco, CA 94080 USA.
   [Seshasayee, Dhaya; Zhang, Juan; Jeet, Surinder; Ramamoorthi, Nandhini; Martin, Flavius; Townsend, Michael; DeVoss, Jason; Lee, Wyne P.; Balazs, Mercedesz] Genentech Inc, Immunol, San Francisco, CA 94080 USA.
   [Newman, Robert J.; Warming, Soren; Kolumam, Ganesh] Genentech Inc, Mol Biol, San Francisco, CA 94080 USA.
   [Horikawa, Keisuke] Australian Natl Univ, John Curtin Sch Med Res, Dept Canc Biol & Therapeut, Canberra, ACT 2601, Australia.
   [Sandoval, Wendy; Yu, Kebing] Genentech Inc, Prot Chem, San Francisco, CA 94080 USA.
   [Ukund, Susmith M.] Genentech Inc, Structural Biol, San Francisco, CA 94080 USA.
   [Liu, Jinfeng] Genentech Inc, Bioinformat, San Francisco, CA 94080 USA.
   [Caplazi, Patrick] Genentech Inc, Pathol, San Francisco, CA 94080 USA.
   [Goodnow, Christopher C.] Garvan Inst Med Res, Div Immunol, Immunogen Lab, Darlinghurst, NSW 2010, Australia.
C3 Roche Holding; Genentech; Roche Holding USA; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech; Australian National University; John Curtin School of Medical Research; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Genentech; Roche Holding USA; Garvan Institute of Medical Research
RP Wertz, IE (corresponding author), Genentech Inc, Discovery Oncol, San Francisco, CA 94080 USA.
EM ingrid@gene.com; dixit@gene.com
FU Genentech Protein Expression Group; Sequencing Facility, Luminex Core Group; Animal Facility and Genotyping Laboratory; Mouse Models Group
NR 50
TC 217
Z9 238
U1 1
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 DEC 17
PY 2015
VL 528
IS 7582
BP 370
EP +
DI 10.1038/nature16165
PG 27
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CY8SM
UT WOS:000366678600046
PM 26649818
DA 2026-03-09
ER

PT J
AU Lauressergues, D
   Couzigou, JM
   Clemente, HS
   Martinez, Y
   Dunand, C
   Bécard, G
   Combier, JP
AF Lauressergues, Dominique
   Couzigou, Jean-Malo
   Clemente, Helene San
   Martinez, Yves
   Dunand, Christophe
   Becard, Guillaume
   Combier, Jean-Philippe
TI Primary transcripts of microRNAs encode regulatory peptidesPrimary transcripts of microRNAs encode regulatory peptides
SO NATURE
LA English
DT Article
ID expression
AB MicroRNAs (miRNAs) are small regulatory RNA molecules that inhibit the expression of specific target genes by binding to and cleaving their messenger RNAs or otherwise inhibiting their translation into proteins(1). miRNAs are transcribed as much larger primary transcripts (pri-miRNAs), the function of which is not fully understood. Here we show that plant pri-miRNAs contain short open reading frame sequences that encode regulatory peptides. The pri-miR171b of Medicago truncatula and the pri-miR165a of Arabid-opsis thaliana produce peptides, which we term miPEP171b and miPEP165a, respectively, that enhance the accumulation of their corresponding mature miRNAs, resulting in downregulation of target genes involved in root development. The mechanism of miRNA-encoded peptide (miPEP) action involves increasing transcription of the pri-miRNA. Five other pri-miRNAs of A. thaliana and M. truncatula encode active miPEPs, suggesting that miPEPs are widespread throughout the plant kingdom. Synthetic miPEP171b and miPEP165a peptides applied to plants specifically trigger the accumulation of miR171b and miR165a, leading to reduction of lateral root development and stimulation of mainroot growth, respectively, suggesting that miPEPs might have agronomical applications.
C1 [Lauressergues, Dominique; Couzigou, Jean-Malo; Clemente, Helene San; Dunand, Christophe; Becard, Guillaume; Combier, Jean-Philippe] Univ Toulouse, UPS, UMR5546, Lab Rech Sci Vegetales, F-31326 Castanet Tolosan, France.
   [Lauressergues, Dominique; Couzigou, Jean-Malo; Clemente, Helene San; Dunand, Christophe; Becard, Guillaume; Combier, Jean-Philippe] CNRS, UMR5546, F-31326 Castanet Tolosan, France.
   [Martinez, Yves] Federat Rech FR3450 CNRS, F-31326 Castanet Tolosan, France.
C3 Universite de Toulouse; Universite Toulouse III - Paul Sabatier; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite de Toulouse; Universite Toulouse III - Paul Sabatier; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB)
RP Combier, JP (corresponding author), Univ Toulouse, UPS, UMR5546, Lab Rech Sci Vegetales, F-31326 Castanet Tolosan, France.
EM combier@lrsv.ups-tlse.fr
FU French ANR project miRcorrhiza [ANR-12-JSV7-0002-01]; CNRS; Paul Sabatier University Toulouse; Toulouse Tech Transfer; Agence Nationale de la Recherche (ANR) [ANR-12-JSV7-0002] Funding Source: Agence Nationale de la Recherche (ANR)
NR 13
TC 376
Z9 444
U1 6
U2 376
PU NATURE PUBLISHING 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 2
PY 2015
VL 520
IS 7545
BP 90
EP U205
DI 10.1038/nature14346
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE7NE
UT WOS:000352027700043
PM 25807486
DA 2026-03-09
ER

PT J
AU Schmidt, H
   Zalyte, R
   Urnavicius, L
   Carter, AP
AF Schmidt, Helgo
   Zalyte, Ruta
   Urnavicius, Linas
   Carter, Andrew P.
TI Structure of human cytoplasmic dynein-2 primed for its power stroke
SO NATURE
LA English
DT Article
ID microtubule-binding; crystal-structure; coiled-coil; domain; image; mechanism; sequence; insights; sites; suite
AB Members of the dynein family, consisting of cytoplasmic and axonemal isoforms, are motors that move towards the minus ends of microtubules. Cytoplasmic dynein-1 (dynein-1) plays roles in mitosis and cellular cargo transport(1), and is implicated in viral infections(2) and neurodegenerative diseases(3). Cytoplasmic dynein-2 (dynein-2) performs intraflagellar transport(4) and is associated with human skeletal ciliopathies(5). Dyneins share a conserved motor domain that couples cycles of ATP hydrolysis with conformational changes to produce movement(6-9). Here we present the crystal structure of the human cytoplasmic dynein-2 motor bound to the ATP-hydrolysis transition state analogue ADP. vanadate(10). The structure reveals a closure of the motor's ring of six AAA+ domains (ATPases associated with various cellular activites: AAA1-AAA6). This induces a steric clash with the linker, the key element for the generation of movement, driving it into a conformation that is primed to produce force. Ring closure also changes the interface between the stalk and buttress coiled-coil extensions of the motor domain. This drives helix sliding in the stalk which causes the microtubule binding domain at its tip to release from the microtubule. Our structure answers the key questions of how ATP hydrolysis leads to linker remodelling and microtubule affinity regulation.
C1 [Schmidt, Helgo; Zalyte, Ruta; Urnavicius, Linas; Carter, Andrew P.] MRC, Mol Biol Lab, Div Struct Studies, Cambridge CB2 0QH, England.
C3 MRC Laboratory Molecular Biology
RP Carter, AP (corresponding author), MRC, Mol Biol Lab, Div Struct Studies, Francis Crick Ave, Cambridge CB2 0QH, England.
EM cartera@mrc-lmb.cam.ac.uk
FU Medical Research Council, UK [MC_UP_A025_1011]; Wellcome Trust New Investigator Award [WT100387]; EMBO Young Investigator Award; MRC [MC_UP_A025_1011] Funding Source: UKRI; Medical Research Council [1274168, 1352465, MC_UP_A025_1011] Funding Source: researchfish
NR 43
TC 126
Z9 155
U1 0
U2 30
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 19
PY 2015
VL 518
IS 7539
BP 435
EP 438
DI 10.1038/nature14023
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400050
PM 25470043
DA 2026-03-09
ER

PT J
AU Jin, J
   MacMillan, DWC
AF Jin, Jian
   MacMillan, David W. C.
TI Alcohols as alkylating agents in heteroarene C-H functionalization
SO NATURE
LA English
DT Article
ID polarity-reversal catalysis; photoredox catalysis; direct arylation; bonds; racemization; activation; discovery; strategy; ethers
AB Redox processes and radical intermediates are found in many biochemical processes, including deoxyribonucleotide synthesis and oxidative DNA damage(1). One of the core principles underlying DNA biosynthesis is the radical-mediated elimination of H2O to deoxygenate ribonucleotides, an example of 'spin-centre shift'(2), during which an alcohol C-O bond is cleaved, resulting in a carbon-centred radical intermediate. Although spin-centre shift is a well-understood biochemical process, it is underused by the synthetic organic chemistry community. We wondered whether it would be possible to take advantage of this naturally occurring process to accomplish mild, non-traditional alkylation reactions using alcohols as radical precursors. Because conventional radical-based alkylation methods require the use of stoichiometric oxidants, increased temperatures or peroxides(3-7), a mild protocol using simple and abundant alkylating agents would have considerable use in the synthesis of diversely functionalized pharmacophores. Here we describe the development of a dual catalytic alkylation of heteroarenes, using alcohols as mild alkylating reagents. This method represents the first, to our knowledge, broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox and hydrogen atom transfer catalysis. The value of this multi-catalytic protocol has been demonstrated through the late-stage functionalization of the medicinal agents, fasudil and milrinone.
C1 [Jin, Jian; 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 NIHGMS [R01 GM103558-03]
NR 28
TC 663
Z9 716
U1 8
U2 477
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 3
PY 2015
VL 525
IS 7567
BP 87
EP 90
DI 10.1038/nature14885
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100030
PM 26308895
DA 2026-03-09
ER

PT J
AU Mirtschink, P
   Krishnan, J
   Grimm, F
   Sarre, A
   Hörl, M
   Kayikci, M
   Fankhauser, N
   Christinat, Y
   Cortijo, C
   Feehan, O
   Vukolic, A
   Sossalla, S
   Stehr, SN
   Ule, J
   Zamboni, N
   Pedrazzini, T
   Krek, W
AF Mirtschink, Peter
   Krishnan, Jaya
   Grimm, Fiona
   Sarre, Alexandre
   Hoerl, Manuel
   Kayikci, Melis
   Fankhauser, Niklaus
   Christinat, Yann
   Cortijo, Cedric
   Feehan, Owen
   Vukolic, Ana
   Sossalla, Samuel
   Stehr, Sebastian N.
   Ule, Jernej
   Zamboni, Nicola
   Pedrazzini, Thierry
   Krek, Wilhelm
TI HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease
SO NATURE
LA English
DT Article
ID cardiac-hypertrophy; mass-spectrometry; messenger-rna; cells; failure; pathway; ketohexokinase; expression; mice; quantification
AB Fructose is a major component of dietary sugar and its overconsumption exacerbates key pathological features of metabolic syndrome. The central fructose-metabolising enzyme is ketohexokinase (KHK), which exists in two isoforms: KHK-A and KHK-C, generated through mutually exclusive alternative splicing of KHK pre-mRNAs. KHK-C displays superior affinity for fructose compared with KHK-A and is produced primarily in the liver, thus restricting fructose metabolism almost exclusively to this organ. Here we show that myocardial hypoxia actuates fructose metabolism in human and mouse models of pathological cardiac hypertrophy through hypoxia-inducible factor 1 alpha (HIF1 alpha) activation of SF3B1 and SF3B1-mediated splice switching of KHK-A to KHK-C. Heart-specific depletion of SF3B1 orgenetic ablation of Khk, but not Khk-A alone, in mice, suppresses pathological stress-induced fructose metabolism, growth and contractile dysfunction, thus defining signalling components and molecular underpinnings of a fructose metabolism regulatory system crucial for pathological growth.
C1 [Mirtschink, Peter; Krishnan, Jaya; Grimm, Fiona; Fankhauser, Niklaus; Christinat, Yann; Cortijo, Cedric; Feehan, Owen; Vukolic, Ana; Krek, Wilhelm] ETH, Inst Mol Hlth Sci, CH-8093 Zurich, Switzerland.
   [Sarre, Alexandre; Pedrazzini, Thierry] Univ Lausanne, Dept Med, CH-1011 Lausanne, Switzerland.
   [Hoerl, Manuel; Zamboni, Nicola] ETH, Inst Mol Syst Biol, CH-8093 Zurich, Switzerland.
   [Kayikci, Melis; Ule, Jernej] MRC Lab Mol Biol, Cambridge CB2 0QH, England.
   [Sossalla, Samuel] Univ Med Gottingen, Klin Kardiol & Pneumol, D-37075 Gottingen, Germany.
   [Sossalla, Samuel] DZHK German Ctr Cardiovasc Res, Partner Site Gottingen, Hamburg, Germany.
   [Stehr, Sebastian N.] Univ Hosp Jena, Dept Anesthesiol & Crit Care Med, D-07747 Jena, Germany.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Lausanne; Swiss Federal Institutes of Technology Domain; ETH Zurich; MRC Laboratory Molecular Biology; University of Gottingen; German Centre for Cardiovascular Research; Friedrich Schiller University of Jena
RP Krek, W (corresponding author), ETH, Inst Mol Hlth Sci, CH-8093 Zurich, Switzerland.
EM wilhelm.krek@biol.ethz.ch
FU Sinergia (Swiss National Science Foundation); Swiss Heart Foundation; Medical Research Council [MC_U105185858, MC_U105185859] Funding Source: researchfish; MRC [MC_U105185858, MC_U105185859] Funding Source: UKRI
NR 48
TC 140
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 JUN 25
PY 2015
VL 522
IS 7557
BP 444
EP +
DI 10.1038/nature14508
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL2OC
UT WOS:000356782900042
PM 26083752
DA 2026-03-09
ER

PT J
AU Biggin, AJ
   Piispa, EJ
   Pesonen, LJ
   Holme, R
   Paterson, GA
   Veikkolainen, T
   Tauxe, L
AF Biggin, A. J.
   Piispa, E. J.
   Pesonen, L. J.
   Holme, R.
   Paterson, G. A.
   Veikkolainen, T.
   Tauxe, L.
TI Palaeomagnetic field intensity variations suggest Mesoproterozoic inner-core nucleation
SO NATURE
LA English
DT Article
ID geomagnetic-field; transport-property; paleointensity; iron; conductivity; evolution
AB The Earth's inner core grows by the freezing of liquid iron at its surface. The point in history at which this process initiated marks a step-change in the thermal evolution of the planet. Recent computational and experimental studies(1-5) have presented radically differing estimates of the thermal conductivity of the Earth's core, resulting in estimates of the timing of inner-core nucleation ranging from less than half a billion to nearly two billion years ago. Recent inner-core nucleation (high thermal conductivity) requires high outer-core temperatures in the early Earth that complicate models of thermal evolution. The nucleation of the core leads to a different convective regime(6) and potentially different magnetic field structures that produce an observable signal in the palaeomagnetic record and allow the date of inner-core nucleation to be estimated directly. Previous studies searching for this signature have been hampered by the paucity of palaeomagnetic intensity measurements, by the lack of an effective means of assessing their reliability, and by shorter-timescale geo-magnetic variations. Here we examine results from an expanded Precambrian database of palaeomagnetic intensity measurements(7) selected using a new set of reliability criteria(8). Our analysis provides intensity-based support for the dominant dipolarity of the time-averaged Precambrian field, a crucial requirement for palaeomagnetic reconstructions of continents. We also present firm evidence for the existence of very long-term variations in geomagnetic strength. The most prominent and robust transition in the record is an increase in both average field strength and variability that is observed to occur between a billion and 1.5 billion years ago. This observation is most readily explained by the nucleation of the inner core occurring during this interval(9); the timing would tend to favour a modest value of core thermal conductivity and supports a simple thermal evolution model for the Earth.
C1 [Biggin, A. J.; Holme, R.] Univ Liverpool, Dept Earth Ocean & Ecol Sci, Liverpool L69 7ZE, Merseyside, England.
   [Piispa, E. J.] Michigan Technol Univ, Dept Geol & Min Engn & Sci, Houghton, MI 49931 USA.
   [Pesonen, L. J.; Veikkolainen, T.] Univ Helsinki, Dept Phys, Div Mat Phys, FI-00014 Helsinki, Finland.
   [Paterson, G. A.] Chinese Acad Sci, Inst Geol & Geophys, Key Lab Earth & Planetary Phys, Beijing 100029, Peoples R China.
   [Tauxe, L.] Univ Calif San Diego, Scripps Inst Oceanog, La Jolla, CA 92093 USA.
C3 University of Liverpool; Michigan Technological University; University of Helsinki; Chinese Academy of Sciences; Institute of Geology & Geophysics, CAS; University of California System; University of California San Diego; Scripps Institution of Oceanography
RP Biggin, AJ (corresponding author), Univ Liverpool, Dept Earth Ocean & Ecol Sci, Liverpool L69 7ZE, Merseyside, England.
EM biggin@liv.ac.uk
FU European Research Council (ERC) [267631]; Research Council of Norway through its Centres of Excellence funding scheme [CEED 223272]; NERC standard grant [NE/H021043/1]; NSFC [41374072]; NSF [EAR 1345003]; European Research Council (ERC) [267631] Funding Source: European Research Council (ERC); Directorate For Geosciences; Division Of Earth Sciences [1345003] Funding Source: National Science Foundation; Natural Environment Research Council [NE/H021043/1] Funding Source: researchfish; NERC [NE/H021043/1] Funding Source: UKRI
NR 32
TC 188
Z9 213
U1 1
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 OCT 8
PY 2015
VL 526
IS 7572
BP 245
EP +
DI 10.1038/nature15523
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS9GV
UT WOS:000362399000045
PM 26450058
DA 2026-03-09
ER

PT J
AU Vampa, G
   Hammond, TJ
   Thiré, N
   Schmidt, BE
   Légaré, F
   McDonald, CR
   Brabec, T
   Corkum, PB
AF Vampa, G.
   Hammond, T. J.
   Thire, N.
   Schmidt, B. E.
   Legare, F.
   McDonald, C. R.
   Brabec, T.
   Corkum, P. B.
TI Linking high harmonics from gases and solids
SO NATURE
LA English
DT Article
ID generation; dynamics; field; ionization
AB When intense light interacts with an atomic gas, recollision between an ionizing electron and its parent ion(1) creates high-order harmonics of the fundamental laser frequency(2). This sub-cycle effect generates coherent soft X-rays(3) and attosecond pulses(4), and provides a means to image molecular orbitals(5). Recently, high harmonics have been generated from bulk crystals(6,7), but what mechanism(8-12) dominates the emission remains uncertain. To resolve this issue, we adapt measurement methods from gas-phase research(13,14) to solid zinc oxide driven by mid-infrared laser fields of 0.25 volts per angstrom. We find that when we alter the generation process with a second-harmonic beam, the modified harmonic spectrum bears the signature of a generalized recollision between an electron and its associated hole(11). In addition, we find that solid-state high harmonics are perturbed by fields so weak that they are present in conventional electronic circuits, thus opening a route to integrate electronics with attosecond and high-harmonic technology. Future experiments will permit the band structure of a solid(15) to be tomographically reconstructed.
C1 [Vampa, G.; Hammond, T. J.; McDonald, C. R.; Brabec, T.; Corkum, P. B.] Univ Ottawa, Dept Phys, Ottawa, ON K1N 6N5, Canada.
   [Thire, N.; Schmidt, B. E.; Legare, F.] INRS EMT, Varennes, PQ J3X 1S2, Canada.
   [Corkum, P. B.] Natl Res Council Canada, Ottawa, ON K1A 0R6, Canada.
C3 University of Ottawa; University of Quebec; Institut national de la recherche scientifique (INRS); National Research Council Canada
RP Corkum, PB (corresponding author), Univ Ottawa, Dept Phys, Ottawa, ON K1N 6N5, Canada.
EM gvamp015@uottawa.ca; paul.corkum@nrc.ca
FU US AFOSR; NSERC; FRQNT; MDEIE; CFI
NR 33
TC 626
Z9 687
U1 6
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 JUN 25
PY 2015
VL 522
IS 7557
BP 462
EP +
DI 10.1038/nature14517
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL2OC
UT WOS:000356782900046
PM 26108855
DA 2026-03-09
ER

PT J
AU Zhao, JH
   Benlekbir, S
   Rubinstein, JL
AF Zhao, Jianhua
   Benlekbir, Samir
   Rubinstein, John L.
TI Electron cryomicroscopy observation of rotational states in a eukaryotic V-ATPase
SO NATURE
LA English
DT Article
ID crystal-structure; saccharomyces-cerevisiae; central stalk; rotary motor; subunit-c; cryo-em; resolution; synthase; reveals; rotor
AB Eukaryotic vacuolar H+-ATPases (V-ATPases) are rotary enzymes that use energy from hydrolysis of ATP to ADP to pump protons across membranes and control the pH of many intracellular compartments. ATP hydrolysis in the soluble catalytic region of the enzyme is coupled to proton translocation through the membrane-bound region by rotation of a central rotor subcomplex, with peripheral stalks preventing the entire membrane-bound region from turning with the rotor. The eukaryotic V-ATPase is the most complex rotary ATPase: it has three peripheral stalks, a hetero-oligomeric proton-conducting proteolipid ring, several subunits not found in other rotary ATPases, and is regulated by reversible dissociation of its catalytic and proton-conducting regions(1,2). Studies of ATP synthases, V-ATPases, and bacterial/archaeal V/A-ATPases have suggested that flexibility is necessary for the catalytic mechanism of rotary ATPases(3-5), but the structures of different rotational states have never been observed experimentally. Here we use electron cryomicroscopy to obtain structures for three rotational states of the V-ATPase from the yeast Saccharomyces cerevisiae. The resulting series of structures shows ten proteolipid subunits in the c-ring, setting the ATP: H+ ratio for proton pumping by the V-ATPase at 3: 10, and reveals long and highly tilted transmembrane alpha-helices in the a-subunit that interact with the c-ring. The three different maps reveal the conformational changes that occur to couple rotation in the symmetry-mismatched soluble catalytic region to the membrane-bound proton-translocating region. Almost all of the subunits of the enzyme undergo conformational changes during the transitions between these three rotational states. The structures of these states provide direct evidence that deformation during rotation enables the smooth transmission of power through rotary ATPases.
C1 [Zhao, Jianhua; Benlekbir, Samir; Rubinstein, John L.] Hosp Sick Children, Res Inst, Mol Struct & Funct Program, Toronto, ON M5G 0A4, Canada.
   [Zhao, Jianhua; Rubinstein, John L.] Univ Toronto, Dept Med Biophys, MaRS Ctr, Toronto, ON M5G 1L7, Canada.
   [Rubinstein, John L.] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada.
C3 University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; University of Toronto
RP Rubinstein, JL (corresponding author), Hosp Sick Children, Res Inst, Mol Struct & Funct Program, 686 Bay St, Toronto, ON M5G 0A4, Canada.
EM john.rubinstein@utoronto.ca
FU Natural Sciences and Engineering Research Council of Canada; Mary Gertrude l'Anson Scholarship; Canadian Institutes of Health Research [MOP 81294]
NR 51
TC 236
Z9 280
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 14
PY 2015
VL 521
IS 7551
BP 241
EP +
DI 10.1038/nature14365
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH9SY
UT WOS:000354377800063
PM 25971514
DA 2026-03-09
ER

PT J
AU Cossell, L
   Iacaruso, MF
   Muir, DR
   Houlton, R
   Sader, EN
   Ko, H
   Hofer, SB
   Mrsic-Flogel, TD
AF Cossell, Lee
   Iacaruso, Maria Florencia
   Muir, Dylan R.
   Houlton, Rachael
   Sader, Elie N.
   Ko, Ho
   Hofer, Sonja B.
   Mrsic-Flogel, Thomas D.
TI Functional organization of excitatory synaptic strength in primary visual cortex
SO NATURE
LA English
DT Article
ID orientation selectivity; receptive-fields; in-vivo; neurons; mouse; connectivity; input; specificity; layer-2/3; network
AB The strength of synaptic connections fundamentally determines how neurons influence each other's firing. Excitatory connection amplitudes between pairs of cortical neurons vary over two orders of magnitude, comprising only very few strong connections among many weaker ones(1-9). Although this highly skewed distribution of connection strengths is observed in diverse cortical areas(1-9), its functional significance remains unknown: it is not clear how connection strength relates to neuronal response properties, nor how strong and weak inputs contribute to information processing in local microcircuits. Here we reveal that the strength of connections between layer 2/3 (L2/3) pyramidal neurons in mouse primary visual cortex (V1) obeys a simple rule-the few strong connections occur between neurons with most correlated responses, while only weak connections link neurons with uncorrelated responses. Moreover, we show that strong and reciprocal connections occur between cells with similar spatial receptive field structure. Although weak connections far outnumber strong connections, each neuron receives the majority of its local excitation from a small number of strong inputs provided by the few neurons with similar responses to visual features. By dominating recurrent excitation, these infrequent yet powerful inputs disproportionately contribute to feature preference and selectivity. Therefore, our results show that the apparently complex organization of excitatory connection strength reflects the similarity of neuronal responses, and suggest that rare, strong connections mediate stimulus-specific response amplification in cortical microcircuits.
C1 [Cossell, Lee; Iacaruso, Maria Florencia; Houlton, Rachael; Sader, Elie N.; Ko, Ho; Hofer, Sonja B.; Mrsic-Flogel, Thomas D.] UCL, Dept Neurosci Physiol & Pharmacol, London WC1E 6DE, England.
   [Cossell, Lee; Iacaruso, Maria Florencia; Muir, Dylan R.; Hofer, Sonja B.; Mrsic-Flogel, Thomas D.] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland.
   [Ko, Ho] Chinese Univ Hong Kong, Fac Med, Lui Che Woo Inst Innovat Med, Shatin, Hong Kong, Peoples R China.
   [Ko, Ho] Chinese Univ Hong Kong, Fac Med, Chow Yuk Ho Technol Ctr Innovat Med, Shatin, Hong Kong, Peoples R China.
C3 University of London; University College London; University of Basel; Chinese University of Hong Kong; Chinese University of Hong Kong
RP Mrsic-Flogel, TD (corresponding author), UCL, Dept Neurosci Physiol & Pharmacol, 21 Univ St, London WC1E 6DE, England.
EM thomas.mrsic-flogel@unibas.ch
FU Wellcome Trust [095074]; European Research council; UCL; University of Basel Young Researchers fund
NR 37
TC 366
Z9 444
U1 3
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 19
PY 2015
VL 518
IS 7539
BP 399
EP 403
DI 10.1038/nature14182
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400042
PM 25652823
DA 2026-03-09
ER

PT J
AU Seelig, JD
   Jayaraman, V
AF Seelig, Johannes D.
   Jayaraman, Vivek
TI Neural dynamics for landmark orientation and angular path integration
SO NATURE
LA English
DT Article
ID drosophila central complex; protocerebral bridge; direction; insect; brain; melanogaster; dissection; behavior; motion; memory
AB Many animals navigate using a combination of visual landmarks and path integration. In mammalian brains, head direction cells integrate these two streams of information by representing an animal's heading relative to landmarks, yet maintaining their directional tuning in darkness based on self-motion cues. Here we use two-photon calcium imaging in head-fixed Drosophila melanogaster walking on a ball in a virtual reality arena to demonstrate that landmark-based orientation and angular path integration are combined in the population responses of neurons whose dendrites tile the ellipsoid body, a toroidal structure in the centre of the fly brain. The neural population encodes the fly's azimuth relative to its environment, tracking visual landmarks when available and relying on self-motion cues in darkness. When both visual and self-motion cues are absent, a representation of the animal's orientation is maintained in this network through persistent activity, a potential substrate for short-term memory. Several features of the population dynamics of these neurons and their circular anatomical arrangement are suggestive of ring attractors, network structures that have been proposed to support the function of navigational brain circuits.
C1 [Seelig, Johannes D.; Jayaraman, Vivek] Janelia Res Campus, Howard Hughes Med Inst, Ashburn, VA 20147 USA.
C3 Howard Hughes Medical Institute
RP Jayaraman, V (corresponding author), Janelia Res Campus, Howard Hughes Med Inst, 19700 Helix Dr, Ashburn, VA 20147 USA.
EM vivek@janelia.hhmi.org
FU Howard Hughes Medical Institute
NR 47
TC 486
Z9 588
U1 5
U2 168
PU NATURE PUBLISHING 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 14
PY 2015
VL 521
IS 7551
BP 186
EP +
DI 10.1038/nature14446
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH9SY
UT WOS:000354377800051
PM 25971509
DA 2026-03-09
ER

PT J
AU Rajniak, J
   Barco, B
   Clay, NK
   Sattely, ES
AF Rajniak, Jakub
   Barco, Brenden
   Clay, Nicole K.
   Sattely, Elizabeth S.
TI A new cyanogenic metabolite in Arabidopsis required for inducible pathogen defence
SO NATURE
LA English
DT Article
ID flagellin perception; plants; indole-3-acetaldoxime; biosynthesis; resistance; conversion; catalyzes; thaliana; pathway
AB Thousands of putative biosynthetic genes in Arabidopsis thaliana have no known function, which suggests that there are numerous molecules contributing to plant fitness that have not yet been discovered(1,2). Prime among these uncharacterized genes are cytochromes P450 upregulated in response to pathogens(3,4). Here we start with a single pathogen-induced P450 (ref. 5), CYP82C2, and use a combination of untargeted metabolomics and coexpression analysis to uncover the complete biosynthetic pathway to 4-hydroxyindole-3-carbonyl nitrile (4-OH-ICN), a previously unknown Arabidopsis metabolite. This metabolite harbours cyanogenic functionality that is unprecedented in plants and exceedingly rare in nature(6,7); furthermore, the aryl cyanohydrin intermediate in the 4-OH-ICN pathway reveals a latent capacity for cyanogenic glucoside biosynthesis(8,9) in Arabidopsis. By expressing 4-OH-ICN biosynthetic enzymes in Saccharomyces cerevisiae and Nicotiana benthamiana, we reconstitute the complete pathway in vitro and in vivo and validate the functions of its enzymes. Arabidopsis 4-OH-ICN pathway mutants show increased susceptibility to the bacterial pathogen Pseudomonas syringae, consistent with a role in inducible pathogen defence. Arabidopsis has been the pre-eminent model system(10,11) for studying the role of small molecules in plant innate immunity(12); our results uncover a new branch of indole metabolism distinct from the canonical camalexin pathway, and support a role for this pathway in the Arabidopsis defence response(13). These results establish a more complete framework for understanding how the model plant Arabidopsis uses small molecules in pathogen defence.
C1 [Rajniak, Jakub; Sattely, Elizabeth S.] Stanford Univ, Dept Chem Engn, Stanford, CA 94305 USA.
   [Barco, Brenden; Clay, Nicole K.] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06511 USA.
C3 Stanford University; Yale University
RP Sattely, ES (corresponding author), Stanford Univ, Dept Chem Engn, Stanford, CA 94305 USA.
EM nicole.clay@yale.edu; sattely@stanford.edu
FU National Science Foundation [MCB-0519898]; National Institutes of Health [R37 GM 48707];  [R00 GM089985];  [DP2 AT008321];  [T32 GM008412-20];  [T32 GM007499-38]; Division Of Integrative Organismal Systems; Direct For Biological Sciences [0929226] Funding Source: National Science Foundation; National Institute of General Medical Sciences [T32GM007499] Funding Source: NIH RePORTER
NR 28
TC 178
Z9 219
U1 4
U2 213
PU NATURE PUBLISHING 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 17
PY 2015
VL 525
IS 7569
BP 376
EP +
DI 10.1038/nature14907
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900043
PM 26352477
DA 2026-03-09
ER

PT J
AU Olling, RP
   Mushotzky, R
   Shaya, EJ
   Rest, A
   Garnavich, PM
   Tucker, BE
   Kasen, D
   Margheim, S
   Filippenko, AV
AF Olling, Rob P.
   Mushotzky, Richard
   Shaya, Edward J.
   Rest, Armin
   Garnavich, Peter M.
   Tucker, Brad E.
   Kasen, Daniel
   Margheim, Steve
   Filippenko, Alexei V.
TI No signature of ejecta interaction with a stellar companion in three type Ia supernovae
SO NATURE
LA English
DT Article
ID sn 2011fe; legacy survey; light curves; rise-time; star; catalog; progenitors; discovery; spectra; 2012cg
AB Type Ia supernovae are thought to be the result of a thermonuclear runaway in carbon/oxygen white dwarfs, but it is uncertain whether the explosion is triggered by accretion from a non-degenerate companion star or by a merger with another white dwarf. Observations of a supernova immediately following the explosion provide unique information on the distribution of ejected material(1) and the progenitor system. Models predict(2) that the interaction of supernova ejecta with a companion star or circumstellar debris lead to a sudden brightening lasting from hours to days. Here we present data for three supernovae that are likely to be type Ia observed during the Kepler mission(3) with a time resolution of 30 minutes. We find no signatures of the supernova ejecta interacting with nearby companions. The lack of observable interaction signatures is consistent with the idea that these three supernovae resulted from the merger of binary white dwarfs or other compact stars such as helium stars.
C1 [Olling, Rob P.; Mushotzky, Richard; Shaya, Edward J.] Univ Maryland, Dept Astron, College Pk, MD 20742 USA.
   [Rest, Armin] Space Telescope Sci Inst, Baltimore, MD 21218 USA.
   [Garnavich, Peter M.] Univ Notre Dame, Dept Phys, Notre Dame, IN 46556 USA.
   [Tucker, Brad E.] Australian Natl Univ, Mt Stromlo Observ, Weston, ACT 2611, Australia.
   [Tucker, Brad E.; Kasen, Daniel; Filippenko, Alexei V.] Univ Calif Berkeley, Dept Astron, Berkeley, CA 94720 USA.
   [Kasen, Daniel] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA.
   [Margheim, Steve] AURA, Southern Operat Ctr, Gemini Observ, La Serena, Chile.
C3 University System of Maryland; University of Maryland College Park; Space Telescope Science Institute; University of Notre Dame; Australian National University; 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 Olling, RP (corresponding author), Univ Maryland, Dept Astron, College Pk, MD 20742 USA.
EM olling@astro.umd.edu
FU Kepler GO3; GO4 [NNX12AC95G, NNX13AC27G]; Kepler grants [NNX12AC89G, NNX11AG95G]; NSF [AST-1211916, GN-2013A-Q-4, GS-2013A-Q-115]; TABASGO Foundation; Christopher R. Redlich Fund; NASA [NAS5-26555]; NASA Office of Space Science [NNX13AC07G]; NASA Science Mission directorate; National Science Foundation (United States); National Research Council (Canada); CONICYT (Chile); Australian Research Council (Australia); Ministerio da Ciencia, Tecnologia e Inovacao (Brazil); Ministerio de Ciencia, Tecnologia e Innovacion Productiva (Argentina); W. M. Keck Foundation; Division Of Astronomical Sciences; Direct For Mathematical & Physical Scien [1211916, 1109896] Funding Source: National Science Foundation
NR 31
TC 125
Z9 144
U1 0
U2 6
PU NATURE PUBLISHING 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 21
PY 2015
VL 521
IS 7552
BP 332
EP +
DI 10.1038/nature14455
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CI5RM
UT WOS:000354816500051
PM 25993963
DA 2026-03-09
ER

PT J
AU He, WW
   Bai, G
   Zhou, HH
   Wei, N
   White, NM
   Lauer, J
   Liu, HQ
   Shi, Y
   Dumitru, CD
   Lettieri, K
   Shubayev, V
   Jordanova, A
   Guergueltcheva, V
   Griffin, PR
   Burgess, RW
   Pfaff, SL
   Yang, XL
AF He, Weiwei
   Bai, Ge
   Zhou, Huihao
   Wei, Na
   White, Nicholas M.
   Lauer, Janelle
   Liu, Huaqing
   Shi, Yi
   Dumitru, Calin Dan
   Lettieri, Karen
   Shubayev, Veronica
   Jordanova, Albena
   Guergueltcheva, Velina
   Griffin, Patrick R.
   Burgess, Robert W.
   Pfaff, Samuel L.
   Yang, Xiang-Lei
TI CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase
SO NATURE
LA English
DT Article
ID mouse als model; tooth type 2d; prolongs survival; gene mutation; gars; disease; degeneration; phenotypes; migration; delivery
AB Selective neuronal loss is a hallmark of neurodegenerative diseases, which, counterintuitively, are often caused by mutations in widely expressed genes'. Charcot-Marie-Tooth (CMT) diseases are the most common hereditary peripheral neuropathies, for which there are no effective therapies(2,3). A subtype of these diseases CMT type 2D (CMT2D)-is caused by dominant mutations in GARS, encoding the ubiquitously expressed enzyme glycyl-transfer RNA (tRNA) synthetase (GlyRS). Despite the broad requirement of GlyRS for protein biosynthesis in all cells, mutations in this gene cause a selective degeneration of peripheral axons, leading to deficits in distal motor function(4). How mutations in GlyRS (GlyRS(CMT2D)) are linked to motor neuron vulnerability has remained elusive. Here we report that GlyRS(CMT2D) acquires a neomorphic binding activity that directly antagonizes an essential signalling pathway for motor neuron survival. We find that CMT2D mutations alter the conformation of GlyRS, enabling GlyRS(CMT2D) to bind the neuropilin 1 (Nrpl) receptor. This aberrant interaction competitively interferes with the binding of the cognate ligand vascular endothelial growth factor (VEGF) to Nrpl. Genetic reduction of Nrpl in mice worsens CMT2D symptoms, whereas enhanced expression of VEGF improves motor function. These findings link the selective pathology of CMT2D to the neomorphic binding activity of GlyRS(CMT2D) that antagonizes the VEGF-Nrp1 interaction, and indicate that the VEGF-Nrp1 signalling axis is an actionable target for treating CMT2D.
C1 [He, Weiwei; Zhou, Huihao; Wei, Na; Shi, Yi; Dumitru, Calin Dan; Yang, Xiang-Lei] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA.
   [He, Weiwei; Zhou, Huihao; Wei, Na; Shi, Yi; Dumitru, Calin Dan; Yang, Xiang-Lei] Scripps Res Inst, Dept Cell & Mol Biol, La Jolla, CA 92037 USA.
   [Bai, Ge; White, Nicholas M.; Lettieri, Karen; Pfaff, Samuel L.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA.
   [Bai, Ge; White, Nicholas M.; Lettieri, Karen; Pfaff, Samuel L.] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA.
   [Lauer, Janelle; Griffin, Patrick R.] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA.
   [Liu, Huaqing; Shubayev, Veronica] Univ Calif San Diego, Dept Anesthesiol, La Jolla, CA 92093 USA.
   [Jordanova, Albena] Univ Antwerp, Mol Neurogen Grp, VIB Dept Mol Genet, BE-2610 Antwerp, Belgium.
   [Guergueltcheva, Velina] Med Univ Sofia, Dept Neurol, Sofia 1431, Bulgaria.
   [Burgess, Robert W.] Jackson Lab, Bar Harbor, ME 04609 USA.
C3 Scripps Research Institute; Scripps Research Institute; Salk Institute; Howard Hughes Medical Institute; Salk Institute; State University System of Florida; University of Florida; Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology; University of California System; University of California San Diego; Flanders Institute for Biotechnology (VIB); University of Antwerp; Medical University Sofia; Jackson Laboratory
RP Yang, XL (corresponding author), Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA.
EM pfaff@salk.edu; xlyang@scripps.edu
FU National Foundation for Cancer Research; Pioneer fund; Howard Hughes Medical Institute; US National Institutes of Health [R01GM088278, R21NS084254, R01NS054154]; Marshall Heritage Foundation; Sol Goldman Trust; aTyr Pharma through Scripps Research Institute; National Cancer Institute [P30CA014195] Funding Source: NIH RePORTER
NR 30
TC 130
Z9 158
U1 0
U2 35
PU NATURE PUBLISHING 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 29
PY 2015
VL 526
IS 7575
BP 710
EP 714
DI 10.1038/nature15510
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CU8ZH
UT WOS:000363832100050
PM 26503042
DA 2026-03-09
ER

PT J
AU Wu, SF
   Buckley, S
   Schaibley, JR
   Feng, LF
   Yan, JQ
   Mandrus, DG
   Hatami, F
   Yao, W
   Vuckovic, J
   Majumdar, A
   Xu, XD
AF Wu, Sanfeng
   Buckley, Sonia
   Schaibley, John R.
   Feng, Liefeng
   Yan, Jiaqiang
   Mandrus, David G.
   Hatami, Fariba
   Yao, Wang
   Vuckovic, Jelena
   Majumdar, Arka
   Xu, Xiaodong
TI Monolayer semiconductor nanocavity lasers with ultralow thresholds
SO NATURE
LA English
DT Article
ID transition; linewidth; diodes
AB Engineering the electromagnetic environment of a nanometre-scale light emitter by use of a photonic cavity can significantly enhance its spontaneous emission rate, through cavity quantum electrodynamics in the Purcell regime. This effect can greatly reduce the lasing threshold of the emitter(1-5), providing a low-threshold laser system with small footprint, low power consumption and ultrafast modulation. An ultralow-threshold nanoscale laser has been successfully developed by embedding quantum dots into a photonic crystal cavity (PCC)(6-8). However, several challenges impede the practical application of this architecture, including the randompositions and compositional fluctuations of the dots(7), extreme difficulty in current injection(8), and lack of compatibility with electronic circuits(7,8). Here we report a new lasing strategy: an atomically thin crystalline semiconductor-that is, a tungsten diselenide monolayer-is non-destructively and deterministically introduced as a gain medium at the surface of a pre-fabricated PCC. A continuous-wave nanolaser operating in the visible regime is thereby achieved with an optical pumping threshold as low as 27 nanowatts at 130 kelvin, similar to the value achieved in quantum-dot PCC lasers(7). The key to the lasing action lies in the monolayer nature of the gain medium, which confines direct-gap excitons to within one nanometre of the PCC surface. The surface-gain geometry gives unprecedented accessibility and hence the ability to tailor gain properties via external controls such as electrostatic gating and current injection, enabling electrically pumped operation. Our scheme is scalable and compatible with integrated photonics for on-chip optical communication technologies.
C1 [Wu, Sanfeng; Schaibley, John R.; Feng, Liefeng; Xu, Xiaodong] Univ Washington, Dept Phys, Seattle, WA 98195 USA.
   [Buckley, Sonia; Vuckovic, Jelena] Stanford Univ, Ginzton Lab, Stanford, CA 94305 USA.
   [Feng, Liefeng] Tianjin Univ, Dept Appl Phys, Tianjin 300072, Peoples R China.
   [Yan, Jiaqiang; Mandrus, David G.] Oak Ridge Natl Lab, Mat Sci & Technol Div, Oak Ridge, TN 37831 USA.
   [Yan, Jiaqiang; Mandrus, David G.] Univ Tennessee, Dept Mat Sci & Engn, Knoxville, TN 37996 USA.
   [Mandrus, David G.] Univ Tennessee, Dept Phys & Astron, Knoxville, TN 37996 USA.
   [Hatami, Fariba] Humboldt Univ, Dept Phys, D-12489 Berlin, Germany.
   [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.
   [Majumdar, Arka] Univ Washington, Dept Elect Engn, Seattle, WA 98195 USA.
   [Xu, Xiaodong] Univ Washington, Dept Mat Sci & Engn, Seattle, WA 98195 USA.
C3 University of Washington; University of Washington Seattle; Stanford University; Tianjin University; United States Department of Energy (DOE); Oak Ridge National Laboratory; University of Tennessee System; University of Tennessee Knoxville; University of Tennessee System; University of Tennessee Knoxville; Humboldt University of Berlin; University of Hong Kong; University of Hong Kong; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle
RP Xu, XD (corresponding author), Univ Washington, Dept Phys, Seattle, WA 98195 USA.
EM arka@uw.edu; xuxd@uw.edu
FU AFOSR [FA9550-14-1-0277]; NSF [ECS-9731293]; State of Washington through the University of Washington Clean Energy Institute; Presidential Early Award for Scientists and Engineers (PECASE) [N00014-08-1-0561]; Stanford Graduate Fellowship; US DoE, BES, Materials Sciences and Engineering Division; European Commission [FP7-ICT-2013-613024-GRASP];  [NSF-EFRI-1433496]; Directorate For Engineering; Div Of Electrical, Commun & Cyber Sys [1542152] Funding Source: National Science Foundation; Emerging Frontiers & Multidisciplinary Activities; Directorate For Engineering [1433496] Funding Source: National Science Foundation
NR 31
TC 795
Z9 946
U1 23
U2 1052
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 2
PY 2015
VL 520
IS 7545
BP 69
EP U142
DI 10.1038/nature14290
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE7NE
UT WOS:000352027700038
PM 25778703
DA 2026-03-09
ER

PT J
AU Zhang, DC
   Chen, G
   Manwani, D
   Mortha, A
   Xu, CL
   Faith, JJ
   Burk, RD
   Kunisaki, Y
   Jang, JE
   Scheiermann, C
   Merad, M
   Frenette, PS
AF Zhang, Dachuan
   Chen, Grace
   Manwani, Deepa
   Mortha, Arthur
   Xu, Chunliang
   Faith, Jeremiah J.
   Burk, Robert D.
   Kunisaki, Yuya
   Jang, Jung-Eun
   Scheiermann, Christoph
   Merad, Miriam
   Frenette, Paul S.
TI Neutrophil ageing is regulated by the microbiome
SO NATURE
LA English
DT Article
ID bone-marrow; granulopoiesis; microdomains; homeostasis
AB Blood polymorphonuclear neutrophils provide immune protection against pathogens, but may also promote tissue injury in inflammatory diseases(1,2). Although neutrophils are generally considered to be a relatively homogeneous population, evidence for heterogeneity is emerging(3,4). Under steady-state conditions, neutrophil heterogeneity may arise from ageing and replenishment by newly released neutrophils from the bone marrow(5). Aged neutrophils upregulate CXCR4, a receptor allowing their clearance in the bone marrow(6,7), with feedback inhibition of neutrophil production via the IL-17/G-CSF axis8, and rhythmic modulation of the haematopoietic stem-cell niche(5). The aged subset also expresses low levels of L-selectin(5,9). Previous studies have suggested that in vitro-aged neutrophils exhibit impaired migration and reduced pro-inflammatory properties(6,10). Here, using in vivo ageing analyses in mice, we show that neutrophil pro-inflammatory activity correlates positively with their ageing whilst in circulation. Aged neutrophils represent an overly active subset exhibiting enhanced alpha(M)beta(2) integrin activation and neutrophil extracellular trap formation under inflammatory conditions. Neutrophil ageing is driven by the microbiota via Toll-like receptor and myeloid differentiation factor 88-mediated signalling pathways. Depletion of the microbiota significantly reduces the number of circulating aged neutrophils and dramatically improves the pathogenesis and inflammation-related organ damage inmodels of sickle-cell disease or endotoxin-induced septic shock. These results identify a role for the microbiota in regulating a disease-promoting neutrophil subset.
C1 [Zhang, Dachuan; Chen, Grace; Xu, Chunliang; Kunisaki, Yuya; Jang, Jung-Eun; Scheiermann, Christoph; Frenette, Paul S.] Albert Einstein Coll Med, Ruth L & David S Gottesman Inst Stem Cell & Regen, Bronx, NY 10461 USA.
   [Zhang, Dachuan; Chen, Grace; Xu, Chunliang; Kunisaki, Yuya; Jang, Jung-Eun; Scheiermann, Christoph; Frenette, Paul S.] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA.
   [Manwani, Deepa; Burk, Robert D.] Albert Einstein Coll Med, Dept Pediat, Bronx, NY USA.
   [Mortha, Arthur; Merad, Miriam] Mt Sinai Sch Med, Dept Oncol Sci, New York, NY 10029 USA.
   [Mortha, Arthur; Faith, Jeremiah J.; Merad, Miriam] Mt Sinai Sch Med, Inst Immunol, New York, NY 10029 USA.
   [Faith, Jeremiah J.] Mt Sinai Sch Med, Inst Genom & Multiscale Biol, New York, NY 10029 USA.
   [Frenette, Paul S.] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA.
C3 Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University
RP Frenette, PS (corresponding author), Albert Einstein Coll Med, Ruth L & David S Gottesman Inst Stem Cell & Regen, Bronx, NY 10461 USA.
EM paul.frenette@einstein.yu.edu
FU American Heart Association [15PRE23010014]; National Institutes of Health [HL069438, DK056638, HL116340]; New York State Stem Cell Science (NYSTEM) Program; American Heart Association (AHA) [15PRE23010014] Funding Source: American Heart Association (AHA); Grants-in-Aid for Scientific Research [15K15364, 15H04859] Funding Source: KAKEN; National Cancer Institute [R01CA154947] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [R01HL069438] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK056638] Funding Source: NIH RePORTER
NR 34
TC 668
Z9 752
U1 6
U2 176
PU NATURE PUBLISHING 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 24
PY 2015
VL 525
IS 7570
BP 528
EP +
DI 10.1038/nature15367
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR8KI
UT WOS:000361599900052
PM 26374999
DA 2026-03-09
ER

PT J
AU Simon-Loriere, E
   Faye, O
   Faye, O
   Koivogui, L
   Magassouba, N
   Keita, S
   Thiberge, JM
   Diancourt, L
   Bouchier, C
   Vandenbogaert, M
   Caro, V
   Fall, G
   Buchmann, JP
   Matranga, CB
   Sabeti, PC
   Manuguerra, JC
   Holmes, EC
   Sall, AA
AF Simon-Loriere, Etienne
   Faye, Ousmane
   Faye, Oumar
   Koivogui, Lamine
   Magassouba, Nfaly
   Keita, Sakoba
   Thiberge, Jean-Michel
   Diancourt, Laure
   Bouchier, Christiane
   Vandenbogaert, Matthias
   Caro, Valerie
   Fall, Gamou
   Buchmann, Jan P.
   Matranga, Christan B.
   Sabeti, Pardis C.
   Manuguerra, Jean-Claude
   Holmes, Edward C.
   Sall, Amadou A.
TI Distinct lineages of Ebola virus in Guinea during the 2014 West African epidemic
SO NATURE
LA English
DT Article
ID transmission; platform; origin; galaxy
AB An epidemic of Ebola virus disease of unprecedented scale has been ongoing for more than a year in West Africa. As of 29 April 2015, there have been 26,277 reported total cases (of which 14,895 have been laboratory confirmed) resulting in 10,899 deaths(1). The source of the outbreak was traced to the prefecture of Gueckedou in the forested region of southeastern Guinea(2,3). The virus later spread to the capital, Conakry, and to the neighbouring countries of Sierra Leone, Liberia, Nigeria, Senegal and Mali(1). In March 2014, when the first cases were detected in Conakry, the Institut Pasteur of Dakar, Senegal, deployed a mobile laboratory in Donka hospital to provide diagnostic services to the greater Conakry urban area and other regions of Guinea. Through this process we sampled 85 Ebola viruses (EBOV) from patients infected from July to November 2014, and report their full genome sequences here. Phylogenetic analysis reveals the sustained transmission of three distinct viral lineages co-circulating in Guinea, including the urban setting of Conakry and its surroundings. One lineage is unique to Guinea and closely related to the earliest sampled viruses of the epidemic. A second lineage contains viruses probably reintroduced from neighbouring Sierra Leone on multiple occasions, while a third lineage later spread from Guinea to Mali. Each lineage is defined by multiple mutations, including non-synonymous changes in the virion protein 35 (VP35), glycoprotein (GP) and RNA-dependent-RNA polymerase (L) proteins. The viral GP is characterized by a glycosylation site modification and mutations in the mucin-like domain that could modify the outer shape of the virion. These data illustrate the ongoing ability of EBOV to develop lineage-specific and potentially phenotypically important variation.
C1 [Simon-Loriere, Etienne] Inst Pasteur, Funct Genet Infect Dis Unit, F-75724 Paris 15, France.
   [Simon-Loriere, Etienne] CNRS, URA3012, F-75015 Paris, France.
   [Faye, Ousmane; Faye, Oumar; Fall, Gamou; Sall, Amadou A.] Inst Pasteur, Arbovirus & Viral Hemorrhag Fever Unit, Dakar, Senegal.
   [Koivogui, Lamine] Inst Natl Sante Publ Guinee, Conakry, Guinea.
   [Magassouba, Nfaly] Univ Gamal Abdel Nasser, Projet Fievres Hemorrag Guinee, Conakry, Guinea.
   [Keita, Sakoba] Minist Hlth, Conakry, Guinea.
   [Thiberge, Jean-Michel; Diancourt, Laure; Vandenbogaert, Matthias; Caro, Valerie; Manuguerra, Jean-Claude] Inst Pasteur, Unite Environm & Risques Infect, Cellule Intervent Biol Urgence, F-75724 Paris 15, France.
   [Bouchier, Christiane] Inst Pasteur, Genom Platform, F-75724 Paris 15, France.
   [Buchmann, Jan P.; Holmes, Edward C.] Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Charles Perkins Ctr, Sch Biol Sci, Sydney, NSW 2006, Australia.
   [Buchmann, Jan P.; Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia.
   [Matranga, Christan B.; Sabeti, Pardis C.] Broad Inst, Cambridge, MA 02142 USA.
   [Sabeti, Pardis C.] Harvard Univ, FAS Ctr Syst Biol, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA.
C3 Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Centre National de la Recherche Scientifique (CNRS); Pasteur Network; Institut Pasteur Dakar; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; University of Sydney; University of Sydney; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University
RP Simon-Loriere, E (corresponding author), Inst Pasteur, Funct Genet Infect Dis Unit, F-75724 Paris 15, France.
EM etienne.simon-loriere@pasteur.fr; edward.holmes@sydney.edu.au; asall@pasteur.sn
FU Pasteur Ebola Task Force (PETF); French government's Investissement d'Avenir programme; Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' [ANR-10-LABX-62-IBEID]; Institut Pasteur de Dakar; NHMRC Australia fellowship
NR 21
TC 78
Z9 101
U1 0
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 6
PY 2015
VL 524
IS 7563
BP 102
EP U210
DI 10.1038/nature14612
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO2QS
UT WOS:000359002300040
PM 26106863
DA 2026-03-09
ER

PT J
AU Meyer, ET
   Georganopoulos, M
   Sparks, WB
   Perlman, E
   van der Marel, RP
   Anderson, J
   Sohn, ST
   Biretta, J
   Norman, C
   Chiaberge, M
AF Meyer, Eileen T.
   Georganopoulos, Markos
   Sparks, William B.
   Perlman, Eric
   van der Marel, Roeland P.
   Anderson, Jay
   Sohn, Sangmo Tony
   Biretta, John
   Norman, Colin
   Chiaberge, Marco
TI A kiloparsec-scale internal shock collision in the jet of a nearby radio galaxy
SO NATURE
LA English
DT Article
ID gamma-ray bursts; hubble-space-telescope; m87 jet; 3c 264; emission; motion; model
AB Jets of highly energized plasma with relativistic velocities are associated with black holes ranging in mass from a few times that of the Sun to the billion-solar-mass black holes at the centres of galaxies(1). A popular but unconfirmed hypothesis to explain how the plasma is energized is the 'internal shock model', in which the relativistic flow is unsteady(2). Faster components in the jet catch up to and collide with slower ones, leading to internal shocks that accelerate particles and generate magnetic fields(3). This mechanism can explain the variable, high-energy emission from a diverse set of objects(4-7), with the best indirect evidence being the unseen fast relativistic flow inferred to energize slower components in X-ray binary jets(8,9). Mapping of the kinematic profiles in resolved jets has revealed precessing and helical patterns in X-ray binaries(10,11), apparent superluminal motions(12,13), and the ejection of knots (bright components) from standing shocks in the jets of active galaxies(14,15). Observations revealing the structure and evolution of an internal shock in action have, however, remained elusive, hindering measurement of the physical parameters and ultimate efficiency of the mechanism. Here we report observations of a collision between two knots in the jet of nearby radio galaxy 3C 264. Abright knot with an apparent speed of (7.0 +/- 0.8)c, where c is the speed of light in a vacuum, is in the incipient stages of a collision with a slower-moving knot of speed (1.8 +/- 0.5)c just downstream, resulting in brightening of both knots-as seen in the most recent epoch of imaging.
C1 [Meyer, Eileen T.; Sparks, William B.; van der Marel, Roeland P.; Anderson, Jay; Biretta, John; Norman, Colin; Chiaberge, Marco] Space Telescope Sci Inst, 3700 San Martin Dr, Baltimore, MD 21218 USA.
   [Meyer, Eileen T.; Georganopoulos, Markos] Univ Maryland Baltimore Cty, Baltimore, MD 21250 USA.
   [Georganopoulos, Markos] NASA, Goddard Space Flight Ctr, Greenbelt, MD 20771 USA.
   [Perlman, Eric] Florida Inst Technol, Melbourne, FL 32901 USA.
   [Sohn, Sangmo Tony; Norman, Colin; Chiaberge, Marco] Johns Hopkins Univ, Baltimore, MD 21218 USA.
   [Chiaberge, Marco] Ist Radio Astron, Ist Nazl Astrofis, I-40129 Bologna, Italy.
C3 Space Telescope Science Institute; University System of Maryland; University of Maryland Baltimore County; National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center; Florida Institute of Technology; Johns Hopkins University; Istituto Nazionale Astrofisica (INAF)
RP Meyer, ET (corresponding author), Space Telescope Sci Inst, 3700 San Martin Dr, Baltimore, MD 21218 USA.
EM eileen.meyer@gmail.com
FU HST [GO-13327]
NR 28
TC 24
Z9 27
U1 0
U2 6
PU NATURE PUBLISHING 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 28
PY 2015
VL 521
IS 7553
BP 495
EP +
DI 10.1038/nature14481
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA DF8BN
UT WOS:000371582000002
PM 26017450
DA 2026-03-09
ER

PT J
AU Zhang, XQ
   Bogunovic, D
   Payelle-Brogard, B
   Francois-Newton, V
   Speer, SD
   Yuan, C
   Volpi, S
   Li, Z
   Sanal, O
   Mansouri, D
   Tezcan, I
   Rice, GI
   Chen, CY
   Mansouri, N
   Mahdaviani, SA
   Itan, Y
   Boisson, B
   Okada, S
   Zeng, L
   Wang, X
   Jiang, H
   Liu, WQ
   Han, TT
   Liu, DL
   Ma, T
   Wang, B
   Liu, MG
   Liu, JY
   Wang, QK
   Yalnizoglu, D
   Radoshevich, L
   Uzé, G
   Gros, P
   Rozenberg, F
   Zhang, SY
   Jouanguy, E
   Bustamante, J
   García-Sastre, A
   Abel, L
   Lebon, P
   Notarangelo, LD
   Crow, YJ
   Boisson-Dupuis, S
   Casanova, JL
   Pellegrini, S
AF Zhang, Xianqin
   Bogunovic, Dusan
   Payelle-Brogard, Beatrice
   Francois-Newton, Veronique
   Speer, Scott D.
   Yuan, Chao
   Volpi, Stefano
   Li, Zhi
   Sanal, Ozden
   Mansouri, Davood
   Tezcan, Ilhan
   Rice, Gillian I.
   Chen, Chunyuan
   Mansouri, Nahal
   Mahdaviani, Seyed Alireza
   Itan, Yuval
   Boisson, Bertrand
   Okada, Satoshi
   Zeng, Lu
   Wang, Xing
   Jiang, Hui
   Liu, Wenqiang
   Han, Tiantian
   Liu, Delin
   Ma, Tao
   Wang, Bo
   Liu, Mugen
   Liu, Jing-Yu
   Wang, Qing K.
   Yalnizoglu, Dilek
   Radoshevich, Lilliana
   Uze, Gilles
   Gros, Philippe
   Rozenberg, Flore
   Zhang, Shen-Ying
   Jouanguy, Emmanuelle
   Bustamante, Jacinta
   Garcia-Sastre, Adolfo
   Abel, Laurent
   Lebon, Pierre
   Notarangelo, Luigi D.
   Crow, Yanick J.
   Boisson-Dupuis, Stephanie
   Casanova, Jean-Laurent
   Pellegrini, Sandra
TI Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation
SO NATURE
LA English
DT Article
ID aicardi-goutieres syndrome; systemic-lupus-erythematosus; basal ganglia calcification; intracranial calcification; expression signature; gene; mutations; immunity; autoimmunity; proteolysis
AB Intracellular ISG15 is an interferon (IFN)-alpha/beta-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-alpha/beta-dependent antiviral immunity in mice(1-4). We previously published a study describing humans with inherited ISG15deficiency but without unusually severe viral diseases(5). We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-gamma-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-alpha/beta immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi-Goutieres syndrome and spondyloenchondrodysplasia(6-9). We further show that an absence of intracellular ISG15 in the patients' cells prevents the accumulation of USP18(10,11), a potent negative regulator of IFN-alpha/beta signalling, resulting in the enhancement and amplification of IFN-alpha/beta responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-alpha/beta immunity. In humans, intracellular ISG15 is IFN-alpha/beta-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-alpha/beta and prevention of IFN-alpha/beta-dependent autoinflammation.
C1 [Zhang, Xianqin; Yuan, Chao; Zeng, Lu; Wang, Xing; Liu, Wenqiang; Han, Tiantian; Ma, Tao; Liu, Mugen; Liu, Jing-Yu; Wang, Qing K.] Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Minist Educ, Key Lab Mol Biophys, Wuhan 430074, Peoples R China.
   [Bogunovic, Dusan; Itan, Yuval; Boisson, Bertrand; Okada, Satoshi; Zhang, Shen-Ying; Abel, Laurent; Boisson-Dupuis, Stephanie] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA.
   [Bogunovic, Dusan; Speer, Scott D.; Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA.
   [Payelle-Brogard, Beatrice; Francois-Newton, Veronique; Li, Zhi; Pellegrini, Sandra] Inst Pasteur, Cytokine Signaling Unit, CNRS URA 1961, F-75724 Paris, France.
   [Speer, Scott D.; Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Global Hlth & Emerging Pathogens Inst, New York, NY 10029 USA.
   [Speer, Scott D.] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, Microbiol Training Area, New York, NY 10029 USA.
   [Volpi, Stefano; Notarangelo, Luigi D.] Childrens Hosp, Div Immunol, Boston, MA 02115 USA.
   [Volpi, Stefano] Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, I-16132 Genoa, Italy.
   [Sanal, Ozden; Tezcan, Ilhan; Yalnizoglu, Dilek] Hacettepe Univ, Childrens Hosp, Div Immunol, TR-06100 Ankara, Turkey.
   [Sanal, Ozden; Tezcan, Ilhan; Yalnizoglu, Dilek] Hacettepe Univ, Childrens Hosp, Pediat Neurol Dept, TR-06100 Ankara, Turkey.
   [Mansouri, Davood; Mansouri, Nahal; Mahdaviani, Seyed Alireza] Shahid Beheshti Univ Med Sci, Natl Res Inst TB & Lung Dis, Pediat Resp Dis Res Ctr, Div Infect Dis & Clin Immunol, Tehran 4739, Iran.
   [Rice, Gillian I.; Crow, Yanick J.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester M13 9NT, Lancs, England.
   [Chen, Chunyuan] Cent S Univ, Xiangya Hosp 3, Dept Pediat, Changsha 410013, Hunan, Peoples R China.
   [Jiang, Hui] BGI Shenzhen, Shenzhen 518083, Peoples R China.
   [Liu, Delin] Sangzhi Cty Peoples Hosp, Sangzhi 427100, Peoples R China.
   [Wang, Bo] Hubei Maternal & Child Hlth Hosp, Genet Lab, Wuhan 430070, Peoples R China.
   [Wang, Qing K.] Cleveland Clin, Lerner Res Inst, Dept Mol Cardiol, Ctr Cardiovasc Genet, Cleveland, OH 44195 USA.
   [Radoshevich, Lilliana] Inst Pasteur, Bacteria Cell Interact Unit, F-75724 Paris, France.
   [Uze, Gilles] Univ Montpellier 2, CNRS UMR5235, F-34095 Montpellier, France.
   [Gros, Philippe] McGill Univ, Dept Biochem, Montreal, PQ H3A 0G4, Canada.
   [Rozenberg, Flore; Lebon, Pierre] Paris Descartes Univ, F-75006 Paris, France.
   [Jouanguy, Emmanuelle; Bustamante, Jacinta; Abel, Laurent; Boisson-Dupuis, Stephanie; Casanova, Jean-Laurent] Necker Hosp Sick Children, INSERM U1163, Necker Branch, Lab Human Genet Infect Dis, F-75015 Paris, France.
   [Jouanguy, Emmanuelle; Bustamante, Jacinta; Abel, Laurent; Crow, Yanick J.; Boisson-Dupuis, Stephanie; Casanova, Jean-Laurent] Paris Descartes Univ, Imagine Inst, F-75015 Paris, France.
   [Bustamante, Jacinta] Necker Hosp Sick Children, Ctr Study Primary Immunodeficiencies, F-75015 Paris, France.
   [Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Div Infect Dis, Dept Med, New York, NY 10029 USA.
   [Crow, Yanick J.] Imagine Inst, Lab Neurogenet & Neuroinflammat, INSERM UMR 1163, F-75006 Paris, France.
   [Casanova, Jean-Laurent] Howard Hughes Med Inst, New York, NY 10065 USA.
   [Casanova, Jean-Laurent] Necker Hosp Sick Children, Pediat Hematol Immunol Unit, F-75015 Paris, France.
C3 Huazhong University of Science & Technology; Rockefeller University; Icahn School of Medicine at Mount Sinai; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; University of Genoa; Hacettepe University; Hacettepe University; Shahid Beheshti University Medical Sciences; University of Manchester; Central South University; Beijing Genomics Institute (BGI); Cleveland Clinic Foundation; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite de Montpellier; McGill University; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Icahn School of Medicine at Mount Sinai; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Howard Hughes Medical Institute; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP
RP Bogunovic, D (corresponding author), Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA.
EM Dusan.Bogunovic@mssm.edu
FU European Research Council (ERC) [309449] Funding Source: European Research Council (ERC); Grants-in-Aid for Scientific Research [25713039, 25670477] Funding Source: KAKEN; European Research Council [309449] Funding Source: Medline; Howard Hughes Medical Institute Funding Source: Medline; NCATS NIH HHS [UL1 TR000043, 8UL1TR000043] Funding Source: Medline; NIAID NIH HHS [P01 AI090935, R01 AI035237, R37 AI095983, U19 AI083025, R00AI106942-02, P01 AI076210, U19AI083025, R00 AI106942, R37AI095983, P01AI090935, 1P01AI076210-01A1] Funding Source: Medline; Academy of Finland (AKA) [309449] Funding Source: Academy of Finland (AKA)
NR 31
TC 446
Z9 507
U1 4
U2 201
PU NATURE PUBLISHING 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 1
PY 2015
VL 517
IS 7532
BP 89
EP U229
DI 10.1038/nature13801
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AX8SI
UT WOS:000347178400041
PM 25307056
DA 2026-03-09
ER

PT J
AU Brown, CT
   Hug, LA
   Thomas, BC
   Sharon, I
   Castelle, CJ
   Singh, A
   Wilkins, MJ
   Wrighton, KC
   Williams, KH
   Banfield, JF
AF Brown, Christopher T.
   Hug, Laura A.
   Thomas, Brian C.
   Sharon, Itai
   Castelle, Cindy J.
   Singh, Andrea
   Wilkins, Michael J.
   Wrighton, Kelly C.
   Williams, Kenneth H.
   Banfield, Jillian F.
TI Unusual biology across a group comprising more than 15% of domain Bacteria
SO NATURE
LA English
DT Article
ID ribosomal-rna; uncultured bacteria; single-cell; protein; genes; organisms; alignment; prediction; sequences; insights
AB A prominent feature of the bacterial domain is a radiation of major lineages that are defined as candidate phyla because they lack isolated representatives. Bacteria from these phyla occur in diverse environments(1) and are thought to mediate carbon and hydrogen cycles(2). Genomic analyses of a few representatives suggested that metabolic limitations have prevented their cultivation(2-6). Here we reconstructed 8 complete and 789 draft genomes from bacteria representing >35 phyla and documented features that consistently distinguish these organisms from other bacteria. We infer that this group, which may comprise >(1)5% of the bacterial domain, has shared evolutionary history, and describe it as the candidate phyla radiation (CPR). All CPR genomes are small and most lack numerous biosynthetic pathways. Owing to divergent 16S ribosomal RNA (rRNA) gene sequences, 50-100% of organisms sampled from specific phyla would evade detection in typical cultivation-independent surveys. CPR organisms often have self-splicing introns and proteins encoded within their rRNA genes, a feature rarely reported in bacteria. Furthermore, they have unusual ribosome compositions. All are missing a ribosomal protein often absent in symbionts, and specific lineages are missing ribosomal proteins and biogenesis factors considered universal in bacteria. This implies different ribosome structures and biogenesis mechanisms, and underlines unusual biology across a large part of the bacterial domain.
C1 [Brown, Christopher T.] Univ Calif Berkeley, Dept Plant & Microbial Biol, Berkeley, CA 94720 USA.
   [Hug, Laura A.; Thomas, Brian C.; Sharon, Itai; Castelle, Cindy J.; Singh, Andrea; Banfield, Jillian F.] Univ Calif Berkeley, Dept Earth & Planetary Sci, Berkeley, CA 94720 USA.
   [Wilkins, Michael J.] Ohio State Univ, Sch Earth Sci, Columbus, OH 43210 USA.
   [Wilkins, Michael J.; Wrighton, Kelly C.] Ohio State Univ, Dept Microbiol, Columbus, OH 43210 USA.
   [Williams, Kenneth H.; Banfield, Jillian F.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Earth Sci, 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 System of Ohio; Ohio State University; University System of Ohio; Ohio State University; 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.
EM jbanfield@berkeley.edu
FU US Department of Energy (DOE), Office of Science, Office of Biological and Environmental Research [DE-AC02-05CH11231, DE-SC0004918]; Natural Sciences and Engineering Research Council postdoctoral fellowship; DOE; U.S. Department of Energy (DOE) [DE-SC0004918] Funding Source: U.S. Department of Energy (DOE)
NR 62
TC 851
Z9 993
U1 11
U2 350
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 9
PY 2015
VL 523
IS 7559
BP 208
EP U173
DI 10.1038/nature14486
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM4ZO
UT WOS:000357695900034
PM 26083755
DA 2026-03-09
ER

PT J
AU Kang, K
   Xie, SE
   Huang, LJ
   Han, YM
   Huang, PY
   Mak, KF
   Kim, CJ
   Muller, D
   Park, J
AF Kang, Kibum
   Xie, Saien
   Huang, Lujie
   Han, Yimo
   Huang, Pinshane Y.
   Mak, Kin Fai
   Kim, Cheol-Joo
   Muller, David
   Park, Jiwoong
TI High-mobility three-atom-thick semiconducting films with wafer-scale homogeneity
SO NATURE
LA English
DT Article
ID high-quality monolayer; electrical-transport property; layer mos2; growth; ws2; transition; evolution
AB The large-scale growth of semiconducting thin films forms the basis of modern electronics and optoelectronics. A decrease in film thickness to the ultimate limit of the atomic, sub-nanometre length scale, a difficult limit for traditional semiconductors (such as Si and GaAs), would bring wide benefits for applications in ultrathin and flexible electronics, photovoltaics and display technology'. For this, transition-metal dichalcogenides (TMDs), which can form stable three-atom-thick monolayers(4), provide ideal semiconducting materials with high electrical carrier mobility'-", and their largescale growth on insulating substrates would enable the batch fabrication of atomically thin high-performance transistors and photodetectors on a technologically relevant scale without film transfer. In addition, their unique electronic band structures provide novel ways of enhancing the functionalities of such devices, including the large excitonic effect", bandgap modulation", indirect-todirect bandgap transition", piezoelectricity' and valleytronics'. However, the large-scale growth of monolayer TMD films with spatial homogeneity and high electrical performance remains an unsolved challenge. Here we report the preparation of high-mobility 4-inch wafer-scale films of monolayer molybdenum disulphide (Mo52) and tungsten disulphide, grown directly on insulating MO, substrates, with excellent spatial homogeneity over the entire films. They are grown with a newly developed, metal-organic chemical vapour deposition technique, and show high electrical performance, including an electron mobility of 30 cm(2) V-1 s(1) at room temperature and 114 cm(2) V-1 s(-1) at 90K for Mo52, with little dependence on position or channel length. With the use of these films we successfully demonstrate the wafer-scale batch fabrication of highperformance monolayer Mo52 field-effect transistors with a 99% device yield and the multi-level fabrication of vertically stacked transistor devices for three-dimensional circuitry. Our work is a step towards the realization of atomically thin integrated circuitry.
C1 [Kang, Kibum; Huang, Lujie; Kim, Cheol-Joo; Park, Jiwoong] Cornell Univ, Dept Chem & Chem Biol, Ithaca, NY 14853 USA.
   [Xie, Saien; Han, Yimo; Huang, Pinshane Y.; Muller, David] Cornell Univ, Sch Appl & Engn Phys, Ithaca, NY 14853 USA.
   [Mak, Kin Fai; Muller, David; Park, Jiwoong] Kavli Inst Cornell Nanoscale Sci, Ithaca, NY 14853 USA.
   [Mak, Kin Fai] Cornell Univ, Lab Atom & Solid State Phys, Ithaca, NY 14853 USA.
C3 Cornell University; Cornell University; Cornell University
RP Park, J (corresponding author), Cornell Univ, Dept Chem & Chem Biol, Ithaca, NY 14853 USA.
EM jpark@cornell.edu
FU AFOSR [FA2386-13-1-4118, FA9550-11-1-0033]; Nano Material Technology Development Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT, and Future Planning [2012M3A7B4049887]; National Science Foundation (NSF) through the Cornell Center for Materials Research [NSF DMR-1120296]; Samsung Advanced Institute for Technology GRO Program; National Science Foundation [ECS-0335765]
NR 30
TC 1530
Z9 1789
U1 47
U2 1948
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 30
PY 2015
VL 520
IS 7549
BP 656
EP 660
DI 10.1038/nature14417
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700045
PM 25925478
DA 2026-03-09
ER

PT J
AU Vinogradova, EV
   Zhang, C
   Spokoyny, AM
   Pentelute, BL
   Buchwald, SL
AF Vinogradova, Ekaterina V.
   Zhang, Chi
   Spokoyny, Alexander M.
   Pentelute, Bradley L.
   Buchwald, Stephen L.
TI Organometallic palladium reagents for cysteine bioconjugation
SO NATURE
LA English
DT Article
ID structural insights; stapled peptides; complexes; chemistry; maleimide; proteins
AB Reactions based on transition metals have found wide use in organic synthesis, in particular for the functionalization of small molecules(1,2). However, there are very few reports of using transition-metal-based reactions to modify complex biomolecules(3,4),, which is due to the need for stringent reaction conditions (for example, aqueous media, low temperature and mild pH) and the existence of multiple reactive functional groups found in biomolecules. Here we report that palladium(II) complexes can be used for efficient and highly selective cysteine conjugation (bioconjugation) reactions that are rapid and robust under a range of bio-compatible reaction conditions. The straightforward synthesis of the palladium reagents from diverse and easily accessible aryl halide and trifluoromethanesulfonate precursors makes the method highly practical, providing access to a large structural space for protein modification. The resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleo-philes. The broad utility of the bioconjugation platform was further corroborated by the synthesis of new classes of stapled peptides and antibody-drug conjugates. These palladium complexes show potential as benchtop reagents for diverse bioconjugation applications.
C1 [Vinogradova, Ekaterina V.; Zhang, Chi; Spokoyny, Alexander M.; Pentelute, Bradley L.; Buchwald, Stephen L.] MIT, Dept Chem, Cambridge, MA 02139 USA.
C3 Massachusetts Institute of Technology (MIT)
RP Pentelute, BL (corresponding author), MIT, Dept Chem, Cambridge, MA 02139 USA.
EM blp@mit.edu; sbuchwal@mit.edu
FU National Institutes of Health [GM-58160, GM-110535, 1F32GM101762]; MIT; Damon Runyon Cancer Research Foundation; Sontag Foundation; George Buchi Research Fellowship; Koch Graduate Fellowship in Cancer Research of MIT; NSF [CHE-9808061, CHE-0946721]
NR 30
TC 403
Z9 468
U1 7
U2 346
PU NATURE PUBLISHING 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 29
PY 2015
VL 526
IS 7575
BP 687
EP 691
DI 10.1038/nature15739
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CU8ZH
UT WOS:000363832100045
PM 26511579
DA 2026-03-09
ER

PT J
AU Antonijevic, SK
   Wagner, LS
   Kumar, A
   Beck, SL
   Long, MD
   Zandt, G
   Tavera, H
   Condori, C
AF Antonijevic, Sanja Knezevic
   Wagner, Lara S.
   Kumar, Abhash
   Beck, Susan L.
   Long, Maureen D.
   Zandt, George
   Tavera, Hernando
   Condori, Cristobal
TI The role of ridges in the formation and longevity of flat slabs
SO NATURE
LA English
DT Article
ID oceanic plateau subduction; sensitivity kernels; laramide orogeny; nazca plate; peru; tomography; beneath; lithosphere; velocity; phase
AB Flat-slab subduction occurs when the descending plate becomes horizontal at some depth before resuming its descent into the mantle. It is often proposed as a mechanism for the uplifting of deep crustal rocks ('thick-skinned' deformation) far from plate boundaries, and for causing unusual patterns of volcanism, as far back as the Proterozoic eon(1). For example, the formation of the expansive Rocky Mountains and the subsequent voluminous volcanism across much of the western USA has been attributed to a broad region of flat-slab subduction beneath North America that occurred during the Laramide orogeny (80-55 million years ago)(2). Here we study the largest modern flat slab, located in Peru, to better understand the processes controlling the formation and extent of flat slabs. We present new data that indicate that the subducting Nazca Ridge is necessary for the development and continued support of the horizontal plate at a depth of about 90 kilometres. By combining constraints from Rayleigh wave phase velocities with improved earthquake locations, we find that the flat slab is shallowest along the ridge, while to the northwest of the ridge, the slab is sagging, tearing, and re-initiating normal subduction. On the basis of our observations, we propose a conceptual model for the temporal evolution of the Peruvian flat slab in which the flat slab forms because of the combined effects of trench retreat along the Peruvian plate boundary, suction, and ridge subduction. We find that while the ridge is necessary but not sufficient for the formation of the flat slab, its removal is sufficient for the flat slab to fail. This provides new constraints on our understanding of the processes controlling the beginning and end of the Laramide orogeny and other putative episodes of flat-slab subduction.
C1 [Antonijevic, Sanja Knezevic; Kumar, Abhash] Univ N Carolina, Dept Geol Sci, Chapel Hill, NC 27599 USA.
   [Wagner, Lara S.] Carnegie Inst Sci, Dept Terr Magnetism, Washington, DC 20015 USA.
   [Beck, Susan L.; Zandt, George] Univ Arizona, Dept Geosci, Tucson, AZ 85721 USA.
   [Long, Maureen D.] Yale Univ, Dept Geol & Geophys, New Haven, CT 06511 USA.
   [Tavera, Hernando; Condori, Cristobal] Inst Geofis Peru, Lima 15012, Peru.
C3 University of North Carolina; University of North Carolina Chapel Hill; Carnegie Institution for Science; University of Arizona; Yale University
RP Antonijevic, SK (corresponding author), Univ N Carolina, Dept Geol Sci, CB 3315, Chapel Hill, NC 27599 USA.
EM sknezevi@live.unc.edu
FU NSF [EAR-0944184, EAR-0943991, EAR-0943962, EAR-0908777, EAR-0907880]; Division Of Earth Sciences; Directorate For Geosciences [0944184, 0943991] Funding Source: National Science Foundation
NR 34
TC 112
Z9 128
U1 2
U2 63
PU NATURE PUBLISHING 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 13
PY 2015
VL 524
IS 7564
BP 212
EP +
DI 10.1038/nature14648
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900030
PM 26268192
DA 2026-03-09
ER

PT J
AU Zhang, DD
   Gao, ZG
   Zhang, KH
   Kiselev, E
   Crane, S
   Wang, J
   Paoletta, S
   Yi, CY
   Ma, LM
   Zhang, WR
   Han, GW
   Liu, H
   Cherezov, V
   Katritch, V
   Jiang, HL
   Stevens, RC
   Jacobson, KA
   Zhao, Q
   Wu, BL
AF Zhang, Dandan
   Gao, Zhan-Guo
   Zhang, Kaihua
   Kiselev, Evgeny
   Crane, Steven
   Wang, Jiang
   Paoletta, Silvia
   Yi, Cuiying
   Ma, Limin
   Zhang, Wenru
   Han, Gye Won
   Liu, Hong
   Cherezov, Vadim
   Katritch, Vsevolod
   Jiang, Hualiang
   Stevens, Raymond C.
   Jacobson, Kenneth A.
   Zhao, Qiang
   Wu, Beili
TI Two disparate ligand-binding sites in the human P2Y1 receptor
SO NATURE
LA English
DT Article
ID nucleotide receptors; crystal-structure; small-molecule; agonist; discovery; antagonists; recognition; mutagenesis; refinement; complex
AB In response to adenosine 59-diphosphate, the P2Y(1) receptor (P2Y(1)R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y(1)R in complex with a nucleotide antagonist MRS2500 at 2.7 angstrom resolution, and with a non-nucleotide antagonist BPTU at 2.2 angstrom resolution. The structures reveal two distinct ligand-binding sites, providing atomic details of P2Y(1)R's unique ligand-binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y(1)R, which is different in shape and location from the nucleotide binding site in the previously determined structure of P2Y(12)R, representative of another P2YR subfamily. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G-protein-coupled receptor (GPCR) ligand located entirely outside of the helical bundle. These high-resolutioninsights into P2Y(1)R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects.
C1 [Zhang, Dandan; Zhang, Kaihua; Wang, Jiang; Yi, Cuiying; Ma, Limin; Zhang, Wenru; Liu, Hong; Zhao, Qiang; Wu, Beili] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China.
   [Gao, Zhan-Guo; Kiselev, Evgeny; Crane, Steven; Paoletta, Silvia; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA.
   [Han, Gye Won; Cherezov, Vadim; Stevens, Raymond C.] Univ So Calif, Dept Chem, Bridge Inst, Los Angeles, CA 90089 USA.
   [Katritch, Vsevolod] Univ So Calif, Bridge Inst, Dept Biol Sci, Los Angeles, CA 90089 USA.
   [Jiang, Hualiang] Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China.
   [Stevens, Raymond C.] ShanghaiTech Univ, iHuman Inst, Shanghai 201203, Peoples R China.
C3 Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); University of Southern California; University of Southern California; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; ShanghaiTech University
RP Wu, BL (corresponding author), Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China.
EM zhaoq@simm.ac.cn; beiliwu@simm.ac.cn
FU National Basic Research Program of China [2012CB518000, 2014CB910400, 2012CB910400]; CAS Strategic Priority Research Program [XDB08020300]; National Science Foundation of China [31422017, 31370729, 91313000]; National Science and Technology Major Project [2013ZX09507001]; NIDDK; NIH Intramural Research Program [Z01 DK031116-26]; National Institutes of Health [U54 GM094618]; National Institute of Diabetes and Digestive and Kidney Diseases [ZIADK031126, ZIADK031116] Funding Source: NIH RePORTER
NR 37
TC 312
Z9 346
U1 2
U2 139
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 16
PY 2015
VL 520
IS 7547
BP 317
EP +
DI 10.1038/nature14287
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG0RI
UT WOS:000352974200031
PM 25822790
DA 2026-03-09
ER

PT J
AU Levayer, R
   Hauert, B
   Moreno, E
AF Levayer, Romain
   Hauert, Barbara
   Moreno, Eduardo
TI Cell mixing induced by myc is required for competitive tissue invasion and destruction
SO NATURE
LA English
DT Article
ID adherens junctions; organ growth; myosin-ii; drosophila; mechanisms; delamination; compartments; migration; apoptosis; polarity
AB Cell-cell intercalation is used in several developmental processes to shape the normal body plan(1). There is no clear evidence that intercalation is involved in pathologies. Here we use the proto-oncogene myc to study a process analogous to early phase of tumour expansion: myc-induced cell competition(2-7). Cell competition is a conserved mechanism(5,6,8,9) driving the elimination of slow-proliferating cells (so-called 'losers') by faster-proliferating neighbours (so-called 'winners') through apoptosis(10) and is important in preventing developmental malformations and maintain tissue fitness(11). Here we show, using long-term live imaging of myc-driven competition in the Drosophila pupal notum and in the wing imaginal disc, that the probability of elimination of loser cells correlates with the surface of contact shared with winners. As such, modifying loser-winner interface morphology can modulate the strength of competition. We further show that elimination of loser clones requires winner-loser cell mixing through cell-cell intercalation. Cell mixing is driven by differential growth and the high tension at winner-winner interfaces relative to winner-loser and loser-loser interfaces, which leads to a preferential stabilization of winner-loser contacts and reduction of clone compactness over time. Differences in tension are generated by a relative difference in F-actin levels between loser and winner junctions, induced by differential levels of the membrane lipid phosphatidylinositol (3,4,5)-trisphosphate. Our results establish the first link between cell-cell intercalation induced by a proto-oncogene and how it promotes invasiveness and destruction of healthy tissues.
C1 [Levayer, Romain; Hauert, Barbara; Moreno, Eduardo] Univ Bern, Inst Cell Biol, CH-3012 Bern, Switzerland.
C3 University of Bern
RP Moreno, E (corresponding author), Univ Bern, Inst Cell Biol, Baltzerstr 4, CH-3012 Bern, Switzerland.
EM eduardo.moreno@izb.unibe.ch
FU EMBO [ALTF 366-2012]; Human Frontier post-doctoral fellowship [LT000178/2013]; European Research Council; Swiss National Science Foundation; Josef Steiner Cancer Research Foundation; Swiss Cancer League
NR 53
TC 105
Z9 118
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 27
PY 2015
VL 524
IS 7566
BP 476
EP +
DI 10.1038/nature14684
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP7LN
UT WOS:000360069300040
PM 26287461
DA 2026-03-09
ER

PT J
AU Wernet, P
   Kunnus, K
   Josefsson, I
   Rajkovic, I
   Quevedo, W
   Beye, M
   Schreck, S
   Grübel, S
   Scholz, M
   Nordlund, D
   Zhang, W
   Hartsock, RW
   Schlotter, WF
   Turner, JJ
   Kennedy, B
   Hennies, F
   de Groot, FMF
   Gaffney, KJ
   Techert, S
   Odelius, M
   Föhlisch, A
AF Wernet, Ph.
   Kunnus, K.
   Josefsson, I.
   Rajkovic, I.
   Quevedo, W.
   Beye, M.
   Schreck, S.
   Gruebel, S.
   Scholz, M.
   Nordlund, D.
   Zhang, W.
   Hartsock, R. W.
   Schlotter, W. F.
   Turner, J. J.
   Kennedy, B.
   Hennies, F.
   de Groot, F. M. F.
   Gaffney, K. J.
   Techert, S.
   Odelius, M.
   Foehlisch, A.
TI Orbital-specific mapping of the ligand exchange dynamics of Fe(CO)5 in solution
SO NATURE
LA English
DT Article
ID bond activation; metal-complexes; spin; chemistry; photosubstitution; photochemistry; interplay; charge
AB Transition-metal complexes have long attracted interest for fundamental chemical reactivity studies and possible use in solar energy conversion(1,2). Electronic excitation, ligand loss from the metal centre, or a combination of both, creates changes in charge and spin density at the metal site(3-11) that need to be controlled to optimize complexes for photocatalytic hydrogen production(8) and selective carbon-hydrogen bond activation(9-11). An understanding at the molecular level of how transition-metal complexes catalyse reactions, and in particular of the role of the short-lived and reactive intermediate states involved, will be critical for such optimization. However, suitable methods for detailed characterization of electronic excited states have been lacking. Here we show, with the use of X-ray laser-based femtosecond-resolution spectroscopy and advanced quantum chemical theory to probe the reaction dynamics of the benchmark transition-metal complex Fe(CO)(5) in solution, that the photo-induced removal of CO generates the 16-electron Fe(CO)(4) species, a homogeneous catalyst(12,13) with an electron deficiency at the Fe centre(14,15), in a hitherto unreported excited singlet state that either converts to the triplet ground state or combines with a CO or solvent molecule to regenerate a penta-coordinated Fe species on a sub-picosecond timescale. This finding, which resolves the debate about the relative importance of different spin channels in the photochemistry of Fe(CO)(5) (refs 4, 16-20), was made possible by the ability of femtosecond X-ray spectroscopy to probe frontier-orbital interactions with atom specificity. We expect the method to be broadly applicable in the chemical sciences, and to complement approaches that probe structural dynamics in ultrafast processes.
C1 [Wernet, Ph.; Kunnus, K.; Beye, M.; Schreck, S.; Foehlisch, A.] Helmholtz Zentrum Berlin Mat & Energie GmbH, Inst Methods & Instrumentat Synchrotron Radiat Re, D-12489 Berlin, Germany.
   [Kunnus, K.; Schreck, S.; Foehlisch, A.] Univ Potsdam, Inst Phys & Astron, D-14476 Potsdam, Germany.
   [Josefsson, I.; Odelius, M.] Stockholm Univ, Dept Phys, AlbaNova Univ Ctr, S-10691 Stockholm, Sweden.
   [Rajkovic, I.; Quevedo, W.; Gruebel, S.; Scholz, M.] Max Planck Inst Biophys Chem, IFG Struct Dynam Bio Chem Syst, D-37077 Gottingen, Germany.
   [Nordlund, D.] SLAC Natl Accelerator Lab, Stanford Synchrotron Radiat Lightsource, Menlo Pk, CA 94025 USA.
   [Zhang, W.; Hartsock, R. W.; Gaffney, K. J.] Stanford Univ, PULSE Inst, SLAC Natl Accelerator Lab, Stanford, CA 94305 USA.
   [Schlotter, W. F.; Turner, J. J.] SLAC Natl Accelerator Lab, Linac Coherent Light Source, Menlo Pk, CA 94025 USA.
   [Kennedy, B.; Hennies, F.] MAX Lab, S-22100 Lund, Sweden.
   [de Groot, F. M. F.] Univ Utrecht, Dept Chem, NL-3584 CG Utrecht, Netherlands.
   [Techert, S.] Univ Gottingen, Inst Xray Phys, D-37077 Gottingen, Germany.
   [Techert, S.] DESY, Struct Dynam Bio Chem Syst, D-22607 Hamburg, Germany.
C3 Helmholtz Association; Helmholtz-Zentrum fuer Materialien und Energie GmbH (HZB); University of Potsdam; Stockholm University; Max Planck Society; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; Utrecht University; University of Gottingen; Helmholtz Association; Deutsches Elektronen-Synchrotron (DESY)
RP Wernet, P (corresponding author), Helmholtz Zentrum Berlin Mat & Energie GmbH, Inst Methods & Instrumentat Synchrotron Radiat Re, Albert Einstein Str 15, D-12489 Berlin, Germany.
EM wernet@helmholtz-berlin.de; odelius@fysik.su.se; alexander.foehlisch@helmholtz-berlin.de
FU Volkswagen Stiftung; Swedish Research Council; Carl Tryggers Foundation; Magnus Bergvall Foundation; Collaborative Research Centers [SFB 755, SFB 1073]; Helmholtz Virtual Institute 'Dynamic Pathways in Multidimensional Landscapes'; AMOS program within the Chemical Sciences, Geosciences, and Biosciences Division of the Office of Basic Energy Sciences, Office of Science, US Department of Energy; LCLS; Stanford University through the Stanford Institute for Materials Energy Sciences (SIMES); Lawrence Berkeley National Laboratory (LBNL); University of Hamburg through the BMBF priority program [FSP 301]; Center for Free Electron Laser Science (CFEL)
NR 30
TC 248
Z9 264
U1 2
U2 315
PU NATURE PUBLISHING 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 2
PY 2015
VL 520
IS 7545
BP 78
EP 81
DI 10.1038/nature14296
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE7NE
UT WOS:000352027700040
PM 25832405
DA 2026-03-09
ER

PT J
AU Arinaminpathy, N
   Dowdy, D
AF Arinaminpathy, Nimalan
   Dowdy, David
TI Understanding the incremental value of novel diagnostic tests for tuberculosis
SO NATURE
LA English
DT Article
ID middle-income country; xpert mtb/rif; mycobacterium-tuberculosis; pulmonary tuberculosis; resistant tuberculosis; empirical-treatment; potential impact; health-systems; prevalence; transmission
AB Tuberculosis is a major source of global mortality caused by infection, partly because of a tremendous ongoing burden of undiagnosed disease. Improved diagnostic technology may play an increasingly crucial part in global efforts to end tuberculosis, but the ability of diagnostic tests to curb tuberculosis transmission is dependent on multiple factors, including the time taken by a patient to seek health care, the patient's symptoms, and the patterns of transmission before diagnosis. Novel diagnostic assays for tuberculosis have conventionally been evaluated on the basis of characteristics such as sensitivity and specificity, using assumptions that probably overestimate the impact of diagnostic tests on transmission. We argue for a shift in focus to the evaluation of such tests' incremental value, defining outcomes that reflect each test's purpose (for example, transmissions averted) and comparing systems with the test against those without, in terms of those outcomes. Incremental value can also be measured in units of outcome per incremental unit of resource (for example, money or human capacity). Using a novel, simplified model of tuberculosis transmission that addresses some of the limitations of earlier tuberculosis diagnostic models, we demonstrate that the incremental value of any novel test depends not just on its accuracy, but also on elements such as patient behaviour, tuberculosis natural history and health systems. By integrating these factors into a single unified framework, we advance an approach to the evaluation of new diagnostic tests for tuberculosis that considers the incremental value at the population level and demonstrates how additional data could inform more-effective implementation of tuberculosis diagnostic tests under various conditions.
C1 [Arinaminpathy, Nimalan] Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Infect Dis Epidemiol, MRC Ctr Outbreak Anal & Modelling, London W2 1PG, England.
   [Dowdy, David] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA.
C3 Imperial College London; Johns Hopkins University; Johns Hopkins Bloomberg School of Public Health
RP Dowdy, D (corresponding author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA.
EM ddowdy1@jhmi.edu
FU B. Frank and Kathleen Polk Assistant Professorship in Epidemiology at the John Hopkins Bloomberg School of Public Health; MRC [MR/K010174/1] Funding Source: UKRI; Medical Research Council [MR/K010174/1, MR/K010174/1B] Funding Source: researchfish
NR 82
TC 20
Z9 24
U1 0
U2 27
PU NATURE PUBLISHING 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 3
PY 2015
VL 528
IS 7580
BP S60
EP S67
DI 10.1038/nature16045
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000012
PM 26633767
DA 2026-03-09
ER

PT J
AU Marsolier, J
   Perichon, M
   DeBarry, JD
   Villoutreix, BO
   Chluba, J
   Lopez, T
   Garrido, C
   Zhou, XZ
   Lu, KP
   Fritsch, L
   Ait-Si-Ali, S
   Mhadhbi, M
   Medjkane, S
   Weitzman, JB
AF Marsolier, J.
   Perichon, M.
   DeBarry, J. D.
   Villoutreix, B. O.
   Chluba, J.
   Lopez, T.
   Garrido, C.
   Zhou, X. Z.
   Lu, K. P.
   Fritsch, L.
   Ait-Si-Ali, S.
   Mhadhbi, M.
   Medjkane, S.
   Weitzman, J. B.
TI Theileria parasites secrete a prolyl isomerase to maintain host leukocyte transformation
SO NATURE
LA English
DT Article
ID c-jun; pin1; annulata; gene; isomerization; buparvaquone; conformation; recognition; cancer; dock
AB Infectious agents develop intricate mechanisms to interact with host cell pathways and hijack their genetic and epigenetic machinery to change host cell phenotypic states. Among the Apicomplexa phylum of obligate intracellular parasites, which cause veterinary and human diseases, Theileria is the only genus that transforms its mammalian host cells(1). Theileria infection of bovine leukocytes induces proliferative and invasive phenotypes associated with activated signalling pathways, notably JNK and AP-1 (ref. 2). The transformed phenotypes are reversed by treatment with the theilericidal drug buparvaquone(3). We used comparative genomics to identify a homologue of the peptidyl-prolyl isomerase PIN1 in T. annulata (TaPIN1) that is secreted into the host cell and modulates oncogenic signalling pathways. Here we show that TaPIN1 is a bona fide prolyl isomerase and that it interacts with the host ubiquitin ligase FBW7, leading to its degradation and subsequent stabilization of c-JUN, which promotes transformation. We performed in vitro and in silico analysis and in vivo zebrafish xenograft experiments to demonstrate that TaPIN1 is directly inhibited by the anti-parasite drug buparvaquone (and other known PIN1 inhibitors) and is mutated in a drug-resistant strain. Prolyl isomerization is thus a conserved mechanism that is important in cancer and is used by Theileria parasites to manipulate host oncogenic signalling.
C1 [Marsolier, J.; Perichon, M.; Fritsch, L.; Ait-Si-Ali, S.; Medjkane, S.; Weitzman, J. B.] Univ Paris Diderot, Sorbonne Paris Cite, Epigenet & Cell Fate, UMR CNRS 7216, F-75013 Paris, France.
   [DeBarry, J. D.] Univ Georgia, Ctr Trop & Emerging Global Dis, Athens, GA 30602 USA.
   [Villoutreix, B. O.] Univ Paris Diderot, Sorbonne Paris Cite, Mol Therapeut Silico, INSERM UMR S 973, F-75013 Paris, France.
   [Chluba, J.; Lopez, T.; Garrido, C.] INSERM, UMR866, Equipe Labellisee Ligue Canc, F-21000 Dijon, France.
   [Chluba, J.; Lopez, T.; Garrido, C.] Lab Excellence LipSTIC, F-21000 Dijon, France.
   [Chluba, J.; Lopez, T.; Garrido, C.] Univ Burgundy, Fac Med & Pharm, F-21000 Dijon, France.
   [Garrido, C.] CGFL, Ctr Anticanc George Francois Leclerc, F-21000 Dijon, France.
   [Zhou, X. Z.; Lu, K. P.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02215 USA.
   [Mhadhbi, M.] Univ Manouba, Ecole Natl Med Vet, Lab Parasitol, Sidi Thabet 2020, Tunisia.
C3 Universite Paris Cite; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); University System of Georgia; University of Georgia; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Bourgogne Europe; Universite Bourgogne Europe; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Universite de la Manouba
RP Weitzman, JB (corresponding author), Univ Paris Diderot, Sorbonne Paris Cite, Epigenet & Cell Fate, UMR CNRS 7216, F-75013 Paris, France.
EM jonathan.weitzman@univ-paris-diderot.fr
FU National Institutes of Health [R01CA167677]; Association for International Cancer Research [08-0111]; French National Research Agency (ANR) [Blanc 11-BSV3-016-01]; "Who Am I?" Laboratory of Excellence - French Government through its "Investments for the Future" program [ANR-11-LABX-0071]; ANR [ANR-11-IDEX-0005-01]
NR 41
TC 104
Z9 119
U1 0
U2 26
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 16
PY 2015
VL 520
IS 7547
BP 378
EP +
DI 10.1038/nature14044
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG0RI
UT WOS:000352974200045
PM 25624101
DA 2026-03-09
ER

PT J
AU Takasato, M
   Er, PX
   Chiu, HS
   Maier, B
   Baillie, GJ
   Ferguson, C
   Parton, RG
   Wolvetang, EJ
   Roost, MS
   Lopes, SMCD
   Little, MH
AF Takasato, Minoru
   Er, Pei X.
   Chiu, Han S.
   Maier, Barbara
   Baillie, Gregory J.
   Ferguson, Charles
   Parton, Robert G.
   Wolvetang, Ernst J.
   Roost, Matthias S.
   Lopes, Susana M. Chuva de Sousa
   Little, Melissa H.
TI Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis
SO NATURE
LA English
DT Article
ID pluripotent stem-cells; intermediate mesoderm; retinoic acid; nephron progenitors; lateral plate; differentiation; population; expression; apoptosis; origin
AB The human kidney contains up to 2 million epithelial nephrons responsible for blood filtration. Regenerating the kidney requires the induction of the more than 20 distinct cell types required for excretion and the regulation of pH, and electrolyte and fluid balance. We have previously described the simultaneous induction of progenitors for both collecting duct and nephrons via the directed differentiation of human pluripotent stem cells(1). Paradoxically, although both are of intermediate mesoderm in origin, collecting duct and nephrons have distinct temporospatial origins. Here we identify the developmental mechanism regulating the preferential induction of collecting duct versus kidney mesenchyme progenitors. Using this knowledge, we have generated kidney organoids that contain nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells. Within these organoids, individual nephrons segment into distal and proximal tubules, early loops of Henle, and glomeruli containing podocytes elaborating foot processes and undergoing vascularization. When transcription profiles of kidney organoids were compared to human fetal tissues, they showed highest congruence with first trimester human kidney. Furthermore, the proximal tubules endocytose dextran and differentially apoptose in response to cisplatin, a nephrotoxicant. Such kidney organoids represent powerful models of the human organ for future applications, including nephrotoxicity screening, disease modelling and as a source of cells for therapy.
C1 [Takasato, Minoru; Er, Pei X.; Little, Melissa H.] Royal Childrens Hosp Melbourne, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia.
   [Takasato, Minoru; Chiu, Han S.; Maier, Barbara; Baillie, Gregory J.; Ferguson, Charles; Parton, Robert G.; Little, Melissa H.] Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia.
   [Wolvetang, Ernst J.] Univ Queensland, Australian Inst Bioengn & Nanotechnol, St Lucia, Qld 4072, Australia.
   [Roost, Matthias S.; Lopes, Susana M. Chuva de Sousa] Leiden Univ, Med Ctr, Dept Anat & Embryol, NL-2333 ZC Leiden, Netherlands.
   [Little, Melissa H.] Univ Melbourne, Dept Paediat, Parkville, Vic 3010, Australia.
C3 Royal Children's Hospital Melbourne; Murdoch Children's Research Institute; University of Queensland; University of Queensland; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); University of Melbourne
RP Takasato, M (corresponding author), Royal Childrens Hosp Melbourne, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia.
EM minoru.takasato@mcri.edu.au; melissa.little@mcri.edu.au
FU National Health and Medical Research Council (NHMRC) of Australia [APP1041277, APP1037320]; Australian Research Council (ARC) [SRI110001002, CE140100036]; Bontius Stiching; Organovo Inc.
NR 31
TC 1174
Z9 1381
U1 14
U2 348
PU NATURE PUBLISHING 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 22
PY 2015
VL 526
IS 7574
BP 564
EP U238
DI 10.1038/nature15695
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV1NX
UT WOS:000364026100048
PM 26444236
DA 2026-03-09
ER

PT J
AU Sibley, CR
   Emmett, W
   Blazquez, L
   Faro, A
   Haberman, N
   Briese, M
   Trabzuni, D
   Ryten, M
   Weale, ME
   Hardy, J
   Modic, M
   Curk, T
   Wilson, SW
   Plagnol, V
   Ule, J
AF Sibley, Christopher R.
   Emmett, Warren
   Blazquez, Lorea
   Faro, Ana
   Haberman, Nejc
   Briese, Michael
   Trabzuni, Daniah
   Ryten, Mina
   Weale, Michael E.
   Hardy, John
   Modic, Miha
   Curk, Tomaz
   Wilson, Stephen W.
   Plagnol, Vincent
   Ule, Jernej
TI Recursive splicing in long vertebrate genes
SO NATURE
LA English
DT Article
ID exon definition; large intron; reveals; transcription; ultrafast; alignment; length; decay
AB It is generally believed that splicing removes introns as single units from precursor messenger RNA transcripts. However, some long Drosophila melanogaster introns contain a cryptic site, known as a recursive splice site (RS-site), that enables a multi-step process of intron removal termed recursive splicing(1,2). The extent to which recursive splicing occurs in other species and its mechanistic basis have not been examined. Here we identify highly conserved RS-sites in genes expressed in the mammalian brain that encode proteins functioning in neuronal development. Moreover, the RS-sites are found in some of the longest introns across vertebrates. We find that vertebrate recursive splicing requires initial definition of an 'RS-exon' that follows the RS-site. The RS-exon is then excluded from the dominant mRNA isoform owing to competition with a reconstituted 59 splice site formed at the RS-site after the first splicing step. Conversely, the RS-exon is included when preceded by cryptic promoters or exons that fail to reconstitute an efficient 59 splice site. Most RS-exons contain a premature stop codon such that their inclusion can decrease mRNA stability. Thus, by establishing a binary splicing switch, RS-sites demarcate different mRNA isoforms emerging from long genes by coupling cryptic elements with inclusion of RS-exons.
C1 [Sibley, Christopher R.; Blazquez, Lorea; Haberman, Nejc; Trabzuni, Daniah; Ryten, Mina; Hardy, John; Ule, Jernej] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England.
   [Sibley, Christopher R.; Briese, Michael; Modic, Miha; Ule, Jernej] MRC Lab Mol Biol, Cambridge CB2 0QH, England.
   [Emmett, Warren; Plagnol, Vincent] UCL, Genet Inst, London WC1E 6BT, England.
   [Faro, Ana; Wilson, Stephen W.] UCL, Dept Cell & Dev Biol, London WC1E 6BT, England.
   [Briese, Michael] Univ Wurzburg, Inst Clin Neurobiol, D-97078 Wurzburg, Germany.
   [Trabzuni, Daniah] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia.
   [Ryten, Mina; Weale, Michael E.] Kings Coll London, Guys Hosp, Dept Med & Mol Genet, London SE1 9RT, England.
   [Modic, Miha] Helmholtz Ctr Munich, Inst Stem Cell Res, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.
   [Curk, Tomaz] Univ Ljubljana, Fac Comp & Informat Sci, Ljubljana 1000, Slovenia.
C3 University of London; University College London; MRC Laboratory Molecular Biology; University of London; University College London; University of London; University College London; University of Wurzburg; King Faisal Specialist Hospital & Research Center; Guy's & St Thomas' NHS Foundation Trust; University of London; King's College London; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; University of Ljubljana
RP Ule, J (corresponding author), UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London WC1N 3BG, England.
EM v.plagnol@ucl.ac.uk; j.ule@ucl.ac.uk
FU European Research Council [206726-CLIP, 617837-Translate]; Marie Curie Post-doctoral Research Fellowship (627783-NeuroCRYSP); Slovenian Research Agency [J7-5460]; UK NIHR Biomedical Research Centre at Moorfields Eye Hospital; UCL Institute of Ophthalmology; Wellcome Trust; UK Medical Research Council (MRC) [U105185858]; MRC [G0901254, G0802462]; MRC Sudden Death Brain Bank; Medical Research Council [G0802462, MC_U105185858, G0901254] Funding Source: researchfish; National Institute for Health Research [ACF-2012-17-017] Funding Source: researchfish; Wellcome Trust [104682/Z/14/Z] Funding Source: researchfish; MRC [G0901254, MC_U105185858, G0802462] Funding Source: UKRI
NR 31
TC 114
Z9 141
U1 1
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 MAY 21
PY 2015
VL 521
IS 7552
BP 371
EP +
DI 10.1038/nature14466
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CI5RM
UT WOS:000354816500060
PM 25970246
DA 2026-03-09
ER

PT J
AU Wang, JZ
   Li, HJ
   Han, ZF
   Zhang, HQ
   Wang, T
   Lin, GZ
   Chang, JB
   Yang, WC
   Chai, JJ
AF Wang, Jizong
   Li, Hongju
   Han, Zhifu
   Zhang, Heqiao
   Wang, Tong
   Lin, Guangzhong
   Chang, Junbiao
   Yang, Weicai
   Chai, Jijie
TI Allosteric receptor activation by the plant peptide hormone phytosulfokine
SO NATURE
LA English
DT Article
ID structural insight; growth-factor; arabidopsis; cells; perception; kinases; bak1; proliferation; software; immunity
AB Phytosulfokine (PSK) is a disulfated pentapeptide that has a ubiquitous role in plant growth and development(1,2). PSK is perceived by its receptor PSKR3,4, a leucine-rich repeat receptor kinase (LRR-RK). The mechanisms underlying the recognition of PSK, the activation of PSKR and the identity of the components downstream of the initial binding remain elusive. Here we report the crystal structures of the extracellular LRR domain of PSKR in free, PSK-and co-receptor-bound forms. The structures reveal that PSK interacts mainly with a b-strand from the island domain of PSKR, forming an anti-b-sheet. The two sulfate moieties of PSK interact directly with PSKR, sensitizing PSKR recognition of PSK. Supported by biochemical, structural and genetic evidence, PSK binding enhances PSKR heterodimerization with the somatic embryogenesis receptor-like kinases (SERKs). However, PSK is not directly involved in PSKR-SERK interaction but stabilizes PSKR island domain for recruitment of a SERK. Our data reveal the structural basis for PSKR recognition of PSK and allosteric activation of PSKR by PSK, opening up new avenues for the design of PSKR-specific small molecules.
C1 [Wang, Jizong; Han, Zhifu; Zhang, Heqiao; Lin, Guangzhong; Chai, Jijie] Tsinghua Univ, Tsinghua Peking Joint Ctr Life Sci, Ctr Struct Biol Sch Life Sci, Minist Educ,Key Lab Prot Sci, Beijing 100084, Peoples R China.
   [Li, Hongju; Wang, Tong; Yang, Weicai] Chinese Acad Sci, Inst Genet & Dev Biol, State Key Lab Mol Dev Biol, Beijing 100101, Peoples R China.
   [Chang, Junbiao] Zhengzhou Univ, Sch Chem & Mol Engn, Zhengzhou 450001, Peoples R China.
C3 Tsinghua University; Chinese Academy of Sciences; Institute of Genetics & Developmental Biology, CAS; Zhengzhou University
RP Chai, JJ (corresponding author), Tsinghua Univ, Tsinghua Peking Joint Ctr Life Sci, Ctr Struct Biol Sch Life Sci, Minist Educ,Key Lab Prot Sci, Beijing 100084, Peoples R China.
EM wcyang@genetics.ac.cn; chaijj@mail.tsinghua.edu.cn
FU Projects of International Cooperation and Exchanges NSFC [31420103906]; Chinese Ministry of Science and Technology [2015CB910200]; State Key Program of National Natural Science of China [31130063]; Chinese Natural Science Foundation [31330053]; Ministry of Science and Technology of China [2015CB910202]
NR 40
TC 210
Z9 249
U1 19
U2 334
PU NATURE PUBLISHING 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 10
PY 2015
VL 525
IS 7568
BP 265
EP +
DI 10.1038/nature14858
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400042
PM 26308901
DA 2026-03-09
ER

PT J
AU Greiner, J
   Mazzali, PA
   Kann, DA
   Krühler, T
   Pian, E
   Prentice, S
   Olivares, EF
   Rossi, A
   Klose, S
   Taubenberger, S
   Knust, F
   Afonso, PMJ
   Ashall, C
   Bolmer, J
   Delvaux, C
   Diehl, R
   Elliott, J
   Filgas, R
   Fynbo, JPU
   Graham, JF
   Guelbenzu, AN
   Kobayashi, S
   Leloudas, G
   Savaglio, S
   Schady, P
   Schmidl, S
   Schweyer, T
   Sudilovsky, V
   Tanga, M
   Updike, AC
   van Eerten, H
   Varela, K
AF Greiner, Jochen
   Mazzali, Paolo A.
   Kann, D. Alexander
   Kruehler, Thomas
   Pian, Elena
   Prentice, Simon
   Felipe Olivares, E.
   Rossi, Andrea
   Klose, Sylvio
   Taubenberger, Stefan
   Knust, Fabian
   Afonso, Paulo M. J.
   Ashall, Chris
   Bolmer, Jan
   Delvaux, Corentin
   Diehl, Roland
   Elliott, Jonathan
   Filgas, Robert
   Fynbo, Johan P. U.
   Graham, John F.
   Guelbenzu, Ana Nicuesa
   Kobayashi, Shiho
   Leloudas, Giorgos
   Savaglio, Sandra
   Schady, Patricia
   Schmidl, Sebastian
   Schweyer, Tassilo
   Sudilovsky, Vladimir
   Tanga, Mohit
   Updike, Adria C.
   van Eerten, Hendrik
   Varela, Karla
TI A very luminous magnetar-powered supernova associated with an ultra-long γ-ray burst
SO NATURE
LA English
DT Article
ID afterglow; emission
AB A new class of ultra-long-duration (more than 10,000 seconds) gamma-ray bursts has recently been suggested(1-3). They may originate in the explosion of stars with much larger radii than those producing normal long-duration gamma-ray bursts(3,4) or in the tidal disruption of a star(3). No clear supernova has yet been associated with an ultra-long-duration gamma-ray burst. Here we report that a supernova (SN 2011kl) was associated with the ultra-long-duration gamma-ray burst GRB 111209A, at a redshift z of 0.677. This supernova is more than three times more luminous than type Ic supernovae associated with long-duration gamma-ray bursts(5-7), and its spectrum is distinctly different. The slope of the continuum resembles those of super-luminous supernovae(8,9), but extends further down into the rest-frame ultraviolet implying a low metal content. The light curve evolves much more rapidly than those of super-luminous supernovae. This combination of high luminosity and low metalline opacity cannot be reconciled with typical type Ic supernovae, but can be reproduced by a model where extra energy is injected by a strongly magnetized neutron star (a magnetar), which has also been proposed as the explanation for super-luminous supernovae(10).
C1 [Greiner, Jochen; Kann, D. Alexander; Knust, Fabian; Bolmer, Jan; Delvaux, Corentin; Diehl, Roland; Elliott, Jonathan; Graham, John F.; Savaglio, Sandra; Schady, Patricia; Schweyer, Tassilo; Sudilovsky, Vladimir; Tanga, Mohit; van Eerten, Hendrik; Varela, Karla] Max Planck Inst Extraterr Phys, D-85748 Garching, Germany.
   [Greiner, Jochen; Kann, D. Alexander] Tech Univ Munich, Excellence Cluster Univ, D-85748 Garching, Germany.
   [Mazzali, Paolo A.; Prentice, Simon; Ashall, Chris; Kobayashi, Shiho] Liverpool John Moores Univ, Astrophys Res Inst, IC2, Liverpool L3 5RF, Merseyside, England.
   [Mazzali, Paolo A.; Taubenberger, Stefan] Max Planck Inst Astrophys, D-85748 Garching, Germany.
   [Kann, D. Alexander; Rossi, Andrea; Klose, Sylvio; Schmidl, Sebastian] Thuringer Landessternwarte Tautenburg, D-07778 Tautenburg, Germany.
   [Kruehler, Thomas] European So Observ, Santiago 19, Chile.
   [Pian, Elena; Rossi, Andrea] Inst Space Astrophys & Cosm Phys, INAF, I-40129 Bologna, Italy.
   [Pian, Elena] Scuola Normale Super Pisa, I-56126 Pisa, Italy.
   [Felipe Olivares, E.] Univ Andres Bello, Dept Ciencias Fis, Santiago, Chile.
   [Taubenberger, Stefan] European So Observ, D-85748 Garching, Germany.
   [Afonso, Paulo M. J.] Amer River Coll, Dept Phys & Astron, Sacramento, CA 95841 USA.
   [Bolmer, Jan; Schweyer, Tassilo] Tech Univ Munich, Phys Dept, D-85748 Garching, Germany.
   [Elliott, Jonathan; Sudilovsky, Vladimir] Harvard Smithonian Ctr Astrophys, Astrophys Data Syst, Cambridge, MA 02138 USA.
   [Filgas, Robert] Czech Tech Univ, Inst Expt & Appl Phys, Prague 12800 2, Czech Republic.
   [Fynbo, Johan P. U.; Leloudas, Giorgos] Univ Copenhagen, DARK Cosmol Ctr, Niels Bohr Inst, DK-2100 Copenhagen, Denmark.
   [Leloudas, Giorgos] Weizmann Inst Sci, Dept Particle Phys & Astrophys, IL-76100 Rehovot, Israel.
   [Savaglio, Sandra] Univ Calabria, I-87036 Arcavacata Di Rende, Italy.
   [Updike, Adria C.] Roger Williams Univ, Bristol, RI 02809 USA.
C3 Max Planck Society; Technical University of Munich; Liverpool John Moores University; Max Planck Society; European Southern Observatory; Istituto Nazionale Astrofisica (INAF); Scuola Normale Superiore di Pisa; Universidad Andres Bello; European Southern Observatory; American River College; Technical University of Munich; Czech Technical University Prague; University of Copenhagen; Niels Bohr Institute; Weizmann Institute of Science; University of Calabria; Roger Williams University
RP Greiner, J (corresponding author), Max Planck Inst Extraterr Phys, Giessenbachstr 1, D-85748 Garching, Germany.
EM jcg@mpe.mpg.de
FU DFG cluster of excellence "Origin and Structure of the Universe"; Alexander von Humboldt Foundation, Germany; EXTraS from the European Union; DFG; Thuringer Ministerium fur Bildung, Wissenschaft und Kultur; FONDECYT; Czech MEYS; Leibniz-Prize; DNRF; Science and Technology Facilities Council [1507817, ST/L00061X/1] Funding Source: researchfish; STFC [ST/L00061X/1] Funding Source: UKRI
NR 44
TC 247
Z9 274
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 JUL 9
PY 2015
VL 523
IS 7559
BP 189
EP U316
DI 10.1038/nature14579
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM4ZO
UT WOS:000357695900029
PM 26156372
DA 2026-03-09
ER

PT J
AU Holleley, CE
   O'Meally, D
   Sarre, SD
   Graves, JAM
   Ezaz, T
   Matsubara, K
   Azad, B
   Zhang, XW
   Georges, A
AF Holleley, Clare E.
   O'Meally, Denis
   Sarre, Stephen D.
   Graves, Jennifer A. Marshall
   Ezaz, Tariq
   Matsubara, Kazumi
   Azad, Bhumika
   Zhang, Xiuwen
   Georges, Arthur
TI Sex reversal triggers the rapid transition from genetic to temperature-dependent sex
SO NATURE
LA English
DT Article
ID adaptive significance; determining systems; pogona-vitticeps; climate-change; dragon lizard; chromosome; parthenogenesis; differentiation; cooccurrence; sequences
AB Sex determination in animals is amazingly plastic. Vertebrates display contrasting strategies ranging from complete genetic control of sex (genotypic sex determination) to environmentally determined sex (for example, temperature-dependent sex determination)(1). Phylogenetic analyses suggest frequent evolutionary transitions between genotypic and temperature-dependent sex determination in environmentally sensitive lineages, including reptiles(2). These transitions are thought to involve a genotypic system becoming sensitive to temperature, with sex determined by gene-environment interactions(3). Most mechanistic models of transitions invoke a role for sex reversal(3-5). Sex reversal has not yet been demonstrated in nature for any amniote, although it occurs in fish(6) and rarely in amphibians(7,8). Here we make the first report of reptile sex reversal in the wild, in the Australian bearded dragon (Pogona vitticeps), and use sex-reversed animals to experimentally induce a rapid transition from genotypic to temperature-dependent sex determination. Controlled mating of normal males to sex-reversed females produces viable and fertile offspring whose phenotypic sex is determined solely by temperature (temperature-dependent sex determination). The W sex chromosome is eliminated from this lineage in the first generation. The instantaneous creation of a lineage of ZZ temperature-sensitive animals reveals a novel, climate-induced pathway for the rapid transition between genetic and temperature-dependent sex determination, and adds to concern about adaptation to rapid global climate change.
C1 [Holleley, Clare E.; O'Meally, Denis; Sarre, Stephen D.; Graves, Jennifer A. Marshall; Ezaz, Tariq; Matsubara, Kazumi; Azad, Bhumika; Zhang, Xiuwen; Georges, Arthur] Univ Canberra, Inst Appl Ecol, Canberra, ACT 2601, Australia.
   [Graves, Jennifer A. Marshall] La Trobe Univ, Sch Life Sci, Melbourne, Vic 3086, Australia.
C3 University of Canberra; La Trobe University
RP Holleley, CE (corresponding author), Univ Canberra, Inst Appl Ecol, Canberra, ACT 2601, Australia.
EM clare@holleley.net; georges@aerg.canberra.edu.au
FU Australian Research Council Discovery Grant [DP110104377]
NR 41
TC 276
Z9 316
U1 8
U2 377
PU NATURE PUBLISHING 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 2
PY 2015
VL 523
IS 7558
BP 79
EP +
DI 10.1038/nature14574
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL7RN
UT WOS:000357169500035
PM 26135451
DA 2026-03-09
ER

PT J
AU Chou, S
   Daugherty, MD
   Peterson, SB
   Biboy, J
   Yang, YY
   Jutras, BL
   Fritz-Laylin, LK
   Ferrin, MA
   Harding, BN
   Jacobs-Wagner, C
   Yang, XF
   Vollmer, W
   Malik, HS
   Mougous, JD
AF Chou, Seemay
   Daugherty, Matthew D.
   Peterson, S. Brook
   Biboy, Jacob
   Yang, Youyun
   Jutras, Brandon L.
   Fritz-Laylin, Lillian K.
   Ferrin, Michael A.
   Harding, Brittany N.
   Jacobs-Wagner, Christine
   Yang, X. Frank
   Vollmer, Waldemar
   Malik, Harmit S.
   Mougous, Joseph D.
TI Transferred interbacterial antagonism genes augment eukaryotic innate immune function
SO NATURE
LA English
DT Article
ID lyme-disease spirochete; vi secretion system; borrelia-burgdorferi; bacteria; peptidoglycan; evolution; sequence; protein; host; performance
AB Horizontal gene transfer allows organisms to rapidly acquire adaptive traits(1). Although documented instances of horizontal gene transfer from bacteria to eukaryotes remain rare, bacteria represent a rich source of new functions potentially available for co-option(2). One benefit that genes of bacterial origin could provide to eukaryotes is the capacity to produce antibacterials, which have evolved in prokaryotes as the result of eons of interbacterial competition. The type VI secretion amidase effector (Tae) proteins are potent bacteriocidal enzymes that degrade the cell wall when delivered into competing bacterial cells by the type VI secretion system(3). Here we show that tae genes have been transferred to eukaryotes on at least six occasions, and that the resulting domesticated amidase effector (dae) genes have been preserved for hundreds of millions of years through purifying selection. We show that the dae genes acquired eukaryotic secretion signals, are expressed within recipient organisms, and encode active antibacterial toxins that possess substrate specificity matching extant Tae proteins of the same lineage. Finally, we show that a dae gene in the deer tick Ixodes scapularis limits proliferation of Borrelia burgdorferi, the aetiologic agent of Lyme disease. Our work demonstrates that a family of horizontally acquired toxins honed to mediate interbacterial antagonism confers previously undescribed antibacterial capacity to eukaryotes. We speculate that the selective pressure imposed by competition between bacteria has produced a reservoir of genes encoding diverse antimicrobial functions that are tailored for co-option by eukaryotic innate immune systems.
C1 [Chou, Seemay; Peterson, S. Brook; Ferrin, Michael A.; Harding, Brittany N.; Mougous, Joseph D.] Univ Washington, Sch Med, Dept Microbiol, Seattle, WA 98195 USA.
   [Daugherty, Matthew D.; Malik, Harmit S.] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA.
   [Daugherty, Matthew D.; Malik, Harmit S.] Fred Hutchinson Canc Res Ctr, Howard Hughes Med Inst, Seattle, WA 98109 USA.
   [Biboy, Jacob; Vollmer, Waldemar] Newcastle Univ, Inst Cell & Mol Biosci, Ctr Bacterial Cell Biol, Newcastle Upon Tyne NE2 4AX, Tyne & Wear, England.
   [Yang, Youyun; Yang, X. Frank] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA.
   [Jutras, Brandon L.; Jacobs-Wagner, Christine] Yale Univ, Microbial Sci Inst, New Haven, CT 06516 USA.
   [Jutras, Brandon L.; Jacobs-Wagner, Christine] Yale Univ, Howard Hughes Med Inst, New Haven, CT 06516 USA.
   [Fritz-Laylin, Lillian K.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA.
   [Jacobs-Wagner, Christine] Yale Univ, Dept Microbial Pathogenesis, New Haven, CT 06516 USA.
   [Jacobs-Wagner, Christine] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06516 USA.
C3 University of Washington; University of Washington Seattle; Fred Hutchinson Cancer Center; Fred Hutchinson Cancer Center; Howard Hughes Medical Institute; Newcastle University - UK; Indiana University System; Indiana University Bloomington; Yale University; Yale University; Howard Hughes Medical Institute; University of California System; University of California San Francisco; Yale University; Yale University
RP Mougous, JD (corresponding author), Univ Washington, Sch Med, Dept Microbiol, Seattle, WA 98195 USA.
EM mougous@u.washington.edu
FU National Institutes of Health [AI080609, AI083640]; Defense Threat Reduction Agency [HDTRA-1-13-014]; BBSRC [BB/I020012/1]; Howard Hughes Medical Institute (HHMI); American Society for Microbiology Undergraduate Research Fellowship; Irvington Institute Fellowship from the Cancer Research Institute; Burroughs Wellcome Fund; Biotechnology and Biological Sciences Research Council [BB/I020012/1] Funding Source: researchfish; National Institute of Allergy and Infectious Diseases [R01AI083640, R01AI080609] Funding Source: NIH RePORTER; BBSRC [BB/I020012/1] Funding Source: UKRI
NR 47
TC 72
Z9 85
U1 1
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 FEB 5
PY 2015
VL 518
IS 7537
BP 98
EP +
DI 10.1038/nature13965
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7LE
UT WOS:000349098000039
PM 25470067
DA 2026-03-09
ER

PT J
AU Sorrells, TR
   Booth, LN
   Tuch, BB
   Johnson, AD
AF Sorrells, Trevor R.
   Booth, Lauren N.
   Tuch, Brian B.
   Johnson, Alexander D.
TI Intersecting transcription networks constrain gene regulatory evolution
SO NATURE
LA English
DT Article
ID historical contingency; cell-type; yeast; binding; protein; divergence; alignment; circuit
AB Epistasis-the non-additive interactions between different genetic loci-constrains evolutionary pathways, blocking some and permitting others(1-8). For biological networks such as transcription circuits, the nature of these constraints and their consequences are largely unknown. Here we describe the evolutionary pathways of a transcription network that controls the response to mating pheromone in yeast(9). A component of this network, the transcription regulator Ste12, has evolved two different modes of binding to a set of its target genes. In one group of species, Ste12 binds to specific DNA binding sites, while in another lineage it occupies DNA indirectly, relying on a second transcription regulator to recognize DNA. We show, through the construction of various possible evolutionary intermediates, that evolution of the direct mode of DNA binding was not directly accessible to the ancestor. Instead, it was contingent on a lineage-specific change to an overlapping transcription network with a different function, the specification of cell type. These results show that analysing and predicting the evolution of cis-regulatory regions requires an understanding of their positions in overlapping networks, as this placement constrains the available evolutionary pathways.
C1 [Sorrells, Trevor R.; Booth, Lauren N.; Tuch, Brian B.; Johnson, Alexander D.] Univ Calif San Francisco, Dept Microbiol & Immunol, Dept Biochem & Biophys, San Francisco, CA 94158 USA.
   [Sorrells, Trevor R.; Booth, Lauren N.; Johnson, Alexander D.] Univ Calif San Francisco, Tetrad Grad Program, San Francisco, CA 94158 USA.
   [Tuch, Brian B.] Univ Calif San Francisco, Biol & Med Informat Grad Program, 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
RP Johnson, AD (corresponding author), Univ Calif San Francisco, Dept Microbiol & Immunol, Dept Biochem & Biophys, San Francisco, CA 94158 USA.
EM ajohnson@cgl.ucsf.edu
FU National Institutes of Health [R01 GM037049]; National Science Foundation; National Institute of General Medical Sciences [R01GM037049] Funding Source: NIH RePORTER
NR 49
TC 58
Z9 76
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 JUL 16
PY 2015
VL 523
IS 7560
BP 361
EP +
DI 10.1038/nature14613
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM8KY
UT WOS:000357950900045
PM 26153861
DA 2026-03-09
ER

PT J
AU Olmos, Y
   Hodgson, L
   Mantell, J
   Verkade, P
   Carlton, JG
AF Olmos, Yolanda
   Hodgson, Lorna
   Mantell, Judith
   Verkade, Paul
   Carlton, Jeremy G.
TI ESCRT-III controls nuclear envelope reformation
SO NATURE
LA English
DT Article
ID aurora-b; endoplasmic-reticulum; hela-cells; cytokinesis; protein; abscission; machinery; chromatin; dynamics; kinase
AB During telophase, the nuclear envelope (NE) reforms around daughter nuclei to ensure proper segregation of nuclear and cytoplasmic contents1-4. NE reformation requires the coating of chromatin by membrane derived from the endoplasmic reticulum, and a subsequent annular fusion step to ensure that the formed envelope is sealed(1,2,4,5). How annular fusion is accomplished is unknown, but it is thought to involve the p97 AAA-ATPase complex and bears a topological equivalence to the membrane fusion event that occurs during the abscission phase of cytokinesis(1,6). Herewe show that the endosomal sorting complex required for transport-III (ESCRT-III) machinery localizes to sites of annular fusion in the forming NE in human cells, and is necessary for proper post-mitotic nucleocytoplasmic compartmentalization. The ESCRT-III component charged multivesicular body protein 2A (CHMP2A) is directed to the forming NE through binding to CHMP4B, and provides an activity essential for NE reformation. Localization also requires the p97 complex member ubiquitin fusion and degradation 1 (UFD1). Our results describe a novel role for the ESCRT machinery in cell division and demonstrate a conservation of themachineries involved in topologically equivalent mitotic membrane remodelling events.
C1 [Olmos, Yolanda; Carlton, Jeremy G.] Kings Coll London, Sect Cell Biol & Imaging, Div Canc Studies, London SE1 1UL, England.
   [Hodgson, Lorna; Mantell, Judith; Verkade, Paul] Univ Bristol, Sch Biochem, Bristol BS8 1TD, Avon, England.
   [Mantell, Judith; Verkade, Paul] Univ Bristol, Wolfson Bioimaging Facil, Bristol BS8 1TD, Avon, England.
   [Verkade, Paul] Univ Bristol, Sch Physiol & Pharmacol, Bristol BS8 1TD, Avon, England.
C3 University of London; King's College London; University of Bristol; University of Bristol; University of Bristol
RP Carlton, JG (corresponding author), Kings Coll London, Sect Cell Biol & Imaging, Div Canc Studies, London SE1 1UL, England.
EM jeremy.carlton@kcl.ac.uk
FU BBSRC [BB/L014181/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/L014181/1] Funding Source: researchfish; Wellcome Trust [093603] Funding Source: Medline
NR 32
TC 289
Z9 340
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 JUN 11
PY 2015
VL 522
IS 7555
BP 236
EP +
DI 10.1038/nature14503
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700043
PM 26040713
DA 2026-03-09
ER

PT J
AU Park, SY
   Peterson, FC
   Mosquna, A
   Yao, J
   Volkman, BF
   Cutler, SR
AF Park, Sang-Youl
   Peterson, Francis C.
   Mosquna, Assaf
   Yao, Jin
   Volkman, Brian F.
   Cutler, Sean R.
TI Agrochemical control of plant water use using engineered abscisic acid receptors
SO NATURE
LA English
DT Article
ID drought tolerance; selective activation; structural basis; gene-expression; aba receptors; snrk2 kinases; mechanism; proteins; ligand; transformation
AB Rising temperatures and lessening fresh water supplies are threatening agricultural productivity and have motivated efforts to improve plant water use and drought tolerance. During water deficit, plants produce elevated levels of abscisic acid (ABA), which improves water consumption and stress tolerance by controlling guard cell aperture and other protective responses(1,2). One attractive strategy for controlling water use is to develop compounds that activate ABA receptors, but agonists approved for use have yet to be developed. In principle, an engineered ABA receptor that can be activated by an existing agrochemical could achieve this goal. Here we describe a variant of the ABA receptor PYRABACTIN RESISTANCE 1 (PYR1) that possesses nanomolar sensitivity to the agrochemical mandipropamid and demonstrate its efficacy for controlling ABA responses and drought tolerance in transgenic plants. Furthermore, crystallographic studies provide a mechanistic basis for its activity and demonstrate the relative ease with which the PYR1 ligand-binding pocket can be altered to accommodate new ligands. Thus, we have successfully repurposed an agrochemical for a new application using receptor engineering. We anticipate that this strategy will be applied to other plant receptors and represents a new avenue for crop improvement.
C1 [Park, Sang-Youl; Mosquna, Assaf; Yao, Jin; Cutler, Sean R.] Univ Calif Riverside, Ctr Plant Cell Biol, Riverside, CA 92521 USA.
   [Park, Sang-Youl; Mosquna, Assaf; Yao, Jin; Cutler, Sean R.] Univ Calif Riverside, Dept Bot & Plant Sci, Riverside, CA 92521 USA.
   [Park, Sang-Youl; Mosquna, Assaf; Yao, Jin; Cutler, Sean R.] Inst Integrat Genome Biol, Riverside, CA 92521 USA.
   [Peterson, Francis C.; Volkman, Brian F.] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA.
C3 University of California System; University of California Riverside; University of California System; University of California Riverside; Medical College of Wisconsin
RP Cutler, SR (corresponding author), Univ Calif Riverside, Ctr Plant Cell Biol, Riverside, CA 92521 USA.
EM sean.cutler@ucr.edu
FU National Science Foundation [IOS 1258175, MCB 1022378]; Syngenta Corporation; United States-Israel Binational Agricultural Research and Development Postdoctoral Fellowship [F1-440-2010]; Direct For Biological Sciences; Div Of Molecular and Cellular Bioscience [1022378] Funding Source: National Science Foundation; Division Of Integrative Organismal Systems; Direct For Biological Sciences [1258175] Funding Source: National Science Foundation
NR 31
TC 211
Z9 240
U1 7
U2 211
PU NATURE PUBLISHING 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 23
PY 2015
VL 520
IS 7548
BP 545
EP +
DI 10.1038/nature14123
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500044
PM 25652827
DA 2026-03-09
ER

PT J
AU Deng, D
   Sun, PC
   Yan, CY
   Ke, M
   Jiang, X
   Xiong, L
   Ren, WL
   Hirata, K
   Yamamoto, M
   Fan, SL
   Yan, N
AF Deng, Dong
   Sun, Pengcheng
   Yan, Chuangye
   Ke, Meng
   Jiang, Xin
   Xiong, Lei
   Ren, Wenlin
   Hirata, Kunio
   Yamamoto, Masaki
   Fan, Shilong
   Yan, Nieng
TI Molecular basis of ligand recognition and transport by glucose transporters
SO NATURE
LA English
DT Article
ID alpha-d-glucose; beta-d-glucose; sugar-transport; swiss-model; crystal-structure; xenopus oocytes; membrane; glut3; binding; proteins
AB The major facilitator superfamily glucose transporters, exemplified by human GLUT1-4, have been central to the study of solute transport. Using lipidic cubic phase crystallization and microfocus X-ray diffraction, we determined the structure of human GLUT3 in complex with D-glucose at 1.5 angstrom resolution in an outward-occluded conformation. The high-resolution structure allows discrimination of both alpha- and beta-anomers of D-glucose. Two additional structures of GLUT3 bound to the exofacial inhibitor maltose were obtained at 2.6 angstrom in the outward-open and 2.4 angstrom in the outward-occluded states. In all three structures, the ligands are predominantly coordinated by polar residues from the carboxy terminal domain. Conformational transition from outward-open to outward-occluded entails a prominent local rearrangement of the extracellular part of transmembrane segment TM7. Comparison of the outward-facing GLUT3 structures with the inward-open GLUT1 provides insights into the alternating access cycle for GLUTs, whereby the C-terminal domain provides the primary substrate-binding site and the amino-terminal domain undergoes rigid-body rotation with respect to the C-terminal domain. Our studies provide an important framework for the mechanistic and kinetic understanding of GLUTs and shed light on structure-guided ligand design.
C1 [Deng, Dong; Sun, Pengcheng; Yan, Chuangye; Ke, Meng; Jiang, Xin; Ren, Wenlin; Yan, Nieng] Tsinghua Univ, State Key Lab Membrane Biol, Beijing 100084, Peoples R China.
   [Deng, Dong; Sun, Pengcheng; Yan, Chuangye; Ke, Meng; Jiang, Xin; Ren, Wenlin; Fan, Shilong; Yan, Nieng] Tsinghua Univ, Struct Biol Ctr, Beijing 100084, Peoples R China.
   [Deng, Dong; Sun, Pengcheng; Yan, Chuangye; Ke, Meng; Xiong, Lei; Yan, Nieng] Tsinghua Univ, Tsinghua Peking Ctr Life Sci, Sch Life Sci, Beijing 100084, Peoples R China.
   [Deng, Dong; Sun, Pengcheng; Yan, Chuangye; Ke, Meng; Xiong, Lei; Yan, Nieng] Tsinghua Univ, Sch Med, Beijing 100084, Peoples R China.
   [Hirata, Kunio; Yamamoto, Masaki] RIKEN SPring 8 Ctr, Adv Photon Technol Div, Res Infrastruct Grp, SR Life Sci Instrumentat Unit, Mikazuki, Hyogo 6795148, Japan.
   [Hirata, Kunio] Japan Sci & Technol Agcy, Precursory Res Embryon Sci & Technol PRESTO, Kawaguchi, Saitama 3320012, Japan.
C3 Tsinghua University; Tsinghua University; Tsinghua University; Tsinghua University; RIKEN; Japan Science & Technology Agency (JST)
RP Yan, N (corresponding author), Tsinghua Univ, State Key Lab Membrane Biol, Beijing 100084, Peoples R China.
EM nyan@tsinghua.edu.cn
FU Ministry of Science and Technology of China [2015CB910101, 2011CB910501, 2014ZX09507003006]; National Natural Science Foundation of China [31130002, 31125009]; Howard Hughes Medical Institute
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NR 65
TC 304
Z9 350
U1 7
U2 369
PU NATURE PUBLISHING 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 15
PY 2015
VL 526
IS 7573
BP 391
EP +
DI 10.1038/nature14655
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200043
PM 26176916
DA 2026-03-09
ER

PT J
AU Sterling, AC
   Moore, RL
   Falconer, DA
   Adams, M
AF Sterling, Alphonse C.
   Moore, Ronald L.
   Falconer, David A.
   Adams, Mitzi
TI Small-scale filament eruptions as the driver of X-ray jets in solar coronal holes
SO NATURE
LA English
DT Article
ID mass ejections; flux emergence; blowout jet; quiet sun; magnetic reconnection; bright points; alfven waves; hot-plasma; flares; hinode
AB Solar X-ray jets are thought to be made by a burst of reconnection of closed magnetic field at the base of a jet with ambient open field(1,2). In the accepted version of the 'emerging-flux' model, such a reconnection occurs at a plasma current sheet between the open field and the emerging closed field, and also forms a localized X-ray brightening that is usually observed at the edge of the jet's base(1,3). Here we report high-resolution X-ray and extreme-ultraviolet observations of 20 randomly selected X-ray jets that form in coronal holes at the Sun's poles. In each jet, contrary to the emerging-flux model, a miniature version of the filament eruptions that initiate coronal mass ejections(4-7) drives the jet-producing reconnection. The X-ray bright point occurs by reconnection of the 'legs' of the minifilament-carrying erupting closed field, analogous to the formation of solar flares in larger-scale eruptions. Previous observations have found that some jets are driven by base-field eruptions(8-11), but only one such study, of only one jet, provisionally questioned the emerging-flux model(12). Our observations support the view that solar filament eruptions are formed by a fundamental explosive magnetic process that occurs on a vast range of scales, from the biggest mass ejections and flare eruptions down to X-ray jets, and perhaps even down to smaller jets that may power coronal heating(10,13,14). A similar scenario has previously been suggested, but was inferred from different observations and based on a different origin of the erupting minifilament(15).
C1 [Sterling, Alphonse C.; Moore, Ronald L.; Falconer, David A.; Adams, Mitzi] NASA, George C Marshall Space Flight Ctr, Huntsville, AL 35812 USA.
   [Moore, Ronald L.; Falconer, David A.] Univ Alabama, Ctr Space Plasma & Aeron Res, Huntsville, AL 35899 USA.
C3 National Aeronautics & Space Administration (NASA); NASA Marshall Space Flight Center; University of Alabama System; University of Alabama Huntsville
RP Sterling, AC (corresponding author), NASA, George C Marshall Space Flight Ctr, Huntsville, AL 35812 USA.
EM alphonse.sterling@nasa.gov; ron.moore@nasa.gov
FU Heliophysics Division of NASA's Science Mission Directorate through the Living With A Star Targeted Research and Technology Program(LWS TRT); Hinode Project
NR 45
TC 306
Z9 320
U1 0
U2 14
PU NATURE PUBLISHING 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 23
PY 2015
VL 523
IS 7561
BP 437
EP U130
DI 10.1038/nature14556
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN4DD
UT WOS:000358378900031
PM 26147079
DA 2026-03-09
ER

PT J
AU Lumley, AJ
   Michalczyk, L
   Kitson, JJN
   Spurgin, LG
   Morrison, CA
   Godwin, JL
   Dickinson, ME
   Martin, OY
   Emerson, BC
   Chapman, T
   Gage, MJG
AF Lumley, Alyson J.
   Michalczyk, Lukasz
   Kitson, James J. N.
   Spurgin, Lewis G.
   Morrison, Catriona A.
   Godwin, Joanne L.
   Dickinson, Matthew E.
   Martin, Oliver Y.
   Emerson, Brent C.
   Chapman, Tracey
   Gage, Matthew J. G.
TI Sexual selection protects against extinction
SO NATURE
LA English
DT Article
ID mutation load; experimental removal; deleterious alleles; female; maintenance; populations; evolution; genetics; model
AB Reproduction through sex carries substantial costs, mainly because only half of sexual adults produce offspring(1). It has been theorized that these costs could be countered if sex allows sexual selection to clear the universal fitness constraint of mutation load(2-4). Under sexual selection, competition between (usually) males and mate choice by (usually) females create important intraspecific filters for reproductive success, so that only a subset of males gains paternity. If reproductive success under sexual selection is dependent on individual condition, which is contingent to mutation load, then sexually selected filtering through 'genic capture'(5) could offset the costs of sex because it provides genetic benefits to populations. Here we test this theory experimentally by comparing whether populations with histories of strong versus weak sexual selection purge mutation load and resist extinction differently. After evolving replicate populations of the flour beetle Tribolium castaneum for 6 to 7 years under conditions that differed solely in the strengths of sexual selection, we revealed mutation load using inbreeding. Lineages from populations that had previously experienced strong sexual selection were resilient to extinction and maintained fitness under inbreeding, with some families continuing to survive after 20 generations of sib 3 sib mating. By contrast, lineages derived from populations that experienced weak or nonexistent sexual selection showed rapid fitness declines under inbreeding, and all were extinct after generation 10. Multiple mutations across the genome with individually small effects can be difficult to clear, yet sum to a significant fitness load; our findings reveal that sexual selection reduces this load, improving population viability in the face of genetic stress.
C1 [Lumley, Alyson J.; Kitson, James J. N.; Spurgin, Lewis G.; Morrison, Catriona A.; Godwin, Joanne L.; Dickinson, Matthew E.; Chapman, Tracey; Gage, Matthew J. G.] Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England.
   [Michalczyk, Lukasz] Jagiellonian Univ, Inst Zool, Dept Entomol, PL-30387 Krakow, Poland.
   [Martin, Oliver Y.] ETH, Inst Integrat Biol, D USYS, CH-8092 Zurich, Switzerland.
   [Emerson, Brent C.] Inst Prod Nat & Agrobiol IPNA CSIC, Isl Ecol & Evolut Res Grp, Santa Cruz De Tenerife 38206, Canary Islands, Spain.
C3 University of East Anglia; Jagiellonian University; Swiss Federal Institutes of Technology Domain; ETH Zurich; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Productos Naturales y Agrobiologia (IPNA)
RP Gage, MJG (corresponding author), Univ E Anglia, Sch Biol Sci, Norwich Res Pk, Norwich NR4 7TJ, Norfolk, England.
EM m.gage@uea.ac.uk
FU Natural Environment Research Council; Leverhulme Trust; NERC [NE/K004697/1, NE/J012416/1, NE/G006881/1] Funding Source: UKRI; Natural Environment Research Council [NE/G006881/1, NE/C004639/1, NE/K004697/1, NE/J012416/1] Funding Source: researchfish
NR 38
TC 151
Z9 167
U1 1
U2 237
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 25
PY 2015
VL 522
IS 7557
BP 470
EP +
DI 10.1038/nature14419
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL2OC
UT WOS:000356782900048
PM 25985178
DA 2026-03-09
ER

PT J
AU Okun, M
   Steinmetz, NA
   Cossell, L
   Iacaruso, MF
   Ko, H
   Barthó, P
   Moore, T
   Hofer, SB
   Mrsic-Flogel, TD
   Carandini, M
   Harris, KD
AF Okun, Michael
   Steinmetz, Nicholas A.
   Cossell, Lee
   Iacaruso, M. Florencia
   Ko, Ho
   Bartho, Peter
   Moore, Tirin
   Hofer, Sonja B.
   Mrsic-Flogel, Thomas D.
   Carandini, Matteo
   Harris, Kenneth D.
TI Diverse coupling of neurons to populations in sensory cortex
SO NATURE
LA English
DT Article
ID primary visual-cortex; functional-organization; projection neurons; in-vivo; dynamics; recordings; responses; state
AB A large population of neurons can, in principle, produce an astronomical number of distinct firing patterns. In cortex, however, these patterns lie in a space of lower dimension(1-4), as if individual neurons were "obedientmembers of a huge orchestra''(5). Here we use recordings from the visual cortex of mouse (Mus musculus) and monkey (Macaca mulatta) to investigate the relationship between individual neurons and the population, and to establish the underlying circuit mechanisms. We show that neighbouring neurons can differ in their coupling to the overall firing of the population, ranging from strongly coupled 'choristers' to weakly coupled 'soloists'. Population coupling is largely independent of sensory preferences, and it is a fixed cellular attribute, invariant to stimulus conditions. Neurons with high population coupling are more strongly affected by non-sensory behavioural variables such as motor intention. Population coupling reflects a causal relationship, predicting the response of a neuron to optogenetically driven increases in local activity. Moreover, population coupling indicates synaptic connectivity; the population coupling of a neuron, measured in vivo, predicted subsequent in vitro estimates of the number of synapses received from its neighbours. Finally, population coupling provides a compact summary of population activity; knowledge of the population couplings of n neurons predicts a substantial portion of their n(2) pairwise correlations. Population coupling therefore represents a novel, simple measure that characterizes the relationship of each neuron to a larger population, explaining seemingly complex network firing patterns in terms of basic circuit variables.
C1 [Okun, Michael; Steinmetz, Nicholas A.; Harris, Kenneth D.] UCL, UCL Inst Neurol, London WC1N 3BG, England.
   [Okun, Michael; Steinmetz, Nicholas A.; Cossell, Lee; Iacaruso, M. Florencia; Ko, Ho; Hofer, Sonja B.; Mrsic-Flogel, Thomas D.; Harris, Kenneth D.] UCL, Dept Neurosci Physiol & Pharmacol, London WC1E 6DE, England.
   [Okun, Michael; Steinmetz, Nicholas A.; Carandini, Matteo] UCL, UCL Inst Ophthalmol, London EC1V 9EL, England.
   [Steinmetz, Nicholas A.; Moore, Tirin] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Steinmetz, Nicholas A.; Moore, Tirin] Stanford Univ, Dept Neurobiol, Stanford, CA 94305 USA.
   [Cossell, Lee; Iacaruso, M. Florencia; Hofer, Sonja B.; Mrsic-Flogel, Thomas D.] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland.
   [Bartho, Peter; Harris, Kenneth D.] Rutgers State Univ, Ctr Mol & Behav Neurosci, Newark, NJ 07102 USA.
C3 University of London; University College London; University of London; University College London; University of London; University College London; Stanford University; Howard Hughes Medical Institute; Stanford University; University of Basel; Rutgers University System; Rutgers University Newark; Rutgers University New Brunswick
RP Okun, M (corresponding author), UCL, UCL Inst Neurol, London WC1N 3BG, England.
EM m.okun@ucl.ac.uk; kenneth.harris@ucl.ac.uk
FU Wellcome Trust; Engineering and Physical Sciences Research Council; European Research Council; Medical Research Council; National Institutes of Health [EY014924]; Simons Foundation; Engineering and Physical Sciences Research Council [EP/K015141/1, EP/I005102/1, EP/I005102/2] Funding Source: researchfish; EPSRC [EP/I005102/1, EP/I005102/2, EP/K015141/1] Funding Source: UKRI; National Eye Institute [R01EY014924] Funding Source: NIH RePORTER; National Institute of General Medical Sciences; National Institute of Mental Health; National Institute on Aging [T32MH020016] Funding Source: NIH RePORTER
NR 42
TC 281
Z9 351
U1 2
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 28
PY 2015
VL 521
IS 7553
BP 511
EP U189
DI 10.1038/nature14273
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ2AN
UT WOS:000355286600041
PM 25849776
DA 2026-03-09
ER

PT J
AU Massironi, M
   Simioni, E
   Marzari, F
   Cremonese, G
   Giacomini, L
   Pajola, M
   Jorda, L
   Naletto, G
   Lowry, S
   El-Maarry, MR
   Preusker, F
   Scholten, F
   Sierks, H
   Barbieri, C
   Lamy, P
   Rodrigo, R
   Koschny, D
   Rickman, H
   Keller, HU
   A'Hearn, MF
   Agarwal, J
   Auger, AT
   Barucci, MA
   Bertaux, JL
   Bertini, I
   Besse, S
   Bodewits, D
   Capanna, C
   Da Deppo, V
   Davidsson, B
   Debei, S
   De Cecco, ML
   Ferri, F
   Fornasier, S
   Fulle, M
   Gaskell, R
   Groussin, O
   Gutiérrez, PJ
   Güttler, C
   Hviid, SF
   Ip, WH
   Knollenberg, J
   Kovacs, G
   Kramm, R
   Kührt, E
   Küppers, M
   La Forgia, F
   Lara, LM
   Lazzarin, M
   Lin, ZY
   Moreno, JJL
   Magrin, S
   Michalik, H
   Mottola, S
   Oklay, N
   Pommerol, A
   Thomas, N
   Tubiana, C
   Vincent, JB
AF Massironi, Matteo
   Simioni, Emanuele
   Marzari, Francesco
   Cremonese, Gabriele
   Giacomini, Lorenza
   Pajola, Maurizio
   Jorda, Laurent
   Naletto, Giampiero
   Lowry, Stephen
   El-Maarry, Mohamed Ramy
   Preusker, Frank
   Scholten, Frank
   Sierks, Holger
   Barbieri, Cesare
   Lamy, Philippe
   Rodrigo, Rafael
   Koschny, Detlef
   Rickman, Hans
   Keller, Horst Uwe
   A'Hearn, Michael F.
   Agarwal, Jessica
   Auger, Anne-Therese
   Barucci, M. Antonella
   Bertaux, Jean-Loup
   Bertini, Ivano
   Besse, Sebastien
   Bodewits, Dennis
   Capanna, Claire
   Da Deppo, Vania
   Davidsson, Bjoern
   Debei, Stefano
   De Cecco, Mario Lino
   Ferri, Francesca
   Fornasier, Sonia
   Fulle, Marco
   Gaskell, Robert
   Groussin, Olivier
   Gutierrez, Pedro J.
   Guettler, Carsten
   Hviid, Stubbe F.
   Ip, Wing-Huen
   Knollenberg, Joerg
   Kovacs, Gabor
   Kramm, Rainer
   Kuehrt, Ekkehard
   Kueppers, Michael
   La Forgia, Fiorangela
   Lara, Luisa M.
   Lazzarin, Monica
   Lin, Zhong-Yi
   Lopez Moreno, Jose J.
   Magrin, Sara
   Michalik, Harald
   Mottola, Stefano
   Oklay, Nilda
   Pommerol, Antoine
   Thomas, Nicolas
   Tubiana, Cecilia
   Vincent, Jean-Baptiste
TI Two independent and primitive envelopes of the bilobate nucleus of comet 67P
SO NATURE
LA English
DT Article
ID deep impact; geology; shape; surface
AB The factors shaping cometary nuclei are still largely unknown, but could be the result of concurrent effects of evolutionary(1,2) and primordial processes(3,4). The peculiar bilobed shape of comet 67P/Churyumov-Gerasimenko may be the result of the fusion of two objects that were once separate or the result of a localized excavation by outgassing at the interface between the two lobes(5). Here we report that the comet's major lobe is enveloped by a nearly continuous set of strata, up to 650 metres thick, which are independent of an analogous stratified envelope on the minor lobe. Gravity vectors computed for the two lobes separately are closer to perpendicular to the strata than those calculated for the entire nucleus and adjacent to the neck separating the two lobes. Therefore comet 67P/Churyumov-Gerasimenko is an accreted body of two distinct objects with 'onion-like' stratification, which formed before they merged. We conclude that gentle, low-velocity collisions occurred between two fully formed kilometre-sized cometesimals in the early stages of the Solar System. The notable structural similarities between the two lobes of comet 67P/Churyumov-Gerasimenko indicate that the early-forming cometesimals experienced similar primordial stratified accretion, even though they formed independently.
C1 [Massironi, Matteo; Giacomini, Lorenza] Univ Padua, Dipartimento Geosci, Via G Gradenigo 6, I-35131 Padua, Italy.
   [Massironi, Matteo; Pajola, Maurizio; Naletto, Giampiero; Bertini, Ivano; Ferri, Francesca] Univ Padua, Ctr Ateneo Studi & Attivita Spaziali Giuseppe Col, I-35131 Padua, Italy.
   [Simioni, Emanuele; Naletto, Giampiero; Da Deppo, Vania] CNR INFN UOS Padova LUXOR, I-35131 Padua, Italy.
   [Marzari, Francesco; Barbieri, Cesare; La Forgia, Fiorangela; Lazzarin, Monica; Magrin, Sara] Univ Padua, Dept Phys & Astron, I-35122 Padua, Italy.
   [Cremonese, Gabriele] Osserv Astron Padova, INAF, I-35122 Padua, Italy.
   [Jorda, Laurent; Lamy, Philippe; Auger, Anne-Therese; Capanna, Claire; Groussin, Olivier] Aix Marseille Univ, CNRS, UMR 7326, LAM, F-13388 Marseille, France.
   [Naletto, Giampiero] Univ Padua, Dept Informat Engn, I-35131 Padua, Italy.
   [Lowry, Stephen] Univ Kent, Sch Phys Sci, Canterbury CT2 7NZ, Kent, England.
   [El-Maarry, Mohamed Ramy; Pommerol, Antoine; Thomas, Nicolas] Univ Bern, Inst Phys, CH-3012 Bern, Switzerland.
   [Preusker, Frank; Scholten, Frank; Hviid, Stubbe F.; Knollenberg, Joerg; Kuehrt, Ekkehard; Mottola, Stefano] Deutsch Zentrum Luft & Raumfahrt DLR, Inst Planetenforsch, D-12489 Berlin, Germany.
   [Sierks, Holger; A'Hearn, Michael F.; Agarwal, Jessica; Guettler, Carsten; Hviid, Stubbe F.; Kovacs, Gabor; Kramm, Rainer; Oklay, Nilda; Tubiana, Cecilia; Vincent, Jean-Baptiste] Max Planck Inst Sonnensyst Forsch, D-37077 Gottingen, Germany.
   [Rodrigo, Rafael] CSIC INTA, Ctr Astrobiol, Madrid 28850, Spain.
   [Rodrigo, Rafael] Int Space Sci Inst, CH-3012 Bern, Switzerland.
   [Koschny, Detlef; Besse, Sebastien] European Space Res & Technol Ctr ESA, Sci Support Off, NL-2201 AZ Noordwijk, Netherlands.
   [Rickman, Hans] Uppsala Univ, Dept Phys & Astron, S-75120 Uppsala, Sweden.
   [Rickman, Hans] PAS Space Res Ctr, PL-00716 Warsaw, Poland.
   [Keller, Horst Uwe] Tech Univ Carolo Wilhelmina Braunschweig, Inst Geophys & Extraterr Phys IGEP, D-38106 Braunschweig, Germany.
   [A'Hearn, Michael F.; Bodewits, Dennis] Univ Maryland, Dept Astron, College Pk, MD 20742 USA.
   [A'Hearn, Michael F.] Akad Wissensch Gottingen, D-37077 Gottingen, Germany.
   [Barucci, M. Antonella; Fornasier, Sonia] Univ Paris Diderot, Univ Paris 06, CNRS, LESIA,Observ Paris, F-92195 Meudon, France.
   [Bertaux, Jean-Loup] UVSQ, CNRS, IPSL, LATMOS, F-78280 Guyancourt, France.
   [Davidsson, Bjoern] Uppsala Univ, Dept Phys & Astron, S-75120 Uppsala, Sweden.
   [Debei, Stefano] Univ Padua, Dept Ind Engn, I-35131 Padua, Italy.
   [De Cecco, Mario Lino] Univ Trent, I-38100 Trento, Italy.
   [Fulle, Marco] Osserv Astron Trieste, INAF, I-34014 Trieste, Italy.
   [Gaskell, Robert] Planetary Sci Inst, Tucson, AZ 85719 USA.
   [Gutierrez, Pedro J.; Lara, Luisa M.; Lopez Moreno, Jose J.] CSIC, Inst Astrofis Andalucia, E-18008 Granada, Spain.
   [Ip, Wing-Huen; Lin, Zhong-Yi] Natl Cent Univ, Grad Inst Astron, Chungli 32054, Taiwan.
   [Kueppers, Michael] European Space Astron Ctr ESA, Operat Dept, Madrid 28691, Spain.
   [Michalik, Harald] TU Braunschweig, Inst Datentech & Kommunikat, D-38106 Braunschweig, Germany.
C3 University of Padua; University of Padua; University of Padua; University of Padua; Istituto Nazionale Astrofisica (INAF); Aix-Marseille Universite; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); University of Padua; University of Kent; University of Bern; Helmholtz Association; German Aerospace Centre (DLR); Max Planck Society; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Centro de Astrobiologia (INTA); Uppsala University; Polish Academy of Sciences; Space Research Centre of the Polish Academy of Sciences; Braunschweig University of Technology; University System of Maryland; University of Maryland College Park; Universite Paris Cite; Universite PSL; Observatoire de Paris; Centre National de la Recherche Scientifique (CNRS); Sorbonne Universite; Universite Paris Saclay; Centre National de la Recherche Scientifique (CNRS); Sorbonne Universite; Universite Paris Cite; Uppsala University; University of Padua; University of Trento; Istituto Nazionale Astrofisica (INAF); Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Astrofisica de Andalucia (IAA); National Central University; European Space Agency; European Space Astronomy Center; Braunschweig University of Technology
RP Massironi, M (corresponding author), Univ Padua, Dipartimento Geosci, Via G Gradenigo 6, I-35131 Padua, Italy.
EM matteo.massironi@unipd.it
FU national funding agency of Germany (DLR); national funding agency of France (CNES); national funding agency of Italy (ASI); national funding agency of Spain (MEC); national funding agency of Sweden (SNSB); ESA Technical Directorate
NR 23
TC 147
Z9 154
U1 1
U2 31
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 15
PY 2015
VL 526
IS 7573
BP 402
EP +
DI 10.1038/nature15511
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200045
PM 26416730
DA 2026-03-09
ER

PT J
AU Iftikhar, Z
   Jezouin, S
   Anthore, A
   Gennser, U
   Parmentier, FD
   Cavanna, A
   Pierre, F
AF Iftikhar, Z.
   Jezouin, S.
   Anthore, A.
   Gennser, U.
   Parmentier, F. D.
   Cavanna, A.
   Pierre, F.
TI Two-channel Kondo effect and renormalization flow with macroscopic quantum charge states
SO NATURE
LA English
DT Article
ID single-electron transistor; coulomb-blockade; carbon nanotubes; channel; metals; conductance; systems; physics
AB Many-body correlations and macroscopic quantum behaviours are fascinating condensed matter problems. A powerful test-bed for the many-body concepts and methods is the Kondo effect(1,2), which entails the coupling of a quantum impurity to a continuum of states. It is central in highly correlated systems(3-5) and can be explored with tunable nanostructures(6-9). Although Kondo physics is usually associated with the hybridization of itinerant electrons with microscopic magnetic moments(10), theory predicts that it can arise whenever degenerate quantum states are coupled to a continuum(4,11-14). Here we demonstrate the previously elusive 'charge' Kondo effect in a hybrid metal-semiconductor implementation of a single-electron transistor, with a quantum pseudospin of 1/2 constituted by two degenerate macroscopic charge states of a metallic island(11,15-20). In contrast to other Kondo nanostructures, each conduction channel connecting the island to an electrode constitutes a distinct and fully tunable Kondo channel(11), thereby providing unprecedented access to the two-channel Kondo effect and a clear path to multi-channel Kondo physics(1,4,21,22). Using a weakly coupled probe, we find the renormalization flow, as temperature is reduced, of two Kondo channels competing to screen the charge pseudospin. This provides a direct view of how the predicted quantum phase transition develops across the symmetric quantum critical point(4,21). Detuning the pseudospin away from degeneracy, we demonstrate, on a fully characterized device, quantitative agreement with the predictions for the finite-temperature crossover from quantum criticality(17).
C1 [Iftikhar, Z.; Jezouin, S.; Anthore, A.; Gennser, U.; Parmentier, F. D.; Cavanna, A.; Pierre, F.] CNRS, Lab Photon & Nanostruct LPN, F-91460 Marcoussis, France.
   [Anthore, A.] Univ Paris Diderot, Sorbonne Paris Cite, LPN, F-91460 Marcoussis, France.
C3 Centre National de la Recherche Scientifique (CNRS); Universite Paris Cite
RP Pierre, F (corresponding author), CNRS, Lab Photon & Nanostruct LPN, F-91460 Marcoussis, France.
EM frederic.pierre@lpn.cnrs.fr
FU ERC [ERC-2010-StG-20091028, 259033]; French RENATECH network; European Research Council (ERC) [259033] Funding Source: European Research Council (ERC)
NR 39
TC 148
Z9 159
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 OCT 8
PY 2015
VL 526
IS 7572
BP 233
EP +
DI 10.1038/nature15384
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS9GV
UT WOS:000362399000042
PM 26450056
DA 2026-03-09
ER

PT J
AU Spranger, S
   Bao, RY
   Gajewski, TF
AF Spranger, Stefani
   Bao, Riyue
   Gajewski, Thomas F.
TI Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity
SO NATURE
LA English
DT Article
ID dendritic cells; mouse model; expression; reveals; immunotherapy; activation; therapy; tumors; subset; gene
AB Melanoma treatment is being revolutionized by the development of effective immunotherapeutic approaches(1,2). These strategies include blockade of immune-inhibitory receptors on activated T cells; for example, using monoclonal antibodies against CTLA-4, PD-1, and PD-L1 (refs 3-5). However, only a subset of patients responds to these treatments, and data suggest that therapeutic benefit is preferentially achieved in patients with a pre-existing T-cell response against their tumour, as evidenced by a baseline CD8(+) T-cell infiltration within the tumour microenvironment(6,7). Understanding the molecular mechanisms that underlie the presence or absence of a spontaneous anti-tumour T-cell response in subsets of cases, therefore, should enable the development of therapeutic solutions for patients lacking a T-cell infiltrate. Here we identify a melanoma-cell-intrinsic oncogenic pathway that contributes to a lack of T-cell infiltration in melanoma. Molecular analysis of human metastatic melanoma samples revealed a correlation between activation of the WNT/beta-catenin signalling pathway and absence of a T-cell gene expression signature. Using autochthonous mouse melanoma models(8,9) we identified the mechanism by which tumour-intrinsic active beta-catenin signalling results in T-cell exclusion and resistance to anti-PD-L1/anti-CTLA-4 monoclonal antibody therapy. Specific oncogenic signals, therefore, can mediate cancer immune evasion and resistance to immunotherapies, pointing to new candidate targets for immune potentiation.
C1 [Spranger, Stefani; Gajewski, Thomas F.] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA.
   [Bao, Riyue] Univ Chicago, Ctr Res Informat, Chicago, IL 60637 USA.
   [Gajewski, Thomas F.] Univ Chicago, Dept Med, Chicago, IL 60637 USA.
C3 University of Chicago; University of Chicago; University of Chicago
RP Gajewski, TF (corresponding author), Univ Chicago, Dept Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA.
EM tgajewsk@medicine.bsd.uchicago.edu
FU Team Science Award from the Melanoma Research Alliance; Translational Research Grant from the Cancer Research Institute; German Research Foundation
NR 43
TC 2250
Z9 2625
U1 12
U2 300
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 9
PY 2015
VL 523
IS 7559
BP 231
EP U261
DI 10.1038/nature14404
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM4ZO
UT WOS:000357695900039
PM 25970248
DA 2026-03-09
ER

PT J
AU Bai, XC
   Yan, CY
   Yang, GH
   Lu, PL
   Ma, D
   Sun, LF
   Zhou, R
   Scheres, SHW
   Shi, YG
AF Bai, Xiao-chen
   Yan, Chuangye
   Yang, Guanghui
   Lu, Peilong
   Ma, Dan
   Sun, Linfeng
   Zhou, Rui
   Scheres, Sjors H. W.
   Shi, Yigong
TI An atomic structure of human γ-secretase
SO NATURE
LA English
DT Article
ID terminal pal motif; alzheimers-disease; catalytic pore; beta-app; presenilin; nicastrin; protein; aph-1; cleavage; endoproteolysis
AB Dysfunction of the intramembrane protease gamma-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human gamma-secretase at 3.4 angstrom resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of c-secretase function.
C1 [Bai, Xiao-chen; Scheres, Sjors H. W.] MRC Lab Mol Biol, Cambridge CB2 0QH, England.
   [Yan, Chuangye; Yang, Guanghui; Lu, Peilong; Ma, Dan; Sun, Linfeng; Zhou, Rui; Shi, Yigong] Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Minist Educ Key Lab Prot Sci,Tsinghua Peking Join, Beijing 100084, Peoples R China.
C3 MRC Laboratory Molecular Biology; Tsinghua University
RP Bai, XC (corresponding author), MRC Lab Mol Biol, Cambridge Biomed Campus, Cambridge CB2 0QH, England.
EM xcbai@mrc-lmb.cam.ac.uk; scheres@mrc-lmb.cam.ac.uk; shi-lab@tsinghua.edu.cn
FU Ministry of Science and Technology [2014ZX09507003006]; National Natural Science Foundation of China [31130002, 31321062]; European Union Marie Curie Fellowship; UK Medical Research Council [MC_UP_A025_1013]; MRC [MC_UP_A025_1013] Funding Source: UKRI; Medical Research Council [MC_UP_A025_1013] Funding Source: researchfish
NR 52
TC 441
Z9 547
U1 7
U2 472
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 10
PY 2015
VL 525
IS 7568
BP 212
EP +
DI 10.1038/nature14892
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400030
PM 26280335
DA 2026-03-09
ER

PT J
AU Cohen, JD
   Meenehan, SM
   MacCabe, GS
   Gröblacher, S
   Safavi-Naeini, AH
   Marsili, F
   Shaw, MD
   Painter, O
AF Cohen, Justin D.
   Meenehan, Sean M.
   MacCabe, Gregory S.
   Groeblacher, Simon
   Safavi-Naeini, Amir H.
   Marsili, Francesco
   Shaw, Matthew D.
   Painter, Oskar
TI Phonon counting and intensity interferometry of a nanomechanical resonator
SO NATURE
LA English
DT Article
ID quantum; noise; laser
AB In optics, the ability to measure individual quanta of light (photons) enables a great many applications, ranging from dynamic imaging within living organisms(1) to secure quantum communication(2). Pioneering photon counting experiments, such as the intensity interferometry performed by Hanbury Brown and Twiss(3) to measure the angular width of visible stars, have played a critical role in our understanding of the full quantum nature of light(4). As with matter at the atomic scale, the laws of quantum mechanics also govern the properties of macroscopic mechanical objects, providing fundamental quantum limits to the sensitivity of mechanical sensors and transducers. Current research in cavity optomechanics seeks to use light to explore the quantum properties of mechanical systems ranging in size from kilogram-mass mirrors to nanoscale membranes(5), as well as to develop technologies for precision sensing(6) and quantum information processing(7,8). Here we use an optical probe and single-photon detection to study the acoustic emission and absorption processes in a silicon nanomechanical resonator, and perform a measurement similar to that used by Hanbury Brown and Twiss to measure correlations in the emitted phonons as the resonator undergoes a parametric instability formally equivalent to that of a laser(9). Owing to the cavity-enhanced coupling of light with mechanical motion, this effective phonon counting technique has a noise equivalent phonon sensitivity of 0.89 +/- 0.05. With straightforward improvements to this method, a variety of quantum state engineering tasks using mesoscopic mechanical resonators would be enabled(10), including the generation and heralding of single-phonon Fock states(11) and the quantum entanglement of remote mechanical elements(12,13).
C1 [Cohen, Justin D.; Meenehan, Sean M.; MacCabe, Gregory S.; Groeblacher, Simon; Painter, Oskar] CALTECH, Inst Quantum Informat & Matter, Pasadena, CA 91125 USA.
   [Cohen, Justin D.; Meenehan, Sean M.; MacCabe, Gregory S.; Groeblacher, Simon; Safavi-Naeini, Amir H.; Painter, Oskar] CALTECH, Thomas J Watson Senior Lab Appl Phys, Pasadena, CA 91125 USA.
   [Groeblacher, Simon] Univ Vienna, Fac Phys, Vienna Ctr Quantum Sci & Technol VCQ, A-1090 Vienna, Austria.
   [Safavi-Naeini, Amir H.] Stanford Univ, Edward L Ginzton Lab, Stanford, CA 94305 USA.
   [Marsili, Francesco; Shaw, Matthew D.] CALTECH, Jet Prop Lab, Pasadena, CA 91109 USA.
C3 California Institute of Technology; California Institute of Technology; University of Vienna; Stanford University; National Aeronautics & Space Administration (NASA); NASA Jet Propulsion Laboratory (JPL); California Institute of Technology
RP Painter, O (corresponding author), CALTECH, Inst Quantum Informat & Matter, Pasadena, CA 91125 USA.
EM opainter@caltech.edu
FU DARPA; Institute for Quantum Information and Matter; NSF Physics Frontiers Center; Gordon and Betty Moore Foundation; Kavli Nanoscience Institute at Caltech; NASA; NSERC; Marie Curie International Out-going Fellowship within the 7th European Community Framework Programme
NR 28
TC 185
Z9 218
U1 4
U2 149
PU NATURE PUBLISHING 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 23
PY 2015
VL 520
IS 7548
BP 522
EP 525
DI 10.1038/nature14349
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500038
PM 25903632
DA 2026-03-09
ER

PT J
AU Ketov, SV
   Sun, YH
   Nachum, S
   Lu, Z
   Checchi, A
   Beraldin, AR
   Bai, HY
   Wang, WH
   Louzguine-Luzgin, DV
   Carpenter, MA
   Greer, AL
AF Ketov, S. V.
   Sun, Y. H.
   Nachum, S.
   Lu, Z.
   Checchi, A.
   Beraldin, A. R.
   Bai, H. Y.
   Wang, W. H.
   Louzguine-Luzgin, D. V.
   Carpenter, M. A.
   Greer, A. L.
TI Rejuvenation of metallic glasses by non-affine thermal strain
SO NATURE
LA English
DT Article
ID deep cryogenic treatment; mechanical-property; structural relaxation; liquid; dynamics; strength
AB When a spatially uniform temperature change is imposed on a solid with more than one phase, or on a polycrystal of a single, non-cubic phase (showing anisotropic expansion-contraction), the resulting thermal strain is inhomogeneous (non-affine). Thermal cycling induces internal stresses, leading to structural and property changes that are usually deleterious. Glasses are the solids that form on cooling a liquid if crystallization is avoided-they might be considered the ultimate, uniform solids, without the microstructural features and defects associated with polycrystals. Here we explore the effects of cryogenic thermal cycling on glasses, specifically metallic glasses. We show that, contrary to the null effect expected from uniformity, thermal cycling induces rejuvenation, reaching less relaxed states of higher energy. We interpret these findings in the context that the dynamics in liquids become heterogeneous on cooling towards the glass transition(1), and that there may be consequent heterogeneities in the resulting glasses. For example, the vibrational dynamics of glassy silica at long wavelengths are those of an elastic continuum, but at wavelengths less than approximately three nanometres the vibrational dynamics are similar to those of a polycrystal with anisotropic grains(2). Thermal cycling of metallic glasses is easily applied, and gives improvements in compressive plasticity. The fact that such effects can be achieved is attributed to intrinsic non-uniformity of the glass structure, giving a non-uniform coefficient of thermal expansion. While metallic glasses may be particularly suitable for thermal cycling, the non-affine nature of strains in glasses in general deserves further study, whether they are induced by applied stresses or by temperature change.
C1 [Ketov, S. V.; Louzguine-Luzgin, D. V.; Greer, A. L.] Tohoku Univ, WPI Adv Inst Mat Res WPI AIMR, Aoba Ku, 2-1-1 Katahira, Sendai, Miyagi 9808577, Japan.
   [Sun, Y. H.; Nachum, S.; Checchi, A.; Beraldin, A. R.; Greer, A. L.] Univ Cambridge, Dept Mat Sci & Met, Cambridge CB3 0FS, England.
   [Lu, Z.; Bai, H. Y.; Wang, W. H.] Chinese Acad Sci, Inst Phys, Beijing 100080, Peoples R China.
   [Checchi, A.; Beraldin, A. R.] Univ Padua, Dept Management & Engn, I-36100 Vicenza, Italy.
   [Carpenter, M. A.] Univ Cambridge, Dept Earth Sci, Cambridge CB2 3EQ, England.
C3 Tohoku University; University of Cambridge; Chinese Academy of Sciences; Institute of Physics, CAS; University of Padua; University of Cambridge
RP Greer, AL (corresponding author), Tohoku Univ, WPI Adv Inst Mat Res WPI AIMR, Aoba Ku, 2-1-1 Katahira, Sendai, Miyagi 9808577, Japan.
EM alg13@cam.ac.uk
FU World Premier International Research Center Initiative (WPI), MEXT, Japan; NSF China; MOST 973 China; Engineering and the Engineering and Physical Sciences Research Council, UK (Materials World Network); China Scholarship Council (CSC); Engineering and Physical Sciences Research Council [EP/I036079/1, EP/I035404/1] Funding Source: researchfish; Natural Environment Research Council [NE/F017081/1, NE/B505738/1] Funding Source: researchfish; EPSRC [EP/I036079/1, EP/I035404/1] Funding Source: UKRI; NERC [NE/F017081/1] Funding Source: UKRI
NR 44
TC 688
Z9 750
U1 6
U2 735
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 13
PY 2015
VL 524
IS 7564
BP 200
EP +
DI 10.1038/nature14674
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900027
PM 26268190
DA 2026-03-09
ER

PT J
AU Baubec, T
   Colombo, DF
   Wirbelauer, C
   Schmidt, J
   Burger, L
   Krebs, AR
   Akalin, A
   Schübeler, D
AF Baubec, Tuncay
   Colombo, Daniele F.
   Wirbelauer, Christiane
   Schmidt, Juliane
   Burger, Lukas
   Krebs, Arnaud R.
   Akalin, Altuna
   Schuebeler, Dirk
TI Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation
SO NATURE
LA English
DT Article
ID embryonic stem-cells; de-novo methylation; pwwp domain; histone h3; wide; mutations; transcription; maintenance; landscapes; elongation
AB DNA methylation is an epigenetic modification associated with transcriptional repression of promoters and is essential for mammalian development. Establishment of DNA methylation is mediated by the de novo DNA methyltransferases DNMT3A and DNMT3B, whereas DNMT1 ensures maintenance of methylation through replication(1). Absence of these enzymes is lethal(2), and somatic mutations in these genes have been associated with several human diseases(3,4). How genomic DNA methylation patterns are regulated remains poorly understood, as the mechanisms that guide recruitment and activity of DNMTs in vivo are largely unknown. To gain insights into this matter we determined genomic binding and site-specific activity of the mammalian de novo DNA methyltransferases DNMT3A and DNMT3B. We show that both enzymes localize to methylated, CpG-dense regions in mouse stem cells, yet are excluded from active promoters and enhancers. By specifically measuring sites of de novo methylation, we observe that enzymatic activity reflects binding. De novo methylation increases with CpG density, yet is excluded from nudeosomes. Notably, we observed selective binding of DNMT3B to the bodies of transcribed genes, which leads to their preferential methylation. This targeting to transcribed sequences requires SETD2-mediated methylation of lysine 36 on histone H3 and a functional PWWP domain of DNMT3B. Together these findings reveal how sequence and chromatin cues guide de novo methyltransferase activity to ensure methylome integrity.
C1 [Baubec, Tuncay; Colombo, Daniele F.; Wirbelauer, Christiane; Schmidt, Juliane; Burger, Lukas; Krebs, Arnaud R.; Akalin, Altuna; Schuebeler, Dirk] Friedrich Miescher Inst Biomed Res, CH-4058 Basel, Switzerland.
   [Burger, Lukas] Swiss Inst Bioinformat, CH-4058 Basel, Switzerland.
   [Schuebeler, Dirk] Univ Basel, Fac Sci, CH-4001 Basel, Switzerland.
C3 Friedrich Miescher Institute for Biomedical Research; Swiss Institute of Bioinformatics; University of Basel
RP Baubec, T (corresponding author), Friedrich Miescher Inst Biomed Res, Maulbeerstr 66, CH-4058 Basel, Switzerland.
EM tuncay.baubec@fmi.ch; dirk@fmi.ch
FU Novartis Research Foundation; European Union (NoE "EpiGeneSys") [FP7- HEALTH-2010-257082]; European Union ("Blueprint" consortium) [FP7-282510]; European Research Council (EpiGePlas); SNF Sinergia program; Swiss initiative in Systems Biology (RTD Cell Plasticity); Boehringer Ingelheim Fonds; EMBO postdoctoral long-term fellowships
NR 51
TC 526
Z9 626
U1 5
U2 157
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 9
PY 2015
VL 520
IS 7546
BP 243
EP U278
DI 10.1038/nature14176
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CF3NA
UT WOS:000352454600044
PM 25607372
DA 2026-03-09
ER

PT J
AU Okubo, TS
   Mackevicius, EL
   Payne, HL
   Lynch, GF
   Fee, MS
AF Okubo, Tatsuo S.
   Mackevicius, Emily L.
   Payne, Hannah L.
   Lynch, Galen F.
   Fee, Michale S.
TI Growth and splitting of neural sequences in songbird vocal development
SO NATURE
LA English
DT Article
ID zebra finch; basal-ganglia; dependent plasticity; forebrain circuit; young songbirds; network model; birdsong; dynamics; generation; neurons
AB Neural sequences are a fundamental feature of brain dynamics underlying diverse behaviours, but the mechanisms by which they develop during learning remain unknown. Songbirds learn vocalizations composed of syllables; in adult birds, each syllable is produced by a different sequence of action potential bursts in the premotor cortical area HVC. Here we carried out recordings of large populations of HVC neurons in singing juvenile birds throughout learning to examine the emergence of neural sequences. Early in vocal development, HVC neurons begin producing rhythmic bursts, temporally locked to a 'prototype' syllable. Different neurons are active at different latencies relative to syllable onset to form a continuous sequence. Through development, as new syllables emerge from the prototype syllable, initially highly overlapping burst sequences become increasingly distinct. We propose a mechanistic model in which multiple neural sequences can emerge from the growth and splitting of a common precursor sequence.
C1 [Okubo, Tatsuo S.; Mackevicius, Emily L.; Lynch, Galen F.; Fee, Michale S.] MIT, Dept Brain & Cognit Sci, McGovern Inst Brain Res, Cambridge, MA 02139 USA.
   [Payne, Hannah L.] Stanford Univ, Dept Neurobiol, Stanford, CA 94305 USA.
C3 Massachusetts Institute of Technology (MIT); Stanford University
RP Fee, MS (corresponding author), MIT, Dept Brain & Cognit Sci, McGovern Inst Brain Res, E25-618, Cambridge, MA 02139 USA.
EM fee@mit.edu
FU NIH [R01DC009183, R25MH062204]; Mathers Foundation; Nakajima Foundation; Schoemaker Fellowship; Department of Defense (DoD) through the National Defense Science & Engineering Graduate Fellowship (NDSEG) Program; National Science Foundation (NSF) Graduate Research Fellowship Program [DGE-114747]; NSF Integrative Graduate Education and Research Traineeship [0801700]; National Institute of Mental Health [R25MH062204] Funding Source: NIH RePORTER; Direct For Education and Human Resources; Division Of Graduate Education [0801700] Funding Source: National Science Foundation
NR 80
TC 88
Z9 118
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 DEC 17
PY 2015
VL 528
IS 7582
BP 352
EP +
DI 10.1038/nature15741
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CY8SM
UT WOS:000366678600043
PM 26618871
DA 2026-03-09
ER

PT J
AU Do, R
   Stitziel, NO
   Won, HH
   Jorgensen, AB
   Duga, S
   Merlini, PA
   Kiezun, A
   Farrall, M
   Goel, A
   Zuk, O
   Guella, I
   Asselta, R
   Lange, LA
   Peloso, GM
   Auer, PL
   Girelli, D
   Martinelli, N
   Farlow, DN
   DePristo, MA
   Roberts, R
   Stewart, AFR
   Saleheen, D
   Danesh, J
   Epstein, SE
   Sivapalaratnam, S
   Hovingh, GK
   Kastelein, JJ
   Samani, NJ
   Schunkert, H
   Erdmann, J
   Shah, SH
   Kraus, WE
   Davies, R
   Nikpay, M
   Johansen, CT
   Wang, J
   Hegele, RA
   Hechter, E
   Marz, W
   Kleber, ME
   Huang, J
   Johnson, AD
   Li, MY
   Burke, GL
   Gross, M
   Liu, YM
   Assimes, TL
   Heiss, G
   Lange, EM
   Folsom, AR
   Taylor, HA
   Olivieri, O
   Hamsten, A
   Clarke, R
   Reilly, DF
   Yin, W
   Rivas, MA
   Donnelly, P
   Rossouw, JE
   Psaty, BM
   Herrington, DM
   Wilson, JG
   Rich, SS
   Bamshad, MJ
   Tracy, RP
   Cupples, LA
   Rader, DJ
   Reilly, MP
   Spertus, JA
   Cresci, S
   Hartiala, J
   Tang, WHW
   Hazen, SL
   Allayee, H
   Reiner, AP
   Carlson, CS
   Kooperberg, C
   Jackson, RD
   Boerwinkle, E
   Lander, ES
   Schwartz, SM
   Siscovick, DS
   McPherson, R
   Tybjaerg-Hansen, A
   Abecasis, GR
   Watkins, H
   Nickerson, DA
   Ardissino, D
   Sunyaev, SR
   O'Donnell, CJ
   Altshuler, D
   Gabriel, S
   Kathiresan, S
AF Do, Ron
   Stitziel, Nathan O.
   Won, Hong-Hee
   Jorgensen, Anders Berg
   Duga, Stefano
   Merlini, Pier Angelica
   Kiezun, Adam
   Farrall, Martin
   Goel, Anuj
   Zuk, Or
   Guella, Illaria
   Asselta, Rosanna
   Lange, Leslie A.
   Peloso, Gina M.
   Auer, Paul L.
   Girelli, Domenico
   Martinelli, Nicola
   Farlow, Deborah N.
   DePristo, Mark A.
   Roberts, Robert
   Stewart, Alexander F. R.
   Saleheen, Danish
   Danesh, John
   Epstein, Stephen E.
   Sivapalaratnam, Suthesh
   Hovingh, G. Kees
   Kastelein, John J.
   Samani, Nilesh J.
   Schunkert, Heribert
   Erdmann, Jeanette
   Shah, Svati H.
   Kraus, William E.
   Davies, Robert
   Nikpay, Majid
   Johansen, Christopher T.
   Wang, Jian
   Hegele, Robert A.
   Hechter, Eliana
   Marz, Winfried
   Kleber, Marcus E.
   Huang, Jie
   Johnson, Andrew D.
   Li, Mingyao
   Burke, Greg L.
   Gross, Myron
   Liu, Yongmei
   Assimes, Themistocles L.
   Heiss, Gerardo
   Lange, Ethan M.
   Folsom, Aaron R.
   Taylor, Herman A.
   Olivieri, Oliviero
   Hamsten, Anders
   Clarke, Robert
   Reilly, Dermot F.
   Yin, Wu
   Rivas, Manuel A.
   Donnelly, Peter
   Rossouw, Jacques E.
   Psaty, Bruce M.
   Herrington, David M.
   Wilson, James G.
   Rich, Stephen S.
   Bamshad, Michael J.
   Tracy, Russell P.
   Cupples, L. Adrienne
   Rader, Daniel J.
   Reilly, Muredach P.
   Spertus, John A.
   Cresci, Sharon
   Hartiala, Jaana
   Tang, W. H. Wilson
   Hazen, Stanley L.
   Allayee, Hooman
   Reiner, Alex P.
   Carlson, Christopher S.
   Kooperberg, Charles
   Jackson, Rebecca D.
   Boerwinkle, Eric
   Lander, Eric S.
   Schwartz, Stephen M.
   Siscovick, David S.
   McPherson, Ruth
   Tybjaerg-Hansen, Anne
   Abecasis, Goncalo R.
   Watkins, Hugh
   Nickerson, Deborah A.
   Ardissino, Diego
   Sunyaev, Shamil R.
   O'Donnell, Christopher J.
   Altshuler, David
   Gabriel, Stacey
   Kathiresan, Sekar
TI Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction
SO NATURE
LA English
DT Article
ID single nucleotide polymorphisms; genome-wide association; coronary-heart-disease; mutations; receptor; cholesterol; susceptibility; triglycerides; discovery; variants
AB Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance(1,2). When MI occurs early in life, genetic inheritance is a major component to risk(1). Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk inindividual families(3-8), whereas common variants at more than 45 loci have been associated with MI risk in the population(9-15). Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (<= 50 years inmales and <= 60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol(16). Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase(15,17) and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.
C1 [Do, Ron; Won, Hong-Hee; Peloso, Gina M.; Altshuler, David; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.
   [Do, Ron; Won, Hong-Hee; Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.
   [Do, Ron; Won, Hong-Hee; Peloso, Gina M.; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA.
   [Do, Ron; Won, Hong-Hee; Kiezun, Adam; Zuk, Or; Peloso, Gina M.; Farlow, Deborah N.; DePristo, Mark A.; Hechter, Eliana; Folsom, Aaron R.; Lander, Eric S.; Sunyaev, Shamil R.; Altshuler, David; Gabriel, Stacey; Kathiresan, Sekar] Broad Inst, Cambridge Ctr 7, Program Med & Populat Genet, Cambridge, MA 02142 USA.
   [Stitziel, Nathan O.; Cresci, Sharon] Washington Univ, Div Cardiovasc, Dept Med, Sch Med, St Louis, MO 63110 USA.
   [Stitziel, Nathan O.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO 63110 USA.
   [Jorgensen, Anders Berg; Tybjaerg-Hansen, Anne] Copenhagen Univ Hosp, Rigshosp, Mol Genet Sect, Dept Clin Biochem KB3011, DK-1165 Copenhagen, Denmark.
   [Jorgensen, Anders Berg; Tybjaerg-Hansen, Anne] Univ Copenhagen, Fac Hlth Sci, DK-1165 Copenhagen, Denmark.
   [Duga, Stefano; Guella, Illaria; Asselta, Rosanna] Univ Milan, Dipartimento Biotecnol Med & Med Traslaz, I-20122 Milan, Italy.
   [Merlini, Pier Angelica] Osped Niguarda Ca Granda, Div Cardiol, I-20162 Milan, Italy.
   [Farrall, Martin; Goel, Anuj; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford OX1 2J, England.
   [Lange, Leslie A.; Lange, Ethan M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.
   [Auer, Paul L.; Folsom, Aaron R.; Reiner, Alex P.; Carlson, Christopher S.; Kooperberg, Charles; Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA.
   [Girelli, Domenico; Martinelli, Nicola; Olivieri, Oliviero] Univ Verona, Dept Med, Sch Med, I-37129 Verona, Italy.
   [Roberts, Robert; Stewart, Alexander F. R.] Univ Ottawa, Inst Heart, John & Jennifer Ruddy Canadian Cardiovasc Genet C, Ottawa, ON K1Y 4W7, Canada.
   [Saleheen, Danish; Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB2 1TN, England.
   [Epstein, Stephen E.] MedStar Hlth Res Inst, Cardiovasc Res Inst, Hyattsville, MD 20782 USA.
   [Sivapalaratnam, Suthesh; Hovingh, G. Kees; Kastelein, John J.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands.
   [Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England.
   [Samani, Nilesh J.] Glenfield Gen Hosp, Leicester NIHR Biomed Res Unit Cardiovasc Dis, Leicester LE3 9QP, Leics, England.
   [Schunkert, Heribert] Tech Univ Munich, DZHK German Res Ctr Cardiovasc Res, Munich Heart Alliance, Deutsch Herzzentrum Munchen, D-13347 Berlin, Germany.
   [Erdmann, Jeanette] Med Univ Lubeck, Med Klin 2, D-23562 Lubeck, Germany.
   [Shah, Svati H.] Duke Univ, Ctr Human Genet, Durham, NC 27708 USA.
   [Shah, Svati H.; Kraus, William E.] Duke Univ, Sch Med, Dept Cardiol, Durham, NC 27708 USA.
   [Shah, Svati H.; Kraus, William E.] Duke Univ, Sch Med, Ctr Genom Med, Durham, NC 27708 USA.
   [Davies, Robert; Nikpay, Majid; McPherson, Ruth] Univ Ottawa, Inst Heart, Div Cardiol, Ottawa, ON K1Y 4W7, Canada.
   [Johansen, Christopher T.; Wang, Jian; Hegele, Robert A.] Univ Western Ontario, Dept Biochem, Schulich Sch Med & Dent, Robarts Res Inst, London, ON N6A 3K7, Canada.
   [Hegele, Robert A.] Univ Western Ontario, Dept Med, Schulich Sch Med & Dent, Robarts Res Inst, London, ON N6A 3K7, Canada.
   [Marz, Winfried; Kleber, Marcus E.] Heidelberg Univ, Med Fac Mannheim, Mannheim Inst Publ Hlth Social & Prevent Med, D-68167 Mannheim, Germany.
   [Marz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, A-8036 Graz, Austria.
   [Marz, Winfried] Synlab Acad, D-68259 Mannheim, Germany.
   [Huang, Jie; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA.
   [Johnson, Andrew D.] NHLBI, Ctr Populat Studies, Framingham Heart Study, Framingham, MA 01702 USA.
   [Li, Mingyao] Univ Penn, Dept Biostat & Epidemiol, Sch Med, Philadelphia, PA 19104 USA.
   [Burke, Greg L.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35233 USA.
   [Gross, Myron] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA.
   [Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27106 USA.
   [Assimes, Themistocles L.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA.
   [Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA.
   [Lange, Ethan M.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA.
   [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA.
   [Taylor, Herman A.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA.
   [Hamsten, Anders] Karolinska Inst, Dept Med, Atherosclerosis Res Unit, S-17177 Stockholm, Sweden.
   [Hamsten, Anders] Karolinska Inst, Ctr Mol Med, S-17177 Stockholm, Sweden.
   [Clarke, Robert] Univ Oxford, Clin Trial Serv Unit, Oxford OX1 2JD, England.
   [Clarke, Robert] Univ Oxford, Epidemiol Studies Unit, Oxford OX1 2JD, England.
   [Reilly, Dermot F.; Yin, Wu] Merck Sharp & Dohme Corp, Rahway, NJ 08889 USA.
   [Rivas, Manuel A.; Donnelly, Peter; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX1 2JD, England.
   [Donnelly, Peter] Univ Oxford, Dept Stat, Oxford OX1 2JD, England.
   [Rossouw, Jacques E.] NHLBI, Bethesda, MD 20824 USA.
   [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA.
   [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98195 USA.
   [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98195 USA.
   [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA.
   [Herrington, David M.] Wake Forest Sch Med, Sect Cardiol & Publ Hlth Sci, Winston Salem, NC 27106 USA.
   [Wilson, James G.] Jackson State Univ, Med Ctr, Univ Mississippi, Jackson Heart Study, Jackson, MS 39217 USA.
   [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22904 USA.
   [Bamshad, Michael J.] Univ Washington, Dept Pediat, Div Med Genet, Seattle, WA 98195 USA.
   [Bamshad, Michael J.] Seattle Childrens Hosp, Seattle, WA 98105 USA.
   [Bamshad, Michael J.; Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.
   [Tracy, Russell P.] Univ Vermont, Dept Biochem, Burlington, VT 05405 USA.
   [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.
   [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA.
   [Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA.
   [Spertus, John A.] Univ Missouri, St Lukes Mid Amer Heart Inst, Kansas City, MO 64111 USA.
   [Cresci, Sharon] Washington Univ, Dept Genet, St Louis, MO 63130 USA.
   [Hartiala, Jaana; Allayee, Hooman] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA.
   [Hartiala, Jaana; Allayee, Hooman] Univ So Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA 90033 USA.
   [Tang, W. H. Wilson; Hazen, Stanley L.] Cleveland Clin, Cleveland, OH 44195 USA.
   [Reiner, Alex P.; Schwartz, Stephen M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.
   [Jackson, Rebecca D.] Ohio State Univ, Columbus, OH 43210 USA.
   [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA.
   [Siscovick, David S.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA.
   [Tybjaerg-Hansen, Anne] Univ Copenhagen, Fac Hlth & Med Sci, DK-2200 Copenhagen N, Denmark.
   [Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MO 48109 USA.
   [Ardissino, Diego] Parma Hosp, Dept Cardiol, I-43100 Parma, Italy.
   [Sunyaev, Shamil R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 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; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Washington University (WUSTL); Washington University (WUSTL); University of Copenhagen; Copenhagen University Hospital; Rigshospitalet; University of Copenhagen; University of Milan; IRCCS Ca Granda Ospedale Maggiore Policlinico; Ospedale Niguarda Ca' Granda; University of Oxford; Wellcome Centre for Human Genetics; University of North Carolina; University of North Carolina Chapel Hill; Fred Hutchinson Cancer Center; University of Verona; University of Ottawa; University of Ottawa Heart Institute; University of Cambridge; MedStar Health Research Institute; University of Amsterdam; Academic Medical Center Amsterdam; University of Leicester; University Hospitals of Leicester NHS Trust; University of Leicester; Glenfield Hospital; Munich Heart Alliance; German Centre for Cardiovascular Research; German Heart Centre Munich; Technical University of Munich; University of Lubeck; Duke University; Duke University; Duke University; University of Ottawa; University of Ottawa Heart Institute; Western University (University of Western Ontario); University Western Ontario Hospital; Western University (University of Western Ontario); University Western Ontario Hospital; Ruprecht Karls University Heidelberg; Medical University of Graz; SYNLAB Group; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI); Framingham Heart Study; Framingham Heart Study; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI); University of Pennsylvania; University of Alabama System; University of Alabama Birmingham; University of Minnesota System; University of Minnesota Twin Cities; Wake Forest University; Wake Forest Baptist Medical Center; Stanford University; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of Minnesota System; University of Minnesota Twin Cities; University of Mississippi Medical Center; University of Mississippi; Karolinska Institutet; Karolinska Institutet; University of Oxford; University of Oxford; Merck & Company; University of Oxford; Wellcome Centre for Human Genetics; University of Oxford; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI); University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Group Health Cooperative; Wake Forest University; University of Mississippi Medical Center; Jackson State University; University of Mississippi; University of Virginia; University of Washington; University of Washington Seattle; Seattle Children's Hospital; University of Washington; University of Washington Seattle; University of Vermont; Boston University; University of Pennsylvania; University of Pennsylvania; Saint Luke's Mid America Heart Institute; University of Missouri System; University of Missouri Kansas City; Washington University (WUSTL); University of Southern California; University of Southern California; Cleveland Clinic Foundation; University of Washington; University of Washington Seattle; University System of Ohio; Ohio State University; University of Texas System; University of Texas Health Science Center Houston; University of Washington; University of Washington Seattle; University of Copenhagen; University of Parma; University Hospital of Parma; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital
RP Kathiresan, S (corresponding author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.
EM skathiresan@partners.org
FU National Heart, Lung, and Blood Institute (NHLBI); National Human Genome Research Institute (NHGRI) of the US National Institutes of Health (NIH); NHLBI [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926, T32HL007604, T32HL007208]; NHGRI [5U54HG003067-11]; NIH [P01 HL076491, P01 HL098055]; Massachusetts General Hospital (MGH); Howard Goodman Fellowship from MGH; Donovan Family Foundation [R01HL107816]; Fondation Leducq; Canadian Institutes of Health Research; NIH/NHLBI [K08HL114642]; Foundation for Barnes-Jewish Hospital;  [RFPS-2007-3-644382]; British Heart Foundation [RG/08/014/24067] Funding Source: researchfish; Medical Research Council [MR/L003120/1] Funding Source: researchfish; National Institute for Health Research [NF-SI-0512-10165, NF-SI-0611-10170, NF-SI-0508-10235] Funding Source: researchfish; Parkinson&apos;s UK [G-0907] Funding Source: researchfish; Wellcome Trust [095552/Z/11/Z] Funding Source: researchfish; MRC [MR/L003120/1] Funding Source: UKRI; National Heart Lung and Blood Institute [T32HL007604, ZIAHL006170, T32HL007208] Funding Source: NIH RePORTER; National Institute on Aging [R01NS017950] Funding Source: NIH RePORTER
NR 48
TC 508
Z9 577
U1 1
U2 91
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 5
PY 2015
VL 518
IS 7537
BP 102
EP +
DI 10.1038/nature13917
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7LE
UT WOS:000349098000040
PM 25487149
DA 2026-03-09
ER

PT J
AU Pipoly, I
   Bókony, V
   Kirkpatrick, M
   Donald, PF
   Székely, T
   Liker, A
AF Pipoly, Ivett
   Bokony, Veronika
   Kirkpatrick, Mark
   Donald, Paul F.
   Szekely, Tomas
   Liker, Andras
TI The genetic sex-determination system predicts adult sex ratios in tetrapods
SO NATURE
LA English
DT Article
ID evolution; populations; selection; birds; phylogeny; conflict; men; too
AB The adult sex ratio (ASR) has critical effects on behaviour, ecology and population dynamics(1,2), but the causes of variation in ASRs are unclear(3,4). Here we assess whether the type of genetic sex determination influences the ASR using data from 344 species in 117 families of tetrapods. We show that taxa with female heterogamety have a significantly more male-biased ASR (proportion of males: 0.55 +/- 0.01 (mean +/- s.e.m.)) than taxa with male heterogamety (0.43 +/- 0.01). The genetic sex-determination system explains 24% of interspecific variation in ASRs in amphibians and 36% in reptiles. We consider several genetic factors that could contribute to this pattern, including meiotic drive and sex-linked deleterious mutations, but further work is needed to quantify their effects. Regardless of the mechanism, the effects of the genetic sex-determination system on the adult sex ratio are likely to have profound effects on the demography and social behaviour of tetrapods.
C1 [Pipoly, Ivett; Bokony, Veronika; Liker, Andras] Univ Pannonia, Dept Limnol, H-8201 Veszprem, Hungary.
   [Bokony, Veronika] Hungarian Acad Sci, Ctr Agr Res, Inst Plant Protect, Lendulet Evolutionary Ecol Res Grp, H-1022 Budapest, Hungary.
   [Kirkpatrick, Mark] Univ Texas Austin, Dept Integrat Biol, Austin, TX 78712 USA.
   [Donald, Paul F.] Royal Soc Protect Birds, RSPB Ctr Conservat Sci, Sandy SG19 2DL, Beds, England.
   [Donald, Paul F.] Univ Cambridge, Dept Zool, Conservat Sci Grp, Cambridge CB2 3EJ, England.
   [Szekely, Tomas] Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath BA2 7AY, Avon, England.
C3 University of Pannonia; HUN-REN; HUN-REN Centre for Agricultural Research; Plant Protection Institute - HAS; Hungarian Academy of Sciences; University of Texas System; University of Texas Austin; Royal Society for Protection of Birds; University of Cambridge; University of Bath
RP Liker, A (corresponding author), Univ Pannonia, Dept Limnol, Pf 158, H-8201 Veszprem, Hungary.
EM aliker@almos.uni-pannon.hu
FU European Union [TAMOP-4.2.2.B-15/1/KONV-2015-0004]; US National Science Foundation [DEB-0819901]; Humboldt Award; MTA-DE 'Lendulet' grant; Hungarian Scientific Research Fund [OTKA K112838]; Marie Curie Intra-European Fellowship
NR 30
TC 96
Z9 110
U1 0
U2 97
PU NATURE PUBLISHING 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 5
PY 2015
VL 527
IS 7576
BP 91
EP 94
DI 10.1038/nature15380
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV4XV
UT WOS:000364270700049
PM 26444239
DA 2026-03-09
ER

PT J
AU Gundem, G
   Van Loo, P
   Kremeyer, B
   Alexandrov, LB
   Tubio, JMC
   Papaemmanuil, E
   Brewer, DS
   Kallio, HML
   Hoegnas, G
   Annala, M
   Kivinummi, K
   Goody, V
   Latimer, C
   O'Meara, S
   Dawson, KJ
   Isaacs, W
   Emmert-Buck, MR
   Nykter, M
   Foster, C
   Kote-Jarai, Z
   Easton, D
   Whitaker, HC
   Neal, DE
   Cooper, CS
   Eeles, RA
   Visakorpi, T
   Campbell, PJ
   McDermott, U
   Wedge, DC
   Bova, GS
AF Gundem, Gunes
   Van Loo, Peter
   Kremeyer, Barbara
   Alexandrov, Ludmil B.
   Tubio, Jose M. C.
   Papaemmanuil, Elli
   Brewer, Daniel S.
   Kallio, Heini M. L.
   Hoegnas, Gunilla
   Annala, Matti
   Kivinummi, Kati
   Goody, Victoria
   Latimer, Calli
   O'Meara, Sarah
   Dawson, Kevin J.
   Isaacs, William
   Emmert-Buck, Michael R.
   Nykter, Matti
   Foster, Christopher
   Kote-Jarai, Zsofia
   Easton, Douglas
   Whitaker, Hayley C.
   Neal, David E.
   Cooper, Colin S.
   Eeles, Rosalind A.
   Visakorpi, Tapio
   Campbell, Peter J.
   McDermott, Ultan
   Wedge, David C.
   Bova, G. Steven
TI The evolutionary history of lethal metastatic prostate cancer
SO NATURE
LA English
DT Article
ID androgen deprivation therapy; pancreatic-cancer; clonal evolution; heterogeneity; progression; resistance; pathogenesis; mutations; signature; patterns
AB Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subdones within a single primary tumour(1-4). This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths(5). However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported(6-8), recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subdonee(9,10). Here we sought definitive evidence for the existence of polydonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgendeprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subdonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.
C1 [Gundem, Gunes; Van Loo, Peter; Kremeyer, Barbara; Alexandrov, Ludmil B.; Tubio, Jose M. C.; Papaemmanuil, Elli; Goody, Victoria; Latimer, Calli; O'Meara, Sarah; Dawson, Kevin J.; Campbell, Peter J.; McDermott, Ultan; Wedge, David C.] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England.
   [Van Loo, Peter] Katholieke Univ Leuven, Dept Human Genet, B-3000 Leuven, Belgium.
   [Van Loo, Peter] Canc Res UK London Res Inst, London WC2A 3LY, England.
   [Brewer, Daniel S.; Cooper, Colin S.] Univ E Anglia, Norwich Med Sch, Norwich NR4 7TJ, Norfolk, England.
   [Brewer, Daniel S.; Cooper, Colin S.] Univ E Anglia, Dept Biol Sci, Norwich NR4 7TJ, Norfolk, England.
   [Brewer, Daniel S.] Genome Anal Ctr, Norwich NR4 7UH, Norfolk, England.
   [Kallio, Heini M. L.; Hoegnas, Gunilla; Annala, Matti; Kivinummi, Kati; Nykter, Matti; Visakorpi, Tapio; Bova, G. Steven] Univ Tampere, BioMediTech, Inst Biosci & Med Technol, FI-33520 Tampere, Finland.
   [Kallio, Heini M. L.; Hoegnas, Gunilla; Annala, Matti; Kivinummi, Kati; Nykter, Matti; Visakorpi, Tapio; Bova, G. Steven] Tampere Univ Hosp, Fimlab Labs, FI-33520 Tampere, Finland.
   [Isaacs, William] Johns Hopkins Sch Med, James Buchanan Brady Urol Inst, Baltimore, MD 21287 USA.
   [Emmert-Buck, Michael R.] NCI, Lab Pathol, NIH, Bethesda, MD 20892 USA.
   [Foster, Christopher] Univ Liverpool, London WC1E 6JA, England.
   [Foster, Christopher] HCA Pathol Labs, London WC1E 6JA, England.
   [Kote-Jarai, Zsofia; Cooper, Colin S.; Eeles, Rosalind A.] Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England.
   [Easton, Douglas] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England.
   [Whitaker, Hayley C.; Neal, David E.] Canc Res UK Cambridge Inst, Urooncol Res Grp, Cambridge CB2 0RE, England.
   [Neal, David E.] Univ Cambridge, Addenbrookes Hosp, Dept Surg Oncol, Cambridge CB2 0QQ, England.
   [Eeles, Rosalind A.] Royal Marsden NHS Fdn Trust, London SW3 6JJ, England.
   [Eeles, Rosalind A.] Royal Marsden NHS Fdn Trust, Sutton SM2 5PT, Surrey, England.
C3 Wellcome Trust Sanger Institute; KU Leuven; Cancer Research UK; University of East Anglia; University of East Anglia; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); Earlham Institute; Tampere University; Tampere University; Tampere University Hospital; Johns Hopkins University; Johns Hopkins Medicine; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); University of Liverpool; University of London; Institute of Cancer Research - UK; Royal Marsden NHS Foundation Trust; University of Cambridge; CRUK Cambridge Institute; Cancer Research UK; University of Cambridge; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; Royal Marsden NHS Foundation Trust; Royal Marsden NHS Foundation Trust
RP Bova, GS (corresponding author), Univ Tampere, BioMediTech, Inst Biosci & Med Technol, FI-33520 Tampere, Finland.
EM um1@sanger.ac.uk; dw9@sanger.ac.uk; g.steven.bova@uta.fi
FU Cancer Research UK; NIH NCI Intramural Program; Academy of Finland; Cancer Society of Finland; PELICAN Autopsy Study family members and friends; John and Kathe Dyson; US National Cancer Institute [CA92234]; American Cancer Society; Johns Hopkins University Department of Pathology; Women's Board of Johns Hopkins Hospital; Grove Foundation; Association for the Cure of Cancer of the Prostate; American Foundation for Urologic Disease; Bob Champion Cancer Trust; Research Foundation - Flanders (FWO) [FWO-G.0687.12]; Cancer Research UK [15007, 17528] Funding Source: researchfish; The Francis Crick Institute [10202] Funding Source: researchfish; Versus Arthritis; Cancer Research UK [20406] Funding Source: researchfish
NR 29
TC 1137
Z9 1270
U1 1
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 APR 16
PY 2015
VL 520
IS 7547
BP 353
EP +
DI 10.1038/nature14347
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG0RI
UT WOS:000352974200040
PM 25830880
DA 2026-03-09
ER

PT J
AU Gavelis, GS
   Hayakawa, S
   White, RA
   Gojobori, T
   Suttle, CA
   Keeling, PJ
   Leander, BS
AF Gavelis, Gregory S.
   Hayakawa, Shiho
   White, Richard A., III
   Gojobori, Takashi
   Suttle, Curtis A.
   Keeling, Patrick J.
   Leander, Brian S.
TI Eye-like ocelloids are built from different endosymbiotically acquired components
SO NATURE
LA English
DT Article
ID dinoflagellate; phylogeny; evolution; erythropsidinium; warnowiidae; alignment; light; fine; gen.; nov
AB Multicellularity is often considered a prerequisite for morphological complexity, as seen in the camera-type eyes found in several groups of animals. A notable exception exists in single-celled eukaryotes called dinoflagellates, some of which have an eye-like 'ocelloid' consisting of subcellular analogues to a cornea, lens, iris, and retina(1). These planktonic cells are uncultivated and rarely encountered in environmental samples, obscuring the function and evolutionary origin of the ocelloid. Here we show, using a combination of electron microscopy, tomography, isolated-organelle genomics, and single-cell genomics, that ocelloids are built from pre-existing organelles, including a cornea-like layer made of mitochondria and a retinal body made of anastomosing plastids. We find that the retinal body forms the central core of a network of peridinin-type plastids, which in dinoflagellates and their relatives originated through an ancient endosymbiosis with a red alga(2). As such, the ocelloid is a chimaeric structure, incorporating organelles with different endosymbiotic histories. The anatomical complexity of single-celled organisms may be limited by the components available for differentiation, but the ocelloid shows that preexisting organelles can be assembled into a structure so complex that it was initially mistaken for a multicellular eye(3). Although mitochondria and plastids are acknowledged chiefly for their metabolic roles, they can also be building blocks for greater structural complexity.
C1 [Gavelis, Gregory S.; Hayakawa, Shiho; Leander, Brian S.] Univ British Columbia, Dept Zool, Vancouver, BC V6T 1Z4, Canada.
   [Hayakawa, Shiho; Suttle, Curtis A.; Keeling, Patrick J.; Leander, Brian S.] Univ British Columbia, Dept Bot, Vancouver, BC V6T 1Z4, Canada.
   [Hayakawa, Shiho; Gojobori, Takashi] Natl Inst Genet, Ctr Informat Biol, Mishima, Shizuoka 4118540, Japan.
   [White, Richard A., III; Suttle, Curtis A.] Univ British Columbia, Dept Microbiol & Immunol, Vancouver, BC V6T 1Z4, Canada.
   [Gojobori, Takashi] King Abdullah Univ Sci & Technol, Computat Biosci Res Ctr, Thuwal 239556900, Saudi Arabia.
   [Suttle, Curtis A.] Univ British Columbia, Dept Earth Ocean & Atmospher Sci, Vancouver, BC V6T 1Z4, Canada.
   [Suttle, Curtis A.; Keeling, Patrick J.; Leander, Brian S.] Canadian Inst Adv Res, Toronto, ON M5G 1Z8, Canada.
C3 University of British Columbia; University of British Columbia; Research Organization of Information & Systems (ROIS); National Institute of Genetics (NIG) - Japan; University of British Columbia; King Abdullah University of Science & Technology; University of British Columbia; Canadian Institute for Advanced Research (CIFAR)
RP Gavelis, GS (corresponding author), Univ British Columbia, Dept Zool, 6270 Univ Blvd, Vancouver, BC V6T 1Z4, Canada.
EM zoark0@gmail.com
FU Natural Sciences and Engineering Research Council of Canada [2014-05258, 227301]; Tula Foundation (Centre for Microbial Diversity and Evolution)
NR 31
TC 68
Z9 73
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 JUL 9
PY 2015
VL 523
IS 7559
BP 204
EP U155
DI 10.1038/nature14593
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM4ZO
UT WOS:000357695900033
PM 26131935
DA 2026-03-09
ER

PT J
AU Blaho, VA
   Galvani, S
   Engelbrecht, E
   Liu, C
   Swendeman, SL
   Kono, M
   Proia, RL
   Steinman, L
   Han, MH
   Hla, T
AF Blaho, Victoria A.
   Galvani, Sylvain
   Engelbrecht, Eric
   Liu, Catherine
   Swendeman, Steven L.
   Kono, Mari
   Proia, Richard L.
   Steinman, Lawrence
   Han, May H.
   Hla, Timothy
TI HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation
SO NATURE
LA English
DT Article
ID sphingosine 1-phosphate receptor; hematopoietic stem-cells; serum-lipid profiles; lymphocyte egress; apolipoprotein-m; cholesterol efflux; progenitor; s1p(1); expression; blood
AB Lipid mediators influence immunity in myriad ways. For example, circulating sphingosine-1-phosphate (S1P) is a key regulator of lymphocyte egress(1,2). Although the majority of plasma S1P is bound to apolipoprotein M (ApoM) in the high-density lipoprotein (HDL) particle(3), the immunological functions of the ApoM-S1P complex are unknown. Here we show that ApoM-S1P is dispensable for lymphocyte trafficking yet restrains lymphopoiesis by activating the S1P1 receptor on bone marrow lymphocyte progenitors. Mice that lacked ApoM (Apom(-/-)) had increased proliferation of Lin(-) Sca-1(+) cKit(+) haematopoietic progenitor cells (LSKs) and common lymphoid progenitors (CLPs) in bone marrow. Pharmacological activation or genetic overexpression of S1P(1) suppressed LSK and CLP cell proliferation in vivo. ApoM was stably associated with bone marrow CLPs, which showed active S1P(1) signalling in vivo(4). Moreover, ApoM-bound S1P, but not albumin-bound S1P, inhibited lymphopoiesis in vitro. Upon immune stimulation, Apom(-/-) mice developed more severe experimental autoimmune encephalomyelitis5, characterized by increased lymphocytes in the central nervous system and breakdown of the blood-brain barrier. Thus, the ApoM-S1P-S1P(1) signalling axis restrains the lymphocyte compartment and, subsequently, adaptive immune responses. Unique biological functions imparted by specific S1P chaperones could be exploited for novel therapeutic opportunities.
C1 [Blaho, Victoria A.; Galvani, Sylvain; Engelbrecht, Eric; Liu, Catherine; Swendeman, Steven L.; Hla, Timothy] Cornell Univ, Weill Med Coll, Dept Pathol & Lab Med, Ctr Vasc Biol, New York, NY 10065 USA.
   [Blaho, Victoria A.; Hla, Timothy] Cornell Univ, Weill Med Coll, Brain & Mind Res Inst, New York, NY 10065 USA.
   [Kono, Mari; Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA.
   [Steinman, Lawrence; Han, May H.] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA.
C3 Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); Stanford University
RP Hla, T (corresponding author), Cornell Univ, Weill Med Coll, Dept Pathol & Lab Med, Ctr Vasc Biol, New York, NY 10065 USA.
EM tih2002@med.cornell.edu
FU National Institutes of Health (NIH) [F32 CA14211]; New York Stem Cell Foundation [C026878]; NIH, Fondation Leducq [HL67330, HL70694, HL89934]; Intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH; Fondation Leducq; Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina [P30 CA138313]; Lipidomics Core in the SC Lipidomics and Pathobiology COBRE [P20 RR017677]; National Cancer Institute [P30CA138313] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [ZIADK056015, ZIADK056018, ZIADK056016, ZIADK056014] Funding Source: NIH RePORTER
NR 48
TC 199
Z9 215
U1 0
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 JUL 16
PY 2015
VL 523
IS 7560
BP 342
EP +
DI 10.1038/nature14462
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM8KY
UT WOS:000357950900041
PM 26053123
DA 2026-03-09
ER

PT J
AU Kim, J
   Ishiguro, KI
   Nambu, A
   Akiyoshi, B
   Yokobayashi, S
   Kagami, A
   Ishiguro, T
   Pendas, AM
   Takeda, N
   Sakakibara, Y
   Kitajima, TS
   Tanno, Y
   Sakuno, T
   Watanabe, Y
AF Kim, Jihye
   Ishiguro, Kei-ichiro
   Nambu, Aya
   Akiyoshi, Bungo
   Yokobayashi, Shihori
   Kagami, Ayano
   Ishiguro, Tadashi
   Pendas, Alberto M.
   Takeda, Naoki
   Sakakibara, Yogo
   Kitajima, Tomoya S.
   Tanno, Yuji
   Sakuno, Takeshi
   Watanabe, Yoshinori
TI Meikin is a conserved regulator of meiosis-I-specific kinetochore function
SO NATURE
LA English
DT Article
ID single-division meiosis; protein phosphatase 2a; centromeric cohesion; homologous chromosm; monopolar attachment; mammalian oocytes; kinase cdc5; aurora-b; cleavage; segregation
AB The kinetochore is the crucial apparatus regulating chromosome segregation in mitosis and meiosis. Particularly in meiosis I, unlike in mitosis, sister kinetochores are captured by microtubules emanating from the same spindle pole (mono-orientation) and centromeric cohesion mediated by cohesin is protected in the following anaphase. Although meiotic kinetochore factors have been identified only in budding and fission yeasts, these molecules and their functions are thought to have diverged earlier. Therefore, a conserved mechanism for meiotic kinetochore regulation remains elusive. Here we have identified in mouse a meiosis-specific kinetochore factor that wetermed MEIKIN, which functions in meiosis I but not in meiosis II or mitosis. MEIKIN plays a crucial role in both mono-orientation and centromeric cohesion protection, partly by stabilizing the localization of the cohesin protector shugoshin. These functions are mediated mainly by the activity of Polo-like kinase PLK1, which is enriched to kinetochores in a MEIKIN-dependent manner. Our integrative analysis indicates that the long-awaited key regulator of meiotic kinetochore function is Meikin, which is conserved from yeasts to humans.
C1 [Kim, Jihye; Ishiguro, Kei-ichiro; Nambu, Aya; Akiyoshi, Bungo; Yokobayashi, Shihori; Kagami, Ayano; Ishiguro, Tadashi; Tanno, Yuji; Sakuno, Takeshi; Watanabe, Yoshinori] Univ Tokyo, Inst Mol & Cellular Biosci, Lab Chromosome Dynam, Tokyo 1130032, Japan.
   [Pendas, Alberto M.] CSIC, USAL, Inst Biol Mol & Celular Canc, Salamanca 37007, Spain.
   [Takeda, Naoki] Kumamoto Univ, Ctr Anim Resources & Dev, Kumamoto 8600811, Japan.
   [Sakakibara, Yogo; Kitajima, Tomoya S.] RIKEN Ctr Dev Biol, Lab Chromosome Segregat, Chuo Ku, Kobe, Hyogo 6500047, Japan.
C3 University of Tokyo; University of Salamanca; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC-USAL - Instituto de Biologia Molecular y Celular del Cancer de Salamanca (IBMCC); Kumamoto University; RIKEN
RP Watanabe, Y (corresponding author), Univ Tokyo, Inst Mol & Cellular Biosci, Lab Chromosome Dynam, 1-1-1Yayoi, Tokyo 1130032, Japan.
EM ywatanab@iam.u-tokyo.ac.jp
FU JSPS Research Fellowship; Uehara Memorial Foundation; RIKEN CDB intramural grant; MEXT, Japan;  [SAF2011-25252]; Grants-in-Aid for Scientific Research [26650072, 26440003, 25000014, 26440093, 221S0001, 26711020] Funding Source: KAKEN
NR 61
TC 137
Z9 156
U1 2
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 JAN 22
PY 2015
VL 517
IS 7535
BP 466
EP +
DI 10.1038/nature14097
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AZ4MU
UT WOS:000348196500030
PM 25533956
DA 2026-03-09
ER

PT J
AU Turner, TN
   Sharma, K
   Oh, EC
   Liu, YFP
   Collins, RL
   Sosa, MX
   Auer, DR
   Brand, H
   Sanders, SJ
   Moreno-De-Luca, D
   Pihur, V
   Plona, T
   Pike, K
   Soppet, DR
   Smith, MW
   Cheung, SW
   Martin, CL
   State, MW
   Talkowski, ME
   Cook, E
   Huganir, R
   Katsanis, N
   Chakravarti, A
AF Turner, Tychele N.
   Sharma, Kamal
   Oh, Edwin C.
   Liu, Yangfan P.
   Collins, Ryan L.
   Sosa, Maria X.
   Auer, Dallas R.
   Brand, Harrison
   Sanders, Stephan J.
   Moreno-De-Luca, Daniel
   Pihur, Vasyl
   Plona, Teri
   Pike, Kristen
   Soppet, Daniel R.
   Smith, Michael W.
   Cheung, Sau Wai
   Martin, Christa Lese
   State, Matthew W.
   Talkowski, Michael E.
   Cook, Edwin
   Huganir, Richard
   Katsanis, Nicholas
   Chakravarti, Aravinda
TI Loss of δ-catenin function in severe autism
SO NATURE
LA English
DT Article
ID structural variation; spectrum disorder; protein; morphogenesis; genetics; complex; synapse; spine; kaiso; rare
AB Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated delta-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.
C1 [Turner, Tychele N.; Sosa, Maria X.; Auer, Dallas R.; Pihur, Vasyl; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, Ctr Complex Dis Genom, Baltimore, MD 21205 USA.
   [Turner, Tychele N.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Predoctoral Training Program Human Genet & Mol Bi, Baltimore, MD 21205 USA.
   [Turner, Tychele N.; Sosa, Maria X.; Auer, Dallas R.; Sanders, Stephan J.; Moreno-De-Luca, Daniel; Pihur, Vasyl; Martin, Christa Lese; State, Matthew W.; Chakravarti, Aravinda] Univ Calif Los Angeles, NIMH, Autism Ctr Excellence ACE Genet Consortium, Los Angeles, CA 90095 USA.
   [Sharma, Kamal; Huganir, Richard] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA.
   [Oh, Edwin C.; Liu, Yangfan P.; Katsanis, Nicholas] Duke Univ, Ctr Human Dis Modeling, Durham, NC 27710 USA.
   [Collins, Ryan L.; Brand, Harrison; Talkowski, Michael E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.
   [Collins, Ryan L.; Brand, Harrison; Talkowski, Michael E.] Harvard Univ, Sch Med, Boston, MA 02114 USA.
   [Brand, Harrison; Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.
   [Sanders, Stephan J.; State, Matthew W.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94158 USA.
   [Moreno-De-Luca, Daniel] Yale Univ, Dept Psychiat, New Haven, CT 06511 USA.
   [Plona, Teri; Pike, Kristen; Soppet, Daniel R.] Leidos Biomed Res Inc, Frederick, MD 21702 USA.
   [Smith, Michael W.] NHGRI, Bethesda, MD 20892 USA.
   [Cheung, Sau Wai] Baylor Coll Med, Houston, TX 77030 USA.
   [Martin, Christa Lese] Geisinger Hlth Syst, Autism & Dev Med Inst, Lewisburg, PA 17837 USA.
   [Cook, Edwin] Univ Illinois, Chicago, IL 60608 USA.
C3 Johns Hopkins University; Johns Hopkins University; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH); University of California System; University of California Los Angeles; Johns Hopkins University; Duke University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; University of California System; University of California San Francisco; Yale University; 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); Baylor College of Medicine; Geisinger Health System; University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital
RP Chakravarti, A (corresponding author), Johns Hopkins Univ, Sch Med, Ctr Complex Dis Genom, Baltimore, MD 21205 USA.
EM aravinda@jhmi.edu
FU National Institute of Mental Health [1U24MH081810]; Simons Foundation; NIMH [MH095867, 5R25MH071584-07, MH19961-14, R01MH081754]; National Institutes of Health [RO1MH074090]; Autism Speaks Dennis Weatherstone pre-doctoral fellowship [7863]; National Institute of General Medical Sciences [T32GM007814] Funding Source: NIH RePORTER; National Institute of Mental Health [T32MH019961, R01MH074090, R25MH071584] Funding Source: NIH RePORTER
NR 54
TC 130
Z9 159
U1 2
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 APR 2
PY 2015
VL 520
IS 7545
BP 51
EP +
DI 10.1038/nature14186
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE7NE
UT WOS:000352027700034
PM 25807484
DA 2026-03-09
ER

PT J
AU Bharat, TAM
   Murshudov, GN
   Sachse, C
   Löwe, J
AF Bharat, Tanmay A. M.
   Murshudov, Garib N.
   Sachse, Carsten
   Loewe, Jan
TI Structures of actin-like ParM filaments show architecture of plasmid-segregating spindles
SO NATURE
LA English
DT Article
ID bacterial actin; f-actin; dna segregation; r1; visualization; replication; reconstruction; refinement; resolution; mechanism
AB Active segregation of Escherichia coli low-copy-number plasmid R1 involves formation of a bipolar spindle made of left-handed double-helical actin-like ParM filaments(1-6). ParR links the filaments with centromeric parC plasmid DNA, while facilitating the addition of subunits to ParM filaments(3,7-9). Growing ParMRC spindles push sister plasmids to the cell poles(9,10). Here, using modern electron cryomicroscopy methods, we investigate the structures and arrangements of ParM filaments in vitro and in cells, revealing at near-atomic resolution how subunits and filaments come together to produce the simplest known mitotic machinery. To understand the mechanism of dynamic instability, we determine structures of ParM filaments in different nucleotide states. The structure of filaments bound to the ATP analogue AMPPNP is determined at 4.3 angstrom resolution and refined. The ParM filament structure shows strong longitudinal interfaces and weaker lateral interactions. Also using electron cryomicroscopy, we reconstruct ParM doublets forming antiparallel spindles. Finally, with whole-cell electron cryotomography, we show that doublets are abundant in bacterial cells containing low-copy-number plasmids with the ParMRC locus, leading to an asynchronous model of R1 plasmid segregation.
C1 [Bharat, Tanmay A. M.; Murshudov, Garib N.; Loewe, Jan] MRC, Mol Biol Lab, Struct Studies Div, Cambridge CB2 0QH, England.
   [Sachse, Carsten] European Mol Biol Lab, Struct & Computat Biol Unit, D-69117 Heidelberg, Germany.
C3 MRC Laboratory Molecular Biology; European Molecular Biology Laboratory (EMBL)
RP Löwe, J (corresponding author), MRC, Mol Biol Lab, Struct Studies Div, Francis Crick Ave, Cambridge CB2 0QH, England.
EM jyl@mrc-lmb.cam.ac.uk
FU Medical Research Council [U105184326, MC-UP-A025-1012]; Wellcome Trust [095514/Z/11/Z]; Federation of European Biochemical Societies (FEBS); European Molecular Biology Organization (EMBO) [ALTF 3-2013]; Medical Research Council [MC_U105184326] Funding Source: researchfish; MRC [MC_U105184326] Funding Source: UKRI
NR 39
TC 56
Z9 72
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 JUL 2
PY 2015
VL 523
IS 7558
BP 106
EP +
DI 10.1038/nature14356
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL7RN
UT WOS:000357169500041
PM 25915019
DA 2026-03-09
ER

PT J
AU Voit, GM
   Donahue, M
   Bryan, GL
   McDonald, M
AF Voit, G. M.
   Donahue, M.
   Bryan, G. L.
   McDonald, M.
TI Regulation of star formation in giant galaxies by precipitation, feedback and conduction
SO NATURE
LA English
DT Article
ID brightest cluster galaxy; galactic nucleus feedback; cool-core clusters; thermal-instability; profile; sample; haloes; flows; gas
AB The Universe's largest galaxies reside at the centres of galaxy clusters and are embedded in hot gas that, if left undisturbed, would cool quickly and create many more new stars than are actually observed(1-5). Cooling can be regulated by feedback from accretion of cooling gas onto the central black hole, but requires an accretion rate finely tuned to the thermodynamic state of the hot gas(6,7). Theoretical models in which cold clouds precipitate out of the hot gas via thermal instability and accrete onto the black hole exhibit the necessary tuning(8-10). Recent observational evidence shows that the abundance of cold gas in the centres of clusters increases rapidly near the predicted threshold for instability(11). Here we report observations showing that this precipitation threshold extends over a large range in cluster radius, cluster mass and cosmic time. We incorporate the precipitation threshold into a framework of theoretical models for the thermodynamic state of hot gas in galaxy clusters. According to that framework, precipitation regulates star formation in some giant galaxies, while thermal conduction prevents star formation in others if it can compensate for radiative cooling and shut off precipitation.
C1 [Voit, G. M.; Donahue, M.] Michigan State Univ, Dept Phys & Astron, E Lansing, MI 48864 USA.
   [Bryan, G. L.] Columbia Univ, Dept Astron, Pupin Phys Lab 1328, New York, NY 10027 USA.
   [McDonald, M.] MIT, MIT Kavli Inst Astrophys & Space Res, Cambridge, MA 02139 USA.
C3 Michigan State University; Columbia University; Massachusetts Institute of Technology (MIT)
RP Voit, GM (corresponding author), Michigan State Univ, Dept Phys & Astron, 567 Wilson Rd, E Lansing, MI 48864 USA.
EM voit@pa.msu.edu
FU NSF [AST-0908819, AST-1008134, AST-1210890]; NASA [NNX12AH41G, NAS 5-26555]; NASA through a Hubble Fellowship - Space Telescope Science Institute [HST-HF51308.01-A]; Division Of Astronomical Sciences; Direct For Mathematical & Physical Scien [1210890] Funding Source: National Science Foundation
NR 30
TC 210
Z9 225
U1 1
U2 14
PU NATURE PUBLISHING 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 12
PY 2015
VL 519
IS 7542
BP 203
EP 206
DI 10.1038/nature14167
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500032
PM 25739501
DA 2026-03-09
ER

PT J
AU Shungin, D
   Winkler, TW
   Croteau-Chonka, DC
   Ferreira, T
   Lockes, AE
   Mägi, R
   Strawbridge, RJ
   Pers, TH
   Fischer, K
   Justice, AE
   Workalemahu, T
   Wu, JMW
   Buchkovich, ML
   Heard-Costa, NL
   Roman, TS
   Drong, AW
   Song, C
   Gustafsson, S
   Day, FR
   Esko, T
   Fall, T
   Kutalik, Z
   Luan, JA
   Randall, JC
   Scherag, A
   Vedantam, S
   Wood, AR
   Chen, J
   Fehrmann, R
   Karjalainen, J
   Kahali, B
   Liu, CT
   Schmidt, EM
   Absher, D
   Amin, N
   Anderson, D
   Beekman, M
   Bragg-Gresham, JL
   Buyske, S
   Demirkan, A
   Ehret, GB
   Feitosa, MF
   Goel, A
   Jackson, AU
   Johnson, T
   Kleber, ME
   Kristiansson, K
   Mangino, M
   Leach, IM
   Medina-Gomez, C
   Palmer, CD
   Pasko, D
   Pechlivaniss, S
   Peters, MJ
   Prokopenko, I
   Stancáková, A
   Sung, YJ
   Tanakam, T
   Teumer, A
   Van Vliet-Ostaptchouk, JV
   Yengo, L
   Zhang, WH
   Albrecht, E
   Arnlöv, J
   Arscott, GM
   Bandinelli, S
   Barrett, A
   Bellis, C
   Bennett, AJ
   Berne, C
   Blüher, M
   Bühringer, S
   Bonnet, F
   Böttcher, Y
   Bruinenberg, M
   Carba, DB
   Caspersen, IH
   Clarke, R
   Daw, EW
   Deelen, J
   Deelman, E
   Delgado, G
   Doney, ASF
   Eklund, N
   Erdos, MR
   Estrada, K
   Eury, E
   Friedrichs, N
   Garcia, ME
   Giedraitis, V
   Gigante, B
   Go, AS
   Golay, A
   Grallert, H
   Grammer, TB
   Grässler, J
   Grewal, J
   Groves, CJ
   Haller, T
   Hallmans, G
   Hartman, CA
   Hassinen, M
   Hayward, C
   Heikkilä, K
   Herzig, KH
   Helmer, Q
   Hillege, HL
   Holmen, O
   Hunt, SC
   Isaacs, A
   Ittermann, T
   James, AL
   Johansson, I
   Juliusdottir, T
   Kalafati, IP
   Kinnunen, L
   Koenig, W
   Kooner, IK
   Kratzer, W
   Lamina, C
   Leander, K
   Lee, NR
   Lichtner, P
   Lind, L
   Lindström, J
   Lobbens, S
   Lorentzon, M
   Mach, F
   Magnusson, PKE
   Mahajan, A
   McArdle, WL
   Menni, C
   Merger, S
   Mihailov, E
   Milani, L
   Mills, R
   Moayyeri, A
   Monda, KL
   Mooijaart, SP
   Mühleisen, TW
   Mulas, A
   Müller, G
   Müller-Nurasyid, M
   Nagaraja, R
   Nalls, MA
   Narisu, N
   Glorioso, N
   Nolte, IM
   Olden, M
   Rayner, NW
   Renstrom, F
   Ried, JS
   Robertson, NR
   Rose, LM
   Sanna, S
   Scharnagl, H
   Scholtens, S
   Sennblad, B
   Seufferlein, T
   Sitlani, CM
   Smith, AV
   Stirrups, K
   Stringhams, HM
   Sundström, J
   Swertz, MA
   Swift, AJ
   Syvänen, AC
   Tayo, BO
   Thorand, B
   Thorleifsson, G
   Tomaschitz, A
   Troffa, C
   van Oort, FVA
   Verweij, N
   Vonk, JM
   Waite, LL
   Wennauer, R
   Wilsgaard, T
   Wojczynski, MK
   Wong, A
   Zhang, QY
   Zhao, JH
   Brennan, EP
   Choi, M
   Eriksson, P
   Folkersen, L
   Franco-Cereceda, A
   Gharavi, AG
   Hedman, ÅK
   Hivert, MF
   Huang, JY
   Kanoni, S
   Karpe, F
   Keildson, S
   Kiryluk, K
   Liang, LM
   Lifton, RP
   Ma, BS
   McKnight, AJ
   McPherson, R
   Metspalu, A
   Min, JL
   Moffatt, MF
   Montgomery, GW
   Murabito, JM
   Nicholson, G
   Nyholt, DR
   Olsson, C
   Perry, JRB
   Reinmaa, E
   Salem, RM
   Sandholm, N
   Schadt, EE
   Scott, R
   Stolk, L
   Vallejo, EE
   Westra, HJ
   Zondervan, KT
   Amouyel, P
   Arveiler, D
   Bakker, SJL
   Beilby, J
   Bergman, RN
   Blangero, J
   Brown, MJ
   Burnier, M
   Campbell, H
   Chakravarti, A
   Chiness, PS
   Claudi-Boehmi, S
   Collins, FS
   Crawford, DC
   Danesh, J
   de Faire, U
   de Geusl, EJC
   Dörr, M
   Erbel, R
   Eriksson, JG
   Farrall, M
   Ferrannini, E
   Ferrières, J
   Forouhi, NG
   Forrester, T
   Franco, OH
   Gansevoort, RT
   Gieger, C
   Gudnason, V
   Haiman, CA
   Harris, TB
   Hattersley, AT
   Heliövaara, M
   Hicks, AA
   Hingorani, AD
   Hoffmann, W
   Hofman, A
   Homuth, G
   Humphries, SE
   Hyppönen, E
   Illig, T
   Jarvelin, MR
   Johansen, B
   Jousilahti, P
   Jula, AM
   Kaprio, J
   Kee, F
   Keinanen-Kiukaanniemi, SM
   Kooner, JS
   Kooperberg, C
   Kovacs, P
   Kraja, AT
   Kumari, M
   Kuulasmaa, K
   Kuusisto, J
   Lakka, TA
   Langenberg, C
   Le Marchand, L
   Lehtimäki, T
   Lyssenko, V
   Männistö, S
   Marette, A
   Matise, TC
   McKenzie, CA
   McKnight, B
   Musk, AW
   Möhlenkamp, S
   Morris, AD
   Nelis, M
   Ohlsson, C
   Oldehinkel, AJ
   Ong, KK
   Palmer, LJ
   Penninx, BW
   Peters, A
   Pramstaller, PP
   Raitakari, OT
   Rankinen, T
   Rao, DC
   Rice, TK
   Ridker, PM
   Ritchie, MD
   Rudan, I
   Salomaa, V
   Samani, NJ
   Saramies, J
   Sarzynski, MA
   Schwarz, PEH
   Shuldiner, AR
   Staessen, JA
   Steinthorsdottir, V
   Stolk, RP
   Strauch, K
   Tönjes, A
   Tremblay, A
   Tremoli, E
   Vohl, MC
   Völker, U
   Vollenweider, P
   Wilson, JF
   Witteman, JC
   Adair, LS
   Bochud, M
   Boehm, BO
   Bornstein, SR
   Bouchard, C
   Cauchi, S
   Caulfield, MJ
   Chambers, JC
   Chasman, DI
   Cooper, RS
   Dedoussis, G
   Ferrucci, L
   Froguel, P
   Grabe, HJ
   Hamsten, A
   Hui, JN
   Hveem, K
   Jöckel, KH
   Kivimaki, M
   Kuh, D
   Laakso, M
   Liu, YM
   März, W
   Munroe, PB
   Njolstad, I
   Oostra, BA
   Palmer, CNA
   Pedersen, NL
   Perola, M
   Pérusse, L
   Peters, U
   Power, C
   Quertermous, T
   Rauramaa, R
   Rivadeneira, F
   Saaristo, TE
   Saleheen, D
   Sinisalo, J
   Slagboom, PE
   Snieder, H
   Spector, TD
   Thorsteinsdottir, UR
   Stumvoll, M
   Tuomilehto, J
   Uitterlinden, AG
   Uusitupa, M
   van der Harst, P
   Veronesi, G
   Walker, M
   Wareham, NJ
   Watkins, H
   Wichmann, HE
   Abecasis, GR
   Assimes, TL
   Berndt, SI
   Boehnkes, M
   Borecki, IB
   Deloukas, P
   Franke, L
   Frayling, TM
   Groop, LC
   Hunter, DJ
   Kaplan, RC
   O'Connell, JR
   Qi, L
   Schlessinger, D
   Strachan, DP
   Stefansson, K
   van Dujin, CM
   Willer, CJ
   Visscher, PM
   Yang, J
   Hirschhorn, JN
   Zillikens, MC
   McCarthy, MI
   Speliotes, EK
   North, KE
   Fox, CS
   Barroso, I
   Franks, PW
   Ingelsson, E
   Heid, IM
   Loos, RJF
   Cupples, LA
   Morris, AP
   Lindgren, CM
   Mohlke, KL
AF Shungin, Dmitry
   Winkler, Thomas W.
   Croteau-Chonka, Damien C.
   Ferreira, Teresa
   Lockes, Adam E.
   Maegi, Reedik
   Strawbridge, Rona J.
   Pers, Tune H.
   Fischer, Krista
   Justice, Anne E.
   Workalemahu, Tsegaselassie
   Wu, Joseph M. W.
   Buchkovich, Martin L.
   Heard-Costa, Nancy L.
   Roman, Tamara S.
   Drong, Alexander W.
   Song, Ci
   Gustafsson, Stefan
   Day, Felix R.
   Esko, Tonu
   Fall, Tove
   Kutalik, Zoltan
   Luan, Jian'an
   Randall, Joshua C.
   Scherag, Andre
   Vedantam, Sailaja
   Wood, Andrew R.
   Chen, Jin
   Fehrmann, Rudolf
   Karjalainen, Juha
   Kahali, Bratati
   Liu, Ching-Ti
   Schmidt, Ellen M.
   Absher, Devin
   Amin, Najaf
   Anderson, Denise
   Beekman, Marian
   Bragg-Gresham, Jennifer L.
   Buyske, Steven
   Demirkan, Ayse
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TI New genetic loci link adipose and insulin biology to body fat distribution
SO NATURE
LA English
DT Article
ID genome-wide association; adipogenic differentiation; abdominal adiposity; sexual-dimorphism; glycemic traits; false discovery; common snps; metaanalysis; variants; risk
AB Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 x 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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   [James, Alan L.] Univ Western Australia, Sch Med & Pharmacol, Crawley, WA 6009, Australia.
   [Kalafati, Ioanna-Panagiota; Dedoussis, George] Harokopio Univ, Dept Dietet Nutr, Athens 17671, Greece.
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   [McArdle, Wendy L.; Min, Josine L.] Univ Bristol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England.
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   [Muehleisen, Thomas W.] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany.
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   [Mueller, Gabriele] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Ctr Evidence Based Healthcare, D-01307 Dresden, Germany.
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   [Hicks, Andrew A.; Pramstaller, Peter P.] Inst Univ Lubeck, D-23562 Lubeck, Germany.
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   [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.
   [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia.
   [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA.
   [Strachan, David P.] St Georges Univ London, Div Populat Hlth Sci & Educ, London SW17 0RE, England.
   [Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.
   [Visscher, Peter M.; Yang, Jian] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia.
   [Visscher, Peter M.; Yang, Jian] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4012, Australia.
   [McCarthy, Mark I.] Oxford Univ Hosp NHS Trust, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England.
   [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA.
   [Barroso, Ines] Univ Cambridge, Metab Res Labs, Inst Metab Sci, Addenbrookes Hosp, Cambridge CB2 OQQ, England.
   [Barroso, Ines] Addenbrookes Hosp, Inst Metab Sci, NIHR Cambridge Biomed Res Ctr, Cambridge CB2 OQQ, England.
   [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.
   [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.
   [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA.
   [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3GA, Merseyside, England.
C3 Lund University; Skane University Hospital; Umea University; University of Regensburg; University of North Carolina; University of North Carolina Chapel Hill; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; University of Oxford; Wellcome Centre for Human Genetics; University of Michigan System; University of Michigan; University of Tartu; Karolinska Institutet; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University; Technical University of Denmark; University of North Carolina; University of North Carolina Chapel Hill; Harvard University; Harvard T.H. Chan School of Public Health; Boston University; Framingham Heart Study; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI); Boston University; Karolinska Institutet; Uppsala University; Uppsala University; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); Swiss Institute of Bioinformatics; University of Lausanne; Wellcome Trust Sanger Institute; University of Exeter; University of Michigan System; University of Michigan; University of Groningen; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; HudsonAlpha Institute for Biotechnology; Erasmus University Rotterdam; Erasmus MC; University of Western Australia; The Kids Research Institute Australia; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); University of Michigan System; University of Michigan; Rutgers University System; Rutgers University New Brunswick; Rutgers University System; Rutgers University New Brunswick; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Johns Hopkins University; University of Geneva; Washington University (WUSTL); University of Oxford; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); Ruprecht Karls University Heidelberg; Ulm University; Finland National Institute for Health & Welfare; University of London; King's College London; University of Groningen; Erasmus University Rotterdam; Erasmus MC; Erasmus University Rotterdam; Erasmus MC; University of Oxford; Imperial College London; University of Eastern Finland; Washington University (WUSTL); National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); Universitat Greifswald; Greifswald Medical School; University of Groningen; Pasteur Network; Universite de Lille; Institut Pasteur Lille; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite de Lille; Universite de Lille; Imperial College London; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Dalarna University; Texas Biomedical Research Institute; Queensland University of Technology (QUT); Leipzig University; Leipzig University; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Universite de Rennes; Institut National de la Sante et de la Recherche Medicale (Inserm); University of Groningen; University of San Carlos; Norwegian University of Science & Technology (NTNU); University of Oxford; University of Oxford; University of Southern California; University of Dundee; University of Helsinki; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI); Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Universitat Greifswald; Greifswald Medical School; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); Uppsala University; Karolinska Institutet; Kaiser Permanente; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; German Center for Diabetes Research (DZD); Technische Universitat Dresden; Carl Gustav Carus University Hospital; University of Groningen; University of Edinburgh; University of Helsinki; University of Oulu; University of Oulu; University of Oulu; Vrije Universiteit Amsterdam; University of Groningen; Norwegian University of Science & Technology (NTNU); Utah System of Higher Education; University of Utah; Universitat Greifswald; Greifswald Medical School; University of Western Australia; Harokopio University Athens; Ulm University; Medical University of Innsbruck; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Uppsala University; University of Gothenburg; University of Bristol; Ulm University; University of Tartu; University of London; University College London; Amgen; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); University of Bonn; University of Bonn; Consiglio Nazionale delle Ricerche (CNR); Istituto di Ricerca Genetica e Biomedica (IRGB-CNR); Technische Universitat Dresden; Carl Gustav Carus University Hospital; University of Munich; University of Munich; German Centre for Cardiovascular Research; Munich Heart Alliance; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); University of Sassari; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Medical University of Graz; Karolinska Institutet; University of Washington; University of Washington Seattle; Icelandic Heart Association; University of Iceland; University of London; Queen Mary University London; Loyola University Chicago; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Decode Genetics; Medical University of Graz; Erasmus University Rotterdam; Erasmus MC; Ulm University; UiT The Arctic University of Tromso; University of London; University College London; University College Dublin; Seoul National University (SNU); Karolinska Institutet; Columbia University; Harvard Pilgrim Health Care; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Shanghai Jiao Tong University; Chinese Academy of Sciences; Harvard University; Harvard T.H. Chan School of Public Health; University of Oxford; Harvard University; Harvard T.H. Chan School of Public Health; Yale University; Howard Hughes Medical Institute; Dalian Maritime University; Queens University Belfast; University of Ottawa; University of Ottawa Heart Institute; Imperial College London; QIMR Berghofer Medical Research Institute; Boston University; University of Oxford; MRC Harwell; Queensland University of Technology (QUT); Aalto University; University of Helsinki; Helsinki University Central Hospital; Folkhalsan Research Center; Icahn School of Medicine at Mount Sinai; Tecnologico de Monterrey; University of Oxford; Pasteur Network; Universite de Lille; Institut Pasteur Lille; Institut National de la Sante et de la Recherche Medicale (Inserm); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; University of Groningen; University of Western Australia; Cedars Sinai Medical Center; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; University of Cambridge; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); University of Edinburgh; Vanderbilt University; Vanderbilt University; University of Cambridge; Vrije Universiteit Amsterdam; Vrije Universiteit Amsterdam; Universitat Greifswald; Greifswald Medical School; German Centre for Cardiovascular Research; University of Helsinki; University of Helsinki; Helsinki University Central Hospital; University of Pisa; CHU de Toulouse; Universite Federale Toulouse Midi-Pyrenees (ComUE); University West Indies Mona Jamaica; University of Southern California; University of London; University College London; University of London; University College London; Adelaide University; University of South Australia; Adelaide University; University of South Australia; South Australian Health & Medical Research Institute (SAHMRI); University of London; University College London; Hannover Medical School; Finland National Institute for Health & Welfare; Imperial College London; University of Oulu; University of Oulu; University of Oulu; University of Oulu; Imperial College London; Fred Hutchinson Cancer Center; University of London; University College London; Kuopio University Hospital; University of Eastern Finland; University of Eastern Finland Hospital; University of Eastern Finland; University of Eastern Finland; Kuopio University Hospital; University of Eastern Finland; University of Eastern Finland Hospital; University of Hawaii System; Cancer Research Center of Hawaii; Tampere University; Tampere University; Steno Diabetes Center; Lund University; Laval University; Laval University Hospital; Laval University; University of Washington; University of Washington Seattle; Sir Charles Gairdner Hospital; University of Western Australia; University of Toronto; University of Toronto; Ontario Institute for Cancer Research; Vrije Universiteit Amsterdam; Krankenhaus Bozen; University of Turku; University of Turku; Louisiana State University System; Louisiana State University; Pennington Biomedical Research Center; Washington University (WUSTL); Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; University of Split; University Hospitals of Leicester NHS Trust; University of Leicester; Glenfield Hospital; German Center for Diabetes Research (DZD); Technische Universitat Dresden; University System of Maryland; University of Maryland Baltimore; University System of Maryland; University of Maryland Baltimore; Geriatric Research Education & Clinical Center; US Department of Veterans Affairs; Veterans Health Administration (VHA); Maastricht University; Laval University; University of Milan; Laval University; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); University of Lausanne; University of North Carolina; University of North Carolina Chapel Hill; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); Nanyang Technological University; Nanyang Technological University; Ulm University; University of London; Queen Mary University London; Universitat Greifswald; Greifswald Medical School; Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE); University of Western Australia; Wake Forest University; SYNLAB Group; Erasmus University Rotterdam; Erasmus MC; Stanford University; Pirkanmaa Hospital District; University of Pennsylvania; University of Helsinki; Helsinki University Central Hospital; University of Iceland; King Abdulaziz University; Danube University Krems; University of Eastern Finland; University of Insubria; Newcastle University - UK; University of Munich; University of Munich; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); NIH National Cancer Institute- Division of Cancer Epidemiology & Genetics; King Abdulaziz University; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; City St Georges, University of London; University of Michigan System; University of Michigan; University of Queensland; University of Queensland; Oxford University Hospitals NHS Foundation Trust; University of North Carolina; University of North Carolina Chapel Hill; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; University of Cambridge; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; University of Liverpool
RP Mohlke, KL (corresponding author), Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.
EM celi@well.ox.ac.uk; mohlke@med.unc.edu
FU British Heart Foundation [RG/08/008/25291, FS/14/55/30806, RG/10/12/28456, RG/13/2/30098, RG/07/008/23674, RG/08/014/24067] Funding Source: researchfish; Cancer Research UK [14136] Funding Source: researchfish; Chief Scientist Office [CZB/4/710] Funding Source: researchfish; Economic and Social Research Council [ES/F02679X/1, ES/J023299/1] Funding Source: researchfish; Lundbeck Foundation [R190-2014-3904] Funding Source: researchfish; Medical Research Council [MC_UU_12013/4, MC_U106179471, MC_U106179472, MC_UU_12015/1, G0401527, MC_UU_12011/1, MR/L003120/1, MR/K013351/1, MC_UU_12013/1, G19/35, G9521010, G0601463, G0400491, G0601261, G1000616, G1001799, MR/N01104X/1, MC_UU_12015/2, MC_UU_12012/1, G0600717B, MC_UP_A100_1003, MC_UU_12012/5/B, MC_U147585824, MC_CF023241, MC_U147585819, MC_UU_12015/5, G0600717, MC_U147585827, G8802774, G0100222, MC_UP_A620_1014, MC_PC_U127561128, G0902037, G1000143, MR/K006584/1, U1475000001, MR/K011480/1, MC_UU_12019/1] Funding Source: researchfish; National Institute for Health Research [NF-SI-0512-10113, NF-SI-0611-10219, NF-SI-0611-10099, NF-SI-0508-10082, NF-SI-0513-10109, NF-SI-0611-10170, NF-SI-0512-10114, NF-SI-0514-10027, NF-SI-0507-10380, NF-SI-0512-10165, NF-SI-0512-10135, NF-SI-0513-10085] Funding Source: researchfish; NNF Center for Basic Metabolic Research [Kilpeläinen Group, Pers Group] Funding Source: researchfish; Novo Nordisk Fonden [NNF13OC0005785, NNF12OC1016467, NNF12OC1016167, NNF14OC0010513, NNF13OC0005781, NNF11OC1014855, NNF15OC0016416, NNF14OC0011039] Funding Source: researchfish; ESRC [ES/J023299/1, ES/F02679X/1] Funding Source: UKRI; MRC [G0400491, MR/K011480/1, MR/N01104X/1, G0902037, MC_UP_A100_1003, G1000616, G9521010, G0600717, MC_U147585827, MC_UU_12012/1, G1001799, MC_PC_U127561128, MC_UU_12015/1, MC_UU_12013/1, G0601261, MC_U106179472, MC_U147585819, MC_UU_12019/1, MC_UU_12015/5, MC_UU_12015/2, G0601463, MR/K013351/1, MR/L003120/1] Funding Source: UKRI; National Cancer Institute [P30CA071789] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [R01HL109946, T32HL069768, T32HL007055, R01HL105756] Funding Source: NIH RePORTER; National Human Genome Research Institute [ZIAHG000024] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK020572, P30DK020541, R01DK072193, R01DK062370, U01DK062370, P30DK040561, R01DK075787, R01DK093757] Funding Source: NIH RePORTER; National Institute on Aging [ZIAAG000675, ZIAAG007390, ZIAAG001050] Funding Source: NIH RePORTER; British Heart Foundation [BHF_RG/08/014/24067, RG/08/008/25291, BHF_RG/10/12/28456, FS/14/55/30806, RG/10/12/28456, BHF_RG/13/2/30098, RG/13/2/30098, BHF_FS/14/55/30806, RG/07/008/23674, RG/08/014/24067, BHF_RG/08/008/25291] Funding Source: Medline; Cancer Research UK [14136, CRUK_14136] Funding Source: Medline; Chief Scientist Office [CZB/4/710, CSO_CZB/4/710] Funding Source: Medline; Diabetes UK [12/0004470, DUK_12/0004470] Funding Source: Medline; Medical Research Council [MRC_MR/K013351/1, G0601261, MRC_MR/L003120/1, MC_U147585827, MRC_MC_U106179472, MRC_G0601261, MC_UU_12015/5, MR/N01104X/1, MRC_G1000143, G0401527, MRC_G0401527, MC_UP_A620_1014, MC_U147585819, MRC_MC_UU_12015/5, MRC_MC_UU_12019/1, MC_UP_A100_1003, MR/K011480/1, MRC_MR/N01104X/1, MC_UU_12013/1, G0601463, MC_UU_12015/1, G0902037, MRC_MC_UU_12015/2, G9521010, G8802774, G1001799, G0400491, MRC_G0601463, MC_UU_12015/2, G19/35, MRC_MC_UU_12011/1, MRC_MC_UP_A620_1014, MC_U106179471, G0100222, MRC_MC_U106179471, MRC_MC_UU_12015/1, MRC_MC_UP_A100_1003, MC_U106179472, MC_UU_12019/1, MR/L003120/1, G1000143, MRC_MR/K011480/1, MC_UU_12012/1, MRC_MC_UU_12013/1, MC_PC_U127561128, MC_UU_12013/4, MR/K006584/1, MRC_MC_PC_U127561128, MC_U147585824, MC_UU_12011/1, G0600717, MRC_MR/K006584/1, G1000616, MRC_G9521010, MRC_MC_UU_12012/1, MR/K013351/1, MRC_G1001799] Funding Source: Medline; NCI NIH HHS [UM1 CA182910, UM1 CA182913, P30 CA071789] Funding Source: Medline; NHGRI NIH HHS [U01 HG007419, U01 HG007416, U01 HG007376, U01 HG007417] Funding Source: Medline; NHLBI NIH HHS [R00 HL094535, R01 HL105756, R01 HL109946, R01 HL117078, T32 HL069768, K01 HL116770, R01 HL120393, R01 HL117626, T32 HL007055] Funding Source: Medline; NIA NIH HHS [R01 AG041517, R01 AG025941, R01 AG033193, U01 AG049505] Funding Source: Medline; NICHD NIH HHS [U54 HD083211] Funding Source: Medline; NIDA NIH HHS [R21 DA027040] Funding Source: Medline; NIDDK NIH HHS [P30 DK072488, P30 DK079637, P30 DK020572, U01 DK062370, R01 DK072193, K23 DK080145, P30 DK040561, P60 DK020541, R01 DK078150, R01 DK075787, R01 DK093757, P30 DK020541, P30 DK056341, R01 DK089256, R01 DK107437, R01 DK062370] Funding Source: Medline; NIGMS NIH HHS [P30 GM103341, T32 GM007092, T32 GM067553] Funding Source: Medline; NIMHD NIH HHS [P20 MD006899] Funding Source: Medline; Wellcome Trust [WT098498, WT098017, 085235, 098017, 098381, 098498, 084766, WT098381, WT100574, WT084766, WT097117, WT085235, 097117, 100574] Funding Source: Medline; Intramural NIH HHS [Z01 HG000024] Funding Source: Medline
NR 95
TC 1259
Z9 1385
U1 2
U2 490
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 12
PY 2015
VL 518
IS 7538
BP 187
EP U378
DI 10.1038/nature14132
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300030
PM 25673412
DA 2026-03-09
ER

PT J
AU Li, PL
   Lahvic, JL
   Binder, V
   Pugach, EK
   Riley, EB
   Tamplin, OJ
   Panigrahy, D
   Bowman, TV
   Barrett, FG
   Heffner, GC
   McKinney-Freeman, S
   Schlaeger, TM
   Daley, GQ
   Zeldin, DC
   Zon, LI
AF Li, Pulin
   Lahvic, Jamie L.
   Binder, Vera
   Pugach, Emily K.
   Riley, Elizabeth B.
   Tamplin, Owen J.
   Panigrahy, Dipak
   Bowman, Teresa V.
   Barrett, Francesca G.
   Heffner, Garrett C.
   McKinney-Freeman, Shannon
   Schlaeger, Thorsten M.
   Daley, George Q.
   Zeldin, Darryl C.
   Zon, Leonard I.
TI Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment
SO NATURE
LA English
DT Article
ID stem-cells; aortic endothelium; zebrafish; migration; runx1; transplantation; identification; expression; invasion; injury
AB Haematopoietic stem and progenitor cell (HSPC) transplant is a widely used treatment for life-threatening conditions such as leukaemia; however, the molecular mechanisms regulating HSPC engraftment of the recipient niche remain incompletely understood. Here we develop a competitive HSPC transplant method in adult zebrafish, using in vivo imaging as a non-invasive readout. We use this system to conduct a chemical screen, and identify epoxyeicosatrienoic acids (EETs) as a family of lipids(1,2) that enhance HSPC engraftment. The pro-haematopoietic effects of EETs were conserved in the developing zebrafish embryo, where 11,12-EET promoted HSPC specification by activating a unique activator protein 1 (AP-1) and runx1 transcription program autonomous to the haemogenic endothelium. This effect required the activation of the phosphatidylinositol-3-OH kinase (PI(3) K) pathway, specifically PI(3) K gamma. In adult HSPCs, 11,12-EET induced transcriptional programs, including AP-1 activation, which modulate several cellular processes, such as migration, to promote engraftment. Furthermore, we demonstrate that the EET effects on enhancing HSPC homing and engraftment are conserved in mammals. Our study establishes a new method to explore the molecular mechanisms of HSPC engraftment, and discovers a previously unrecognized, evolutionarily conserved pathway regulating multiple haematopoietic generation and regeneration processes. EETs may have clinical application in marrow or cord blood transplantation.
C1 [Li, Pulin; Lahvic, Jamie L.; Binder, Vera; Pugach, Emily K.; Riley, Elizabeth B.; Tamplin, Owen J.; Bowman, Teresa V.; Barrett, Francesca G.; Heffner, Garrett C.; Schlaeger, Thorsten M.; Daley, George Q.; Zon, Leonard I.] Harvard Univ, Sch Med, Stem Cell Program, Boston, MA 02115 USA.
   [Li, Pulin; Lahvic, Jamie L.; Binder, Vera; Pugach, Emily K.; Riley, Elizabeth B.; Tamplin, Owen J.; Bowman, Teresa V.; Barrett, Francesca G.; Heffner, Garrett C.; Schlaeger, Thorsten M.; Daley, George Q.; Zon, Leonard I.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Haematol Oncol, Boston, MA 02115 USA.
   [Li, Pulin; Lahvic, Jamie L.; Binder, Vera; Pugach, Emily K.; Riley, Elizabeth B.; Tamplin, Owen J.; Bowman, Teresa V.; Barrett, Francesca G.; Heffner, Garrett C.; Schlaeger, Thorsten M.; Daley, George Q.; Zon, Leonard I.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dana Farber Canc Inst, Boston, MA 02115 USA.
   [Li, Pulin; Zon, Leonard I.] Harvard Univ, Chem Biol Program, Cambridge, MA 02138 USA.
   [Binder, Vera] Univ Munich, Dr von Hauner Childrens Hosp, Dept Hematol & Oncol, D-80337 Munich, Germany.
   [Panigrahy, Dipak] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Ctr Vasc Biol Res, Boston, MA 02115 USA.
   [McKinney-Freeman, Shannon] St Jude Childrens Res Hosp, Dept Haematol, Memphis, TN 38105 USA.
   [Zeldin, Darryl C.] Natl Inst Environm Hlth Sci, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA.
C3 Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard Medical School; Howard Hughes Medical Institute; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; University of Munich; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; St Jude Children's Research Hospital; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS)
RP Zon, LI (corresponding author), Harvard Univ, Sch Med, Stem Cell Program, Boston, MA 02115 USA.
EM zon@enders.tch.harvard.edu
FU NIH [P50-NS40828, P30-HD18655]; HHMI; National Institutes of Health (NIH) [R01 HL04880, P015PO1HL32262-32, 5P30 DK49216, 5R01 DK53298, 5U01 HL10001-05, R24 DK092760, 1R01HL097794-04]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES025034]; National Cancer Institute [ROCA148633-01A5]; DFG; Care-for-Rare Foundation; National Institute of Environmental Health Sciences [ZIAES025034] Funding Source: NIH RePORTER
NR 38
TC 86
Z9 113
U1 0
U2 26
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 23
PY 2015
VL 523
IS 7561
BP 468
EP U203
DI 10.1038/nature14569
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN4DD
UT WOS:000358378900038
PM 26201599
DA 2026-03-09
ER

PT J
AU Wohlers, A
   Wood, BJ
AF Wohlers, Anke
   Wood, Bernard J.
TI A Mercury-like component of early Earth yields uranium in the core and high mantle 142Nd
SO NATURE
LA English
DT Article
ID silicate liquids; planetary cores; solar-system; potassium; evolution; sulfide; lead; messenger; model
AB Recent Nd-142 isotope data indicate that the silicate Earth (its crust plus the mantle) has a samarium to neodymium elemental ratio (Sm/Nd) that is greater than that of the supposed chondritic building blocks of the planet. This elevated Sm/Nd has been ascribed either to a 'hidden' reservoir in the Earth(1,2) or to loss of an early-formed terrestrial crust by impact ablation(3). Since removal of crust by ablation would also remove the heatproducing elements potassium, uranium and thorium such removal would make it extremely difficult to balance terrestrial heat production with the observed heat flow(3). In the 'hidden' reservoir alternative, a complementary low-Sm/Nd layer is usually considered to reside unobserved in the silicate lower mantle. We have previously shown, however, that the core is a likely reservoir for some lithophile elements such as niobium(4). We therefore address the question of whether core formation could have fractionated Nd from Sm and also acted as a sink for heat-producing elements. We show here that addition of a reduced Mercury-like body (or, alternatively, an enstatitechondrite-like body) rich in sulfur to the early Earth would generate a superchondritic Sm/Nd in the mantle and an Nd-142/Nd-144 anomaly of approximately +14 parts per million relative to chondrite. In addition, the sulfur-rich core would partition uranium strongly and thorium slightly, supplying a substantial part of the 'missing' heat source for the geodynamo.
C1 [Wohlers, Anke; Wood, Bernard J.] Univ Oxford, Dept Earth Sci, Oxford OX1 3AN, England.
C3 University of Oxford
RP Wohlers, A (corresponding author), Univ Oxford, Dept Earth Sci, South Parks Rd, Oxford OX1 3AN, England.
EM anke.wohlers@earth.ox.ac.uk; berniew@earth.ox.ac.uk
FU European Research Council [267764]; NERC [NE/F018266/1, NE/M000370/1] Funding Source: UKRI; Natural Environment Research Council [NE/F018266/1] Funding Source: researchfish
NR 31
TC 66
Z9 70
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 APR 16
PY 2015
VL 520
IS 7547
BP 337
EP +
DI 10.1038/nature14350
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG0RI
UT WOS:000352974200036
PM 25877203
DA 2026-03-09
ER

PT J
AU Hou, X
   Hu, YH
   Grinthal, A
   Khan, M
   Aizenberg, J
AF Hou, Xu
   Hu, Yuhang
   Grinthal, Alison
   Khan, Mughees
   Aizenberg, Joanna
TI Liquid-based gating mechanism with tunable multiphase selectivity and antifouling behaviour
SO NATURE
LA English
DT Article
ID membranes; water; permeation; nanopores
AB Living organisms make extensive use of micro- and nanometre-sized pores as gatekeepers for controlling the movement of fluids, vapours and solids between complex environments. The ability of such pores to coordinate multiphase transport, in a highly selective and subtly triggered fashion and without clogging, has inspired interest in synthetic gated pores for applications ranging from fluid processing to 3D printing and lab-on-chip systems(1-10). But although specific gating and transport behaviours have been realized by precisely tailoring pore surface chemistries and pore geometries(6,11-17), a single system capable of controlling complex, selective multiphase transport has remained a distant prospect, and fouling is nearly inevitable(11,12). Here we introduce a gating mechanism that uses a capillary-stabilized liquid as a reversible, reconfigurable gate that fills and seals pores in the closed state, and creates a non-fouling, liquid-lined pore in the open state. Theoretical modelling and experiments demonstrate that for each transport substance, the gating threshold-the pressure needed to open the pores-can be rationally tuned over a wide pressure range. This enables us to realize in one system differential response profiles for a variety of liquids and gases, even letting liquids flow through the pore while preventing gas from escaping. These capabilities allow us to dynamically modulate gas-liquid sorting in a microfluidic flow and to separate a three-phase air-water-oil mixture, with the liquid lining ensuring sustained antifouling behaviour. Because the liquid gating strategy enables efficient long-term operation and can be applied to a variety of pore structures and membrane materials, and to micro- as well as macroscale fluid systems, we expect it to prove useful in a wide range of applications.
C1 [Hou, Xu; Hu, Yuhang; Grinthal, Alison; Aizenberg, Joanna] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA.
   [Hou, Xu; Khan, Mughees; Aizenberg, Joanna] Harvard Univ, Wyss Inst Biol Inspired Engn, Cambridge, MA 02138 USA.
C3 Harvard University; Harvard University
RP Aizenberg, J (corresponding author), Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA.
EM jaiz@seas.harvard.edu
FU Advanced Research Projects Agency-Energy (ARPA-E), US Department of Energy [DE-AR0000326]
NR 30
TC 421
Z9 469
U1 15
U2 1133
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 5
PY 2015
VL 519
IS 7541
BP 70
EP 73
DI 10.1038/nature14253
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC4EQ
UT WOS:000350304000037
PM 25739629
DA 2026-03-09
ER

PT J
AU Andersen, MB
   Elliott, T
   Freymuth, H
   Sims, KWW
   Niu, YL
   Kelley, KA
AF Andersen, Morten B.
   Elliott, Tim
   Freymuth, Heye
   Sims, Kenneth W. W.
   Niu, Yaoling
   Kelley, Katherine A.
TI The terrestrial uranium isotope cycle
SO NATURE
LA English
DT Article
ID altered oceanic-crust; east pacific rise; th-pb systematics; juan-de-fuca; solar-system; u-235-pa-231 disequilibria; hydrothermal alteration; temperature-dependence; continental-crust; beneath hawaii
AB Changing conditions on the Earth's surface can have a remarkable influence on the composition of its overwhelmingly more massive interior. The global distribution of uranium is a notable example. In early Earth history, the continental crust was enriched in uranium. Yet after the initial rise in atmospheric oxygen, about 2.4 billion years ago, the aqueous mobility of oxidized uranium resulted in its significant transport to the oceans and, ultimately, by means of subduction, back to the mantle(1-8). Here we explore the isotopic characteristics of this global uranium cycle. We show that the subducted flux of uranium is isotopically distinct, with high U-238/U-235 ratios, as a result of alteration processes at the bottom of an oxic ocean. We also find that mid-ocean-ridge basalts (MORB s) have U-238/U-235 ratios higher than does the bulk Earth, confirming the widespread pollution of the upper mantle with this recycled uranium. Although many ocean island basalts (OIBs) are argued to contain a recycled componene, their uranium isotopic compositions do not differ from those of the bulk Earth. Because subducted uranium was probably isotopically unfractionated before full oceanic oxidation, about 600 million years ago, this observation reflects the greater antiquity of OIB sources. Elemental and isotope systematics of uranium in OIBs are strikingly consistent with previous OIB lead model ages(10), indicating that these mantle reservoirs formed between 2.4 and 1.8 billion years ago. In contrast, the uranium isotopic composition of MORB requires the convective stirring of recycled uranium throughout the upper mantle within the past 600 million years.
C1 [Andersen, Morten B.; Elliott, Tim; Freymuth, Heye] Univ Bristol, Sch Earth Sci, Bristol Isotope Grp, Bristol B58 1RJ, Avon, England.
   [Andersen, Morten B.] ETH, Dept Earth Sci, Inst Geochem & Petrol, CH-8092 Zurich, Switzerland.
   [Sims, Kenneth W. W.] Univ Wyoming, Dept Geol & Geophys, Laramie, WY 82071 USA.
   [Niu, Yaoling] Univ Durham, Dept Earth Sci, Durham DH1 3LE, England.
   [Kelley, Katherine A.] Univ Rhode Isl, Grad Sch Oceanog, Narragansett, RI 02882 USA.
C3 University of Bristol; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Wyoming; Durham University; University of Rhode Island
RP Andersen, MB (corresponding author), Univ Bristol, Sch Earth Sci, Bristol Isotope Grp, Bristol B58 1RJ, Avon, England.
EM morten.andersen@erdw.ethz.ch
FU NERC [NE/H023933/1]; Natural Environment Research Council [NE/H023933/1] Funding Source: researchfish; NERC [NE/H023933/1] Funding Source: UKRI
NR 107
TC 149
Z9 172
U1 12
U2 173
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 15
PY 2015
VL 517
IS 7534
BP 356
EP U463
DI 10.1038/nature14062
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300043
PM 25592542
DA 2026-03-09
ER

PT J
AU Islam, R
   Ma, RC
   Preiss, PM
   Tai, ME
   Lukin, A
   Rispoli, M
   Greiner, M
AF Islam, Rajibul
   Ma, Ruichao
   Preiss, Philipp M.
   Tai, M. Eric
   Lukin, Alexander
   Rispoli, Matthew
   Greiner, Markus
TI Measuring entanglement entropy in a quantum many-body system
SO NATURE
LA English
DT Article
ID trapped ions; states; interference; simulations
AB Entanglement is one of the most intriguing features of quantum mechanics. It describes non-local correlations between quantum objects, and is at the heart of quantum information sciences. Entanglement is now being studied in diverse fields ranging from condensed matter to quantum gravity. However, measuring entanglement remains a challenge. This is especially so in systems of interacting delocalized particles, for which a direct experimental measurement of spatial entanglement has been elusive. Here, we measure entanglement in such a system of itinerant particles using quantum interference of many-body twins. Making use of our single-site-resolved control of ultracold bosonic atoms in optical lattices, we prepare two identical copies of a many-body state and interfere them. This enables us to directly measure quantum purity, Renyi entanglement entropy, and mutual information. These experiments pave the way for using entanglement to characterize quantum phases and dynamics of strongly correlated many-body systems.
C1 [Islam, Rajibul; Ma, Ruichao; Preiss, Philipp M.; Tai, M. Eric; Lukin, Alexander; Rispoli, Matthew; 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 Gordon Foundation EPiQS Initiative [GBMF3795]; Betty Moore Foundation EPiQS Initiative [GBMF3795]; NSF through the Center for Ultracold Atoms; Army Research Office; DARPA OLE programme; MURI programme; Air Force Office of Scientific Research MURI programme; NSF Graduate Research Fellowship; Division Of Physics; Direct For Mathematical & Physical Scien [1125846] Funding Source: National Science Foundation; Gordon and Betty Moore Foundation (GBMF) [GBMF3795] Funding Source: Gordon and Betty Moore Foundation (GBMF)
NR 51
TC 931
Z9 1038
U1 13
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 DEC 3
PY 2015
VL 528
IS 7580
BP 77
EP 83
DI 10.1038/nature15750
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000051
PM 26632587
DA 2026-03-09
ER

PT J
AU Payne, KAP
   White, MD
   Fisher, K
   Khara, B
   Bailey, SS
   Parker, D
   Rattray, NJW
   Trivedi, DK
   Goodacre, R
   Beveridge, R
   Barran, P
   Rigby, SEJ
   Scrutton, NS
   Hay, S
   Leys, D
AF Payne, Karl A. P.
   White, Mark D.
   Fisher, Karl
   Khara, Basile
   Bailey, Samuel S.
   Parker, David
   Rattray, Nicholas J. W.
   Trivedi, Drupad K.
   Goodacre, Royston
   Beveridge, Rebecca
   Barran, Perdita
   Rigby, Stephen E. J.
   Scrutton, Nigel S.
   Hay, Sam
   Leys, David
TI New cofactor supports α,β-unsaturated acid decarboxylation via 1,3-dipolar cycloaddition
SO NATURE
LA English
DT Article
ID escherichia-coli; sorbic acid; coenzyme-q; biosynthesis; ubix; enzyme; genes; carboxylases; aspergillus; evolution
AB The bacterial ubiD and ubiX or the homologous fungal fdc1 and pad1 genes have been implicated in the non-oxidative reversible decarboxylation of aromatic substrates, and play a pivotal role in bacterial ubiquinone (also known as coenzyme Q) biosynthesis(1-3) or microbial biodegradation of aromatic compounds(4-6), respectively. Despite biochemical studies on individual gene products, the composition and cofactor requirement of the enzyme responsible for in vivo decarboxylase activity remained unclear(7-9). Here we show that Fdc1 is solely responsible for the reversible decarboxylase activity, and that it requires a new type of cofactor: a prenylated flavin synthesized by the associated UbiX/Pad1(10). Atomic resolution crystal structures reveal that two distinct isomers of the oxidized cofactor can be observed, an isoalloxazine N5-iminium adduct and a N5 secondary ketimine species with markedly altered ring structure, both having azomethine ylide character. Substrate binding positions the dipolarophile enoic acid group directly above the azomethine ylide group. The structure of a covalent inhibitor-cofactor adduct suggests that 1,3-dipolar cycloaddition chemistry supports reversible decarboxylation in these enzymes. Although 1,3-dipolar cycloaddition is commonly used in organic chemistry(11,12), we propose that this presents the first example, to our knowledge, of an enzymatic 1,3-dipolar cycloaddition reaction. Our model for Fdc1/UbiD catalysis offers new routes in alkene hydrocarbon production or aryl (de) carboxylation.
C1 [Payne, Karl A. P.; White, Mark D.; Fisher, Karl; Khara, Basile; Bailey, Samuel S.; Rattray, Nicholas J. W.; Trivedi, Drupad K.; Goodacre, Royston; Beveridge, Rebecca; Barran, Perdita; Rigby, Stephen E. J.; Scrutton, Nigel S.; Hay, Sam; Leys, David] Univ Manchester, Manchester Inst Biotechnol, Ctr Synthet Biol Fine & Special Chem, Manchester M1 7DN, Lancs, England.
   [Parker, David] Westhollow Technol Ctr, Innovat Biodomain Shell Int Explorat & Prod, Houston, TX 77082 USA.
C3 University of Manchester
RP Leys, D (corresponding author), Univ Manchester, Manchester Inst Biotechnol, Ctr Synthet Biol Fine & Special Chem, 131 Princess St, Manchester M1 7DN, Lancs, England.
EM david.leys@manchester.ac.uk
FU BBSRC [BB/K017802/1, BB/M/017702/1]; EU [FP-7 256808]; Royal Society; BBSRC [BB/M017702/1, BB/E013007/1, BB/K017802/1, BB/H021523/1] Funding Source: UKRI; EPSRC [EP/J020192/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/H021523/1, BB/K017802/1, BB/E013007/1, 1482350, BB/M017702/1] Funding Source: researchfish; Engineering and Physical Sciences Research Council [EP/J020192/1] Funding Source: researchfish
NR 37
TC 182
Z9 231
U1 3
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 JUN 25
PY 2015
VL 522
IS 7557
BP 497
EP +
DI 10.1038/nature14560
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL2OC
UT WOS:000356782900054
PM 26083754
DA 2026-03-09
ER

PT J
AU Doughty, CE
   Metcalfe, DB
   Girardin, CAJ
   Amézquita, FF
   Cabrera, DG
   Huasco, WH
   Silva-Espejo, JE
   Araujo-Murakami, A
   da Costa, MC
   Rocha, W
   Feldpausch, TR
   Mendoza, ALM
   da Costa, ACL
   Meir, P
   Phillips, OL
   Malhi, Y
AF Doughty, Christopher E.
   Metcalfe, D. B.
   Girardin, C. A. J.
   Farfan Amezquita, F.
   Galiano Cabrera, D.
   Huaraca Huasco, W.
   Silva-Espejo, J. E.
   Araujo-Murakami, A.
   da Costa, M. C.
   Rocha, W.
   Feldpausch, T. R.
   Mendoza, A. L. M.
   da Costa, A. C. L.
   Meir, P.
   Phillips, O. L.
   Malhi, Y.
TI Drought impact on forest carbon dynamics and fluxes in Amazonia
SO NATURE
LA English
DT Article
ID net primary productivity; tropical forest; throughfall exclusion; rain-forest; allocation; ecosystem; respiration; balance; sensitivity; biomass
AB In 2005 and 2010 the Amazon basin experienced two strong droughts', driven by shifts in the tropical hydrological regime(2) possibly associated with global climate change(3), as predicted by some global models'. Tree mortality increased after the 2005 drought(4), and regional atmospheric inversion modelling showed basin-wide decreases in CO2 uptake in 2010 compared with 2011 (ref. 5). But the response of tropical forest carbon cycling to these droughts is not fully understood and there has been no detailed multi-site investigation in situ. Here we use several years of data from a network of thirteen 1-ha forest plots spread throughout South America, where each component of net primary production (NPP), autotrophic respiration and heterotrophic respiration is measured separately, to develop a better mechanistic understanding of the impact of the 2010 drought on the Amazon forest. We find that total NPP remained constant throughout the drought. However, towards the end of the drought, autotrophic respiration, especially in roots and stems, declined significantly compared with measurements in 2009 made in the absence of drought, with extended decreases in autotrophic respiration in the three driest plots. In the year after the drought, total NPP remained constant but the allocation of carbon shifted towards canopy NPP and away from fine-root NPP. Both leaf-level and plot-level measurements indicate that severe drought suppresses photosynthesis. Scaling these measurements to the entire Amazon basin with rainfall data, we estimate that drought suppressed Amazon-wide photosynthesis in 2010 by 0.38 petagrams of carbon (0.23-0.53 petagrams of carbon). Overall, we find that during this drought, instead of reducing total NPP, trees prioritized growth by reducing autotrophic respiration that was unrelated to growth. This suggests that trees decrease investment in tissue maintenance and defence, in line with eco-evolutionary theories that trees are competitively disadvantaged in the absence of growth(6). We propose that weakened maintenance and defence investment may, in turn, cause the increase in post-drought tree mortality observed at our plots.
C1 [Doughty, Christopher E.; Girardin, C. A. J.; Malhi, Y.] Univ Oxford, Sch Geog & Environm, Environm Change Inst, Oxford OX1 3QY, England.
   [Metcalfe, D. B.] Lund Univ, Dept Phys Geog & Ecosyst Sci, S-22362 Lund, Sweden.
   [Farfan Amezquita, F.; Galiano Cabrera, D.; Huaraca Huasco, W.; Silva-Espejo, J. E.; Mendoza, A. L. M.] Univ Nacl San Antonio Abad Cusco, Cuzco, Peru.
   [Araujo-Murakami, A.] Univ Autonoma Gabriel Rene Moreno, Museo Hist Nat Noel Kempff Mercado, Santa Cruz, Bolivia.
   [da Costa, M. C.; da Costa, A. C. L.] Fed Univ Para, Inst Geociencias, Fac Meteorol, BR-66075110 Belem, Para, Brazil.
   [Rocha, W.] IPAM Inst Pesquisa Ambiental Amazonia, BR-78640000 Canarana, Mato Grosso, Brazil.
   [Feldpausch, T. R.] Univ Exeter, Coll Life & Environm Sci, Dept Geog, Exeter EX4 4RJ, Devon, England.
   [Meir, P.] Univ Edinburgh, Sch Geosci, Edinburgh EH9 3FF, Midlothian, Scotland.
   [Meir, P.] Australian Natl Univ, Res Sch Biol, Canberra, ACT 2601, Australia.
   [Phillips, O. L.] Univ Leeds, Sch Geog, Leeds LS2 9JT, W Yorkshire, England.
C3 University of Oxford; Lund University; Universidad Nacional de San Antonio Abad del Cusco; Universidade Federal do Para; University of Exeter; University of Edinburgh; Australian National University; University of Leeds
RP Doughty, CE (corresponding author), Univ Oxford, Sch Geog & Environm, Environm Change Inst, S Parks Rd, Oxford OX1 3QY, England.
EM chris.doughty@ouce.ox.ac.uk
FU Gordon and Betty Moore Foundation; Andes Biodiversity and Ecosystems Research Group (ABERG); UK Natural Environment Research Council [NE/D01025X/1, NE/D014174/1, NE/F002149/1, NE/J011002/1]; NERC AMAZONICA consortium grant [NE/F005776/1]; EU [282664, 283080]; National Council for Scientific and Technological Development (CNPq, Brazil); ARC [FT110100457]; ERC Advanced Investigator Award; Royal Society Wolfson Research Merit Award; Jackson Foundation; John Fell Fund; NERC [NE/J011002/1, NE/D01025X/1, NE/D010306/1, NE/I02982X/1, NE/D01185X/1, NE/J023418/1, NE/F005776/1, NE/D011191/1, NE/D014174/1] Funding Source: UKRI; Natural Environment Research Council [NE/B504630/1, NE/F002149/1, NE/I02982X/1, NE/D01025X/1, NER/A/S/2003/00608/2, NE/D011191/1, NE/D014174/1, NE/J011002/1, NE/D01185X/1, NE/D010306/1, NE/F005776/1, NE/J023418/1] Funding Source: researchfish
NR 48
TC 507
Z9 571
U1 18
U2 749
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 5
PY 2015
VL 519
IS 7541
BP 78
EP U140
DI 10.1038/nature14213
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC4EQ
UT WOS:000350304000039
PM 25739631
DA 2026-03-09
ER

PT J
AU Izawa, D
   Pines, J
AF Izawa, Daisuke
   Pines, Jonathon
TI The mitotic checkpoint complex binds a second CDC20 to inhibit active APC/C
SO NATURE
LA English
DT Article
ID spindle assembly checkpoint; bubr1; mad2; mitosis; destruction; apc(cdc20); mechanism; turnover; supports; arrest
AB The spindle assembly checkpoint (SAC) maintains genomic stability by delaying chromosome segregation until the last chromosome has attached to the mitotic spindle. The SAC prevents the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase from recognizing cyclin B and securin by catalysing the incorporation of the APC/C co-activator, CDC20, into a complex called the mitotic checkpoint complex (MCC). The SAC works through unattached kinetochores generating a diffusible 'wait anaphase' signal(1,2) that inhibits the APC/C in the cytoplasm, but the nature of this signal remains a key unsolved problem. Moreover, the SAC and the APC/C are highly responsive to each other: the APC/C quickly targets cyclin B and securin once all the chromosomes attach in metaphase, but is rapidly inhibited should kinetochore attachment be perturbed(3,4). How this is achieved is also unknown. Here, we show that the MCC can inhibit a second CDC20 that has already bound and activated the APC/C. We show how the MCC inhibits active APC/C and that this is essential for the SAC. Moreover, this mechanism can prevent anaphase in the absence of kinetochore signalling. Thus, we propose that the diffusible 'wait anaphase' signal could be the MCC itself, and explain how reactivating the SAC can rapidly inhibit active APC/C.
C1 [Izawa, Daisuke; Pines, Jonathon] Gurdon Inst, Cambridge CB2 1QN, England.
   [Izawa, Daisuke; Pines, Jonathon] Dept Zool, Cambridge CB2 1QN, England.
RP Pines, J (corresponding author), Gurdon Inst, Tennis Court Rd, Cambridge CB2 1QN, England.
EM jp103@cam.ac.uk
FU Cancer Research UK; Wellcome Trust; CR UK; Cancer Research UK [13678, 13959] Funding Source: researchfish
NR 29
TC 161
Z9 207
U1 1
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 JAN 29
PY 2015
VL 517
IS 7536
BP 631
EP U245
DI 10.1038/nature13911
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA2ZL
UT WOS:000348775000047
PM 25383541
DA 2026-03-09
ER

PT J
AU Zabow, G
   Dodd, SJ
   Koretsky, AP
AF Zabow, G.
   Dodd, S. J.
   Koretsky, A. P.
TI Shape-changing magnetic assemblies as high-sensitivity NMR-readable nanoprobes
SO NATURE
LA English
DT Article
ID intracellular ph; responsive hydrogel; multispectral mri; contrast agents; paracest agents; resonance; complexes; biology; probes
AB Fluorescent and plasmonic labels and sensors have revolutionized molecular biology, helping visualize cellular and biomolecular processes(1-3). Increasingly, such probes are now being designed to respond to wavelengths in the near-infrared region, where reduced tissue autofluorescence and photon attenuation enable subsurface in vivo sensing(4). But even in the near-infrared region, optical resolution and sensitivity decrease rapidly with increasing depth. Here we present a sensor design that obviates the need for optical addressability by operating in the nuclear magnetic resonance (NMR) radio-frequency spectrum, where signal attenuation and distortion by tissue and biological media are negligible, where background interferences vanish, and where sensors can be spatially located using standard magnetic resonance imaging(MRI) equipment. The radio-frequency-addressable sensor assemblies presented here comprise pairs of magnetic disks spaced by swellable hydrogel material; they reversibly reconfigure in rapid response to chosen stimuli, to give geometry-dependent, dynamic NMR spectral signatures. The sensors can be made from biocompatible materials, are themselves detectable down to low concentrations, and offer potential responsive NMR spectral shifts that are close to a million times greater than those of traditional magnetic resonance spectroscopies. Inherent adaptability should allow such shape-changing systems to measure numerous different environmental and physiological indicators, thus providing broadly generalizable, MRI-compatible, radio-frequency analogues to optically based probes for use in basic chemical, biological, medical and engineering research.
C1 [Zabow, G.; Dodd, S. J.; Koretsky, A. P.] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA.
   [Zabow, G.] NIST, Electromagnet Div, Phys Measurements Lab, Boulder, CO 80305 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS); National Institute of Standards & Technology (NIST) - USA
RP Zabow, G (corresponding author), NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA.
EM gary.zabow@nist.gov
FU NIH NINDS Intramural Research Program; National Institute of Neurological Disorders and Stroke [ZIANS003047] Funding Source: NIH RePORTER
NR 39
TC 55
Z9 67
U1 4
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 2
PY 2015
VL 520
IS 7545
BP 73
EP U157
DI 10.1038/nature14294
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE7NE
UT WOS:000352027700039
PM 25778701
DA 2026-03-09
ER

PT J
AU Cuthbertson, JD
   MacMillan, DWC
AF Cuthbertson, James D.
   MacMillan, David W. C.
TI The direct arylation of allylic sp3 C-H bonds via organic and photoredox catalysis
SO NATURE
LA English
DT Article
ID activation; photochemistry; oxidation; aldehydes; alkyl
AB The direct functionalization of unactivated sp(3) C-H bonds is still one of the most challenging problems facing synthetic organic chemists. The appeal of such transformations derives from their capacity to facilitate the construction of complex organic molecules via the coupling of simple and otherwise inert building blocks, without introducing extraneous functional groups. Despite notable recent efforts', the establishment of general and mild strategies for the engagement of sp(3) C-H bonds in C-C bond forming reactions has proved difficult. Within this context, the discovery of chemical transformations that are able to directly functionalize allylic methyl, methylene and methine carbons in a catalytic manner is a priority. Although protocols for direct oxidation and amination of allylic C-H bonds (that is, C-H bonds where an adjacent carbon is involved in a C=C bond) have become widely established(2,3), the engagement of allylic substrates in C-C bond forming reactions has thus far required the use of pre-functionalized coupling partners'. In particular, the direct arylation of non-functionalized allylic systems would enable access to a series of known pharmacophores (molecular features responsible for a drug's action), though a general solution to this long-standing challenge remains elusive. Here we report the use of both photoredox and organic catalysis to accomplish a mild, broadly effective direct allylic C-H arylation. This C-C bond forming reaction readily accommodates abroad range of alkene and electron-deficient arene reactants, and has been used in the direct arylation of benzylic C-H bonds.
C1 [Cuthbertson, James D.; 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 NIHGMS [R01 GM103558-03]; Merck; Amgen; Marie Curie Actions
NR 21
TC 454
Z9 485
U1 14
U2 506
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 5
PY 2015
VL 519
IS 7541
BP 74
EP 77
DI 10.1038/nature14255
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC4EQ
UT WOS:000350304000038
PM 25739630
DA 2026-03-09
ER

PT J
AU Sztainberg, Y
   Chen, HM
   Swann, JW
   Hao, S
   Tang, B
   Wu, ZY
   Tang, JR
   Wan, YW
   Liu, ZD
   Rigo, F
   Zoghbi, HY
AF Sztainberg, Yehezkel
   Chen, Hong-mei
   Swann, John W.
   Hao, Shuang
   Tang, Bin
   Wu, Zhenyu
   Tang, Jianrong
   Wan, Ying-Wooi
   Liu, Zhandong
   Rigo, Frank
   Zoghbi, Huda Y.
TI Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides
SO NATURE
LA English
DT Article
ID mouse model; learning-deficits; overexpression; therapeutics; behavior; therapy; dosage; xlmr; rna
AB Copy number variations have been frequently associated with developmental delay, intellectual disability and autism spectrum disorders(1). MECP2 duplication syndrome is one of the most common genomic rearrangements in males(2) and is characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections and early death(3-5). The broad range of deficits caused by methyl-CpG-binding protein 2 (MeCP2) overexpression poses a daunting challenge to traditional biochemical-pathway-based therapeutic approaches. Accordingly, we sought strategies that directly target MeCP2 and are amenable to translation into clinical therapy. The first question that we addressed was whether the neurological dysfunction is reversible after symptoms set in. Reversal of phenotypes in adult symptomatic mice has been demonstrated in some models of monogenic loss-of-function neurological disorders(6-8), including loss of MeCP2 in Rett syndrome(9), indicating that, at least in some cases, the neuroanatomy may remain sufficiently intact so that correction of the molecular dysfunction underlying these disorders can restore healthy physiology. Given the absence of neurodegeneration in MECP2 duplication syndrome, we propose that restoration of normal MeCP2 levels in MECP2 duplication adult mice would rescue their phenotype. By generating and characterizing a conditional Mecp2-overexpressing mouse model, here we show that correction of MeCP2 levels largely reverses the behavioural, molecular and electrophysiological deficits. We also reduced MeCP2 using an antisense oligonucleotide strategy, which has greater translational potential. Antisense oligonucleotides are small, modified nucleic acids that can selectively hybridize with messenger RNA transcribed from a target gene and silence it(10,11), and have been successfully used to correct deficits in different mouse models(12-18). We find that antisense oligonucleotide treatment induces a broad phenotypic rescue in adult symptomatic transgenic MECP2 duplication mice (MECP2-TG)(19,20), and corrected MECP2 levels in lymphoblastoid cells from MECP2 duplication patients in a dose-dependent manner.
C1 [Sztainberg, Yehezkel; Zoghbi, Huda Y.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.
   [Sztainberg, Yehezkel; Hao, Shuang; Tang, Bin; Wu, Zhenyu; Tang, Jianrong; Wan, Ying-Wooi; Liu, Zhandong; Zoghbi, Huda Y.] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA.
   [Chen, Hong-mei; Swann, John W.] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Cain Fdn Labs, Houston, TX 77030 USA.
   [Chen, Hong-mei; Swann, John W.] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA.
   [Chen, Hong-mei; Swann, John W.; Hao, Shuang; Tang, Bin; Wu, Zhenyu; Tang, Jianrong; Liu, Zhandong; Zoghbi, Huda Y.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA.
   [Wan, Ying-Wooi] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA.
   [Rigo, Frank] ISIS Pharmaceut, Carlsbad, CA 92010 USA.
   [Zoghbi, Huda Y.] Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA.
C3 Baylor College of Medicine; Baylor College of Medicine; Baylor College Medical Hospital; Baylor College of Medicine; Baylor College Medical Hospital; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Ionis Pharmaceuticals, Inc.; Howard Hughes Medical Institute; Baylor College of Medicine
RP Zoghbi, HY (corresponding author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.
EM hzoghbi@bcm.edu
FU National Institutes of Health [5R01NS057819, 5P30HD024064]; Rett Syndrome Research Trust (401 Project); Carl. C. Anderson, Sr and Marie Jo Anderson Charitable Foundation; Howard Hughes Medical Institute; NSF [DMS-1263932]; Baylor Intellectual Disabilities Research Center [1U54HD083092]; National Institute of Neurological Disorders and Stroke [R01NS057819] Funding Source: NIH RePORTER; Direct For Mathematical & Physical Scien; Division Of Mathematical Sciences [1263932] Funding Source: National Science Foundation
NR 37
TC 160
Z9 190
U1 2
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 3
PY 2015
VL 528
IS 7580
BP 123
EP +
DI 10.1038/nature16159
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000061
PM 26605526
DA 2026-03-09
ER

PT J
AU De Sanctis, MC
   Ammannito, E
   Raponi, A
   Marchi, S
   McCord, TB
   McSween, HY
   Capaccioni, F
   Capria, MT
   Carrozzo, FG
   Ciarniello, M
   Longobardo, A
   Tosi, F
   Fonte, S
   Formisano, M
   Frigeri, A
   Giardino, M
   Magni, G
   Palomba, E
   Turrini, D
   Zambon, F
   Combe, JP
   Feldman, W
   Jaumann, R
   McFadden, LA
   Pieters, CM
   Prettyman, T
   Toplis, M
   Raymond, CA
   Russell, CT
AF De Sanctis, M. C.
   Ammannito, E.
   Raponi, A.
   Marchi, S.
   McCord, T. B.
   McSween, H. Y.
   Capaccioni, F.
   Capria, M. T.
   Carrozzo, F. G.
   Ciarniello, M.
   Longobardo, A.
   Tosi, F.
   Fonte, S.
   Formisano, M.
   Frigeri, A.
   Giardino, M.
   Magni, G.
   Palomba, E.
   Turrini, D.
   Zambon, F.
   Combe, J. -P.
   Feldman, W.
   Jaumann, R.
   McFadden, L. A.
   Pieters, C. M.
   Prettyman, T.
   Toplis, M.
   Raymond, C. A.
   Russell, C. T.
TI Ammoniated phyllosilicates with a likely outer Solar System origin on (1) Ceres
SO NATURE
LA English
DT Article
ID surface-composition; optical-constants; spectral variability; crystalline h2o-ice; clay-minerals; mu-m; reflectance; asteroids; spectroscopy; temperature
AB Studies of the dwarf planet (1) Ceres using ground-based and orbiting telescopes have concluded that its closest meteoritic analogues are the volatile-rich CI and CM carbonaceous chondrites(1,2). Water in clay minerals(3), ammoniated phyllosilicates(4), or a mixture of Mg(OH)(2) (brucite), Mg2CO3 and iron-rich serpentine(5,6) have all been proposed to exist on the surface. In particular, brucite has been suggested from analysis of the mid-infrared spectrum of Ceres(6). But the lack of spectral data across telluric absorption bands in the wavelength region 2.5 to 2.9 micrometres-where the OH stretching vibration and the H2O bending overtone are found-has precluded definitive identifications. In addition, water vapour around Ceres has recently been reported(7), possibly originating from localized sources. Here we report spectra of Ceres from 0.4 to 5 micrometres acquired at distances from similar to 82,000 to 4,300 kilometres from the surface. Our measurements indicate widespread ammoniated phyllosilicates across the surface, but no detectable water ice. Ammonia, accreted either as organic matter or as ice, may have reacted with phyllosilicates on Ceres during differentiation. This suggests that material from the outer Solar System was incorporated into Ceres, either during its formation at great heliocentric distance or by incorporation of material transported into the main asteroid belt.
C1 [De Sanctis, M. C.; Ammannito, E.; Raponi, A.; Marchi, S.; Capaccioni, F.; Capria, M. T.; Carrozzo, F. G.; Ciarniello, M.; Longobardo, A.; Tosi, F.; Fonte, S.; Formisano, M.; Frigeri, A.; Giardino, M.; Magni, G.; Palomba, E.; Turrini, D.; Zambon, F.] INAF, Ist Astrofis & Planetol Spaziali, I-00133 Rome, Italy.
   [Ammannito, E.; Russell, C. T.] Univ Calif Los Angeles, Inst Geophys & Planetary Phys, Los Angeles, CA 90095 USA.
   [Marchi, S.] SW Res Inst, Boulder, CO 80302 USA.
   [McCord, T. B.; Combe, J. -P.] Bear Fight Inst, Winthrop, WA 98862 USA.
   [McSween, H. Y.] Univ Tennessee, Dept Earth & Planetary Sci, Knoxville, TN 37996 USA.
   [Feldman, W.; Prettyman, T.] Planetary Sci Inst, Tucson, AZ 85719 USA.
   [Jaumann, R.] German Aerosp Ctr DLR, Inst Planetary Res, D-12489 Berlin, Germany.
   [McFadden, L. A.] NASA, Goddard Space Flight Ctr, Greenbelt, MD 20771 USA.
   [Pieters, C. M.] Brown Univ, Dept Earth Environm & Planetary Sci, Providence, RI 02912 USA.
   [Toplis, M.] Univ Toulouse 3, Observ Midi Pyrenees, Inst Rech Astrophys & Planetol, F-31400 Toulouse, France.
   [Raymond, C. A.] CALTECH, Jet Prop Lab, Pasadena, CA USA.
C3 Istituto Nazionale Astrofisica (INAF); University of California System; University of California Los Angeles; University of Tennessee System; University of Tennessee Knoxville; Helmholtz Association; German Aerospace Centre (DLR); National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center; Brown University; Universite de Toulouse; Universite Toulouse III - Paul Sabatier; California Institute of Technology; National Aeronautics & Space Administration (NASA); NASA Jet Propulsion Laboratory (JPL)
RP De Sanctis, MC (corresponding author), INAF, Ist Astrofis & Planetol Spaziali, Via Fosso del Cavaliere 100, I-00133 Rome, Italy.
EM mariacristina.desanctis@iaps.inaf.it
FU Italian Space Agency (ASI); National Aeronautic and Space Administration (NASA, USA); Deutsches Zentrum fur Luft- und Raumfahrt (DLR, Germany); Italian Space Agency
NR 43
TC 288
Z9 311
U1 0
U2 71
PU NATURE PUBLISHING 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 10
PY 2015
VL 528
IS 7581
BP 241
EP +
DI 10.1038/nature16172
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX9VH
UT WOS:000366053300036
PM 26659184
DA 2026-03-09
ER

PT J
AU Grün, D
   Lyubimova, A
   Kester, L
   Wiebrands, K
   Basak, O
   Sasaki, N
   Clevers, H
   van Oudenaarden, A
AF Grun, Dominic
   Lyubimova, Anna
   Kester, Lennart
   Wiebrands, Kay
   Basak, Onur
   Sasaki, Nobuo
   Clevers, Hans
   van Oudenaarden, Alexander
TI Single-cell messenger RNA sequencing reveals rare intestinal cell types
SO NATURE
LA English
DT Article
ID stem-cells; seq; differentiation; heterogeneity; lineage; colon; crypt
AB Understanding the development and function of an organ requires the characterization of all of its cell types. Traditional methods for visualizing and isolating subpopulations of cells are based on messenger RNA or protein expression of only a few known marker genes. The unequivocal identification of a specific marker gene, however, poses a major challenge, particularly if this cell type is rare. Identifying rare cell types, such as stem cells, short-lived progenitors, cancer stem cells, or circulating tumour cells, is crucial to acquire a better understanding of normal or diseased tissue biology. To address this challenge we first sequenced the transcriptome of hundreds of randomly selected cells from mouse intestinal organoids(1), cultured self-organizing epithelial structures that contain all cell lineages of the mammalian intestine. Organoid buds, like intestinal crypts, harbour stem cells that continuously differentiate into a variety of cell types, occurring at widely different abundances(2). Since available computational methods can only resolve more abundant cell types, we developed RaceID, an algorithm for rare cell type identification in complex populations of single cells. We demonstrate that this algorithm can resolve cell types represented by only a single cell in a population of randomly sampled organoid cells. We use this algorithm to identify Reg4 as a novel marker for enteroendocrine cells, a rare population of hormone-producing intestinal cells(3). Next, we use Reg4 expression to enrich for these rare cells and investigate the heterogeneity within this population. RaceID confirmed the existence of known enteroendocrine lineages, and moreover discovered novel subtypes, which we subsequently validated in vivo. Having validated RaceID we then applied the algorithm to ex vivo-isolated Lgr5-positive stem cells and their direct progeny. We find that Lgr5-positive cells represent a homogenous abundant population of stem cells mixed with a rare population of Lgr5-positive secretory cells. We envision broad applicability of our method for discovering rare cell types and the corresponding marker genes in healthy and diseased organs.
C1 [Grun, Dominic; Lyubimova, Anna; Kester, Lennart; Wiebrands, Kay; Basak, Onur; Sasaki, Nobuo; Clevers, Hans; van Oudenaarden, Alexander] Royal Netherlands Acad Arts & Sci, Hubrecht Inst KNAW, NL-3584 CT Utrecht, Netherlands.
   [Grun, Dominic; Lyubimova, Anna; Kester, Lennart; Wiebrands, Kay; Basak, Onur; Sasaki, Nobuo; Clevers, Hans; van Oudenaarden, Alexander] Univ Med Ctr Utrecht, Canc Genom Netherlands, NL-3584 CG Utrecht, Netherlands.
C3 Royal Netherlands Academy of Arts & Sciences; Hubrecht Institute (KNAW); Utrecht University; Utrecht University Medical Center
RP van Oudenaarden, A (corresponding author), Royal Netherlands Acad Arts & Sci, Hubrecht Inst KNAW, NL-3584 CT Utrecht, Netherlands.
EM a.vanoudenaarden@hubrecht.eu
FU European Research Council [ERC-AdG 294325-GeneNoiseControl]; Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Vici award
NR 31
TC 905
Z9 1142
U1 7
U2 316
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 10
PY 2015
VL 525
IS 7568
BP 251
EP +
DI 10.1038/nature14966
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400039
PM 26287467
DA 2026-03-09
ER

PT J
AU Rubio, M
   Elmegreen, BG
   Hunter, DA
   Brinks, E
   Cortés, JR
   Cigan, P
AF Rubio, Monica
   Elmegreen, Bruce G.
   Hunter, Deidre A.
   Brinks, Elias
   Cortes, Juan R.
   Cigan, Phil
TI Dense cloud cores revealed by CO in the low metallicity dwarf galaxy WLM
SO NATURE
LA English
DT Article
ID galactic molecular clouds; star-formation; irregular galaxy; milky-way; gas; clusters; stellar; carbon; things; mass
AB Understanding stellar birth requires observations of the clouds in which they form. These clouds are dense and self-gravitating, and in all existing observations they are molecular, with H-2 the dominant species and carbon monoxide (CO) the best available tracer(1,2). When the abundances of carbon and oxygen are low compared with that of hydrogen, and the opacity from dust is also low, as in primeval galaxies and local dwarf irregular galaxies(3), CO forms slowly and is easily destroyed, so it is difficult for it to accumulate inside dense clouds(4). Here we report interferometric observations of CO clouds in the local group dwarf irregular galaxy Wolf-Lundmark-Melotte (WLM)(5), which has a metallicity that is 13 per cent of the solar value(6,7) and 50 per cent lower than the previous CO detection threshold. The clouds are tiny compared to the surrounding atomic and H-2 envelopes, but they have typical densities and column densities for CO clouds in the Milky Way. The normal CO density explains why star clusters forming in dwarf irregulars have similar densities to star clusters in giant spiral galaxies. The low cloud masses suggest that these clusters will also be low mass, unless some galaxy-scale compression occurs, such as an impact from a cosmic cloud or other galaxy. If the massive metal-poor globular clusters in the halo of the Milky Way formed in dwarf galaxies, as is commonly believed, then they were probably triggered by such an impact.
C1 [Rubio, Monica] Univ Chile, Dept Astron, Santiago 8320000, Chile.
   [Elmegreen, Bruce G.] IBM Corp, Div Res, TJ Watson Res Ctr, Yorktown Hts, NY 10598 USA.
   [Hunter, Deidre A.] Lowell Observ, Flagstaff, AZ 86001 USA.
   [Brinks, Elias] Univ Hertfordshire, Ctr Astrophys Res, Hatfield AL10 9AB, Herts, England.
   [Cortes, Juan R.] Joint ALMA Observ, Santiago 7630355, Chile.
   [Cortes, Juan R.] Natl Radio Astron Observ, Santiago 7630197, Chile.
   [Cigan, Phil] New Mexico Inst Min & Technol, Socorro, NM 87801 USA.
C3 Universidad de Chile; International Business Machines (IBM); IBM USA; University of Hertfordshire; National Radio Astronomy Observatory (NRAO); New Mexico Institute of Mining Technology
RP Elmegreen, BG (corresponding author), IBM Corp, Div Res, TJ Watson Res Ctr, 1101 Kitchawan Rd, Yorktown Hts, NY 10598 USA.
EM bge@us.ibm.com
FU Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) through FONDECYT [1140839]; CONICYT [BASAL PFB-06]; Lowell Observatory Research Fund; NASA (National Aeronautics and Space Administration) JPL RSA [1433776, 1456896]; STFC [ST/M001008/1] Funding Source: UKRI; Science and Technology Facilities Council [ST/M001008/1] Funding Source: researchfish
NR 30
TC 78
Z9 82
U1 0
U2 11
PU NATURE PUBLISHING 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 10
PY 2015
VL 525
IS 7568
BP 218
EP +
DI 10.1038/nature14901
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400031
PM 26354481
DA 2026-03-09
ER

PT J
AU Heler, R
   Samai, P
   Modell, JW
   Weiner, C
   Goldberg, GW
   Bikard, D
   Marraffini, LA
AF Heler, Robert
   Samai, Poulami
   Modell, Joshua W.
   Weiner, Catherine
   Goldberg, Gregory W.
   Bikard, David
   Marraffini, Luciano A.
TI Cas9 specifies functional viral targets during CRISPR-Cas adaptation
SO NATURE
LA English
DT Article
ID adaptive bacterial immunity; streptococcus-thermophilus; escherichia-coli; nucleotide-sequence; spacer acquisition; structural basis; dual-rna; dna; system; endonuclease
AB Clustered regularly interspaced short palindromic repeat (CRISPR) loci and their associated (Cas) proteins provide adaptive immunity against viral infection in prokaryotes. Upon infection, short phage sequences known as spacers integrate between CRISPR repeats and are transcribed into small RNA molecules that guide the Cas9 nuclease to the viral targets (protospacers). Streptococcus pyogenes Cas9 cleavage of the viral genome requires the presence of a 5'-NGG-3' protospacer adjacent motif (PAM) sequence immediately downstream of the viral target. It is not known whether and how viral sequences flanked by the correct PAM are chosen as new spacers. Here we show that Cas9 selects functional spacers by recognizing their PAM during spacer acquisition. The replacement of cas9 with alleles that lack the PAM recognition motif or recognize an NGGNG PAM eliminated or changed PAM specificity during spacer acquisition, respectively. Cas9 associates with other proteins of the acquisition machinery (Cas1, Cas2 and Csn2), presumably to provide PAM-specificity to this process. These results establish a new function for Cas9 in the genesis of prokaryotic immunological memory.
C1 [Heler, Robert; Samai, Poulami; Modell, Joshua W.; Weiner, Catherine; Goldberg, Gregory W.; Bikard, David; Marraffini, Luciano A.] Rockefeller Univ, Bacteriol Lab, New York, NY 10065 USA.
   [Bikard, David] Inst Pasteur, Synthet Biol Grp, F-75015 Paris, France.
C3 Rockefeller University; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris
RP Bikard, D (corresponding author), Rockefeller Univ, Bacteriol Lab, 1230 York Ave, New York, NY 10065 USA.
EM david.bikard@pasteur.fr; marraffini@rockefeller.edu
FU Howard Hughes International Student Research Fellowship; Helmsley Postdoctoral Fellowship for Basic and Translational Research on Disorders of the Digestive Systemat The Rockefeller University; Harvey L. Karp Discovery Award; Bettencourt Schuller Foundation; Rita Allen Scholars Program; IrmaT. Hirschl Award; Sinsheimer Foundation Award; NIH Director's New Innovator Award [1DP2AI104556-01]
NR 34
TC 309
Z9 430
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 MAR 12
PY 2015
VL 519
IS 7542
BP 199
EP +
DI 10.1038/nature14245
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500031
PM 25707807
DA 2026-03-09
ER

PT J
AU Gabel, HW
   Kinde, B
   Stroud, H
   Gilbert, CS
   Harmin, DA
   Kastan, NR
   Hemberg, M
   Ebert, DH
   Greenberg, ME
AF Gabel, Harrison W.
   Kinde, Benyam
   Stroud, Hume
   Gilbert, Caitlin S.
   Harmin, David A.
   Kastan, Nathaniel R.
   Hemberg, Martin
   Ebert, Daniel H.
   Greenberg, Michael E.
TI Disruption of DNA-methylation-dependent long gene repression in Rett syndrome
SO NATURE
LA English
DT Article
ID bdnf transcription; expression changes; binding domain; messenger-rnas; mouse models; mecp2; phosphorylation; purification; duplication; chromatin
AB Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism(1). MECP2 encodes a methyl-DNA-binding protein(2) that has been proposed to function as a transcriptional repressor, but despite numerous mouse studies examining neuronal gene expression in Mecp2 mutants, no clear model has emerged for how MeCP2 protein regulates transcription(3-9). Here we identify a genome-wide length-dependent increase in gene expression in MeCP2 mutant mouse models and human RTT brains. We present evidence that MeCP2 represses gene expression by binding to methylated CA sites within long genes, and that in neurons lacking MeCP2, decreasing the expression of long genes attenuates RTT-associated cellular deficits. In addition, we find that long genes as a population are enriched for neuronal functions and selectively expressed in the brain. These findings suggest that mutations in MeCP2 may cause neurological dysfunction by specifically disrupting long gene expression in the brain.
C1 [Gabel, Harrison W.; Kinde, Benyam; Stroud, Hume; Gilbert, Caitlin S.; Harmin, David A.; Kastan, Nathaniel R.; Ebert, Daniel H.; Greenberg, Michael E.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA.
   [Hemberg, Martin] Harvard Univ, Ctr Brain Sci, Childrens Hosp Boston, Dept Ophthalmol, Boston, MA 02115 USA.
   [Hemberg, Martin] Harvard Univ, Swartz Ctr Theoret Neurosci, Boston, MA 02115 USA.
C3 Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University
RP Greenberg, ME (corresponding author), Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA.
EM michael_greenberg@hms.harvard.edu
FU Rett Syndrome Research Trust; National Institutes of Health (NIH) [1RO1NS048276]; Damon Runyon Cancer Research Foundation [DRG-2048-10]; William Randolf Hearst fund; NIH [T32GM007753]; HHMI; National Institute of General Medical Sciences [T32GM007753] Funding Source: NIH RePORTER
NR 53
TC 440
Z9 528
U1 1
U2 97
PU NATURE PUBLISHING 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 4
PY 2015
VL 522
IS 7554
BP 89
EP U221
DI 10.1038/nature14319
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ5QP
UT WOS:000355543400035
PM 25762136
DA 2026-03-09
ER

PT J
AU Plata, G
   Henry, CS
   Vitkup, D
AF Plata, German
   Henry, Christopher S.
   Vitkup, Dennis
TI Long-term phenotypic evolution of bacteria
SO NATURE
LA English
DT Article
ID genetic interaction networks; generation; conservation; strains
AB For many decades comparative analyses of protein sequences and structures have been used to investigate fundamental principles of molecular evolution(1,2). In contrast, relatively little is known about the long-term evolution of species' phenotypic and genetic properties. This represents an important gap in our understanding of evolution, as exactly these proprieties play key roles in natural selection and adaptation to diverse environments. Here we perform a comparative analysis of bacterial growth and gene deletion phenotypes using hundreds of genome-scale metabolic models. Overall, bacterial phenotypic evolution can be described by a two-stage process with a rapid initial phenotypic diversification followed by a slow long-term exponential divergence. The observed average divergence trend, with approximately similar fractions of phenotypic properties changing per unit time, continues for billions of years. We experimentally confirm the predicted divergence trend using the phenotypic profiles of 40 diverse bacterial species across more than 60 growth conditions. Our analysis suggests that, at long evolutionary distances, gene essentiality is significantly more conserved than the ability to utilize different nutrients, while synthetic lethality is significantly less conserved. We also find that although a rapid phenotypic evolution is sometimes observed within the same species, a transition from high to low phenotypic similarity occurs primarily at the genus level.
C1 [Plata, German; Vitkup, Dennis] Columbia Univ, Dept Syst Biol, Ctr Computat Biol & Bioinformat, New York, NY 10032 USA.
   [Plata, German] Columbia Univ, Integrated Program Cellular Mol Struct & Genet St, New York, NY 10032 USA.
   [Henry, Christopher S.] Argonne Natl Lab, Div Math & Comp Sci, Argonne, IL 60439 USA.
   [Vitkup, Dennis] Columbia Univ, Dept Biomed Informat, New York, NY 10032 USA.
C3 Columbia University; Columbia University; United States Department of Energy (DOE); Argonne National Laboratory; Columbia University
RP Vitkup, D (corresponding author), Columbia Univ, Dept Syst Biol, Ctr Computat Biol & Bioinformat, New York, NY 10032 USA.
EM dv2121@columbia.edu
FU National Institute of General Medical Sciences [GM079759, U54CA121852]; Department of Energy, as part of the SB Knowledgebase [DE-AC02-06CH11357]
NR 30
TC 65
Z9 73
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 JAN 15
PY 2015
VL 517
IS 7534
BP 369
EP U498
DI 10.1038/nature13827
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300046
PM 25363780
DA 2026-03-09
ER

PT J
AU Tailo, M
   D'Antona, F
   Vesperini, E
   Di Criscienzo, M
   Ventura, P
   Milone, AP
   Bellini, A
   Dotter, A
   Decressin, T
   D'Ercole, A
   Caloi, V
   Capuzzo-Dolcetta, R
AF Tailo, Marco
   D'Antona, Francesca
   Vesperini, Enrico
   Di Criscienzo, Marcella
   Ventura, Paolo
   Milone, Antonino P.
   Bellini, Andrea
   Dotter, Aaron
   Decressin, Thibaut
   D'Ercole, Annibale
   Caloi, Vittoria
   Capuzzo-Dolcetta, Roberto
TI Rapidly rotating second-generation progenitors for the 'blue hook' stars of ω Centauri
SO NATURE
LA English
DT Article
ID horizontal-branch stars; low-mass stars; angular-momentum evolution; globular-cluster stars; dwarf cooling curve; ultraviolet extinction; stellar populations; internal-rotation; atomic diffusion; giant branch
AB Horizontal branch stars belong to an advanced stage in the evolution of the oldest stellar galactic population, occurring either as field halo stars or grouped in globular clusters. The discovery of multiple populations in clusters(1,2) that were previously believed to have single populations gave rise to the currently accepted theory that the hottest horizontal branch members (the 'blue hook' stars, which had late helium-core flash ignition(3), followed by deep mixing(4,5)) are the progeny of a helium-rich 'second generation' of stars(6,7). It is not known why such a supposedly rare event(8,9) (a late flash followed by mixing) is so common that the blue hook of omega Centauri contains approximately 30 per cent of the horizontal branch stars in the cluster(10), or why the blue hook luminosity range in this massive cluster cannot be reproduced by models. Here we report that the presence of helium core masses up to about 0.04 solar masses larger than the core mass resulting from evolution is required to solve the luminosity range problem. We model this by taking into account the dispersion in rotation rates achieved by the progenitors, whose pre-main-sequence accretion disk suffered an early disruption in the dense environment of the cluster's central regions, where second-generation stars form(11). Rotation may also account for frequent late-flash-mixing events in massive globular clusters.
C1 [Tailo, Marco; D'Antona, Francesca; Di Criscienzo, Marcella; Ventura, Paolo; Decressin, Thibaut] INAF Osservatorio Astron Roma, I-00040 Rome, Italy.
   [Tailo, Marco; Capuzzo-Dolcetta, Roberto] Univ Roma La Sapienza, Dipartimento Fis, I-00185 Rome, Italy.
   [Vesperini, Enrico] Indiana Univ, Dept Astron, Bloomington, IN 47405 USA.
   [Milone, Antonino P.; Dotter, Aaron] Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT 2611, Australia.
   [Bellini, Andrea] Space Telescope Sci Inst, Baltimore, MD 21218 USA.
   [D'Ercole, Annibale] INAF Osservatorio Astron Bologna, I-40127 Bologna, Italy.
   [Caloi, Vittoria] IAPS, INAF, I-00133 Rome, Italy.
C3 Istituto Nazionale Astrofisica (INAF); Sapienza University Rome; Indiana University System; Indiana University Bloomington; Australian National University; Space Telescope Science Institute; Istituto Nazionale Astrofisica (INAF); Istituto Nazionale Astrofisica (INAF)
RP D'Antona, F (corresponding author), INAF Osservatorio Astron Roma, I-00040 Rome, Italy.
EM franca.dantona@gmail.com
FU Australian Research Council [DE150101816]; PRIN INAF "Multiple populations in globular clusters: their role in the Galaxy assembly''; PRIN MIUR, project "The Chemical and Dynamical Evolution of the Milky Way and Local Group Galaxies''; UE Program (FP7) of Astronomy Fellowships in Italy (ASTROFit) [267251]; INAF-OAR; STScI grant [AR-12656];  [NASANNX13AF45G]; Australian Research Council [DE150101816] Funding Source: Australian Research Council
NR 46
TC 35
Z9 36
U1 0
U2 4
PU NATURE PUBLISHING 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 16
PY 2015
VL 523
IS 7560
BP 318
EP +
DI 10.1038/nature14516
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM8KY
UT WOS:000357950900035
PM 26098367
DA 2026-03-09
ER

PT J
AU Ghalambor, CK
   Hoke, KL
   Ruell, EW
   Fischer, EK
   Reznick, DN
   Hughes, KA
AF Ghalambor, Cameron K.
   Hoke, Kim L.
   Ruell, Emily W.
   Fischer, Eva K.
   Reznick, David N.
   Hughes, Kimberly A.
TI Non-adaptive plasticity potentiates rapid adaptive evolution of gene expression in nature
SO NATURE
LA English
DT Article
ID life-history evolution; phenotypic plasticity; trinidadian guppy; adaptation; divergence; populations; predation; selection; marine
AB Phenotypic plasticity is the capacity for an individual genotype to produce different phenotypes in response to environmental variation(1). Most traits are plastic, but the degree to which plasticity is adaptive or non-adaptive depends on whether environmentally induced phenotypes are closer or further away from the local optimum(2-4). Existing theories make conflicting predictions about whether plasticity constrains or facilitates adaptive evolution(4-12). Debate persists because few empirical studies have tested the relationship between initial plasticity and subsequent adaptive evolution in natural populations. Here we show that the direction of plasticity in gene expression is generally opposite to the direction of adaptive evolution. We experimentally transplanted Trinidadian guppies (Poecilia reticulata) adapted to living with cichlid predators to cichlid-free streams, and tested for evolutionary divergence in brain gene expression patterns after three to four generations. We find 135 transcripts that evolved parallel changes in expression within the replicated introduction populations. These changes are in the same direction exhibited in a native cichlid-free population, suggesting rapid adaptive evolution. We find 89% of these transcripts exhibited non-adaptive plastic changes in expression when the source population was reared in the absence of predators, as they are in the opposite direction to the evolved changes. By contrast, the remaining transcripts exhibiting adaptive plasticity show reduced population divergence. Furthermore, the most plastic transcripts in the source population evolved reduced plasticity in the introduction populations, suggesting strong selection against non-adaptive plasticity. These results support models predicting that adaptive plasticity constrains evolution(6-8), whereas non-adaptive plasticity potentiates evolution by increasing the strength of directional selection(11,12). The role of non-adaptive plasticity in evolution has received relatively little attention; however, our results suggest that it may be an important mechanism that predicts evolutionary responses to new environments.
C1 [Ghalambor, Cameron K.; Hoke, Kim L.; Ruell, Emily W.; Fischer, Eva K.] Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA.
   [Ghalambor, Cameron K.; Hoke, Kim L.] Colorado State Univ, Grad Degree Program Ecol, Ft Collins, CO 80523 USA.
   [Reznick, David N.] Univ Calif Riverside, Dept Biol, Riverside, CA 92521 USA.
   [Hughes, Kimberly A.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA.
C3 Colorado State University System; Colorado State University Fort Collins; Colorado State University System; Colorado State University Fort Collins; University of California System; University of California Riverside; State University System of Florida; Florida State University
RP Ghalambor, CK (corresponding author), Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA.
EM cameron1@colostate.edu; kahughes@bio.fsu.edu
FU National Science Foundation [DEB-0846175, EF-0623632, IOS-0934451, IOS-1354775]; Direct For Biological Sciences; Division Of Environmental Biology [1258231, 0846175] Funding Source: National Science Foundation
NR 41
TC 451
Z9 550
U1 4
U2 453
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 17
PY 2015
VL 525
IS 7569
BP 372
EP +
DI 10.1038/nature15256
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900042
PM 26331546
DA 2026-03-09
ER

PT J
AU Chen, C
   Buhl, E
   Xu, M
   Croset, V
   Rees, JS
   Lilley, KS
   Benton, R
   Hodge, JJL
   Stanewsky, R
AF Chen, Chenghao
   Buhl, Edgar
   Xu, Min
   Croset, Vincent
   Rees, Johanna S.
   Lilley, Kathryn S.
   Benton, Richard
   Hodge, James J. L.
   Stanewsky, Ralf
TI Drosophila Ionotropic Receptor 25a mediates circadian clock resetting by temperature
SO NATURE
LA English
DT Article
ID glutamate receptors; synchronization; cryptochrome; expression; channel; gene; hygrosensation; preference; mutants; neurons
AB Circadian clocks are endogenous timers adjusting behaviour and physiology with the solar day(1). Synchronized circadian clocks improve fitness(2) and are crucial for our physical and mental well-being(3). Visual and non-visual photoreceptors are responsible for synchronizing circadian clocks to light(4,5), but clock-resetting is also achieved by alternating day and night temperatures with only 2-4 degrees C difference(6-8). This temperature sensitivity is remarkable considering that the circadian clock period (similar to 24 h) is largely independent of surrounding ambient temperatures(1,8). Here we show that Drosophila Ionotropic Receptor 25a (IR25a) is required for behavioural synchronization to low-amplitude temperature cycles. This channel is expressed in sensory neurons of internal stretch receptors previously implicated in temperature synchronization of the circadian clock(9). IR25a is required for temperature-synchronized clock protein oscillations in subsets of central clock neurons. Extracellular leg nerve recordings reveal temperature-and IR25a-dependent sensory responses, and IR25a misexpression confers temperature-dependent firing of heterologous neurons. We propose that IR25a is part of an input pathway to the circadian clock that detects small temperature differences. This pathway operates in the absence of known 'hot' and 'cold' sensors in the Drosophila antenna(10,11), revealing the existence of novel periphery-to-brain temperature signalling channels.
C1 [Chen, Chenghao; Xu, Min; Stanewsky, Ralf] UCL, Dept Cell & Dev Biol, London WC1E 6DE, England.
   [Buhl, Edgar; Hodge, James J. L.] Univ Bristol, Sch Physiol & Pharmacol, Bristol BS8 1TD, Avon, England.
   [Croset, Vincent; Benton, Richard] Univ Lausanne, Fac Biol & Med, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland.
   [Rees, Johanna S.; Lilley, Kathryn S.] Univ Cambridge, Dept Biochem, Cambridge Ctr Prote, Cambridge CB2 1QW, England.
   [Rees, Johanna S.; Lilley, Kathryn S.] Univ Cambridge, Cambridge Syst Biol Ctr, Cambridge CB2 1QW, England.
C3 University of London; University College London; University of Bristol; University of Lausanne; University of Cambridge; University of Cambridge
RP Chen, C (corresponding author), UCL, Dept Cell & Dev Biol, 21 Univ St, London WC1E 6DE, England.
EM r.stanewsky@ucl.ac.uk
FU BBSRC [BB/H001204, BB/J0-18589/-17221]; CSC PhD fellowship; Boehringer Ingelheim Foundation Fellowship; European Research Council [205202, 615094]; Wellcome Trust [099135/Z/12/Z]; Wellcome Trust [099135/Z/12/Z] Funding Source: Wellcome Trust; European Research Council (ERC) [205202] Funding Source: European Research Council (ERC); BBSRC [BB/H001204/1, BB/J018589/2, BB/J017221/1, BB/J018589/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/J018589/1, BB/J017221/1, BB/J018589/2, BB/H001204/1] Funding Source: researchfish
NR 43
TC 137
Z9 160
U1 3
U2 99
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 516
EP U238
DI 10.1038/nature16148
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500048
PM 26580016
DA 2026-03-09
ER

PT J
AU Wegener, G
   Krukenberg, V
   Riedel, D
   Tegetmeyer, HE
   Boetius, A
AF Wegener, Gunter
   Krukenberg, Viola
   Riedel, Dietmar
   Tegetmeyer, Halina E.
   Boetius, Antje
TI Intercellular wiring enables electron transfer between methanotrophic archaea and bacteria
SO NATURE
LA English
DT Article
ID anaerobic oxidation; microbial community; methane; sulfate; protein; genome; identification; reduction; enzymes; methanogenesis
AB The anaerobic oxidation of methane (AOM) with sulfate controls the emission of the greenhouse gas methane from the ocean floor(1,2). In marine sediments, AOM is performed by dual-species consortia of anaerobic methanotrophic archaea (ANME) and sulfate-reducing bacteria (SRB) inhabiting the methane-sulfate transition zone(3-5). The biochemical pathways and biological adaptations enabling this globally relevant process are not fully understood. Here we study the syntrophic interaction in thermophilic AOM (TAOM) between ANME-1 archaea and their consortium partner SRB HotSeep-1 (ref. 6) at 60 degrees C to test the hypothesis of a direct interspecies exchange of electrons(7,8.) The activity of TAOM consortia was compared to the first ANME-free culture of an AOM partner bacterium that grows using hydrogen as the sole electron donor. The thermophilic ANME-1 do not produce sufficient hydrogen to sustain the observed growth of the HotSeep-1 partner. Enhancing the growth of the HotSeep-1 partner by hydrogen addition represses methane oxidation and the metabolic activity of ANME-1. Further supporting the hypothesis of direct electron transfer between the partners, we observe that under TAOM conditions, both ANME and the HotSeep-1 bacteria overexpress genes for extracellular cytochrome production and form cell-to-cell connections that resemble the nanowire structures responsible for interspecies electron transfer between syntrophic consortia of Geobacter(9,10). HotSeep-1 highly expresses genes for pili production only during consortial growth using methane, and the nanowire-like structures are absent in HotSeep-1 cells isolated with hydrogen. These observations suggest that direct electron transfer is a principal mechanism in TAOM, which may also explain the enigmatic functioning and specificity of other methanotrophic ANME-SRB consortia.
C1 [Wegener, Gunter; Krukenberg, Viola; Boetius, Antje] Max Planck Inst Marine Mikrobiol, D-28359 Bremen, Germany.
   [Wegener, Gunter; Boetius, Antje] Univ Bremen, Ctr Marine Environm Sci, MARUM, D-28359 Bremen, Germany.
   [Riedel, Dietmar] Max Planck Inst Biophys Chem, D-37077 Gottingen, Germany.
   [Tegetmeyer, Halina E.; Boetius, Antje] Alfred Wegener Inst Helmholtz Ctr Polar & Marine, D-27570 Bremerhaven, Germany.
   [Tegetmeyer, Halina E.] Univ Bielefeld, Ctr Biotechnol, D-33615 Bielefeld, Germany.
C3 Max Planck Society; University of Bremen; Max Planck Society; Helmholtz Association; Alfred Wegener Institute, Helmholtz Centre for Polar & Marine Research; University of Bielefeld
RP Wegener, G (corresponding author), Max Planck Inst Marine Mikrobiol, D-28359 Bremen, Germany.
EM gwegener@mpi-bremen.de; vkrukenb@mpi-bremen.de
FU DFG Leibniz program; DFG excellence cluster MARUM, Center of Marine Environmental Sciences, Bremen; Max Planck Society
NR 54
TC 430
Z9 512
U1 23
U2 770
PU NATURE PUBLISHING 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 22
PY 2015
VL 526
IS 7574
BP 587
EP U315
DI 10.1038/nature15733
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV1NX
UT WOS:000364026100053
PM 26490622
DA 2026-03-09
ER

PT J
AU Sternberg, SH
   LaFrance, B
   Kaplan, M
   Doucina, JA
AF Sternberg, Samuel H.
   LaFrance, Benjamin
   Kaplan, Matias
   Doucina, Jennifer A.
TI Conformational control of DNA target cleavage by CRISPR-Cas9
SO NATURE
LA English
DT Article
ID staphylococcus-aureus cas9; r-loop formation; crystal-structure; endonuclease cas9; adaptive immunity; guide rna; complex; recognition; specificity; systems
AB Cas9 is an RNA-guided DNA endonuclease that targets foreign DNA for destruction as part of a bacterial adaptive immune system mediated by clustered regularly interspaced short palindromic repeats (CRISPR)(1,2). Together with single-guide RNAs3, Cas9 also functions as a powerful genome engineering tool in plants and animals(4-6), and efforts are underway to increase the efficiency and specificity of DNA targeting for potential therapeutic applicatione(7,8). Studies of off-target effects have shown that DNA binding is far more promiscuous than DNA cleavage(9-11), yet the molecular cues that govern strand scission have not been elucidated. Here we show that the conformational state of the HNH nuclease domain directly controls DNA cleavage activity. Using intramolecular Forster resonance energy transfer experiments to detect relative orientations of the Cas9 catalytic domains when associated with on- and off-target DNA, we find that DNA cleavage efficiencies scale with the extent to which the HNH domain samples an activated conformation. We furthermore uncover a surprising mode of allosteric communication that ensures concerted firing of both Cas9 nuclease domains. Our results highlight a proofreading mechanism beyond initial protospacer adjacent motif (PAM) recognition(12) and RNA-DNA base-pairing(3) that serves as a final specificity checkpoint before DNA double-strand break formation.
C1 [Sternberg, Samuel H.; Doucina, Jennifer A.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
   [LaFrance, Benjamin; Doucina, Jennifer A.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
   [Kaplan, Matias; Doucina, Jennifer A.] Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA.
   [Doucina, Jennifer A.] Univ Calif Berkeley, Innovat Genom Initiat, Berkeley, CA 94720 USA.
   [Doucina, Jennifer A.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Phys Biosci Div, 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; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; University of California System; University of California Berkeley
RP Doucina, JA (corresponding author), Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
EM doudna@berkeley.edu
FU National Science Foundation; National Defense Science & Engineering Graduate Research Fellowship programs; National Institutes of Health National Research Service Award Training Grant [T32GM007232]; National Institute of General Medical Sciences [T32GM007232] Funding Source: NIH RePORTER
NR 29
TC 480
Z9 671
U1 4
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 NOV 5
PY 2015
VL 527
IS 7576
BP 110
EP 113
DI 10.1038/nature15544
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV4XV
UT WOS:000364270700053
PM 26524520
DA 2026-03-09
ER

PT J
AU Marth, CJ
   Gallego, GM
   Lee, JC
   Lebold, TP
   Kulyk, S
   Kou, KGM
   Qin, J
   Lilien, R
   Sarpong, R
AF Marth, C. J.
   Gallego, G. M.
   Lee, J. C.
   Lebold, T. P.
   Kulyk, S.
   Kou, K. G. M.
   Qin, J.
   Lilien, R.
   Sarpong, R.
TI Network-analysis-guided synthesis of weisaconitine D and liljestrandinine
SO NATURE
LA English
DT Article
ID asymmetric diels-alder; development kit cdk; source java library; molecular-oxygen; chemistry; alkaloids; olefins
AB General strategies for the chemical synthesis of organic compounds, especially of architecturally complex natural products, are not easily identified. Here we present a method to establish a strategy for such syntheses, which uses network analysis. This approach has led to the identification of a versatile synthetic intermediate that facilitated syntheses of the diterpenoid alkaloids weisaconitine D and liljestrandinine, and the core of gomandonine. We also developed a web-based graphing program that allows network analysis to be easily performed on molecules with complex frameworks. The diterpenoid alkaloids comprise some of the most architecturally complex and functional-group-dense secondary metabolites isolated. Consequently, they present a substantial challenge for chemical synthesis. The synthesis approach described here is a notable departure from other single-target-focused strategies adopted for the syntheses of related structures. Specifically, it affords not only the targeted natural products, but also intermediates and derivatives in the three families of diterpenoid alkaloids (C-18, C-19 and C-20), and so provides a unified synthetic strategy for these natural products. This work validates the utility of network analysis as a starting point for identifying strategies for the syntheses of architecturally complex secondary metabolites.
C1 [Marth, C. J.; Gallego, G. M.; Lee, J. C.; Lebold, T. P.; Kulyk, S.; Kou, K. G. M.; Sarpong, R.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
   [Qin, J.; Lilien, R.] Cadre Res Labs, Chicago, IL 60654 USA.
C3 University of California System; University of California Berkeley
RP Sarpong, R (corresponding author), Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
EM rsarpong@berkeley.edu
FU National Institute of General Medical Sciences [RO1 GM084906]; National Science Foundation; NIH [5F31GM095238, S10-RR027172, SRR023679A, 1S10RR016634-01]; NSERC (Canada); NSF [CHE 9633007, CHE-0130862]
NR 43
TC 123
Z9 147
U1 2
U2 100
PU NATURE PUBLISHING 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 24
PY 2015
VL 528
IS 7583
BP 493
EP 498
DI 10.1038/nature16440
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900040
PM 26675722
DA 2026-03-09
ER

PT J
AU Keller, CB
   Schoene, B
   Barboni, M
   Samperton, KM
   Husson, JM
AF Keller, C. Brenhin
   Schoene, Blair
   Barboni, Melanie
   Samperton, Kyle M.
   Husson, Jon M.
TI Volcanic-plutonic parity and the differentiation of the continental crust
SO NATURE
LA English
DT Article
ID arc magmas; phase-relations; high-pressure; subduction; water; h2o; evolution; genesis; melts; crystallization
AB The continental crust is central to the biological and geological history of Earth. However, crustal heterogeneity has prevented a thorough geochemical comparison of its primary igneous building blocks-volcanic and plutonic rocks-and the processes by which they differentiate to felsic compositions. Our analysis of a comprehensive global data set of volcanic and plutonic whole-rock geochemistry shows that differentiation trends from primitive basaltic to felsic compositions for volcanic versus plutonic samples are generally indistinguishable in subduction-zone settings, but are divergent in continental rifts. Offsets in major- and trace-element differentiation patterns in rift settings suggest higher water content in plutonic magmas and reduced eruptibility of hydrous silicate magmas relative to dry rift volcanics. In both tectonic settings, our results indicate that fractional crystallization, rather than crustal melting, is predominantly responsible for the production of intermediate and felsic magmas, emphasizing the role of mafic cumulates as a residue of crustal differentiation.
C1 [Keller, C. Brenhin; Schoene, Blair; Barboni, Melanie; Samperton, Kyle M.; Husson, Jon M.] Princeton Univ, Dept Geosci, Princeton, NJ 08544 USA.
   [Barboni, Melanie] Univ Calif Los Angeles, Dept Earth Planetary & Space Sci, Los Angeles, CA 90095 USA.
   [Husson, Jon M.] Univ Wisconsin, Dept Geosci, Madison, WI 53706 USA.
C3 Princeton University; University of California System; University of California Los Angeles; University of Wisconsin System; University of Wisconsin Madison
RP Keller, CB (corresponding author), Princeton Univ, Dept Geosci, Guyot Hall, Princeton, NJ 08544 USA.
EM cbkeller@princeton.edu
FU US Department of Energy Office of Science [DE-FG02-97ER25308]; National Energy Research Scientific Computing Center under DOE Office of Science [DE-AC02-05CH11231]
NR 66
TC 224
Z9 270
U1 7
U2 135
PU NATURE PUBLISHING 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 16
PY 2015
VL 523
IS 7560
BP 301
EP +
DI 10.1038/nature14584
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM8KY
UT WOS:000357950900032
PM 26178961
DA 2026-03-09
ER

PT J
AU Friis, EM
   Crane, PR
   Pedersen, KR
   Stampanoni, M
   Marone, F
AF Friis, Else Marie
   Crane, Peter R.
   Pedersen, Kaj Raunsgaard
   Stampanoni, Marco
   Marone, Federica
TI Exceptional preservation of tiny embryos documents seed dormancy in early angiosperms
SO NATURE
LA English
DT Article
ID amborella amborellaceae; dispersal systems; basal angiosperm; cretaceous plant; fossil flowers; evolution; image; size; endosperm; history
AB The rapid diversification of angiosperms through the Early Cretaceous period, between about 130-100 million years ago, initiated fundamental changes in the composition of terrestrial vegetation and is increasingly well understood on the basis of a wealth of palaeobotanical discoveries over the past four decades(1-5) and their integration with improved knowledge of living angiosperms(3,6). Prevailing hypotheses, based on evidence both from living and from fossil plants, emphasize that the earliest angiosperms were plants of small stature(7-12) with rapid life cycles(7,8,12,13) that exploited disturbed habitats(3,9,11,13,14) in open(3,9,11,13,14), or perhaps understorey, conditions(15,16). However, direct palaeontogical data relevant to understanding the seed biology and germination ecology of Early Cretaceous angiosperms are sparse. Here we report the discovery of embryos and their associated nutrient storage tissues in exceptionally well-preserved angiosperm seeds from the Early Cretaceous. Synchrotron radiation X-ray tomographic microscopy of the fossil embryos from many taxa reveals that all were tiny at the time of dispersal. These results support hypotheses based on extant plants that tiny embryos and seed dormancy are basic for angiosperms as a whole(17,18). The minute size of the fossil embryos, and the modest nutrient storage tissues dictated by the overall small seed size, is also consistent with the interpretation that many early angiosperms were opportunistic, early successional colonizers of disturbance-prone habitats(2,15,16).
C1 [Friis, Else Marie] Swedish Museum Nat Hist, Dept Palaeobiol, SE-10405 Stockholm, Sweden.
   [Friis, Else Marie; Crane, Peter R.; Pedersen, Kaj Raunsgaard] Yale Univ, Sch Forestry & Environm Studies, New Haven, CT 06511 USA.
   [Pedersen, Kaj Raunsgaard] Univ Aarhus, Dept Earth Sci, DK-8000 Aarhus, Denmark.
   [Stampanoni, Marco; Marone, Federica] Paul Scherrer Inst, Swiss Light Source, CH-5232 Villigen, Switzerland.
   [Stampanoni, Marco] Swiss Fed Inst Technol Zurich, Inst Biomed Engn, CH-8092 Zurich, Switzerland.
C3 Swedish Museum of Natural History; Yale University; Aarhus University; Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute; Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Friis, EM (corresponding author), Swedish Museum Nat Hist, Dept Palaeobiol, SE-10405 Stockholm, Sweden.
EM else.marie.friis@nrm.se
FU Swedish Research Council; Edward P. Bass Distinguished Visiting Fellowship; European Community's Seventh Framework Programme (FP7) [312284]
NR 35
TC 37
Z9 45
U1 2
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 DEC 24
PY 2015
VL 528
IS 7583
BP 551
EP +
DI 10.1038/nature16441
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900052
PM 26675723
DA 2026-03-09
ER

PT J
AU Head, JJ
   Polly, PD
AF Head, Jason J.
   Polly, P. David
TI Evolution of the snake body form reveals homoplasy in amniote Hox gene function
SO NATURE
LA English
DT Article
ID lateral somitic frontier; vertebral numbers; plan; mesoderm; skeleton; embryos; domains; code
AB Hox genes regulate regionalization of the axial skeleton invertebrates(1-7), and changes in their expression have been proposed to be a fundamental mechanism driving the evolution of new body forms(8-14). The origin of the snake-like body form, with its deregionalized pre-cloacal axial skeleton, has been explained as either homogenization of Hox gene expression domains(9), or retention of standard vertebrate Hox domains with alteration of downstream expression that suppresses development of distinct regions(10-13). Both models assume a highly regionalized ancestor, but the extent of deregionalization of the primaxial domain (vertebrae, dorsal ribs) of the skeleton in snake-like body forms has never been analysed. Here we combine geometric morphometrics and maximum-likelihood analysis to show that the pre-cloacal primaxial domain of elongate, limb-reduced lizards and snakes is not deregionalized compared with limbed taxa, and that the phylogenetic structure of primaxial morphology in reptiles does not support a loss of regionalization in the evolution of snakes. We demonstrate that morphometric regional boundaries correspond to mapped gene expression domains in snakes, suggesting that their primaxial domain is patterned by a normally functional Hox code. Comparison of primaxial osteology in fossil and modern amniotes with Hox gene distributions within Amniota indicates that a functional, sequentially expressed Hox code patterned a subtle morphological gradient along the anterior-posterior axis in stem members of amniote clades and extant lizards, including snakes. The highly regionalized skeletons of extant archosaurs and mammals result from independent evolution in the Hox code and do not represent ancestral conditions for clades with snake-like body forms. The developmental origin of snakes is best explained by decoupling of the primaxial and abaxial domains and by increases in somite number(15), not by changes in the function of primaxial Hox genes(9,10).
C1 [Head, Jason J.] Univ Nebraska, Dept Earth & Atmospher Sci, Lincoln, NE 68588 USA.
   [Head, Jason J.] Univ Nebraska, Nebraska State Museum Nat Hist, Lincoln, NE 68588 USA.
   [Polly, P. David] Indiana Univ, Dept Geol Sci, Bloomington, IN 47405 USA.
   [Polly, P. David] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA.
   [Polly, P. David] Indiana Univ, Dept Anthropol, Bloomington, IN 47405 USA.
C3 University of Nebraska System; University of Nebraska Lincoln; University of Nebraska System; University of Nebraska Lincoln; Indiana University System; Indiana University Bloomington; Indiana University System; Indiana University Bloomington; Indiana University System; Indiana University Bloomington
RP Head, JJ (corresponding author), Univ Nebraska, Dept Earth & Atmospher Sci, Lincoln, NE 68588 USA.
EM jhead2@unl.edu; pdpolly@indiana.edu
FU US National Science Foundation Postdoctoral Fellowship in Biological Informatics [DBI-0204082]; Natural Sciences and Engineering Research Council of Canada; US National Science Foundation Grant [EAR-0843935]
NR 30
TC 108
Z9 125
U1 2
U2 140
PU NATURE PUBLISHING 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 2
PY 2015
VL 520
IS 7545
BP 86
EP U190
DI 10.1038/nature14042
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE7NE
UT WOS:000352027700042
PM 25539083
DA 2026-03-09
ER

PT J
AU Li, Y
   Klena, NT
   Gabriel, GC
   Liu, XQ
   Kim, AJ
   Lemke, K
   Chen, Y
   Chatterjee, B
   Devine, W
   Damerla, RR
   Chang, CF
   Yagi, H
   San Agustin, JT
   Thahir, M
   Anderton, S
   Lawhead, C
   Vescovi, A
   Pratt, H
   Morgan, J
   Haynes, L
   Smith, CL
   Eppig, JT
   Reinholdt, L
   Francis, R
   Leatherbury, L
   Ganapathiraju, MK
   Tobita, K
   Pazour, GJ
   Lo, CW
AF Li, You
   Klena, Nikolai T.
   Gabriel, George C.
   Liu, Xiaoqin
   Kim, Andrew J.
   Lemke, Kristi
   Chen, Yu
   Chatterjee, Bishwanath
   Devine, William
   Damerla, Rama Rao
   Chang, Chienfu
   Yagi, Hisato
   San Agustin, Jovenal T.
   Thahir, Mohamed
   Anderton, Shane
   Lawhead, Caroline
   Vescovi, Anita
   Pratt, Herbert
   Morgan, Judy
   Haynes, Leslie
   Smith, Cynthia L.
   Eppig, Janan T.
   Reinholdt, Laura
   Francis, Richard
   Leatherbury, Linda
   Ganapathiraju, Madhavi K.
   Tobita, Kimimasa
   Pazour, Gregory J.
   Lo, Cecilia W.
TI Global genetic analysis in mice unveils central role for cilia in congenital heart disease
SO NATURE
LA English
DT Article
ID fetal echocardiography; heterotaxy syndrome; defects; mouse; diagnosis; mutations; spectrum; accuracy; protein; screen
AB Congenital heart disease (CHD) is the most prevalent birth defect, affecting nearly 1% of live births(1); the incidence of CHD is up to tenfold higher inhumanfetuses(2,3). Agenetic contributionis strongly suggested by the association of CHD with chromosome abnormalities and high recurrence risk(4). Here we report findings from a recessive forward genetic screen in fetal mice, showing that cilia and ciliatransduced cell signalling have important roles in the pathogenesis of CHD. The cilium is an evolutionarily conserved organelle projecting from the cell surface with essential roles in diverse cellular processes. Using echocardiography, we ultrasound scanned 87,355 chemically mutagenized C57BL/6J fetal mice and recovered 218 CHD mouse models. Whole-exome sequencing identified 91 recessive CHD mutations in 61 genes. This included 34 cilia-related genes, 16 genes involved in cilia-transduced cell signalling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signalling. Surprisingly, many CHD genes encoded interacting proteins, suggesting that an interactome protein network may provide a larger genomic context for CHD pathogenesis. These findings provide novel insights into the potential Mendelian genetic contribution to CHD in the fetal population, a segment of the human population not well studied. We note that the pathways identified show overlap with CHD candidate genes recovered in CHD patients(5), suggesting that they may have relevance to the more complex genetics of CHD overall. These CHD mouse models and >8,000 incidental mutations have been sperm archived, creating a rich public resource for human disease modelling.
C1 [Li, You; Klena, Nikolai T.; Gabriel, George C.; Liu, Xiaoqin; Kim, Andrew J.; Lemke, Kristi; Chen, Yu; Chatterjee, Bishwanath; Damerla, Rama Rao; Chang, Chienfu; Yagi, Hisato; Anderton, Shane; Lawhead, Caroline; Vescovi, Anita; Francis, Richard; Tobita, Kimimasa; Lo, Cecilia W.] Univ Pittsburgh, Sch Med, Dept Dev Biol, Pittsburgh, PA 15201 USA.
   [Devine, William] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15261 USA.
   [San Agustin, Jovenal T.; Pazour, Gregory J.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA.
   [Thahir, Mohamed; Ganapathiraju, Madhavi K.] Univ Pittsburgh, Sch Med, Dept Biomed Informat, Pittsburgh, PA 15206 USA.
   [Thahir, Mohamed; Ganapathiraju, Madhavi K.] Univ Pittsburgh, Sch Arts & Sci, Intelligent Syst Program, Pittsburgh, PA 16260 USA.
   [Pratt, Herbert; Morgan, Judy; Haynes, Leslie; Smith, Cynthia L.; Eppig, Janan T.; Reinholdt, Laura] Jackson Lab, Bar Harbor, ME 04609 USA.
   [Leatherbury, Linda] Childrens Natl Med Ctr, Ctr Heart, Washington, DC 20010 USA.
C3 Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Massachusetts System; University of Massachusetts Worcester; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Jackson Laboratory; Children's National Health System
RP Lo, CW (corresponding author), Univ Pittsburgh, Sch Med, Dept Dev Biol, Pittsburgh, PA 15201 USA.
EM cel36@pitt.edu
FU National Heart, Lung, and Blood Institute [U01HL098180, U01HL098188]; National Institute of Mental Health [R01MH094564]; National Human Genome Research Institute [HG000330]; University of Pittsburgh School of Medicine; National Institute of General Medical Sciences [R01GM060992] Funding Source: NIH RePORTER
NR 30
TC 343
Z9 401
U1 2
U2 63
PU NATURE PUBLISHING 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 28
PY 2015
VL 521
IS 7553
BP 520
EP U224
DI 10.1038/nature14269
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ2AN
UT WOS:000355286600043
PM 25807483
DA 2026-03-09
ER

PT J
AU Piou, T
   Rovis, T
AF Piou, Tiffany
   Rovis, Tomislav
TI Rhodium-catalysed syn-carboamination of alkenes via a transient directing group
SO NATURE
LA English
DT Article
ID c-h activation; functionalization; hydroamination
AB Alkenes are the most ubiquitous prochiral functional groups-those that can be converted from achiral to chiral in a single step that are accessible to synthetic chemists. For this reason, difunctionalization reactions of alkenes (whereby two functional groups are added to the same double bond) are particularly important, as they can be used to produce highly complex molecular architectures(1,2). Stereoselective oxidation reactions, including dihydroxylation, aminohydroxylation and halogenation(3-6), are well established methods for functionalizing alkenes. However, the intermolecular incorporation of both carbon- and nitrogen-based functionalities stereoselectively across an alkene has not been reported. Here we describe the rhodium-catalysed carboamination of alkenes at the same (syn) face of a double bond, initiated by a carbon-hydrogen activation event that uses enoxyphthalimides as the source of both the carbon and the nitrogen functionalities. The reaction methodology allows for the intermolecular, stereospecific formation of one carbon-carbon and one carbon-nitrogen bond across an alkene, which is, to our knowledge, unprecedented. The reaction design involves the in situ generation of a bidentate directing group and the use of a new cyclopentadienyl ligand to control the reactivity of rhodium. The results provide a new way of synthesizing functionalized alkenes, and should lead to the convergent and stereoselective assembly of amine-containing acyclic molecules.
C1 [Piou, Tiffany; Rovis, Tomislav] Colorado State Univ, Dept Chem, Ft Collins, CO 80523 USA.
C3 Colorado State University System; Colorado State University Fort Collins
RP Rovis, T (corresponding author), Colorado State Univ, Dept Chem, Ft Collins, CO 80523 USA.
EM rovis@colostate.edu
FU National Institute of General Medical Sciences [GM80442]; National Institute of General Medical Sciences [R01GM080442] Funding Source: NIH RePORTER
NR 26
TC 206
Z9 232
U1 2
U2 211
PU NATURE PUBLISHING 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 5
PY 2015
VL 527
IS 7576
BP 86
EP 90
DI 10.1038/nature15691
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV4XV
UT WOS:000364270700048
PM 26503048
DA 2026-03-09
ER

PT J
AU Sandler, O
   Mizrahi, SP
   Weiss, N
   Agam, O
   Simon, I
   Balaban, NQ
AF Sandler, Oded
   Mizrahi, Sivan Pearl
   Weiss, Noga
   Agam, Oded
   Simon, Itamar
   Balaban, Nathalie Q.
TI Lineage correlations of single cell division time as a probe of cell-cycle dynamics
SO NATURE
LA English
DT Article
ID gene-expression; generation times; model; noise; variability; bacteria; series
AB Stochastic processes in cells are associated with fluctuations in mRNA(1), protein production and degradation(2,3), noisy partition of cellular components at division(4), and other cell processes. Variability within a clonal population of cells originates from such stochastic processes, which may be amplified or reduced by deterministic factors(5). Cell-to-cell variability, such as that seen in the heterogeneous response of bacteria to antibiotics, or of cancer cells to treatment, is understood as the inevitable consequence of stochasticity. Variability in cell-cycle duration was observed long ago; however, its sources are still unknown. A central question is whether the variance of the observed distribution originates from stochastic processes, or whether it arises mostly from a deterministic process that only appears to be random. A surprising feature of cell-cycle-duration inheritance is that it seems to be lost within one generation but to be still present in the next generation, generating poor correlation between mother and daughter cells but high correlation between cousin cells(6). This observation suggests the existence of underlying deterministic factors that determine the main part of cell-to-cell variability. We developed an experimental system that precisely measures the cell-cycle duration of thousands of mammalian cells along several generations and a mathematical framework that allows discrimination between stochastic and deterministic processes in lineages of cells. We show that the inter-and intra-generation correlations reveal complex inheritance of the cell-cycle duration. Finally, we build a deterministic nonlinear toy model for cell-cycle inheritance that reproduces the main features of our data. Our approach constitutes a general method to identify deterministic variability in lineages of cells or organisms, which may help to predict and, eventually, reduce cell-to-cell heterogeneity in various systems, such as cancer cells under treatment.
C1 [Sandler, Oded; Mizrahi, Sivan Pearl; Simon, Itamar] Hebrew Univ Jerusalem, Hadassah Med Sch, IMRIC, Dept Microbiol & Mol Genet, IL-91120 Jerusalem, Israel.
   [Sandler, Oded; Mizrahi, Sivan Pearl; Weiss, Noga; Agam, Oded; Balaban, Nathalie Q.] Hebrew Univ Jerusalem, Racah Inst Phys, Edmond J Safra Campus, IL-91904 Jerusalem, Israel.
C3 Hebrew University of Jerusalem; Hebrew University of Jerusalem
RP Balaban, NQ (corresponding author), Hebrew Univ Jerusalem, Racah Inst Phys, Edmond J Safra Campus, IL-91904 Jerusalem, Israel.
EM agam@phys.huji.ac.il; itamarsi@ekmd.huji.ac.il; nathalieqb@phys.huji.ac.il
FU ISF [592/10, 567/10, 9/09, 302/14]; ERC [281306, 260871]; Chief Scientist Office of the Israel Ministry of Health; Weinkselbaum family medical research fund; Clore Foundation; European Research Council (ERC) [281306, 260871] Funding Source: European Research Council (ERC)
NR 31
TC 105
Z9 128
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 MAR 26
PY 2015
VL 519
IS 7544
BP 468
EP +
DI 10.1038/nature14318
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA DF8BH
UT WOS:000371581400002
PM 25762143
DA 2026-03-09
ER

PT J
AU Rasmussen, M
   Sikora, M
   Albrechtsen, A
   Korneliussen, TS
   Moreno-Mayar, JV
   Poznik, GD
   Zollikofer, CPE
   de Leon, MSP
   Allentoft, ME
   Moltke, I
   Jonsson, K
   Valdiosera, C
   Malhi, RS
   Orlando, L
   Bustamante, CD
   Stafford, TW
   Meltzer, DJ
   Nielsen, R
   Willerslev, E
AF Rasmussen, Morten
   Sikora, Martin
   Albrechtsen, Anders
   Korneliussen, Thorfinn Sand
   Moreno-Mayar, J. Victor
   Poznik, G. David
   Zollikofer, Christoph P. E.
   de Leon, Marcia S. Ponce
   Allentoft, Morten E.
   Moltke, Ida
   Jonsson, Kon
   Valdiosera, Cristina
   Malhi, Ripan S.
   Orlando, Ludovic
   Bustamante, Carlos D.
   Stafford, Thomas W., Jr.
   Meltzer, David J.
   Nielsen, Rasmus
   Willerslev, Eske
TI The ancestry and affiliations of Kennewick Man
SO NATURE
LA English
DT Article
ID gordon creek woman; genome; population; america; history; dna
AB Kennewick Man, referred to as the Ancient One by Native Americans, is a male human skeleton discovered in Washington state (USA) in 1996 and initially radiocarbon dated to 8,340-9,200 calibrated years before present (BP)(1). His population affinities have been the subject of scientific debate and legal controversy. Based on an initial study of cranial morphology it was asserted that Kennewick Man was neither Native American nor closely related to the claimant Plateau tribes of the Pacific Northwest, who claimed ancestral relationship and requested repatriation under the Native American Graves Protection and Repatriation Act (NAGPRA). The morphological analysis was important to judicial decisions that Kennewick Man was not Native American and that therefore NAGPRA did not apply. Instead of repatriation, additional studies of the remains were permitted(2). Subsequent craniometric analysis affirmed Kennewick Man to be more closely related to circumpacific groups such as the Ainu and Polynesians than he is to modern Native Americans(2). In order to resolve Kennewick Man's ancestry and affiliations, we have sequenced his genome to similar to 1x coverage and compared it to worldwide genomic data including for the Ainu and Polynesians. We find that Kennewick Man is closer to modern Native Americans than to any other population worldwide. Among the Native American groups for whom genome-wide data are available for comparison, several seem to be descended from a population closely related to that of Kennewick Man, including the Confederated Tribes of the Colville Reservation (Colville), one of the five tribes claiming Kennewick Man. We revisit the cranial analyses and find that, as opposed to genome-wide comparisons, it is not possible on that basis to affiliate Kennewick Man to specific contemporary groups. We therefore conclude based on genetic comparisons that Kennewick Man shows continuity with Native North Americans over at least the last eight millennia.
C1 [Rasmussen, Morten; Sikora, Martin; Korneliussen, Thorfinn Sand; Moreno-Mayar, J. Victor; Allentoft, Morten E.; Jonsson, Kon; Valdiosera, Cristina; Orlando, Ludovic; Stafford, Thomas W., Jr.; Nielsen, Rasmus; Willerslev, Eske] Univ Copenhagen, Nat Hist Museum Denmark, Ctr GeoGenet, DK-1350 Copenhagen K, Denmark.
   [Rasmussen, Morten] Stanford Univ, Sch Med, Dept Genet, Littlefield Ctr, Stanford, CA 94305 USA.
   [Albrechtsen, Anders] Univ Copenhagen, Dept Biol, Bioinformat Ctr, DK-2200 Copenhagen N, Denmark.
   [Poznik, G. David] Stanford Univ, Program Biomed Informat, Stanford, CA 94305 USA.
   [Zollikofer, Christoph P. E.] Univ Zurich, Inst Anthropol, CH-8057 Zurich, Switzerland.
   [Valdiosera, Cristina] La Trobe Univ, Dept Archaeol & Hist, Melbourne, Vic 3086, Australia.
   [Malhi, Ripan S.] Univ Illinois, Dept Anthropol, Urbana, IL 61801 USA.
   [Malhi, Ripan S.] Univ Illinois, Carl R Woese Inst Genom Biol, Urbana, IL 61801 USA.
   [Bustamante, Carlos D.] Stanford Univ, Ctr Evolutionary & Human Genom, Littlefield Ctr, Stanford, CA 94305 USA.
   [Stafford, Thomas W., Jr.] Univ Aarhus, Dept Phys & Astron, C Dating Ctr, DK-8000 Aarhus C, Denmark.
   [Meltzer, David J.] So Methodist Univ, Dept Anthropol, Dallas, TX 75275 USA.
   [Nielsen, Rasmus] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA.
C3 University of Copenhagen; Stanford University; University of Copenhagen; Stanford University; University of Zurich; La Trobe University; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; Stanford University; Aarhus University; Southern Methodist University; University of California System; University of California Berkeley
RP Willerslev, E (corresponding author), Univ Copenhagen, Nat Hist Museum Denmark, Ctr GeoGenet, Oster Voldgade 5-7, DK-1350 Copenhagen K, Denmark.
EM ewillerslev@snm.ku.dk
FU Danish National Research Foundation; Lundbeck Foundation; Danish Council for Independent Research [12-131829]; 'Consejo Nacional de Ciencia y Tecnologia' (Mexico); National Science Foundation Graduate Research Fellowship [DGE-1147470]; DFF-YDUN grant from the Danish Council for Independent Research; Marie Curie Intra-European Fellowship [FP7-People-PIEF-GA-2009-255503]; Lundbeck Foundation [R155-2013-16338, R38-2008-3048, R109-2012-9995, R24-2008-2527, R70-2010-6286] Funding Source: researchfish; Villum Fonden [00007171, 00010120] Funding Source: researchfish; National Library of Medicine; National Institute of Allergy and Infectious Diseases [T15LM007033] Funding Source: NIH RePORTER; Direct For Mathematical & Physical Scien; Division Of Mathematical Sciences [1201234] Funding Source: National Science Foundation
NR 28
TC 169
Z9 214
U1 1
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 JUL 23
PY 2015
VL 523
IS 7561
BP 455
EP U159
DI 10.1038/nature14625
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN4DD
UT WOS:000358378900035
PM 26087396
DA 2026-03-09
ER

PT J
AU Dubrovinsky, L
   Dubrovinskaia, N
   Bykova, E
   Bykov, M
   Prakapenka, V
   Prescher, C
   Glazyrin, K
   Liermann, HP
   Hanfland, M
   Ekholm, M
   Feng, Q
   Pourovskii, LV
   Katsnelson, MI
   Wills, JM
   Abrikosov, IA
AF Dubrovinsky, L.
   Dubrovinskaia, N.
   Bykova, E.
   Bykov, M.
   Prakapenka, V.
   Prescher, C.
   Glazyrin, K.
   Liermann, H. -P.
   Hanfland, M.
   Ekholm, M.
   Feng, Q.
   Pourovskii, L. V.
   Katsnelson, M. I.
   Wills, J. M.
   Abrikosov, I. A.
TI The most incompressible metal osmium at static pressures above 750 gigapascals
SO NATURE
LA English
DT Article
ID equation-of-state; van-der-waals; electronic-structure; diamond; transition; anomaly; alkali; limit; mgo; zn
AB Metallic osmium (Os) is one of the most exceptional elemental materials, having, at ambient pressure, the highest known density and one of the highest cohesive energies and melting temperatures(1). It is also very incompressible(2-4), but its high-pressure behaviour is not well understood because it has been studied(2-6) so far only at pressures below 75 gigapascals. Here we report powder X-ray diffraction measurements on Os at multi-megabar pressures using both conventional and double-stage diamond anvil cells(7), with accurate pressure determination ensured by first obtaining self-consistent equations of state of gold, platinum, and tungsten in static experiments up to 500 gigapascals. These measurements allow us to show that Os retains its hexagonal close-packed structure upon compression to over 770 gigapascals. But although its molar volume monotonically decreases with pressure, the unit cell parameter ratio of Os exhibits anomalies at approximately 150 gigapascals and 440 gigapascals. Dynamical mean-field theory calculations suggest that the former anomaly is a signature of the topological change of the Fermi surface for valence electrons. However, the anomaly at 440 gigapascals might be related to an electronic transition associated with pressure-induced interactions between core electrons. The ability to affect the core electrons under static high-pressure experimental conditions, even for incompressible metals such as Os, opens up opportunities to search for new states of matter under extreme compression.
C1 [Dubrovinsky, L.; Bykova, E.] Univ Bayreuth, Bavarian Res Inst Expt Geochem & Geophys, D-95440 Bayreuth, Germany.
   [Dubrovinskaia, N.; Bykova, E.; Bykov, M.] Univ Bayreuth, Crystallog Lab, D-95440 Bayreuth, Germany.
   [Prakapenka, V.; Prescher, C.] Univ Chicago, Ctr Adv Radiat Sources, Argonne, IL 60437 USA.
   [Glazyrin, K.; Liermann, H. -P.] Deutsch Elektronen Synchrotron DESY, Photon Sci, D-22603 Hamburg, Germany.
   [Hanfland, M.] European Synchrotron Radiat Facil, F-38043 Grenoble, France.
   [Ekholm, M.; Feng, Q.; Pourovskii, L. V.] Linkoping Univ, Swedish E Sci Res Ctr SeRC, SE-58183 Linkoping, Sweden.
   [Ekholm, M.; Feng, Q.; Abrikosov, I. A.] Linkoping Univ, Dept Phys Chem & Biol IFM, SE-58183 Linkoping, Sweden.
   [Pourovskii, L. V.] Ecole Polytech, CNRS, Ctr Phys Theor, F-91128 Palaiseau, France.
   [Katsnelson, M. I.] Radboud Univ Nijmegen, Inst Mol & Mat, NL-6525 AJ Nijmegen, Netherlands.
   [Katsnelson, M. I.] Ural Fed Univ, Dept Theoret & Appl Mech, Ekaterinburg 620002, Russia.
   [Wills, J. M.] Los Alamos Natl Lab, Div Theoret, Los Alamos, NM 87545 USA.
   [Abrikosov, I. A.] Natl Univ Sci & Technol MISIS, Mat Modeling & Dev Lab, Moscow 119049, Russia.
C3 University of Bayreuth; University of Bayreuth; University of Chicago; Helmholtz Association; Deutsches Elektronen-Synchrotron (DESY); European Synchrotron Radiation Facility (ESRF); Linkoping University; Linkoping University; Institut Polytechnique de Paris; Ecole Polytechnique; Centre National de la Recherche Scientifique (CNRS); Radboud University Nijmegen; Ural Federal University; United States Department of Energy (DOE); Los Alamos National Laboratory; National University of Science & Technology (MISIS)
RP Dubrovinsky, L (corresponding author), Univ Bayreuth, Bavarian Res Inst Expt Geochem & Geophys, D-95440 Bayreuth, Germany.
EM Leonid.Dubrovinsky@uni-bayreuth.de; Igor.Abrikosov@ifm.liu.se
FU Deutsche Forschungsgemeinschaft (DFG); Federal Ministry of Education and Research (BMBF), Germany; DFG through Heisenberg Program; DFG [DU 954-8/1]; BMBF [5K13WC3, O5K2013]; Swedish Foundation for Strategic Research programme SRL [10-0026]; Swedish Research Council (VR) [621-2011-4426]; Swedish Government Strategic Research Area Grant Swedish e-Science Research Centre (SeRC); Materials Science "Advanced Functional Materials" (AFM); Ministry of Education and Science of the Russian Federation [14.Y26.31.0005]; ERC [338957]; NWO; National Science Foundation - Earth Sciences [EAR-1128799]; Department of Energy - GeoSciences [DE-FG02-94ER14466]; DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]; European Research Council (ERC) [338957] Funding Source: European Research Council (ERC)
NR 59
TC 179
Z9 221
U1 0
U2 170
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 10
PY 2015
VL 525
IS 7568
BP 226
EP +
DI 10.1038/nature14681
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400033
PM 26302297
DA 2026-03-09
ER

PT J
AU Landau, DA
   Tausch, E
   Taylor-Weiner, AN
   Stewart, C
   Reiter, JG
   Bahlo, J
   Kluth, S
   Bozic, I
   Lawrence, M
   Böttcher, S
   Carter, SL
   Cibulskis, K
   Mertens, D
   Sougnez, CL
   Rosenberg, M
   Hess, JM
   Edelmann, J
   Kless, S
   Kneba, M
   Ritgen, M
   Fink, A
   Fischer, K
   Gabriel, S
   Lander, ES
   Nowak, MA
   Doehner, H
   Hallek, M
   Neuberg, D
   Getz, G
   Stilgenbauer, S
   Wu, CJ
AF Landau, Dan A.
   Tausch, Eugen
   Taylor-Weiner, Amaro N.
   Stewart, Chip
   Reiter, Johannes G.
   Bahlo, Jasmin
   Kluth, Sandra
   Bozic, Ivana
   Lawrence, Mike
   Boettcher, Sebastian
   Carter, Scott L.
   Cibulskis, Kristian
   Mertens, Daniel
   Sougnez, Carrie L.
   Rosenberg, Mara
   Hess, Julian M.
   Edelmann, Jennifer
   Kless, Sabrina
   Kneba, Michael
   Ritgen, Matthias
   Fink, Anna
   Fischer, Kirsten
   Gabriel, Stacey
   Lander, Eric S.
   Nowak, Martin A.
   Doehner, Hartmut
   Hallek, Michael
   Neuberg, Donna
   Getz, Gad
   Stilgenbauer, Stephan
   Wu, Catherine J.
TI Mutations driving CLL and their evolution in progression and relapse
SO NATURE
LA English
DT Article
ID chronic lymphocytic-leukemia; braf mutations; cancer; heterogeneity; reveals; driver; myc
AB Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized putative cancer drivers (RPS15, IKZF3), and collectively identify RNA processing and export, MYC activity, and MAPK signalling as central pathways involved in CLL. Clonality analysis of this large data set further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution. Thus, large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome.
C1 [Landau, Dan A.; Taylor-Weiner, Amaro N.; Stewart, Chip; Reiter, Johannes G.; Lawrence, Mike; Carter, Scott L.; Cibulskis, Kristian; Sougnez, Carrie L.; Rosenberg, Mara; Hess, Julian M.; Gabriel, Stacey; Lander, Eric S.; Getz, Gad; Wu, Catherine J.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.
   [Landau, Dan A.; Reiter, Johannes G.; Wu, Catherine J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.
   [Landau, Dan A.; Wu, Catherine J.] Brigham & Womens Hosp, Dept Internal Med, Boston, MA 02115 USA.
   [Landau, Dan A.; Wu, Catherine J.] Harvard Univ, Sch Med, Boston, MA 02115 USA.
   [Tausch, Eugen; Mertens, Daniel; Edelmann, Jennifer; Kless, Sabrina; Doehner, Hartmut; Stilgenbauer, Stephan] Univ Ulm, Dept Internal Med 3, D-89081 Ulm, Germany.
   [Reiter, Johannes G.] IST Austria, A-3400 Klosterneuburg, Austria.
   [Reiter, Johannes G.; Bozic, Ivana; Nowak, Martin A.] Harvard Univ, Program Evolutionary Dynam, Cambridge, MA 02138 USA.
   [Bahlo, Jasmin; Kluth, Sandra; Fink, Anna; Fischer, Kirsten; Hallek, Michael] Univ Hosp, Dept Internal Med, D-50937 Cologne, Germany.
   [Bahlo, Jasmin; Kluth, Sandra; Fink, Anna; Fischer, Kirsten; Hallek, Michael] Univ Hosp, Ctr Integrated Oncol Cologne Bonn, D-50937 Cologne, Germany.
   [Bozic, Ivana; Nowak, Martin A.] Harvard Univ, Dept Math, Cambridge, MA 02138 USA.
   [Boettcher, Sebastian; Kneba, Michael; Ritgen, Matthias] Univ Hosp Schleswig Holstein, Dept Internal Med 2, D-24105 Kiel, Germany.
   [Carter, Scott L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Joint Ctr Canc Precis Med,Dana Farber Canc Inst, Boston, MA 02215 USA.
   [Mertens, Daniel] German Canc Res Ctr, Mechanisms Leukemogenesis, D-69121 Heidelberg, Germany.
   [Nowak, Martin A.] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA.
   [Hallek, Michael] Cologne Cluster Excellence Cellular Stress Respon, D-50931 Cologne, Germany.
   [Neuberg, Donna] Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA.
   [Getz, Gad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA.
   [Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02129 USA.
C3 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; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Ulm University; Institute of Science & Technology - Austria; Harvard University; University of Cologne; University of Cologne; Harvard University; University of Kiel; Schleswig Holstein University Hospital; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard Medical School; Dana-Farber Cancer Institute; Helmholtz Association; German Cancer Research Center (DKFZ); Harvard University; University of Cologne; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital
RP Wu, CJ (corresponding author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.
EM gadgetz@broadinstitute.org; Stephan.Stilgenbauer@uniklinik-ulm.de; cwu@partners.org
FU ACS; ASH; Burroughs Wellcome Fund Career Award for Medical Scientists; NIH Big Data to Knowledge initiative (BD2K) [1K01ES025431-01]; European Research Council (ERC) [279307]; Austrian Science Fund (FWF) [P23499-N23]; FWF NFN [S11407-N23 RiSE]; German Jose Carreras Leukemia Foundation [R06/03v]; Deutsche Forschungsgemeinschaft [KFO 286, SFB 1074]; Else Kroner-Fresenius-Stiftung [2010_Kolleg24, 2012_A146]; Virtual Helmholtz Institute [VH-VI-404]; CLL Global Research Foundation (Alliance); Blavatnik Family Foundation; AACR; NIH/NCI [1R01CA182461-02, 1R01CA184922-01, 1U10CA180861-01]
NR 38
TC 858
Z9 976
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 OCT 22
PY 2015
VL 526
IS 7574
BP 525
EP U132
DI 10.1038/nature15395
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV1NX
UT WOS:000364026100040
PM 26466571
DA 2026-03-09
ER

PT J
AU Yang, SH
   Wang, L
   Huang, J
   Zhang, XH
   Yuan, Y
   Chen, JQ
   Hurst, LD
   Tian, DC
AF Yang, Sihai
   Wang, Long
   Huang, Ju
   Zhang, Xiaohui
   Yuan, Yang
   Chen, Jian-Qun
   Hurst, Laurence D.
   Tian, Dacheng
TI Parent-progeny sequencing indicates higher mutation rates in heterozygotes
SO NATURE
LA English
DT Article
ID dna; coevolution; framework; breaks
AB Mutation rates vary within genomes, but the causes of this remain unclear(1). As many prior inferences rely on methods that assume an absence of selection, potentially leading to artefactual results(2), we call mutation events directly using a parent-offspring sequencing strategy focusing on Arabidopsis and using rice and honey bee for replication. Here we show that mutation rates are higher in heterozygotes and in proximity to crossover events. A correlation between recombination rate and intraspecific diversity is in part owing to a higher mutation rate in domains of high recombination/ diversity. Implicating diversity per se as a cause, we find an similar to 3.5-fold higher mutation rate in heterozygotes than in homozygotes, with mutations occurring in closer proximity to heterozygous sites than expected by chance. In a genome that is a patchwork of heterozygous and homozygous domains, mutations occur disproportionately more often in the heterozygous domains. If segregating mutations predispose to a higher local mutation rate, clusters of genes dominantly under purifying selection (more commonly homozygous) and under balancing selection (more commonly heterozygous), might have low and high mutation rates, respectively. Our results are consistent with this, there being a ten times higher mutation rate in pathogen resistance genes, expected to be under positive or balancing selection. Consequently, we do not necessarily need to evoke extremely weak(1,2) selection on the mutation rate to explain why mutational hot and cold spots might correspond to regions under positive/balancing and purifying selection, respectively(3,4).
C1 [Yang, Sihai; Wang, Long; Huang, Ju; Zhang, Xiaohui; Yuan, Yang; Chen, Jian-Qun; Tian, Dacheng] Nanjing Univ, Sch Life Sci, State Key Lab Pharmaceut Biotechnol, Nanjing 210023, Peoples R China.
   [Hurst, Laurence D.] Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath BA2 7AY, Avon, England.
C3 Nanjing University; University of Bath
RP Tian, DC (corresponding author), Nanjing Univ, Sch Life Sci, State Key Lab Pharmaceut Biotechnol, Nanjing 210023, Peoples R China.
EM bssldh@bath.ac.uk; dtian@nju.edu.cn
FU National Natural Science Foundation of China [91331205, 91231102, 31170210]; Program for Changjiang Scholars and Innovative Research Team [IRT_14R27]; Jiangsu Collaborative Innovation Center for Modern Crop Production
NR 43
TC 138
Z9 168
U1 0
U2 170
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 23
PY 2015
VL 523
IS 7561
BP 463
EP U187
DI 10.1038/nature14649
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN4DD
UT WOS:000358378900037
PM 26176923
DA 2026-03-09
ER

PT J
AU Mochida, K
   Oikawa, Y
   Kimura, Y
   Kirisako, H
   Hirano, H
   Ohsumi, Y
   Nakatogawa, H
AF Mochida, Keisuke
   Oikawa, Yu
   Kimura, Yayoi
   Kirisako, Hiromi
   Hirano, Hisashi
   Ohsumi, Yoshinori
   Nakatogawa, Hitoshi
TI Receptor-mediated selective autophagy degrades the endoplasmic reticulum and the nucleus
SO NATURE
LA English
DT Article
ID saccharomyces-cerevisiae; vacuolar hydrolases; yeast; proteins; mutants; recognition; degradation; delivery; triggers; strains
AB Macroautophagy (hereafter referred to as autophagy) degrades various intracellular constituents to regulate a wide range of cellular functions, and is also closely linked to several human diseases(1,2). In selective autophagy, receptor proteins recognize degradation targets and direct their sequestration by double-membrane vesicles called autophagosomes, which transport them into lysosomes or vacuoles(3). Although recent studies have shown that selective autophagy is involved in quality/quantity control of some organelles, including mitochondria and peroxisomes(4), it remains unclear how extensively it contributes to cellular organelle homeostasis. Here we describe selective autophagy of the endoplasmic reticulum (ER) and nucleus in the yeast Saccharomyces cerevisiae. We identify two novel proteins, Atg39 and Atg40, as receptors specific to these pathways. Atg39 localizes to the perinuclear ER (or the nuclear envelope) and induces autophagic sequestration of part of the nucleus. Atg40 is enriched in the cortical and cytoplasmic ER, and loads these ER subdomains into autophagosomes. Atg39-dependent autophagy of the perinuclear ER/nucleus is required for cell survival under nitrogen-deprivation conditions. Atg40 is probably the functional counterpart of FAM134B, an autophagy receptor for the ER in mammals that has been implicated in sensory neuropathy(5). Our results provide fundamental insight into the pathophysiological roles and mechanisms of 'ER-phagy' and 'nucleophagy' in other organisms.
C1 [Mochida, Keisuke; Kirisako, Hiromi; Nakatogawa, Hitoshi] Tokyo Inst Technol, Grad Sch Biosci & Biotechnol, Yokohama, Kanagawa 2268503, Japan.
   [Oikawa, Yu; Ohsumi, Yoshinori] Tokyo Inst Technol, Frontier Res Ctr, Yokohama, Kanagawa 2268503, Japan.
   [Kimura, Yayoi; Hirano, Hisashi] Yokohama City Univ, Adv Med Res Ctr, Yokohama, Kanagawa 2360004, Japan.
   [Kirisako, Hiromi; Nakatogawa, Hitoshi] Japan Sci & Technol Agcy, CREST, Kawaguchi, Saitama 3320012, Japan.
C3 Institute of Science Tokyo; Tokyo Institute of Technology; Institute of Science Tokyo; Tokyo Institute of Technology; Yokohama City University; Japan Science & Technology Agency (JST)
RP Nakatogawa, H (corresponding author), Tokyo Inst Technol, Grad Sch Biosci & Biotechnol, Yokohama, Kanagawa 2268503, Japan.
EM hnakatogawa@bio.titech.ac.jp
FU Ministry of Education, Culture, Sports, Science and Technology of Japan [25111003, 25711005, 23000015]; Grants-in-Aid for Scientific Research [23000015, 15J11855, 25111003, 25711005] Funding Source: KAKEN
NR 32
TC 510
Z9 581
U1 7
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 JUN 18
PY 2015
VL 522
IS 7556
BP 359
EP +
DI 10.1038/nature14506
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK7PU
UT WOS:000356425400057
PM 26040717
DA 2026-03-09
ER

PT J
AU Nguyen, THD
   Galej, WP
   Bai, XC
   Savva, CG
   Newman, AJ
   Scheres, SHW
   Nagai, K
AF Thi Hoang Duong Nguyen
   Galej, Wojciech P.
   Bai, Xiao-chen
   Savva, Christos G.
   Newman, Andrew J.
   Scheres, Sjors H. W.
   Nagai, Kiyoshi
TI The architecture of the spliceosomal U4/U6.U5 tri-snRNP
SO NATURE
LA English
DT Article
ID pre-messenger-rna; splicing factor prp8; u5 snrnp; crystal-structure; cryo-em; conformational-changes; genetic interactions; structural basis; catalytic core; protein
AB U4/U6.U5 tri-snRNP is a 1.5-megadalton pre-assembled spliceosomal complex comprising U5 small nuclear RNA (snRNA), extensively base-paired U4/U6 snRNAs and more than 30 proteins, including the key components Prp8, Brr2 and Snu114. The tri-snRNP combines with a precursor messenger RNA substrate bound to U1 and U2 small nuclear ribonucleoprotein particles (snRNPs), and transforms into a catalytically active spliceosome after extensive compositional and conformational changes triggered by unwinding of the U4 and U6 (U4/U6) snRNAs. Here we use cryo-electron microscopy single-particle reconstruction of Saccharomyces cerevisiae tri-snRNP at 5.9 angstrom resolution to reveal the essentially complete organization of its RNA and protein components. The single-stranded region of U4 snRNA between its 39 stem-loop and the U4/U6 snRNA stem I is loaded into the Brr2 helicase active site ready for unwinding. Snu114 and the amino-terminal domain of Prp8 position U5 snRNA to insert its loop I, which aligns the exons for splicing, into the Prp8 active site cavity. The structure provides crucial insights into the activation process and the active site of the spliceosome.
C1 [Thi Hoang Duong Nguyen; Galej, Wojciech P.; Bai, Xiao-chen; Savva, Christos G.; Newman, Andrew J.; Scheres, Sjors H. W.; Nagai, Kiyoshi] MRC, Mol Biol Lab, Cambridge CB2 0QH, England.
C3 MRC Laboratory Molecular Biology
RP Nguyen, THD (corresponding author), MRC, Mol Biol Lab, Francis Crick Ave, Cambridge CB2 0QH, England.
EM knguyen@mrc-lmb.cam.ac.uk; kn@mrc-lmb.cam.ac.uk
FU Herchel Smith Research Studentship; European Union; Medical Research Council [MC_U105184330, MC_UP_A025_1013]; Medical Research Council [MC_U105184330, MC_UP_A025_1013] Funding Source: researchfish; MRC [MC_UP_A025_1013, MC_U105184330] Funding Source: UKRI
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NR 75
TC 187
Z9 229
U1 1
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 JUL 2
PY 2015
VL 523
IS 7558
BP 47
EP +
DI 10.1038/nature14548
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL7RN
UT WOS:000357169500028
PM 26106855
DA 2026-03-09
ER

PT J
AU Sato, TK
   Asai, M
   Borschevsky, A
   Stora, T
   Sato, N
   Kaneya, Y
   Tsukada, K
   Düllmann, CE
   Eberhardt, K
   Eliav, E
   Ichikawa, S
   Kaldor, U
   Kratz, JV
   Miyashita, S
   Nagame, Y
   Ooe, K
   Osa, A
   Renisch, D
   Runke, J
   Schädel, M
   Thörle-Pospiech, P
   Toyoshima, A
   Trautmann, N
AF Sato, T. K.
   Asai, M.
   Borschevsky, A.
   Stora, T.
   Sato, N.
   Kaneya, Y.
   Tsukada, K.
   Duellmann, Ch E.
   Eberhardt, K.
   Eliav, E.
   Ichikawa, S.
   Kaldor, U.
   Kratz, J. V.
   Miyashita, S.
   Nagame, Y.
   Ooe, K.
   Osa, A.
   Renisch, D.
   Runke, J.
   Schaedel, M.
   Thoerle-Pospiech, P.
   Toyoshima, A.
   Trautmann, N.
TI Measurement of the first ionization potential of lawrencium, element 103
SO NATURE
LA English
DT Article
ID transition energy; chemical-characterization; basis-sets; lutetium
AB The chemical properties of an element are primarily governed by the configuration of electrons in the valence shell. Relativistic effects influence the electronic structure of heavy elements in the sixth row of the periodic table, and these effects increase dramatically in the seventh row including the actinides even affecting ground-state configurations(1,2). Atomic s and p(1/2) orbitals are stabilized by relativistic effects, whereas p(3/2), d and f orbitals are destabilized, so that ground-state configurations of heavy elements may differ from those of lighter elements in the same group. The first ionization potential (IP1) is a measure of the energy required to remove one valence electron from a neutral atom, and is an atomic property that reflects the outermost electronic configuration. Precise and accurate experimental determination of IP1 gives information on the binding energy of valence electrons, and also, therefore, on the degree of relativistic stabilization. However, such measurements are hampered by the difficulty in obtaining the heaviest elements on scales of more than one atom at a time(3-5). Here we report that the experimentally obtained IP1 of the heaviest actinide, lawrencium (Lr, atomic number 103), is 4.96(-0.07)(+0.08) electronvolts. The IP1 of Lr was measured with Lr-256. (half-life 27 seconds) using an efficient surface ion-source and a radioisotope detection system coupled to a mass separator. The measured IP1 is in excellent agreement with the value of 4.963(15) electronvolts predicted here by state-of-the-art relativistic calculations. The present work provides a reliable benchmark for theoretical calculations and also opens the way for IP1 measurements of superheavy elements (that is, transactinides) on an atom-at-a-time scale.
C1 [Sato, T. K.; Asai, M.; Sato, N.; Kaneya, Y.; Tsukada, K.; Ichikawa, S.; Nagame, Y.; Osa, A.; Schaedel, M.; Toyoshima, A.] JAEA, Tokai, Ibaraki 3191195, Japan.
   [Borschevsky, A.] Massey Univ, New Zealand Inst Adv Study, Ctr Theoret Chem & Phys, Auckland, New Zealand.
   [Borschevsky, A.; Duellmann, Ch E.; Eberhardt, K.; Thoerle-Pospiech, P.] Helmholtz Inst Mainz, D-55099 Mainz, Germany.
   [Stora, T.] CERN, ISOLDE, CH-1211 Geneva 23, Switzerland.
   [Kaneya, Y.; Nagame, Y.] Ibaraki Univ, Grad Sch Sci & Engn, Mito, Ibaraki 3108512, Japan.
   [Duellmann, Ch E.; Runke, J.] GSI Helmholtzzentrum Schwerionenforsch, D-64291 Darmstadt, Germany.
   [Duellmann, Ch E.; Eberhardt, K.; Kratz, J. V.; Renisch, D.; Thoerle-Pospiech, P.; Trautmann, N.] Johannes Gutenberg Univ Mainz, Inst Kernchem, D-55099 Mainz, Germany.
   [Eliav, E.; Kaldor, U.] Tel Aviv Univ, Sch Chem, IL-69978 Tel Aviv, Israel.
   [Ichikawa, S.] RIKEN, Nishina Ctr Accelerator Based Sci, Wako, Saitama 3510198, Japan.
   [Miyashita, S.] Hiroshima Univ, Grad Sch Sci, Kagamiyama, Higashi Hiroshi 7398526, Japan.
   [Ooe, K.] Niigata Univ, Inst Sci & Technol, Niigata 9102181, Japan.
C3 Japan Atomic Energy Agency; Massey University; European Organization for Nuclear Research (CERN); Ibaraki University; Helmholtz Association; GSI Helmholtz-Center for Heavy Ion Research; Johannes Gutenberg University of Mainz; Tel Aviv University; RIKEN; Hiroshima University; Niigata University
RP Nagame, Y (corresponding author), JAEA, Tokai, Ibaraki 3191195, Japan.
EM nagame.yuichiro@jaea.go.jp
FU Office of Science, Office of Basic Energy Sciences, Chemical Sciences, Geosciences, and Biosciences Division of the US Department of Energy; Helmholtz-Institut Mainz; Ministry of Education, Science, Sports and Culture (MEXT) [26390119]; Grants-in-Aid for Scientific Research [26288028, 26390119] Funding Source: KAKEN
NR 34
TC 116
Z9 133
U1 2
U2 101
PU NATURE PUBLISHING 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 9
PY 2015
VL 520
IS 7546
BP 209
EP U153
DI 10.1038/nature14342
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CF3NA
UT WOS:000352454600036
PM 25855457
DA 2026-03-09
ER

PT J
AU Bailey, JE
   Nagayama, T
   Loisel, GP
   Rochau, GA
   Blancard, C
   Colgan, J
   Cosse, P
   Faussurier, G
   Fontes, CJ
   Gilleron, F
   Golovkin, I
   Hansen, SB
   Iglesias, CA
   Kilcrease, DP
   MacFarlane, JJ
   Mancini, RC
   Nahar, SN
   Orban, C
   Pain, JC
   Pradhan, AK
   Sherrill, M
   Wilson, BG
AF Bailey, J. E.
   Nagayama, T.
   Loisel, G. P.
   Rochau, G. A.
   Blancard, C.
   Colgan, J.
   Cosse, Ph.
   Faussurier, G.
   Fontes, C. J.
   Gilleron, F.
   Golovkin, I.
   Hansen, S. B.
   Iglesias, C. A.
   Kilcrease, D. P.
   MacFarlane, J. J.
   Mancini, R. C.
   Nahar, S. N.
   Orban, C.
   Pain, J-C.
   Pradhan, A. K.
   Sherrill, M.
   Wilson, B. G.
TI A higher-than-predicted measurement of iron opacity at solar interior temperatures
SO NATURE
LA English
DT Article
ID detailed configuration; photoabsorption; radiation; models; films; abundances; plasma; region; hot; cr
AB Nearly a century ago it was recognized(1) that radiation absorption by stellar matter controls the internal temperature profiles within stars. Laboratory opacity measurements, however, have never been performed at stellar interior conditions, introducing uncertainties in stellar models(2-5). A particular problem arose(2,3,6-8) when refined photosphere spectral analysis(9,10) led to reductions of 30-50 per cent in the inferred amounts of carbon, nitrogen and oxygen in the Sun. Standard solar models(11) using the revised element abundances disagree with helioseismic observations that determine the internal solar structure using acoustic oscillations. This could be resolved if the true mean opacity for the solar interior matter were roughly 15 per cent higher than predicted(2,3,6-8), because increased opacity compensates for the decreased element abundances. Iron accounts for a quarter of the total opacity(2,12) at the solar radiation/convection zone boundary. Here we report measurements of wavelength-resolved iron opacity at electron temperatures of 1.9-2.3 million kelvin and electron densities of (0.7-4.0) x 10(22) per cubic centimetre, conditions very similar to those in the solar region that affects the discrepancy the most: the radiation/convection zone boundary. The measured wavelength-dependent opacity is 30-400 per cent higher than predicted. This represents roughly half the change in the mean opacity needed to resolve the solar discrepancy, even though iron is only one of many elements that contribute to opacity.
C1 [Bailey, J. E.; Nagayama, T.; Loisel, G. P.; Rochau, G. A.; Hansen, S. B.] Sandia Natl Labs, Albuquerque, NM 87185 USA.
   [Blancard, C.; Cosse, Ph.; Faussurier, G.; Gilleron, F.; Pain, J-C.] Commissariat Energie Atom CEA & Energie Alternat, F-91297 Arpajon, France.
   [Colgan, J.; Fontes, C. J.; Kilcrease, D. P.; Sherrill, M.] Los Alamos Natl Lab, Los Alamos, NM 87545 USA.
   [Golovkin, I.; MacFarlane, J. J.] Prism Computat Sci, Madison, WI 53711 USA.
   [Iglesias, C. A.; Wilson, B. G.] Lawrence Livermore Natl Lab, Livermore, CA 94550 USA.
   [Mancini, R. C.] Univ Nevada, Reno, NV 89557 USA.
   [Nahar, S. N.; Orban, C.; Pradhan, A. K.] Ohio State Univ, Columbus, OH 43210 USA.
C3 United States Department of Energy (DOE); Sandia National Laboratories; United States Department of Energy (DOE); Los Alamos National Laboratory; United States Department of Energy (DOE); Lawrence Livermore National Laboratory; Nevada System of Higher Education (NSHE); University of Nevada Reno; University System of Ohio; Ohio State University
RP Bailey, JE (corresponding author), Sandia Natl Labs, 1515 Eubank SE, Albuquerque, NM 87185 USA.
EM jebaile@sandia.gov
FU United States Department of Energy [DE-AC04-94AL85000, DE-AC5206NA25396]; Direct For Mathematical & Physical Scien; Division Of Astronomical Sciences [1409207, 1312441] Funding Source: National Science Foundation
NR 41
TC 392
Z9 443
U1 6
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 JAN 1
PY 2015
VL 517
IS 7532
BP 56
EP U120
DI 10.1038/nature14048
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AX8SI
UT WOS:000347178400033
PM 25557711
DA 2026-03-09
ER

PT J
AU Finisguerra, V
   Di Conza, G
   Di Matteo, M
   Serneels, J
   Costa, S
   Thompson, AAR
   Wauters, E
   Walmsley, S
   Prenen, H
   Granot, Z
   Casazza, A
   Mazzone, M
AF Finisguerra, Veronica
   Di Conza, Giusy
   Di Matteo, Mario
   Serneels, Jens
   Costa, Sandra
   Thompson, A. A. Roger
   Wauters, Els
   Walmsley, Sarah
   Prenen, Hans
   Granot, Zvi
   Casazza, Andrea
   Mazzone, Massimiliano
TI MET is required for the recruitment of anti-tumoural neutrophils
SO NATURE
LA English
DT Article
ID hepatocyte growth-factor; oncogene addiction; cell; protooncogene; inflammation; expression; differentiation; mobilization; modulation; inhibitors
AB Mutations or amplification of the MET proto-oncogene are involved in the pathogenesis of several tumours(1-4), which rely on the constitutive engagement of this pathway for their growth and survival(1,5). However, MET is expressed not only by cancer cells but also by tumour-associated stromal cells, although its precise role in this compartment is not well characterized(6-11). Here we show that MET is required for neutrophil chemoattraction and cytotoxicity in response to its ligand hepatocyte growth factor (HGF). Met deletion in mouse neutrophils enhances tumour growth and metastasis. This phenotype correlates with reduced neutrophil infiltration to both the primary tumour and metastatic sites. Similarly, Met is necessary for neutrophil transudation during colitis, skin rash or peritonitis. Mechanistically, Met is induced by tumour-derived tumour necrosis factor (TNF)-alpha or other inflammatory stimuli in both mouse and human neutrophils. This induction is instrumental for neutrophil transmigration across an activated endothelium and for inducible nitric oxide synthase production upon HGF stimulation. Consequently, HGF/MET-dependent nitric oxide release by neutrophils promotes cancer cell killing, which abates tumour growth and metastasis. After systemic administration of a MET kinase inhibitor, we prove that the therapeutic benefit of MET targeting in cancer cells is partly countered by the pro-tumoural effect arising from MET blockade in neutrophils. Our work identifies an unprecedented role of MET in neutrophils, suggests a potential 'Achilles' heel' of MET-targeted therapies in cancer, and supports the rationale for evaluating anti-MET drugs in certain inflammatory diseases.
C1 [Finisguerra, Veronica; Di Conza, Giusy; Di Matteo, Mario; Serneels, Jens; Costa, Sandra; Casazza, Andrea; Mazzone, Massimiliano] VIB, Vesalius Res Ctr, Lab Mol Oncol & Angiogenesis, B-3000 Leuven, Belgium.
   [Finisguerra, Veronica; Di Conza, Giusy; Di Matteo, Mario; Serneels, Jens; Costa, Sandra; Casazza, Andrea; Mazzone, Massimiliano] Katholieke Univ Leuven, Dept Oncol, Vesalius Res Ctr, Lab Mol Oncol & Angiogenesis, B-3000 Leuven, Belgium.
   [Costa, Sandra] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, P-4710057 Braga, Portugal.
   [Costa, Sandra] ICVS 3Bs PT Govt Associate Lab, P-4710057 Braga, Portugal.
   [Thompson, A. A. Roger; Walmsley, Sarah] Univ Sheffield, Dept Infect & Immun, Sheffield S10 2RX, S Yorkshire, England.
   [Wauters, Els] Univ Hosp Gasthuisberg, Resp Div, B-3000 Leuven, Belgium.
   [Wauters, Els] VIB, Vesalius Res Ctr, Lab Translat Genet, B-3000 Leuven, Belgium.
   [Wauters, Els] Katholieke Univ Leuven, Dept Oncol, Vesalius Res Ctr, Lab Translat Genet, B-3000 Leuven, Belgium.
   [Prenen, Hans] Katholieke Univ Leuven, Dept Oncol, Univ Hosp Gasthuisberg, Digest Oncol Unit, B-3000 Leuven, Belgium.
   [Granot, Zvi] Hebrew Univ Jerusalem, Inst Med Res Israel Canada, Dept Dev Biol & Canc Res, IL-91120 Jerusalem, Israel.
C3 Flanders Institute for Biotechnology (VIB); KU Leuven; Universidade do Minho; Laboratorio Associado ICVS 3B's; University of Sheffield; KU Leuven; University Hospital Leuven; Flanders Institute for Biotechnology (VIB); KU Leuven; KU Leuven; University Hospital Leuven; Hebrew University of Jerusalem
RP Mazzone, M (corresponding author), VIB, Vesalius Res Ctr, Lab Mol Oncol & Angiogenesis, B-3000 Leuven, Belgium.
EM andrea.casazza@vib-kuleuven.be; massimiliano.mazzone@vib-kuleuven.be
FU Fonds Wetenschappelijk Onderzoek (FWO); Fondazione Umberto Veronesi; Wellcome Trust; European Research Council; Medical Research Council [G0802255] Funding Source: researchfish; National Institute for Health Research [ACF-2006-04-005] Funding Source: researchfish; MRC [G0802255] Funding Source: UKRI
NR 35
TC 413
Z9 461
U1 1
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 18
PY 2015
VL 522
IS 7556
BP 349
EP +
DI 10.1038/nature14407
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK7PU
UT WOS:000356425400055
PM 25985180
DA 2026-03-09
ER

PT J
AU Koh, MJ
   Khan, RKM
   Torker, S
   Yu, M
   Mikus, MS
   Hoveyda, AH
AF Koh, Ming Joo
   Khan, R. Kashif M.
   Torker, Sebastian
   Yu, Miao
   Mikus, Malte S.
   Hoveyda, Amir H.
TI High-value alcohols and higher-oxidation-state compounds by catalytic Z-selective cross-metathesis
SO NATURE
LA English
DT Article
ID ring-opening/cross-metathesis; natural-product synthesis; olefin metathesis; complexes; macrolide; carbene
AB Olefin metathesis catalysts provide access to molecules that are indispensable to physicians and researchers in the life sciences(1,2). A persisting problem, however, is the dearth of chemical transformations that directly generate acyclic Z allylic alcohols, including products that contain a hindered neighbouring substituent or reactive functional units such as a phenol, an aldehyde, or a carboxylic acid. Here we present an electronically modified ruthenium-disulfide catalyst that is effective in generating such high-value compounds by cross-metathesis. The ruthenium complex is prepared from a commercially available precursor and an easily generated air-stable zinc catechothiolate. Transformations typically proceed with 5.0 mole per cent of the complex and an inexpensive reaction partner in 4-8 hours under ambient conditions; products are obtained in up to 80 per cent yield and 98:2 Z:E diastereoselectivity. The use of this catalyst is demonstrated in the synthesis of the naturally occurring anti-tumour agent neopeltolide and in a single-step stereoselective gram-scale conversion of a renewable feedstock (oleic acid) to an anti-fungal agent. In this conversion, the new catalyst promotes cross-metathesis more efficiently than the commonly used dichloro-ruthenium complexes, indicating that its utility may extend beyond Z-selective processes.
C1 [Koh, Ming Joo; Khan, R. Kashif M.; Torker, Sebastian; Yu, Miao; Mikus, Malte S.; Hoveyda, Amir H.] Boston Coll, Dept Chem, Merkert Chem Ctr, Chestnut Hill, MA 02467 USA.
C3 Boston College
RP Hoveyda, AH (corresponding author), Boston Coll, Dept Chem, Merkert Chem Ctr, Chestnut Hill, MA 02467 USA.
EM amir.hoveyda@bc.edu
FU National Science Foundation [CHE-1362763]; Direct For Mathematical & Physical Scien; Division Of Chemistry [1362763] Funding Source: National Science Foundation
NR 30
TC 184
Z9 206
U1 2
U2 169
PU NATURE PUBLISHING 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 8
PY 2015
VL 517
IS 7533
BP 181
EP 186
DI 10.1038/nature14061
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600032
PM 25567284
DA 2026-03-09
ER

PT J
AU Feng, YQ
   van der Veeken, J
   Shugay, M
   Putintseva, EV
   Osmanbeyoglu, HU
   Dikiy, S
   Hoyos, BE
   Moltedo, B
   Hemmers, S
   Treuting, P
   Leslie, CS
   Chudakov, DM
   Rudensky, AY
AF Feng, Yongqiang
   van der Veeken, Joris
   Shugay, Mikhail
   Putintseva, Ekaterina V.
   Osmanbeyoglu, Hatice U.
   Dikiy, Stanislav
   Hoyos, Beatrice E.
   Moltedo, Bruno
   Hemmers, Saskia
   Treuting, Piper
   Leslie, Christina S.
   Chudakov, Dmitriy M.
   Rudensky, Alexander Y.
TI A mechanism for expansion of regulatory T-cell repertoire and its role in self-tolerance
SO NATURE
LA English
DT Article
ID negative selection; differentiation; recognition; induction; responses; disease; thymus; gene; inkt; tcr
AB T-cell receptor (TCR) signalling has a key role in determining T-cell fate. Precursor cells expressing TCRs within a certain low-affinity range for complexes of self-peptide and major histocompatibility complex (MHC) undergo positive selection and differentiate into naive T cells expressing a highly diverse self-MHC-restricted TCR repertoire. In contrast, precursors displaying TCRs with a high affinity for 'self' are either eliminated through TCR-agonist-induced apoptosis (negative selection)(1) or restrained by regulatory T (T-reg) cells, whose differentiation and function are controlled by the X-chromosome-encoded transcription factor Foxp3 (reviewed in ref. 2). Foxp3 is expressed in a fraction of self-reactive T cells that escape negative selection in response to agonist-driven TCR signals combined with interleukin 2 (IL-2) receptor signalling. In addition to Treg cells, TCR-agonist-driven selection results in the generation of several other specialized T-cell lineages such as natural killer T cells and innate mucosal-associated invariant T cells(3). Although the latter exhibit a restricted TCR repertoire, Treg cells display a highly diverse collection of TCRs(4-6). Here we explore in mice whether a specialized mechanism enables agonist-driven selection of T-reg cells with a diverse TCR repertoire, and the importance this holds for self-tolerance. We show that the intronic Foxp3 enhancer conserved noncoding sequence 3 (CNS3) acts as an epigenetic switch that confers a poised state to the Foxp3 promoter in precursor cells to make T-reg cell lineage commitment responsive to a broad range of TCR stimuli, particularly to suboptimal ones. CNS3-dependent expansion of the TCR repertoire enables T-reg cells to control self-reactive T cells effectively, especially when thymic negative selection is genetically impaired. Our findings highlight the complementary roles of these two main mechanisms of self-tolerance.
C1 [Feng, Yongqiang; van der Veeken, Joris; Dikiy, Stanislav; Hoyos, Beatrice E.; Moltedo, Bruno; Hemmers, Saskia; Rudensky, Alexander Y.] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA.
   [Feng, Yongqiang; van der Veeken, Joris; Dikiy, Stanislav; Hoyos, Beatrice E.; Moltedo, Bruno; Hemmers, Saskia; Rudensky, Alexander Y.] Mem Sloan Kettering Canc Ctr, Program Immunol, Ludwig Ctr, New York, NY 10065 USA.
   [Shugay, Mikhail; Putintseva, Ekaterina V.; Chudakov, Dmitriy M.] Shemyakin Ovchinnikov Inst Bioorgan Chem RAS, Moscow 117997, Russia.
   [Shugay, Mikhail; Chudakov, Dmitriy M.] Pirogov Russian Natl Res Med Univ, Moscow 117997, Russia.
   [Shugay, Mikhail; Putintseva, Ekaterina V.; Chudakov, Dmitriy M.] Masaryk Univ, Cent European Inst Technol, Brno 62500, Czech Republic.
   [Osmanbeyoglu, Hatice U.; Leslie, Christina S.] Mem Sloan Kettering Canc Ctr, Computat Biol Program, New York, NY 10065 USA.
   [Treuting, Piper] Univ Washington, Sch Med, Dept Comparat Med, Seattle, WA 98195 USA.
C3 Memorial Sloan Kettering Cancer Center; Howard Hughes Medical Institute; Memorial Sloan Kettering Cancer Center; Russian Academy of Sciences; Pushchino Scientific Center for Biological Research (PSCBI) of the Russian Academy of Sciences; Institute of Bioorganic Chemistry of the Russian Academy of Sciences; Pirogov Russian National Research Medical University; Masaryk University; Memorial Sloan Kettering Cancer Center; University of Washington; University of Washington Seattle
RP Rudensky, AY (corresponding author), Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA.
EM rudenska@mskcc.org
FU Cancer Research Institute; NIH [R37 AI034206, U01 HG007893]; Cancer Center Support Grant [P30 CA008748]; Howard Hughes Medical Institute; MCB program RAS; RFBR [14-04-01247, 15-34-21052]; National Cancer Institute [P30CA008748] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [R01AI034206] Funding Source: NIH RePORTER
NR 42
TC 129
Z9 158
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 3
PY 2015
VL 528
IS 7580
BP 132
EP +
DI 10.1038/nature16141
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000063
PM 26605529
DA 2026-03-09
ER

PT J
AU Wrobel, L
   Topf, U
   Bragoszewski, P
   Wiese, S
   Sztolsztener, ME
   Oeljeklaus, S
   Varabyova, A
   Lirski, M
   Chroscicki, P
   Mroczek, S
   Januszewicz, E
   Dziembowski, A
   Koblowska, M
   Warscheid, B
   Chacinska, A
AF Wrobel, Lidia
   Topf, Ulrike
   Bragoszewski, Piotr
   Wiese, Sebastian
   Sztolsztener, Malgorzata E.
   Oeljeklaus, Silke
   Varabyova, Aksana
   Lirski, Maciej
   Chroscicki, Piotr
   Mroczek, Seweryn
   Januszewicz, Elzbieta
   Dziembowski, Andrzej
   Koblowska, Marta
   Warscheid, Bettina
   Chacinska, Agnieszka
TI Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol
SO NATURE
LA English
DT Article
ID ubiquitin-proteasome system; intermembrane space; presequence translocase; 20s proteasome; import; degradation; cooperation; chaperones; longevity; cytoscape
AB Most of the mitochondrial proteome originates from nuclear genes and is transported into the mitochondria after synthesis in the cytosol. Complex machineries which maintain the specificity of protein import and sorting include the TIM23 translocase responsible for the transfer of precursor proteins into the matrix, and the mitochondrial intermembrane space import and assembly (MIA) machinery required for the biogenesis of intermembrane space proteins. Dysfunction of mitochondrial protein sorting pathways results in diminishing specific substrate proteins, followed by systemic pathology of the organelle and organismal death(1-4). The cellular responses caused by accumulation of mitochondrial precursor proteins in the cytosol are mainly unknown. Here we present a comprehensive picture of the changes in the cellular transcriptome and proteome in response to a mitochondrial import defect and precursor over-accumulation stress. Pathways were identified that protect the cell against mitochondrial biogenesis defects by inhibiting protein synthesis and by activation of the proteasome, a major machine for cellular protein clearance. Proteasomal activity is modulated in proportion to the quantity of mislocalized mitochondrial precursor proteins in the cytosol. We propose that this type of unfolded protein response activated by mistargeting of proteins (UPRam) is beneficial for the cells. UPRam provides a means for buffering the consequences of physiological slowdown in mitochondrial protein import and for counteracting pathologies that are caused or contributed by mitochondrial dysfunction.
C1 [Wrobel, Lidia; Topf, Ulrike; Bragoszewski, Piotr; Sztolsztener, Malgorzata E.; Varabyova, Aksana; Chroscicki, Piotr; Januszewicz, Elzbieta; Chacinska, Agnieszka] Int Inst Mol & Cell Biol, PL-02109 Warsaw, Poland.
   [Wiese, Sebastian; Oeljeklaus, Silke; Warscheid, Bettina] Univ Freiburg, Dept Biochem & Funct Prote, Fac Biol, D-79104 Freiburg, Germany.
   [Wiese, Sebastian; Oeljeklaus, Silke; Warscheid, Bettina] Univ Freiburg, BIOSS Ctr Biol Signalling Studies, D-79104 Freiburg, Germany.
   [Wiese, Sebastian; Warscheid, Bettina] Univ Freiburg, ZBSA Ctr Biol Syst Anal, D-79104 Freiburg, Germany.
   [Lirski, Maciej; Mroczek, Seweryn; Dziembowski, Andrzej; Koblowska, Marta] Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland.
   [Mroczek, Seweryn; Dziembowski, Andrzej] Univ Warsaw, Fac Biol, Dept Genet & Biotechnol, PL-02106 Warsaw, Poland.
   [Koblowska, Marta] Univ Warsaw, Fac Biol, Lab Syst Biol, PL-02106 Warsaw, Poland.
C3 Miedzynarodowy Instytut Biologii Molekularnej i Komorkowej; University of Freiburg; University of Freiburg; University of Freiburg; Polish Academy of Sciences; Institute of Biochemistry & Biophysics - Polish Academy of Sciences; University of Warsaw; University of Warsaw
RP Chacinska, A (corresponding author), Int Inst Mol & Cell Biol, PL-02109 Warsaw, Poland.
EM bettina.warscheid@biologie.uni-freiburg.de; achacinska@iimcb.gov.pl
FU PRIDE Team, EBI; Deutsche Forschungsgemeinschaft; Excellence Initiative of the German Federal Government [EXC 294 BIOSS]; Excellence Initiative of the German State Government [EXC 294 BIOSS]; Foundation for Polish Science - Welcome Programme - EU within the European Regional Development Fund; National Science Centre [2011/02/B/NZ2/01402, 2013/11/B/NZ3/00974, 2013/08/T/NZ1/00770, 2013/11/D/NZ1/02294]; Ministerial Ideas Plus schema [000263]; Swiss National Science Foundation [PP300P3-147899]
NR 53
TC 346
Z9 371
U1 0
U2 83
PU NATURE PUBLISHING 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 27
PY 2015
VL 524
IS 7566
BP 485
EP +
DI 10.1038/nature14951
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP7LN
UT WOS:000360069300042
PM 26245374
DA 2026-03-09
ER

PT J
AU Zhu, JJ
   Sammons, MA
   Donahue, G
   Dou, ZX
   Vedadi, M
   Getlik, M
   Barsyte-Lovejoy, D
   Al-Awar, R
   Katona, BW
   Shilatifard, A
   Huang, J
   Hua, XX
   Arrowsmith, CH
   Berger, SL
AF Zhu, Jiajun
   Sammons, Morgan A.
   Donahue, Greg
   Dou, Zhixun
   Vedadi, Masoud
   Getlik, Matthaus
   Barsyte-Lovejoy, Dalia
   Al-Awar, Rima
   Katona, Bryson W.
   Shilatifard, Ali
   Huang, Jing
   Hua, Xianxin
   Arrowsmith, Cheryl H.
   Berger, Shelley L.
TI Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth
SO NATURE
LA English
DT Article
ID mixed-lineage leukemia; li-fraumeni-syndrome; hox gene-expression; methyltransferase activity; histone methyltransferase; mll; menin; transcription; inhibitors; binding
AB TP53 (which encodes p53 protein) is the most frequently mutated gene among all human cancers. Prevalent p53 missense mutations abrogate its tumour suppressive function and lead to a 'gain-of-function' (GOF) that promotes cancer. Here we show that p53 GOF mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1 (also known as KMT2A), MLL2 (also known as KMT2D), and acetyltransferase MOZ (also known as KAT6A or MYST3), resulting in genome-wide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas shows specific upregulation of MLL1, MLL2, and MOZ in p53 GOF patient-derived tumours, but not in wild-type p53 or p53 null tumours. Cancer cell proliferation is markedly lowered by genetic knockdown of MLL1 or by pharmacological inhibition of the MLL1 methyltransferase complex. Our study reveals a novel chromatin mechanism underlying the progression of tumours with GOF p53, and suggests new possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent GOF p53 mutations.
C1 [Zhu, Jiajun; Sammons, Morgan A.; Donahue, Greg; Dou, Zhixun; Berger, Shelley L.] Univ Penn, Cell & Dev Biol, Perelman Sch Med, Philadelphia, PA 19104 USA.
   [Zhu, Jiajun; Sammons, Morgan A.; Donahue, Greg; Dou, Zhixun; Berger, Shelley L.] Univ Penn, Epigenet Program, Philadelphia, PA 19104 USA.
   [Zhu, Jiajun] Univ Penn, Perelman Sch Med, Biomed Grad Studies, Philadelphia, PA 19104 USA.
   [Vedadi, Masoud; Barsyte-Lovejoy, Dalia; Arrowsmith, Cheryl H.] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada.
   [Vedadi, Masoud; Al-Awar, Rima] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8, Canada.
   [Getlik, Matthaus; Al-Awar, Rima] Ontario Inst Canc Res, Drug Discovery Program, Toronto, ON M5G 0A3, Canada.
   [Katona, Bryson W.; Hua, Xianxin] Univ Penn, Perelman Sch Med, Dept Canc Biol, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA.
   [Shilatifard, Ali] Northwestern Univ, Dept Biochem & Mol Genet, Feinberg Sch Med, Chicago, IL 60611 USA.
   [Huang, Jing] NCI, Canc & Stem Cell Epigenet, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA.
   [Arrowsmith, Cheryl H.] Univ Toronto, Princess Margaret Canc Ctr, Toronto, ON M5G 2C4, Canada.
   [Arrowsmith, Cheryl H.] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2C4, Canada.
C3 University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Toronto; Structural Genomics Consortium; University of Toronto; University of Toronto; Ontario Institute for Cancer Research; University of Pennsylvania; Northwestern University; Feinberg School of Medicine; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; University of Toronto
RP Berger, SL (corresponding author), Univ Penn, Cell & Dev Biol, Perelman Sch Med, Philadelphia, PA 19104 USA.
EM bergers@upenn.edu
FU NIH [R01 CA078831, R01 GM069905]; American Cancer Society; ITMAT of the University of Pennsylvania; AbbVie; Bayer; Boehringer Ingelheim; Genome Canada through the Ontario Genomics Institute [OGI-055]; GlaxoSmithKline; Janssen; Lilly Canada; Merck; Novartis Research Foundation; Ontario Ministry of Economic Development and Innovation; Pfizer; Takeda; Wellcome Trust [092809/Z/10/Z]; Canadian Cancer Society Research Institute; National Cancer Institute [R01CA078831, P30CA060553] Funding Source: NIH RePORTER; National Institute of Environmental Health Sciences [P30ES013508] Funding Source: NIH RePORTER
NR 42
TC 383
Z9 468
U1 0
U2 107
PU NATURE PUBLISHING 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 10
PY 2015
VL 525
IS 7568
BP 206
EP +
DI 10.1038/nature15251
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400029
PM 26331536
DA 2026-03-09
ER

PT J
AU Prezioso, M
   Merrikh-Bayat, F
   Hoskins, BD
   Adam, GC
   Likharev, KK
   Strukov, DB
AF Prezioso, M.
   Merrikh-Bayat, F.
   Hoskins, B. D.
   Adam, G. C.
   Likharev, K. K.
   Strukov, D. B.
TI Training andoperation of an integrated neuromorphic network based on metal-oxide memristors
SO NATURE
LA English
DT Article
ID circuits; device; memory
AB Despite much progress in semiconductor integrated circuit technology, the extreme complexity of the human cerebral cortex(1), with its approximately 10(14) synapses, makes the hardware implementation of neuromorphic networks with a comparable number of devices exceptionally challenging. To provide comparable complexity while operating much faster and with manageable power dissipation, networks(2) based on circuits(3,4) combining complementary metaloxide-semiconductors (CMOSs) and adjustable two-terminal resistive devices (memristors) have been developed. In such circuits, the usual CMOS stack is augmented with one(3) or several(4) crossbar layers, with memristors at each crosspoint. There have recently been notable improvements in the fabrication of such memristive crossbars and their integration with CMOS circuits(5-12), including first demonstrations(5,6,12) of their vertical integration. Separately, discrete memristors have been used as artificial synapses in neuromorphic networks(13-18). Very recently, such experiments have been extended(19) to crossbar arrays of phase-change memristive devices. The adjustment of such devices, however, requires an additional transistor at each crosspoint, and hence these devices are much harder to scale than metal-oxide memristors(11,20,21), whose nonlinear current-voltage curves enable transistor-free operation. Here we report the experimental implementation of transistor-free metal-oxide memristor crossbars, with device variability sufficiently low to allow operation of integrated neural networks, in a simple network: a single-layer perceptron (an algorithm for linear classification). The network can be taught in situ using a coarse-grain variety of the delta rule algorithm(22) to perform the perfect classification of 3 3 3-pixel black/white images into three classes (representing letters). This demonstration is an important step towards much larger and more complex memristive neuromorphic networks.
C1 [Prezioso, M.; Merrikh-Bayat, F.; Hoskins, B. D.; Adam, G. C.; Strukov, D. B.] Univ Calif Santa Barbara, Dept Elect & Comp Engn, Santa Barbara, CA 93106 USA.
   [Likharev, K. K.] SUNY Stony Brook, Dept Phys & Astron, Stony Brook, NY 11794 USA.
C3 University of California System; University of California Santa Barbara; State University of New York (SUNY) System; Stony Brook University
RP Prezioso, M (corresponding author), Univ Calif Santa Barbara, Dept Elect & Comp Engn, Santa Barbara, CA 93106 USA.
EM mprezioso@ece.ucsb.edu; strukov@ece.ucsb.edu
FU AFOSR under the MURI [FA9550-12-1-0038]; DARPA via BAE Systems [HR0011-13-C-0051UPSIDE]; DENSO Corporation, Japan
NR 30
TC 2482
Z9 2762
U1 60
U2 1827
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 7
PY 2015
VL 521
IS 7550
BP 61
EP 64
DI 10.1038/nature14441
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH4YS
UT WOS:000354040900032
PM 25951284
DA 2026-03-09
ER

PT J
AU Saeed, M
   Andreo, U
   Chung, HY
   Espiritu, C
   Branch, AD
   Silva, JM
   Rice, CM
AF Saeed, Mohsan
   Andreo, Ursula
   Chung, Hyo-Young
   Espiritu, Christine
   Branch, Andrea D.
   Silva, Jose M.
   Rice, Charles M.
TI SEC14L2 enables pan-genotype HCV replication in cell culture
SO NATURE
LA English
DT Article
ID hepatitis-c virus; infectious cdna-clones; efficient replication; protein; rna; mutations; replicons; 2a; 1a; 3a
AB Since its discovery in 1989, efforts to grow clinical isolates of the hepatitis C virus (HCV) in cell culture have met with limited success. Only the JFH-1 isolate has the capacity to replicate efficiently in cultured hepatoma cells without cell culture-adaptive mutations(1-3). We hypothesized that cultured cells lack one or more factors required for the replication of clinical isolates. To identify the missing factors, we transduced Huh-7.5 human hepatoma cells with a pooled lentivirus-based human complementary DNA (cDNA) library, transfected the cells with HCV subgenomic replicons lacking adaptive mutations, and selected for stable replicon colonies. This led to the identification of a single cDNA, SEC14L2, that enabled RNA replication of diverse HCV genotypes in several hepatoma cell lines. This effect was dose-dependent, and required the continuous presence of SEC14L2. Full-length HCV genomes also replicated and produced low levels of infectious virus. Remarkably, SEC14L2-expressing Huh-7.5 cells also supported HCV replication following inoculation with patient sera. Mechanistic studies suggest that SEC14L2 promotes HCV infection by enhancing vitamin E-mediated protection against lipid peroxidation. This provides a foundation for development of in vitro replication systems for all HCV isolates, creating a useful platform to dissect the mechanisms by which cell culture-adaptive mutations act.
C1 [Saeed, Mohsan; Andreo, Ursula; Chung, Hyo-Young; Espiritu, Christine; Rice, Charles M.] Rockefeller Univ, Lab Virol & Infect Dis, Ctr Study Hepatitis C, New York, NY 10065 USA.
   [Branch, Andrea D.] Icahn Sch Med Mt Sinai, Div Liver Dis, New York, NY 10029 USA.
   [Silva, Jose M.] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA.
C3 Rockefeller University; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai
RP Rice, CM (corresponding author), Rockefeller Univ, Lab Virol & Infect Dis, Ctr Study Hepatitis C, New York, NY 10065 USA.
EM ricec@mail.rockefeller.edu
FU National Institutes of Health, NCI [R01CA057973]; NIAID [R01AI072613, R01AI099284]; NIDDK [R01DK090317]; NIDA [DA031095]; Helmsley Postdoctoral Fellowship for Basic and Translational Research on Disorders of the Digestive System at The Rockefeller University; American Association for the Study of Liver Diseases; Greenberg Medical Research Institute; Starr Foundation; Ronald A. Shellow, M.D. Memorial Fund
NR 45
TC 97
Z9 112
U1 0
U2 27
PU NATURE PUBLISHING 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 27
PY 2015
VL 524
IS 7566
BP 471
EP +
DI 10.1038/nature14899
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP7LN
UT WOS:000360069300039
PM 26266980
DA 2026-03-09
ER

PT J
AU Zhong, MJ
   Hedges, MP
   Ahlefeldt, RL
   Bartholomew, JG
   Beavan, SE
   Wittig, SM
   Longdell, JJ
   Sellars, MJ
AF Zhong, Manjin
   Hedges, Morgan P.
   Ahlefeldt, Rose L.
   Bartholomew, John G.
   Beavan, Sarah E.
   Wittig, Sven M.
   Longdell, Jevon J.
   Sellars, Matthew J.
TI Optically addressable nuclear spins in a solid with a six-hour coherence time
SO NATURE
LA English
DT Article
ID entanglement distribution; quantum repeaters; atomic ensembles; temperature; storage; memory
AB Space-like separation of entangled quantum states is a central concept in fundamental investigations of quantum mechanics and in quantum communication applications. Optical approaches are ubiquitous in the distribution of entanglement because entangled photons are easy to generate and transmit. However, extending this direct distribution beyond a range of a few hundred kilometres(1,2) to a worldwide network is prohibited by losses associated with scattering, diffraction and absorption during transmission. A proposal to overcome this range limitation is the quantum repeater protocol(3,4), which involves the distribution of entangled pairs of optical modes among many quantum memories stationed along the transmission channel. To be effective, the memories must store the quantum information encoded on the optical modes for times that are long compared to the direct optical transmission time of the channel(5). Here we measure a decoherence rate of 8 x 10(-5) per second over 100 milliseconds, which is the time required for light transmission on a global scale. The measurements were performed on a ground-state hyperfine transition of europium ion dopants in yttrium orthosilicate (Eu-151(3+):Y2SiO5) using optically detected nuclear magnetic resonance techniques. The observed decoherence rate is at least an order of magnitude lower than that of any other system suitable for an optical quantum memory. Furthermore, by employing dynamic decoupling, a coherence time of 370 +/- 60 minutes was achieved at 2 kelvin. It has been almost universally assumed that light is the best long-distance carrier for quantum information. However, the coherence time observed here is long enough that nuclear spins travelling at 9 kilometres per hour in a crystal would have a lower decoherence with distance than light in an optical fibre. This enables some very early approaches(6,7) to entanglement distribution to be revisited, in particular those in which the spins are transported rather than the light.
C1 [Zhong, Manjin; Hedges, Morgan P.; Ahlefeldt, Rose L.; Bartholomew, John G.; Beavan, Sarah E.; Wittig, Sven M.; Sellars, Matthew J.] Australian Natl Univ, Laser Phys Ctr, Ctr Quantum Computat & Commun Technol, GPO Box 4, Canberra, ACT 0200, Australia.
   [Hedges, Morgan P.] Princeton Univ, Dept Phys, Princeton, NJ 08554 USA.
   [Ahlefeldt, Rose L.] Univ Paris Sud, Lab Aime Cotton, CNRS UPR 3321, F-91405 Orsay, France.
   [Ahlefeldt, Rose L.] ENS Cachan, F-91405 Orsay, France.
   [Beavan, Sarah E.] Univ Munich, Fak Phys, D-80539 Munich, Germany.
   [Beavan, Sarah E.] Univ Munich, Ctr Nanosci CeNS, D-80539 Munich, Germany.
   [Wittig, Sven M.] Kayser Threde GmbH, D-81379 Munich, Germany.
   [Longdell, Jevon J.] Univ Otago, Dodd Walls Ctr Photon & Quantum Technol, Dunedin 9016, New Zealand.
   [Longdell, Jevon J.] Univ Otago, Dept Phys, Dunedin 9016, New Zealand.
C3 Australian National University; Princeton University; Universite Paris Saclay; Centre National de la Recherche Scientifique (CNRS); University of Munich; University of Munich; Kayser-Threde GmbH; University of Otago; University of Otago
RP Zhong, MJ (corresponding author), Australian Natl Univ, Laser Phys Ctr, Ctr Quantum Computat & Commun Technol, GPO Box 4, Canberra, ACT 0200, Australia.
EM grace.zhong@anu.edu.au
FU Australian Research Council Centre of Excellence for Quantum Computation and Communication Technology [CE110001027]; Australian Research Council Future Fellowship [FT110100919]; Marsden Fund of the Royal Society of New Zealand [UOO1221]; Australian Research Council [FT110100919] Funding Source: Australian Research Council
NR 30
TC 596
Z9 686
U1 6
U2 179
PU NATURE PUBLISHING 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 8
PY 2015
VL 517
IS 7533
BP 177
EP +
DI 10.1038/nature14025
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600031
PM 25567283
DA 2026-03-09
ER

PT J
AU Levison, HF
   Kretke, KA
   Duncan, MJ
AF Levison, Harold F.
   Kretke, Katherine A.
   Duncan, Martin J.
TI Growing the gas-giant planets by the gradual accumulation of pebbles
SO NATURE
LA English
DT Article
ID solar-system; growth; accretion; cores; evolution; nebula; mass; instability; planetesimals; particles
AB It is widely held that the first step in forming gas-giant planets, such as Jupiter and Saturn, was the production of solid 'cores' each with a mass roughly ten times that of the Earth1,2. Getting the cores to form before the solar nebula dissipates (in about one to ten million years; ref. 3) has been a major challenge for planet formation models(4,5). Recently models have emerged in which 'pebbles' (centimetre-to-metre-sized objects) are first concentrated by aerodynamic drag and then gravitationally collapse to form objects 100 to 1,000 kilometres in size(6-9). These 'planetesimals' can then efficiently accrete left-over pebbles(10) and directly form the cores of giant planets(11,12). This model is known as 'pebble accretion'; theoretically, it can produce cores of ten Earth masses in only a few thousand years(11,13). Unfortunately, full simulations of this process(13) show that, rather than creating a few such cores, it produces a population of hundreds of Earth-mass objects that are inconsistent with the structure of the Solar System. Here we report that this difficulty can be overcome if pebbles form slowly enough to allow the planetesimals to gravitationally interact with one another. In this situation, the largest planetesimals have time to scatter their smaller siblings out of the disk of pebbles, thereby stifling their growth. Our models show that, for a large and physically reasonable region of parameter space, this typically leads to the formation of one to four gas giants between 5 and 15 astronomical units from the Sun, in agreement with the observed structure of the Solar System.
C1 [Levison, Harold F.; Kretke, Katherine A.] SW Res Inst, Boulder, CO 80302 USA.
   [Levison, Harold F.; Kretke, Katherine A.] NASA Solar Syst Explorat Res Virtual Inst, Boulder, CO 80302 USA.
   [Duncan, Martin J.] Queens Univ, Dept Phys Engn Phys & Astron, Kingston, ON K7L 3N6, Canada.
C3 National Aeronautics & Space Administration (NASA); Queens University - Canada
RP Levison, HF (corresponding author), SW Res Inst, 1050 Walnut St,Suite 300, Boulder, CO 80302 USA.
EM hal@boulder.swri.edu
FU NSF
NR 39
TC 189
Z9 207
U1 0
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 AUG 20
PY 2015
VL 524
IS 7565
BP 322
EP +
DI 10.1038/nature14675
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP2NN
UT WOS:000359714000029
PM 26289203
DA 2026-03-09
ER

PT J
AU Jordan, DM
   Frangakis, SG
   Golzio, C
   Cassa, CA
   Kurtzberg, J
   Davis, EE
   Sunyaev, SR
   Katsanis, N
AF Jordan, Daniel M.
   Frangakis, Stephan G.
   Golzio, Christelle
   Cassa, Christopher A.
   Kurtzberg, Joanne
   Davis, Erica E.
   Sunyaev, Shamil R.
   Katsanis, Nicholas
TI Identification of cis-suppression of human disease mutations by comparative genomics
SO NATURE
LA English
DT Article
ID incompatibility; epistasis; evolution; exome; variants
AB Patterns of amino acid conservation have served as a tool for understanding protein evolution(1). The same principles have also found broad application in human genomics, driven by the need to interpret the pathogenic potential of variants in patients(2). Here we performed a systematic comparative genomics analysis of human disease-causing missense variants. We found that an appreciable fraction of disease-causing alleles are fixed in the genomes of other species, suggesting a role for genomic context. We developed a model of genetic interactions that predicts most of these to be simple pairwise compensations. Functional testing of this model on two known human disease genes(3,4) revealed discrete cis amino acid residues that, although benign on their own, could rescue the human mutations in vivo. This approach was also applied to ab initio gene discovery to support the identification of a de novo disease driver in BTG2 that is subject to protective cis-modification in more than 50 species. Finally, on the basis of our data and models, we developed a computational tool to predict candidate residues subject to compensation. Taken together, our data highlight the importance of cis-genomic context as a contributor to protein evolution; they provide an insight into the complexity of allele effect on phenotype; and they are likely to assist methods for predicting allele pathogenicity(5,6).
C1 [Jordan, Daniel M.; Cassa, Christopher A.; Sunyaev, Shamil R.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA.
   [Jordan, Daniel M.; Cassa, Christopher A.; Sunyaev, Shamil R.] Harvard Univ, Sch Med, Boston, MA 02115 USA.
   [Frangakis, Stephan G.; Golzio, Christelle; Davis, Erica E.; Katsanis, Nicholas] Duke Univ, Ctr Human Dis Modeling, Durham, NC 27701 USA.
   [Kurtzberg, Joanne] Duke Univ, Dept Pediat, Div Pediat Blood & Marrow Transplantat, Durham, NC 27701 USA.
C3 Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Duke University; Duke University
RP Sunyaev, SR (corresponding author), Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA.
EM ssunyaev@rics.bwh.harvard.edu; nicholas.katsanis@dm.duke.edu
FU NARSAD;  [R01HD04260];  [R01DK072301];  [R01DK075972];  [R01 GM078598];  [R01 MH101244];  [R01 DK095721];  [U01 HG006500];  [R01EY021872]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD042601] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK072301] Funding Source: NIH RePORTER; National Institute of Mental Health [R01MH101244] Funding Source: NIH RePORTER
NR 36
TC 79
Z9 94
U1 0
U2 30
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 13
PY 2015
VL 524
IS 7564
BP 225
EP +
DI 10.1038/nature14497
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900033
PM 26123021
DA 2026-03-09
ER

PT J
AU Tanouchi, Y
   Pai, A
   Park, H
   Huang, SQ
   Stamatov, R
   Buchler, NE
   You, LC
AF Tanouchi, Yu
   Pai, Anand
   Park, Heungwon
   Huang, Shuqiang
   Stamatov, Rumen
   Buchler, Nicolas E.
   You, Lingchong
TI A noisy linear map underlies oscillations in cell size and gene expression in bacteria
SO NATURE
LA English
DT Article
ID chromosome-replication; single-cell; growth; metabolism
AB During bacterial growth, a cell approximately doubles in size before division, after which it splits into two daughter cells. This process is subjected to the inherent perturbations of cellular noise(1,2) and thus requires regulation for cell-size homeostasis. The mechanisms underlying the control and dynamics of cell size remain poorly understood owing to the difficulty in sizing individual bacteria over long periods of time in a high-throughput manner. Here we measure and analyse long-term, single-cell growth and division across different Escherichia coli strains and growth conditions(3). We show that a subset of cells in a population exhibit transient oscillations in cell size with periods that stretch across several (more than ten) generations. Our analysis reveals that a simple law governing cell-size control-a noisy linear map-explains the origins of these cell-size oscillations across all strains. This noisy linear map implements a negative feedback on cell-size control: a cell with a larger initial size tends to divide earlier, whereas one with a smaller initial size tends to divide later. Combining simulations of cell growth and division with experimental data, we demonstrate that this noisy linear map generates transient oscillations, not just in cell size, but also in constitutive gene expression. Our work provides new insights into the dynamics of bacterial cell-size regulation with implications for the physiological processes involved.
C1 [Tanouchi, Yu; Pai, Anand; Huang, Shuqiang; You, Lingchong] Duke Univ, Dept Biomed Engn, Durham, NC 27708 USA.
   [Park, Heungwon; Buchler, Nicolas E.] Duke Univ, Dept Phys, Durham, NC 27708 USA.
   [Park, Heungwon; Buchler, Nicolas E.] Duke Univ, Dept Biol, Durham, NC 27708 USA.
   [Stamatov, Rumen] Duke Univ, Computat Biol & Bioinformat, Durham, NC 27708 USA.
   [Buchler, Nicolas E.; You, Lingchong] Duke Univ, Ctr Genom & Computat Biol, Durham, NC 27708 USA.
C3 Duke University; Duke University; Duke University; Duke University; Duke University
RP You, LC (corresponding author), Duke Univ, Dept Biomed Engn, Durham, NC 27708 USA.
EM you@duke.edu
FU National Science Foundation; National Institutes of Health [R01GM098642, R01GM110494]; DuPont Young Professorship; David and Lucile Packard Fellowship; DARPA Biochronicity Grant [DARPA-BAA-11-66]; NIH [DP2 OD008654-01]; Burroughs Wellcome Fund [BWF 1005769.01]; National Institute of General Medical Sciences [R01GM098642] Funding Source: NIH RePORTER
NR 30
TC 117
Z9 157
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 16
PY 2015
VL 523
IS 7560
BP 357
EP +
DI 10.1038/nature14562
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM8KY
UT WOS:000357950900044
PM 26040722
DA 2026-03-09
ER

PT J
AU Finlay, K
   Vogt, RJ
   Bogard, MJ
   Wissel, B
   Tutolo, BM
   Simpson, GL
   Leavitt, PR
AF Finlay, Kerri
   Vogt, Richard J.
   Bogard, Matthew J.
   Wissel, Bjoern
   Tutolo, Benjamin M.
   Simpson, Gavin L.
   Leavitt, Peter R.
TI Decrease in CO2 efflux from northern hardwater lakes with increasing atmospheric warming
SO NATURE
LA English
DT Article
ID hard-water lakes; carbon-dioxide; temporal variability; caspian sea; ice cover; exchange; flux; climate; regularization; bacteria
AB Boreal lakes are biogeochemical hotspots that alter carbon fluxes by sequestering particulate organic carbon in sediments(1,2) and by oxidizing terrestrial dissolved organic matter to carbon dioxide (CO2) or methane through microbial processes(3,4). At present, such dilute lakes release similar to 1.4 petagrams of carbon annually to the atmosphere(3,4), and this carbon efflux may increase in the future in response to elevated temperatures(5) and increased hydrological delivery of mineralizable dissolved organic matter to lakes(6,7). Much less is known about the potential effects of climate changes on carbon fluxes from carbonate-rich hardwater and saline lakes that account for about 20 per cent of inland water surface area(4,8). Here we show that atmospheric warming may reduce CO2 emissions from hardwater lakes. We analyse decadal records of meteorological variability, CO2 fluxes and water chemistry to investigate the processes affecting variations in pH and carbon exchange(9,10) in hydrologically diverse lakes of central North America. We find that the lakes have shifted progressively from being substantial CO2 sources in the mid-1990s to sequestering CO2 by 2010, with a steady increase in annual mean pH. We attribute the observed changes in pH and CO2 uptake to an atmospheric-warming induced decline in ice cover in spring that decreases CO2 accumulation under ice, increases spring and summer pH, and enhances the chemical uptake of CO2 in hardwater lakes. Our study suggests that rising temperatures do not invariably increase CO2 emissions from aquatic ecosystems.
C1 [Finlay, Kerri; Vogt, Richard J.; Bogard, Matthew J.; Leavitt, Peter R.] Univ Regina, Dept Biol, Limnol Lab, Regina, SK S4S 0A2, Canada.
   [Wissel, Bjoern; Simpson, Gavin L.; Leavitt, Peter R.] Univ Regina, Inst Environm Change & Soc, Regina, SK S4S 0A2, Canada.
   [Tutolo, Benjamin M.] Univ Minnesota, Dept Earth Sci, Minneapolis, MN 55455 USA.
C3 University of Regina; University of Regina; University of Minnesota System; University of Minnesota Twin Cities
RP Leavitt, PR (corresponding author), Univ Regina, Dept Biol, Limnol Lab, Regina, SK S4S 0A2, Canada.
EM peter.leavitt@uregina.ca
FU NSERC Canada; Canada Foundation for Innovation; Province of Saskatchewan; Canada Research Chair programme
NR 50
TC 135
Z9 159
U1 8
U2 266
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 12
PY 2015
VL 519
IS 7542
BP 215
EP 218
DI 10.1038/nature14172
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500035
PM 25731167
DA 2026-03-09
ER

PT J
AU Kim, SH
   Kim, H
   Kim, NJ
AF Kim, Sang-Heon
   Kim, Hansoo
   Kim, Nack J.
TI Brittle intermetallic compound makes ultrastrong low-density steel with large ductility
SO NATURE
LA English
DT Article
ID dual-phase steels; mechanical-property; fracture-toughness; titanium-alloys; tensile; behavior; plasticity; ti-6al-4v
AB Although steel has been the workhorse of the automotive industry since the 1920s, the share by weight of steel and iron in an average light vehicle is now gradually decreasing, from 68.1 per cent in 1995 to 60.1 per cent in 2011 (refs 1, 2). This has been driven by the low strength-to-weight ratio (specific strength) of iron and steel, and the desire to improve such mechanical properties with other materials. Recently, high-aluminium low-density steels have been actively studied as a means of increasing the specific strength of an alloy by reducing its density(3-5). But with increasing aluminium content a problem is encountered: brittle intermetallic compounds can formin the resulting alloys, leading to poor ductility. Here we show that an FeAl-type brittle but hard intermetallic compound (B2) can be effectively used as a strengthening second phase in high-aluminiumlow-density steel, while alleviating its harmful effect on ductility by controlling its morphology and dispersion. The specific tensile strength and ductility of the developed steel improve on those of the lightest and strongest metallic materials known, titanium alloys. We found that alloying of nickel catalyses the precipitation of nanometre-sized B2 particles in the face-centred cubic matrix of high-aluminiumlow-density steel during heat treatment of cold-rolled sheet steel. Our results demonstrate how intermetallic compounds can be harnessed in the alloy design of lightweight steels for structural applications and others.
C1 [Kim, Sang-Heon; Kim, Hansoo; Kim, Nack J.] POSTECH, Grad Inst Ferrous Technol, Pohang 790784, South Korea.
C3 Pohang University of Science & Technology (POSTECH)
RP Kim, H (corresponding author), POSTECH, Grad Inst Ferrous Technol, Pohang 790784, South Korea.
EM hansoo-kim@postech.ac.kr
FU Steel Innovation Program of POSCO
NR 28
TC 699
Z9 788
U1 45
U2 932
PU NATURE PUBLISHING 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 5
PY 2015
VL 518
IS 7537
BP 77
EP +
DI 10.1038/nature14144
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7LE
UT WOS:000349098000034
PM 25652998
DA 2026-03-09
ER

PT J
AU Wong, TN
   Ramsingh, G
   Young, AL
   Miller, CA
   Touma, W
   Welch, JS
   Lamprecht, TL
   Shen, D
   Hundal, J
   Fulton, RS
   Heath, S
   Baty, JD
   Klco, JM
   Ding, L
   Mardis, ER
   Westervelt, P
   DiPersio, JF
   Walter, MJ
   Graubert, TA
   Ley, TJ
   Druley, TE
   Link, DC
   Wilson, RK
AF Wong, Terrence N.
   Ramsingh, Giridharan
   Young, Andrew L.
   Miller, Christopher A.
   Touma, Waseem
   Welch, John S.
   Lamprecht, Tamara L.
   Shen, Dong
   Hundal, Jasreet
   Fulton, Robert S.
   Heath, Sharon
   Baty, Jack D.
   Klco, Jeffery M.
   Ding, Li
   Mardis, Elaine R.
   Westervelt, Peter
   DiPersio, John F.
   Walter, Matthew J.
   Graubert, Timothy A.
   Ley, Timothy J.
   Druley, Todd E.
   Link, Daniel C.
   Wilson, Richard K.
TI Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia
SO NATURE
LA English
DT Article
ID clonal evolution; p53; dynamics
AB Therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy(1). There are several features that distinguish t-AML from de novo AMI, induding a higher incidence of TP53 mutations(3,3) abnormalities of chromosomes 5 or 7, complex cytogenetics and a reduced response to chemotherapy'. However, it is not clear how prior exposure to cytotoxic therapy influences leukaemogenesis. In particular, the mechanism by which TP53 mutations are selectively enriched in t-ANIL/t-MDS is unknown. Here, by sequencing the genomes of 22 patients with t-AML, we show that the total number of somatic single-nucleotide variants and the percentage of chemotherapy-related transversions are similar in t-AML and de novo AML, indicating that previous chemotherapy does not induce genome-wide DNA damage. We identified four cases of t-ANIL/ t-MDS in which the exact TP53 mutation found at diagnosis was also present at low frequencies (0.003-0.7%) in mobilized blood leukocytes or bone marrow 1-6 years before the development of t-AML/tMDS, including two cases in which the relevant TP53 mutation was detected before any chemotherapy. Moreover, functional TP53 mutations were identified in small populations of peripheral blood cells of healthy chemotherapy-naive elderly individuals. Finally, in mouse bone marrow chimaeras containing both wild-type and Tp53(+/-) haematopoietic stein/progenitor cells (HSPCs), the Tp53(+/-) HSPCs preferentially expanded after exposure to chemotherapy. These data suggest that cytotoxic therapy does not directly induce TP53 mutations. Rather, they support a model in which rare HSPCs carrying age-related TP53 mutations are resistant to chemotherapy and expand preferentially after treatment. The early acquisition of TP53 mutations in the founding HSPC clone probably contributes to the frequent cytogenetic abnormalities and poor responses to chemotherapy that are typical of patients with t-AML/t-MDS.
C1 [Wong, Terrence N.; Touma, Waseem; Welch, John S.; Lamprecht, Tamara L.; Heath, Sharon; Ding, Li; Westervelt, Peter; DiPersio, John F.; Walter, Matthew J.; Graubert, Timothy A.; Ley, Timothy J.; Link, Daniel C.] Washington Univ, Dept Med, Div Oncol, St Louis, MO 63110 USA.
   [Ramsingh, Giridharan] Univ So Calif, Dept Med, Jane Anne Nohl Div Hematol, Los Angeles, CA 90089 USA.
   [Young, Andrew L.; Druley, Todd E.] Washington Univ, Dept Pediat, Div Hematol Oncol, St Louis, MO 63110 USA.
   [Miller, Christopher A.; Hundal, Jasreet; Fulton, Robert S.; Mardis, Elaine R.; Wilson, Richard K.] Washington Univ, Genome Inst, St Louis, MO 63110 USA.
   [Welch, John S.; Ding, Li; Mardis, Elaine R.; Westervelt, Peter; DiPersio, John F.; Walter, Matthew J.; Graubert, Timothy A.; Ley, Timothy J.; Link, Daniel C.; Wilson, Richard K.] Washington Univ, Siteman Canc Ctr, St Louis, MO 63110 USA.
   [Shen, Dong] AstraZeneca, Gaithersburg, MD 20878 USA.
   [Baty, Jack D.] Washington Univ, Div Biostat, St Louis, MO 63110 USA.
   [Klco, Jeffery M.] Washington Univ, Dept Pathol & Immunol, St Louis, MO 63110 USA.
   [Mardis, Elaine R.; Wilson, Richard K.] Washington Univ, Dept Genet, St Louis, MO 63110 USA.
C3 Washington University (WUSTL); University of Southern California; Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Siteman Cancer Center; AstraZeneca; Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL)
RP Link, DC (corresponding author), Washington Univ, Dept Med, Div Oncol, St Louis, MO 63110 USA.
EM dlink@dom.wustl.edu
FU National Institutes of Health [PO1 CA101937, U54 HG003079]; Leukemia & Lymphoma Society; National Cancer Institute [P01CA101937, P50CA171963] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [T32HL007088] Funding Source: NIH RePORTER
NR 24
TC 714
Z9 786
U1 3
U2 100
PU NATURE PUBLISHING 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 26
PY 2015
VL 518
IS 7540
BP 552
EP 555
DI 10.1038/nature13968
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC1JP
UT WOS:000350097300050
PM 25487151
DA 2026-03-09
ER

PT J
AU Palatinszky, M
   Herbold, C
   Jehmlich, N
   Pogoda, M
   Han, P
   von Bergen, M
   Lagkouvardos, I
   Karst, SM
   Galushko, A
   Koch, H
   Berry, D
   Daims, H
   Wagner, M
AF Palatinszky, Marton
   Herbold, Craig
   Jehmlich, Nico
   Pogoda, Mario
   Han, Ping
   von Bergen, Martin
   Lagkouvardos, Ilias
   Karst, Soren M.
   Galushko, Alexander
   Koch, Hanna
   Berry, David
   Daims, Holger
   Wagner, Michael
TI Cyanate as an energy source for nitrifiers
SO NATURE
LA English
DT Article
ID nitrite-oxidizing bacteria; sp-nov; alignment; growth; populations; hydrogen; ammonium; cyanide; nitrate; version
AB Ammonia- and nitrite-oxidizing microorganisms are collectively responsible for the aerobic oxidation of ammonia via nitrite to nitrate and have essential roles in the global biogeochemical nitrogen cycle. The physiology of nitrifiers has been intensively studied, and urea and ammonia are the only recognized energy sources that promote the aerobic growth of ammonia-oxidizing bacteria and archaea. Here we report the aerobic growth of a pure culture of the ammonia-oxidizing thaumarchaeote Nitrososphaera gargensis(1) using cyanate as the sole source of energy and reductant; to our knowledge, the first organism known to do so. Cyanate, a potentially important source of reduced nitrogen in aquatic and terrestrial ecosystems(2), is converted to ammonium and carbon dioxide in Nitrososphaera gargensis by a cyanase enzyme that is induced upon addition of this compound. Within the cyanase gene family, this cyanase is a member of a distinct clade also containing cyanases of nitrite-oxidizing bacteria of the genus Nitrospira. We demonstrate by co-culture experiments that these nitrite oxidizers supply cyanase-lacking ammonia oxidizers with ammonium from cyanate, which is fully nitrified by this microbial consortium through reciprocal feeding. By screening a comprehensive set of more than 3,000 publically available metagenomes from environmental samples, we reveal that cyanase-encoding genes clustering with the cyanases of these nitrifiers are widespread in the environment. Our results demonstrate an unexpected metabolic versatility of nitri-fying microorganisms, and suggest a previously unrecognized importance of cyanate in cycling of nitrogen compounds in the environment.
C1 [Palatinszky, Marton; Herbold, Craig; Pogoda, Mario; Han, Ping; Lagkouvardos, Ilias; Galushko, Alexander; Koch, Hanna; Berry, David; Daims, Holger; Wagner, Michael] Univ Vienna, Dept Microbiol & Ecosyst Sci, Div Microbial Ecol, A-1090 Vienna, Austria.
   [Jehmlich, Nico; von Bergen, Martin] UFZ Helmholtz Ctr Environm Res, Dept Prote, D-04318 Leipzig, Germany.
   [von Bergen, Martin] UFZ Helmholtz Ctr Environm Res, Dept Metabol, D-04318 Leipzig, Germany.
   [von Bergen, Martin; Karst, Soren M.] Aalborg Univ, Dept Chem & Biosci, Fac Engn & Sci, DK-9220 Aalborg, Denmark.
   [Lagkouvardos, Ilias] Tech Univ Munich, ZIEL Res Ctr Nutr & Food Sci, Gregor Mendel Str 2, D-85354 Freising Weihenstephan, Germany.
   [Galushko, Alexander] Agrophys Res Inst, 14 Grazhdanskiy Pr, St Petersburg 195220, Russia.
C3 University of Vienna; Helmholtz Association; Helmholtz Center for Environmental Research (UFZ); Helmholtz Association; Helmholtz Center for Environmental Research (UFZ); Aalborg University; Technical University of Munich; Agrophysics Research Institute
RP Wagner, M (corresponding author), Univ Vienna, Dept Microbiol & Ecosyst Sci, Div Microbial Ecol, Althanstr 14, A-1090 Vienna, Austria.
EM wagner@microbial-ecology.net
FU European Research Council [294343]; Austrian Science Fund (FWF) [P25231-B21, P26127-B20]; European Regional Development Funds (EFRE-Europe funds Saxony); Helmholtz Association; Collaborative Research Centre AquaDiva of the German Research Foundation; Austrian Science Fund (FWF) [P25231] Funding Source: Austrian Science Fund (FWF)
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NR 47
TC 203
Z9 247
U1 8
U2 280
PU NATURE PUBLISHING 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 6
PY 2015
VL 524
IS 7563
BP 105
EP +
DI 10.1038/nature14856
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO2QS
UT WOS:000359002300041
PM 26222031
DA 2026-03-09
ER

PT J
AU Bai, Y
   Müller, DB
   Srinivas, G
   Garrido-Oter, R
   Potthoff, E
   Rott, M
   Dombrowski, N
   Münch, PC
   Spaepen, S
   Remus-Emsermann, M
   Hüttel, B
   McHardy, AC
   Vorholt, JA
   Schulze-Lefert, P
AF Bai, Yang
   Mueller, Daniel B.
   Srinivas, Girish
   Garrido-Oter, Ruben
   Potthoff, Eva
   Rott, Matthias
   Dombrowski, Nina
   Muench, Philipp C.
   Spaepen, Stijn
   Remus-Emsermann, Mitja
   Huettel, Bruno
   McHardy, Alice C.
   Vorholt, Julia A.
   Schulze-Lefert, Paul
TI Functional overlap of the Arabidopsis leaf and root microbiota
SO NATURE
LA English
DT Article
ID plant; community; association; nutrition; sequences; insights; growth
AB Roots and leaves of healthy plants host taxonomically structured bacterial assemblies, and members of these communities contribute to plant growth and health. We established Arabidopsis leaf-and root-derived microbiota culture collections representing the majority of bacterial species that are reproducibly detectable by culture-independent community sequencing. We found an extensive taxonomic overlap between the leaf and root microbiota. Genome drafts of 400 isolates revealed a large overlap of genome-encoded functional capabilities between leaf-and root-derived bacteria with few significant differences at the level of individual functional categories. Using defined bacterial communities and a gnotobiotic Arabidopsis plant system we show that the isolates form assemblies resembling natural microbiota on their cognate host organs, but are also capable of ectopic leaf or root colonization. While this raises the possibility of reciprocal relocation between root and leaf microbiota members, genome information and recolonization experiments also provide evidence for microbiota specialization to their respective niche.
C1 [Bai, Yang; Srinivas, Girish; Garrido-Oter, Ruben; Rott, Matthias; Dombrowski, Nina; Spaepen, Stijn; Schulze-Lefert, Paul] Max Planck Inst Plant Breeding Res, Dept Plant Microbe Interact, D-50829 Cologne, Germany.
   [Mueller, Daniel B.; Potthoff, Eva; Remus-Emsermann, Mitja; Vorholt, Julia A.] ETH, Inst Microbiol, CH-8093 Zurich, Switzerland.
   [Garrido-Oter, Ruben] Univ Dusseldorf, Dept Algorithm Bioinformat, D-40225 Dusseldorf, Germany.
   [Garrido-Oter, Ruben; McHardy, Alice C.; Schulze-Lefert, Paul] Max Planck Inst Plant Breeding Res, Cluster Excellence Plant Sci CEPLAS, D-50829 Cologne, Germany.
   [Muench, Philipp C.; McHardy, Alice C.] Helmholtz Ctr Infect Res, Computat Biol Infect Res, D-38124 Braunschweig, Germany.
   [Muench, Philipp C.] Univ Munich, Max von Pettenkofer Inst, German Ctr Infect Res DZIF, Partner Site LMU Munich, D-80336 Munich, Germany.
   [Muench, Philipp C.] German Ctr Infect Res DZIF, Partner Site Hannover Braunschweig, D-38124 Braunschweig, Germany.
   [Huettel, Bruno] Max Planck Inst Plant Breeding Res, Max Planck Genome Ctr, D-50829 Cologne, Germany.
C3 Max Planck Society; Swiss Federal Institutes of Technology Domain; ETH Zurich; Heinrich Heine University Dusseldorf; Max Planck Society; University of Cologne; Helmholtz Association; Helmholtz-Center for Infection Research; German Center for Infection Research; University of Munich; German Center for Infection Research; Max Planck Society
RP Vorholt, JA (corresponding author), ETH, Inst Microbiol, CH-8093 Zurich, Switzerland.
EM jvorholt@ethz.ch; schlef@mpipz.mpg.de
FU Max Planck Society; European Research Council; 'Cluster of Excellence on Plant Sciences' program - Deutsche Forschungsgemeinschaft; German Center for Infection Research (DZIF); ETH Zurich [ETH-41 14-2]; Swiss National Research Foundation [310030B_152835]; Swiss National Science Foundation (SNF) [310030B_152835] Funding Source: Swiss National Science Foundation (SNF)
NR 44
TC 949
Z9 1092
U1 45
U2 1287
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 17
PY 2015
VL 528
IS 7582
BP 364
EP +
DI 10.1038/nature16192
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CY8SM
UT WOS:000366678600045
PM 26633631
DA 2026-03-09
ER

PT J
AU Barkley, D
   Song, BF
   Mukund, V
   Lemoult, G
   Avila, M
   Hof, B
AF Barkley, Dwight
   Song, Baofang
   Mukund, Vasudevan
   Lemoult, Gregoire
   Avila, Marc
   Hof, Bjoern
TI The rise of fully turbulent flow
SO NATURE
LA English
DT Article
ID pipe; transition; intermittency; spots; puffs
AB Over a century of research into the origin of turbulence in wall-bounded shear flows has resulted in a puzzling picture in which turbulence appears in a variety of different states competing with laminar background flow(1-6). At moderate flow speeds, turbulence is confined to localized patches; it is only at higher speeds that the entire flow becomes turbulent. The origin of the different states encountered during this transition, the front dynamics of the turbulent regions and the transformation to full turbulence have yet to be explained. By combining experiments, theory and computer simulations, here we uncover a bifurcation scenario that explains the transformation to fully turbulent pipe flow and describe the front dynamics of the different states encountered in the process. Key to resolving this problem is the interpretation of the flow as a bistable system with nonlinear propagation (advection) of turbulent fronts. These findings bridge the gap between our understanding of the onset of turbulence(7) and fully turbulent flows(8,9).
C1 [Barkley, Dwight] Univ Warwick, Inst Math, Coventry CV4 7AL, W Midlands, England.
   [Song, Baofang; Mukund, Vasudevan; Lemoult, Gregoire; Hof, Bjoern] IST Austria, A-3400 Klosterneuburg, Austria.
   [Song, Baofang] Max Planck Inst Dynam & Self Org, D-37073 Gottingen, Germany.
   [Song, Baofang] Univ Erlangen Nurnberg, Inst Multiscale Simulat, D-91052 Erlangen, Germany.
   [Avila, Marc] Univ Erlangen Nurnberg, Inst Fluid Mech, D-91058 Erlangen, Germany.
C3 University of Warwick; Institute of Science & Technology - Austria; Max Planck Society; University of Erlangen Nuremberg; University of Erlangen Nuremberg
RP Barkley, D (corresponding author), Univ Warwick, Inst Math, Coventry CV4 7AL, W Midlands, England.
EM D.Barkley@warwick.ac.uk; bhof@ist.ac.at
FU Deutsche Forschungsgemeinschaft [FOR 1182]; European Research Council under the European Union [306589]; Chinese State Scholarship Fund [2010629145]; International Max Planck Research School for the Physics of Biological and Complex Systems; Gottingen Graduate School for Neurosciences and Molecular Biosciences; Julich Supercomputing Centre [HGU16]; European Research Council (ERC) [306589] Funding Source: European Research Council (ERC); Division Of Mathematical Sciences; Direct For Mathematical & Physical Scien [1440415] Funding Source: National Science Foundation
NR 36
TC 148
Z9 164
U1 1
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 OCT 22
PY 2015
VL 526
IS 7574
BP 550
EP U191
DI 10.1038/nature15701
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV1NX
UT WOS:000364026100045
PM 26490621
DA 2026-03-09
ER

PT J
AU Gao, T
   Estrecho, E
   Bliokh, KY
   Liew, TCH
   Fraser, MD
   Brodbeck, S
   Kamp, M
   Schneider, C
   Höfling, S
   Yamamoto, Y
   Nori, F
   Kivshar, YS
   Truscott, AG
   Dall, RG
   Ostrovskaya, EA
AF Gao, T.
   Estrecho, E.
   Bliokh, K. Y.
   Liew, T. C. H.
   Fraser, M. D.
   Brodbeck, S.
   Kamp, M.
   Schneider, C.
   Hoefling, S.
   Yamamoto, Y.
   Nori, F.
   Kivshar, Y. S.
   Truscott, A. G.
   Dall, R. G.
   Ostrovskaya, E. A.
TI Observation of non-Hermitian degeneracies in a chaotic exciton-polariton billiard
SO NATURE
LA English
DT Article
AB Exciton-polaritons are hybrid light-matter quasiparticles formed by strongly interacting photons and excitons (electron-hole pairs) in semiconductor microcavities(1-3). They have emerged as a robust solid-state platform for next-generation optoelectronic applications as well as for fundamental studies of quantum many-body physics. Importantly, exciton-polaritons are a profoundly open (that is, non-Hermitian(4,5)) quantum system, which requires constant pumping of energy and continuously decays, releasing coherent radiation(6). Thus, the exciton-polaritons always exist in a balanced potential landscape of gain and loss. However, the inherent non-Hermitian nature of this potential has so far been largely ignored in exciton-polariton physics. Here we demonstrate that non-Hermiticity dramatically modifies the structure of modes and spectral degeneracies in exciton-polariton systems, and, therefore, will affect their quantum transport, localization and dynamical properties(7-9). Using a spatially structured optical pump(10-12), we create a chaotic exciton-polariton billiard-a two-dimensional area enclosed by a curved potential barrier. Eigenmodes of this billiard exhibit multiple non-Hermitian spectral degeneracies, known as exceptional points(13,14). Such points can cause remarkable wave phenomena, such as unidirectional transport(15), anomalous lasing/absorption(16,17) and chiral modes(18). By varying parameters of the billiard, we observe crossing and anti-crossing of energy levels and reveal the non-trivial topological modal structure exclusive to non-Hermitian systems(9,13-22). We also observe mode switching and a topological Berry phase for a parameter loop encircling the exceptional point(23,24). Our findings pave the way to studies of non-Hermitian quantum dynamics of exciton-polaritons, which may uncover novel operating principles for polariton-based devices.
C1 [Gao, T.; Estrecho, E.; Bliokh, K. Y.; Kivshar, Y. S.; Truscott, A. G.; Dall, R. G.; Ostrovskaya, E. A.] Australian Natl Univ, Res Sch Phys & Engn, Canberra, ACT 2601, Australia.
   [Bliokh, K. Y.; Fraser, M. D.; Nori, F.] RIKEN, Ctr Emergent Matter Sci, Wako, Saitama 3510198, Japan.
   [Liew, T. C. H.] Nanyang Technol Univ, Sch Phys & Math Sci, Singapore 637371, Singapore.
   [Brodbeck, S.; Kamp, M.; Schneider, C.; Hoefling, S.] Univ Wurzburg, Tech Phys & Wilhelm Conrad Rontgen Res Ctr Comple, D-97074 Wurzburg, Germany.
   [Hoefling, S.] Univ St Andrews, Sch Phys & Astron, SUPA, St Andrews KY16 9SS, Fife, Scotland.
   [Yamamoto, Y.] Japan Sci & Technol Agcy, ImPACT Project, Chiyoda Ku, Tokyo 1020076, Japan.
   [Yamamoto, Y.] Stanford Univ, Edward L Ginzton Lab, Stanford, CA 94305 USA.
   [Nori, F.] Univ Michigan, Dept Phys, Ann Arbor, MI 48109 USA.
C3 Australian National University; RIKEN; Nanyang Technological University; University of Wurzburg; University of St Andrews; Japan Science & Technology Agency (JST); Stanford University; University of Michigan System; University of Michigan
RP Ostrovskaya, EA (corresponding author), Australian Natl Univ, Res Sch Phys & Engn, GPO Box 4, Canberra, ACT 2601, Australia.
EM elena.ostrovskaya@anu.edu.au
FU Australian Research Council; ImPACT Program of the Council for Science, Technology and Innovation (Cabinet Office, Government of Japan); RIKEN iTHES Project; MURI Center for Dynamic Magneto-Optics; State of Bavaria
NR 41
TC 512
Z9 552
U1 8
U2 230
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 22
PY 2015
VL 526
IS 7574
BP 554
EP U203
DI 10.1038/nature15522
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV1NX
UT WOS:000364026100046
PM 26458102
DA 2026-03-09
ER

PT J
AU Allentoft, ME
   Sikora, M
   Sjögren, KG
   Rasmussen, S
   Rasmussen, M
   Stenderup, J
   Damgaard, PB
   Schroeder, H
   Ahlström, T
   Vinner, L
   Malaspinas, AS
   Margaryan, A
   Higham, T
   Chivall, D
   Lynnerup, N
   Harvig, L
   Baron, J
   Della Casa, P
   Dabrowski, P
   Duffy, PR
   Ebel, AV
   Epimakhov, A
   Frei, K
   Furmanek, M
   Gralak, T
   Gromov, A
   Gronkiewicz, S
   Grupe, G
   Hajdu, T
   Jarysz, R
   Khartanovich, V
   Khokhlov, A
   Kiss, V
   Kolár, J
   Kriiska, A
   Lasak, I
   Longhi, C
   McGlynn, G
   Merkevicius, A
   Merkyte, I
   Metspalu, M
   Mkrtchyan, R
   Moiseyev, V
   Paja, L
   Pálfi, G
   Pokutta, D
   Pospieszny, L
   Price, TD
   Saag, L
   Sablin, M
   Shishlina, N
   Smrcka, V
   Soenov, VI
   Szeverényi, V
   Tóth, G
   Trifanova, SV
   Varul, L
   Vicze, M
   Yepiskoposyan, L
   Zhitenev, V
   Orlando, L
   Sicheritz-Pontén, T
   Brunak, S
   Nielsen, R
   Kristiansen, K
   Willerslev, E
AF Allentoft, Morten E.
   Sikora, Martin
   Sjogren, Karl-Goran
   Rasmussen, Simon
   Rasmussen, Morten
   Stenderup, Jesper
   Damgaard, Peter B.
   Schroeder, Hannes
   Ahlstrom, Torbjorn
   Vinner, Lasse
   Malaspinas, Anna-Sapfo
   Margaryan, Ashot
   Higham, Tom
   Chivall, David
   Lynnerup, Niels
   Harvig, Lise
   Baron, Justyna
   Della Casa, Philippe
   Dabrowski, Pawel
   Duffy, Paul R.
   Ebel, Alexander V.
   Epimakhov, Andrey
   Frei, Karin
   Furmanek, Miroslaw
   Gralak, Tomasz
   Gromov, Andrey
   Gronkiewicz, Stanislaw
   Grupe, Gisela
   Hajdu, Tamas
   Jarysz, Radoslaw
   Khartanovich, Valeri
   Khokhlov, Alexandr
   Kiss, Viktoria
   Kolar, Jan
   Kriiska, Aivar
   Lasak, Irena
   Longhi, Cristina
   McGlynn, George
   Merkevicius, Algimantas
   Merkyte, Inga
   Metspalu, Mait
   Mkrtchyan, Ruzan
   Moiseyev, Vyacheslav
   Paja, Laszlo
   Palfi, Gyoergy
   Pokutta, Dalia
   Pospieszny, Lukasz
   Price, T. Douglas
   Saag, Lehti
   Sablin, Mikhail
   Shishlina, Natalia
   Smrcka, Vaclav
   Soenov, Vasilii I.
   Szeverenyi, Vajk
   Toth, Gusztav
   Trifanova, Synaru V.
   Varul, Liivi
   Vicze, Magdolna
   Yepiskoposyan, Levon
   Zhitenev, Vladislav
   Orlando, Ludovic
   Sicheritz-Ponten, Thomas
   Brunak, Soren
   Nielsen, Rasmus
   Kristiansen, Kristian
   Willerslev, Eske
TI Population genomics of Bronze Age Eurasia
SO NATURE
LA English
DT Article
ID hunter-gatherers; sequence; europe
AB The Bronze Age of Eurasia (around 3000-1000 BC) was a period of major cultural changes. However, there is debate about whether these changes resulted from the circulation of ideas or from human migrations, potentially also facilitating the spread of languages and certain phenotypic traits. We investigated this by using new, improved methods to sequence low-coverage genomes from 101 ancient humans from across Eurasia. We show that the Bronze Age was a highly dynamic period involving large-scale population migrations and replacements, responsible for shaping major parts of present-day demographic structure in both Europe and Asia. Our findings are consistent with the hypothesized spread of Indo-European languages during the Early Bronze Age. We also demonstrate that light skin pigmentation in Europeans was already present at high frequency in the Bronze Age, but not lactose tolerance, indicating a more recent onset of positive selection on lactose tolerance than previously thought.
C1 [Allentoft, Morten E.; Sikora, Martin; Rasmussen, Morten; Stenderup, Jesper; Damgaard, Peter B.; Schroeder, Hannes; Vinner, Lasse; Malaspinas, Anna-Sapfo; Margaryan, Ashot; Orlando, Ludovic; Willerslev, Eske] Univ Copenhagen, Ctr GeoGenet, Nat Hist Museum, DK-1350 Copenhagen K, Denmark.
   [Sjogren, Karl-Goran; Pokutta, Dalia; Kristiansen, Kristian] Univ Gothenburg, Dept Hist Studies, S-40530 Gothenburg, Sweden.
   [Rasmussen, Simon; Sicheritz-Ponten, Thomas; Brunak, Soren] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark.
   [Schroeder, Hannes] Leiden Univ, Fac Archaeol, NL-2300 Leiden, Netherlands.
   [Ahlstrom, Torbjorn] Lund Univ, Dept Archaeol & Ancient Hist, S-22100 Lund, Sweden.
   [Higham, Tom; Chivall, David] Univ Oxford, Oxford Radiocarbon Accelerator Unit, Oxford OX1 3QY, England.
   [Lynnerup, Niels; Harvig, Lise] Univ Copenhagen, Dept Forens Med, Unit Forens Anthropol, DK-2100 Copenhagen, Denmark.
   [Baron, Justyna; Furmanek, Miroslaw; Gralak, Tomasz; Lasak, Irena] Univ Wroclaw, Inst Archaeol, PL-50139 Wroclaw, Poland.
   [Della Casa, Philippe] Univ Zurich, Archaeol Inst, CH-8006 Zurich, Switzerland.
   [Dabrowski, Pawel] Wroclaw Med Univ, Dept Anat, PL-50368 Wroclaw, Poland.
   [Duffy, Paul R.] Univ Toronto, Dept Anthropol, Toronto, ON M5S 2S2, Canada.
   [Ebel, Alexander V.] Gorno Altaisk State Univ, Dept Archeol & Gen Hist, Gorno Altaisk 649000, Russia.
   [Epimakhov, Andrey] South Ural State Univ, South Ural Dept, Inst Hist & Archaeol RAS, Chelyabinsk 454080, Russia.
   [Frei, Karin] Natl Museum Denmark, Environm Res & Mat Sci, DK-1471 Copenhagen K, Denmark.
   [Frei, Karin] Natl Museum Denmark, Ctr Text Res, DK-1471 Copenhagen K, Denmark.
   [Gromov, Andrey; Khartanovich, Valeri; Moiseyev, Vyacheslav] Peter Great Museum Anthropol & Ethnog Kunstkamera, St Petersburg 199034, Russia.
   [Gronkiewicz, Stanislaw] Polish Acad Sci, Dept Anthropol, PL-50449 Wroclaw, Poland.
   [Grupe, Gisela; McGlynn, George] Univ Munich, Bioctr, D-82152 Munich, Germany.
   [Hajdu, Tamas] Eotvos Lorand Univ, Inst Biol, Dept Biol Anthropol, H-1117 Budapest, Hungary.
   [Hajdu, Tamas] Hungarian Nat Hist Museum, Dept Anthropol, H-1083 Budapest, Hungary.
   [Jarysz, Radoslaw] Archaeol Museum Wroclaw, PL-50077 Wroclaw, Poland.
   [Khokhlov, Alexandr] Samara State Acad Social Sci & Humanities, Samara 443099, Russia.
   [Kiss, Viktoria; Szeverenyi, Vajk] Hungarian Acad Sci, Res Ctr Humanities, Inst Archaeol, H-1250 Budapest, Hungary.
   [Kolar, Jan] Masaryk Univ, Fac Arts, Inst Archaeol & Museol, CZ-60200 Brno, Czech Republic.
   [Kolar, Jan] Acad Sci Czech Republ, Inst Bot, Dept Vegetat Ecol, CZ-60200 Brno, Czech Republic.
   [Kriiska, Aivar; Varul, Liivi] Univ Tartu, Dept Archaeol, EE-51003 Tartu, Estonia.
   [Longhi, Cristina] Archaeol Superintendence Lombardy, I-20123 Milan, Italy.
   [Merkevicius, Algimantas] Vilnius State Univ, Dept Archaeol, LT-01513 Vilnius, Lithuania.
   [Merkyte, Inga] Univ Copenhagen, SAXO Inst, DK-2300 Copenhagen S, Denmark.
   [Metspalu, Mait; Saag, Lehti] Estonian Bioctr, Dept Evolutionary Biol, EE-51010 Tartu, Estonia.
   [Metspalu, Mait; Saag, Lehti] Univ Tartu, EE-51010 Tartu, Estonia.
   [Mkrtchyan, Ruzan] Yerevan State Univ, Dept Hist, Yerevan 0025, Armenia.
   [Paja, Laszlo] Hungarian Natl Museum, H-1083 Budapest, Hungary.
   [Paja, Laszlo; Palfi, Gyoergy] Univ Szeged, Dept Biol Anthropol, H-6726 Szeged, Hungary.
   [Pospieszny, Lukasz] Polish Acad Sci, Inst Archaeol & Ethnol, PL-61612 Poznan, Poland.
   [Price, T. Douglas] Univ Wisconsin, Lab Archaeol Chem, Madison, WI 53706 USA.
   [Sablin, Mikhail] Russian Acad Sci, Inst Zool, St Petersburg 199034, Russia.
   [Shishlina, Natalia] State Hist Museum, Dept Archaeol, Moscow 109012, Russia.
   [Smrcka, Vaclav] Charles Univ Prague, Fac Med 1, Inst Hist Med & Foreign Languages, Prague 12108, Czech Republic.
   [Soenov, Vasilii I.; Trifanova, Synaru V.] Gorno Altaisk State Univ, Res Ctr Hist & Culture Turk Peoples, Gorno Altaisk 649000, Russia.
   [Toth, Gusztav] Eotvos Lorand Univ, Fac Humanities, Inst Archaeol Sci, Dept Pre & Early Hist, H-1088 Budapest, Hungary.
   [Vicze, Magdolna] Matrica Museum, H-2440 Szazhalombatta, Hungary.
   [Yepiskoposyan, Levon] Natl Acad Sci, Inst Mol Biol, Lab Ethnogen, Yerevan 0014, Armenia.
   [Zhitenev, Vladislav] Moscow MV Lomonosov State Univ, Fac Hist, Dept Archaeol, Moscow 119991, Russia.
   [Brunak, Soren] Univ Copenhagen, Ctr Prot Res, Novo Nordisk Fdn, DK-2200 Copenhagen, Denmark.
   [Nielsen, Rasmus] Univ Calif Berkeley, Ctr Theoret Evolutionary Genet, Berkeley, CA 94720 USA.
C3 University of Copenhagen; University of Gothenburg; Technical University of Denmark; Leiden University - Excl LUMC; Leiden University; Lund University; University of Oxford; University of Copenhagen; University of Wroclaw; University of Zurich; Wroclaw Medical University; University of Toronto; Gorno-Altaisk State University; South Ural State University; Institute of History & Archaeology of the Ural Branch of the Russian Academy of Sciences; Russian Academy of Sciences; The Kunstkamera; Polish Academy of Sciences; University of Munich; Eotvos Lorand University; Samara State University of Social Sciences & Education; Eotvos Lorand University; ELTE Research Centre for the Humanities; Institute of Archaeology - HAS; Hungarian Academy of Sciences; Masaryk University; Czech Academy of Sciences; Institute of Botany of the Czech Academy of Sciences; University of Tartu; Vilnius University; University of Copenhagen; Estonian Biocentre; University of Tartu; Yerevan State University; Szeged University; Polish Academy of Sciences; Institute of Archaeology & Ethnology of the Polish Academy of Sciences; University of Wisconsin System; University of Wisconsin Madison; Russian Academy of Sciences; Zoological Institute of the Russian Academy of Sciences; Charles University Prague; Gorno-Altaisk State University; Eotvos Lorand University; National Academy of Sciences of Armenia; Institute of Molecular Biology - NAS RA; Lomonosov Moscow State University; University of Copenhagen; Novo Nordisk Foundation; University of California System; University of California Berkeley
RP Willerslev, E (corresponding author), Univ Copenhagen, Ctr GeoGenet, Nat Hist Museum, Oster Voldgade 5-7, DK-1350 Copenhagen K, Denmark.
EM ewillerslev@snm.ku.dk
FU European Research Council [269442]; University of Copenhagen; Marie Curie Actions of the European Union [300554]; Villum Foundation [10120]; Miller Institute, University of California, Berkeley; Lundbeck Foundation; Danish National Research Foundation; European Research Council (ERC) [269442] Funding Source: European Research Council (ERC); National Health and Medical Research Council (NHMRC) [300554] Funding Source: National Health and Medical Research Council (NHMRC); Direct For Social, Behav & Economic Scie; Division Of Behavioral and Cognitive Sci [1226439] Funding Source: National Science Foundation; Lundbeck Foundation [R38-2008-3048, R155-2013-16338, R24-2008-2527, R70-2010-6286, R109-2012-9995] Funding Source: researchfish; Villum Fonden [00010120] Funding Source: researchfish
NR 54
TC 1089
Z9 1231
U1 5
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 JUN 11
PY 2015
VL 522
IS 7555
BP 167
EP +
DI 10.1038/nature14507
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700029
PM 26062507
DA 2026-03-09
ER

PT J
AU Nicenboim, J
   Malkinson, G
   Lupo, T
   Asaf, L
   Sela, Y
   Mayseless, O
   Gibbs-Bar, L
   Senderovich, N
   Hashimshony, T
   Shin, M
   Jerafi-Vider, A
   Avraham-Davidi, I
   Krupalnik, V
   Hofi, R
   Almog, G
   Astin, JW
   Golani, O
   Ben-Dor, S
   Crosier, PS
   Herzog, W
   Lawson, ND
   Hanna, JH
   Yanai, I
   Yaniv, K
AF Nicenboim, J.
   Malkinson, G.
   Lupo, T.
   Asaf, L.
   Sela, Y.
   Mayseless, O.
   Gibbs-Bar, L.
   Senderovich, N.
   Hashimshony, T.
   Shin, M.
   Jerafi-Vider, A.
   Avraham-Davidi, I.
   Krupalnik, V.
   Hofi, R.
   Almog, G.
   Astin, J. W.
   Golani, O.
   Ben-Dor, S.
   Crosier, P. S.
   Herzog, W.
   Lawson, N. D.
   Hanna, J. H.
   Yanai, I.
   Yaniv, K.
TI Lymphatic vessels arise from specialized angioblasts within a venous niche
SO NATURE
LA English
DT Article
ID acts downstream; gene-expression; beta-catenin; stem-cells; coup-tfii; zebrafish; mechanisms; reveals; origin; prox1
AB How cells acquire their fate is a fundamental question in developmental and regenerative biology. Multipotent progenitors undergo cell-fate restriction in response to cues from the microenvironment, the nature of which is poorly understood. In the case of the lymphatic system, venous cells from the cardinal vein are thought to generate lymphatic vessels through trans-differentiation. Here we show that in zebrafish, lymphatic progenitors arise from a previously uncharacterized niche of specialized angioblasts within the cardinal vein, which also generates arterial and venous fates. We further identify Wnt5b as a novel lymphatic inductive signal and show that it also promotes the 'angioblast-to-lymphatic' transition in human embryonic stem cells, suggesting that this process is evolutionarily conserved. Our results uncover a novel mechanism of lymphatic specification, and provide the first characterization of the lymphatic inductive niche. More broadly, our findings highlight the cardinal vein as a heterogeneous structure, analogous to the haematopoietic niche in the aortic floor.
C1 [Nicenboim, J.; Malkinson, G.; Lupo, T.; Asaf, L.; Sela, Y.; Mayseless, O.; Gibbs-Bar, L.; Jerafi-Vider, A.; Avraham-Davidi, I.; Hofi, R.; Almog, G.; Yaniv, K.] Weizmann Inst Sci, Dept Biol Regulat, IL-76100 Rehovot, Israel.
   [Senderovich, N.; Hashimshony, T.; Yanai, I.] Technion Israel Inst Technol, Fac Biol, IL-32000 Haifa, Israel.
   [Shin, M.; Lawson, N. D.] Univ Massachusetts Med Sch, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA.
   [Krupalnik, V.; Hanna, J. H.] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel.
   [Astin, J. W.; Crosier, P. S.] Univ Auckland, Sch Med Sci, Auckland 1142, New Zealand.
   [Golani, O.; Ben-Dor, S.] Weizmann Inst Sci, Biol Serv Unit, IL-76100 Rehovot, Israel.
   [Herzog, W.] Univ Munster, D-48149 Munster, Germany.
   [Herzog, W.] Max Plank Inst Mol Biomed, D-48149 Munster, Germany.
C3 Weizmann Institute of Science; Technion Israel Institute of Technology; University of Massachusetts System; University of Massachusetts Worcester; Weizmann Institute of Science; University of Auckland; Weizmann Institute of Science; University of Munster; Max Planck Society
RP Yaniv, K (corresponding author), Weizmann Inst Sci, Dept Biol Regulat, IL-76100 Rehovot, Israel.
EM karina.yaniv@weizmann.ac.il
FU Marie Curie Actions-International Reintegration grants [FP7-PEOPLE-2009-RG 256393]; Minerva Foundation [711128]; German-Israeli Foundation [1967/2009]; Israel Cancer Research Foundation; Lymphatic Research and Education Network; Northrine Westphalia Return fellowship; US National Institutes of Health (NIH) [R01 HL122599]; JSPS; ERC [310927]; Karen Siem Fellowship for Women in Science; Willner Family Center for Vascular Biology; estate of Paul Ourieff; Carolito Stiftung; Adelis Foundation; European Research Council (ERC) [310927] Funding Source: European Research Council (ERC)
NR 60
TC 168
Z9 204
U1 2
U2 28
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 4
PY 2015
VL 522
IS 7554
BP 56
EP U100
DI 10.1038/nature14425
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ5QP
UT WOS:000355543400028
PM 25992545
DA 2026-03-09
ER

PT J
AU Vinayak, S
   Pawlowic, MC
   Sateriale, A
   Brooks, CF
   Studstill, CJ
   Bar-Peled, Y
   Cipriano, MJ
   Striepen, B
AF Vinayak, Sumiti
   Pawlowic, Mattie C.
   Sateriale, Adam
   Brooks, Carrie F.
   Studstill, Caleb J.
   Bar-Peled, Yael
   Cipriano, Michael J.
   Striepen, Boris
TI Genetic modification of the diarrhoeal pathogen Cryptosporidium parvum
SO NATURE
LA English
DT Article
ID randomized controlled-trial; plasmodium-falciparum; zambian children; infection; nitazoxanide; assay; time; mortality; parasites; strains
AB Recent studies into the global causes of severe diarrhoea in young children have identified the protozoan parasite Cryptosporidium as the second most important diarrhoeal pathogen after rotavirus(1-3). Diarrhoeal disease is estimated to be responsible for 10.5% of overall child mortality(4). Cryptosporidium is also an opportunistic pathogen in the contexts of human immunodeficiency virus (HIV)-caused AIDS and organ transplantation(5,6). There is no vaccine and only a single approved drug that provides no benefit for those in gravest danger: malnourished children and immunocompromised patients(7,8). Cryptosporidiosisdrug and vaccine development is limited by the poor tractability of the parasite, which includes a lack of systems for continuous culture, facile animal models, and molecular genetic tools(3,9). Here we describe an experimental framework to genetically modify this important human pathogen. We established and optimized transfection of C. parvum sporozoites in tissue culture. To isolate stable transgenics we developed a mouse model that delivers sporozoites directly into the intestine, aCryptosporidium clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system, and in vivo selection for aminoglycoside resistance. We derived reporter parasites suitable for in vitro and in vivo drug screening, and we evaluated the basis of drug susceptibility by gene knockout. We anticipate that the ability to genetically engineer this parasite will be transformative for Cryptosporidium research. Genetic reporters will provide quantitative correlates for disease, cure and protection, and the role of parasite genes in these processes is now open to rigorous investigation.
C1 [Vinayak, Sumiti; Pawlowic, Mattie C.; Sateriale, Adam; Brooks, Carrie F.; Studstill, Caleb J.; Bar-Peled, Yael; Cipriano, Michael J.; Striepen, Boris] Univ Georgia, Ctr Trop & Emerging Global Dis, Paul D Coverdell Ctr, Athens, GA 30602 USA.
   [Striepen, Boris] Univ Georgia, Dept Cellular Biol, Paul D Coverdell Ctr, Athens, GA 30602 USA.
C3 University System of Georgia; University of Georgia; University System of Georgia; University of Georgia
RP Striepen, B (corresponding author), Univ Georgia, Ctr Trop & Emerging Global Dis, Paul D Coverdell Ctr, 500 DW Brooks Dr, Athens, GA 30602 USA.
EM striepen@uga.edu
FU National Institutes of Health (NIH) [R01AI112427]; Centers for Disease Control; University of Georgia Research Foundation;  [NIH T32AI060546]; National Institute of Allergy and Infectious Diseases [R01AI112427, T32AI060546] Funding Source: NIH RePORTER
NR 41
TC 266
Z9 313
U1 1
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 JUL 23
PY 2015
VL 523
IS 7561
BP 477
EP U232
DI 10.1038/nature14651
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN4DD
UT WOS:000358378900040
PM 26176919
DA 2026-03-09
ER

PT J
AU Hultman, J
   Waldrop, MP
   Mackelprang, R
   David, MM
   McFarland, J
   Blazewicz, SJ
   Harden, J
   Turetsky, MR
   McGuire, AD
   Shah, MB
   VerBerkmoes, NC
   Lee, LH
   Mavrommatis, K
   Jansson, JK
AF Hultman, Jenni
   Waldrop, Mark P.
   Mackelprang, Rachel
   David, Maude M.
   McFarland, Jack
   Blazewicz, Steven J.
   Harden, Jennifer
   Turetsky, Merritt R.
   McGuire, A. David
   Shah, Manesh B.
   VerBerkmoes, Nathan C.
   Lee, Lang Ho
   Mavrommatis, Kostas
   Jansson, Janet K.
TI Multi-omics of permafrost, active layer and thermokarst bog soil microbiomes
SO NATURE
LA English
DT Article
ID thaw; bacterial; climate; carbon
AB Over 20% of Earth's terrestrial surface is underlain by permafrost with vast stores of carbon that, once thawed, may represent the largest future transfer of carbon from the biosphere to the atmosphere(1). This process is largely dependent on microbial responses, but we know little about microbial activity in intact, let alone in thawing, permafrost. Molecular approaches have recently revealed the identities and functional gene composition of microorganismsin some permafrost soils(2-4) and a rapid shift in functional gene composition during short-term thaw experiments(3). However, the fate of permafrost carbon depends on climatic, hydrological and microbial responses to thaw at decadal scales(5,6). Here we use the combination of several molecular 'omics' approaches to determine the phylogenetic composition of the microbial communities, including several draft genomes of novel species, their functional potential and activity in soils representing different states of thaw: intact permafrost, seasonally thawed active layer and thermokarst bog. The multi-omics strategy reveals a good correlation of process rates to omics data for dominant processes, such as methanogenesis in the bog, as well as novel survival strategies for potentially active microbes in permafrost.
C1 [Hultman, Jenni; David, Maude M.; Jansson, Janet K.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Earth Sci, Berkeley, CA 94720 USA.
   [Waldrop, Mark P.; McFarland, Jack; Blazewicz, Steven J.; Harden, Jennifer] US Geol Survey, Menlo Pk, CA 94025 USA.
   [Mackelprang, Rachel] Calif State Univ Northridge, Biol Dept, Northridge, CA 91330 USA.
   [Mackelprang, Rachel; Mavrommatis, Kostas; Jansson, Janet K.] US DOE, Joint Genome Inst, Walnut Creek, CA 94598 USA.
   [Turetsky, Merritt R.] Univ Guelph, Dept Integrat Biol, Guelph, ON N1G 2W1, Canada.
   [McGuire, A. David] Univ Alaska Fairbanks, Alaska Cooperat Fish & Wildlife Res Unit, US Geol Survey, Fairbanks, AK 99775 USA.
   [Shah, Manesh B.; VerBerkmoes, Nathan C.] Oak Ridge Natl Lab, Chem Sci Div, Oak Ridge, TN 37831 USA.
   [Lee, Lang Ho] Univ Tennessee, Grad Sch Genome Sci & Technol, Knoxville, TN 37996 USA.
   [Lee, Lang Ho] Oak Ridge Natl Lab, Knoxville, TN 37996 USA.
   [Jansson, Janet K.] Univ Calif Berkeley, Dept Plant & Microbial Biol, Berkeley, CA 94720 USA.
   [Jansson, Janet K.] Univ Copenhagen, Dept Biol, Ctr Permafrost Res CENPERM, DK-2100 Copenhagen, Denmark.
C3 University of California System; University of California Berkeley; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; United States Department of the Interior; United States Geological Survey; California State University System; California State University Northridge; United States Department of Energy (DOE); Joint Genome Institute - JGI; Joint BioEnergy Institute - JBEI; University of Guelph; United States Department of the Interior; United States Geological Survey; University of Alaska System; University of Alaska Fairbanks; United States Department of Energy (DOE); Oak Ridge National Laboratory; University of Tennessee System; University of Tennessee Knoxville; United States Department of Energy (DOE); Oak Ridge National Laboratory; University of California System; University of California Berkeley; University of Copenhagen
RP Jansson, JK (corresponding author), Pacific NW Natl Lab, Div Biol Sci, 902 Battelle Blvd, Richland, WA 99352 USA.
EM janet.jansson@pnnl.gov
FU Office of Science, Office of Biological and Environmental Research, Climate and Environmental [JGI CSP - 152]; Lawrence Berkeley National Laboratory Laboratory Directed Research & Development (LDRD) grant [DE-AC02-05CH11231]; Pacific Northwest National Laboratory [DE-AC05-76RL01830]; Danish National Research Foundation [CENPERM DNRF100]; Office of Science of the US Department of Energy [DE-AC02-05CH11231]; Bonanza Creek Long-Term Ecological Research Program - National Science Foundation [DEB 1026415]; US Department of Agriculture Forest Service, Pacific Northwest Research Station [PNW01-JV112619320-16]; US Geological Survey Climate RD Program; Alaska Climate Science Center; Academy of Finland [135669]; Academy of Finland (AKA) [135669] Funding Source: Academy of Finland (AKA); Direct For Biological Sciences; Division Of Environmental Biology [1026415] Funding Source: National Science Foundation
NR 30
TC 403
Z9 457
U1 18
U2 584
PU NATURE PUBLISHING 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 14
PY 2015
VL 521
IS 7551
BP 208
EP +
DI 10.1038/nature14238
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH9SY
UT WOS:000354377800056
PM 25739499
DA 2026-03-09
ER

PT J
AU Krishnaswamy, A
   Yamagata, M
   Duan, X
   Hong, YK
   Sanes, JR
AF Krishnaswamy, Arjun
   Yamagata, Masahito
   Duan, Xin
   Hong, Y. Kate
   Sanes, Joshua R.
TI Sidekick 2 directs formation of a retinal circuit that detects differential motion
SO NATURE
LA English
DT Article
ID ganglion-cells; mouse retina; synaptic connections; transgenic mice; amacrine cells; expression; light; organization; modulation; excitation
AB In the mammalian retina, processes of approximately 70 types of interneurons form specific synapses on roughly 30 types of retinal ganglion cells (RGCs) in a neuropil called the inner plexiform layer. Each RGC type extracts salient features from visual input, which are sent deeper into the brain for further processing(1-4). The specificity and stereotypy of synapses formed in the inner plexiform layer account for the feature-detecting ability of RGCs. Here we analyse the development and function of synapses on one mouse RGC type, called the W3B-RGC(5,6). These cells have the remarkable property of responding when the timing of the movement of a small object differs from that of the background, but not when they coincide(6). Such cells, known as local edge detectors or object motion sensors, can distinguish moving objects from a visual scene that is also moving(6-12). We show that W3B-RGCs receive strong and selective input from an unusual excitatory amacrine cell type known as VG3-AC (vesicular glutamate transporter 3). Both W3B-RGCs and VG3-ACs express the immunoglobulin superfamily recognition molecule sidekick 2 (Sdk2)(13,14), and both loss-and gain-of-function studies indicate that Sdk2-dependent homophilic interactions are necessary for the selectivity of the connection. The Sdk2-specified synapse is essential for visual responses of W3B-RGCs: whereas bipolar cells relay visual input directly to most RGCs, the W3B-RGCs receive much of their input indirectly, via the VG3-ACs. This non-canonical circuit introduces a delay into the pathway from photoreceptors in the centre of the receptive field to W3B-RGCs, which could improve their ability to judge the synchrony of local and global motion.
C1 [Krishnaswamy, Arjun; Yamagata, Masahito; Duan, Xin; Hong, Y. Kate; Sanes, Joshua R.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA.
   [Krishnaswamy, Arjun; Yamagata, Masahito; Duan, Xin; Hong, Y. Kate; Sanes, Joshua R.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA.
C3 Harvard University; Harvard University
RP Sanes, JR (corresponding author), Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA.
EM sanesj@mcb.harvard.edu
FU NIH [NS029169, EY022073, F31 NS055488]; NSERC (Canada); Banting Postdoctoral Fellowships; HHMI-Life Sciences Research Foundation
NR 53
TC 123
Z9 159
U1 1
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 AUG 27
PY 2015
VL 524
IS 7566
BP 466
EP +
DI 10.1038/nature14682
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP7LN
UT WOS:000360069300038
PM 26287463
DA 2026-03-09
ER

PT J
AU Cheng, ZY
   Li, JF
   Niu, YJ
   Zhang, XC
   Woody, OZ
   Xiong, Y
   Djonovic, S
   Millet, Y
   Bush, J
   McConkey, BJ
   Sheen, J
   Ausubel, FM
AF Cheng, Zhenyu
   Li, Jian-Feng
   Niu, Yajie
   Zhang, Xue-Cheng
   Woody, Owen Z.
   Xiong, Yan
   Djonovic, Slavica
   Millet, Yves
   Bush, Jenifer
   McConkey, Brendan J.
   Sheen, Jen
   Ausubel, Frederick M.
TI Pathogen-secreted proteases activate a novel plant immune pathway
SO NATURE
LA English
DT Article
ID pseudomonas-aeruginosa; gene-expression; protein-kinase; xanthomonas-campestris; arabidopsis-thaliana; rack1; transformation; interacts; identification; iv
AB Mitogen-activated protein kinase (MAPK) cascades play central roles in innate immune signalling networks in plants and animals(1,2). In plants, however, the molecular mechanisms of how signal perception is transduced to MAPK activation remain elusive(1). Here we report that pathogen-secreted proteases activate a previously unknown signalling pathway in Arabidopsis thaliana involving the G alpha, G beta, and G gamma subunits of heterotrimeric G-protein complexes, which function upstream of an MAPK cascade. In this pathway, receptor for activated C kinase 1 (RACK1) functions as a novel scaffold that binds to the G beta subunit as well as to all three tiers of the MAPK cascade, thereby linking upstream G-protein signalling to downstream activation of an MAPK cascade. The protease-G-protein-RACK1-MAPK cascade modules identified in these studies are distinct from previously described plant immune signalling pathways such as that elicited by bacterial flagellin, in which G proteins function downstream of or in parallel to an MAPK cascade without the involvement of the RACK1 scaffolding protein. The discovery of the new protease-mediated immune signalling pathway described here was facilitated by the use of the broad host range, opportunistic bacterial pathogen Pseudomonas aeruginosa. The ability of P. aeruginosa to infect both plants and animals makes it an excellent model to identify novel immunoregulatory strategies that account for its niche adaptation to diverse host tissues and immune systems.
C1 [Cheng, Zhenyu; Li, Jian-Feng; Niu, Yajie; Zhang, Xue-Cheng; Xiong, Yan; Djonovic, Slavica; Millet, Yves; Bush, Jenifer; Sheen, Jen; Ausubel, Frederick M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.
   [Cheng, Zhenyu; Li, Jian-Feng; Niu, Yajie; Zhang, Xue-Cheng; Xiong, Yan; Djonovic, Slavica; Millet, Yves; Bush, Jenifer; Sheen, Jen; Ausubel, Frederick M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
   [Woody, Owen Z.; McConkey, Brendan J.] Univ Waterloo, Dept Biol, Waterloo, ON N2L 3G1, Canada.
C3 Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; University of Waterloo
RP Ausubel, FM (corresponding author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.
EM ausubel@molbio.mgh.harvard.edu
FU Natural Sciences and Engineering Research Council of Canada; Banting Postdoctoral Fellowships; National Science Foundation [MCB-0519898, IOS-0929226, IOS-0618292]; National Institutes of Health [R37-GM48707, P30 DK040561, R01-GM70567]; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK040561] Funding Source: NIH RePORTER; Direct For Biological Sciences; Division Of Integrative Organismal Systems [0929226] Funding Source: National Science Foundation
NR 39
TC 195
Z9 228
U1 10
U2 269
PU NATURE PUBLISHING 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 14
PY 2015
VL 521
IS 7551
BP 213
EP +
DI 10.1038/nature14243
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH9SY
UT WOS:000354377800057
PM 25731164
DA 2026-03-09
ER

PT J
AU Orthwein, A
   Noordermeer, SM
   Wilson, MD
   Landry, S
   Enchev, RI
   Sherker, A
   Munro, M
   Pinder, J
   Salsman, J
   Dellaire, G
   Xia, B
   Peter, M
   Durocher, D
AF Orthwein, Alexandre
   Noordermeer, Sylvie M.
   Wilson, Marcus D.
   Landry, Sebastien
   Enchev, Radoslav I.
   Sherker, Alana
   Munro, Meagan
   Pinder, Jordan
   Salsman, Jayme
   Dellaire, Graham
   Xia, Bing
   Peter, Matthias
   Durocher, Daniel
TI RETRACTED: A mechanism for the suppression of homologous recombination in G1 cells (Retracted Article)
SO NATURE
LA English
DT Article; Retracted Publication
ID strand break repair; dna-end resection; 11 usp11; 53bp1; palb2; accumulation; inhibition; interacts; enzyme; brca2
AB DNA repair by homologous recombination(1) is highly suppressed in G1 cells(2,3) to ensure that mitotic recombination occurs solely between sister chromatids(4). Although many homologous recombination factors are cell-cycle regulated, the identity of the events that are both necessary and sufficient to suppress recombination in G1 cells is unknown. Here we report that the cell cycle controls the interaction of BRCA1 with PALB2-BRCA2 to constrain BRCA2 function to the S/G2 phases in human cells. We found that the BRCA1-interaction site on PALB2 is targeted by an E3 ubiquitin ligase composed of KEAP1, a PALB2-interacting protein(5), in complex with cullin-3 (CUL3)-RBX1 (ref.6). PALB2 ubiquitylation suppresses its interaction with BRCA1 and is counteracted by the deubiquitylase USP11, which is itself under cell cycle control. Restoration of the BRCA1-PALB2 interaction combined with the activation of DNA-end resection is sufficient to induce homologous recombination in G1, as measured by RAD51 recruitment, unscheduled DNA synthesis and a CRISPR-Cas9-based gene-targeting assay. We conclude that the mechanism prohibiting homologous recombination in G1 minimally consists of the suppression of DNA-end resection coupled with a multi-step block of the recruitment of BRCA2 to DNA damage sites that involves the inhibition of BRCA1-PALB2-BRCA2 complex assembly. We speculate that the ability to induce homologous recombination in G1 cells with defined factors could spur the development of gene-targeting applications in non-dividing cells.
C1 [Orthwein, Alexandre; Noordermeer, Sylvie M.; Wilson, Marcus D.; Landry, Sebastien; Sherker, Alana; Munro, Meagan; Durocher, Daniel] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada.
   [Enchev, Radoslav I.; Peter, Matthias] ETH, Inst Biochem, Dept Biol, CH-8093 Zurich, Switzerland.
   [Sherker, Alana; Durocher, Daniel] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada.
   [Pinder, Jordan; Salsman, Jayme; Dellaire, Graham] Dalhousie Univ, Dept Pathol, Halifax, NS B3H 4R2, Canada.
   [Pinder, Jordan; Salsman, Jayme; Dellaire, Graham] Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS B3H 4R2, Canada.
   [Xia, Bing] Rutgers State Univ, Rutgers Canc Inst New Jersey, Dept Radiat Oncol, New Brunswick, NJ 08901 USA.
   [Xia, Bing] Rutgers State Univ, Robert Wood Johnson Med Sch, New Brunswick, NJ 08901 USA.
C3 University of Toronto; Sinai Health System Toronto; Lunenfeld Tanenbaum Research Institute; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Toronto; Dalhousie University; Dalhousie University; Rutgers University System; Rutgers University New Brunswick; Rutgers University Biomedical & Health Sciences; Rutgers Cancer Institute of New Jersey; Rutgers University System; Rutgers University New Brunswick; Rutgers University Biomedical & Health Sciences
RP Durocher, D (corresponding author), Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, 600 Univ Ave, Toronto, ON M5G 1X5, Canada.
EM durocher@lunenfeld.ca
FU Dutch Cancer Society (KWF); Human Frontier Science Program fellowship; Ontario Graduate Scholarship; Marie Curie postdoctoral fellowship; Beatrice Hunter Cancer Research Institute (BHCRI); Harvey Graham Cancer Research Fund as part of the Terry Fox Foundation Strategic Health Research Training Program in Cancer Research at the Canadian Institutes of Health Research (CIHR); Krembil Foundation; CIHR [FDN143343, MOP84260]; National Cancer Institute [R01CA138804] Funding Source: NIH RePORTER
NR 39
TC 377
Z9 485
U1 14
U2 125
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 17
PY 2015
VL 528
IS 7582
BP 422
EP +
DI 10.1038/nature16142
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CY8SM
UT WOS:000366678600058
PM 26649820
DA 2026-03-09
ER

PT J
AU Veldhorst, M
   Yang, CH
   Hwang, JCC
   Huang, W
   Dehollain, JP
   Muhonen, JT
   Simmons, S
   Laucht, A
   Hudson, FE
   Itoh, KM
   Morello, A
   Dzurak, AS
AF Veldhorst, M.
   Yang, C. H.
   Hwang, J. C. C.
   Huang, W.
   Dehollain, J. P.
   Muhonen, J. T.
   Simmons, S.
   Laucht, A.
   Hudson, F. E.
   Itoh, K. M.
   Morello, A.
   Dzurak, A. S.
TI A two-qubit logic gate in silicon
SO NATURE
LA English
DT Article
ID quantum-dot; electron-spin; qubit; entanglement; oscillations; computation; fidelity
AB Quantum computation requires qubits that can be coupled in a scalable manner, together with universal and high-fidelity one-and two-qubit logic gates(1,2). Many physical realizations of qubits exist, including single photons(3), trapped ions(4), superconducting circuits(5), single defects or atoms in diamond(6,7) and silicon(8), and semiconductor quantum dots(9), with single-qubit fidelities that exceed the stringent thresholds required for fault-tolerant quantum computing(10). Despite this, high-fidelity two-qubit gates in the solid state that can be manufactured using standard lithographic techniques have so far been limited to superconducting qubits(5), owing to the difficulties of coupling qubits and dephasing in semiconductor systems(11-13). Here we present a two-qubit logic gate, which uses single spins in isotopically enriched silicon(14) and is realized by performing single-and two-qubit operations in a quantum dot system using the exchange interaction, as envisaged in the Loss-DiVincenzo proposal(2). We realize CNOT gates via controlled-phase operations combined with single-qubit operations. Direct gate-voltage control provides single-qubit addressability, together with a switchable exchange interaction that is used in the two-qubit controlled-phase gate. By independently reading out both qubits, we measure clear anticorrelations in the two-spin probabilities of the CNOT gate.
C1 [Veldhorst, M.; Yang, C. H.; Hwang, J. C. C.; Huang, W.; Dehollain, J. P.; Muhonen, J. T.; Simmons, S.; Laucht, A.; Hudson, F. E.; Morello, A.; Dzurak, A. S.] Univ New S Wales, Sch Elect Engn & Telecommun, Ctr Quantum Computat & Commun Technol, Sydney, NSW 2052, Australia.
   [Itoh, K. M.] Keio Univ, Sch Fundamental Sci & Technol, Kohoku Ku, Yokohama, Kanagawa 2238522, Japan.
C3 University of New South Wales Sydney; Keio University
RP Veldhorst, M (corresponding author), Univ New S Wales, Sch Elect Engn & Telecommun, Ctr Quantum Computat & Commun Technol, Sydney, NSW 2052, Australia.
EM M.Veldhorst@unsw.edu.au; A.Dzurak@unsw.edu.au
FU Australian Research Council [CE11E0001017]; US Army Research Office [W911NF-13-1-0024]; NSW Node of the Australian National Fabrication Facility; Netherlands Organization for Scientific Research (NWO) through Rubicon Grant; MEXT; NanoQuine; FIRST; JSPS Core-to-Core Program; Grants-in-Aid for Scientific Research [26220602] Funding Source: KAKEN
NR 27
TC 767
Z9 939
U1 8
U2 400
PU NATURE PUBLISHING 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 15
PY 2015
VL 526
IS 7573
BP 410
EP 414
DI 10.1038/nature15263
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200047
PM 26436453
DA 2026-03-09
ER

PT J
AU DaRosa, PA
   Wang, ZZ
   Jiang, XM
   Pruneda, JN
   Cong, F
   Klevit, RE
   Xu, WQ
AF DaRosa, Paul A.
   Wang, Zhizhi
   Jiang, Xiaomo
   Pruneda, Jonathan N.
   Cong, Feng
   Klevit, Rachel E.
   Xu, Wenqing
TI Allosteric activation of the RNF146 ubiquitin ligase by a poly(ADP-ribosyl)ation signal
SO NATURE
LA English
DT Article
ID crystal-structure; structural basis; complex reveals; e3 ligase; recognition; mechanism; axin; proteins; insights; system
AB Protein poly(ADP-ribosyl)ation (PARylation) has a role in diverse cellular processes such as DNA repair, transcription, Wnt signalling, andcell death(1-6). Recent studies have shown that PARylation can serve as a signal for the polyubiquitination and degradation of several crucial regulatory proteins, including Axin and 3BP2 (refs 7-9). The RING-type E3 ubiquitin ligase RNF146 (also known as Iduna) is responsible for PARylation-dependent ubiquitination (PARdU)(10-12). Here we provide a structural basis for RNF146-catalysed PARdU and how PARdU specificity is achieved. First, we show that iso-ADP-ribose (iso-ADPr), the smallest internal poly(ADP-ribose) (PAR) structural unit, binds between the WWE and RING domains of RNF146 and functions as an allosteric signal that switches the RING domain from a catalytically inactive state to an active one. In the absence of PAR, the RING domain is unable to bind and activate a ubiquitin-conjugating enzyme (E2) efficiently. Binding of PAR or iso-ADPr induces a major conformational change that creates a functional RING structure. Thus, RNF146 represents a new mechanistic class of RING E3 ligases, the activities of which are regulated by non-covalent ligand binding, and that may provide a template for designing inducible protein-degradation systems. Second, we find that RNF146 directly interacts with the PAR polymerase tankyrase (TNKS). Disruption of the RNF146-TNKS interaction inhibits turnover of the substrate Axin in cells. Thus, both substrate PARylation and PARdU are catalysed by enzymes within the same protein complex, and PARdU substrate specificity may be primarily determined by the substrate-TNKS interaction. We propose that the maintenance of unliganded RNF146 in an inactive state may serve to maintain the stability of the RNF146-TNKS complex, which in turn regulates the homeostasis of PARdU activity in the cell.
C1 [DaRosa, Paul A.; Pruneda, Jonathan N.; Klevit, Rachel E.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA.
   [DaRosa, Paul A.; Wang, Zhizhi; Xu, Wenqing] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA.
   [Jiang, Xiaomo; Cong, Feng] Novartis Inst Biomed Res, Cambridge, MA 02139 USA.
C3 University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Novartis; Novartis USA
RP Xu, WQ (corresponding author), Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA.
EM klevit@uw.edu; wxu@uw.edu
FU National Institutes of Health (NIH) [R01 GM099766, T32 GM07270]
NR 38
TC 191
Z9 215
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 JAN 8
PY 2015
VL 517
IS 7533
BP 223
EP U275
DI 10.1038/nature13826
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600041
PM 25327252
DA 2026-03-09
ER

PT J
AU Zhang, F
   Yao, J
   Ke, JY
   Zhang, L
   Lam, VQ
   Xin, XF
   Zhou, XE
   Chen, J
   Brunzelle, J
   Griffin, PR
   Zhou, MG
   Xu, HE
   Melcher, K
   He, SY
AF Zhang, Feng
   Yao, Jian
   Ke, Jiyuan
   Zhang, Li
   Lam, Vinh Q.
   Xin, Xiu-Fang
   Zhou, X. Edward
   Chen, Jian
   Brunzelle, Joseph
   Griffin, Patrick R.
   Zhou, Mingguo
   Xu, H. Eric
   Melcher, Karsten
   He, Sheng Yang
TI Structural basis of JAZ repression of MYC transcription factors in jasmonate signalling
SO NATURE
LA English
DT Article
ID activation domains; gene-expression; arabidopsis; proteins; coronatine; mediator; receptor; defense; complex; responses
AB The plant hormone jasmonate plays crucial roles in regulating plant responses to herbivorous insects and microbial pathogens and is an important regulator of plant growth and development(1-7). Keymediators of jasmonate signalling include MYC transcription factors, which are repressed by jasmonate ZIM-domain (JAZ) transcriptional repressors in the resting state. In the presence of active jasmonate, JAZ proteins function as jasmonate co-receptors by forming a hormone-dependent complex with COI1, the F-box subunit of an SCF-type ubiquitin E3 ligase(8-11). The hormone-dependent formation of the COI1-JAZ co-receptor complex leads to ubiquitination and proteasome-dependent degradation of JAZ repressors and release of MYC proteins from transcriptional repression(3,10,12). The mechanism by which JAZ proteins repress MYC transcription factors and how JAZ proteins switch between the repressor function in the absence of hormone and the co-receptor function in the presence of hormone remain enigmatic. Here we show that Arabidopsis MYC3 undergoes pronounced conformational changes when bound to the conserved Jas motif of the JAZ9 repressor. The Jas motif, previously shown to bind to hormone as a partly unwound helix, forms a complete alpha-helix that displaces the amino (N)-terminal helix ofMYC3 and becomes an integral part of theMYC N-terminal fold. In this position, the Jas helix competitively inhibits MYC3 interaction with the MED25 subunit of the transcriptional Mediator complex. Our structural and functional studies elucidate a dynamic molecular switchmechanism that governs the repression and activation of a major plant hormone pathway.
C1 [Zhang, Feng; Ke, Jiyuan; Zhou, X. Edward; Chen, Jian; Xu, H. Eric; Melcher, Karsten] Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA.
   [Zhang, Feng; Ke, Jiyuan; Zhou, X. Edward; Chen, Jian; Xu, H. Eric; Melcher, Karsten] Van Andel Res Inst, Lab Struct Biol & Biochem, Grand Rapids, MI 49503 USA.
   [Zhang, Feng; Yao, Jian; Zhang, Li; Xin, Xiu-Fang; He, Sheng Yang] Michigan State Univ, DOE Plant Res Lab, E Lansing, MI 48824 USA.
   [Zhang, Feng; Zhou, Mingguo] Nanjing Agr Univ, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China.
   [Yao, Jian] Western Michigan Univ, Dept Biol Sci, Kalamazoo, MI 49008 USA.
   [Zhang, Li; He, Sheng Yang] Michigan State Univ, Dept Plant Biol, E Lansing, MI 48824 USA.
   [Lam, Vinh Q.; Griffin, Patrick R.] Scripps Florida, Scripps Res Inst, Translat Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA.
   [Chen, Jian] Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou 310018, Zhejiang, Peoples R China.
   [Brunzelle, Joseph] Northwestern Univ, Synchrotron Res Ctr, Dept Mol Pharmacol & Biol Chem, Life Sci Collaborat Access Team, Argonne, IL 60439 USA.
   [Xu, H. Eric] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Key Lab Receptor Res,VARI SIMM Ctr,Ctr Struct & F, Shanghai 200031, Peoples R China.
   [He, Sheng Yang] Michigan State Univ, Howard Hughes Med Inst, E Lansing, MI 48824 USA.
C3 Van Andel Institute; Van Andel Research Institute; Van Andel Institute; Van Andel Research Institute; United States Department of Energy (DOE); Michigan State University; Nanjing Agricultural University; Western Michigan University; Michigan State University; State University System of Florida; University of Florida; Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology; Zhejiang Sci-Tech University; Northwestern University; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Howard Hughes Medical Institute; Michigan State University
RP Xu, HE (corresponding author), Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA.
EM Eric.Xu@vai.org; Karsten.Melcher@vai.org; hes@msu.edu
FU Gordon and Betty Moore Foundation [GBMF3037]; China Scholarship Council; Van Andel Research Institute; National Institutes of Health [R01 GM102545, R01AI060761]; Department of Energy (the Chemical Sciences, Geosciences, and Biosciences Division, Office of Basic Energy Sciences, Office of Science) [DE-FG02-91ER20021]; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor [085P1000817]; Office of Science of the US Department of Energy [DE-AC02-06CH11357]
NR 43
TC 291
Z9 337
U1 18
U2 443
PU NATURE PUBLISHING 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 10
PY 2015
VL 525
IS 7568
BP 269
EP +
DI 10.1038/nature14661
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400043
PM 26258305
DA 2026-03-09
ER

PT J
AU Dixon, JR
   Jung, I
   Selvaraj, S
   Shen, Y
   Antosiewicz-Bourget, JE
   Lee, AY
   Ye, Z
   Kim, A
   Rajagopal, N
   Xie, W
   Diao, YR
   Liang, J
   Zhao, HM
   Lobanenkov, VV
   Ecker, JR
   Thomson, JA
   Ren, B
AF Dixon, Jesse R.
   Jung, Inkyung
   Selvaraj, Siddarth
   Shen, Yin
   Antosiewicz-Bourget, Jessica E.
   Lee, Ah Young
   Ye, Zhen
   Kim, Audrey
   Rajagopal, Nisha
   Xie, Wei
   Diao, Yarui
   Liang, Jing
   Zhao, Huimin
   Lobanenkov, Victor V.
   Ecker, Joseph R.
   Thomson, James A.
   Ren, Bing
TI Chromatin architecture reorganization during stem cell differentiation
SO NATURE
LA English
DT Article
ID human genome; gene-expression; histone modifications; dna methylation; regulatory dna; nuclear lamina; enhancers; organization; principles; landscape
AB Higher-order chromatin structure is emerging as an important regulator of gene expression. Although dynamic chromatin structures have been identified in the genome, the full scope of chromatin dynamics during mammalian development and lineage specification remains to be determined. By mapping genome-wide chromatin interactions in human embryonic stem(ES) cells and four human ES-cell-derived lineages, we uncover extensive chromatin reorganization during lineage specification. We observe that although self-associating chromatin domains are stable during differentiation, chromatin interactions both within and between domains change in a striking manner, altering 36% of active and inactive chromosomal compartments throughout the genome. By integrating chromatin interaction maps with haplotype-resolved epigenome and transcriptome data sets, we find widespread allelic bias in gene expression correlated with allele-biased chromatin states of linked promoters and distal enhancers. Our results therefore provide a global view of chromatin dynamics and a resource for studying long-range control of gene expression in distinct human cell lineages.
C1 [Dixon, Jesse R.; Jung, Inkyung; Selvaraj, Siddarth; Shen, Yin; Lee, Ah Young; Ye, Zhen; Kim, Audrey; Rajagopal, Nisha; Diao, Yarui; Ren, Bing] Ludwig Inst Canc Res, La Jolla, CA 92093 USA.
   [Dixon, Jesse R.] Univ Calif San Diego, Med Scientist Training Program, La Jolla, CA 92093 USA.
   [Selvaraj, Siddarth] Univ Calif San Diego, Bioinformat & Syst Biol Grad Program, La Jolla, CA 92093 USA.
   [Antosiewicz-Bourget, Jessica E.; Thomson, James A.] Morgridge Inst Res, Madison, WI 53715 USA.
   [Xie, Wei] Tsinghua Univ, Tsinghua Univ Peking Univ Ctr Life Sci, Sch Life Sci, Beijing 100084, Peoples R China.
   [Liang, Jing; Zhao, Huimin] Univ Illinois, Dept Chem & Biomol Engn, Urbana, IL 61801 USA.
   [Lobanenkov, Victor V.] NIAID, Lab Immunogenet, Twinbrook NIAID Facil 1, Rockville, MD 20852 USA.
   [Ecker, Joseph R.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA.
   [Thomson, James A.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Cell & Regenerat Biol, Madison, WI 53706 USA.
   [Thomson, James A.] Univ Calif Santa Barbara, Dept Mol Cellular & Dev Biol, Santa Barbara, CA 93106 USA.
   [Ren, Bing] Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, Inst Genom Med, La Jolla, 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; University of Wisconsin System; University of Wisconsin Madison; The Morgridge Institute for Research, Inc.; Tsinghua University; University of Illinois System; University of Illinois Urbana-Champaign; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Howard Hughes Medical Institute; Salk Institute; University of Wisconsin System; University of Wisconsin Madison; University of California System; University of California Santa Barbara; University of California System; University of California San Diego
RP Ren, B (corresponding author), Ludwig Inst Canc Res, 9500 Gilman Dr, La Jolla, CA 92093 USA.
EM biren@ucsd.edu
FU Ludwig Institute for Cancer Research; NIH Roadmap Epigenome Project [U01 ES017166, R01 ES024984]; California Institute of Regenerative Medicine [RN2-00905]; Human Frontier Science Program [LT000576/2014-L]; National Institute of Allergy and Infectious Diseases [ZIAAI000860] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007198] Funding Source: NIH RePORTER
NR 45
TC 1157
Z9 1493
U1 2
U2 243
PU NATURE PUBLISHING 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 19
PY 2015
VL 518
IS 7539
BP 331
EP 336
DI 10.1038/nature14222
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400029
PM 25693564
DA 2026-03-09
ER

PT J
AU Krönke, J
   Fink, EC
   Hollenbach, PW
   MacBeth, KJ
   Hurst, SN
   Udeshi, ND
   Chamberlain, PP
   Mani, DR
   Man, HW
   Gandhi, AK
   Svinkina, T
   Schneider, RK
   McConkey, M
   Järås, M
   Griffiths, E
   Wetzler, M
   Bullinger, L
   Cathers, BE
   Carr, SA
   Chopra, R
   Ebert, BL
AF Kroenke, Jan
   Fink, Emma C.
   Hollenbach, Paul W.
   MacBeth, Kyle J.
   Hurst, Slater N.
   Udeshi, Namrata D.
   Chamberlain, Philip P.
   Mani, D. R.
   Man, Hon Wah
   Gandhi, Anita K.
   Svinkina, Tanya
   Schneider, Rebekka K.
   McConkey, Marie
   Jaeras, Marcus
   Griffiths, Elizabeth
   Wetzler, Meir
   Bullinger, Lars
   Cathers, Brian E.
   Carr, Steven A.
   Chopra, Rajesh
   Ebert, Benjamin L.
TI Lenalidomide induces ubiquitination and degradation of CK1a in del(5q) MDS
SO NATURE
LA English
DT Article
ID commonly deleted region; casein kinase; myelodysplastic syndrm; multiple-myeloma; gene; identification; thalidomide; complex; efficacy; therapy
AB Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1 alpha) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)), resulting in CK1 alpha degradation. CK1 alpha is encoded by a gene within the common deleted region for del(5q) MDS and haploin sufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1 alpha. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4(CRBN). These findings have implications for the clinical activity of lenalidomide and related compounds, and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases.
C1 [Kroenke, Jan; Fink, Emma C.; Hurst, Slater N.; Schneider, Rebekka K.; McConkey, Marie; Jaeras, Marcus; Ebert, Benjamin L.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA.
   [Kroenke, Jan; Bullinger, Lars] Univ Hosp Ulm, Dept Internal Med 3, D-89081 Ulm, Germany.
   [Kroenke, Jan; Fink, Emma C.; Udeshi, Namrata D.; Mani, D. R.; Svinkina, Tanya; Carr, Steven A.; Ebert, Benjamin L.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Hollenbach, Paul W.; MacBeth, Kyle J.; Chamberlain, Philip P.; Man, Hon Wah; Gandhi, Anita K.; Cathers, Brian E.; Chopra, Rajesh] Celgene Corp, San Diego, CA 92121 USA.
   [Griffiths, Elizabeth; Wetzler, Meir] Roswell Pk Canc Inst, Buffalo, NY 14263 USA.
C3 Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Ulm University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Bristol-Myers Squibb; Celgene Corporation; Roswell Park Comprehensive Cancer Center
RP Ebert, BL (corresponding author), Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA.
EM bebert@partners.org
FU NIH [R01HL082945, P01CA108631]; Edward P. Evans Foundation; Gabrielle's Angel Foundation; Leukemia and Lymphoma Society Scholar Award; German Research Foundation (DFG, Emmy Noether Fellowship) [Kr3886/2-1, Kr3886/1-1, SFB1074]; Else-Kroner Fresenius Foundation; National Institute of General Medical Sciences [T32GM007753]; National Cancer Institute [P01CA066996] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [R01HL082945] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007753] Funding Source: NIH RePORTER; Cancer Research UK [11566] Funding Source: researchfish
NR 38
TC 717
Z9 875
U1 5
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 JUL 9
PY 2015
VL 523
IS 7559
BP 183
EP U102
DI 10.1038/nature14610
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM4ZO
UT WOS:000357695900028
PM 26131937
DA 2026-03-09
ER

PT J
AU Mandal, P
   Pitcher, MJ
   Alaria, J
   Niu, H
   Borisov, P
   Stamenov, P
   Claridge, JB
   Rosseinsky, MJ
AF Mandal, P.
   Pitcher, M. J.
   Alaria, J.
   Niu, H.
   Borisov, P.
   Stamenov, P.
   Claridge, J. B.
   Rosseinsky, M. J.
TI Designing switchable polarization and magnetization at room temperature in an oxide
SO NATURE
LA English
DT Article
ID phase-transitions; boundary
AB Ferroelectric and ferromagnetic materials exhibit long-range order of atomic-scale electric or magnetic dipoles that can be switched by applying an appropriate electric or magnetic field, respectively. Both switching phenomena form the basis of non-volatile random access memory(1), but in the ferroelectric case, this involves destructive electrical reading and in the magnetic case, a high writing energy is required(2). In principle, low-power and high-density information storage that combines fast electrical writing and magnetic reading can be realized with magnetoelectric multiferroic materials(3). These materials not only simultaneously display ferroelectricity and ferromagnetism, but also enable magnetic moments to be induced by an external electric field, or electric polarization by a magnetic field(4,5). However, synthesizing bulk materials with both long-range orders at room temperature in a single crystalline structure is challenging because conventional ferroelectricity requires closed-shell d(0) or s(2) cations, whereas ferromagnetic order requires open-shell d(n) configurations with unpaired electrons(6). These opposing requirements pose considerable difficulties for atomic-scale design strategies such as magnetic ion substitution into ferroelectrics(7,8). One material that exhibits both ferroelectric and magnetic order is BiFeO3, but its cycloidal magnetic structure(9) precludes bulk magnetization and linear magnetoelectric coupling(10). A solid solution of a ferroelectric and a spin-glass perovskite combines switchable polarization(11) with glassy magnetization, although it lacks long-range magnetic order(12). Crystal engineering of a layered perovskite has recently resulted in room-temperature polar ferromagnets(13), but the electrical polarization has not been switchable. Here we combine ferroelectricity and ferromagnetism at room temperature in a bulk perovskite oxide, by constructing a percolating network of magnetic ions with strong superexchange interactions within a structural scaffold exhibiting polar lattice symmetries at a morphotropic phase boundary(14) (the compositional boundary between two polar phases with different polarization directions, exemplified by the PbZrO3-PbTiO3 system) that both enhances polarization switching and permits canting of the ordered magnetic moments. We expect this strategy to allow the generation of a range of tunable multiferroic materials.
C1 [Mandal, P.; Pitcher, M. J.; Niu, H.; Borisov, P.; Claridge, J. B.; Rosseinsky, M. J.] Univ Liverpool, Dept Chem, Liverpool L69 7ZD, Merseyside, England.
   [Alaria, J.] Univ Liverpool, Dept Phys, Liverpool L69 7ZE, Merseyside, England.
   [Stamenov, P.] Univ Dublin Trinity Coll, CRANN, Dublin 2, Ireland.
C3 University of Liverpool; University of Liverpool; Trinity College Dublin
RP Rosseinsky, MJ (corresponding author), Univ Liverpool, Dept Chem, Liverpool L69 7ZD, Merseyside, England.
EM j.b.claridge@liv.ac.uk; m.j.rosseinsky@liv.ac.uk
FU EPSRC [EP/H000925/1]; Engineering and Physical Sciences Research Council [EP/H000925/1] Funding Source: researchfish; EPSRC [EP/H000925/1] Funding Source: UKRI
NR 29
TC 126
Z9 138
U1 4
U2 589
PU NATURE PUBLISHING 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 17
PY 2015
VL 525
IS 7569
BP 363
EP +
DI 10.1038/nature14881
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900040
PM 26381984
DA 2026-03-09
ER

PT J
AU Iwasaki, S
   Sasaki, HM
   Sakaguchi, Y
   Suzuki, T
   Tadakuma, H
   Tomari, Y
AF Iwasaki, Shintaro
   Sasaki, Hiroshi M.
   Sakaguchi, Yuriko
   Suzuki, Tsutomu
   Tadakuma, Hisashi
   Tomari, Yukihide
TI Defining fundamental steps in the assembly of the Drosophila RNAi enzyme complex
SO NATURE
LA English
DT Article
ID risc; argonaute; hsp90; dicer; sirna; interference; cleaves; mirnas; strand; c3po
AB SmallRNAs suchas small interfering RNAs(siRNAs) and microRNAs (miRNAs) silence the expression of their complementary target messenger RNAs1,2 via the formation of effector RNA-induced silencing complexes (RISCs), which contain Argonaute (Ago) family proteins at their core. Although loading of siRNA duplexes into Drosophila Ago2 requires the Dicer-2-R2D2 heterodimer(3-5) and the Hsc70/Hsp90 (Hsp90 also known as Hsp83) chaperone machinery6-8, the details of RISC assembly remain unclear. Here we reconstitute RISC assembly using only Ago2, Dicer-2, R2D2, Hsc70, Hsp90, Hop, Droj2 (an Hsp40 homologue) and p23. By following the assembly of single RISC molecules, we find that, in the absence of the chaperone machinery, an siRNA bound to Dicer-2-R2D2 associates with Ago2 only transiently. The chaperone machinery extends the dwell time of the Dicer-2-R2D2-siRNA complex on Ago2, in a manner dependent on recognition of the 59-phosphate on the siRNA guide strand. We propose that the chaperone machinery supports a productive state of Ago2, allowing it to load siRNA duplexes from Dicer-2-R2D2 and thereby assemble RISC.
C1 [Iwasaki, Shintaro; Sasaki, Hiroshi M.; Tomari, Yukihide] Univ Tokyo, Inst Mol & Cellular Biosci, Bunkyo Ku, Tokyo 1130032, Japan.
   [Sakaguchi, Yuriko; Suzuki, Tsutomu] Univ Tokyo, Grad Sch Engn, Dept Chem & Biotechnol, Bunkyo Ku, Tokyo 1130033, Japan.
   [Tadakuma, Hisashi; Tomari, Yukihide] Univ Tokyo, Dept Med Genome Sci, Grad Sch Frontier Sci, Bunkyo Ku, Tokyo 1130032, Japan.
C3 University of Tokyo; University of Tokyo; University of Tokyo
RP Tomari, Y (corresponding author), Univ Tokyo, Inst Mol & Cellular Biosci, Bunkyo Ku, Tokyo 1130032, Japan.
EM tadakuma@k.u-tokyo.ac.jp; tomari@iam.u-tokyo.ac.jp
FU Ministry of Education, Culture, Sports, Science and Technology in Japan; Grants-in-Aid for Scientific Research [24687018, 26113003, 25620125, 24657115, 26113007, 26650047, 26220205, 26113001] Funding Source: KAKEN
NR 42
TC 104
Z9 122
U1 1
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 MAY 28
PY 2015
VL 521
IS 7553
BP 533
EP U274
DI 10.1038/nature14254
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ2AN
UT WOS:000355286600046
PM 25822791
DA 2026-03-09
ER

PT J
AU Bond, M
   Tejedor, MF
   Campbell, KE
   Chornogubsky, L
   Novo, N
   Francisco, G
AF Bond, Mariano
   Tejedor, Marcelo F.
   Campbell, Kenneth E., Jr.
   Chornogubsky, Laura
   Novo, Nelson
   Francisco Goin
TI Eocene primates of South America and the African origins of New World monkeys
SO NATURE
LA English
DT Article
ID late middle eocene; evolution
AB The platyrrhine primates, or New World monkeys, are immigrant mammals whose fossil record comes from Tertiary and Quaternary sediments of South America and the Caribbean Greater Antilles(1,2). The time and place of platyrrhine origins are some of the most controversial issues in primate palaeontology, although an African Palaeogene ancestry has been presumed by most primatologists(3,4). Until now, the oldest fossil records of New World monkeys have come from Salla, Bolivia(5,6), and date to approximately 26 million years ago(7), or the Late Oligocene epoch. Here we report the discovery of new primates from the ? Late Eocene epoch of Amazonian Peru, which extends the fossil record of primates in South America back approximately 10 million years. The new specimens are important for understanding the origin and early evolution of modern platyrrhine primates because they bear little resemblance to any extinct or living South American primate, but they do bear striking resemblances to Eocene African anthropoids, and our phylogenetic analysis suggests a relationship with African taxa. The discovery of these new primates brings the first appearance datum of caviomorph rodents and primates in South America back into close correspondence, but raises new questions about the timing and means of arrival of these two mammalian groups.
C1 Consejo Nacl Invest Cient & Tecn, Museo Ciencias Nat La Plata, Div Paleontol Vertebrados, La Plata, Buenos Aires, Argentina.
   Consejo Nacl Invest Cient & Tecn, Ctr Nacl Patagon, RA-9120 Puerto Madryn, Chubut, Argentina.
   Fac Ciencias Nat, Sede Trelew, Argentina.
   Univ Nacl Patagonia San Juan Bosco, RA-9100 Trelew, Chubut, Argentina.
   Nat Hist Museum Los Angeles Cty, Vertebrate Zool, Los Angeles, CA 90007 USA.
   Consejo Nacl Invest Cient & Tecn, Museo Argentino Ciencias Nat Bernardino Rivadavia, Secc Paleontol Vertebrados, Buenos Aires, DF, Argentina.
   Univ Nacl Lujan, Dept Ciencias Basicas, RA-6700 Lujan, Buenos Aires, Argentina.
C3 National University of La Plata; Museo La Plata; Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); Centro Nacional Patagonico (CENPAT); Universidad Nacional de la Patagonia San Juan Bosco; Museo Argentino de Ciencias Naturales Bernardino Rivadavia (MACN); Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); Universidad Nacional de Lujan
RP Campbell, KE (corresponding author), Nat Hist Museum Los Angeles Cty, Vertebrate Zool, Los Angeles, CA 90007 USA.
EM kcampbell@nhm.org
FU National Geographic Society; National Science Foundation [DBI-0216506]
NR 27
TC 137
Z9 163
U1 2
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 23
PY 2015
VL 520
IS 7548
BP 538
EP +
DI 10.1038/nature14120
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500042
PM 25652825
DA 2026-03-09
ER

PT J
AU Kleinstiver, BP
   Prew, MS
   Tsai, SQ
   Topkar, VV
   Nguyen, NT
   Zheng, ZL
   Gonzales, APW
   Li, ZY
   Peterson, RT
   Yeh, JRJ
   Aryee, MJ
   Joung, JK
AF Kleinstiver, Benjamin P.
   Prew, Michelle S.
   Tsai, Shengdar Q.
   Topkar, Ved V.
   Nguyen, Nhu T.
   Zheng, Zongli
   Gonzales, Andrew P. W.
   Li, Zhuyun
   Peterson, Randall T.
   Yeh, Jing-Ruey Joanna
   Aryee, Martin J.
   Joung, J. Keith
TI Engineered CRISPR-Cas9 nucleases with altered PAM specificities
SO NATURE
LA English
DT Article
ID directed evolution; dual-rna; cas9; endonuclease; recognition; cleavage
AB Although CRISPR-Cas9 nucleases are widely used for genome editing(1,2), the range of sequences that Cas9 can recognize is constrained by the need for a specific protospacer adjacent motif (PAM)(3-6). As a result, it can often be difficult to target double-stranded breaks (DSBs) with the precision that is necessary for various genome-editing applications. The ability to engineer Cas9 derivatives with purposefully altered PAM specificities would address this limitation. Here we show that the commonly used Streptococcus pyogenes Cas9 (SpCas9) can be modified to recognize alternative PAM sequences using structural information, bacterial selection-based directed evolution, and combinatorial design. These altered PAM specificity variants enable robust editing of endogenous gene sites in zebrafish and human cells not currently targetable by wild-type SpCas9, and their genome-wide specificities are comparable to wild-type SpCas9 as judged by GUIDE-seq analysis(7). In addition, we identify and characterize another SpCas9 variant that exhibits improved specificity in human cells, possessing better discrimination against off-target sites with non-canonical NAG and NGAPAMs and/or mismatched spacers. We also find that two smaller-size Cas9 orthologues, Streptococcus thermophilus Cas9 (St1Cas9) and Staphylococcus aureus Cas9 (SaCas9), function efficiently in the bacterial selection systems and in human cells, suggesting that our engineering strategies could be extended to Cas9s from other species. Our findings provide broadly useful SpCas9 variants and, more importantly, establish the feasibility of engineering a wide range of Cas9s with altered and improved PAM specificities.
C1 [Kleinstiver, Benjamin P.; Prew, Michelle S.; Tsai, Shengdar Q.; Topkar, Ved V.; Nguyen, Nhu T.; Zheng, Zongli; Aryee, Martin J.; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA.
   [Kleinstiver, Benjamin P.; Prew, Michelle S.; Tsai, Shengdar Q.; Topkar, Ved V.; Nguyen, Nhu T.; Zheng, Zongli; Aryee, Martin J.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA.
   [Kleinstiver, Benjamin P.; Prew, Michelle S.; Tsai, Shengdar Q.; Topkar, Ved V.; Nguyen, Nhu T.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA 02129 USA.
   [Kleinstiver, Benjamin P.; Tsai, Shengdar Q.; Zheng, Zongli; Aryee, Martin J.; Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA.
   [Zheng, Zongli] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden.
   [Gonzales, Andrew P. W.; Li, Zhuyun; Peterson, Randall T.; Yeh, Jing-Ruey Joanna] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA.
   [Gonzales, Andrew P. W.; Peterson, Randall T.] Harvard Univ, Dept Syst Biol, Sch Med, Boston, MA 02115 USA.
   [Gonzales, Andrew P. W.; Peterson, Randall T.] Broad Inst, Cambridge, MA 02142 USA.
   [Yeh, Jing-Ruey Joanna] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.
   [Aryee, Martin J.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.
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 Medical School; Karolinska Institutet; 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 Medical School; Harvard University; Harvard T.H. Chan School of Public Health
RP Joung, JK (corresponding author), Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA.
EM jjoung@mgh.harvard.edu
FU National Institutes of Health (NIH) [DP1 GM105378]; NIH [R01 GM107427, R01 GM088040]; Jim and Ann Orr Research Scholar Award; National Sciences and Engineering Research Council of Canada
NR 36
TC 1323
Z9 1888
U1 17
U2 547
PU NATURE PUBLISHING 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 23
PY 2015
VL 523
IS 7561
BP 481
EP U249
DI 10.1038/nature14592
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN4DD
UT WOS:000358378900041
PM 26098369
DA 2026-03-09
ER

PT J
AU Liu, D
   Xu, HP
   Shih, CM
   Wan, ZR
   Ma, XP
   Ma, WW
   Luo, D
   Qi, H
AF Liu, Dan
   Xu, Heping
   Shih, Changming
   Wan, Zurong
   Ma, Xiaopeng
   Ma, Weiwei
   Luo, Dan
   Qi, Hai
TI T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction
SO NATURE
LA English
DT Article
ID follicular helper-cell; affinity maturation; memory; differentiation; activation; selection; effector; surface; ligand
AB The germinal centre(GC) reaction supports affinity-based B-cell competition and generates high-affinity bone-marrow plasma cells (BMPCs)(1,2). How follicular T-helper (T-FH) cells regulate GC selection is not clear(3,4). Using competitive mixed chimaera, we show here that, beyond the role in promoting T-FH development(5-7), ICOSL (inducible T-cell co-stimulator ligand, also known as ICOSLG) is important for individual B cells to competitively participate in the GC reaction and to develop into BMPCs. Using intravital imaging aided by a calcium reporter, we further show that ICOSL promotes an 'entangled' mode of T-FH-B-cell interactions, characterized by brief but extensive surface engagement, productive T-cell calcium spikes, and B-cell acquisition of CD40 signals. Reiterated entanglement promotes outer-zone co-localization of outcompeting GC B cells together with T-FH cells, affording the former increased access to T-cell help. ICOSL on GC B cells is upregulated by CD40 signals. Such an intercellular positive feedback between contact-dependent help and ICOSL-controlled entanglement promotes positive selection and BMPC development, as evidenced by observations that higher-affinity B-cell receptor variants are enriched in the ICOSLhigh fraction, that numerically disadvantaged ICOSL-deficient GC B cells or BMPCs exhibit strong affinity compensation in competitive chimaera, and that when GC competition proceeds without ICOSL, selection of high-affinity variants in otherwise normal GC reactions is impaired. By demonstrating entanglement as the basic form of GC T-FH-B-cell interactions, identifying ICOSL as a molecular linkage between T-B interactional dynamics and positive selection for high-affinity BMPC formation, our study reveals a pathway by which T-FH cells control the quality of long-lived humoral immunity.
C1 [Liu, Dan; Xu, Heping; Shih, Changming; Wan, Zurong; Ma, Weiwei; Luo, Dan; Qi, Hai] Tsinghua Univ, Sch Med, Lab Dynam Immunobiol, Tsinghua Peking Ctr Life Sci, Beijing 100084, Peoples R China.
   [Ma, Xiaopeng] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China.
C3 Tsinghua University; Tsinghua University
RP Qi, H (corresponding author), Tsinghua Univ, Sch Med, Lab Dynam Immunobiol, Tsinghua Peking Ctr Life Sci, Beijing 100084, Peoples R China.
EM qihai@tsinghua.edu.cn
FU Ministry of Science and Technology '973' program [2014CB542501]; National Natural Science Foundation of China [81330070, 81361120397]; Tsinghua University Initiative Scientific Research Program [20131089224]; Institut Merieux; Tsinghua-Peking Center for Life Sciences
NR 19
TC 332
Z9 410
U1 0
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 JAN 8
PY 2015
VL 517
IS 7533
BP 214
EP U241
DI 10.1038/nature13803
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600039
PM 25317561
DA 2026-03-09
ER

PT J
AU Yang, R
   Willett, SD
   Goren, L
AF Yang, Rong
   Willett, Sean D.
   Goren, Liran
TI In situ low-relief landscape formation as a result of river network disruption
SO NATURE
LA English
DT Article
ID surface uplift; stream-power; tibetan plateau; tectonics; evolution; deformation; constraints; growth; margin; east
AB Landscapes on Earth retain a record of the tectonic, environmental and climatic history under which they formed. Landscapes tend towards an equilibrium in which rivers attain a stable grade that balances the tectonic production of elevation and with hillslopes that attain a gradient steep enough to transport material to river channels. Equilibrium low-relief surfaces are typically found at low elevations, graded to sea level. However, there are many examples of high-elevation, low-relief surfaces, often referred to as relict landscapes(1,2), or as elevated peneplains(3). These do not grade to sea level and are typically interpreted as uplifted old landscapes, preserving former, more moderate tectonic conditions(4). Here we test this model of landscape evolution through digital topographic analysis of a set of purportedly relict landscapes on the southeastern margin of the Tibetan Plateau, one of the most geographically complex, climatically varied and biologically diverse regions of the world. We find that, in contrast to theory, the purported surfaces are not consistent with progressive establishment of a new, steeper, river grade, and therefore they cannot necessarily be interpreted as a remnant of an old, low relief surface. We propose an alternative model, supported by numerical experiments, in which tectonic deformation has disrupted the regional river network, leaving remnants of it isolated and starved of drainage area and thus unable to balance tectonic uplift. The implication is that the state of low relief with low erosion rate is developing in situ, rather than preserving past erosional conditions.
C1 [Yang, Rong; Willett, Sean D.] Swiss Fed Inst Technol, Geol Inst, CH-8092 Zurich, Switzerland.
   [Goren, Liran] Ben Gurion Univ Negev, Geol & Environm Sci, IL-84105 Beer Sheva, Israel.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich; Ben-Gurion University of the Negev
RP Yang, R (corresponding author), Swiss Fed Inst Technol, Geol Inst, CH-8092 Zurich, Switzerland.
EM rong.yang@erdw.ethz.ch
NR 33
TC 248
Z9 312
U1 3
U2 178
PU NATURE PUBLISHING 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 23
PY 2015
VL 520
IS 7548
BP 526
EP +
DI 10.1038/nature14354
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500039
PM 25903633
DA 2026-03-09
ER

PT J
AU Eirew, P
   Steif, A
   Khattra, J
   Ha, G
   Yap, D
   Farahani, H
   Gelmon, K
   Chia, S
   Mar, C
   Wan, A
   Laks, E
   Biele, J
   Shumansky, K
   Rosner, J
   McPherson, A
   Nielsen, C
   Roth, AJL
   Lefebvre, C
   Bashashati, A
   de Souza, C
   Siu, C
   Aniba, R
   Brimhall, J
   Oloumi, A
   Osako, T
   Bruna, A
   Sandoval, JL
   Algara, T
   Greenwood, W
   Leung, K
   Cheng, HW
   Xue, H
   Wang, YZ
   Lin, D
   Mungall, AJ
   Moore, R
   Zhao, YJ
   Lorette, J
   Nguyen, L
   Huntsman, D
   Eaves, CJ
   Hansen, C
   Marra, MA
   Caldas, C
   Shah, SP
   Aparicio, S
AF Eirew, Peter
   Steif, Adi
   Khattra, Jaswinder
   Ha, Gavin
   Yap, Damian
   Farahani, Hossein
   Gelmon, Karen
   Chia, Stephen
   Mar, Colin
   Wan, Adrian
   Laks, Emma
   Biele, Justina
   Shumansky, Karey
   Rosner, Jamie
   McPherson, Andrew
   Nielsen, Cydney
   Roth, Andrew J. L.
   Lefebvre, Calvin
   Bashashati, Ali
   de Souza, Camila
   Siu, Celia
   Aniba, Radhouane
   Brimhall, Jazmine
   Oloumi, Arusha
   Osako, Tomo
   Bruna, Alejandra
   Sandoval, Jose L.
   Algara, Teresa
   Greenwood, Wendy
   Leung, Kaston
   Cheng, Hongwei
   Xue, Hui
   Wang, Yuzhuo
   Lin, Dong
   Mungall, Andrew J.
   Moore, Richard
   Zhao, Yongjun
   Lorette, Julie
   Long Nguyen
   Huntsman, David
   Eaves, Connie J.
   Hansen, Carl
   Marra, Marco A.
   Caldas, Carlos
   Shah, Sohrab P.
   Aparicio, Samuel
TI Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution
SO NATURE
LA English
DT Article
ID evolution; metastasis; reveals
AB Human cancers, including breast cancers, comprise clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution(1,2), underpinning important emergent features such as drug resistance and metastasis(3-7). Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours(8-10). However, the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours have not been systematically examined at single-cell resolution. Here we show, using deep-genome and single-cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single-cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies using patient-derived breast cancer xenoengraftment.
C1 [Eirew, Peter; Steif, Adi; Khattra, Jaswinder; Ha, Gavin; Yap, Damian; Farahani, Hossein; Wan, Adrian; Laks, Emma; Biele, Justina; Shumansky, Karey; Rosner, Jamie; McPherson, Andrew; Nielsen, Cydney; Roth, Andrew J. L.; Lefebvre, Calvin; Bashashati, Ali; de Souza, Camila; Siu, Celia; Aniba, Radhouane; Brimhall, Jazmine; Oloumi, Arusha; Osako, Tomo; Algara, Teresa; Shah, Sohrab P.; Aparicio, Samuel] British Columbia Canc Agcy, Dept Mol Oncol, Vancouver, BC V5Z 1L3, Canada.
   [Eirew, Peter; Steif, Adi; Khattra, Jaswinder; Ha, Gavin; Yap, Damian; Farahani, Hossein; Laks, Emma; Biele, Justina; McPherson, Andrew; Nielsen, Cydney; Roth, Andrew J. L.; Lefebvre, Calvin; Bashashati, Ali; Aniba, Radhouane; Oloumi, Arusha; Osako, Tomo; Algara, Teresa; Huntsman, David; Shah, Sohrab P.; Aparicio, Samuel] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V6T 2B5, Canada.
   [Gelmon, Karen; Chia, Stephen; Mar, Colin] British Columbia Canc Agcy, Dept Med Oncol, Vancouver, BC V5Z 4E6, Canada.
   [Bruna, Alejandra; Sandoval, Jose L.; Greenwood, Wendy; Caldas, Carlos] Univ Cambridge, Dept Oncol, Cambridge CB2 2XZ, England.
   [Bruna, Alejandra; Sandoval, Jose L.; Greenwood, Wendy; Caldas, Carlos] Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Res Inst, Cambridge CB2 0RE, England.
   [Leung, Kaston; Hansen, Carl] Univ British Columbia, Ctr High Throughput Biol, Vancouver, BC V6T 1Z4, Canada.
   [Leung, Kaston; Hansen, Carl] Univ British Columbia, Dept Phys & Astron, Vancouver, BC V6T 1Z1, Canada.
   [Cheng, Hongwei; Xue, Hui; Wang, Yuzhuo; Lin, Dong] British Columbia Canc Agcy, Dept Expt Therapeut, Vancouver, BC V5Z 1L3, Canada.
   [Cheng, Hongwei; Xue, Hui; Wang, Yuzhuo; Lin, Dong] Vancouver Gen Hosp, Vancouver Prostate Ctr, Vancouver, BC V5Z 1M9, Canada.
   [Cheng, Hongwei; Xue, Hui; Wang, Yuzhuo; Lin, Dong] Univ British Columbia, Dept Urol Sci, Vancouver, BC V5Z 1M9, Canada.
   [Mungall, Andrew J.; Moore, Richard; Zhao, Yongjun; Marra, Marco A.; Shah, Sohrab P.; Aparicio, Samuel] Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada.
   [Lorette, Julie; Huntsman, David; Aparicio, Samuel] British Columbia Canc Agcy, Ctr Translat & Appl Genom, Vancouver, BC V5Z 4E6, Canada.
   [Long Nguyen; Eaves, Connie J.] Univ British Columbia, Dept Med Genet, Vancouver, BC V6T 1Z3, Canada.
   [Long Nguyen; Eaves, Connie J.] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada.
C3 British Columbia Cancer Agency; University of British Columbia; British Columbia Cancer Agency; University of Cambridge; University of Cambridge; CRUK Cambridge Institute; Cancer Research UK; University of British Columbia; University of British Columbia; British Columbia Cancer Agency; University of British Columbia; University of British Columbia; British Columbia Cancer Agency; University of British Columbia; British Columbia Cancer Agency
RP Aparicio, S (corresponding author), British Columbia Canc Agcy, Dept Mol Oncol, 675 West 10th Ave, Vancouver, BC V5Z 1L3, Canada.
EM sshah@bccrc.ca; saparicio@bccrc.ca
FU Canada Research Chairs; Michael Smith Foundation for Health Research (MSFHR) Fellowship; NSERC CREATE scholarship through the graduate program in Genome Science and Technology at UBC; BC Cancer Foundation; Canadian Breast Cancer Foundation; Canadian Cancer Society Research Institute; Terry Fox Research Institute; Genome Canada; Canadian Institutes for Health Research (CIHR); Cancer Research UK [16942] Funding Source: researchfish; National Institute for Health Research [NF-SI-0611-10154] Funding Source: researchfish
NR 24
TC 501
Z9 580
U1 0
U2 105
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 19
PY 2015
VL 518
IS 7539
BP 422
EP 426
DI 10.1038/nature13952
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400047
PM 25470049
DA 2026-03-09
ER

PT J
AU Mullins, EA
   Shi, RX
   Parsons, ZD
   Yuen, PK
   David, SS
   Igarashi, Y
   Eichman, BF
AF Mullins, Elwood A.
   Shi, Rongxin
   Parsons, Zachary D.
   Yuen, Philip K.
   David, Sheila S.
   Igarashi, Yasuhiro
   Eichman, Brandt F.
TI The DNA glycosylase AlkD uses a non-base-flipping mechanism to excise bulky lesions
SO NATURE
LA English
DT Article
ID damage recognition; pi-interactions; alkylated dna; repair; enzyme; superfamily; yatakemycin; resistance; chemistry; contacts
AB Threats to genomic integrity arising from DNA damage are mitigated by DNA glycosylases, which initiate the base excision repair pathway by locating and excising aberrant nucleobases(1,2). How these enzymes find small modifications within the genome is a current area of intensive research. A hallmark of these and other DNA repair enzymes is their use of base flipping to sequester modified nucleotides from the DNA helix and into an active site pocket(2-5). Consequently, base flipping is generally regarded as an essential aspect of lesion recognition and a necessary precursor to base excision. Here we present the first, to our knowledge, DNA glycosylase mechanism that does not require base flipping for either binding or catalysis. Using the DNA glycosylase AlkD from Bacillus cereus, we crystallographically monitored excision of an alkylpurine substrate as a function of time, and reconstructed the steps along the reaction coordinate through structures representing substrate, intermediate and product complexes. Instead of directly interacting with the damaged nucleobase, AlkD recognizes aberrant base pairs through interactions with the phosphoribose backbone, while the lesion remains stacked in the DNA duplex. Quantum mechanical calculations revealed that these contacts include catalytic charge-dipole and CH-p interactions that preferentially stabilize the transition state. We show in vitro and in vivo how this unique means of recognition and catalysis enables AlkD to repair large adducts formed by yatakemycin, a member of the duocarmycin family of antimicrobial natural products exploited in bacterial warfare and chemotherapeutic trials(6,7). Bulky adducts of this or any type are not excised by DNA glycosylases that use a traditional base-flipping mechanism(5). Hence, these findings represent a new model for DNA repair and provide insights into catalysis of base excision.
C1 [Mullins, Elwood A.; Shi, Rongxin; Parsons, Zachary D.; Eichman, Brandt F.] Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37232 USA.
   [Mullins, Elwood A.; Shi, Rongxin; Parsons, Zachary D.; Eichman, Brandt F.] Vanderbilt Univ, Ctr Struct Biol, Nashville, TN 37232 USA.
   [Yuen, Philip K.; David, Sheila S.] Univ Calif Davis, Dept Chem, Davis, CA 95616 USA.
   [Igarashi, Yasuhiro] Toyama Prefectural Univ, Biotechnol Res Ctr, Toyama 9390398, Japan.
C3 Vanderbilt University; Vanderbilt University; University of California System; University of California Davis; Toyama Prefectural University
RP Eichman, BF (corresponding author), Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37232 USA.
EM brandt.eichman@vanderbilt.edu
FU National Science Foundation [MCB-1122098, MCB-1517695]; National Institutes of Health [R01ES019625, R01CA067985, S10RR026915]; US Department of Energy [DE-AC02-06CH11357]; Vanderbilt Training Program in Environmental Toxicology [T32ES07028]; Div Of Molecular and Cellular Bioscience; Direct For Biological Sciences [1122098, 1517695] Funding Source: National Science Foundation; National Cancer Institute [R01CA067985] Funding Source: NIH RePORTER; National Institute of Environmental Health Sciences [T32ES007028] Funding Source: NIH RePORTER
NR 56
TC 52
Z9 67
U1 0
U2 50
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 12
PY 2015
VL 527
IS 7577
BP 254
EP +
DI 10.1038/nature15728
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700049
PM 26524531
DA 2026-03-09
ER

PT J
AU Horton, DE
   Johnson, NC
   Singh, D
   Swain, DL
   Rajaratnam, B
   Diffenbaugh, NS
AF Horton, Daniel E.
   Johnson, Nathaniel C.
   Singh, Deepti
   Swain, Daniel L.
   Rajaratnam, Bala
   Diffenbaugh, Noah S.
TI Contribution of changes in atmospheric circulation patterns to extreme temperature trends
SO NATURE
LA English
DT Article
ID arctic sea-ice; planetary-waves; amplification; climate; uncertainty; winters
AB Surface weather conditions are closely governed by the large-scale circulation of the Earth's atmosphere. Recent increases in the occurrence of some extreme weather phenomena(1,2) have led to multiple mechanistic hypotheses linking changes in atmospheric circulation to increasing probability of extreme events(3-5). However, observed evidence of long-term change in atmospheric circulation remains inconclusive(6-8). Here we identify statistically significant trends in the occurrence of atmospheric circulation patterns, which partially explain observed trends in surface temperature extremes over seven mid-latitude regions of the Northern Hemisphere. Using self-organizing map cluster analysis(9-12), we detect robust circulation pattern trends in a subset of these regions during both the satellite observation era (1979-2013) and the recent period of rapid Arctic sea-ice decline (1990-2013). Particularly substantial influences include the contribution of increasing trends in anticyclonic circulations to summer and autumn hot extremes over portions of Eurasia and North America, and the contribution of increasing trends in northerly flow to winter cold extremes over central Asia. Our results indicate that although a substantial portion of the observed change in extreme temperature occurrence has resulted from regional-and global-scale thermodynamic changes, the risk of extreme temperatures over some regions has also been altered by recent changes in the frequency, persistence and maximum duration of regional circulation patterns.
C1 [Horton, Daniel E.; Singh, Deepti; Swain, Daniel L.; Rajaratnam, Bala; Diffenbaugh, Noah S.] Stanford Univ, Dept Earth Syst Sci, Stanford, CA 94305 USA.
   [Horton, Daniel E.; Rajaratnam, Bala; Diffenbaugh, Noah S.] Stanford Univ, Woods Inst Environm, Stanford, CA 94305 USA.
   [Johnson, Nathaniel C.] Univ Hawaii Manoa, Int Pacific Res Ctr, Honolulu, HI 96822 USA.
   [Johnson, Nathaniel C.] Univ Calif San Diego, Scripps Inst Oceanog, La Jolla, CA 92093 USA.
   [Johnson, Nathaniel C.] Princeton Univ, Cooperat Inst Climate Sci, Princeton, NJ 08540 USA.
   [Rajaratnam, Bala] Stanford Univ, Dept Stat, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; University of Hawaii System; University of Hawaii Manoa; University of California System; University of California San Diego; Scripps Institution of Oceanography; Princeton University; Stanford University
RP Horton, DE (corresponding author), Stanford Univ, Dept Earth Syst Sci, Stanford, CA 94305 USA.
EM danethan@stanford.edu
FU NSF CAREER Award [0955283]; DOE Integrated Assessment Research Program [DE-SC005171DE-SC005171]; G.J. Lieberman Fellowship; NOAA [NA14OAR4310189]; US Air Force Office of Scientific Research [FA9550-13-1-0043]; US National Science Foundation [DMS-0906392, DMS-CMG-1025465, AGS-1003823, DMS-1106642, DMS-CAREER-1352656]; Defense Advanced Research Projects Agency [DARPA YFA N66001-111-4131]; UPS Foundation (SMC-DBNKY); Directorate For Geosciences; Div Atmospheric & Geospace Sciences [0955283, 1003823] Funding Source: National Science Foundation
NR 42
TC 561
Z9 626
U1 19
U2 418
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 25
PY 2015
VL 522
IS 7557
BP 465
EP +
DI 10.1038/nature14550
PG 25
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL2OC
UT WOS:000356782900047
PM 26108856
DA 2026-03-09
ER

PT J
AU Becker, TW
   Lowry, AR
   Faccenna, C
   Schmandt, B
   Borsa, A
   Yu, CQ
AF Becker, Thorsten W.
   Lowry, Anthony R.
   Faccenna, Claudio
   Schmandt, Brandon
   Borsa, Adrian
   Yu, Chunquan
TI Western US intermountain seismicity caused by changes in upper mantle flow
SO NATURE
LA English
DT Article
ID dynamic topography; united-states; travel-times; lithosphere; crustal; convection; apennines; elevation; viscosity; support
AB Understanding the causes of intraplate earthquakes is challenging, as it requires extending plate tectonic theory to the dynamics of continental deformation. Seismicity in the western United States away from the plate boundary is clustered along a meandering, north-south trending 'intermountain' belt(1). This zone coincides with a transition from thin, actively deforming to thicker, less tectonically active crust and lithosphere. Although such structural gradients have been invoked to explain seismicity localization(2,3), the underlying cause of seismicity remains unclear. Here we show results fromimproved mantle flowmodels that reveal a relationship between seismicity and the rate change of 'dynamic topography' (that is, vertical normal stress from mantle flow). The associated predictive skill is greater than that of any of the other forcings we examined. Wesuggest that active mantle flow is amajor contributor to seismogenic intraplate deformation, while gravitational potential energy variations have a minor role. Seismicity localization should occur where convective changes in vertical normal stress are modulated by lithospheric strength heterogeneities. Our results on deformation processes appear consistent with findings from other mobile belts(4), and imply that mantle flow plays a significant and quantifiable part in shaping topography, tectonics, and seismic hazard within intraplate settings.
C1 [Becker, Thorsten W.] Univ So Calif, Dept Earth Sci, Los Angeles, CA 90089 USA.
   [Lowry, Anthony R.] Utah State Univ, Dept Geol, Logan, UT 84322 USA.
   [Faccenna, Claudio] Univ Roma Tre, Dept Sci, I-00146 Rome, Italy.
   [Schmandt, Brandon] Univ New Mexico, Dept Earth & Planetary Sci, Albuquerque, NM 87131 USA.
   [Borsa, Adrian] Univ Calif San Diego, Scripps Inst Oceanog, La Jolla, CA 92093 USA.
   [Yu, Chunquan] MIT, Dept Earth Atmospher & Planetary Sci, Cambridge, MA 02139 USA.
C3 University of Southern California; Utah System of Higher Education; Utah State University; Italfarmaco; Roma Tre University; University of New Mexico; University of California System; University of California San Diego; Scripps Institution of Oceanography; Massachusetts Institute of Technology (MIT)
RP Becker, TW (corresponding author), Univ So Calif, Dept Earth Sci, Los Angeles, CA 90089 USA.
EM twb@usc.edu
FU National Science Foundation (NSF) [EAR-0350028, EAR-0732947]; NSF/US Geological Survey Southern California Earthquake Center;  [EAR-1215720]; [EAR-1215757];  [EAR-0955909];  [EAR-1358622]; Directorate For Geosciences; Division Of Earth Sciences [0955909, 1261833] Funding Source: National Science Foundation; Directorate For Geosciences; Division Of Earth Sciences [1460479, 1358622] Funding Source: National Science Foundation
NR 49
TC 51
Z9 62
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 27
PY 2015
VL 524
IS 7566
BP 458
EP +
DI 10.1038/nature14867
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP7LN
UT WOS:000360069300036
PM 26310767
DA 2026-03-09
ER

PT J
AU Osswald, M
   Jung, E
   Sahm, F
   Solecki, G
   Venkataramani, V
   Blaes, J
   Weil, S
   Horstmann, H
   Wiestler, B
   Syed, M
   Huang, LL
   Ratliff, M
   Jazi, KK
   Kurz, FT
   Schmenger, T
   Lemke, D
   Gömmel, M
   Pauli, M
   Liao, YX
   Häring, P
   Pusch, S
   Herl, V
   Steinhäuser, C
   Krunic, D
   Jarahian, M
   Miletic, H
   Berghoff, AS
   Griesbeck, O
   Kalamakis, G
   Garaschuk, O
   Preusser, M
   Weiss, S
   Liu, HK
   Heiland, S
   Platten, M
   Huber, PE
   Kuner, T
   von Deimling, A
   Wick, W
   Winkler, F
AF Osswald, Matthias
   Jung, Erik
   Sahm, Felix
   Solecki, Gergely
   Venkataramani, Varun
   Blaes, Jonas
   Weil, Sophie
   Horstmann, Heinz
   Wiestler, Benedikt
   Syed, Mustafa
   Huang, Lulu
   Ratliff, Miriam
   Jazi, Kianush Karimian
   Kurz, Felix T.
   Schmenger, Torsten
   Lemke, Dieter
   Goemmel, Miriam
   Pauli, Martin
   Liao, Yunxiang
   Haering, Peter
   Pusch, Stefan
   Herl, Verena
   Steinhaeuser, Christian
   Krunic, Damir
   Jarahian, Mostafa
   Miletic, Hrvoje
   Berghoff, Anna S.
   Griesbeck, Oliver
   Kalamakis, Georgios
   Garaschuk, Olga
   Preusser, Matthias
   Weiss, Samuel
   Liu, Haikun
   Heiland, Sabine
   Platten, Michael
   Huber, Peter E.
   Kuner, Thomas
   von Deimling, Andreas
   Wick, Wolfgang
   Winkler, Frank
TI Brain tumour cells interconnect to a functional and resistant network
SO NATURE
LA English
DT Article
ID calcium waves; self-renewal; stem-cells; growth; glioma; astrocytes; nanotubes; gap-43; cancer; trk
AB Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.
C1 [Osswald, Matthias; Jung, Erik; Solecki, Gergely; Blaes, Jonas; Weil, Sophie; Wiestler, Benedikt; Syed, Mustafa; Huang, Lulu; Jazi, Kianush Karimian; Schmenger, Torsten; Lemke, Dieter; Goemmel, Miriam; Liao, Yunxiang; Platten, Michael; Wick, Wolfgang; Winkler, Frank] Univ Heidelberg Hosp, Neurol Clin, D-69120 Heidelberg, Germany.
   [Osswald, Matthias; Jung, Erik; Solecki, Gergely; Blaes, Jonas; Weil, Sophie; Wiestler, Benedikt; Syed, Mustafa; Huang, Lulu; Jazi, Kianush Karimian; Schmenger, Torsten; Lemke, Dieter; Goemmel, Miriam; Liao, Yunxiang; Platten, Michael; Wick, Wolfgang; Winkler, Frank] Univ Heidelberg Hosp, Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany.
   [Osswald, Matthias; Jung, Erik; Solecki, Gergely; Blaes, Jonas; Weil, Sophie; Wiestler, Benedikt; Syed, Mustafa; Huang, Lulu; Ratliff, Miriam; Jazi, Kianush Karimian; Schmenger, Torsten; Lemke, Dieter; Goemmel, Miriam; Liao, Yunxiang; Wick, Wolfgang; Winkler, Frank] German Canc Res Ctr, Clin Cooperat Unit Neurooncol, German Canc Consortium DKTK, D-69120 Heidelberg, Germany.
   [Sahm, Felix; Pusch, Stefan; von Deimling, Andreas] Heidelberg Univ, Inst Pathol, Dept Neuropathol, D-69120 Heidelberg, Germany.
   [Sahm, Felix; Pusch, Stefan; von Deimling, Andreas] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, German Canc Consortium DKTK, D-69120 Heidelberg, Germany.
   [Venkataramani, Varun; Horstmann, Heinz; Kuner, Thomas] Heidelberg Univ, Inst Anat & Cell Biol, Dept Funct Neuroanat, D-69120 Heidelberg, Germany.
   [Wiestler, Benedikt] Tech Univ Munich, Klinikum Rechts Isar, Dept Diagnost & Intervent Neuroradiol, D-81675 Munich, Germany.
   [Ratliff, Miriam] Univ Heidelberg Hosp, Neurosurg Clin, D-69120 Heidelberg, Germany.
   [Kurz, Felix T.; Heiland, Sabine] Univ Heidelberg Hosp, Dept Neuroradiol, D-69120 Heidelberg, Germany.
   [Pauli, Martin] Univ Wurzburg, Inst Physiol, Dept Neurophysiol, D-97070 Wurzburg, Germany.
   [Haering, Peter] German Canc Res Ctr, Dept Med Phys, D-69120 Heidelberg, Germany.
   [Herl, Verena; Steinhaeuser, Christian] Univ Bonn, Inst Cellular Neurosci, Fac Med, D-53105 Bonn, Germany.
   [Krunic, Damir] German Canc Res Ctr, Light Microscopy Facil, D-69120 Heidelberg, Germany.
   [Jarahian, Mostafa] German Canc Res Ctr, Dept Translat Immunol, D-69120 Heidelberg, Germany.
   [Miletic, Hrvoje] Univ Bergen, Dept Biomed, N-5009 Bergen, Norway.
   [Berghoff, Anna S.] Med Univ Vienna, Inst Neurol, Vienna, Austria.
   [Berghoff, Anna S.; Preusser, Matthias] Med Univ Vienna, CNS Unit, Ctr Comprehens Canc, A-1090 Vienna, Austria.
   [Griesbeck, Oliver] Max Planck Inst Neurobiol, Tools Bioimaging, D-82152 Martinsried, Germany.
   [Kalamakis, Georgios; Garaschuk, Olga] Univ Tubingen, Inst Physiol 2, D-72074 Tubingen, Germany.
   [Preusser, Matthias] Med Univ Vienna, Dept Med 1, Vienna, Austria.
   [Weiss, Samuel] Univ Calgary, Fac Med, Hotchkiss Brain Inst, Calgary, AB T2N 4N1, Canada.
   [Weiss, Samuel] Univ Calgary, Fac Med, Dept Cell Biol & Anat, Calgary, AB T2N 4Z6, Canada.
   [Weiss, Samuel] Univ Calgary, Fac Med, Southern Alberta Canc Res Inst, Clark Smith Brain Tumor Res Ctr, Calgary, AB T2N 4N1, Canada.
   [Liu, Haikun] German Canc Res Ctr, DKFZ ZMBH Alliance, Normal & Neoplast CNS Stem Cells, Helmholtz Young Investigator Grp, D-69120 Heidelberg, Germany.
   [Platten, Michael] German Canc Res Ctr, German Canc Consortium DKTK, Clin Cooperat Unit Neuroimmunol & Brain Tumor Imm, D-69120 Heidelberg, Germany.
   [Huber, Peter E.] German Canc Res Ctr, CCU Mol & Radiat Oncol, D-69120 Heidelberg, Germany.
   [Huber, Peter E.] Univ Heidelberg Hosp, Dept Radiat Oncol, D-69120 Heidelberg, Germany.
C3 Ruprecht Karls University Heidelberg; Helmholtz Association; German Cancer Research Center (DKFZ); Ruprecht Karls University Heidelberg; National Center for Tumor Diseases; Helmholtz Association; German Cancer Research Center (DKFZ); Ruprecht Karls University Heidelberg; Helmholtz Association; German Cancer Research Center (DKFZ); Ruprecht Karls University Heidelberg; Technical University of Munich; Ruprecht Karls University Heidelberg; Ruprecht Karls University Heidelberg; University of Wurzburg; Helmholtz Association; German Cancer Research Center (DKFZ); University of Bonn; Helmholtz Association; German Cancer Research Center (DKFZ); Helmholtz Association; German Cancer Research Center (DKFZ); University of Bergen; Medical University of Vienna; Medical University of Vienna; Max Planck Society; Eberhard Karls University of Tubingen; Medical University of Vienna; University of Calgary; University of Calgary; University of Calgary; Helmholtz Association; German Cancer Research Center (DKFZ); Helmholtz Association; German Cancer Research Center (DKFZ); Helmholtz Association; German Cancer Research Center (DKFZ); Ruprecht Karls University Heidelberg
RP Winkler, F (corresponding author), Univ Heidelberg Hosp, Neurol Clin, INF 400, D-69120 Heidelberg, Germany.
EM frank.winkler@med.uni-heidelberg.de
FU German Research Foundation (DFG) [WI 1930/5-1]; Major Equipment Grant INST [114089/26-1 FUGG]; DKFZ; Heinrich F.C. Behr-Stipend
NR 64
TC 843
Z9 949
U1 10
U2 194
PU NATURE PUBLISHING 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 3
PY 2015
VL 528
IS 7580
BP 93
EP +
DI 10.1038/nature16071
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000054
PM 26536111
DA 2026-03-09
ER

PT J
AU Sperling, EA
   Wolock, CJ
   Morgan, AS
   Gill, BC
   Kunzmann, M
   Halverson, GP
   Macdonald, FA
   Knoll, AH
   Johnston, DT
AF Sperling, Erik A.
   Wolock, Charles J.
   Morgan, Alex S.
   Gill, Benjamin C.
   Kunzmann, Marcus
   Halverson, Galen P.
   Macdonald, Francis A.
   Knoll, Andrew H.
   Johnston, David T.
TI Statistical analysis of iron geochemical data suggests limited late Proterozoic oxygenation
SO NATURE
LA English
DT Article
ID ferruginous conditions; ocean oxygenation; new-model; rise; redox; eukaryotes; sulfide; sulfate; anoxia
AB Sedimentary rocks deposited across the Proterozoic-Phanerozoic transition record extreme climate fluctuations, a potential rise in atmospheric oxygen or re-organization of the seafloor redox landscape, and the initial diversification of animals(1,2). It is widely assumed that the inferred redox change facilitated the observed trends in biodiversity. Establishing this palaeoenvironmental context, however, requires that changes in marine redox structure be tracked by means of geochemical proxies and translated into estimates of atmospheric oxygen. Iron-based proxies are among the most effective tools for tracking the redox chemistry of ancient oceans(3,4). These proxies are inherently local, but have global implications when analysed collectively and statistically. Here we analyse about 4,700 iron-speciation measurements from shales 2,300 to 360 million years old. Our statistical analyses suggest that subsurface water masses in mid-Proterozoic oceans were predominantly anoxic and ferruginous (depleted in dissolved oxygen and iron-bearing), but with a tendency towards euxinia (sulfide-bearing) that is not observed in the Neoproterozoic era. Analyses further indicate that early animals did not experience appreciable benthic sulfide stress. Finally, unlike proxies based on redox-sensitive trace-metal abundances(1,5,6), iron geochemical data do not show a statistically significant change in oxygen content through the Ediacaran and Cambrian periods, sharply constraining the magnitude of the end-Proterozoic oxygen increase. Indeed, this re-analysis of trace-metal data is consistent with oxygenation continuing well into the Palaeozoic era. Therefore, if changing redox conditions facilitated animal diversification, it did so through a limited rise in oxygen past critical functional and ecological thresholds, as is seen in modern oxygen minimum zone benthic animal communities(7-9).
C1 [Sperling, Erik A.; Morgan, Alex S.; Macdonald, Francis A.; Knoll, Andrew H.; Johnston, David T.] Harvard Univ, Dept Earth & Planetary Sci, Cambridge, MA 02138 USA.
   [Sperling, Erik A.] Scripps Inst Oceanog, Integrat Oceanog Div, La Jolla, CA 90089 USA.
   [Wolock, Charles J.] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA.
   [Gill, Benjamin C.] Virginia Polytech Inst & State Univ, Dept Geosci, Blacksburg, VA 24061 USA.
   [Kunzmann, Marcus; Halverson, Galen P.] McGill Univ, Dept Earth & Planetary Sci, GEOTOP, Montreal, PQ H3A 0E8, Canada.
C3 Harvard University; University of California System; University of California San Diego; Scripps Institution of Oceanography; Harvard University; Virginia Polytechnic Institute & State University; McGill University
RP Sperling, EA (corresponding author), Stanford Univ, Dept Geol & Environm Sci, Stanford, CA 94305 USA.
EM esper@stanford.edu; johnston@eps.harvard.edu
FU Agouron Geobiology Fellowship; NAI Postdoctoral Fellowship; NSF-EAR [1324095]; NASA Astrobiology Institute; Directorate For Geosciences; Division Of Earth Sciences [1324095] Funding Source: National Science Foundation
NR 33
TC 551
Z9 622
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 JUL 23
PY 2015
VL 523
IS 7561
BP 451
EP 454
DI 10.1038/nature14589
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN4DD
UT WOS:000358378900034
PM 26201598
DA 2026-03-09
ER

PT J
AU Tan, TR
   Gaebler, JP
   Lin, Y
   Wan, Y
   Bowler, R
   Leibfried, D
   Wineland, DJ
AF Tan, T. R.
   Gaebler, J. P.
   Lin, Y.
   Wan, Y.
   Bowler, R.
   Leibfried, D.
   Wineland, D. J.
TI Multi-element logic gates for trapped-ion qubits
SO NATURE
LA English
DT Article
ID quantum; state
AB Precision control over hybrid physical systems at the quantum level is important for the realization of many quantum-based technologies. In the field of quantum information processing (QIP) and quantum networking, various proposals discuss the possibility of hybrid architectures(1) where specific tasks are delegated to the most suitable subsystem. For example, in quantum networks, it may be advantageous to transfer information from a subsystem that has good memory properties to another subsystem that is more efficient at transporting information between nodes in the network. For trapped ions, a hybrid system formed of different species introduces extra degrees of freedom that can be exploited to expand and refine the control of the system. Ions of different elements have previously been used in QIP experiments for sympathetic cooling(2), creation of entanglement through dissipation(3), and quantum non-demolition measurement of one species with another(4). Here we demonstrate an entangling quantum gate between ions of different elements which can serve as an important building block of QIP, quantum networking, precision spectroscopy, metrology, and quantum simulation. A geometric phase gate between a Be-9(+) ion and a Mg-25(+) ion is realized through an effective spin-spin interaction generated by state-dependent forces induced with laser beams(5-9). Combined with single-qubit gates and same-species entangling gates, this mixed-element entangling gate provides a complete set of gates over such a hybrid system for universal QIP(10-12). Using a sequence of such gates, we demonstrate a CNOT (controlled-NOT) gate and a SWAP gate(13). We further demonstrate the robustness of these gates against thermal excitation and show improved detection in quantum logic spectroscopy(14). We also observe a strong violation of a CHSH (Clauser-Horne-Shimony-Holt)-type Bell inequality(15) on entangled states composed of different ion species.
C1 [Tan, T. R.; Gaebler, J. P.; Lin, Y.; Wan, Y.; Bowler, R.; Leibfried, D.; Wineland, D. J.] NIST, Boulder, CO 80305 USA.
C3 National Institute of Standards & Technology (NIST) - USA
RP Tan, TR (corresponding author), NIST, 325 Broadway, Boulder, CO 80305 USA.
EM tingrei.tan@nist.gov
FU Office of the Director of National Intelligence (ODNI) Intelligence Advanced Research Projects Activity (IARPA), ONR; NIST Quantum Information Program; US Army Research Office through MURI grant [W911NF-11-1-0400]
NR 31
TC 142
Z9 168
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 DEC 17
PY 2015
VL 528
IS 7582
BP 380
EP +
DI 10.1038/nature16186
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CY8SM
UT WOS:000366678600048
PM 26672553
DA 2026-03-09
ER

PT J
AU Acar, M
   Kocherlakota, KS
   Murphy, MM
   Peyer, JG
   Oguro, H
   Inra, CN
   Jaiyeola, C
   Zhao, ZY
   Luby-Phelps, K
   Morrison, SJ
AF Acar, Melih
   Kocherlakota, Kiranmai S.
   Murphy, Malea M.
   Peyer, James G.
   Oguro, Hideyuki
   Inra, Christopher N.
   Jaiyeola, Christabel
   Zhao, Zhiyu
   Luby-Phelps, Katherine
   Morrison, Sean J.
TI Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal
SO NATURE
LA English
DT Article
ID hematopoietic stem; endothelial-cells; progenitor cells; mouse-brain; niche; maintenance; microenvironment; sinusoids; mice
AB Haematopoietic stem cells (HSCs) reside in a perivascular niche but the specific location of this niche remains controversial(1). HSCs are rare and few can be found in thin tissue sections(2,3) or upon live imaging(4), making it difficult to comprehensively localize dividing and non-dividing HSCs. Here, using a green fluorescent protein (GFP) knock-in for the gene Ctnnal1 in mice (hereafter denoted as alpha-catulin(GFP)), we discover that alpha-catulin(GFP) is expressed by only 0.02% of bone marrow haematopoietic cells, including almost all HSCs. We find that approximately 30% of alpha-catulin-GFP(+)c-kit(+) cells give long-term multilineage reconstitution of irradiated mice, indicating that alpha-catulin-GFP(+)c-kit(+) cells are comparable in HSC purity to cells obtained using the best markers currently available. We optically cleared the bone marrow to perform deep confocal imaging, allowing us to image thousands of alpha-catulin-GFP(+)c-kit(+) cells and to digitally reconstruct large segments of bone marrow. The distribution of alpha-catulin-GFP(+)c-kit(+) cells indicated that HSCs were more common in central marrow than near bone surfaces, and in the diaphysis relative to the metaphysis. Nearly all HSCs contacted leptin receptor positive (Lepr(+)) and Cxcl12(high) niche cells, and approximately 85% of HSCs were within 10 mm of a sinusoidal blood vessel. Most HSCs, both dividing (Ki-67(+)) and non-dividing (Ki-67(-)), were distant from arterioles, transition zone vessels, and bone surfaces. Dividing and non-dividing HSCs thus reside mainly in perisinusoidal niches with Lepr(+)Cxcl12(high) cells throughout the bone marrow.
C1 [Kocherlakota, Kiranmai S.; Morrison, Sean J.] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA.
   [Acar, Melih; Kocherlakota, Kiranmai S.; Murphy, Malea M.; Peyer, James G.; Oguro, Hideyuki; Inra, Christopher N.; Jaiyeola, Christabel; Zhao, Zhiyu; Morrison, Sean J.] Univ Texas SW Med Ctr Dallas, Childrens Res Inst, Dallas, TX 75390 USA.
   [Acar, Melih; Kocherlakota, Kiranmai S.; Murphy, Malea M.; Peyer, James G.; Oguro, Hideyuki; Inra, Christopher N.; Jaiyeola, Christabel; Zhao, Zhiyu; Morrison, Sean J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA.
   [Luby-Phelps, Katherine] Univ Texas SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA.
C3 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 Morrison, SJ (corresponding author), Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA.
EM sean.morrison@utsouthwestern.edu
FU National Research Service Award from NIH; NIH NHLBI [HL097760]; NIH Shared Instrumentation grant [NIH S10RR029731]; National Cancer Institute [P30CA142543] Funding Source: NIH RePORTER
NR 46
TC 545
Z9 644
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 OCT 1
PY 2015
VL 526
IS 7571
BP 126
EP +
DI 10.1038/nature15250
PG 26
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS5CY
UT WOS:000362095100047
PM 26416744
DA 2026-03-09
ER

PT J
AU Wu, XB
   Wang, FG
   Fan, XH
   Yi, WM
   Zuo, WW
   Bian, FY
   Jiang, LH
   McGreer, ID
   Wang, R
   Yang, JY
   Yang, Q
   Thompson, D
   Beletsky, Y
AF Wu, Xue-Bing
   Wang, Feige
   Fan, Xiaohui
   Yi, Weimin
   Zuo, Wenwen
   Bian, Fuyan
   Jiang, Linhua
   McGreer, Ian D.
   Wang, Ran
   Yang, Jinyi
   Yang, Qian
   Thompson, David
   Beletsky, Yuri
TI An ultraluminous quasar with a twelve-billion-solar-mass black hole at redshift 6.30
SO NATURE
LA English
DT Article
ID digital sky survey; z-similar-to-6 quasars; luminosity function; data release; evolution; discovery; emission; masses; sample
AB So far, roughly 40 quasars with redshifts greater than z = 6 have been discovered(1-8). Each quasar contains a black hole with a mass of about one billion solar masses (10(9) M-circle dot)(2,6,7,9-13). The existence of such black holes when the Universe was less than one billion years old presents substantial challenges to theories of the formation and growth of black holes and the coevolution of black holes and galaxies(14). Here we report the discovery of an ultraluminous quasar, SDSS J010013.02+280225.8, at redshift z = 6.30. It has an optical and near-infrared luminosity a few times greater than those of previously known z > 6 quasars. On the basis of the deep absorption trough(15) on the blue side of the Lyman-alpha emission line in the spectrum, we estimate the proper size of the ionized proximity zone associated with the quasar to be about 26 million light years, larger than found with other z > 6.1 quasars with lower luminosities(16). We estimate (on the basis of a near-infrared spectrum) that the black hole has a mass of similar to 1.2 x 10(10) M-circle dot, which is consistent with the 1.3 x 10(10) M-circle dot derived by assuming an Eddington-limited accretion rate.
C1 [Wu, Xue-Bing; Wang, Feige; Yang, Jinyi; Yang, Qian] Peking Univ, Sch Phys, Dept Astron, Beijing 100871, Peoples R China.
   [Wu, Xue-Bing; Wang, Feige; Fan, Xiaohui; Jiang, Linhua; Wang, Ran; Yang, Jinyi; Yang, Qian] Peking Univ, Kavli Inst Astron & Astrophys, Beijing 100871, Peoples R China.
   [Fan, Xiaohui; McGreer, Ian D.] Univ Arizona, Steward Observ, Tucson, AZ 85721 USA.
   [Yi, Weimin] Chinese Acad Sci, Yunnan Observ, Kunming 650011, Peoples R China.
   [Yi, Weimin] Univ Chinese Acad Sci, Beijing 100049, Peoples R China.
   [Yi, Weimin] Chinese Acad Sci, Key Lab Struct & Evolut Celestial Objects, Kunming 650011, Peoples R China.
   [Zuo, Wenwen] Chinese Acad Sci, Shanghai Astron Observ, Shanghai 200030, Peoples R China.
   [Bian, Fuyan] Australian Natl Univ, Res Sch Astron & Astrophys, Mt Stromlo Observ, Weston, ACT 2611, Australia.
   [Thompson, David] Univ Arizona, Large Binocular Telescope Observ, Tucson, AZ 85721 USA.
   [Beletsky, Yuri] Carnegie Inst Sci, Las Campanas Observ, La Serena, Chile.
C3 Peking University; Peking University; University of Arizona; Chinese Academy of Sciences; Yunnan Astronomical Observatory, NAOC, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; Chinese Academy of Sciences; Shanghai Astronomical Observatory, CAS; Australian National University; University of Arizona; Carnegie Institution for Science
RP Wu, XB (corresponding author), Peking Univ, Sch Phys, Dept Astron, Beijing 100871, Peoples R China.
EM wuxb@pku.edu.cn
FU NSFC [11033001, 11373008, 11443002]; Strategic Priority Research Program 'The Emergence of Cosmological Structures' of the Chinese Academy of Sciences [XDB09000000]; National Key Basic Research Program of China [2014CB845700]; US NSF [AST 08-06861, AST 11-07682]; Chinese Academy of Sciences; People's Government of Yunnan Province; Strategic Priority Research Program 'The Emergence of Cosmological Structures' [XDB09000000]; National Astronomical Observatories, Chinese Academy of Sciences; Special Fund for Astronomy from the Ministry of Finance of China; Division Of Astronomical Sciences; Direct For Mathematical & Physical Scien [1107682] Funding Source: National Science Foundation
NR 30
TC 638
Z9 694
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 26
PY 2015
VL 518
IS 7540
BP 512
EP 515
DI 10.1038/nature14241
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC1JP
UT WOS:000350097300041
PM 25719667
DA 2026-03-09
ER

PT J
AU Galy, V
   Peucker-Ehrenbrink, B
   Eglinton, T
AF Galy, Valier
   Peucker-Ehrenbrink, Bernhard
   Eglinton, Timothy
TI Global carbon export from the terrestrial biosphere controlled by erosion
SO NATURE
LA English
DT Article
ID particulate organic-carbon; mountain rivers; transport; burial; ocean; sediment; system; climate; impact; rates
AB Riverine export of particulate organic carbon (POC) to the ocean affects the atmospheric carbon inventory over a broad range of timescales(1-5). On geological timescales, the balance between sequestration of POC from the terrestrial biosphere and oxidation of rock-derived (petrogenic) organic carbon sets the magnitude of the atmospheric carbon and oxygen reservoirs(6,7). Over shorter timescales, variations in the rate of exchange between carbon reservoirs, such as soils and marine sediments, also modulate atmospheric carbon dioxide levels(1). The respective fluxes of biospheric and petrogenic organic carbon are poorly constrained, however, and mechanisms controlling POC export have remained elusive, limiting our ability to predict POC fluxes quantitatively as a result of climatic or tectonic changes. Here we estimate biospheric and petrogenic POC fluxes for a suite of river systems representative of the natural variability in catchment properties. We show that export yields of both biospheric and petrogenic POC are positively related to the yield of suspended sediment, revealing that POC export is mostly controlled by physical erosion. Using a global compilation of gauged suspended sediment flux, we derive separate estimates of global biospheric and petrogenic POC fluxes of 157(-50)(+74) and 43(-25)(+61) megatonnes of carbon per year, respectively. We find that biospheric POC export is primarily controlled by the capacity of rivers to mobilize and transport POC, and is largely insensitive to the magnitude of terrestrial primary production. Globally, physical erosion rates affect the rate of biospheric POC burial in marine sediments more strongly than carbon sequestration through silicate weathering. We conclude that burial of biospheric POC in marine sediments becomes the dominant long-term atmospheric carbon dioxide sink under enhanced physical erosion.
C1 [Galy, Valier; Peucker-Ehrenbrink, Bernhard; Eglinton, Timothy] Woods Hole Oceanog Inst, Dept Marine Chem & Geochem, Woods Hole, MA 02543 USA.
   [Eglinton, Timothy] ETH, Inst Geol, Dept Earth Sci, CH-8092 Zurich, Switzerland.
C3 Woods Hole Oceanographic Institution; Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Galy, V (corresponding author), Woods Hole Oceanog Inst, Dept Marine Chem & Geochem, 360 Woods Hole Rd, Woods Hole, MA 02543 USA.
EM vgaly@whoi.edu
FU US National Science Foundation (NSF) [OCE-0851015]; NSF [OCE-0928582]; Swiss National Science Foundation [200021_140850]; Swiss National Science Foundation (SNF) [200021_140850] Funding Source: Swiss National Science Foundation (SNF)
NR 39
TC 474
Z9 535
U1 20
U2 722
PU NATURE PUBLISHING 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 14
PY 2015
VL 521
IS 7551
BP 204
EP +
DI 10.1038/nature14400
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH9SY
UT WOS:000354377800055
PM 25971513
DA 2026-03-09
ER

PT J
AU Bah, A
   Vernon, RM
   Siddiqui, Z
   Krzeminski, M
   Muhandiram, R
   Zhao, C
   Sonenberg, N
   Kay, LE
   Forman-Kay, JD
AF Bah, Alaji
   Vernon, Robert M.
   Siddiqui, Zeba
   Krzeminski, Mickael
   Muhandiram, Ranjith
   Zhao, Charlie
   Sonenberg, Nahum
   Kay, Lewis E.
   Forman-Kay, Julie D.
TI Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch
SO NATURE
LA English
DT Article
ID translation initiation; order transition; binding; 4e-bp1; eif4e; eukaryotes
AB Intrinsically disordered proteins play important roles in cell signalling, transcription, translation and cell cycle regulation(1.2). Although they lack stable tertiary structure, many intrinsically disordered proteins undergo disorder-to-order transitions upon binding to partners(3,4). Similarly, several folded proteins use regulated order-to-disorder transitions to mediate biological function(5,6). In principle, the function of intrinsically disordered proteins may be controlled by post-translational modifications that lead to structural changes such as folding, although this has not been observed. Here we show that multisite phosphorylation induces folding of the intrinsically disordered 4E-BP2, the major neural isoform of the family of three mammalian proteins that bind eIF4E and suppress cap-dependent translation initiation. In its non-phosphorylated state, 4E-BP2 interacts tightly with eIF4E using both a canonical YXXXXL Phi motif (starting at Y54) that undergoes a disorder-to-helix transition upon binding and a dynamic secondary binding site(7-11). We demonstrate that phosphorylation at T37 and T46 induces folding of residues P18-R62 of 4E-BP2 into a four-stranded beta-domain that sequesters the helical YXXXXL Phi motif into a partly buried beta-strand, blocking its accessibility to eIF4E. The folded state of pT37pT46 4E-BP2 is wealdy stable, decreasing affinity by 100-fold and leading to an order-to-disorder transition upon binding to eIF4E, whereas fully phosphorylated 4E-BP2 is more stable, decreasing affinity by a factor of approximately 4,000. These results highlight stabilization of a phosphorylation-induced fold as the essential mechanism for phospho-regulation of the 4E-BP:eIF4E interaction and exemplify a new mode of biological regulation mediated by intrinsically disordered proteins.
C1 [Bah, Alaji; Vernon, Robert M.; Siddiqui, Zeba; Krzeminski, Mickael; Zhao, Charlie; Kay, Lewis E.; Forman-Kay, Julie D.] Hosp Sick Children, Mol Struct & Funct Program, Toronto, ON M5G 0A4, Canada.
   [Bah, Alaji; Vernon, Robert M.; Krzeminski, Mickael; Muhandiram, Ranjith; Kay, Lewis E.; Forman-Kay, Julie D.] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada.
   [Muhandiram, Ranjith; Kay, Lewis E.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada.
   [Sonenberg, Nahum] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada.
   [Sonenberg, Nahum] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3G 1Y6, Canada.
   [Kay, Lewis E.] Univ Toronto, Dept Chem, Toronto, ON M5S 3H6, Canada.
C3 University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; University of Toronto; McGill University; McGill University; University of Toronto
RP Forman-Kay, JD (corresponding author), Hosp Sick Children, Mol Struct & Funct Program, Toronto, ON M5G 0A4, Canada.
EM forman@sickkids.ca
FU Canadian Institutes of Health Research [MOP-114985, MOP-119579]; Canadian Cancer Society; Hospital for Sick Children; Canadian Institutes of Health Research (CIHR); CIHR Strategic Training Program in Protein Folding and Interaction Dynamics; Summer Research Program at the Hospital for Sick Children
NR 36
TC 456
Z9 551
U1 3
U2 321
PU NATURE PUBLISHING 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 5
PY 2015
VL 519
IS 7541
BP 106
EP U240
DI 10.1038/nature13999
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC4EQ
UT WOS:000350304000045
PM 25533957
DA 2026-03-09
ER

PT J
AU Zhang, Q
   Zhao, K
   Shen, QC
   Han, YM
   Gu, Y
   Li, X
   Zhao, DZ
   Liu, YQ
   Wang, CM
   Zhang, X
   Su, XP
   Liu, J
   Ge, W
   Levine, RL
   Li, N
   Cao, XT
AF Zhang, Qian
   Zhao, Kai
   Shen, Qicong
   Han, Yanmei
   Gu, Yan
   Li, Xia
   Zhao, Dezhi
   Liu, Yiqi
   Wang, Chunmei
   Zhang, Xiang
   Su, Xiaoping
   Liu, Juan
   Ge, Wei
   Levine, Ross L.
   Li, Nan
   Cao, Xuetao
TI Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6
SO NATURE
LA English
DT Article
ID kappa-b-zeta; cell self-renewal; dna demethylation; gene-expression; autoimmune-diseases; interferon-gamma; t-cells; cytokine; innate; 5-methylcytosine
AB Epigenetic modifiers have fundamental roles in defining unique cellular identity through the establishment and maintenance of lineage-specific chromatin and methylation status(1). Several DNA modifications such as 5-hydroxymethylcytosine (5hmC) are catalysed by the ten eleven translocation (Tet) methylcytosine dioxygenase family members2, and the roles of Tet proteins in regulating chromatin architecture and gene transcription independently of DNA methylation have been gradually uncovered(3). However, the regulation of immunity and inflammation by Tet proteins independent of their role in modulating DNA methylation remains largely unknown. Here we show that Tet2 selectively mediates active repression of interleukin-6 (IL-6) transcription during inflammation resolution in innate myeloid cells, including dendritic cells and macrophages. Loss of Tet2 resulted in the upregulation of several inflammatory mediators, including IL-6, at late phase during the response to lipopolysaccharide challenge. Tet2-deficient mice were more susceptible to endotoxin shock and dextran-sulfate-sodium-induced colitis, displaying a more severe inflammatory phenotype and increased IL-6 production compared to wild-type mice. I kappa B zeta, an IL-6-specific transcription factor, mediated specific targeting of Tet2 to the Il6 promoter, further indicating opposite regulatory roles of I kappa B zeta at initial and resolution phases of inflammation. For the repression mechanism, independent of DNA methylation and hydroxymethylation, Tet2 recruited Hdac2 and repressed transcription of Il6 via histone deacetylation. We provide mechanistic evidence for the gene-specific transcription repression activity of Tet2 via histone deacetylation and for the prevention of constant transcription activation at the chromatin level for resolving inflammation.
C1 [Zhang, Qian; Zhao, Kai; Li, Xia; Zhao, Dezhi; Wang, Chunmei; Ge, Wei; Cao, Xuetao] Chinese Acad Med Sci, Inst Basic Med Sci, Peking Union Med Coll, Natl Key Lab Med Mol Biol, Beijing 100005, Peoples R China.
   [Zhang, Qian; Zhao, Kai; Li, Xia; Zhao, Dezhi; Wang, Chunmei; Ge, Wei; Cao, Xuetao] Chinese Acad Med Sci, Inst Basic Med Sci, Peking Union Med Coll, Dept Immunol, Beijing 100005, Peoples R China.
   [Zhang, Qian; Shen, Qicong; Han, Yanmei; Gu, Yan; Liu, Yiqi; Zhang, Xiang; Su, Xiaoping; Liu, Juan; Li, Nan; Cao, Xuetao] Second Mil Med Univ, Natl Key Lab Med Immunol, Shanghai 200433, Peoples R China.
   [Zhang, Qian; Shen, Qicong; Han, Yanmei; Gu, Yan; Liu, Yiqi; Zhang, Xiang; Su, Xiaoping; Liu, Juan; Li, Nan; Cao, Xuetao] Second Mil Med Univ, Inst Immunol, Shanghai 200433, Peoples R China.
   [Levine, Ross L.] Mem Sloan Kettering Canc, Human Oncol & Pathogenesis Program, New York, NY 10016 USA.
   [Levine, Ross L.] Mem Sloan Kettering Canc, Leukemia Serv, Dept Med, New York, NY 10016 USA.
C3 Institute of Basic Medical Sciences - CAMS; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Institute of Basic Medical Sciences - CAMS; Naval Medical University; Naval Medical University; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center
RP Cao, XT (corresponding author), Chinese Acad Med Sci, Inst Basic Med Sci, Peking Union Med Coll, Natl Key Lab Med Mol Biol, Beijing 100005, Peoples R China.
EM caoxt@immunol.org
FU National Key Basic Research Program of China [2013CB530503]; National Natural Science Foundation of China [31200654, 31390431, 81230074, 81123006]; National Cancer Institute [P30CA008748, R01CA173636] Funding Source: NIH RePORTER
NR 29
TC 662
Z9 767
U1 5
U2 196
PU NATURE PUBLISHING 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 17
PY 2015
VL 525
IS 7569
BP 389
EP +
DI 10.1038/nature15252
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900046
PM 26287468
DA 2026-03-09
ER

PT J
AU Lujan, E
   Zunder, ER
   Ng, YH
   Goronzy, IN
   Nolan, GP
   Wernig, M
AF Lujan, Ernesto
   Zunder, Eli R.
   Ng, Yi Han
   Goronzy, Isabel N.
   Nolan, Garry P.
   Wernig, Marius
TI Early reprogramming regulators identified by prospective isolation and mass cytometry
SO NATURE
LA English
DT Article
ID pluripotent stem-cells; somatic-cells; molecular roadmap; fibroblasts; expression; induction; markers
AB In the context of most induced pluripotent stem(iPS) cell reprogramming methods, heterogeneous populations of non-productive and staggered productive intermediates arise at different reprogramming time points(1-11). Despite recent reports claiming substantially increased reprogramming efficiencies using genetically modified donor cells(12,13), prospectively isolating distinct reprogramming intermediates remains an important goal to decipher reprogramming mechanisms. Previous attempts to identify surface markers of intermediate cell populations were based on the assumption that, during reprogramming, cells progressively lose donor cell identity and gradually acquire iPS cell properties(1,2,7,8,10). Here we report that iPS cell and epithelial markers, such as SSEA1 and EpCAM, respectively, are not predictive of reprogramming during early phases. Instead, in a systematic functional surface marker screen, we find that early reprogramming-prone cells express a unique set of surface markers, including CD73, CD49d and CD200, that are absent in both fibroblasts and iPS cells. Single-cell mass cytometry and prospective isolation show that these distinct intermediates are transient and bridge the gap between donor cell silencing and pluripotency marker acquisition during the early, presumably stochastic, reprogramming phase(2). Expression profiling reveals early upregulation of the transcriptional regulators Nr0b1 and Etv5 in this reprogramming state, preceding activation of key pluripotency regulators such asRex1 (also known as Zfp42), Dppa2, Nanog and Sox2. Both factors are required for the generation of the early intermediate state and fully reprogrammed iPS cells, and thus represent some of the earliest known regulators of iPS cell induction. Our study deconvolutes the first steps in a hierarchical series of events that lead to pluripotency acquisition.
C1 [Lujan, Ernesto; Ng, Yi Han; Goronzy, Isabel N.; Wernig, Marius] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA.
   [Lujan, Ernesto] Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
   [Lujan, Ernesto; Ng, Yi Han; Goronzy, Isabel N.; Wernig, Marius] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA.
   [Zunder, Eli R.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA.
   [Ng, Yi Han] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; Stanford University; Stanford University; Stanford University
RP Wernig, M (corresponding author), Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA.
EM wernig@stanford.edu
FU California Institute of Regenerative Medicine [RB2-01592]; Institute for Stem Cell Biology and Regenerative Medicine at Stanford; New York Stem Cell Foundation-Robertson Investigator Award; California Institute for Regenerative Medicine Predoctoral Fellowship [TG2-01159]; National Science Foundation Graduate Research Fellowship [DGE-114747]; National Institutes of Health National Research Service Award [F32 GM093508-01]; National Institute of Allergy and Infectious Diseases [T32AI007328] Funding Source: NIH RePORTER
NR 31
TC 77
Z9 105
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 MAY 21
PY 2015
VL 521
IS 7552
BP 352
EP +
DI 10.1038/nature14274
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CI5RM
UT WOS:000354816500056
PM 25830878
DA 2026-03-09
ER

PT J
AU Herzfeld, DJ
   Kojima, Y
   Soetedjo, R
   Shadmehr, R
AF Herzfeld, David J.
   Kojima, Yoshiko
   Soetedjo, Robijanto
   Shadmehr, Reza
TI Encoding of action by the Purkinje cells of the cerebellum
SO NATURE
LA English
DT Article
ID caudal fastigial nucleus; saccadic eye-movements; oculomotor vermis; macaque monkey; spike activity; mossy fibers; adaptation; generation; patterns; cortex
AB Execution of accurate eye movements depends critically on the cerebellum(1-3), suggesting that the major output neurons of the cerebellum, Purkinje cells, may predict motion of the eye. However, this encoding of action for rapid eye movements (saccades) has remained unclear: Purkinje cells show little consistent modulation with respect to saccade amplitude(4,5) or direction(4), and critically, their discharge lasts longer than the duration of a saccade(6,7). Here we analysed Purkinje-cell discharge in the oculomotor vermis of behaving rhesus monkeys (Macaca mulatta)(8,9) and found neurons that increased or decreased their activity during saccades. We estimated the combined effect of these two populations via their projections to the caudal fastigial nucleus, and uncovered a simple-spike population response that precisely predicted the real-time motion of the eye. When we organized the Purkinje cells according to each cell's complex-spike directional tuning, the simple-spike population response predicted both the real-time speed and direction of saccade multiplicatively via a gain field. This suggests that the cerebellum predicts the real-time motion of the eye during saccades via the combined inputs of Purkinje cells onto individual nucleus neurons. A gain-field encoding of simple spikes emerges if the Purkinje cells that project onto a nucleus neuron are not selected at random but share a common complex-spike property.
C1 [Herzfeld, David J.; Shadmehr, Reza] Johns Hopkins Univ, Sch Med, Lab Computat Motor Control, Dept Biomed Engn, Baltimore, MD 21205 USA.
   [Kojima, Yoshiko; Soetedjo, Robijanto] Univ Washington, Dept Physiol & Biophys, Washington Natl Primate Ctr, Seattle, WA 98195 USA.
C3 Johns Hopkins University; University of Washington; University of Washington Seattle
RP Herzfeld, DJ (corresponding author), Johns Hopkins Univ, Sch Med, Lab Computat Motor Control, Dept Biomed Engn, Baltimore, MD 21205 USA.
EM dherzfe1@jhmi.edu; shadmehr@jhu.edu
FU NIH [R01NS078311, R01EY019258, R01EY023277, F31NS090860]; National Eye Institute [R01EY023277] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [R01NS078311] Funding Source: NIH RePORTER; NIH Office of the Director [P51OD010425] Funding Source: NIH RePORTER
NR 28
TC 221
Z9 257
U1 1
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 OCT 15
PY 2015
VL 526
IS 7573
BP 439
EP +
DI 10.1038/nature15693
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200053
PM 26469054
DA 2026-03-09
ER

PT J
AU Keller, AJ
   Peeters, L
   Moca, CP
   Weymann, I
   Mahalu, D
   Umansky, V
   Zaránd, G
   Goldhaber-Gordon, D
AF Keller, A. J.
   Peeters, L.
   Moca, C. P.
   Weymann, I.
   Mahalu, D.
   Umansky, V.
   Zarand, G.
   Goldhaber-Gordon, D.
TI Universal Fermi liquid crossover and quantum criticality in a mesoscopic system
SO NATURE
LA English
DT Article
ID renormalization-group; kondo system; heavy; conductance; behavior
AB Quantum critical systems derive their finite-temperature properties from the influence of a zero-temperature quantum phase transition(1). The paradigm is essential for understanding unconventional high-T-c superconductors and the non-Fermi liquid properties of heavy fermion compounds. However, the microscopic origins of quantum phase transitions in complex materials are often debated. Here we demonstrate experimentally, with support from numerical renormalization group calculations, a universal crossover from quantum critical non-Fermi liquid behaviour to distinct Fermi liquid ground states in a highly controllable quantum dot device. Our device realizes the non-Fermi liquid two-channel Kondo state(2,3), based on a spin-1/2 impurity exchange-coupled equally to two independent electronic reservoirs(4). On detuning the exchange couplings we observe the Fermi liquid scale T*, at energies below which the spin is screened conventionally by the more strongly coupled channel. We extract a quadratic dependence of T* on gate voltage close to criticality, and validate an asymptotically exact description of the universal crossover between strongly correlated non-Fermi liquid and Fermi liquid states(5,6).
C1 [Keller, A. J.; Peeters, L.; Goldhaber-Gordon, D.] Stanford Univ, Geballe Lab Adv Mat, Stanford, CA 94305 USA.
   [Moca, C. P.; Zarand, G.] Budapest Univ Technol & Econ, Inst Phys, BME MTA Exot Quantum Phases Lendulet Grp, H-1521 Budapest, Hungary.
   [Moca, C. P.] Univ Oradea, Dept Phys, Oradea 410087, Romania.
   [Weymann, I.] Adam Mickiewicz Univ, Fac Phys, PL-61614 Poznan, Poland.
   [Mahalu, D.; Umansky, V.] Weizmann Inst Sci, Dept Condensed Matter Phys, IL-96100 Rehovot, Israel.
C3 Stanford University; Budapest University of Technology & Economics; University of Oradea; Adam Mickiewicz University; Weizmann Institute of Science
RP Goldhaber-Gordon, D (corresponding author), Stanford Univ, Geballe Lab Adv Mat, Stanford, CA 94305 USA.
EM goldhaber-gordon@stanford.edu
FU Gordon and Betty Moore Foundation [GBMF3429]; Hungarian research grant [OTKA K105149]; Polish National Science Centre project [DEC-2013/10/E/ST3/00213]; EU [CIG-303 689]; National Science Foundation [DMR-0906062]; US-Israel BSF [2008149]; Stanford Graduate Fellowship
NR 45
TC 92
Z9 101
U1 0
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 OCT 8
PY 2015
VL 526
IS 7572
BP 237
EP +
DI 10.1038/nature15261
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS9GV
UT WOS:000362399000043
PM 26450057
DA 2026-03-09
ER

PT J
AU Frank, DD
   Jouandet, GC
   Kearney, PJ
   Macpherson, LJ
   Gallio, M
AF Frank, Dominic D.
   Jouandet, Genevieve C.
   Kearney, Patrick J.
   Macpherson, Lindsey J.
   Gallio, Marco
TI Temperature representation in the Drosophila brain
SO NATURE
LA English
DT Article
ID fluorescent proteins; antennal lobe; circuit; neurons; melanogaster; neurobiology; marker; gfp
AB In Drosophila, rapid temperature changes are detected at the periphery by dedicated receptors forming a simple sensory map for hot and cold in the brain(1). However, flies show a host of complex innate and learned responses to temperature, indicating that they are able to extract a range of information from this simple input. Here we define the anatomical and physiological repertoire for temperature representation in the Drosophila brain. First, we use a photolabelling strategy(2) to trace the connections that relay peripheral thermosensory information to higher brain centres, and show that they largely converge onto three target regions: the mushroom body, the lateral horn (both of which are well known centres for sensory processing) and the posterior lateral protocerebrum, a region we now define as a major site of thermosensory representation. Next, using in vivo calcium imaging(3), we describe the thermosensory projection neurons selectively activated by hot or cold stimuli. Fast-adapting neurons display transient ON and OFF responses and track rapid temperature shifts remarkably well, while slow-adapting cell responses better reflect the magnitude of simple thermal changes. Unexpectedly, we also find a population of broadly tuned cells that respond to both heating and cooling, and show that they are required for normal behavioural avoidance of both hot and cold in a simple two-choice temperature preference assay. Taken together, our results uncover a coordinated ensemble of neural responses to temperature in the Drosophila brain, demonstrate that a broadly tuned thermal line contributes to rapid avoidance behaviour, and illustrate how stimulus quality, temporal structure, and intensity can be extracted from a simple glomerular map at a single synaptic station.
C1 [Frank, Dominic D.; Jouandet, Genevieve C.; Kearney, Patrick J.; Gallio, Marco] Northwestern Univ, Dept Neurobiol, Evanston, IL 60208 USA.
   [Macpherson, Lindsey J.] Columbia Univ, Dept Biochem, New York, NY 10032 USA.
   [Macpherson, Lindsey J.] Columbia Univ, Dept Mol Biophys, New York, NY 10032 USA.
C3 Northwestern University; Columbia University; Columbia University
RP Gallio, M (corresponding author), Northwestern Univ, Dept Neurobiol, Evanston, IL 60208 USA.
EM marco.gallio@northwestern.edu
FU NIH [1R01NS086859-01];  [2T32MH067564]; National Institute of Mental Health [T32MH067564] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [R01NS086859] Funding Source: NIH RePORTER
NR 22
TC 126
Z9 156
U1 3
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 MAR 19
PY 2015
VL 519
IS 7543
BP 358
EP +
DI 10.1038/nature14284
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD6AY
UT WOS:000351171900042
PM 25739506
DA 2026-03-09
ER

PT J
AU Wilson, TW
   Ladino, LA
   Alpert, PA
   Breckels, MN
   Brooks, IM
   Browse, J
   Burrows, SM
   Carslaw, KS
   Huffman, JA
   Judd, C
   Kilthau, WP
   Mason, RH
   McFiggans, G
   Miller, LA
   Najera, JJ
   Polishchuk, E
   Rae, S
   Schiller, CL
   Si, M
   Temprado, JV
   Whale, TF
   Wong, JPS
   Wurl, O
   Yakobi-Hancock, JD
   Abbatt, JPD
   Aller, JY
   Bertram, AK
   Knopf, DA
   Murray, BJ
AF Wilson, Theodore W.
   Ladino, Luis A.
   Alpert, Peter A.
   Breckels, Mark N.
   Brooks, Ian M.
   Browse, Jo
   Burrows, Susannah M.
   Carslaw, Kenneth S.
   Huffman, J. Alex
   Judd, Christopher
   Kilthau, Wendy P.
   Mason, Ryan H.
   McFiggans, Gordon
   Miller, Lisa A.
   Najera, Juan J.
   Polishchuk, Elena
   Rae, Stuart
   Schiller, Corinne L.
   Si, Meng
   Temprado, Jesus Vergara
   Whale, Thomas F.
   Wong, Jenny P. S.
   Wurl, Oliver
   Yakobi-Hancock, Jacqueline D.
   Abbatt, Jonathan P. D.
   Aller, Josephine Y.
   Bertram, Allan K.
   Knopf, Daniel A.
   Murray, Benjamin J.
TI A marine biogenic source of atmospheric ice-nucleating particles
SO NATURE
LA English
DT Article
ID transmission x-ray; sea-surface microlayer; transparent exopolymer particles; spray aerosol composition; dissolved organic-carbon; forming nuclei; mineral dust; arctic-ocean; matter; water
AB The amount of ice present in clouds can affect cloud lifetime, precipitation and radiative properties(1,2). The formation of ice in clouds is facilitated by the presence of airborne ice-nucleating particles(1,2). Sea spray is one of the major global sources of atmospheric particles, but it is unclear to what extent these particles are capable of nucleating ice(3-11). Sea-spray aerosol contains large amounts of organic material that is ejected into the atmosphere during bubble bursting at the organically enriched sea-air interface or sea surface microlayer(12-19). Here we show that organic material in the sea surface microlayer nucleates ice under conditions relevant for mixed-phase cloud and high-altitude ice cloud formation. The ice-nucleating material is probably biogenic and less than approximately 0.2 micrometres in size. We find that exudates separated from cells of the marine diatom Thalassiosira pseudonana nucleate ice, and propose that organic material associated with phytoplankton cell exudates is a likely candidate for the observed ice-nucleating ability of the microlayer samples. Global model simulations of marine organic aerosol, in combination with our measurements, suggest that marine organic material may be an important source of ice-nucleating particles in remote marine environments such as the Southern Ocean, North Pacific Ocean and North Atlantic Ocean.
C1 [Wilson, Theodore W.; Brooks, Ian M.; Browse, Jo; Carslaw, Kenneth S.; Judd, Christopher; Temprado, Jesus Vergara; Whale, Thomas F.; Murray, Benjamin J.] Univ Leeds, Sch Earth & Environm, Leeds LS2 9JT, W Yorkshire, England.
   [Ladino, Luis A.; Wong, Jenny P. S.; Yakobi-Hancock, Jacqueline D.; Abbatt, Jonathan P. D.] Univ Toronto, Dept Chem, Toronto, ON M5S 3H6, Canada.
   [Alpert, Peter A.; Knopf, Daniel A.] SUNY Stony Brook, Sch Marine & Atmospher Sci, Inst Terr & Planetary Atmospheres, Stony Brook, NY 11794 USA.
   [Breckels, Mark N.] Univ Essex, Sch Biol Sci, Colchester CO4 3SQ, Essex, England.
   [Burrows, Susannah M.] Pacific NW Natl Lab, Atmospher Sci & Global Change Div, Richland, WA 99354 USA.
   [Huffman, J. Alex] Univ Denver, Dept Chem & Biochem, Denver, CO 80208 USA.
   [Kilthau, Wendy P.; Aller, Josephine Y.] SUNY Stony Brook, Sch Marine & Atmospher Sci, Stony Brook, NY 11794 USA.
   [Mason, Ryan H.; Polishchuk, Elena; Si, Meng; Bertram, Allan K.] Univ British Columbia, Dept Chem, Vancouver, BC V6T 1Z1, Canada.
   [McFiggans, Gordon; Najera, Juan J.; Rae, Stuart] Univ Manchester, Sch Earth Atmospher & Environm Sci, Manchester M13 9PL, Lancs, England.
   [Miller, Lisa A.] Fisheries & Oceans Canada, Inst Ocean Sci, Sidney, BC V8L 4B2, Canada.
   [Schiller, Corinne L.] Environm Canada, Air Qual Sci Unit, Vancouver, BC V6C 3S5, Canada.
   [Wurl, Oliver] Leibniz Inst Balt Sea Res Warnemunde, Dept Biol Oceanog, D-18119 Rostock, Germany.
C3 University of Leeds; University of Toronto; State University of New York (SUNY) System; Stony Brook University; University of Essex; United States Department of Energy (DOE); Pacific Northwest National Laboratory; University of Denver; State University of New York (SUNY) System; Stony Brook University; University of British Columbia; University of Manchester; Fisheries & Oceans Canada; Environment & Climate Change Canada; Leibniz Institut fur Ostseeforschung Warnemunde
RP Wilson, TW (corresponding author), Univ Leeds, Sch Earth & Environm, Woodhouse Lane, Leeds LS2 9JT, W Yorkshire, England.
EM theo.w.wilson@gmail.com; luis.ladinomoreno@utoronto.ca
FU Office of Science, Office of Basic Energy Sciences of the US Department of Energy [DE-AC02-05CH11231 (ALS-05955)]; Natural Environment Research Council [NE/K004417/1, NE/I020059/1, NE/I013466/1, NE/I028696/1, NE/I019057/1, NE/H009485/1]; European Research Council [240449, 603445]; UK Aerosol Society; National Science Foundation [AGS-1232203]; German Research Foundation [WU585/6-1]; Climate Change and Atmospheric Research Program of the Natural Sciences and Engineering Research Council of Canada; Fisheries and Oceans Canada; Environment Canada; NOAA's Climate Program Office; DOE Office of Science (BER) Earth System Modeling Program; European Research Council (ERC) [240449] Funding Source: European Research Council (ERC); NERC [NE/K004417/1, NE/H009485/1, NE/I028858/1, NE/L007827/1, NE/I028696/1, NE/I020059/1, NE/I013466/1] Funding Source: UKRI; Natural Environment Research Council [NE/I028696/1, NE/I013466/1, 1047972, NE/K004417/1, 1230241, NE/I020059/1, NE/L007827/1, NE/H009485/1, NE/I028858/1] Funding Source: researchfish
NR 72
TC 494
Z9 577
U1 9
U2 599
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 10
PY 2015
VL 525
IS 7568
BP 234
EP +
DI 10.1038/nature14986
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400035
PM 26354482
DA 2026-03-09
ER

PT J
AU Liu, ZD
   Gerner, MY
   Van Panhuys, N
   Levine, AG
   Rudensky, AY
   Germain, RN
AF Liu, Zhiduo
   Gerner, Michael Y.
   Van Panhuys, Nicholas
   Levine, Andrew G.
   Rudensky, Alexander Y.
   Germain, Ronald N.
TI Immune homeostasis enforced by co-localized effector and regulatory T cells
SO NATURE
LA English
DT Article
ID dendritic cells; interleukin-2; il-2; responses; mechanisms; generation; tolerance; absence; ctla-4; cd73
AB FOXP3(+) regulatory T cells (T-reg cells) prevent autoimmunity by limiting the effector activity of T cells that have escaped thymic negative selection or peripheral inactivation. Despite the information available about molecular factors mediating the suppressive function of T-reg cells, the relevant cellular events in intact tissues remain largely unexplored, and whether Treg cells prevent activation of self-specific T cells or primarily limit damage from such cells has not been determined. Here we use multiplex, quantitative imaging in mice to show that, within secondary lymphoid tissues, highly suppressive Treg cells expressing phosphorylated STAT5 exist in discrete clusters with rare IL-2-positive T cells that are activated by self-antigens. This local IL-2 induction of STAT5 phosphorylation in T-reg cells is part of a feedback circuit that limits further autoimmune responses. Inducible ablation of T cell receptor expression by T-reg cells reduces their regulatory capacity and disrupts their localization in clusters, resulting in uncontrolled effector T cell responses. Our data thus reveal that autoreactive T cells are activated to cytokine production on a regular basis, with physically co-clustering T cell receptor-stimulated T-reg cells responding in a negative feedback manner to suppress incipient autoimmunity and maintain immune homeostasis.
C1 [Liu, Zhiduo; Gerner, Michael Y.; Van Panhuys, Nicholas; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA.
   [Levine, Andrew G.; Rudensky, Alexander Y.] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA.
   [Levine, Andrew G.; Rudensky, Alexander Y.] Mem Sloan Kettering Canc Ctr, Immunol Program, New York, NY 10065 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Memorial Sloan Kettering Cancer Center; Howard Hughes Medical Institute; Memorial Sloan Kettering Cancer Center
RP Germain, RN (corresponding author), NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
EM rgermain@nih.gov
FU NIAID, NIH; US National Institutes of Health [R37AI034206, T32GM007739]; Ludwig Cancer Center at Memorial Sloan-Kettering Cancer Center; Howard Hughes Medical Institute; National Institute of Allergy and Infectious Diseases [ZIAAI000545, ZIAAI000758] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007739] Funding Source: NIH RePORTER
NR 36
TC 243
Z9 288
U1 0
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 DEC 10
PY 2015
VL 528
IS 7581
BP 225
EP +
DI 10.1038/nature16169
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX9VH
UT WOS:000366053300033
PM 26605524
DA 2026-03-09
ER

PT J
AU Nillegoda, NB
   Kirstein, J
   Szlachcic, A
   Berynskyy, M
   Stank, A
   Stengel, F
   Arnsburg, K
   Gao, XC
   Scior, A
   Aebersold, R
   Guilbride, DL
   Wade, RC
   Morimoto, RI
   Mayer, MP
   Bukau, B
AF Nillegoda, Nadinath B.
   Kirstein, Janine
   Szlachcic, Anna
   Berynskyy, Mykhaylo
   Stank, Antonia
   Stengel, Florian
   Arnsburg, Kristin
   Gao, Xuechao
   Scior, Annika
   Aebersold, Ruedi
   Guilbride, D. Lys
   Wade, Rebecca C.
   Morimoto, Richard I.
   Mayer, Matthias P.
   Bukau, Bernd
TI Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation
SO NATURE
LA English
DT Article
ID nucleotide exchange factors; swiss-model repository; cross-linked peptides; j-domain; molecular chaperones; yeast cytosol; in-vitro; diffusional association; functional specificity; cochaperone dnaj
AB Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states(1,2). Healthy metazoan cells effectively eliminate intracellular protein aggregates(3,4,) indicating that efficient disaggregation and/or degradation mechanisms exist. However, metazoans lack the key heat-shock protein disaggregase HSP100 of non-metazoan HSP70-dependent protein disaggregation systems(5,6), and the human HSP70 system alone, even with the crucial HSP110 nucleotide exchange factor, has poor disaggregation activity in vitro4,7. This unresolved conundrum is central to protein quality control biology. Here we show that synergic cooperation between complexed J-protein co-chaperones of classes A and B unleashes highly efficient protein disaggregation activity in human and nematode HSP70 systems. Metazoan mixed-class J-protein complexes are transient, involve complementary charged regions conserved in the J-domains and carboxy-terminal domains of each J-protein class, and are flexible with respect to subunit composition. Complex formation allows J-proteins to initiate transient higher order chaperone structures involving HSP70 and interacting nucleotide exchange factors. A network of cooperative class A and B J-protein interactions therefore provides the metazoan HSP70 machinery with powerful, flexible, and finely regulatable disaggregase activity and a further level of regulation crucial for cellular protein quality control.
C1 [Nillegoda, Nadinath B.; Szlachcic, Anna; Gao, Xuechao; Guilbride, D. Lys; Wade, Rebecca C.; Mayer, Matthias P.; Bukau, Bernd] Univ Heidelberg ZMBH, German Canc Res Ctr DKFZ, Ctr Mol Biol, DKFZ ZMBH Alliance, D-69120 Heidelberg, Germany.
   [Kirstein, Janine; Arnsburg, Kristin; Scior, Annika] Leibniz Inst Mol Pharmacol FMP, D-13125 Berlin, Germany.
   [Berynskyy, Mykhaylo; Stank, Antonia; Wade, Rebecca C.] HITS, D-69118 Heidelberg, Germany.
   [Stank, Antonia] Heidelberg Univ, Heidelberg Grad Sch Math & Computat Methods Sci, D-69120 Heidelberg, Germany.
   [Stengel, Florian; Aebersold, Ruedi] Swiss Fed Inst Technol, Inst Mol Syst Biol, Dept Biol, CH-8093 Zurich, Switzerland.
   [Aebersold, Ruedi] Univ Zurich, Fac Sci, CH-8057 Zurich, Switzerland.
   [Wade, Rebecca C.] Heidelberg Univ, Interdisciplinary Ctr Sci Comp IWR, D-69120 Heidelberg, Germany.
   [Morimoto, Richard I.] Northwestern Univ, Rice Inst Biomed Res, Dept Mol Biosci, Evanston, IL 60208 USA.
C3 Ruprecht Karls University Heidelberg; Helmholtz Association; German Cancer Research Center (DKFZ); Leibniz Association; Leibniz Forschungsinstitut furr Molekulare Pharmakologie (FMP); Ruprecht Karls University Heidelberg; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Zurich; Ruprecht Karls University Heidelberg; Northwestern University
RP Bukau, B (corresponding author), Univ Heidelberg ZMBH, German Canc Res Ctr DKFZ, Ctr Mol Biol, DKFZ ZMBH Alliance, D-69120 Heidelberg, Germany.
EM n.nillegoda@zmbh.uni-heidelberg.de; bukau@zmbh.uni-heidelberg.de
FU Deutsche Forschungsgemeinschaft [SFB1036, BU617/19-1, EXC257, SFB740]; Alexander von Humboldt Foundation; National Institutes of Health (NIGMS); National Institutes of Health (NIA); National Institutes of Health (NIMS); Ellison Medical Foundation; Daniel F. and Ada L. Rice Foundation; German Federal Ministry of Education and Research (BMBF) Virtual Liver Network; EU FEP Flagship Programme Human Brain Project [0315749, 604102]; Klaus Tschira Foundation; Sir Henry Wellcome Postdoctoral Fellowship; ETH Zurich; ERC [233226]; National Cancer Institute [P30CA060553] Funding Source: NIH RePORTER
NR 59
TC 282
Z9 341
U1 0
U2 97
PU NATURE PUBLISHING 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 13
PY 2015
VL 524
IS 7564
BP 247
EP +
DI 10.1038/nature14884
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900038
PM 26245380
DA 2026-03-09
ER

PT J
AU des Georges, A
   Dhote, V
   Kuhn, L
   Hellen, CUT
   Pestova, TV
   Frank, J
   Hashem, Y
AF des Georges, Amedee
   Dhote, Vidya
   Kuhn, Lauriane
   Hellen, Christopher U. T.
   Pestova, Tatyana V.
   Frank, Joachim
   Hashem, Yaser
TI Structure of mammalian eIF3 in the context of the 43S preinitiation complex
SO NATURE
LA English
DT Article
ID eukaryotic translation initiation; messenger-rna recruitment; particle electron cryomicroscopy; cryoelectron microscopy; recognition motif; 26s proteasome; molecular-dynamics; ribosomal-subunit; crystal-structure; cop9 signalosome
AB During eukaryotic translation initiation, 43S complexes, comprising a 40S ribosomal subunit, initiator transfer RNA and initiation factors (eIF) 2, 3, 1 and 1A, attach to the 59-terminal region of messenger RNA and scan along it to the initiation codon. Scanning on structured mRNAs also requires the DExH-box protein DHX29. Mammalian eIF3 contains 13 subunits and participates in nearly all steps of translation initiation. Eight subunits having PCI (proteasome, COP9 signalosome, eIF3) or MPN (Mpr1, Pad1, amino-terminal) domains constitute the structural core of eIF3, to which five peripheral subunits are flexibly linked. Here we present a cryo-electron microscopy structure of eIF3 in the context of the DHX29-bound 43S complex, showing the PCI/MPN core at,6 angstrom resolution. It reveals the organization of the individual subunits and their interactions with components of the 43S complex. We were able to build near-complete polyalanine-level models of the eIF3 PCI/MPN core and of two peripheral subunits. The implications for understanding mRNA ribosomal attachment and scanning are discussed.
C1 [des Georges, Amedee; Frank, Joachim] Columbia Univ, Dept Biochem & Mol Biophys, HHMI, New York, NY 10032 USA.
   [Dhote, Vidya; Hellen, Christopher U. T.; Pestova, Tatyana V.] Suny Downstate Med Ctr, Dept Cell Biol, Brooklyn, NY 11203 USA.
   [Kuhn, Lauriane] CNRS, Prote Platform Strasbourg Esplanade, F-67084 Strasbourg, France.
   [Frank, Joachim] Columbia Univ, Dept Biol Sci, New York, NY 10032 USA.
   [Hashem, Yaser] Univ Strasbourg, CNRS, Architecture & React ARN, F-67084 Strasbourg, France.
C3 Howard Hughes Medical Institute; Columbia University; State University of New York (SUNY) System; SUNY Downstate Health Sciences University; Centre National de la Recherche Scientifique (CNRS); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Columbia University; Centre National de la Recherche Scientifique (CNRS); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg
RP Pestova, TV (corresponding author), Suny Downstate Med Ctr, Dept Cell Biol, Brooklyn, NY 11203 USA.
EM Tatyana.Pestova@downstate.edu; jf2192@cumc.columbia.edu; y.hashem@ibmc-cnrs.unistra.fr
FU HHMI; NIH [R01 GM29169, R01 GM59660]; French National Research Agency as part of the Investments for the future program
NR 68
TC 198
Z9 234
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 SEP 24
PY 2015
VL 525
IS 7570
BP 491
EP +
DI 10.1038/nature14891
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR8KI
UT WOS:000361599900044
PM 26344199
DA 2026-03-09
ER

PT J
AU Zhao, L
   Chen, XJ
   Zhu, J
   Xi, YB
   Yang, X
   Hu, LD
   Ouyang, H
   Patel, SH
   Jin, X
   Lin, DN
   Wu, F
   Flagg, K
   Cai, HM
   Li, G
   Cao, GQ
   Lin, Y
   Chen, D
   Wen, C
   Chung, C
   Wang, YD
   Qiu, A
   Yeh, E
   Wang, WQ
   Hu, X
   Grob, S
   Abagyan, R
   Su, ZG
   Tjondro, HC
   Zhao, XJ
   Luo, HR
   Hou, R
   Perry, JJP
   Gao, WW
   Kozak, I
   Granet, D
   Li, YR
   Sun, XD
   Wang, J
   Zhang, LF
   Liu, YZ
   Yan, YB
   Zhang, K
AF Zhao, Ling
   Chen, Xiang-Jun
   Zhu, Jie
   Xi, Yi-Bo
   Yang, Xu
   Hu, Li-Dan
   Ouyang, Hong
   Patel, Sherrina H.
   Jin, Xin
   Lin, Danni
   Wu, Frances
   Flagg, Ken
   Cai, Huimin
   Li, Gen
   Cao, Guiqun
   Lin, Ying
   Chen, Daniel
   Wen, Cindy
   Chung, Christopher
   Wang, Yandong
   Qiu, Austin
   Yeh, Emily
   Wang, Wenqiu
   Hu, Xun
   Grob, Seanna
   Abagyan, Ruben
   Su, Zhiguang
   Tjondro, Harry Christianto
   Zhao, Xi-Juan
   Luo, Hongrong
   Hou, Rui
   Perry, J. Jefferson P.
   Gao, Weiwei
   Kozak, Igor
   Granet, David
   Li, Yingrui
   Sun, Xiaodong
   Wang, Jun
   Zhang, Liangfang
   Liu, Yizhi
   Yan, Yong-Bin
   Zhang, Kang
TI Lanosterol reverses protein aggregation in cataracts
SO NATURE
LA English
DT Article
ID selenite-induced cataractogenesis; dominant congenital cataract; human oxidosqualene cyclase; alpha-b-crystallin; sequencing data; chinese family; lens; mutation; expression; prevention
AB The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra-or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people(1), and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.
C1 [Zhao, Ling; Cai, Huimin; Li, Gen; Cao, Guiqun; Hu, Xun; Su, Zhiguang; Zhang, Kang] Sichuan Univ, Mol Med Res Ctr, State Key Lab Biotherapy, West China Hosp, Chengdu 610041, Peoples R China.
   [Zhao, Ling; Ouyang, Hong; Lin, Ying; Wang, Yandong; Liu, Yizhi; Zhang, Kang] Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China.
   [Zhao, Ling; Zhu, Jie; Ouyang, Hong; Patel, Sherrina H.; Lin, Danni; Wu, Frances; Flagg, Ken; Lin, Ying; Chen, Daniel; Wen, Cindy; Chung, Christopher; Qiu, Austin; Yeh, Emily; Wang, Wenqiu; Grob, Seanna; Luo, Hongrong; Gao, Weiwei; Granet, David; Zhang, Liangfang; Zhang, Kang] Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA.
   [Zhao, Ling; Zhu, Jie; Ouyang, Hong; Patel, Sherrina H.; Lin, Danni; Wu, Frances; Flagg, Ken; Lin, Ying; Chen, Daniel; Wen, Cindy; Chung, Christopher; Qiu, Austin; Yeh, Emily; Wang, Wenqiu; Grob, Seanna; Luo, Hongrong; Gao, Weiwei; Granet, David; Zhang, Liangfang; Zhang, Kang] Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA.
   [Chen, Xiang-Jun; Xi, Yi-Bo; Hu, Li-Dan; Tjondro, Harry Christianto; Zhao, Xi-Juan] Tsinghua Univ, Sch Life Sci, State Key Lab Membrane Biol, Beijing 100084, Peoples R China.
   [Zhu, Jie; Yan, Yong-Bin] Fourth Mil Med Univ, Xijing Hosp, Dept Ophthalmol, Xian 710032, Peoples R China.
   [Yang, Xu; Jin, Xin; Li, Yingrui; Wang, Jun] BGI Shenzhen, Shenzhen 518083, Peoples R China.
   [Cai, Huimin; Hou, Rui] Guangzhou KangRui Biol Pharmaceut Technol Co, Guangzhou 510005, Guangdong, Peoples R China.
   [Qiu, Austin] CapitalBio Genom Co Ltd, Dongguan 523808, Peoples R China.
   [Wang, Wenqiu; Sun, Xiaodong] Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 1, Dept Ophthalmol, Shanghai 20080, Peoples R China.
   [Abagyan, Ruben] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA.
   [Perry, J. Jefferson P.] Univ Calif Riverside, Dept Biochem, Riverside, CA 92521 USA.
   [Gao, Weiwei; Zhang, Liangfang; Zhang, Kang] Univ Calif San Diego, Dept Nanoengn, La Jolla, CA 92093 USA.
   [Kozak, Igor] King Khalid Eye Specialist Hosp, Riyadh, Saudi Arabia.
   [Zhang, Kang] Vet Adm Healthcare Syst, San Diego, CA 92093 USA.
C3 Sichuan University; Sun Yat Sen University; University of California System; University of California San Diego; University of California System; University of California San Diego; Tsinghua University; Air Force Medical University; Beijing Genomics Institute (BGI); CapitalBio; Shanghai Jiao Tong University; University of California System; University of California San Diego; University of California System; University of California Riverside; University of California System; University of California San Diego; King Khaled Eye Specialist Hospital
RP Zhang, K (corresponding author), Sichuan Univ, Mol Med Res Ctr, State Key Lab Biotherapy, West China Hosp, Chengdu 610041, Peoples R China.
EM zhang@ucsd.edu; yzliu62@yahoo.com; ybyan@tsinghua.edu.cn; kang.zhang@gmail.com
FU 973 Project [2015CB94600, 2012CB917304]; 863 Program [2014AA021604]; NSFC [31327901]; State Key Laboratory of Ophthalmology; State Key Laboratory of Membrane Biology
NR 35
TC 372
Z9 423
U1 7
U2 436
PU NATURE PUBLISHING 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 30
PY 2015
VL 523
IS 7562
BP 607
EP +
DI 10.1038/nature14650
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN7ZL
UT WOS:000358655200048
PM 26200341
DA 2026-03-09
ER

PT J
AU Cubitt, TS
   Perez-Garcia, D
   Wolf, MM
AF Cubitt, Toby S.
   Perez-Garcia, David
   Wolf, Michael M.
TI Undecidability of the spectral gap
SO NATURE
LA English
DT Article
ID complexity; quantum; antiferromagnet; lattice; state
AB The spectral gap-the energy difference between the ground state and first excited state of a system-is central to quantum many-body physics. Many challenging open problems, such as the Haldane conjecture, the question of the existence of gapped topological spin liquid phases, and the Yang-Mills gap conjecture, concern spectral gaps. These and other problems are particular cases of the general spectral gap problem: given the Hamiltonian of a quantum many-body system, is it gapped or gapless? Here we prove that this is an undecidable problem. Specifically, we construct families of quantum spin systems on a two-dimensional lattice with translationally invariant, nearest-neighbour interactions, for which the spectral gap problem is undecidable. This result extends to undecidability of other low-energy properties, such as the existence of algebraically decaying ground-state correlations. The proof combines Hamiltonian complexity techniques with aperiodic tilings, to construct a Hamiltonian whose ground state encodes the evolution of a quantum phase-estimation algorithm followed by a universal Turing machine. The spectral gap depends on the outcome of the corresponding 'halting problem'. Our result implies that there exists no algorithm to determine whether an arbitrary model is gapped or gapless, and that there exist models for which the presence or absence of a spectral gap is independent of the axioms of mathematics.
C1 [Cubitt, Toby S.] UCL, Dept Comp Sci, London WC1E 6BT, England.
   [Cubitt, Toby S.] Univ Cambridge, Ctr Math Sci, DAMTP, Cambridge CB3 0WA, England.
   [Perez-Garcia, David] Univ Complutense Madrid, Fac CC Matemat, Dept Anal Matemat, E-28040 Madrid, Spain.
   [Perez-Garcia, David] Univ Complutense Madrid, Fac CC Matemat, IMI, E-28040 Madrid, Spain.
   [Perez-Garcia, David] ICMAT, Madrid 28049, Spain.
   [Wolf, Michael M.] Tech Univ Munich, Dept Math, D-85748 Garching, Germany.
C3 University of London; University College London; University of Cambridge; Complutense University of Madrid; Complutense University of Madrid; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Ciencias Matematicas (ICMAT); Technical University of Munich
RP Cubitt, TS (corresponding author), UCL, Dept Comp Sci, Gower St, London WC1E 6BT, England.
EM t.cubitt@ucl.ac.uk
FU Royal Society; MINECO [MTM2011-26912, PRI-PIMCHI-2011-1071]; Comunidad de Madrid [S2013/ICE-2801]; European Research Council (ERC) under the European Union [648913]; John Templeton Foundation [48322]
NR 29
TC 162
Z9 189
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 DEC 10
PY 2015
VL 528
IS 7581
BP 207
EP 211
DI 10.1038/nature16059
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX9VH
UT WOS:000366053300030
PM 26659181
DA 2026-03-09
ER

PT J
AU Conroy, C
   van Dokkum, PG
   Choi, J
AF Conroy, Charlie
   van Dokkum, Pieter G.
   Choi, Jieun
TI Ubiquitous time variability of integrated stellar populations
SO NATURE
LA English
DT Article
ID long-period variables; asymptotic giant branch; gravitational lensing experiment.; ogle-iii catalog; magellanic clouds; mira variables; agb stars; m87; evolution; project
AB Long-period variable stars arise in the final stages of the asymptotic giant branch phase of stellar evolution. They have periods of up to about 1,000 days and amplitudes that can exceed a factor of three in the I-band flux. These stars pulsate predominantly in their fundamental mode(1-3), which is a function of mass and radius, and so the pulsation periods are sensitive to the age of the underlying stellar population(4). The overall number of long-period variables in a population is directly related to their lifetimes, which is difficult to predict from first principles because of uncertainties associated with stellar mass-loss and convective mixing. The time variability of these stars has not previously been taken into account when modelling the spectral energy distributions of galaxies. Here we construct time-dependent stellar population models that include the effects of long-period variable stars, and report the ubiquitous detection of this expected 'pixel shimmer' in the massive metal-rich galaxy M87. The pixel light curves display a variety of behaviours. The observed variation of 0.1 to 1 per cent is very well matched to the predictions of our models. The data provide a strong constraint on the properties of variable stars in an old and metal-rich stellar population, and we infer that the lifetime of long-period variables in M87 is shorter by approximately 30 per cent compared to predictions from the latest stellar evolution models.
C1 [Conroy, Charlie; Choi, Jieun] Harvard Univ, Dept Astron, Cambridge, MA 02138 USA.
   [van Dokkum, Pieter G.] Yale Univ, Dept Astron, New Haven, CT 06511 USA.
C3 Harvard University; Yale University
RP Conroy, C (corresponding author), Harvard Univ, Dept Astron, Cambridge, MA 02138 USA.
EM cconroy@cfa.harvard.edu
NR 28
TC 8
Z9 13
U1 0
U2 10
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 488
EP +
DI 10.1038/nature15731
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500041
PM 26570999
DA 2026-03-09
ER

PT J
AU Asante, EA
   Smidak, M
   Grimshaw, A
   Houghton, R
   Tomlinson, A
   Jeelani, A
   Jakubcova, T
   Hamdan, S
   Richard-Londt, A
   Linehan, JM
   Brandner, S
   Alpers, M
   Whitfield, J
   Mead, S
   Wadsworth, JDF
   Collinge, J
AF Asante, Emmanuel A.
   Smidak, Michelle
   Grimshaw, Andrew
   Houghton, Richard
   Tomlinson, Andrew
   Jeelani, Asif
   Jakubcova, Tatiana
   Hamdan, Shyma
   Richard-Londt, Angela
   Linehan, Jacqueline M.
   Brandner, Sebastian
   Alpers, Michael
   Whitfield, Jerome
   Mead, Simon
   Wadsworth, Jonathan D. F.
   Collinge, John
TI A naturally occurring variant of the human prion protein completely prevents prion disease
SO NATURE
LA English
DT Article
ID creutzfeldt-jakob-disease; transgenic mice; bse; cjd; phenotype; susceptibility; strains; prp
AB Mammalian prions, transmissible agents causing lethal neuro-degenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP)(1). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru-an acquired prion disease epidemic of the Fore population in Papua New Guinea-and appeared to provide strong protection against disease in the heterozygous state(2). Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G -> V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.
C1 [Asante, Emmanuel A.; Smidak, Michelle; Grimshaw, Andrew; Houghton, Richard; Tomlinson, Andrew; Jeelani, Asif; Jakubcova, Tatiana; Hamdan, Shyma; Richard-Londt, Angela; Linehan, Jacqueline M.; Brandner, Sebastian; Alpers, Michael; Whitfield, Jerome; Mead, Simon; Wadsworth, Jonathan D. F.; Collinge, John] UCL Inst Neurol, Dept Neurodegenerat Dis, MRC Prion Unit, London WC1N 3BG, England.
   [Alpers, Michael; Whitfield, Jerome] Papua New Guinea Inst Med Res, Goroka, Eastern Highlan, Papua N Guinea.
C3 University of London; University College London; PNG Institute Of Medical Research
RP Collinge, J (corresponding author), UCL Inst Neurol, Dept Neurodegenerat Dis, MRC Prion Unit, London WC1N 3BG, England.
EM j.collinge@prion.ucl.ac.uk
FU UK Medical Research Council; Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme; MRC [MC_U123192748, MC_U123160655, MC_U123160653] Funding Source: UKRI; Medical Research Council [MC_U123160655, MC_U123160653, MC_U123192748] Funding Source: researchfish
NR 30
TC 134
Z9 165
U1 3
U2 100
PU NATURE PUBLISHING 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 25
PY 2015
VL 522
IS 7557
BP 478
EP +
DI 10.1038/nature14510
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL2OC
UT WOS:000356782900050
PM 26061765
DA 2026-03-09
ER

PT J
AU Rodriguez, JA
   Ivanova, MI
   Sawaya, MR
   Cascio, D
   Reyes, FE
   Shi, D
   Sangwan, S
   Guenther, EL
   Johnson, LM
   Zhang, M
   Jiang, L
   Arbing, MA
   Nannenga, BL
   Hattne, J
   Whitelegge, J
   Brewster, AS
   Messerschmidt, M
   Boutet, B
   Sauter, NK
   Gonen, T
   Eisenberg, DS
AF Rodriguez, Jose A.
   Ivanova, Magdalena I.
   Sawaya, Michael R.
   Cascio, Duilio
   Reyes, Francis E.
   Shi, Dan
   Sangwan, Smriti
   Guenther, Elizabeth L.
   Johnson, Lisa M.
   Zhang, Meng
   Jiang, Lin
   Arbing, Mark A.
   Nannenga, Brent L.
   Hattne, Johan
   Whitelegge, Julian
   Brewster, Aaron S.
   Messerschmidt, Marc
   Boutet, Bastien
   Sauter, Nicholas K.
   Gonen, Tamir
   Eisenberg, David S.
TI Structure of the toxic core of α-synuclein from invisible crystals
SO NATURE
LA English
DT Article
ID amyloid-like fibrils; parkinsons-disease; x-ray; macromolecular structures; maximum-likelihood; in-vivo; protein; beta; mutation; refinement
AB The protein alpha-synuclein is the main component of Lewy bodies, the neuron-associated aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which we term NACore, appears to be responsible for amyloid formation and cytotoxicity of human alpha-synuclein. Here we describe crystals of NACore that have dimensions smaller than the wavelength of visible light and thus are invisible by optical microscopy. As the crystals are thousands of times too small for structure determination by synchrotron X-ray diffraction, we use micro-electron diffraction to determine the structure at atomic resolution. The 1.4 angstrom resolution structure demonstrates that this method can determine previously unknown protein structures and here yields, to our knowledge, the highest resolution achieved by any cryo-electron microscopy method to date. The structure exhibits protofibrils built of pairs of face-to-face b-sheets. X-ray fibre diffraction patterns show the similarity of NACore to toxic fibrils of full-length alpha-synuclein. The NACore structure, together with that of a second segment, inspires a model for most of the ordered portion of the toxic, full-length alpha-synuclein fibril, presenting opportunities for the design of inhibitors of alpha-synuclein fibrils.
C1 [Rodriguez, Jose A.; Ivanova, Magdalena I.; Sawaya, Michael R.; Cascio, Duilio; Sangwan, Smriti; Guenther, Elizabeth L.; Johnson, Lisa M.; Zhang, Meng; Jiang, Lin; Arbing, Mark A.; Eisenberg, David S.] Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Biol Chem, Dept Chem,Dept Biochem,UCLA DOE Inst, Los Angeles, CA 90095 USA.
   [Reyes, Francis E.; Shi, Dan; Nannenga, Brent L.; Hattne, Johan; Gonen, Tamir] Howard Hughes Med Inst, Ashburn, VA 20147 USA.
   [Whitelegge, Julian] Univ Calif Los Angeles, NPI Semel Inst, Los Angeles, CA 90024 USA.
   [Brewster, Aaron S.; Sauter, Nicholas K.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA.
   [Messerschmidt, Marc; Boutet, Bastien] SLAC Natl Accelerator Lab, Linac Coherent Light Source, Menlo Pk, CA 94025 USA.
C3 University of California System; University of California Los Angeles; United States Department of Energy (DOE); Howard Hughes Medical Institute; Howard Hughes Medical Institute; University of California System; University of California Los Angeles; University of California System; University of California Berkeley; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory
RP Eisenberg, DS (corresponding author), Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Biol Chem, Dept Chem,Dept Biochem,UCLA DOE Inst, Box 951570, Los Angeles, CA 90095 USA.
EM gonent@janelia.hhmi.org; david@mbi.ucla.edu
FU National Institute of General Medical Sciences from the National Institutes of Health [P41 GM103403]; DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]; NIH [GM095887, GM102520]; Office of Science, Department of Energy (DOE) [DE-AC02-05CH11231]; US Department of Energy Office of Science, Office of Biological and Environmental Research program [DE-FC02-02ER63421]; National Science Foundation [MCB-0958111]; National Institutes of Health [1R01-AG029430]; Alzheimer's Disease Research (ADRC) at UCLA [NIH-AG016570]; HHMI; Giannini Foundation; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK063491] Funding Source: NIH RePORTER; Direct For Biological Sciences; Div Of Molecular and Cellular Bioscience [0958111] Funding Source: National Science Foundation
NR 60
TC 523
Z9 626
U1 5
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 SEP 24
PY 2015
VL 525
IS 7570
BP 486
EP +
DI 10.1038/nature15368
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR8KI
UT WOS:000361599900043
PM 26352473
DA 2026-03-09
ER

PT J
AU Dong, JC
   Panchakshari, RA
   Zhang, TT
   Zhang, Y
   Hu, JZ
   Volpi, SA
   Meyers, RM
   Ho, YJ
   Du, Z
   Robbiani, DF
   Meng, FL
   Gostissa, M
   Nussenzweig, MC
   Manis, JP
   Alt, FW
AF Dong, Junchao
   Panchakshari, Rohit A.
   Zhang, Tingting
   Zhang, Yu
   Hu, Jiazhi
   Volpi, Sabrina A.
   Meyers, Robin M.
   Ho, Yu-Jui
   Du, Zhou
   Robbiani, Davide F.
   Meng, Feilong
   Gostissa, Monica
   Nussenzweig, Michel C.
   Manis, John P.
   Alt, Frederick W.
TI Orientation-specific joining of AID-initiated DNA breaks promotes antibody class switching
SO NATURE
LA English
DT Article
ID b-cells; region recombination; v(d)j recombination; chromosome breaks; translocations; mechanisms; resection; lymphoma; 53bp1; rearrangements
AB During B-cell development, RAG endonuclease cleaves immunoglobulin heavy chain (IgH) V, D, and J gene segments and orchestrates their fusion as deletional events that assemble a V(D) J exon in the same transcriptional orientation as adjacent C mu constant region exons(1,2). In mice, six additional sets of constant region exons (C(H)s) lie 100-200 kilobases downstream in the same transcriptional orientation as V(D) J and C mu exons(2). Long repetitive switch (S) regions precede C mu and downstream C(H)s. In mature B cells, class switch recombination (CSR) generates different antibody classes by replacing C mu with a downstream C-H (ref. 2). Activation-induced cytidine deaminase (AID) initiates CSR by promoting deamination lesions within S mu and a downstream acceptor S region(2,3); these lesions are converted into DNA double-strand breaks (DSBs) by general DNA repair factors(3). Productive CSR must occur in a deletional orientation by joining the upstream end of an S mu DSB to the downstream end of an acceptor S-region DSB. However, the relative frequency of deletional to inversional CSR junctions has not been measured. Thus, whether orientation-specific joining is a programmed mechanistic feature of CSR as it is for V(D) J recombination and, if so, how this is achieved is unknown. To address this question, we adapt high-throughput genome-wide translocation sequencing(4) into a highly sensitive DSB end-joining assay and apply it to endogenous AID-initiated S-region DSBs in mouse B cells. We show that CSR is programmed to occur in a productive deletional orientation and does so via an unprecedented mechanism that involves in cis Igh organizational features in combination with frequent S-region DSBs initiated by AID. We further implicate ATM-dependent DSB-response factors in enforcing this mechanism and provide an explanation of why CSR is so reliant on the 53BP1 DSB-response factor.
C1 [Dong, Junchao; Panchakshari, Rohit A.; Zhang, Tingting; Zhang, Yu; Hu, Jiazhi; Meyers, Robin M.; Ho, Yu-Jui; Du, Zhou; Meng, Feilong; Gostissa, Monica; Alt, Frederick W.] Harvard Univ, Sch Med, Boston Childrens Hosp, Howard Hughes Med Inst,Program Cellular & Mol Med, Boston, MA 02115 USA.
   [Dong, Junchao; Panchakshari, Rohit A.; Zhang, Tingting; Zhang, Yu; Hu, Jiazhi; Meyers, Robin M.; Ho, Yu-Jui; Du, Zhou; Meng, Feilong; Gostissa, Monica; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
   [Volpi, Sabrina A.; Manis, John P.] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA 02115 USA.
   [Volpi, Sabrina A.; Manis, John P.] Harvard Univ, Sch Med, Joint Program Transfus Med, Boston, MA 02115 USA.
   [Robbiani, Davide F.; Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, Lab Mol Immunol, New York, NY 10065 USA.
C3 Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Harvard University Medical Affiliates; Boston Children's Hospital; Program in Cellular & Molecular Medicine (PCMM); Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard Medical School; Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Rockefeller University
RP Alt, FW (corresponding author), Harvard Univ, Sch Med, Boston Childrens Hosp, Howard Hughes Med Inst,Program Cellular & Mol Med, Boston, MA 02115 USA.
EM manis@enders.tch.harvard.edu; alt@enders.tch.harvard.edu
FU National Institute of Health [AI077595, CA133781, AI112602, AI037526, AI072529]; NIH [T32HL066987]; Robertson Foundation/Cancer Research Institute Irvington Fellowship; National Heart Lung and Blood Institute [T32HL066987] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [R37AI037526] Funding Source: NIH RePORTER
NR 40
TC 92
Z9 121
U1 0
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 SEP 3
PY 2015
VL 525
IS 7567
BP 134
EP +
DI 10.1038/nature14970
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100040
PM 26308889
DA 2026-03-09
ER

PT J
AU Vaughan, AE
   Brumwell, AN
   Xi, Y
   Gotts, JE
   Brownfield, DG
   Treutlein, B
   Tan, K
   Tan, V
   Liu, FC
   Looney, MR
   Matthay, MA
   Rock, JR
   Chapman, HA
AF Vaughan, Andrew E.
   Brumwell, Alexis N.
   Xi, Ying
   Gotts, Jeffrey E.
   Brownfield, Doug G.
   Treutlein, Barbara
   Tan, Kevin
   Tan, Victor
   Liu, Feng Chun
   Looney, Mark R.
   Matthay, Michael A.
   Rock, Jason R.
   Chapman, Harold A.
TI Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury
SO NATURE
LA English
DT Article
ID stem-cells; in-vitro; alveolar; maintenance; repair; airway; mouse; notch; transplantation; biology
AB Broadly, tissue regeneration is achieved in two ways: by proliferation of common differentiated cells and/or by deployment of specialized stem/progenitor cells. Which of these pathways applies is both organ-and injury-specific(1-4). Current models in the lung posit that epithelial repair can be attributed to cells expressing mature lineage markers(5-8). By contrast, here we define the regenerative role of previously uncharacterized, rare lineage-negative epithelial stem/progenitor (LNEP) cells present within normal distal lung. Quiescent LNEPs activate a Delta Np63 (a p63 splice variant) and cytokeratin 5 remodelling program after influenza or bleomycin injury in mice. Activated cells proliferate and migrate widely to occupy heavily injured areas depleted of mature lineages, at which point they differentiate towards mature epithelium. Lineage tracing revealed scant contribution of pre-existing mature epithelial cells in such repair, whereas orthotopic transplantation of LNEPs, isolated by a definitive surface profile identified through single-cell sequencing, directly demonstrated the proliferative capacity and multipotency of this population. LNEPs require Notch signalling to activate the DNp63 and cytokeratin 5 program, and subsequent Notch blockade promotes an alveolar cell fate. Persistent Notch signalling after injury led to parenchymal 'micro-honeycombing' (alveolar cysts), indicative of failed regeneration. Lungs from patients with fibrosis show analogous honeycomb cysts with evidence of hyperactive Notch signalling. Our findings indicate that distinct stem/progenitor cell pools repopulate injured tissue depending on the extent of the injury, and the outcomes of regeneration or fibrosis may depend in part on the dynamics of LNEP Notch signalling.
C1 [Vaughan, Andrew E.; Brumwell, Alexis N.; Xi, Ying; Gotts, Jeffrey E.; Tan, Kevin; Tan, Victor; Liu, Feng Chun; Looney, Mark R.; Matthay, Michael A.; Chapman, Harold A.] Univ Calif San Francisco, Dept Med, Cardiovasc Res Inst, San Francisco, CA 94143 USA.
   [Brownfield, Doug G.] Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA.
   [Brownfield, Doug G.] Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Treutlein, Barbara] Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, D-04103 Leipzig, Germany.
   [Rock, Jason R.] Univ Calif San Francisco, Sch Med, Dept Anat, San Francisco, CA 94143 USA.
C3 University of California System; University of California San Francisco; Stanford University; Howard Hughes Medical Institute; Max Planck Society; University of California System; University of California San Francisco
RP Vaughan, AE (corresponding author), Univ Calif San Francisco, Dept Med, Cardiovasc Res Inst, San Francisco, CA 94143 USA.
EM andrew.vaughan@ucsf.edu; hal.chapman@ucsf.edu
FU National Institutes of Health (NIH) [R01 HL44712, U01 HL111054]; Daiichi Pharmaceuticals;  [F32 HL117600-01]
NR 24
TC 533
Z9 628
U1 3
U2 120
PU NATURE PUBLISHING 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 29
PY 2015
VL 517
IS 7536
BP 621
EP U211
DI 10.1038/nature14112
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA2ZL
UT WOS:000348775000045
PM 25533958
DA 2026-03-09
ER

PT J
AU Li, ZF
   Bishop, AC
   Alyamani, M
   Garcia, JA
   Dreicer, R
   Bunch, D
   Liu, JY
   Upadhyay, SK
   Auchus, RJ
   Sharifi, N
AF Li, Zhenfei
   Bishop, Andrew C.
   Alyamani, Mohammad
   Garcia, Jorge A.
   Dreicer, Robert
   Bunch, Dustin
   Liu, Jiayan
   Upadhyay, Sunil K.
   Auchus, Richard J.
   Sharifi, Nima
TI Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer
SO NATURE
LA English
DT Article
ID 3-beta-hydroxysteroid dehydrogenase; cyp17a1 inhibition; increased survival; androgen receptor; testosterone; enzalutamide; rationale; mechanism; exposure; target
AB Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5 alpha-dihydrotestosterone (DHT), promoting signalling by the androgen receptor and the development of castration-resistant prostate cancer(1-3). Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly requires enzymatic reactions by 3 beta-hydroxysteroid dehydrogenase (3 beta HSD), steroid-5 alpha-reductase (SRD5A) and 17 beta-hydroxysteroid dehydrogenase (17 beta HSD) isoenzymes(4,5). Abiraterone, a steroidal 17 alpha-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival(6,7). We hypothesized that abiraterone is converted by an enzyme to the more active Delta(4)-abiraterone (D4A), which blocks multiple steroidogenic enzymes and antagonizes the androgen receptor, providing an additional explanation for abiraterone's clinical activity. Here we show that abiraterone is converted to D4A in mice and patients with prostate cancer. D4A inhibits CYP17A1, 3 beta HSD and SRD5A, which are required for DHT synthesis. Furthermore, competitive androgen receptor antagonism by D4A is comparable to the potent antagonist enzalutamide. D4A also has more potent anti-tumour activity against xenograft tumours than abiraterone. Our findings suggest an additional explanation-conversion to a more active agent-for abiraterone's survival extension. We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment.
C1 [Li, Zhenfei; Bishop, Andrew C.; Alyamani, Mohammad; Sharifi, Nima] Cleveland Clin, Lerner Res Inst, Dept Canc Biol, Cleveland, OH 44195 USA.
   [Garcia, Jorge A.; Dreicer, Robert; Sharifi, Nima] Cleveland Clin, Taussig Canc Inst, Dept Hematol & Oncol, Cleveland, OH 44195 USA.
   [Garcia, Jorge A.; Dreicer, Robert; Sharifi, Nima] Cleveland Clin, Glickman Urol & Kidney Inst, Dept Urol, Cleveland, OH 44195 USA.
   [Bunch, Dustin] Cleveland Clin, Dept Lab Med Pathol & Lab, Inst Med, Cleveland, OH 44195 USA.
   [Liu, Jiayan; Upadhyay, Sunil K.; Auchus, Richard J.] Univ Michigan, Sch Med, Dept Internal Med, Div Endocrinol & Metab, Ann Arbor, MI 48109 USA.
   [Auchus, Richard J.] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA.
C3 Cleveland Clinic Foundation; Cleveland Clinic Foundation; Cleveland Clinic Foundation; Cleveland Clinic Foundation; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan
RP Sharifi, N (corresponding author), Cleveland Clin, Lerner Res Inst, Dept Canc Biol, Cleveland, OH 44195 USA.
EM sharifn@ccf.org
FU Howard Hughes Physician-Scientist Early Career Award; Prostate Cancer Foundation; American Cancer Society [12-038-01-CCE]; US Army Medical Research and Materiel Command [PC080193, PC121382]; National Cancer Institute [R01CA168899, R01CA172382, R01CA190289]; National Cancer Institute [R01CA172382] Funding Source: NIH RePORTER
NR 26
TC 214
Z9 248
U1 0
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 JUL 16
PY 2015
VL 523
IS 7560
BP 347
EP +
DI 10.1038/nature14406
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM8KY
UT WOS:000357950900042
PM 26030522
DA 2026-03-09
ER

PT J
AU Andersen, DS
   Colombani, J
   Palmerini, V
   Chakrabandhu, K
   Boone, E
   Röthlisberger, M
   Toggweiler, J
   Basler, K
   Mapelli, M
   Hueber, AO
   Léopold, P
AF Andersen, Ditte S.
   Colombani, Julien
   Palmerini, Valentina
   Chakrabandhu, Krittalak
   Boone, Emilie
   Roethlisberger, Michael
   Toggweiler, Janine
   Basler, Konrad
   Mapelli, Marina
   Hueber, Anne-Odile
   Leopold, Pierre
TI The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth
SO NATURE
LA English
DT Article
ID tumor-suppressor; retinal degeneration; genetic screen; crumbs complex; oncogenic ras; eiger; superfamily; melanogaster; activation; mechanism
AB Disruption of epithelial polarity is a key event in the acquisition of neoplastic growth. JNK signalling is known to play an important part in driving the malignant progression of many epithelial tumours, although the link between loss of polarity and JNK signalling remains elusive. In a Drosophila genome-wide genetic screen designed to identify molecules implicated in neoplastic growth(1), we identified grindelwald (grnd), a gene encoding a transmembrane protein with homology to members of the tumour necrosis factor receptor (TNFR) superfamily. Here we show that Grnd mediates the pro-apoptotic functions of Eiger (Egr), the unique Drosophila TNF, and that overexpression of an active form of Grnd lacking the extracellular domain is sufficient to activate JNK signalling in vivo. Grnd also promotes the invasiveness of Ras(V12)/scrib(-/-) tumours through Egr-dependent Matrix metallo-protease-1 (Mmp1) expression. Grnd localizes to the subapical membrane domain with the cell polarity determinant Crumbs (Crb) and couples Crb-induced loss of polarity with JNK activation and neoplastic growth through physical interaction with Veli (also known as Lin-7). Therefore, Grnd represents the first example of a TNFR that integrates signals from both Egr and apical polarity determinants to induce JNK-dependent cell death or tumour growth.
C1 [Andersen, Ditte S.; Colombani, Julien; Chakrabandhu, Krittalak; Boone, Emilie; Hueber, Anne-Odile; Leopold, Pierre] Univ Nice Sophia Antipolis, Inst Biol Valrose, F-06108 Nice, France.
   [Andersen, Ditte S.; Colombani, Julien; Chakrabandhu, Krittalak; Boone, Emilie; Hueber, Anne-Odile; Leopold, Pierre] CNRS, Inst Biol Valrose, F-06108 Nice, France.
   [Andersen, Ditte S.; Colombani, Julien; Chakrabandhu, Krittalak; Boone, Emilie; Hueber, Anne-Odile; Leopold, Pierre] INSERM, Inst Biol Valrose, F-06108 Nice, France.
   [Andersen, Ditte S.; Colombani, Julien; Boone, Emilie; Leopold, Pierre] Inst Biol Valrose, Genet & Physiol Growth Lab, F-06108 Nice, France.
   [Palmerini, Valentina; Mapelli, Marina] European Inst Oncol, Dept Expt Oncol, I-20139 Milan, Italy.
   [Chakrabandhu, Krittalak; Hueber, Anne-Odile] Inst Biol Valrose, Death Receptors Signalling & Canc Therapy Lab, F-06108 Nice, France.
   [Roethlisberger, Michael; Toggweiler, Janine; Basler, Konrad] Univ Zurich, Inst Mol Life Sci, CH-8057 Zurich, Switzerland.
C3 Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Cote d'Azur; Centre National de la Recherche Scientifique (CNRS); Universite Cote d'Azur; Institut National de la Sante et de la Recherche Medicale (Inserm); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Cote d'Azur; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Cote d'Azur; IRCCS European Institute of Oncology (IEO); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Cote d'Azur; University of Zurich
RP Colombani, J (corresponding author), Univ Nice Sophia Antipolis, Inst Biol Valrose, Parc Valrose, F-06108 Nice, France.
EM julien.colombani@unice.fr; leopold@unice.fr
FU CNRS; INSERM; Agence Nationale de la Recherche; Fondation pour la Recherche Medicale; Association pour la Recherche contre le Cancer [PJA20131200042]; European Research Council [268813]; Marie Curie Life Long Training grant [252373]; Labex Signalife program [ANR-11-LABX-0028-01]; Italian Association for Cancer Research (AIRC) [IG-12877]; Italian Ministry of Health [GR-2008-1134103]
NR 33
TC 141
Z9 159
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 JUN 25
PY 2015
VL 522
IS 7557
BP 482
EP +
DI 10.1038/nature14298
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL2OC
UT WOS:000356782900051
PM 25874673
DA 2026-03-09
ER

PT J
AU Gurdasani, D
   Carstensen, T
   Tekola-Ayele, F
   Pagani, L
   Tachmazidou, I
   Hatzikotoulas, K
   Karthikeyan, S
   Iles, L
   Pollard, MO
   Choudhury, A
   Ritchie, GS
   Xue, YL
   Asimit, J
   Nsubuga, RN
   Young, EH
   Pomilla, C
   Kivinen, K
   Rockett, K
   Kamali, A
   Doumatey, AP
   Asiki, G
   Seeley, J
   Sisay-Joof, F
   Jallow, M
   Tollman, S
   Mekonnen, E
   Ekong, R
   Oljira, T
   Bradman, N
   Bojang, K
   Ramsay, M
   Adeyemo, A
   Bekele, E
   Motala, A
   Norris, SA
   Pirie, F
   Kaleebu, P
   Kwiatkowski, D
   Tyler-Smith, C
   Rotimi, C
   Zeggini, E
   Sandhu, MS
AF Gurdasani, Deepti
   Carstensen, Tommy
   Tekola-Ayele, Fasil
   Pagani, Luca
   Tachmazidou, Ioanna
   Hatzikotoulas, Konstantinos
   Karthikeyan, Savita
   Iles, Louise
   Pollard, Martin O.
   Choudhury, Ananyo
   Ritchie, GrahamR. S.
   Xue, Yali
   Asimit, Jennifer
   Nsubuga, Rebecca N.
   Young, Elizabeth H.
   Pomilla, Cristina
   Kivinen, Katja
   Rockett, Kirk
   Kamali, Anatoli
   Doumatey, Ayo P.
   Asiki, Gershim
   Seeley, Janet
   Sisay-Joof, Fatoumatta
   Jallow, Muminatou
   Tollman, Stephen
   Mekonnen, Ephrem
   Ekong, Rosemary
   Oljira, Tamiru
   Bradman, Neil
   Bojang, Kalifa
   Ramsay, Michele
   Adeyemo, Adebowale
   Bekele, Endashaw
   Motala, Ayesha
   Norris, Shane A.
   Pirie, Fraser
   Kaleebu, Pontiano
   Kwiatkowski, Dominic
   Tyler-Smith, Chris
   Rotimi, Charles
   Zeggini, Eleftheria
   Sandhu, Manjinder S.
TI The African Genome Variation Project shapes medical genetics in Africa
SO NATURE
LA English
DT Article
ID population-genetics; malaria; selection; wide; susceptibility; reveals; association; diversity; variants; ancestry
AB Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa.
C1 [Gurdasani, Deepti; Carstensen, Tommy; Pagani, Luca; Tachmazidou, Ioanna; Hatzikotoulas, Konstantinos; Karthikeyan, Savita; Iles, Louise; Pollard, Martin O.; Ritchie, GrahamR. S.; Xue, Yali; Asimit, Jennifer; Young, Elizabeth H.; Pomilla, Cristina; Kivinen, Katja; Adeyemo, Adebowale; Kwiatkowski, Dominic; Tyler-Smith, Chris; Zeggini, Eleftheria; Sandhu, Manjinder S.] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.
   [Gurdasani, Deepti; Carstensen, Tommy; Karthikeyan, Savita; Iles, Louise; Young, Elizabeth H.; Pomilla, Cristina; Sandhu, Manjinder S.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England.
   [Tekola-Ayele, Fasil; Doumatey, Ayo P.; Adeyemo, Adebowale; Rotimi, Charles] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20891 USA.
   [Pagani, Luca] Univ Bologna, Dept Biol Geol & Environm Sci, I-40126 Bologna, Italy.
   [Iles, Louise] Univ York, Dept Archaeol, York YO1 7EP, N Yorkshire, England.
   [Choudhury, Ananyo; Ramsay, Michele] Univ Witwatersrand, SBIMB, Johannesburg, Gauteng, South Africa.
   [Ritchie, GrahamR. S.] European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England.
   [Nsubuga, Rebecca N.; Kamali, Anatoli; Asiki, Gershim; Seeley, Janet; Kaleebu, Pontiano] Uganda Virus Res Inst, MRC, Entebbe, Uganda.
   [Rockett, Kirk; Kwiatkowski, Dominic] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.
   [Sisay-Joof, Fatoumatta; Jallow, Muminatou; Bojang, Kalifa] MRC Unit, Banjul, Gambia.
   [Tollman, Stephen] MRC, Sch Publ Hlth, Wits Rural Publ Hlth & Hlth Transit Unit, Johannesburg, Gauteng, South Africa.
   [Tollman, Stephen] INDEPTH Network, Accra, Ghana.
   [Mekonnen, Ephrem] Univ Addis Ababa, Inst Biotechnol, Addis Ababa, Ethiopia.
   [Ekong, Rosemary] UCL, Dept Genet Evolut & Environm, London, England.
   [Oljira, Tamiru] Univ Haramaya, Dept Biol, Dire Dawa, Ethiopia.
   [Bradman, Neil] Henry Stewart Grp, London WC1A 2HN, England.
   [Ramsay, Michele] Natl Hlth Lab Serv, Div Human Genet, ZA-2000 Johannesburg, South Africa.
   [Ramsay, Michele] Univ Witwatersrand, Fac Hlth Sci, Sch Pathol, ZA-2000 Johannesburg, South Africa.
   [Bekele, Endashaw] Univ Addis Ababa, Coll Nat Sci, Dept Microbial Cellular & Mol Biol, Addis Ababa, Ethiopia.
   [Motala, Ayesha; Pirie, Fraser] Univ KwaZulu Natal, Dept Endocrinol & Diabet, ZA-4013 Durban, South Africa.
   [Norris, Shane A.] Univ Witwatersrand, Dept Paediat, Johannesburg, Gauteng, South Africa.
C3 Wellcome Trust Sanger Institute; University of Cambridge; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI); University of Bologna; University of York - UK; University of Witwatersrand; European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute; Uganda Virus Research Institute; University of Oxford; Wellcome Centre for Human Genetics; University of London; London School of Hygiene & Tropical Medicine; INDEPTH Network; Addis Ababa University; University of London; University College London; Haramaya University; National Health Laboratory Service; University of Witwatersrand; Addis Ababa University; University of Kwazulu Natal; University of Witwatersrand
RP Sandhu, MS (corresponding author), Wellcome Trust Sanger Inst, Genome Campus, Cambridge CB10 1SA, England.
EM dg11@sanger.ac.uk; cts@sanger.ac.uk; rotimic@mail.nih.gov; eleftheria@sanger.ac.uk; ms23@sanger.ac.uk
FU Wellcome Trust [WT077383/Z/05/Z]; Wellcome Trust Sanger Institute [WT098051]; Bill and Melinda Gates Foundation; Foundation for the National Institutes of Health [566]; UK Medical Research Council [G0901213-92157, G0801566, G0600718, MR/K013491/1]; South African Sugar Association; Servier South Africa; Victor Daitz Foundation; National Institute on Minority Health and Health Disparities; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Human Genome Research Institute (NHGRI); Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH) [Z01HG200362]; MRC Centre for Genomics and Global Health; Cambridge Commonwealth Scholarship; MRC [G0600718, G0901213, G1001333, MR/K013491/1, G0801566, MC_UP_A900_1118] Funding Source: UKRI; Medical Research Council [MC_UP_A900_1118, G0901213, G0600718, G0801566, G1001333, MR/K013491/1] Funding Source: researchfish; National Institute for Health Research [NF-SI-0513-10012] Funding Source: researchfish; National Human Genome Research Institute [ZIAHG200362] Funding Source: NIH RePORTER
NR 50
TC 450
Z9 514
U1 0
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 15
PY 2015
VL 517
IS 7534
BP 327
EP U397
DI 10.1038/nature13997
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300037
PM 25470054
DA 2026-03-09
ER

PT J
AU White, MD
   Payne, KAP
   Fisher, K
   Marshall, SA
   Parker, D
   Rattray, NJW
   Trivedi, DK
   Goodacre, R
   Rigby, SEJ
   Scrutton, NS
   Hay, S
   Leys, D
AF White, Mark D.
   Payne, Karl A. P.
   Fisher, Karl
   Marshall, Stephen A.
   Parker, David
   Rattray, Nicholas J. W.
   Trivedi, Drupad K.
   Goodacre, Royston
   Rigby, Stephen E. J.
   Scrutton, Nigel S.
   Hay, Sam
   Leys, David
TI UbiX is a flavin prenyltransferase required for bacterial ubiquinone biosynthesis
SO NATURE
LA English
DT Article
ID isopentenyl diphosphate isomerase; coenzyme-q; acid decarboxylase; flavoenzymes; catalysts; identification; carboxylases; pathways; pad1
AB Ubiquinone (also known as coenzyme Q) is a ubiquitous lipid-soluble redox cofactor that is an essential component of electron transfer chains(1). Eleven genes have been implicated in bacterial ubiquinone biosynthesis, including ubiX and ubiD, which are responsible for decarboxylation of the 3-octaprenyl-4-hydroxy-benzoate precursor(2). Despite structural and biochemical characterization of UbiX as a flavin mononucleotide (FMN)-binding protein, no decarboxylase activity has been detected(3,4). Here we report that UbiX produces a novel flavin-derived cofactor required for the decarboxylase activity of UbiD(5). UbiX acts as a flavin prenyltransferase, linking a dimethylallyl moiety to the flavin N5 and C6 atoms. This adds a fourth non-aromatic ring to the flavin isoalloxazine group. In contrast to other prenyltransferases(6,7), UbiX is metal-independent and requires dimethylallyl-monophosphate as substrate. Kinetic crystallography reveals that the prenyltransferase mechanism of UbiX resembles that of the terpene synthases(8). The active site environment is dominated by pi systems, which assist phosphate-C1' bond breakage following FMN reduction, leading to formation of the N5-C1' bond. UbiX then acts as a chaperone for adduct reorientation, via transient carbocation species, leading ultimately to formation of the dimethylallyl C3'-C6 bond. Our findings establish the mechanism for formation of a new flavin-derived cofactor, extending both flavin and terpenoid biochemical repertoires.
C1 [White, Mark D.; Payne, Karl A. P.; Fisher, Karl; Marshall, Stephen A.; Rattray, Nicholas J. W.; Trivedi, Drupad K.; Goodacre, Royston; Rigby, Stephen E. J.; Scrutton, Nigel S.; Hay, Sam; Leys, David] Univ Manchester, Manchester Inst Biotechnol, Ctr Synthet Biol Fine & Special Chem, Manchester M1 7DN, Lancs, England.
   [Parker, David] Westhollow Technol Ctr, Innovat Biodomain Shell Int Explorat & Prod, Houston, TX 77082 USA.
C3 University of Manchester
RP Leys, D (corresponding author), Univ Manchester, Manchester Inst Biotechnol, Ctr Synthet Biol Fine & Special Chem, Manchester M1 7DN, Lancs, England.
EM david.leys@manchester.ac.uk
FU BBSRC [BB/K017802/1, BB/M017702/1]; Royal Society; BBSRC [BB/E013007/1, BB/H021523/1, BB/K017802/1, BB/M017702/1] Funding Source: UKRI; EPSRC [EP/J020192/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/E013007/1, BB/M017702/1, BB/K017802/1, BB/H021523/1] Funding Source: researchfish; Engineering and Physical Sciences Research Council [EP/J020192/1] Funding Source: researchfish
NR 30
TC 154
Z9 206
U1 3
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 JUN 25
PY 2015
VL 522
IS 7557
BP 502
EP +
DI 10.1038/nature14559
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL2OC
UT WOS:000356782900055
PM 26083743
DA 2026-03-09
ER

PT J
AU Simakov, O
   Kawashima, T
   Marlétaz, F
   Jenkins, J
   Koyanagi, R
   Mitros, T
   Hisata, K
   Bredeson, J
   Shoguchi, E
   Gyoja, F
   Yue, JX
   Chen, YC
   Freeman, RM
   Sasaki, A
   Hikosaka-Katayama, T
   Sato, A
   Fujie, M
   Baughman, KW
   Levine, J
   Gonzalez, P
   Cameron, C
   Fritzenwanker, JH
   Pani, AM
   Goto, H
   Kanda, M
   Arakaki, N
   Yamasaki, S
   Qu, J
   Cree, A
   Ding, Y
   Dinh, HH
   Dugan, S
   Holder, M
   Jhangiani, SN
   Kovar, CL
   Lee, SL
   Lewis, LR
   Morton, D
   Nazareth, LV
   Okwuonu, G
   Santibanez, J
   Chen, R
   Richards, S
   Muzny, DM
   Gillis, A
   Peshkin, L
   Wu, M
   Humphreys, T
   Su, YH
   Putnam, NH
   Schmutz, J
   Fujiyama, A
   Yu, JK
   Tagawa, K
   Worley, KC
   Gibbs, RA
   Kirschner, MW
   Lowe, CJ
   Satoh, N
   Rokhsar, DS
   Gerhart, J
AF Simakov, Oleg
   Kawashima, Takeshi
   Marletaz, Ferdinand
   Jenkins, Jerry
   Koyanagi, Ryo
   Mitros, Therese
   Hisata, Kanako
   Bredeson, Jessen
   Shoguchi, Eiichi
   Gyoja, Fuki
   Yue, Jia-Xing
   Chen, Yi-Chih
   Freeman, Robert M., Jr.
   Sasaki, Akane
   Hikosaka-Katayama, Tomoe
   Sato, Atsuko
   Fujie, Manabu
   Baughman, Kenneth W.
   Levine, Judith
   Gonzalez, Paul
   Cameron, Christopher
   Fritzenwanker, Jens H.
   Pani, Ariel M.
   Goto, Hiroki
   Kanda, Miyuki
   Arakaki, Nana
   Yamasaki, Shinichi
   Qu, Jiaxin
   Cree, Andrew
   Ding, Yan
   Dinh, Huyen H.
   Dugan, Shannon
   Holder, Michael
   Jhangiani, Shalini N.
   Kovar, Christie L.
   Lee, Sandra L.
   Lewis, Lora R.
   Morton, Donna
   Nazareth, Lynne V.
   Okwuonu, Geoffrey
   Santibanez, Jireh
   Chen, Rui
   Richards, Stephen
   Muzny, Donna M.
   Gillis, Andrew
   Peshkin, Leonid
   Wu, Michael
   Humphreys, Tom
   Su, Yi-Hsien
   Putnam, Nicholas H.
   Schmutz, Jeremy
   Fujiyama, Asao
   Yu, Jr-Kai
   Tagawa, Kunifumi
   Worley, Kim C.
   Gibbs, Richard A.
   Kirschner, Marc W.
   Lowe, Christopher J.
   Satoh, Noriyuki
   Rokhsar, Daniel S.
   Gerhart, John
TI Hemichordate genomes and deuterostome origins
SO NATURE
LA English
DT Article
ID ptychodera-flava; phylogenetic analyses; regulatory landscape; chordate origins; evolution; organization; database; identification; expression; genes
AB Acorn worms, also known as enteropneust (literally, 'gut-breathing') hemichordates, are marine invertebrates that share features with echinoderms and chordates. Together, these three phyla comprise the deuterostomes. Here we report the draft genome sequences of two acorn worms, Saccoglossus kowalevskii and Ptychodera flava. By comparing them with diverse bilaterian genomes, we identify shared traits that were probably inherited from the last common deuterostome ancestor, and then explore evolutionary trajectories leading from this ancestor to hemichordates, echinoderms and chordates. The hemichordate genomes exhibit extensive conserved synteny with amphioxus and other bilaterians, and deeply conserved non-coding sequences that are candidates for conserved gene-regulatory elements. Notably, hemichordates possess a deuterostome-specific genomic cluster of four ordered transcription factor genes, the expression of which is associated with the development of pharyngeal 'gill' slits, the foremost morphological innovation of early deuterostomes, and is probably central to their filter-feeding lifestyle. Comparative analysis reveals numerous deuterostome-specific gene novelties, including genes found in deuterostomes and marine microbes, but not other animals. The putative functions of these genes can be linked to physiological, metabolic and developmental specializations of the filter-feeding ancestor.
C1 [Simakov, Oleg; Rokhsar, Daniel S.] Grad Univ, Okinawa Inst Sci & Technol, Mol Genet Unit, Onna, Okinawa 9040495, Japan.
   [Simakov, Oleg] Heidelberg Univ, Dept Mol Evolut, Ctr Organismal Studies, D-69115 Heidelberg, Germany.
   [Kawashima, Takeshi; Hisata, Kanako; Shoguchi, Eiichi; Gyoja, Fuki; Baughman, Kenneth W.; Satoh, Noriyuki] Grad Univ, Okinawa Inst Sci & Technol, Marine Genom Unit, Onna, Okinawa 9040495, Japan.
   [Marletaz, Ferdinand] Univ Oxford, Dept Zool, Oxford OX1 3PS, England.
   [Jenkins, Jerry; Schmutz, Jeremy] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA.
   [Koyanagi, Ryo; Fujie, Manabu; Goto, Hiroki; Kanda, Miyuki; Arakaki, Nana; Yamasaki, Shinichi] Grad Univ, Okinawa Inst Sci & Technol, DNA Sequencing Sect, Onna, Okinawa 9040495, Japan.
   [Mitros, Therese; Bredeson, Jessen; Wu, Michael; Rokhsar, Daniel S.; Gerhart, John] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
   [Yue, Jia-Xing; Putnam, Nicholas H.] Rice Univ, Dept Ecol & Evolutionary Biol, Houston, TX 77005 USA.
   [Chen, Yi-Chih; Su, Yi-Hsien; Yu, Jr-Kai] Acad Sinica, Inst Cellular & Organism Biol, Taipei 11529, Taiwan.
   [Freeman, Robert M., Jr.; Peshkin, Leonid; Kirschner, Marc W.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA.
   [Sasaki, Akane; Tagawa, Kunifumi] Hiroshima Univ, Grad Sch Sci, Marine Biol Lab, Onomichi, Hiroshima 7220073, Japan.
   [Hikosaka-Katayama, Tomoe] Hiroshima Univ, Gene Sci Div, Nat Sci Ctr Basic Res & Dev, Hiroshima 7398527, Japan.
   [Sato, Atsuko] Marine Biol Assoc UK, Lab, Plymouth PL1 2PB, Devon, England.
   [Levine, Judith; Gonzalez, Paul; Fritzenwanker, Jens H.; Lowe, Christopher J.] Stanford Univ, Dept Biol, Hopkins Marine Stn, Pacific Grove, CA 93950 USA.
   [Cameron, Christopher] Univ Montreal, Dept Sci Biol, Montreal, PQ H3C 3J7, Canada.
   [Pani, Ariel M.] Univ N Carolina, Chapel Hill, NC 27599 USA.
   [Qu, Jiaxin; Cree, Andrew; Ding, Yan; Dinh, Huyen H.; Dugan, Shannon; Holder, Michael; Jhangiani, Shalini N.; Kovar, Christie L.; Lee, Sandra L.; Lewis, Lora R.; Morton, Donna; Nazareth, Lynne V.; Okwuonu, Geoffrey; Santibanez, Jireh; Chen, Rui; Richards, Stephen; Muzny, Donna M.; Worley, Kim C.; Gibbs, Richard A.] Baylor Coll Med, Dept Mol & Human Genet, Human Genome Sequencing Ctr, Houston, TX 77030 USA.
   [Gillis, Andrew] Univ Cambridge, Dept Zool, Cambridge CB2 3EJ, England.
   [Humphreys, Tom] Univ Hawaii, Inst Biogenesis Res, Honolulu, HI 96822 USA.
   [Fujiyama, Asao] Natl Inst Genet, Mishima, Shizuoka 4113540, Japan.
   [Rokhsar, Daniel S.] US DOE, Joint Genome Inst, Walnut Creek, CA 94598 USA.
C3 Okinawa Institute of Science & Technology Graduate University; Ruprecht Karls University Heidelberg; Okinawa Institute of Science & Technology Graduate University; University of Oxford; HudsonAlpha Institute for Biotechnology; Okinawa Institute of Science & Technology Graduate University; University of California System; University of California Berkeley; Rice University; Academia Sinica - Taiwan; Harvard University; Harvard Medical School; Hiroshima University; Hiroshima University; Marine Biological Association United Kingdom; Stanford University; Universite de Montreal; University of North Carolina; University of North Carolina Chapel Hill; Baylor College of Medicine; University of Cambridge; University of Hawaii System; Research Organization of Information & Systems (ROIS); National Institute of Genetics (NIG) - Japan; United States Department of Energy (DOE); Joint BioEnergy Institute - JBEI; Joint Genome Institute - JGI
RP Simakov, O (corresponding author), Grad Univ, Okinawa Inst Sci & Technol, Mol Genet Unit, Onna, Okinawa 9040495, Japan.
EM oleg.simakov@oist.jp; norisky@oist.jp; dsrokhsar@gmail.com; jgerhart@berkeley.edu
FU MEXT; OIST, Japan; USPHS [HD42724, HD37277]; NASA [FDNAG2-1605, NNX13AI68G]; FP7/ERC grant [268513]; Molecular Genetics Unit of the Okinawa Institute of Science and Technology Graduate University; Marine Genomics Unit of the Okinawa Institute of Science and Technology Graduate University; Academia Sinica; Ministry of Science and Technology, Taiwan; NIH [R01HD073104]; National Human Genome Research Institute, National Institutes of Health [U54 HG003273]; NASA [473378, NNX13AI68G] Funding Source: Federal RePORTER; Eunice Kennedy Shriver National Institute of Child Health and Human Development [T32HD055164, R01HD073104] Funding Source: NIH RePORTER
NR 68
TC 195
Z9 211
U1 2
U2 102
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 459
EP +
DI 10.1038/nature16150
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500036
PM 26580012
DA 2026-03-09
ER

PT J
AU Stüeken, EE
   Buick, R
   Guy, BM
   Koehler, MC
AF Stueeken, Eva E.
   Buick, Roger
   Guy, Bradley M.
   Koehler, Matthew C.
TI Isotopic evidence for biological nitrogen fixation by molybdenum-nitrogenase from 3.2 Gyr
SO NATURE
LA English
DT Article
ID ocean; fractionation; oxygenation; limitation; chemistry; ammonia; nitrate
AB Nitrogen is an essential nutrient for all organisms that must have been available since the origin of life. Abiotic processes including hydrothermal reduction', photochemical reactions', or lightning disc(h)arge' could have converted atmospheric Ny into assimilable NH4, HCN, or NO species, collectively termed fixed nitrogen. But these sources may have been small on the early Earth, severely limiting the size of the primordial biosphere'. The evolution of the nitrogenfixing enzyme nitrogenase, which reduces atmospheric Ny to organic NH4, thus represented a major breakthrough in the radiation of life, but its timing is uncertain'''. Here we present nitrogen isotope ratios with a mean of 0.0 1.2%0 from marine and fluvial sedimentary rocks of prehnite-pumpellyite to greenschist metamorphic grade between 3.2 and 2.75 billion years ago. These data cannot readily be explained by abiotic processes and therefore suggest biological nitrogen fixation, most probably using molybdenum-based nitrogenase as opposed to other variants that impart significant negative fractionations'. Our data place a minimum age constraint of 3.2 billion years on the origin of biological nitrogen fixation and suggest that molybdenum was bioavailable in the mid-Archaean ocean long before the Great Oxidation Event.
C1 [Stueeken, Eva E.; Buick, Roger; Koehler, Matthew C.] Univ Washington, Dept Earth & Space Sci, Seattle, WA 98195 USA.
   [Stueeken, Eva E.; Buick, Roger; Koehler, Matthew C.] Univ Washington, Astrobiol Program, Seattle, WA 98195 USA.
   [Guy, Bradley M.] Univ Johannesburg, Dept Geol, ZA-2006 Auckland Pk, South Africa.
C3 University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Johannesburg
RP Stüeken, EE (corresponding author), Univ Washington, Dept Earth & Space Sci, Seattle, WA 98195 USA.
EM evast@uw.edu
FU Virtual Planetary Laboratory at the University of Washington; Geological Society of America; Agouron Institute; Division Of Earth Sciences; Directorate For Geosciences [1338810] Funding Source: National Science Foundation
NR 38
TC 235
Z9 278
U1 7
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 APR 30
PY 2015
VL 520
IS 7549
BP 666
EP U178
DI 10.1038/nature14180
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700047
PM 25686600
DA 2026-03-09
ER

PT J
AU Ceccaldi, R
   Liu, JC
   Amunugama, R
   Hajdu, I
   Primack, B
   Petalcorin, MIR
   O'Connor, KW
   Konstantinopoulos, PA
   Elledge, SJ
   Boulton, SJ
   Yusufzai, T
   D'Andrea, AD
AF Ceccaldi, Raphael
   Liu, Jessica C.
   Amunugama, Ravindra
   Hajdu, Ildiko
   Primack, Benjamin
   Petalcorin, Mark I. R.
   O'Connor, Kevin W.
   Konstantinopoulos, Panagiotis A.
   Elledge, Stephen J.
   Boulton, Simon J.
   Yusufzai, Timur
   D'Andrea, Alan D.
TI Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair
SO NATURE
LA English
DT Article
ID strand break repair; dna-damage; ovarian-cancer; genomic instability; hematopoietic stem; fanconi-anemia; human-cells; polymerase; pathway; chemotherapy
AB Large-scale genomic studies have shown that half of epithelial ovarian cancers (EOCs) have alterations in genes regulating homologous recombination (HR) repair(1). Loss of HR accounts for the genomic instability of EOCs and for their cellular hyper-dependence on alternative poly-ADP ribose polymerase (PARP)-mediated DNA repair mechanisms(2-5). Previous studies have implicated the DNA polymerase theta (Pol theta also known as POLQ, encoded by POLQ) 6 in a pathway required for the repair of DNA double-strand breaks(7-9), referred to as the error-prone microhomology-mediated end-joining (MMEJ) pathway(10-13). Whether Pol theta interacts with canonical DNA repair pathways to prevent genomic instability remains unknown. Here we report an inverse correlation between HR activity and Pol theta expression in EOCs. Knockdown of Pol theta in HR-proficient cells upregulates HR activity and RAD51 nucleofilament assembly, while knockdown of Pol theta in HR-deficient EOCs enhances cell death. Consistent with these results, genetic inactivation of an HR gene (Fancd2) and Polq in mice results in embryonic lethality. Moreover, Pol theta contains RAD51 binding motifs and it blocks RAD51-mediated recombination. Our results reveal a synthetic lethal relationship between the HR pathway and Pol theta-mediated repair in EOCs, and identify Pol theta as a novel druggable target for cancer therapy.
C1 [Ceccaldi, Raphael; Liu, Jessica C.; Primack, Benjamin; O'Connor, Kevin W.; Yusufzai, Timur; D'Andrea, Alan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA.
   [Liu, Jessica C.; Yusufzai, Timur] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA.
   [Liu, Jessica C.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA.
   [Amunugama, Ravindra] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA.
   [Hajdu, Ildiko; Elledge, Stephen J.] Brigham & Womens Hosp, Howard Hughes Med Inst, Div Genet, Boston, MA 02215 USA.
   [Petalcorin, Mark I. R.; Boulton, Simon J.] London Res Inst, Canc Res UK, DNA Damage Response Lab, S Mimms EN6 3LD, Herts, England.
   [Konstantinopoulos, Panagiotis A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Med Gynecol Oncol Program, Boston, MA 02215 USA.
C3 Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University; Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Cancer Research UK; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute
RP D'Andrea, AD (corresponding author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA.
EM alan_dandrea@dfci.harvard.edu
FU Philippe Foundation; Ovarian Cancer Research Fellowship (OCRF); NIH [P50CA168504, R01HL52725]; OCRF; BCRF; 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 [P50CA168504] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [R01HL052725] Funding Source: NIH RePORTER
NR 39
TC 716
Z9 913
U1 4
U2 149
PU NATURE PUBLISHING 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 12
PY 2015
VL 518
IS 7538
BP 258
EP U306
DI 10.1038/nature14184
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300044
PM 25642963
DA 2026-03-09
ER

PT J
AU Spitale, RC
   Flynn, RA
   Zhang, QC
   Crisalli, P
   Lee, B
   Jung, JW
   Kuchelmeister, HY
   Batista, PJ
   Torre, EA
   Kool, ET
   Chang, HY
AF Spitale, Robert C.
   Flynn, Ryan A.
   Zhang, Qiangfeng Cliff
   Crisalli, Pete
   Lee, Byron
   Jung, Jong-Wha
   Kuchelmeister, Hannes Y.
   Batista, Pedro J.
   Torre, Eduardo A.
   Kool, Eric T.
   Chang, Howard Y.
TI Structural imprints in vivo decode RNA regulatory mechanisms
SO NATURE
LA English
DT Article
ID genome-wide measurement; secondary structure; reveals; methylation; sequences; recognition; expression; vertebrate; proteins
AB Visualizing the physical basis for molecular behaviour inside living cells is a great challenge for biology. RNAs are central to biological regulation, and the ability of RNA to adopt specific structures intimately controls every step of the gene expression program(1). However, our understanding of physiological RNA structures is limited; current in vivo RNA structure profiles include only two of the four nucleotides that make up RNA(2,3). Here we present a novel biochemical approach, in vivo click selective 2'-hydroxyl acylation and profiling experiment (icSHAPE), which enables the first global view, to our knowledge, of RNA secondary structures in living cells for all four bases. icSHAPE of the mouse embryonic stem cell transcriptome versus purified RNA folded in vitro shows that the structural dynamics of RNA in the cellular environment distinguish different classes of RNAs and regulatory elements. Structural signatures at translational start sites and ribosome pause sites are conserved from in vitro conditions, suggesting that these RNA elements are programmed by sequence. In contrast, focal structural rearrangements in vivo reveal precise interfaces of RNA with RNA-binding proteins or RNA-modification sites that are consistent with atomic-resolution structural data. Such dynamic structural footprints enable accurate prediction of RNA-protein interactions and N-6-methyladenosine (m(6)A) modification genome wide. These results open the door for structural genomics of RNA in living cells and reveal key physiological structures controlling gene expression.
C1 [Spitale, Robert C.; Flynn, Ryan A.; Zhang, Qiangfeng Cliff; Lee, Byron; Batista, Pedro J.; Torre, Eduardo A.; Chang, Howard Y.] Stanford Univ, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA.
   [Spitale, Robert C.; Flynn, Ryan A.; Zhang, Qiangfeng Cliff; Lee, Byron; Batista, Pedro J.; Torre, Eduardo A.; Chang, Howard Y.] Stanford Univ, Program Epithelial Biol, Sch Med, Stanford, CA 94305 USA.
   [Crisalli, Pete; Jung, Jong-Wha; Kuchelmeister, Hannes Y.; Kool, Eric T.] Stanford Univ, Dept Chem, Stanford, CA 94305 USA.
C3 Stanford University; Howard Hughes Medical Institute; Stanford University; Stanford University
RP Chang, HY (corresponding author), Stanford Univ, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA.
EM kool@stanford.edu; howchang@stanford.edu
FU National Institutes of Health (NIH) [R01HG004361, P50HG007735]; California Institute for Regenerative Medicine; NIH [R01068122, T32AR007422, F30CA189514]; A.P. Giannini Foundation; Stanford Dean's Fellowship; Stanford Medical Scientist Training Program; National Cancer Institute [T32CA009302] Funding Source: NIH RePORTER; National Institute of Arthritis and Musculoskeletal and Skin Diseases [T32AR007422] Funding Source: NIH RePORTER
NR 38
TC 581
Z9 800
U1 2
U2 212
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 26
PY 2015
VL 519
IS 7544
BP 486
EP +
DI 10.1038/nature14263
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE1WF
UT WOS:000351602800059
PM 25799993
DA 2026-03-09
ER

PT J
AU Wiesner, T
   Lee, W
   Obenauf, AC
   Ran, LL
   Murali, R
   Zhang, QF
   Wong, EWP
   Hu, WH
   Scott, SN
   Shah, RH
   Landa, I
   Button, J
   Lailler, N
   Sboner, A
   Gao, D
   Murphy, DA
   Cao, Z
   Shukla, S
   Hollmann, TJ
   Wang, L
   Borsu, L
   Merghoub, T
   Schwartz, GK
   Postow, MA
   Ariyan, CE
   Fagin, JA
   Zheng, DY
   Ladanyi, M
   Busam, KJ
   Berger, MF
   Chen, Y
   Chi, P
AF Wiesner, Thomas
   Lee, William
   Obenauf, Anna C.
   Ran, Leili
   Murali, Rajmohan
   Zhang, Qi Fan
   Wong, Elissa W. P.
   Hu, Wenhuo
   Scott, Sasinya N.
   Shah, Ronak H.
   Landa, Inigo
   Button, Julia
   Lailler, Nathalie
   Sboner, Andrea
   Gao, Dong
   Murphy, Devan A.
   Cao, Zhen
   Shukla, Shipra
   Hollmann, Travis J.
   Wang, Lu
   Borsu, Laetitia
   Merghoub, Taha
   Schwartz, Gary K.
   Postow, Michael A.
   Ariyan, Charlotte E.
   Fagin, James A.
   Zheng, Deyou
   Ladanyi, Marc
   Busam, Klaus J.
   Berger, Michael F.
   Chen, Yu
   Chi, Ping
TI Alternative transcription initiation leads to expression of a novel ALK isoform in cancer
SO NATURE
LA English
DT Article
ID dna-sequencing data; gene; neuroblastoma; mutations; receptor; seq; identification; discovery; framework; chromatin
AB Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in similar to 11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novelALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK(ATI). In ALK(ATI)-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites(1). ALK(ATI) is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK(ATI) transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK(ATI) stimulates multiple oncogenic signalling pathways, drives growth-factor-independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK(ATI), suggesting that patients with ALK(ATI)-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation.
C1 [Wiesner, Thomas; Ran, Leili; Zhang, Qi Fan; Wong, Elissa W. P.; Hu, Wenhuo; Scott, Sasinya N.; Shah, Ronak H.; Landa, Inigo; Button, Julia; Gao, Dong; Murphy, Devan A.; Cao, Zhen; Shukla, Shipra; Fagin, James A.; Ladanyi, Marc; Berger, Michael F.; Chen, Yu; Chi, Ping] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA.
   [Wiesner, Thomas] Med Univ Graz, Dept Dermatol, A-8010 Graz, Austria.
   [Lee, William] Mem Sloan Kettering Canc Ctr, Computat Biol Program, New York, NY 10065 USA.
   [Lee, William] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10065 USA.
   [Obenauf, Anna C.] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA.
   [Murali, Rajmohan; Scott, Sasinya N.; Shah, Ronak H.; Hollmann, Travis J.; Wang, Lu; Borsu, Laetitia; Ladanyi, Marc; Busam, Klaus J.; Berger, Michael F.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA.
   [Murali, Rajmohan; Lailler, Nathalie; Berger, Michael F.] Mem Sloan Kettering Canc Ctr, Marie Josee & Henry R Kravis Ctr Mol Oncol, New York, NY 10065 USA.
   [Sboner, Andrea] New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA.
   [Sboner, Andrea] New York Presbyterian Hosp, Weill Cornell Med Coll, Inst Computat Biomed, New York, NY 10065 USA.
   [Sboner, Andrea] New York Presbyterian Hosp, Weill Cornell Med Coll, Inst Precis Med, New York, NY 10065 USA.
   [Merghoub, Taha] Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY USA.
   [Schwartz, Gary K.] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Ctr Canc, New York, NY 10032 USA.
   [Postow, Michael A.; Fagin, James A.; Chen, Yu; Chi, Ping] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA.
   [Postow, Michael A.; Fagin, James A.; Chen, Yu; Chi, Ping] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA.
   [Ariyan, Charlotte E.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA.
   [Zheng, Deyou] Yeshiva Univ Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10461 USA.
   [Zheng, Deyou] Yeshiva Univ Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA.
   [Zheng, Deyou] Yeshiva Univ Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA.
C3 Memorial Sloan Kettering Cancer Center; Medical University of Graz; 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; NewYork-Presbyterian Hospital; Cornell University; Weill Cornell Medicine; NewYork-Presbyterian Hospital; Cornell University; Weill Cornell Medicine; NewYork-Presbyterian Hospital; Memorial Sloan Kettering Cancer Center; Columbia University; Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine; Memorial Sloan Kettering Cancer Center; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine
RP Chen, Y (corresponding author), Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA.
EM cheny1@mskcc.org; chip@mskcc.org
FU Harry J. Lloyd Trust; Jubilaumsfonds of the Oesterreichische Nationalbank [15461]; Charles H. Revson Senior Fellowship; National Institutes of Health (NIH) [DP2CA174499, K08CA151660]; Geoffrey Beene Cancer Research Fund; NIH [K08CA140946, P50CA172012, P01CA12943, P30 CA008748]; Alfred Bressler Scholars Endowment Fund; Gerstner Young Investigator Award; National Cancer Institute [P30CA008748] Funding Source: NIH RePORTER
NR 39
TC 201
Z9 254
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 OCT 15
PY 2015
VL 526
IS 7573
BP 453
EP +
DI 10.1038/nature15258
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200056
PM 26444240
DA 2026-03-09
ER

PT J
AU Moon, C
   Baldridge, MT
   Wallace, MA
   Burnham, CAD
   Virgin, HW
   Stappenbeck, TS
AF Moon, Clara
   Baldridge, Megan T.
   Wallace, Meghan A.
   Burnham, Carey-Ann D.
   Virgin, Herbert W.
   Stappenbeck, Thaddeus S.
TI Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation
SO NATURE
LA English
DT Article
ID t-cell responses; proteolytic degradation; intestinal microbiota; immunoglobulin; transport; component; bacteria; receptor; mice
AB The proliferation of genetically modified mouse models has exposed phenotypic variation between investigators and institutions that has been challenging to control(1-5). In many cases, the microbiota is the presumed cause of the variation. Current solutions to account for phenotypic variability include littermate and maternal controls or defined microbial consortia ingnotobiotic mice(6,7). Inconventionally raised mice, the microbiome is transmitted from the dam(2,8,9). Here we show that microbially driven dichotomous faecal immunoglobulin-A (IgA) levels in wild-type mice within the same facility mimic the effects of chromosomal mutations. We observe in multiple facilities that vertically transmissible bacteria in IgA-low mice dominantly lower faecal IgA levels in IgA-high mice after co-housing or faecal transplantation. In response to injury, IgA-low mice show increased damage that is transferable by faecal transplantation and driven by faecal IgA differences. We find that bacteria from IgA-low mice degrade the secretory component of secretory IgA as well as IgA itself. These data indicate that phenotypic comparisons between mice must take into account the non-chromosomal hereditary variation between different breeders. We propose faecal IgA as one marker of microbial variability and conclude that co-housing and/or faecal transplantation enables analysis of progeny from different dams.
C1 [Moon, Clara; Baldridge, Megan T.; Wallace, Meghan A.; Burnham, Carey-Ann D.; Virgin, Herbert W.; Stappenbeck, Thaddeus S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA.
C3 Washington University (WUSTL)
RP Virgin, HW (corresponding author), Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA.
EM virgin@wustl.edu; stappenb@pathology.wustl.edu
FU National Institutes of Health (NIH) [AI08488702, DK7161907]; Crohn's & Colitis Foundation of America Genetics Initiative; Rainin Foundation; Helmsley Charitable Trust; NIH [T32AI007163, T32CA009547, P30AR048335, P30DK052574]; W.M. Keck Fellowship from Washington University; National Cancer Institute [T32CA009547] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [T32AI007163] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK052574] Funding Source: NIH RePORTER
NR 35
TC 210
Z9 264
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 MAY 7
PY 2015
VL 521
IS 7550
BP 90
EP U209
DI 10.1038/nature14139
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH4YS
UT WOS:000354040900039
PM 25686606
DA 2026-03-09
ER

PT J
AU McKinney, EF
   Lee, JC
   Jayne, DRW
   Lyons, PA
   Smith, KGC
AF McKinney, Eoin F.
   Lee, James C.
   Jayne, David R. W.
   Lyons, Paul A.
   Smith, Kenneth G. C.
TI T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection
SO NATURE
LA English
DT Article
ID acute hepatitis-c; gene-expression; predicts prognosis; activity index; disease; interferon; signature; responses; biology
AB The clinical course of autoimmune and infectious disease varies greatly, even between individuals with the same condition. An understanding of the molecular basis for this heterogeneity could lead to significant improvements in both monitoring and treatment. During chronic infection the process of T-cell exhaustion inhibits the immune response, facilitating viral persistence(1). Here we show that a transcriptional signature reflecting CD8 T-cell exhaustion is associated with poor clearance of chronic viral infection, but conversely predicts better prognosis in multiple autoimmune diseases. The development of CD8 T-cell exhaustion during chronic infection is driven both by persistence of antigen and by a lack of accessory 'help' signals. In autoimmunity, we find that where evidence of CD4 T-cell co-stimulation is pronounced, that of CD8 T-cell exhaustion is reduced. We can reproduce the exhaustion signature by modifying the balance of persistent stimulation of T-cell antigen receptors and specific CD2-induced co-stimulation provided to human CD8 T cells in vitro, suggesting that each process plays a role in dictating outcome in autoimmune disease. The 'non-exhausted' T-cell state driven by CD2-induced co-stimulation is reduced by signals through the exhaustion-associated inhibitory receptor PD-1, suggesting that induction of exhaustion may be a therapeutic strategy in autoimmune and inflammatory disease. Using expression of optimal surrogate markers of co-stimulation/exhaustion signatures in independent data sets, we confirm an association with good clinical outcome or response to therapy in infection (hepatitis C virus) and vaccination (yellow fever, malaria, influenza), but poor outcome in autoimmune and inflammatory disease (type 1 diabetes, anti-neutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, idiopathic pulmonary fibrosis and dengue haemorrhagic fever). Thus, T-cell exhaustion plays a central role in determining outcome in autoimmune disease and targeted manipulation of this process could lead to new therapeutic opportunities.
C1 [McKinney, Eoin F.; Lee, James C.; Jayne, David R. W.; Lyons, Paul A.; Smith, Kenneth G. C.] Univ Cambridge, Sch Clin Med, Addenbrookes Hosp, Dept Med, Cambridge CB2 0QQ, England.
   [McKinney, Eoin F.; Lee, James C.; Lyons, Paul A.; Smith, Kenneth G. C.] Univ Cambridge, Cambridge Inst Med Res, Cambridge CB2 0XY, England.
C3 University of Cambridge; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; University of Cambridge
RP McKinney, EF (corresponding author), Univ Cambridge, Sch Clin Med, Addenbrookes Hosp, Dept Med, Hills Rd, Cambridge CB2 0QQ, England.
EM efm30@cam.ac.uk; kgcs2@cam.ac.uk
FU National Institute of Health Research (NIHR); Cambridge Biomedical Research Centre; Wellcome Trust [094227/Z/10/Z, 083650/Z/07/Z, 079895]; Lister Prize Fellowship; Lupus Research Institute; Beit Foundation [104064/Z/14/Z]; MRC [MR/L019027/1, G0400929] Funding Source: UKRI; Wellcome Trust [104064/Z/14/Z, 094227/Z/10/Z] Funding Source: Wellcome Trust; Medical Research Council [MR/L019027/1, G0400929] Funding Source: researchfish
NR 55
TC 555
Z9 640
U1 3
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 JUL 30
PY 2015
VL 523
IS 7562
BP 612
EP +
DI 10.1038/nature14468
PG 28
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN7ZL
UT WOS:000358655200049
PM 26123020
DA 2026-03-09
ER

PT J
AU Skoglund, P
   Mallick, S
   Bortolini, MC
   Chennagiri, N
   Hünemeier, T
   Petzl-Erler, ML
   Salzano, FM
   Patterson, N
   Reich, D
AF Skoglund, Pontus
   Mallick, Swapan
   Bortolini, Maria Catira
   Chennagiri, Niru
   Huenemeier, Tabita
   Petzl-Erler, Maria Luiza
   Salzano, Francisco Mauro
   Patterson, Nick
   Reich, David
TI Genetic evidence for two founding populations of the Americas
SO NATURE
LA English
DT Article
ID human skeletal remains; late pleistocene human; genome sequence; 1st americans; new-world; history; morphology; neanderthal; admixture; survival
AB Genetic studies have consistently indicated a single common origin of Native American groups from Central and South America(1-4). However, some morphological studies have suggested a more complex picture, whereby the northeast Asian affinities of present-day Native Americans contrast with a distinctive morphology seen in some of the earliest American skeletons, which share traits with present-day Australasians (indigenous groups in Australia, Melanesia, and island Southeast Asia)(5-8). Here we analyse genome-wide data to show that some Amazonian Native Americans descend partly from a Native American founding population that carried ancestry more closely related to indigenous Australians, New Guineans and Andaman Islanders than to any present-day Eurasians or Native Americans. This signature is not present to the same extent, or at all, in present-day Northern and Central Americans or in a similar to 12,600-year-old Clovis-associated genome, suggesting a more diverse set of founding populations of the Americas than previously accepted.
C1 [Skoglund, Pontus; Mallick, Swapan; Chennagiri, Niru; Reich, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
   [Skoglund, Pontus; Mallick, Swapan; Chennagiri, Niru; Patterson, Nick; Reich, David] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.
   [Mallick, Swapan; Reich, David] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA.
   [Bortolini, Maria Catira; Salzano, Francisco Mauro] Univ Fed Rio Grande do Sul, Inst Biociencias, BR-91501970 Porto Alegre, RS, Brazil.
   [Huenemeier, Tabita] Univ Sao Paulo, Dept Genet Biol Evolut, BR-05508090 Sao Paulo, SP, Brazil.
   [Petzl-Erler, Maria Luiza] Univ Fed Parana, Dept Genet, BR-81531980 Curitiba, PR, Brazil.
C3 Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Universidade Federal do Rio Grande do Sul; Universidade de Sao Paulo; Universidade Federal do Parana
RP Skoglund, P (corresponding author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
EM skoglund@genetics.med.harvard.edu; reich@genetics.med.harvard.edu
FU Conselho Nacional do Desenvolvimento Cientifico e Tecnologico (Brazil); Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (Brazil); Wenner-Gren foundation; Swedish Research Council (VR) [2014-453]; US National Science Foundation HOMINID [BCS-1032255]; US National Institutes of Health [GM100233]; Simons Foundation [280376]; Howard Hughes Medical Institute
NR 38
TC 263
Z9 316
U1 1
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 SEP 3
PY 2015
VL 525
IS 7567
BP 104
EP +
DI 10.1038/nature14895
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100034
PM 26196601
DA 2026-03-09
ER

PT J
AU Freibaum, BD
   Lu, YB
   Lopez-Gonzalez, R
   Kim, NC
   Almeida, S
   Lee, KH
   Badders, N
   Valentine, M
   Miller, BL
   Wong, PC
   Petrucelli, L
   Kim, HJ
   Gao, FB
   Taylor, JP
AF Freibaum, Brian D.
   Lu, Yubing
   Lopez-Gonzalez, Rodrigo
   Kim, Nam Chul
   Almeida, Sandra
   Lee, Kyung-Ha
   Badders, Nisha
   Valentine, Marc
   Miller, Bruce L.
   Wong, Philip C.
   Petrucelli, Leonard
   Kim, Hong Joo
   Gao, Fen-Biao
   Taylor, J. Paul
TI GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport
SO NATURE
LA English
DT Article
ID amyotrophic-lateral-sclerosis; nuclear-pore complex; rna-export mediator; stem-cell models; messenger-rna; frontotemporal dementia; hexanucleotide repeat; mutations; nucleoporins; trafficking
AB The GGGGCC (G(4)C(2)) repeat expansion in a noncoding region of C9orf72 is the most common cause of sporadic and familial forms of amyotrophic lateral sclerosis and frontotemporal dementia(1,2). The basis for pathogenesis is unknown. To elucidate the consequences of G(4)C(2) repeat expansion in a tractable genetic system, we generated transgenic fly lines expressing 8, 28 or 58 G(4)C(2)-repeat-containing transcripts that do not have a translation start site (AUG) but contain an open-reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation. We show that these transgenic animals display dosage-dependent, repeat-length-dependent degeneration in neuronal tissues and RAN translation of dipeptide repeat (DPR) proteins, as observed in patients with C9orf72-related disease. This model was used in a large-scale, unbiased genetic screen, ultimately leading to the identification of 18 genetic modifiers that encode components of the nuclear pore complex (NPC), as well as the machinery that coordinates the export of nuclear RNA and the import of nuclear proteins. Consistent with these results, we found morphological abnormalities in the architecture of the nuclear envelope in cells expressing expanded G(4)C(2) repeats in vitro and in vivo. Moreover, we identified a substantial defect in RNA export resulting in retention of RNA in the nuclei of Drosophila cells expressing expanded G(4)C(2) repeats and also in mammalian cells, including aged induced pluripotent stem-cell-derived neurons from patients with C9orf72-related disease. These studies show that a primary consequence of G(4)C(2) repeat expansion is the compromise of nucleocytoplasmic transport through the nuclear pore, revealing a novel mechanism of neurodegeneration.
C1 [Freibaum, Brian D.; Kim, Nam Chul; Lee, Kyung-Ha; Badders, Nisha; Valentine, Marc; Kim, Hong Joo] St Jude Childrens Res Hosp, Dept Cell & Mol Biol, Memphis, TN 38105 USA.
   [Lu, Yubing; Lopez-Gonzalez, Rodrigo; Almeida, Sandra; Gao, Fen-Biao] Univ Massachusetts, Dept Neurol, Sch Med, Worcester, MA 01605 USA.
   [Miller, Bruce L.] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94158 USA.
   [Wong, Philip C.] Johns Hopkins Univ, Dept Pathol, Sch Med, Baltimore, MD 21205 USA.
   [Petrucelli, Leonard] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA.
   [Taylor, J. Paul] St Jude Childrens Res Hosp, Howard Hughes Med Inst, Dept Cell & Mol Biol, Memphis, TN 38105 USA.
C3 St Jude Children's Research Hospital; University of Massachusetts System; University of Massachusetts Worcester; University of California System; University of California San Francisco; Johns Hopkins University; Mayo Clinic; St Jude Children's Research Hospital; Howard Hughes Medical Institute
RP Taylor, JP (corresponding author), St Jude Childrens Res Hosp, Howard Hughes Med Inst, Dept Cell & Mol Biol, Memphis, TN 38105 USA.
EM fen-biao.gao@umassmed.edu; jpaul.taylor@stjude.org
FU Target ALS; Packard Center for ALS Research at the Johns Hopkins University; ALS Association; ALS Therapy Alliance; NIH [N079725, NS079725, AG019724]; American-Lebanese-Syrian Associated Charities; National Cancer Institute [P30CA021765] Funding Source: NIH RePORTER; National Institute on Aging [P01AG019724] Funding Source: NIH RePORTER
NR 36
TC 657
Z9 775
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 SEP 3
PY 2015
VL 525
IS 7567
BP 129
EP +
DI 10.1038/nature14974
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100039
PM 26308899
DA 2026-03-09
ER

PT J
AU Fischer, KR
   Durrans, A
   Lee, S
   Sheng, JT
   Li, FH
   Wong, STC
   Choi, HJ
   El Rayes, T
   Ryu, SH
   Troeger, J
   Schwabe, RF
   Vahdat, LT
   Altorki, NK
   Mittal, V
   Gao, DC
AF Fischer, Kari R.
   Durrans, Anna
   Lee, Sharrell
   Sheng, Jianting
   Li, Fuhai
   Wong, Stephen T. C.
   Choi, Hyejin
   El Rayes, Tina
   Ryu, Seongho
   Troeger, Juliane
   Schwabe, Robert F.
   Vahdat, Linda T.
   Altorki, Nasser K.
   Mittal, Vivek
   Gao, Dingcheng
TI Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance
SO NATURE
LA English
DT Article
ID cancer-cells; mir-200 family; stem-cells; breast; expression; plasticity; resistance; induction; therapy; model
AB The role of epithelial-to-mesenchymal transition (EMT) in metastasis is a longstanding source of debate, largely owing to an inability to monitor transient and reversible EMT phenotypes in vivo. Here we establish an EMT lineage-tracing system to monitor this process in mice, using a mesenchymal-specific Cre-mediated fluorescent marker switch system in spontaneous breast-to-lung metastasis models. We show that within a predominantly epithelial primary tumour, a small proportion of tumour cells undergo EMT. Notably, lung metastases mainly consist of non-EMT tumour cells that maintain their epithelial phenotype. Inhibiting EMT by overexpressing the microRNA miR-200 does not affect lung metastasis development. However, EMT cells significantly contribute to recurrent lung metastasis formation after chemotherapy. These cells survived cyclophosphamide treatment owing to reduced proliferation, apoptotic tolerance and increased expression of chemoresistance-related genes. Overexpression of miR-200 abrogated this resistance. This study suggests the potential of an EMT-targeting strategy, in conjunction with conventional chemotherapies, for breast cancer treatment.
C1 [Fischer, Kari R.; Durrans, Anna; Lee, Sharrell; Choi, Hyejin; El Rayes, Tina; Ryu, Seongho; Altorki, Nasser K.; Mittal, Vivek; Gao, Dingcheng] Cornell Univ, Weill Cornell Med Coll, Dept Cardiothorac Surg, 1300 York Ave, New York, NY 10065 USA.
   [Fischer, Kari R.; Durrans, Anna; Lee, Sharrell; Choi, Hyejin; El Rayes, Tina; Mittal, Vivek; Gao, Dingcheng] Cornell Univ, Weill Cornell Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA.
   [Fischer, Kari R.; Durrans, Anna; Lee, Sharrell; Choi, Hyejin; El Rayes, Tina; Ryu, Seongho; Altorki, Nasser K.; Mittal, Vivek; Gao, Dingcheng] Cornell Univ, Weill Cornell Med Coll, Neuberger Berman Lung Canc Ctr, New York, NY 10065 USA.
   [Fischer, Kari R.; Choi, Hyejin; El Rayes, Tina] Cornell Univ, Weill Cornell Med Coll, Weill Cornell Grad Sch Med Sci, New York, NY 10065 USA.
   [Sheng, Jianting; Li, Fuhai; Wong, Stephen T. C.] Houston Methodist Hosp, Houston Methodist Res Inst, Dept Syst Med & Bioengn, Houston, TX 77030 USA.
   [Wong, Stephen T. C.] Houston Methodist Hosp, Methodist Canc Ctr, Houston, TX 77030 USA.
   [Ryu, Seongho] Soonchunhyang Univ, Soonchunhyang Inst Medi Bio Sci SIMS, Cheonan Si 31151, Chungcheongnam, South Korea.
   [Troeger, Juliane; Schwabe, Robert F.] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY 10032 USA.
   [Troeger, Juliane; Schwabe, Robert F.] Columbia Univ, Inst Human Nutr, New York, NY 10032 USA.
   [Vahdat, Linda T.] Cornell Univ, Weill Cornell Med Coll, Dept Med 1, 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; Houston Methodist; Houston Methodist; Soonchunhyang University; Columbia University; Columbia University; Cornell University; Weill Cornell Medicine
RP Mittal, V (corresponding author), Cornell Univ, Weill Cornell Med Coll, Dept Cardiothorac Surg, 1300 York Ave, New York, NY 10065 USA.
EM vim2010@med.cornell.edu; dig2009@med.cornell.edu
FU US Department of Defense CDMRP LCRP [LC110643]; NIH [1 F31 CA186510-01]; National Cancer Institute [U54 CA149196-05]; WCMC Meyer Cancer Center Pilot Funding; Neuberger Berman Foundation Lung Cancer Research Center; Arthur and Myra Mahon Donor-Advised Fund; Liz Claiborne and Art Ortenberg Foundation; Douglas AMP; Katherine McCormick Family Foundation; R. AMP; M. Goldberg Family Foundation; P. AMP; C. Collins Fund; Eliot Stewart 'Wren' Fund; William and Shelby Modell Family Foundation Trust; Division of Thoracic Surgery
NR 35
TC 1493
Z9 1745
U1 4
U2 288
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 472
EP +
DI 10.1038/nature15748
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500038
PM 26560033
DA 2026-03-09
ER

PT J
AU Spang, A
   Saw, JH
   Jorgensen, SL
   Zaremba-Niedzwiedzka, K
   Martijn, J
   Lind, AE
   van Eijk, R
   Schleper, C
   Guy, L
   Ettema, TJG
AF Spang, Anja
   Saw, Jimmy H.
   Jorgensen, Steffen L.
   Zaremba-Niedzwiedzka, Katarzyna
   Martijn, Joran
   Lind, Anders E.
   van Eijk, Roel
   Schleper, Christa
   Guy, Lionel
   Ettema, Thijs J. G.
TI Complex archaea that bridge the gap between prokaryotes and eukaryotes
SO NATURE
LA English
DT Article
ID multiple sequence alignment; escrt machinery; cell-division; origin; evolution; genome; tree; genes; actin; annotation
AB The origin of the eukaryotic cell remains one of the most contentious puzzles in modern biology. Recent studies have provided support for the emergence of the eukaryotic host cell from within the archaeal domain of life, but the identity and nature of the putative archaeal ancestor remain a subject of debate. Here we describe the discovery of 'Lokiarchaeota', a novel candidate archaeal phylum, which forms a monophyletic group with eukaryotes in phylogenomic analyses, and whose genomes encode an expanded repertoire of eukaryotic signature proteins that are suggestive of sophisticated membrane remodelling capabilities. Our results provide strong support for hypotheses in which the eukaryotic host evolved from a bona fide archaeon, and demonstrate that many components that underpin eukaryote-specific features were already present in that ancestor. This provided the host with a rich genomic 'starter-kit' to support the increase in the cellular and genomic complexity that is characteristic of eukaryotes.
C1 [Spang, Anja; Saw, Jimmy H.; Zaremba-Niedzwiedzka, Katarzyna; Martijn, Joran; Lind, Anders E.; van Eijk, Roel; Guy, Lionel; Ettema, Thijs J. G.] Uppsala Univ, Sci Life Lab, Dept Cell & Mol Biol, SE-75123 Uppsala, Sweden.
   [Saw, Jimmy H.; Schleper, Christa] Univ Bergen, Dept Biol, Ctr Geobiol, N-5020 Bergen, Norway.
   [Schleper, Christa] Univ Vienna, Div Archaea Biol & Ecogen, Dept Ecogen & Syst Biol, A-1090 Vienna, Austria.
   [Guy, Lionel] Uppsala Univ, Dept Med Biochem & Microbiol, SE-75123 Uppsala, Sweden.
C3 Uppsala University; University of Bergen; University of Vienna; Uppsala University
RP Ettema, TJG (corresponding author), Uppsala Univ, Sci Life Lab, Dept Cell & Mol Biol, SE-75123 Uppsala, Sweden.
EM lionel.guy@imbim.uu.se; thijs.ettema@icm.uu.se
FU Swedish Research Council (VR) [621-2009-4813]; European Research Council (ERC) [310039-PUZZLE_CELL]; Swedish Foundation for Strategic Research [SSF-FFL5]; Carl Tryggers Stiftelse for Vetenskaplig Forskning; Wenner-Gren Stiftelserna; Marie Curie IIF [331291]; IEF by the European Union [625521]; H2DEEP project through the EuroMARC program; Research Council of Norway through the Centre for Geobiology, University of Bergen; Austrian Science Fund (FWF) [P27017]; Austrian Science Fund (FWF) [P27017] Funding Source: Austrian Science Fund (FWF)
NR 98
TC 843
Z9 973
U1 15
U2 595
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 14
PY 2015
VL 521
IS 7551
BP 173
EP +
DI 10.1038/nature14447
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH9SY
UT WOS:000354377800049
PM 25945739
DA 2026-03-09
ER

PT J
AU Newbold, T
   Hudson, LN
   Hill, SLL
   Contu, S
   Lysenko, I
   Senior, RA
   Börger, L
   Bennett, DJ
   Choimes, A
   Collen, B
   Day, J
   De Palma, A
   Díaz, S
   Echeverria-Londoño, S
   Edgar, MJ
   Feldman, A
   Garon, M
   Harrison, MLK
   Alhusseini, T
   Ingram, DJ
   Itescu, Y
   Kattge, J
   Kemp, V
   Kirkpatrick, L
   Kleyer, M
   Correia, DLP
   Martin, CD
   Meiri, S
   Novosolov, M
   Pan, Y
   Phillips, HRP
   Purves, DW
   Robinson, A
   Simpson, J
   Tuck, SL
   Weiher, E
   White, HJ
   Ewers, RM
   Mace, GM
   Scharlemann, JPW
   Purvis, A
AF Newbold, Tim
   Hudson, Lawrence N.
   Hill, Samantha L. L.
   Contu, Sara
   Lysenko, Igor
   Senior, Rebecca A.
   Boerger, Luca
   Bennett, Dominic J.
   Choimes, Argyrios
   Collen, Ben
   Day, Julie
   De Palma, Adriana
   Diaz, Sandra
   Echeverria-Londono, Susy
   Edgar, Melanie J.
   Feldman, Anat
   Garon, Morgan
   Harrison, Michelle L. K.
   Alhusseini, Tamera
   Ingram, Daniel J.
   Itescu, Yuval
   Kattge, Jens
   Kemp, Victoria
   Kirkpatrick, Lucinda
   Kleyer, Michael
   Correia, David Laginha Pinto
   Martin, Callum D.
   Meiri, Shai
   Novosolov, Maria
   Pan, Yuan
   Phillips, Helen R. P.
   Purves, Drew W.
   Robinson, Alexandra
   Simpson, Jake
   Tuck, Sean L.
   Weiher, Evan
   White, Hannah J.
   Ewers, Robert M.
   Mace, Georgina M.
   Scharlemann, Joern P. W.
   Purvis, Andy
TI Global effects of land use on local terrestrial biodiversity
SO NATURE
LA English
DT Article
ID plant community composition; bombus spp. hymenoptera; dung beetle coleoptera; bumblebee nest density; bird species richness; sariska-tiger reserve; post-logging recovery; volant small mammals; tropical forest; rain-forest
AB Human activities, especially conversion and degradation of habitats, are causing global biodiversity declines. How local ecological assemblages are responding is less clear-a concern given their importance for many ecosystem functions and services. We analysed a terrestrial assemblage database of unprecedented geographic and taxonomic coverage to quantify local biodiversity responses to land use and related changes. Here we show that in the worst-affected habitats, these pressures reducewithin-sample species richness by anaverage of 76.5%, total abundance by 39.5% andrarefaction-based richness by 40.3%. We estimate that, globally, these pressures have already slightly reduced average within-sample richness (by 13.6%), total abundance (10.7%) and rarefaction-based richness (8.1%), with changes showing marked spatial variation. Rapid further losses are predicted under a business-as-usual land-use scenario; within-sample richness is projected to fall by a further 3.4% globally by 2100, with losses concentrated in biodiverse but economically poor countries. Strongmitigationcan delivermuchmore positive biodiversity changes (up to a 1.9% average increase) that are less strongly related to countries' socioeconomic status.
C1 [Newbold, Tim; Hill, Samantha L. L.; Senior, Rebecca A.; Scharlemann, Joern P. W.] World Conservat Monitoring Ctr, United Nations Environm Programme, Cambridge CB3 0DL, England.
   [Newbold, Tim; Purves, Drew W.] Microsoft Res Cambridge, Computat Sci Lab, Cambridge CB1 2FB, England.
   [Hudson, Lawrence N.; Hill, Samantha L. L.; Contu, Sara; Choimes, Argyrios; De Palma, Adriana; Echeverria-Londono, Susy; Edgar, Melanie J.; Correia, David Laginha Pinto; Phillips, Helen R. P.; Purvis, Andy] Nat Hist Museum, Dept Life Sci, London SW7 5BD, England.
   [Lysenko, Igor; Bennett, Dominic J.; Choimes, Argyrios; Day, Julie; De Palma, Adriana; Garon, Morgan; Harrison, Michelle L. K.; Alhusseini, Tamera; Ingram, Daniel J.; Kemp, Victoria; Kirkpatrick, Lucinda; Martin, Callum D.; Pan, Yuan; Phillips, Helen R. P.; Robinson, Alexandra; Simpson, Jake; White, Hannah J.; Ewers, Robert M.; Purvis, Andy] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, Ascot SL5 7PY, Berks, England.
   [Boerger, Luca] Swansea Univ, Coll Sci, Dept Biosci, Swansea SA2 8PP, W Glam, Wales.
   [Collen, Ben; Mace, Georgina M.] UCL, Ctr Biodivers & Environm Res, Dept Genet Evolut & Environm, London WC1E 6BT, England.
   [Diaz, Sandra] Univ Nacl Cordoba, Inst Multidisciplinario Biol Vegetal CONICET UNC, RA-5000 Cordoba, Argentina.
   [Diaz, Sandra] Univ Nacl Cordoba, FCEFyN, RA-5000 Cordoba, Argentina.
   [Feldman, Anat; Itescu, Yuval; Meiri, Shai; Novosolov, Maria] Tel Aviv Univ, Fac Life Sci, Dept Zool, IL-6997801 Tel Aviv, Israel.
   [Kattge, Jens] Max Planck Inst Biogeochem, D-07743 Jena, Germany.
   [Kattge, Jens] German Ctr Integrat Biodivers Res iDiv Halle Jane, D-04103 Leipzig, Germany.
   [Kleyer, Michael] Carl von Ossietzky Univ Oldenburg, Inst Biol & Environm Sci, Landscape Ecol Grp, D-26111 Oldenburg, Germany.
   [Tuck, Sean L.] Univ Oxford, Dept Plant Sci, Oxford OX1 3RB, England.
   [Weiher, Evan] Univ Wisconsin, Biol Dept, Eau Claire, WI 54701 USA.
   [Scharlemann, Joern P. W.] Univ Sussex, Sch Life Sci, Brighton BN1 9QG, E Sussex, England.
C3 Microsoft; Microsoft United Kingdom; Natural History Museum London; Imperial College London; Swansea University; University of London; University College London; National University of Cordoba; Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); National University of Cordoba; Tel Aviv University; Max Planck Society; German Research Foundation (DFG); German Centre for Integrative Biodiversity Research (iDiv); Carl von Ossietzky Universitat Oldenburg; University of Oxford; University of Wisconsin System; University of Sussex
RP Newbold, T (corresponding author), World Conservat Monitoring Ctr, United Nations Environm Programme, 219 Huntingdon Rd, Cambridge CB3 0DL, England.
EM Tim.Newbold@unep-wcmc.org
FU UK Natural Environment Research Council (NERC) [NE/J011193/1]; Biotechnology and Biological Sciences Research Council [BB/F017324/1]; TRY initiative on plant traits, whose database is maintained at Max-Planck-Institute for Biogeochemistry, Jena, Germany; DIVERSITAS; IGBP; Global Land Project; NERC; French Foundation for Biodiversity Research; GIS 'Climat, Environnement et Societe' France; Biotechnology and Biological Sciences Research Council [982737] Funding Source: researchfish; Natural Environment Research Council [NE/J011193/1, 1282072, NE/J011193/2] Funding Source: researchfish; NERC [NE/J011193/2, NE/J011193/1] Funding Source: UKRI
NR 395
TC 3135
Z9 3668
U1 109
U2 2880
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 2
PY 2015
VL 520
IS 7545
BP 45
EP +
DI 10.1038/nature14324
PG 25
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE7NE
UT WOS:000352027700033
PM 25832402
DA 2026-03-09
ER

PT J
AU Wculek, SK
   Malanchi, I
AF Wculek, Stefanie K.
   Malanchi, Ilaria
TI Neutrophils support lung colonization of metastasis-initiating breast cancer cells
SO NATURE
LA English
DT Article
ID stem-cells; tumor-metastasis; mice; recruitment; leukotrienes; progression; expression; mediator; immune; niche
AB Despite progress in the development of drugs that efficiently target cancer cells, treatments for metastatic tumours are often ineffective. The now well-established dependency of cancer cells on their microenvironment(1) suggests that targeting the non-cancer-cell component of the tumour might form a basis for the development of novel therapeutic approaches. However, the as-yet poorly characterized contribution of host responses during tumour growth and metastatic progression represents a limitation to exploiting this approach. Here we identify neutrophils as the main component and driver of metastatic establishment within the (pre-) metastatic lung microenvironment in mouse breast cancer models. Neutrophils have a fundamental role in inflammatory responses and their contribution to tumorigenesis is still controversial(2-4). Using various strategies to block neutrophil recruitment to the pre-metastatic site, we demonstrate that neutrophils specifically support metastatic initiation. Importantly, we find that neutrophil-derived leukotrienes aid the colonization of distant tissues by selectively expanding the sub-pool of cancer cells that retain high tumorigenic potential. Genetic or pharmacological inhibition of the leukotriene-generating enzyme arachidonate 5-lipoxygenase (Alox5) abrogates neutrophil pro-metastatic activity and consequently reduces metastasis. Our results reveal the efficacy of using targeted therapy against a specific tumour microenvironment component and indicate that neutrophil Alox5 inhibition may limit metastatic progression.
C1 [Wculek, Stefanie K.; Malanchi, Ilaria] Francis Crick Inst, Lincolns Inn Fields Labs, London WC2A 3LY, England.
C3 Francis Crick Institute
RP Malanchi, I (corresponding author), Francis Crick Inst, Lincolns Inn Fields Labs, 44 Lincolns Inn Fields, London WC2A 3LY, England.
EM ilaria.malanchi@crick.ac.uk
FU Cancer Research UK; Cancer Research UK [14257] Funding Source: researchfish; The Francis Crick Institute [10112] Funding Source: researchfish
NR 39
TC 840
Z9 938
U1 4
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 DEC 17
PY 2015
VL 528
IS 7582
BP 413
EP +
DI 10.1038/nature16140
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CY8SM
UT WOS:000366678600056
PM 26649828
DA 2026-03-09
ER

PT J
AU Terrett, JA
   Cuthbertson, JD
   Shurtleff, VW
   MacMillan, DWC
AF Terrett, Jack A.
   Cuthbertson, James D.
   Shurtleff, Valerie W.
   MacMillan, David W. C.
TI Switching on elusive organometallic mechanisms with photoredox catalysis
SO NATURE
LA English
DT Article
ID oxygen-atom transfer; reductive-elimination; merging photoredox; nitrous-oxide; nickel; activation; arylation; halides
AB Transition-metal-catalysed cross-coupling reactions have become one of the most used carbon-carbon and carbon-heteroatom bond-forming reactions in chemical synthesis. Recently, nickel catalysis has been shown to participate in a wide variety of C-C bond-forming reactions, most notably Negishi, Suzuki-Miyaura, Stille, Kumada and Hiyama couplings(1,2). Despite the tremendous advances in C-C fragment couplings, the ability to forge C-O bonds in a general fashion via nickel catalysis has been largely unsuccessful. The challenge for nickel-mediated alcohol couplings has been the mechanistic requirement for the critical C-O bond-forming step (formally known as the reductive elimination step) to occur via a Ni(III) alkoxide intermediate. Here we demonstrate that visible-light-excited photoredox catalysts can modulate the preferred oxidation states of nickel alkoxides in an operative catalytic cycle, thereby providing transient access to Ni(III) species that readily participate in reductive elimination. Using this synergistic merger of photoredox and nickel catalysis, we have developed a highly efficient and general carbon-oxygen coupling reaction using abundant alcohols and aryl bromides. More notably, we have developed a general strategy to 'switch on' important yet elusive organometallic mechanisms via oxidation state modulations using only weak light and single-electron-transfer catalysts.
C1 [Terrett, Jack A.; Cuthbertson, James D.; Shurtleff, Valerie W.; 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 National Institute of General Medical Sciences [R01 GM093213-01]; Bristol-Myers Squibb; Marie Curie Actions for an International Outgoing Fellowship
NR 30
TC 536
Z9 593
U1 15
U2 767
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 20
PY 2015
VL 524
IS 7565
BP 330
EP 334
DI 10.1038/nature14875
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP2NN
UT WOS:000359714000031
PM 26266976
DA 2026-03-09
ER

PT J
AU Lavallée, Y
   Dingwell, DB
   Johnson, JB
   Cimarelli, C
   Hornby, AJ
   Kendrick, JE
   von Aulock, FW
   Kennedy, B
   Andrews, BJ
   Wadsworth, FB
   Rhodes, E
   Chigna, G
AF Lavallee, Yan
   Dingwell, Donald B.
   Johnson, Jeffrey B.
   Cimarelli, Corrado
   Hornby, Adrian J.
   Kendrick, Jackie E.
   von Aulock, Felix W.
   Kennedy, Ben M.
   Andrews, Benjamin J.
   Wadsworth, Fabian B.
   Rhodes, Emma
   Chigna, Gustavo
TI Thermal vesiculation during volcanic eruptions
SO NATURE
LA English
DT Article
ID magma fragmentation; melting processes; dome; solubility; growth; ascent; flow; h2o; crystallization; conduit
AB Terrestrial volcanic eruptions are the consequence of magmas ascending to the surface of the Earth. This ascent is driven by buoyancy forces, which are enhanced by bubble nucleation and growth (vesiculation) that reduce the density of magma(1). The development of vesicularity also greatly reduces the 'strength' of magma(2), a material parameter controlling fragmentation and thus the explosive potential of the liquid rock(3). The development of vesicularity in magmas has until now been viewed (both thermodynamically and kinetically) in terms of the pressure dependence of the solubility of water in the magma, and its role in driving gas saturation, exsolution and expansion during decompression. In contrast, the possible effects of the well documented negative temperature dependence of solubility of water in magma has largely been ignored. Recently, petrological constraints have demonstrated that considerable heating of magma may indeed be a common result of the latent heat of crystallization(4) as well as viscous(5,6) and frictional(7) heating in areas of strain localization. Here we present field and experimental observations of magma vesiculation and fragmentation resulting from heating (rather than decompression). Textural analysis of volcanic ash from Santiaguito volcano in Guatemala reveals the presence of chemically heterogeneous filaments hosting micrometre-scale vesicles. The textures mirror those developed by disequilibrium melting induced via rapid heating during fault friction experiments, demonstrating that friction can generate sufficient heat to induce melting and vesiculation of hydrated silicic magma. Consideration of the experimentally determined temperature and pressure dependence of water solubility in magma reveals that, for many ascent paths, exsolution may be more efficiently achieved by heating than by decompression. We conclude that the thermal path experienced by magma during ascent strongly controls degassing, vesiculation, magma strength and the effusive-explosive transition in volcanic eruptions.
C1 [Lavallee, Yan; Hornby, Adrian J.; Kendrick, Jackie E.; von Aulock, Felix W.; Rhodes, Emma] Univ Liverpool, Dept Earth Ocean & Ecol Sci, Liverpool L69 3GP, Merseyside, England.
   [Dingwell, Donald B.; Cimarelli, Corrado; Wadsworth, Fabian B.] Tech Univ Munich, Dept Earth & Environm Sci, D-80333 Munich, Germany.
   [Johnson, Jeffrey B.] Boise State Univ, Dept Geosci, Boise, ID 83725 USA.
   [Kennedy, Ben M.; Rhodes, Emma] Univ Canterbury, Geol Sci, Christchurch 8140, New Zealand.
   [Andrews, Benjamin J.] Smithsonian Inst, Dept Mineral Sci, Washington, DC 20560 USA.
   [Chigna, Gustavo] Inst Nacl Sismol Vulcanol Meteorol & Hydrol INSIV, Guatemala City, Guatemala.
C3 University of Liverpool; Technical University of Munich; Boise State University; University of Canterbury; Smithsonian Institution; Smithsonian National Museum of Natural History
RP Lavallée, Y (corresponding author), Univ Liverpool, Dept Earth Ocean & Ecol Sci, Liverpool L69 3GP, Merseyside, England.
EM yan.lavallee@liverpool.ac.uk
FU European Research Council [306488, 247076]; National Science Foundation EAR [1151662]; European Union [282759]; AXA; Division Of Earth Sciences; Directorate For Geosciences [1151662] Funding Source: National Science Foundation
NR 35
TC 56
Z9 69
U1 2
U2 71
PU NATURE PUBLISHING 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 24
PY 2015
VL 528
IS 7583
BP 544
EP +
DI 10.1038/nature16153
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900050
PM 26701056
DA 2026-03-09
ER

PT J
AU Tran, TH
   Hsiao, YS
   Jo, J
   Chou, CY
   Dietrich, LEP
   Walz, T
   Tong, L
AF Tran, Timothy H.
   Hsiao, Yu-Shan
   Jo, Jeanyoung
   Chou, Chi-Yuan
   Dietrich, Lars E. P.
   Walz, Thomas
   Tong, Liang
TI Structure and function of a single-chain, multi-domain long-chain acyl-CoA carboxylase
SO NATURE
LA English
DT Article
ID pseudomonas-aeruginosa pao1; complete genome sequence; pyruvate-carboxylase; crystal-structure; carboxyltransferase domain; acetyl-coenzyme; biotin; environment; mechanism; software
AB Biotin-dependent carboxylases are widely distributed in nature and have important functions in the metabolism of fatty acids, amino acids, carbohydrates, cholesterol and other compounds(1-6). Defective mutations in several of these enzymes have been linked to serious metabolic diseases in humans, and acetyl-CoA carboxylase is a target for drug discovery in the treatment of diabetes, cancer and other diseases(7-9). Here we report the identification and biochemical, structural and functional characterizations of a novel single-chain (120 kDa), multi-domain biotin-dependent carboxylase in bacteria. It has preference for long-chain acyl-CoA substrates, although it is also active towards short-chain and medium-chainacyl-CoAs, and we have named it long-chain acyl-CoA carboxylase. The holoenzyme is a homo-hexamer with molecular mass of 720 kDa. The 3.0 angstrom crystal structure of the long-chain acyl-CoA carboxylase holoenzyme from Mycobacterium avium subspecies paratuberculosis revealed an architecture that is strikingly different from those of related biotin-dependent carboxylases(10,11). In addition, the domains of each monomer have no direct contact with each other. They are instead extensively swapped in the holoenzyme, such that one cycle of catalysis involves the participation of four monomers. Functional studies in Pseudomonas aeruginosa suggest that the enzyme is involved in the utilization of selected carbon and nitrogen sources.
C1 [Tran, Timothy H.; Jo, Jeanyoung; Chou, Chi-Yuan; Dietrich, Lars E. P.; Tong, Liang] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA.
   [Hsiao, Yu-Shan; Walz, Thomas] Harvard Univ, Dept Cell Biol, Sch Med, Boston, MA 02115 USA.
   [Walz, Thomas] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA.
C3 Columbia University; Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Harvard University; Harvard Medical School
RP Tong, L (corresponding author), Columbia Univ, Dept Biol Sci, New York, NY 10027 USA.
EM ltong@columbia.edu
FU National Institutes of Health (NIH) [S10OD012018]; NIH [R01DK067238, R01AI103369, NCRR 1S10RR028832-01]; Protein Structure Initiative of the NIH [U54GM094597]; National Institute of Allergy and Infectious Diseases [R01AI103369] Funding Source: NIH RePORTER
NR 45
TC 26
Z9 33
U1 0
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 FEB 5
PY 2015
VL 518
IS 7537
BP 120
EP +
DI 10.1038/nature13912
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7LE
UT WOS:000349098000044
PM 25383525
DA 2026-03-09
ER

PT J
AU van Kessel, MAHJ
   Speth, DR
   Albertsen, M
   Nielsen, PH
   Op den Camp, HJM
   Kartal, B
   Jetten, MSM
   Lücker, S
AF van Kessel, Maartje A. H. J.
   Speth, Daan R.
   Albertsen, Mads
   Nielsen, Per H.
   Op den Camp, Huub J. M.
   Kartal, Boran
   Jetten, Mike S. M.
   Lucker, Sebastian
TI Complete nitrification by a single microorganism
SO NATURE
LA English
DT Article
ID nitrite-oxidizing bacteria; in-situ hybridization; ammonia monooxygenase; nitrosomonas-europaea; physiology; urea; tool; microautoradiography; combination; diversity
AB Nitrification is a two-step process where ammonia is first oxidized to nitrite by ammonia-oxidizing bacteria and/or archaea, and subsequently to nitrate by nitrite-oxidizing bacteria. Already described by Winogradsky in 18901, this division of labour between the two functional groups is a generally accepted characteristic of the biogeochemical nitrogen cycle(2). Complete oxidation of ammonia to nitrate in one organism (complete ammonia oxidation; comammox) is energetically feasible, and it was postulated that this process could occur under conditions selecting for species with lower growth rates but higher growth yields than canonical ammonia-oxidizing microorganisms(3). Still, organisms catalysing this process have not yet been discovered. Here we report the enrichment and initial characterization of two Nitrospira species that encode all the enzymes necessary for ammonia oxidation via nitrite to nitrate in their genomes, and indeed completely oxidize ammonium to nitrate to conserve energy. Their ammonia monooxygenase (AMO) enzymes are phylogenetically distinct from currently identified AMOs, rendering recent acquisition by horizontal gene transfer from known ammonia-oxidizing microorganisms unlikely. We also found highly similar amoA sequences (encoding the AMO subunit A) in public sequence databases, which were apparently misclassified as methane monooxygenases. This recognition of a novel amoA sequence group will lead to an improved understanding of the environmental abundance and distribution of ammonia-oxidizing microorganisms. Furthermore, the discovery of the long-sought-after comammox process will change our perception of the nitrogen cycle.
C1 [van Kessel, Maartje A. H. J.; Speth, Daan R.; Op den Camp, Huub J. M.; Kartal, Boran; Jetten, Mike S. M.; Lucker, Sebastian] Radboud Univ Nijmegen, IWWR, Dept Microbiol, NL-6525 AJ Nijmegen, Netherlands.
   [Albertsen, Mads; Nielsen, Per H.] Aalborg Univ, Dept Chem & Biosci, Ctr Microbial Communities, DK-9220 Aalborg, Denmark.
   [Kartal, Boran] Univ Ghent, Microbiol Lab, B-9000 Ghent, Belgium.
   [Jetten, Mike S. M.] Delft Univ Technol, Dept Biotechnol, NL-2628 BC Delft, Netherlands.
C3 Radboud University Nijmegen; Aalborg University; Ghent University; Delft University of Technology
RP Lücker, S (corresponding author), Radboud Univ Nijmegen, IWWR, Dept Microbiol, Heyendaalseweg 135, NL-6525 AJ Nijmegen, Netherlands.
EM s.luecker@science.ru.nl
FU Technology Foundation STW [13146]; BE-Basic Foundation [fs7-002]; Danish Council for Independent Research [DFF 4005-00369]; European Research Council (ERC) [anammox 232937, Eco_MoM 339880]; Dutch Ministry of Education, Culture and Science [SIAM 024002002]; Netherlands Organization for Scientific Research (NWO VENI) [863.11.003, 863.14.019]; Radboud Excellence Initiative
NR 64
TC 1465
Z9 1626
U1 60
U2 2037
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 24
PY 2015
VL 528
IS 7583
BP 555
EP +
DI 10.1038/nature16459
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900053
PM 26610025
DA 2026-03-09
ER

PT J
AU Lawson, DA
   Bhakta, NR
   Kessenbrock, K
   Prummel, KD
   Yu, Y
   Takai, K
   Zhou, A
   Eyob, H
   Balakrishnan, S
   Wang, CY
   Yaswen, P
   Goga, A
   Werb, Z
AF Lawson, Devon A.
   Bhakta, Nirav R.
   Kessenbrock, Kai
   Prummel, Karin D.
   Yu, Ying
   Takai, Ken
   Zhou, Alicia
   Eyob, Henok
   Balakrishnan, Sanjeev
   Wang, Chih-Yang
   Yaswen, Paul
   Goga, Andrei
   Werb, Zena
TI Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells
SO NATURE
LA English
DT Article
ID transcriptome analysis; mammary-gland; identification; fate; inhibition; commitment; markers; growth; tumors; genes
AB Despite major advances in understanding the molecular and genetic basis of cancer, metastasis remains the cause of >90% of cancer-related mortality(1). Understanding metastasis initiation and progression is critical to developing new therapeutic strategies to treat and prevent metastatic disease. Prevailing theories hypothesize that metastases are seeded by rare tumour cells with unique properties, which may function like stem cells in their ability to initiate and propagate metastatic tumours(2-5). However, the identity of metastasis-initiating cells in human breast cancer remains elusive, and whether metastases are hierarchically organized is unknown(2). Here we show at the single-cell level that early stage metastatic cells possess a distinct stem-like gene expression signature. To identify and isolate metastatic cells from patient-derived xenograft models of human breast cancer, we developed a highly sensitive fluorescence-activated cell sorting (FACS)-based assay, which allowed us to enumerate metastatic cells in mouse peripheral tissues. We compared gene signatures in metastatic cells from tissues with low versus high metastatic burden. Metastatic cells from low-burden tissues were distinct owing to their increased expression of stem cell, epithelial-to-mesenchymal transition, pro-survival, and dormancy-associated genes. By contrast, metastatic cells from high-burden tissues were similar to primary tumour cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. Transplantation of stem-like metastatic cells from low-burden tissues showed that they have considerable tumour-initiating capacity, and can differentiate to produce luminal-like cancer cells. Progression to high metastatic burden was associated with increased proliferation and MYC expression, which could be attenuated by treatment with cyclin-dependent kinase (CDK) inhibitors. These findings support a hierarchical model for metastasis, in which metastases are initiated by stem-like cells that proliferate and differentiate to produce advanced metastatic disease.
C1 [Lawson, Devon A.; Kessenbrock, Kai; Prummel, Karin D.; Yu, Ying; Takai, Ken; Wang, Chih-Yang; Werb, Zena] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA.
   [Bhakta, Nirav R.; Goga, Andrei] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.
   [Kessenbrock, Kai; Zhou, Alicia; Eyob, Henok; Balakrishnan, Sanjeev; Goga, Andrei] Univ Calif San Francisco, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA.
   [Wang, Chih-Yang] Natl Cheng Kung Univ, Coll Med, Inst Basic Med Sci, Tainan 70101, Taiwan.
   [Yaswen, Paul] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Dept Cell & Mol Biol, 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; National Cheng Kung University; University of California System; University of California Berkeley; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory
RP Werb, Z (corresponding author), Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA.
EM andrei.goga@ucsf.edu; zena.werb@ucsf.edu
FU National Cancer Institute [CA180039, CA136717]; Stand Up To Cancer/AACR [DT0409]; Era of Hope Scholar Award [W81XWH-12-1-0272]; Breast Cancer Research Foundation; Atwater Foundation; US Department of Defense Congressionally Directed Medical Research Program postdoctoral fellowship [11-1-0742]; Ministry of Science and Technology, Taiwan [104-2917-I-006-002]; National Cancer Institute [T32CA108462] Funding Source: NIH RePORTER
NR 33
TC 741
Z9 894
U1 0
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 1
PY 2015
VL 526
IS 7571
BP 131
EP +
DI 10.1038/nature15260
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS5CY
UT WOS:000362095100048
PM 26416748
DA 2026-03-09
ER

PT J
AU Chaisson, MJP
   Huddleston, J
   Dennis, MY
   Sudmant, PH
   Malig, M
   Hormozdiari, F
   Antonacci, F
   Surti, U
   Sandstrom, R
   Boitano, M
   Landolin, JM
   Stamatoyannopoulos, JA
   Hunkapiller, MW
   Korlach, J
   Eichler, EE
AF Chaisson, Mark J. P.
   Huddleston, John
   Dennis, Megan Y.
   Sudmant, Peter H.
   Malig, Maika
   Hormozdiari, Fereydoun
   Antonacci, Francesca
   Surti, Urvashi
   Sandstrom, Richard
   Boitano, Matthew
   Landolin, Jane M.
   Stamatoyannopoulos, John A.
   Hunkapiller, Michael W.
   Korlach, Jonas
   Eichler, Evan E.
TI Resolving the complexity of the human genome using single-molecule sequencing
SO NATURE
LA English
DT Article
ID alignment; program; gaps
AB The human genome is arguably the most complete mammalian reference assembly(1-3), yetmore than 160 euchromatic gaps remain(4-6) and aspects of its structural variation remain poorly understood ten years after its completion(7-9). To identify missing sequence and genetic variation, here we sequence and analyse ahaploid human genome (CHM1) using single-molecule, real-time DNA sequencing(10). We close or extend 55% of the remaining interstitial gaps in the human GRCh37 reference genome-78% of which carried long runs of degenerate short tandem repeats, often several kilobases in length, embedded within (G+C)-rich genomic regions. We resolve the complete sequence of 26,079 euchromatic structural variants at the base-pair level, including inversions, complex insertions and long tracts of tandem repeats. Most have not been previously reported, with the greatest increases in sensitivity occurring for events less than 5 kilobases in size. Compared to the human reference, we find a significant insertional bias (3: 1) in regions corresponding to complex insertions and long short tandem repeats. Our results suggest a greater complexity of the human genome in the form of variation of longer and more complex repetitive DNA that can now be largely resolved with the application of this longer-read sequencing technology.
C1 [Chaisson, Mark J. P.; Huddleston, John; Dennis, Megan Y.; Sudmant, Peter H.; Malig, Maika; Hormozdiari, Fereydoun; Sandstrom, Richard; Stamatoyannopoulos, John A.; Eichler, Evan E.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA.
   [Huddleston, John; Eichler, Evan E.] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA.
   [Antonacci, Francesca] Univ Bari Aldo Moro, Dipartimento Biol, I-70125 Bari, Italy.
   [Surti, Urvashi] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15261 USA.
   [Boitano, Matthew; Landolin, Jane M.; Hunkapiller, Michael W.; Korlach, Jonas] Pacific Biosci Calif Inc, Menlo Pk, CA 94025 USA.
C3 University of Washington; University of Washington Seattle; Howard Hughes Medical Institute; University of Washington; University of Washington Seattle; Universita degli Studi di Bari Aldo Moro; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh
RP Eichler, EE (corresponding author), Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA.
EM eee@gs.washington.edu
FU US National Institutes of Health (NIH) [HG002385, HG007497]; US National Institute of Neurological Disorders and Stroke [K99NS083627]; National Human Genome Research Institute [R01HG002385] Funding Source: NIH RePORTER
NR 27
TC 561
Z9 705
U1 6
U2 160
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 29
PY 2015
VL 517
IS 7536
BP 608
EP U163
DI 10.1038/nature13907
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA2ZL
UT WOS:000348775000042
PM 25383537
DA 2026-03-09
ER

PT J
AU Perera, R
   Stoykova, S
   Nicolay, BN
   Ross, KN
   Fitamant, J
   Boukhali, M
   Lengrand, J
   Deshpande, V
   Selig, MK
   Ferrone, CR
   Settleman, J
   Stephanopoulos, G
   Dyson, NJ
   Zoncu, R
   Ramaswamy, S
   Haas, W
   Bardeesy, N
AF Perera, RushikaM.
   Stoykova, Svetlana
   Nicolay, Brandon N.
   Ross, Kenneth N.
   Fitamant, Julien
   Boukhali, Myriam
   Lengrand, Justine
   Deshpande, Vikram
   Selig, Martin K.
   Ferrone, Cristina R.
   Settleman, Jeff
   Stephanopoulos, Gregory
   Dyson, Nicholas J.
   Zoncu, Roberto
   Ramaswamy, Sridhar
   Haas, Wilhelm
   Bardeesy, Nabeel
TI Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism
SO NATURE
LA English
DT Article
ID nuclear import; genomic analyses; tumor-growth; protein; biogenesis; cells; mtor; tfeb; p53; clearance
AB Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers(1). The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy(2-4), a conserved self-degradative process(5). However, the regulatory circuits that activate autophagy and reprogram PDA cell metabolism are unknown. Here we show that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family of transcription factors. In human PDA cells, the MiT/TFE proteins(6)-MITF, TFE3 and TFEB-are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosome activation is specifically required to maintain intracellular amino acid pools. These results identify the MiT/TFE proteins as master regulators of metabolic reprogramming in pancreatic cancer and demonstrate that transcriptional activation of clearance pathways converging on the lysosome is a novel hallmark of aggressive malignancy.
C1 [Perera, RushikaM.; Stoykova, Svetlana; Nicolay, Brandon N.; Ross, Kenneth N.; Fitamant, Julien; Boukhali, Myriam; Lengrand, Justine; Ferrone, Cristina R.; Settleman, Jeff; Dyson, Nicholas J.; Ramaswamy, Sridhar; Haas, Wilhelm; Bardeesy, Nabeel] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA.
   [Perera, RushikaM.; Stoykova, Svetlana; Ross, Kenneth N.; Fitamant, Julien; Lengrand, Justine; Ramaswamy, Sridhar; Bardeesy, Nabeel] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.
   [Perera, RushikaM.; Nicolay, Brandon N.; Ross, Kenneth N.; Fitamant, Julien; Deshpande, Vikram; Ferrone, Cristina R.; Dyson, Nicholas J.; Ramaswamy, Sridhar; Haas, Wilhelm; Bardeesy, Nabeel] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA.
   [Deshpande, Vikram; Selig, Martin K.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.
   [Ferrone, Cristina R.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA.
   [Stephanopoulos, Gregory] MIT, Dept Chem Engn, Cambridge, MA 02139 USA.
   [Zoncu, Roberto] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 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; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Massachusetts Institute of Technology (MIT); University of California System; University of California Berkeley
RP Bardeesy, N (corresponding author), Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA.
EM Bardeesy.Nabeel@MGH.Harvard.edu
FU National Institutes of Health [P50CA1270003, P01 CA117969-07, R01 CA133557-05]; Linda J. Verville Cancer Research Foundation; Hirshberg Foundation for Pancreatic Cancer; National Cancer Institute [P01CA117969, P50CA127003] Funding Source: NIH RePORTER
NR 46
TC 672
Z9 783
U1 2
U2 230
PU NATURE PUBLISHING 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 20
PY 2015
VL 524
IS 7565
BP 361
EP U251
DI 10.1038/nature14587
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP2NN
UT WOS:000359714000038
PM 26168401
DA 2026-03-09
ER

PT J
AU Elsässer, SJ
   Noh, KM
   Diaz, N
   Allis, CD
   Banaszynski, LA
AF Elsasser, Simon J.
   Noh, Kyung-Min
   Diaz, Nichole
   Allis, C. David
   Banaszynski, Laura A.
TI Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells
SO NATURE
LA English
DT Article
ID dna; retrotransposons; chromatin; distinct; chaperone; genome; genes; daxx; transcription; repression
AB Transposable elements comprise roughly 40% of mammalian genomes(1). They have an active role in genetic variation, adaptation and evolution through the duplication or deletion of genes or their regulatory elements(2-4), and transposable elements themselves can act as alternative promoters for nearby genes, resulting in noncanonical regulation of transcription(5,6). However, transposable element activity can lead to detrimental genome instability(7), and hosts have evolved mechanisms to silence transposable element mobility appropriately(8,9). Recent studies have demonstrated that a subset of transposable elements, endogenous retroviral elements (ERVs) containing long terminal repeats (LTRs), are silenced through trimethylation of histone H3 on lysine 9 (H3K9me3) by ESET (also known as SETDB1 or KMT1E)(10) and a co-repressor complex containing KRAB-associated protein 1 (KAP1; also known as TRIM28)(11) in mouse embryonic stem cells. Here we show that the replacement histone variant H3.3 is enriched at class I and class II ERVs, notably those of the early transposon (ETn)/MusD family and intracisternal A-type particles (IAPs). Deposition at a subset of these elements is dependent upon the H3.3 chaperone complex containing alpha-thalassaemia/mental retardation syndrome X-linked (ATRX) 12 and death-domain-associated protein (DAXX)(12-14). We demonstrate that recruitment of DAXX, H3.3 and KAP1 to ERVs is co-dependent and occurs upstream of ESET, linking H3.3 to ERV-associated H3K9me3. Importantly, H3K9me3 is reduced at ERVs upon H3.3 deletion, resulting in derepression and dysregulation of adjacent, endogenous genes, along with increased retrotransposition of IAPs. Our study identifies a unique heterochromatin state marked by the presence of both H3.3 and H3K9me3, and establishes an important role for H3.3 in control of ERV retrotransposition in embryonic stem cells.
C1 [Elsasser, Simon J.] MRC Lab Mol Biol, Cambridge CB2 0QH, England.
   [Elsasser, Simon J.] Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, S-17121 Stockholm, Sweden.
   [Noh, Kyung-Min; Diaz, Nichole; Allis, C. David; Banaszynski, Laura A.] Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA.
   [Banaszynski, Laura A.] Univ Texas SW Med Ctr Dallas, Cecil H & Ida Green Ctr Reprod Biol Sci, Dallas, TX 75390 USA.
   [Banaszynski, Laura A.] Univ Texas SW Med Ctr Dallas, Childrens Med Ctr Res Inst, Dallas, TX 75390 USA.
C3 MRC Laboratory Molecular Biology; Karolinska Institutet; Rockefeller University; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center
RP Elsässer, SJ (corresponding author), MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England.
EM simon.elsasser@scilifelab.se; alliscd@rockefeller.edu; laura.banaszynski@utsouthwestern.edu
FU Rockefeller University Fund; Tri-Institutional Stem Cell Initiative; EMBO ALTF [1232-2011]; Cambridge University Herchel Smith Fund; National Institute of General Medical Sciences [R01GM040922] Funding Source: NIH RePORTER
NR 40
TC 289
Z9 355
U1 0
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 JUN 11
PY 2015
VL 522
IS 7555
BP 240
EP U323
DI 10.1038/nature14345
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700044
PM 25938714
DA 2026-03-09
ER

PT J
AU Mitchell, DA
   Batich, KA
   Gunn, MD
   Huang, MN
   Sanchez-Perez, L
   Nair, SK
   Congdon, KL
   Reap, EA
   Archer, GE
   Desjardins, A
   Friedman, AH
   Friedman, HS
   Herndon, JE
   Coan, A
   McLendon, RE
   Reardon, DA
   Vredenburgh, JJ
   Bigner, DD
   Sampson, JH
AF Mitchell, Duane A.
   Batich, Kristen A.
   Gunn, Michael D.
   Huang, Min-Nung
   Sanchez-Perez, Luis
   Nair, Smita K.
   Congdon, Kendra L.
   Reap, Elizabeth A.
   Archer, Gary E.
   Desjardins, Annick
   Friedman, Allan H.
   Friedman, Henry S.
   Herndon, James E., II
   Coan, April
   McLendon, Roger E.
   Reardon, David A.
   Vredenburgh, James J.
   Bigner, Darell D.
   Sampson, John H.
TI Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients
SO NATURE
LA English
DT Article
ID human cytomegalovirus; malignant glioma; peripheral-blood; melanoma-cells; t-cells; responses; immunity; tumors; mip-1-alpha; vaccination
AB After stimulation, dendritic cells(DCs) mature andmigrate to draining lymph nodes to induce immune responses(1). As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers(2-4) including glioblastoma(5-7), the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs8 or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65(pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain(9-12), providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.
C1 [Mitchell, Duane A.; Archer, Gary E.; Desjardins, Annick; Friedman, Allan H.; Friedman, Henry S.; McLendon, Roger E.; Reardon, David A.; Vredenburgh, James J.; Bigner, Darell D.; Sampson, John H.] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr, Durham, NC 27710 USA.
   [Mitchell, Duane A.; Batich, Kristen A.; Sanchez-Perez, Luis; Congdon, Kendra L.; Reap, Elizabeth A.; Archer, Gary E.; Desjardins, Annick; Friedman, Allan H.; Friedman, Henry S.; Reardon, David A.; Vredenburgh, James J.; Bigner, Darell D.; Sampson, John H.] Duke Univ, Med Ctr, Div Neurosurg, Dept Surg, Durham, NC 27710 USA.
   [Mitchell, Duane A.; Batich, Kristen A.; McLendon, Roger E.; Bigner, Darell D.; Sampson, John H.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA.
   [Gunn, Michael D.] Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA.
   [Gunn, Michael D.; Huang, Min-Nung; Sampson, John H.] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA.
   [Nair, Smita K.] Duke Univ, Med Ctr, Dept Surg, Div Surg Sci, Durham, NC 27710 USA.
   [Herndon, James E., II; Coan, April] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA.
   [Sampson, John H.] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC 27710 USA.
C3 Duke University; Duke University; Duke University; Duke University; Duke University; Duke University; Duke University; Duke University
RP Sampson, JH (corresponding author), Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr, Durham, NC 27710 USA.
EM duane.mitchell@neurosurgery.ufl.edu; john.sampson@duke.edu
FU National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke [P50-CA108786]; SRC on Primary and Metastatic Tumors of the CNS [P50-NS20023]; NIH [R01-CA177476-01, R01-NS067037, R01-CA134844, P01-CA154291-01A1]; National Brain Tumor Society; American Brain Tumor Association; Accelerate Brain Cancer Cure Foundation; Kinetics Foundation; Ben and Catherine Ivy Foundation; Duke University from the National Institutes of Health National Center for Research Resources [1UL2 RR024128-01]; National Institute of Allergy and Infectious Diseases [T32AI052077] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007171] Funding Source: NIH RePORTER
NR 29
TC 431
Z9 506
U1 2
U2 186
PU NATURE PUBLISHING 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 19
PY 2015
VL 519
IS 7543
BP 366
EP +
DI 10.1038/nature14320
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD6AY
UT WOS:000351171900044
PM 25762141
DA 2026-03-09
ER

PT J
AU Huang, YH
   Zhu, C
   Kondo, Y
   Anderson, AC
   Gandhi, A
   Russell, A
   Dougan, SK
   Petersen, BS
   Melum, E
   Pertel, T
   Clayton, KL
   Raab, M
   Chen, Q
   Beauchemin, N
   Yazaki, PJ
   Pyzik, M
   Ostrowski, MA
   Glickman, JN
   Rudd, CE
   Ploegh, HL
   Franke, A
   Petsko, GA
   Kuchroo, VK
   Blumberg, RS
AF Huang, Yu-Hwa
   Zhu, Chen
   Kondo, Yasuyuki
   Anderson, Ana C.
   Gandhi, Amit
   Russell, Andrew
   Dougan, Stephanie K.
   Petersen, Britt-Sabina
   Melum, Espen
   Pertel, Thomas
   Clayton, Kiera L.
   Raab, Monika
   Chen, Qiang
   Beauchemin, Nicole
   Yazaki, Paul J.
   Pyzik, Michal
   Ostrowski, Mario A.
   Glickman, Jonathan N.
   Rudd, Christopher E.
   Ploegh, Hidde L.
   Franke, Andre
   Petsko, Gregory A.
   Kuchroo, Vijay K.
   Blumberg, Richard S.
TI CEACAM1 regulates TIM-3-mediated tolerance and exhaustion
SO NATURE
LA English
DT Article
ID cd4(+) t-cells; crystal-structure; murine; tim-3; receptor; adhesion; protein; antigen; binding; induction
AB T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers'. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition(6-10). Biochemical, biophysical and X-ray crystallography studies show that the membranedistal immunoglobulin-variable (IgV) -like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM 1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in cis through the highly related membranedistal N-terminal domains of each molecule. CEACAM 1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM 1 -deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-specific CEACAM 1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM 1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity.
C1 [Huang, Yu-Hwa; Kondo, Yasuyuki; Gandhi, Amit; Melum, Espen; Pyzik, Michal; Blumberg, Richard S.] Harvard Univ, Sch Med, Dept Med, Div Gastroenterol,Brigham & Womens Hosp, Boston, MA 02115 USA.
   [Zhu, Chen; Anderson, Ana C.; Pertel, Thomas; Kuchroo, Vijay K.] Harvard Univ, Sch Med, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA.
   [Zhu, Chen; Anderson, Ana C.; Pertel, Thomas; Kuchroo, Vijay K.] Brigham & Womens Hosp, Harvard Inst Med, Boston, MA 02115 USA.
   [Russell, Andrew; Petsko, Gregory A.] Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA.
   [Dougan, Stephanie K.; Ploegh, Hidde L.] MIT, Whitehead Inst, Cambridge, MA 02142 USA.
   [Petersen, Britt-Sabina; Franke, Andre] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany.
   [Melum, Espen] Oslo Univ Hosp, Norwegian PSC Res Ctr, Div Canc Med Surg & Transplantat, N-0424 Oslo, Norway.
   [Clayton, Kiera L.; Ostrowski, Mario A.] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada.
   [Raab, Monika; Rudd, Christopher E.] Univ Cambridge, Dept Pathol, Cell Signalling Sect, Cambridge CB2 1QP, England.
   [Chen, Qiang] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China.
   [Beauchemin, Nicole] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3G 1Y6, Canada.
   [Yazaki, Paul J.] City Hope Natl Med Ctr, Beckman Inst, Duarte, CA 91010 USA.
   [Ostrowski, Mario A.] St Michaels Hosp, Keenan Res Ctr, Toronto, ON M5S 1A8, Canada.
   [Glickman, Jonathan N.] Miraca Life Sci, GI Pathol, Newton, MA 02464 USA.
C3 Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; Brandeis University; Massachusetts Institute of Technology (MIT); Whitehead Institute; University of Kiel; University of Oslo; University of Toronto; University of Cambridge; Sichuan University; McGill University; City of Hope; Beckman Research Institute of City of Hope; University of Toronto; Saint Michaels Hospital Toronto
RP Blumberg, RS (corresponding author), Harvard Univ, Sch Med, Dept Med, Div Gastroenterol,Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.
EM rblumberg@partners.org
FU American Cancer Society [RSG-11-057-01-LIB]; Norwegian PSC research center; Unger Vetlesen Medical Fund; Crohn's & Colitis Foundation of America fellowship grant; Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence 'Inflammation at Interfaces' Award; Harvard Clinical Translational Science Center [UL1 TR001102]; National Basic Research Program of China [2010CB529906]; Canadian Institute of Health Research [MOP-93787]; AACR-Pancreatic Cancer Action Network; National Institutes of Health (NIH) [GM32415, AI073748, NS045937, AI039671, AI056299, DK044319, DK051362, DK053056, DK088199]; Harvard Digestive Diseases Center (HDDC) [DK0034854]; High Point Foundation; National Institute of Allergy and Infectious Diseases [P01AI056299, P01AI039671] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK051362, R01DK053056, P30DK034854, R01DK044319, R01DK088199] Funding Source: NIH RePORTER
NR 56
TC 576
Z9 707
U1 9
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 JAN 15
PY 2015
VL 517
IS 7534
BP 386
EP U566
DI 10.1038/nature13848
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300050
PM 25363763
DA 2026-03-09
ER

PT J
AU Oka, Y
   Ye, MY
   Zuker, CS
AF Oka, Yuki
   Ye, Mingyu
   Zuker, Charles S.
TI Thirst driving and suppressing signals encoded by distinct neural populations in the brain
SO NATURE
LA English
DT Article
ID sensory circumventricular organs; subfornical organ; gabaergic neurons; stimulation; taste
AB Thirst is the basic instinct to drink water. Previously, it was shown that neurons in several circumventricular organs of the hypothalamus are activated by thirst-inducing conditions(1). Here we identify two distinct, genetically separable neural populations in the subfornical organ that trigger or suppress thirst. We show that optogenetic activation of subfornical organ excitatory neurons, marked by the expression of the transcription factor ETV-1, evokes intense drinking behaviour, and does so even in fully water-satiated animals. The light-induced response is highly specific for water, immediate and strictly locked to the laser stimulus. In contrast, activation of a second population of subfornical organ neurons, marked by expression of the vesicular GABA transporter VGAT, drastically suppresses drinking, even in water-craving thirsty animals. These results reveal an innate brain circuit that can turn an animal's water-drinking behaviour on and off, and probably functions as a centre for thirst control in the mammalian brain.
C1 [Oka, Yuki; Ye, Mingyu; Zuker, Charles S.] Columbia Univ, Howard Hughes Med Inst, Columbia Coll Phys & Surg, Dept Biochem & Mol Biophys, New York, NY 10032 USA.
   [Oka, Yuki; Ye, Mingyu; Zuker, Charles S.] Columbia Univ, Howard Hughes Med Inst, Columbia Coll Phys & Surg, Dept Neurosci, New York, NY 10032 USA.
C3 Columbia University; Howard Hughes Medical Institute; Howard Hughes Medical Institute; Columbia University
RP Oka, Y (corresponding author), CALTECH, Div Biol & Biol Engn 216 76, Pasadena, CA 91125 USA.
EM yoka@caltech.edu
FU National Institute on Drug Abuse; National Institute of Neurological Disorders and Stroke
NR 32
TC 185
Z9 228
U1 2
U2 66
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 16
PY 2015
VL 520
IS 7547
BP 349
EP +
DI 10.1038/nature14108
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG0RI
UT WOS:000352974200039
PM 25624099
DA 2026-03-09
ER

PT J
AU Cox, TR
   Rumney, RMH
   Schoof, EM
   Perryman, L
   Hoye, AM
   Agrawal, A
   Bird, D
   Ab Latif, N
   Forrest, H
   Evans, HR
   Huggins, ID
   Lang, G
   Linding, R
   Gartland, A
   Erler, JT
AF Cox, Thomas R.
   Rumney, Robin M. H.
   Schoof, Erwin M.
   Perryman, Lara
   Hoye, Anette M.
   Agrawal, Ankita
   Bird, Demelza
   Ab Latif, Norain
   Forrest, Hamish
   Evans, Holly R.
   Huggins, Iain D.
   Lang, Georgina
   Linding, Rune
   Gartland, Alison
   Erler, Janine T.
TI RETRACTED: The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase (Retracted Article)
SO NATURE
LA English
DT Article; Retracted Publication
ID gene-expression; proliferation; recruitment; resorption; receptor
AB Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia(1). Tumour-secreted proteins play a crucial role in these interactions(2-5) and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable(6). Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality(6,7). The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis, independent of RANK ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications.
C1 [Cox, Thomas R.; Perryman, Lara; Hoye, Anette M.; Linding, Rune; Erler, Janine T.] Univ Copenhagen UCPH, Biotech Res & Innovat Ctr BRIC, DK-2200 Copenhagen, Denmark.
   [Cox, Thomas R.; Bird, Demelza; Lang, Georgina; Erler, Janine T.] Inst Canc Res, Hypoxia & Metastasis Team, Canc Res UK Tumour Cell Signalling Unit, London SW3 6JB, England.
   [Rumney, Robin M. H.; Agrawal, Ankita; Ab Latif, Norain; Forrest, Hamish; Evans, Holly R.; Huggins, Iain D.; Gartland, Alison] Univ Sheffield, Mellanby Ctr Bone Res, Sheffield S10 2RX, S Yorkshire, England.
   [Schoof, Erwin M.; Linding, Rune] Tech Univ Denmark, Cellular Signal Integrat Grp C SIG, DK-2800 Lyngby, Denmark.
C3 Royal Marsden NHS Foundation Trust; University of London; Institute of Cancer Research - UK; University of Sheffield; Technical University of Denmark
RP Erler, JT (corresponding author), Univ Copenhagen UCPH, Biotech Res & Innovat Ctr BRIC, DK-2200 Copenhagen, Denmark.
EM a.gartland@shef.ac.uk; janine.erler@bric.ku.dk
FU Cancer Research UK [C107/A10433]; Biotech Research and Innovation Centre (BRIC, University of Copenhagen); University of Sheffield; National Institute for Health Research Sheffield Clinical Research Facility; Breast Cancer Campaign [2012MayPR086]; Danish Cancer Society [R56-A2971-12-S2]; Lundbeck Foundation; Velux Foundations (VKR) [VKR 022758]; Novo Nordisk Foundation; Breast Cancer Campaign [2012MayPR086] Funding Source: researchfish; Novo Nordisk Fonden [NNF12OC1015992] Funding Source: researchfish
NR 30
TC 391
Z9 458
U1 2
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 JUN 4
PY 2015
VL 522
IS 7554
BP 106
EP U279
DI 10.1038/nature14492
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ5QP
UT WOS:000355543400039
PM 26017313
DA 2026-03-09
ER

PT J
AU D'Orazio, DJ
   Haiman, Z
   Schiminovich, D
AF D'Orazio, Daniel J.
   Haiman, Zoltan
   Schiminovich, David
TI Relativistic boost as the cause of periodicity in a massive black-hole binary candidate
SO NATURE
LA English
DT Article
ID active galactic nuclei; accretion disks; central cavity; quasar; variability; simulation; dynamics; systems; models; driven
AB Because most large galaxies contain a central black hole, and galaxies often merge(1), black-hole binaries are expected to be common in galactic nuclei(2). Although they cannot be imaged, periodicities in the light curves of quasars have been interpreted as evidence for binaries(3-5), most recently in PG 1302-102, which has a short rest-frame optical period of four years (ref. 6). If the orbital period of the black-hole binary matches this value, then for the range of estimated black-hole masses, the components would be separated by 0.007-0.017 parsecs, implying relativistic orbital speeds. There has been much debate over whether black-hole orbits could be smaller than one parsec (ref. 7). Here we report that the amplitude and the sinusoid-like shape of the variability of the light curve of PG 1302-102 can be fitted by relativistic Doppler boosting of emission from a compact, steadily accreting, unequal-mass binary. We predict that brightness variations in the ultraviolet light curve track those in the optical, but with a two to three times larger amplitude. This prediction is relatively insensitive to the details of the emission process, and is consistent with archival ultraviolet data. Follow-up ultraviolet and optical observations in the next few years can further test this prediction and confirm the existence of a binary black hole in the relativistic regime.
C1 [D'Orazio, Daniel J.; Haiman, Zoltan; Schiminovich, David] Columbia Univ, Dept Astron, New York, NY 10027 USA.
C3 Columbia University
RP Haiman, Z (corresponding author), Columbia Univ, Dept Astron, 550 West 120th St, New York, NY 10027 USA.
EM zoltan@astro.columbia.edu
FU National Science Foundation Graduate Research Fellowship [DGE1144155]; NASA [NNX11AE05G]
NR 45
TC 165
Z9 190
U1 0
U2 7
PU NATURE PUBLISHING 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 17
PY 2015
VL 525
IS 7569
BP 351
EP +
DI 10.1038/nature15262
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900037
PM 26381982
DA 2026-03-09
ER

PT J
AU Zhou, J
   Wan, J
   Gao, XW
   Zhang, XQ
   Jaffrey, SR
   Qian, SB
AF Zhou, Jun
   wan, Ji
   Gao, Xiangwei
   Zhang, Xingqian
   Jaffrey, Samie R.
   Qian, Shu-Bing
TI Dynamic m6A mRNA methylation directs translational control of heat shock response
SO NATURE
LA English
DT Article
ID gene-expression; stress-response; n-6-methyladenosine; initiation; reveals; hsp70; mechanism; distinct; program; leader
AB The most abundant mRNA post-transcriptional modification is N-6-methyladenosine (m(6)A), which has broad roles in RNA biology(1-5). In mammalian cells, the asymmetric distribution of m(6)A along mRNAs results in relatively less methylation in the 5' untranslated region (5'UTR) compared to other regions(6,7). However, whether and how 5'UTR methylation is regulated is poorly understood. Despite the crucial role of the 5'UTR in translation initiation, very little is known about whether m(6)A modification influences mRNA translation. Here we show that in response to heat shock stress, certain adenosines within the 5'UTR of newly transcribed mRNAs are preferentially methylated. Wefind that the dynamic 5'UTR methylation is a result of stress-induced nuclear localization of YTHDF2, a well-characterized m(6)A 'reader'. Upon heat shock stress, the nuclear YTHDF2 preserves 5'UTR methylation of stress-induced transcripts by limiting the m(6)A 'eraser' FTO from demethylation. Remarkably, the increased 5'UTR methylation in the form of m(6)A promotes cap-independent translation initiation, providing a mechanism for selective mRNA translation under heat shock stress. Using Hsp70 mRNA as an example, we demonstrate that a single m(6)A modification site in the 5'UTR enables translation initiation independent of the 5' end N-7-methylguanosine cap. The elucidation of the dynamic features of 5'UTR methylation and its critical role in cap-independent translation not only expands the breadth of physiological roles of m(6)A, but also uncovers a previously unappreciated translational control mechanism in heat shock response.
C1 [Zhou, Jun; wan, Ji; Gao, Xiangwei; Zhang, Xingqian; Qian, Shu-Bing] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA.
   [Jaffrey, Samie R.] Cornell Univ, Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10065 USA.
C3 Cornell University; Cornell University; Weill Cornell Medicine
RP Qian, SB (corresponding author), Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA.
EM sq38@cornell.edu
FU US National Institutes of Health [DP2 OD006449, R01AG042400]; NIDA [DA037150]; US Department of Defense [W81XWH-14-1-0068]; National Cancer Institute [R01CA186702] Funding Source: NIH RePORTER
NR 33
TC 1056
Z9 1247
U1 5
U2 218
PU NATURE PUBLISHING 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 22
PY 2015
VL 526
IS 7574
BP 591
EP U332
DI 10.1038/nature15377
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV1NX
UT WOS:000364026100054
PM 26458103
DA 2026-03-09
ER

PT J
AU Cao, Y
   Kulkarni, SR
   Howell, DA
   Gal-Yam, A
   Kasliwal, MM
   Valenti, S
   Johansson, J
   Amanullah, R
   Goobar, A
   Sollerman, J
   Taddia, F
   Horesh, A
   Sagiv, I
   Cenko, SB
   Nugent, PE
   Arcavi, I
   Surace, J
   Wozniak, PR
   Moody, DI
   Rebbapragada, UD
   Bue, BD
   Gehrels, N
AF Cao, Yi
   Kulkarni, S. R.
   Howell, D. Andrew
   Gal-Yam, Avishay
   Kasliwal, Mansi M.
   Valenti, Stefano
   Johansson, J.
   Amanullah, R.
   Goobar, A.
   Sollerman, J.
   Taddia, F.
   Horesh, Assaf
   Sagiv, Ilan
   Cenko, S. Bradley
   Nugent, Peter E.
   Arcavi, Iair
   Surace, Jason
   Wozniak, P. R.
   Moody, Daniela I.
   Rebbapragada, Umaa D.
   Bue, Brian D.
   Gehrels, Neil
TI A strong ultraviolet pulse from a newborn type Ia supernova
SO NATURE
LA English
DT Article
ID time optical-spectra; sn 2011fe; low-resolution; progenitor; swift; spectrograph; constraints; companions; galaxy; single
AB Type Ia supernovae(1) are destructive explosions of carbon-oxygen white dwarfs(2,3). Although they are used empirically to measure cosmological distances(4-6), the nature of their progenitors remains mysterious(3). One of the leading progenitor models, called the single degenerate channel, hypothesizes that a white dwarf accretes matter from a companion star and the resulting increase in its central pressure and temperature ignites thermonuclear explosion(3,7,8). Here we report observations with the Swift Space Telescope of strong but declining ultraviolet emission from a type Ia supernova within four days of its explosion. This emission is consistent with theoretical expectations of collision between material ejected by the supernova and a companion star(9), and therefore provides evidence that some type Ia supernovae arise from the single degenerate channel.
C1 [Cao, Yi; Kulkarni, S. R.] CALTECH, Dept Astron, Pasadena, CA 91125 USA.
   [Kulkarni, S. R.] CALTECH, Caltech Opt Observ, Pasadena, CA 91125 USA.
   [Howell, D. Andrew; Valenti, Stefano; Arcavi, Iair] Las Cumbres Observ Global Telescope Network, Goleta, CA 93117 USA.
   [Howell, D. Andrew; Valenti, Stefano] Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA.
   [Gal-Yam, Avishay; Horesh, Assaf; Sagiv, Ilan] Weizmann Inst Sci, Dept Particle Phys & Astrophys, IL-76100 Rehovot, Israel.
   [Kasliwal, Mansi M.] Observ Carnegie Inst Sci, Pasadena, CA 91101 USA.
   [Johansson, J.; Amanullah, R.; Goobar, A.] Stockholm Univ, Dept Phys, Oskar Klein Ctr, SE-10691 Stockholm, Sweden.
   [Sollerman, J.; Taddia, F.] Stockholm Univ, Dept Astron, Oskar Klein Ctr, SE-10691 Stockholm, Sweden.
   [Cenko, S. Bradley; Gehrels, Neil] NASA, Goddard Space Flight Ctr, Astrophys Sci Div, Greenbelt, MD 20771 USA.
   [Nugent, Peter E.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA.
   [Nugent, Peter E.] Univ Calif Berkeley, Dept Astron, Berkeley, CA 94720 USA.
   [Arcavi, Iair] Univ Calif Santa Barbara, Kavli Inst Theoret Phys, Santa Barbara, CA 93106 USA.
   [Surace, Jason] CALTECH, Spitzer Sci Ctr, Pasadena, CA 91125 USA.
   [Wozniak, P. R.; Moody, Daniela I.] Los Alamos Natl Lab, Los Alamos, NM 87545 USA.
   [Rebbapragada, Umaa D.; Bue, Brian D.] CALTECH, Jet Prop Lab, Pasadena, CA 91109 USA.
C3 California Institute of Technology; California Institute of Technology; University of California System; University of California Santa Barbara; Weizmann Institute of Science; Carnegie Institution for Science; Oskar Klein Centre; Stockholm University; Stockholm University; Oskar Klein Centre; National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center; 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 Santa Barbara; 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 Cao, Y (corresponding author), CALTECH, Dept Astron, Pasadena, CA 91125 USA.
EM ycao@astro.caltech.edu
FU W. M. Keck Foundation; National Science Foundation; EU/FP7 via an ERC grant; "Quantum Universe" I-Core programme; ISF; Minerva and Weizmann-UK grants; Kimmel Award; Carnegie-Princeton fellowship; Swedish Research Council; Knut and Alice Wallenberg Foundation; Office of Science of the US Department of Energy [DE-AC02-05CH11231]; US Department of Energy as part of the Laboratory Directed Research and Development programme; National Aeronautics and Space Administration; Division Of Astronomical Sciences; Direct For Mathematical & Physical Scien [1313484, 1009987] Funding Source: National Science Foundation
NR 62
TC 164
Z9 176
U1 1
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 MAY 21
PY 2015
VL 521
IS 7552
BP 328
EP +
DI 10.1038/nature14440
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CI5RM
UT WOS:000354816500050
PM 25993962
DA 2026-03-09
ER

PT J
AU Ramdya, P
   Lichocki, P
   Cruchet, S
   Frisch, L
   Tse, W
   Floreano, D
   Benton, R
AF Ramdya, Pavan
   Lichocki, Pawel
   Cruchet, Steeve
   Frisch, Lukas
   Tse, Winnie
   Floreano, Dario
   Benton, Richard
TI Mechanosensory interactions drive collective behaviour in Drosophila
SO NATURE
LA English
DT Article
ID stimulation; neurons; taste
AB Collective behaviour enhances environmental sensing and decision-making in groups of animals(1,2). Experimental and theoretical investigations of schooling fish, flocking birds and human crowds have demonstrated that simple interactions between individuals can explain emergent group dynamics(3,4). These findings indicate the existence of neural circuits that support distributed behaviours, but the molecular and cellular identities of relevant sensory pathways are unknown. Here we show that Drosophila melanogaster exhibits collective responses to an aversive odour: individual flies weakly avoid the stimulus, but groups show enhanced escape reactions. Using high-resolution behavioural tracking, computational simulations, genetic perturbations, neural silencing and optogenetic activation we demonstrate that this collective odour avoidance arises from cascades of appendage touch interactions between pairs of flies. Interfly touch sensing and collective behaviour require the activity of distal leg mechanosensory sensilla neurons and the mechanosensory channel NOMPC5,6. Remarkably, through these inter-fly encounters, wild-type flies can elicit avoidance behaviour in mutant animals that cannot sense the odour-a basic form of communication. Our data highlight the unexpected importance of social context in the sensory responses of a solitary species and open the door to a neural-circuit-level understanding of collective behaviour in animal groups.
C1 [Ramdya, Pavan; Cruchet, Steeve; Benton, Richard] Univ Lausanne, Fac Biol & Med, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland.
   [Ramdya, Pavan; Lichocki, Pawel; Floreano, Dario] Ecole Polytech Fed Lausanne, Lab Intelligent Syst, CH-1015 Lausanne, Switzerland.
   [Lichocki, Pawel] Univ Lausanne, Dept Ecol & Evolut, CH-1015 Lausanne, Switzerland.
   [Frisch, Lukas; Tse, Winnie] Ecole Polytech Fed Lausanne, Masters Program Microengn, Inst Microengn, CH-1015 Lausanne, Switzerland.
C3 University of Lausanne; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; University of Lausanne; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne
RP Benton, R (corresponding author), Univ Lausanne, Fac Biol & Med, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland.
EM ramdya@gmail.com; Richard.Benton@unil.ch
FU Human Frontier Science Program Long-term Fellowship; Swiss National Science Foundation [200021_127143, CR32I3_141063/1]; FP7-FET European Project INSIGHT [308943]; European Research Council [205202, 615094]; Swiss National Science Foundation (SNF) [CR32I3_141063, 200021_127143] Funding Source: Swiss National Science Foundation (SNF); European Research Council (ERC) [205202] Funding Source: European Research Council (ERC)
NR 33
TC 145
Z9 181
U1 1
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 MAR 12
PY 2015
VL 519
IS 7542
BP 233
EP +
DI 10.1038/nature14024
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500039
PM 25533959
DA 2026-03-09
ER

PT J
AU van Kleunen, M
   Dawson, W
   Essl, F
   Pergl, J
   Winter, M
   Weber, E
   Kreft, H
   Weigelt, P
   Kartesz, J
   Nishino, M
   Antonova, LA
   Barcelona, JF
   Cabezas, FJ
   Cárdenas, D
   Cárdenas-Toro, J
   Castaño, N
   Chacón, E
   Chatelain, C
   Ebel, AL
   Figueiredo, E
   Fuentes, N
   Groom, QJ
   Henderson, L
   Inderjit
   Kupriyanov, A
   Masciadri, S
   Meerman, J
   Morozova, O
   Moser, D
   Nickrent, DL
   Patzelt, A
   Pelser, PB
   Baptiste, MP
   Poopath, M
   Schulze, M
   Seebens, H
   Shu, WS
   Thomas, J
   Velayos, M
   Wieringa, JJ
   Pysek, P
AF van Kleunen, Mark
   Dawson, Wayne
   Essl, Franz
   Pergl, Jan
   Winter, Marten
   Weber, Ewald
   Kreft, Holger
   Weigelt, Patrick
   Kartesz, John
   Nishino, Misako
   Antonova, Liubov A.
   Barcelona, Julie F.
   Cabezas, Francisco J.
   Cardenas, Dairon
   Cardenas-Toro, Juliana
   Castano, Nicolas
   Chacon, Eduardo
   Chatelain, Cyrille
   Ebel, Aleksandr L.
   Figueiredo, Estrela
   Fuentes, Nicol
   Groom, Quentin J.
   Henderson, Lesley
   Inderjit
   Kupriyanov, Andrey
   Masciadri, Silvana
   Meerman, Jan
   Morozova, Olga
   Moser, Dietmar
   Nickrent, Daniel L.
   Patzelt, Annette
   Pelser, Pieter B.
   Baptiste, Maria P.
   Poopath, Manop
   Schulze, Maria
   Seebens, Hanno
   Shu, Wen-sheng
   Thomas, Jacob
   Velayos, Mauricio
   Wieringa, Jan J.
   Pysek, Petr
TI Global exchange and accumulation of non-native plants
SO NATURE
LA English
DT Article
ID invasions; diversity; patterns; island; flora; us
AB All around the globe, humans have greatly altered the abiotic and biotic environment with ever-increasing speed. One defining feature of the Anthropocene epoch(1,2) is the erosion of biogeographical barriers by human-mediated dispersal of species into new regions, where they can naturalize and cause ecological, economic and social damage(3). So far, no comprehensive analysis of the global accumulation and exchange of alien plant species between continents has been performed, primarily because of a lack of data. Here we bridge this knowledge gap by using a unique global database on the occurrences of naturalized alien plant species in 481 mainland and 362 island regions. In total, 13,168 plant species, corresponding to 3.9% of the extant global vascular flora, or approximately the size of the native European flora, have become naturalized somewhere on the globe as a result of human activity. North America has accumulated the largest number of naturalized species, whereas the Pacific Islands show the fastest increase in species numbers with respect to their land area. Continents in the Northern Hemisphere have been the major donors of naturalized alien species to all other continents. Our results quantify for the first time the extent of plant naturalizations worldwide, and illustrate the urgent need for globally integrated efforts to control, manage and understand the spread of alien species.
C1 [van Kleunen, Mark; Dawson, Wayne] Univ Konstanz, Dept Biol, Ecol, D-78464 Constance, Germany.
   [Essl, Franz; Chacon, Eduardo; Moser, Dietmar] Univ Vienna, Div Conservat Vegetat & Landscape Ecol, A-1030 Vienna, Austria.
   [Pergl, Jan; Pysek, Petr] Czech Acad Sci, Dept Invas Ecol, Inst Bot, CZ-25243 Pruhonice, Czech Republic.
   [Winter, Marten] German Ctr Integrat Biodivers Res iDiv, D-04103 Leipzig, Germany.
   [Weber, Ewald] Univ Potsdam, Inst Biochem & Biol, D-14469 Potsdam, Germany.
   [Kreft, Holger; Weigelt, Patrick] Univ Gottingen, Biodivers Macroecol & Conservat Biogeog, D-37077 Gottingen, Germany.
   [Kartesz, John; Nishino, Misako] Biota North Amer Program BONAP, Chapel Hill, NC 27516 USA.
   [Antonova, Liubov A.] Russian Acad Sci, Far East Branch, Inst Aquat & Ecol Problems, Khabarovsk 680000, Russia.
   [Barcelona, Julie F.; Pelser, Pieter B.] Univ Canterbury, Sch Biol Sci, Christchurch 8140, New Zealand.
   [Cabezas, Francisco J.; Velayos, Mauricio] CSIC, Dept Biodiversidad & Conservacio, Real Jardin Bot, E-28014 Madrid, Spain.
   [Cardenas, Dairon; Castano, Nicolas] Herbario Amazonico Colombiano, Inst Amazon Invest Cienti Sinchi, Bogota 110311, Colombia.
   [Cardenas-Toro, Juliana; Baptiste, Maria P.] Inst Invest Recursos Biol Alexander von Humboldt, Bogota 111311, Colombia.
   [Cardenas-Toro, Juliana] Monash Univ, Arts Fac, Melbourne, Vic 3145, Australia.
   [Chacon, Eduardo] Univ Costa Rica, Escuela Biol, San Jose 11501, Costa Rica.
   [Chatelain, Cyrille] Conservatoire & Jardin Botan Ville Geneve, CH-1292 Geneva, Switzerland.
   [Ebel, Aleksandr L.] Tomsk State Univ, Lab Plant Taxon & Phylogeny, Tomsk 634050, Russia.
   [Figueiredo, Estrela] Nelson Mandela Metropolitan Univ, Dept Bot, ZA-6031 Port Elizabeth, South Africa.
   [Figueiredo, Estrela] Univ Coimbra, Ctr Funct Ecol, Dept Ciencias Vida, P-3001455 Coimbra, Portugal.
   [Fuentes, Nicol] Univ Concepcion, Inst Ecol & Biodiversidad, Fac Ciencias Forest, Concepcion 403000, Chile.
   [Groom, Quentin J.] Botan Garden Meise, B-1860 Meise, Belgium.
   [Henderson, Lesley] ARC Plant Protect Res Inst, ZA-0001 Pretoria, South Africa.
   [Inderjit] Univ Delhi, Dept Environm Studies, Delhi 110007, India.
   [Inderjit] Univ Delhi, Ctr Environm Management Degraded Ecosyst, Delhi 110007, India.
   [Kupriyanov, Andrey] Inst Human Ecol SB RAS, Kemerovo 650065, Russia.
   [Masciadri, Silvana] Univ Fed Rio Grande do Norte, Programa Posgrad Ecol, BR-59078900 Natal, RN, Brazil.
   [Masciadri, Silvana] Univ Republica, Oceanol & Ecol Marina, Fac Ciencias, Montevideo 11400, Uruguay.
   [Meerman, Jan] Belize Trop Forest Studies, Belmopan, Belize.
   [Morozova, Olga] Inst Geog RAS, Moscow 119017, Russia.
   [Nickrent, Daniel L.] So Illinois Univ, Dept Plant Biol, Carbondale, IL 62901 USA.
   [Patzelt, Annette] Diwan Royal Court, Oman Bot Garden, Muscat 122, Oman.
   [Poopath, Manop] Wildlife & Plant Conservat, Dept Natl Pk, Forest Herbarium BKF, Bangkok 10900, Thailand.
   [Schulze, Maria] Univ Halle Wittenberg, Dept Biol, D-06108 Halle, Germany.
   [Seebens, Hanno] Carl von Ossietzky Univ Oldenburg, Inst Chem & Biol Marine Environm, D-26111 Oldenburg, Germany.
   [Shu, Wen-sheng] Sun Yat Sen Univ, State Key Lab Biocontrol, Guangzhou 510275, Guangdong, Peoples R China.
   [Shu, Wen-sheng] Sun Yat Sen Univ, Coll Ecol & Evolut, Guangdong Key Lab Plant Resources, Guangzhou 510275, Guangdong, Peoples R China.
   [Thomas, Jacob] King Saud Univ, Coll Sci, Dept Bot & Microbiol, Riyadh 11451, Saudi Arabia.
   [Wieringa, Jan J.] Nat Biodivers Ctr, Bot Sect, NL-2333 CR Leiden, Netherlands.
   [Wieringa, Jan J.] Wageningen Univ, Biosystemat Grp, NL-6708 PB Wageningen, Netherlands.
   [Pysek, Petr] Charles Univ Prague, Fac Sci, Dept Ecol, CZ-12844 Prague, Czech Republic.
   Univ Stellenbosch, Dept Bot & Zool, Ctr Invest Biol, ZA-7602 Matieland, South Africa.
C3 University of Konstanz; University of Vienna; Czech Academy of Sciences; Institute of Botany of the Czech Academy of Sciences; German Research Foundation (DFG); German Centre for Integrative Biodiversity Research (iDiv); University of Potsdam; University of Gottingen; Russian Academy of Sciences; University of Canterbury; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Real Jardin Botanico de Madrid; Alliance; International Center for Tropical Agriculture - CIAT; Monash University; Universidad Costa Rica; Tomsk State University; Nelson Mandela University; Universidade de Coimbra; Universidad de Concepcion; University of Delhi; University of Delhi; Universidade Federal do Rio Grande do Norte; Universidad de la Republica, Uruguay; Institute of Geography, Russian Academy of Sciences; Russian Academy of Sciences; Southern Illinois University System; Southern Illinois University; Martin Luther University Halle Wittenberg; Carl von Ossietzky Universitat Oldenburg; Sun Yat Sen University; Sun Yat Sen University; King Saud University; Naturalis Biodiversity Center; Wageningen University & Research; Charles University Prague; Stellenbosch University
RP van Kleunen, M (corresponding author), Univ Konstanz, Dept Biol, Ecol, Univ Str 10, D-78464 Constance, Germany.
EM mark.vankleunen@uni-konstanz.de
FU Deutsche Forschungsgemeinschaft [KL 1866/9-1]; Austrian Climate and Energy Fund (SpecAdapt) [KR11AC0K00355]; Centre of Excellence PLADIAS (Czech Science Foundation) [14-36079G]; Czech Academy of Sciences [RVO 67985939]; Praemium Academiae award from The Czech Academy of Sciences; Helmholtz Centre for Environmental Research (UFZ); German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig [DFG FZT 118]; Deutsche Forschungsgemeinschaft (DFG) Free Floater Program in the Excellence Initiative at the University of Gottingen; BEFmate project from the Ministry of Science and Culture of Lower Saxony; German VW-Foundation; project Flora de Guinea Ecuatorial [CGL2012-32934]; Project ICM [05-002]; Project Fondecyt Postdoc [3120125]; Research Center of the College of Science, King Saud University, Riyadh, Saudi Arabia;  [PFB-23]
NR 35
TC 822
Z9 933
U1 29
U2 885
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 3
PY 2015
VL 525
IS 7567
BP 100
EP +
DI 10.1038/nature14910
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100033
PM 26287466
DA 2026-03-09
ER

PT J
AU Xu, HJ
   Xue, J
   Lu, B
   Zhang, XC
   Zhuo, JC
   He, SF
   Ma, XF
   Jiang, YQ
   Fan, HW
   Xu, JY
   Ye, YX
   Pan, PL
   Li, Q
   Bao, YY
   Nijhout, HF
   Zhang, CX
AF Xu, Hai-Jun
   Xue, Jian
   Lu, Bo
   Zhang, Xue-Chao
   Zhuo, Ji-Chong
   He, Shu-Fang
   Ma, Xiao-Fang
   Jiang, Ya-Qin
   Fan, Hai-Wei
   Xu, Ji-Yu
   Ye, Yu-Xuan
   Pan, Peng-Lu
   Li, Qiao
   Bao, Yan-Yuan
   Nijhout, H. Frederik
   Zhang, Chuan-Xi
TI Two insulin receptors determine alternative wing morphs in planthoppers
SO NATURE
LA English
DT Article
ID nilaparvata-lugens; brown planthopper; juvenile-hormone; growth-control; drosophila; insects; polymorphism; pathway; form; polyphenism
AB Wing polyphenism is an evolutionarily successful feature found in a wide range of insects(1). Long-winged morphs can fly, which allows them to escape adverse habitats and track changing resources, whereas short-winged morphs are flightless, but usually possess higher fecundity than the winged morphs(1-3). Studies on aphids, crickets and planthoppers have revealed that alternative wing morphs develop in response to various environmental cues(1,2,4-8), and that the response to these cuesmay be mediated by developmental hormones, although research in this area has yielded equivocal and conflicting results about exactly which hormones are involved(4,8-10). As it stands, the molecular mechanism underlying wing morph determination in insects has remained elusive. Here we show that two insulin receptors in the migratory brown planthopper Nilaparvata lugens, InR1 and InR2, have opposing roles in controlling long wing versus short wing development by regulating the activity of the forkhead transcription factor Foxo. InR1, acting via the phosphatidylinositol-3-OH kinase (PI(3)K)-protein kinase B (Akt) signalling cascade, leads to the long-winged morph if active and the short-winged morph if inactive. InR2, by contrast, functions as a negative regulator of the InR1-PI(3)K-Akt pathway: suppression of InR2 results in development of the long-winged morph. The brain-secreted ligand Ilp3 triggers development of long-winged morphs. Our findings provide the first evidence of a molecular basis for the regulation of wing polyphenism in insects, and they are also the first demonstration-to our knowledge-of binary control over alternative developmental outcomes, and thus deepen our understanding of the development and evolution of phenotypic plasticity.
C1 [Xu, Hai-Jun; Xue, Jian; Lu, Bo; Zhang, Xue-Chao; Zhuo, Ji-Chong; He, Shu-Fang; Ma, Xiao-Fang; Jiang, Ya-Qin; Fan, Hai-Wei; Xu, Ji-Yu; Ye, Yu-Xuan; Pan, Peng-Lu; Li, Qiao; Bao, Yan-Yuan; Zhang, Chuan-Xi] Zhejiang Univ, Inst Insect Sci, State Key Lab Rice Biol, Hangzhou 310058, Zhejiang, Peoples R China.
   [Xu, Hai-Jun; Xue, Jian; Lu, Bo; Zhang, Xue-Chao; Zhuo, Ji-Chong; He, Shu-Fang; Ma, Xiao-Fang; Jiang, Ya-Qin; Fan, Hai-Wei; Xu, Ji-Yu; Ye, Yu-Xuan; Pan, Peng-Lu; Li, Qiao; Bao, Yan-Yuan; Zhang, Chuan-Xi] Zhejiang Univ, Inst Insect Sci, Minist Agr, Key Lab Agr Entomol, Hangzhou 310058, Zhejiang, Peoples R China.
   [Nijhout, H. Frederik] Duke Univ, Dept Biol, Durham, NC 27708 USA.
C3 Zhejiang University; Zhejiang University; Duke University
RP Zhang, CX (corresponding author), Zhejiang Univ, Inst Insect Sci, State Key Lab Rice Biol, Hangzhou 310058, Zhejiang, Peoples R China.
EM haijunxu@zju.edu.cn; chxzhang@zju.edu.cn
FU National Basic Research Program of China (973 Program) [2010CB126205]; National Science Foundation of China [31201509, 31471765]; Division Of Integrative Organismal Systems; Direct For Biological Sciences [1121065] Funding Source: National Science Foundation
CR Braendle C, 2006, HEREDITY, V97, P192, DOI 10.1038/sj.hdy.6800863
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   Brogiolo W, 2001, CURR BIOL, V11, P213, DOI 10.1016/S0960-9822(01)00068-9
   Cantley LC, 2002, SCIENCE, V296, P1655, DOI 10.1126/science.296.5573.1655
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   Nakae J, 2001, ENDOCR REV, V22, P818, DOI 10.1210/edrv.22.6.0452
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NR 37
TC 392
Z9 465
U1 10
U2 508
PU NATURE PUBLISHING 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 26
PY 2015
VL 519
IS 7544
BP 464
EP +
DI 10.1038/nature14286
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE1WF
UT WOS:000351602800055
PM 25799997
DA 2026-03-09
ER

PT J
AU Li, N
   Chen, TW
   Guo, ZV
   Gerfen, CR
   Svoboda, K
AF Li, Nuo
   Chen, Tsai-Wen
   Guo, Zengcai V.
   Gerfen, Charles R.
   Svoboda, Karel
TI A motor cortex circuit for motor planning and movement
SO NATURE
LA English
DT Article
ID functional-organization; sensorimotor cortex; intended movement; cortical activity; neuronal-activity; transgenic mice; single neurons; monkey; mouse; direction
AB Activity in motor cortex predicts specific movements seconds before they occur, but how this preparatory activity relates to upcoming movements is obscure. We dissected the conversion of preparatory activity to movement within a structured motor cortex circuit. An anterior lateral region of the mouse cortex (a possible homologue of prernotor cortex in primates) contains equal proportions of intermingled neurons predicting ipsi- or contralateral movements, yet unilateral inactivation of this cortical region during movement planning disrupts contralateral movements. Using cell-type-specific electrophysiology, cellular imaging and optogenetic perturbation, we show that layer 5 neurons projecting within the cortex have unbiased laterality. Activity with a contralateral population bias arises specifically in layer 5 neurons projecting to the brairtstern, and only late during movement planning. These results reveal the transformation of distributed preparatory activity into movement commands within hierarchically organized cortical circuits.
C1 [Li, Nuo; Chen, Tsai-Wen; Guo, Zengcai V.; Svoboda, Karel] Howard Hughes Med Inst, Ashburn, VA 20147 USA.
   [Gerfen, Charles R.] NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA.
C3 Howard Hughes Medical Institute; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH)
RP Svoboda, K (corresponding author), Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA.
EM svobodak@janelia.hhmi.org
FU Howard Hughes Medical Institute; National Institute of Mental Health [ZIAMH002497] Funding Source: NIH RePORTER
NR 54
TC 402
Z9 481
U1 7
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 MAR 5
PY 2015
VL 519
IS 7541
BP 51
EP U88
DI 10.1038/nature14178
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC4EQ
UT WOS:000350304000033
PM 25731172
DA 2026-03-09
ER

PT J
AU Stuart-Smith, RD
   Edgar, GJ
   Barrett, NS
   Kininmonth, SJ
   Bates, AE
AF Stuart-Smith, Rick D.
   Edgar, Graham J.
   Barrett, Neville S.
   Kininmonth, Stuart J.
   Bates, Amanda E.
TI Thermal biases and vulnerability to warming in the world's marine fauna
SO NATURE
LA English
DT Article
ID climate-change; range shifts; oxygen limitation; temperature; biodiversity; conservation; tolerance; coastal; traits; limits
AB A critical assumption underlying projections of biodiversity change associated with global warming is that ecological communities comprise balanced mixes of warm-affinity and cool-affinity species which, on average, approximate local environmental temperatures. Nevertheless, here we find that most shallow water marine species occupy broad thermal distributions that are aggregated in either temperate or tropical realms. These distributional trends result in ocean-scale spatial thermal biases, where communities are dominated by species with warmer or cooler affinity than local environmental temperatures. We use community-level thermal deviations from local temperatures as a form of sensitivity to warming, and combine these with projected ocean warming data to predict warming-related loss of species from present-day communities over the next century. Large changes in local species composition appear likely, and proximity to thermal limits, as inferred from present-day species' distributional ranges, outweighs spatial variation in warming rates in contributing to predicted rates of local species loss.
C1 [Stuart-Smith, Rick D.; Edgar, Graham J.; Barrett, Neville S.; Kininmonth, Stuart J.] Univ Tasmania, Inst Marine & Antarctic Studies, Hobart, Tas 7001, Australia.
   [Kininmonth, Stuart J.] Stockholm Univ, Stockholm Resilience Ctr, SE-10691 Kraftriket Stockholm, Sweden.
   [Bates, Amanda E.] Univ Southampton, Ocean & Earth Sci, Natl Oceanog Ctr Southampton, Southampton SO14 3ZH, Hants, England.
C3 University of Tasmania; Stockholm University; University of Southampton; NERC National Oceanography Centre
RP Stuart-Smith, RD (corresponding author), Univ Tasmania, Inst Marine & Antarctic Studies, Hobart, Tas 7001, Australia.
EM rstuarts@utas.edu.au
FU Ian Potter Foundation; CoastWest; National Geographic Society; Conservation International; Wildlife Conservation Society Indonesia; Winston Churchill Memorial Trust; Australian-American Fulbright Commission; ASSEMBLE Marine
NR 44
TC 175
Z9 192
U1 4
U2 158
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 3
PY 2015
VL 528
IS 7580
BP 88
EP +
DI 10.1038/nature16144
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000053
PM 26560025
DA 2026-03-09
ER

PT J
AU Santander-García, M
   Rodríguez-Gil, P
   Corradi, RLM
   Jones, D
   Miszalski, B
   Boffin, HMJ
   Rubio-Díez, MM
   Kotze, MM
AF Santander-Garcia, M.
   Rodriguez-Gil, P.
   Corradi, R. L. M.
   Jones, D.
   Miszalski, B.
   Boffin, H. M. J.
   Rubio-Diez, M. M.
   Kotze, M. M.
TI The double-degenerate, super-Chandrasekhar nucleus of the planetary nebula Henize 2-428
SO NATURE
LA English
DT Article
ID binary central stars; orbital-period; evolution; companion; mercator; light
AB The planetary nebula stage is the ultimate fate of stars with masses one to eight times that of the Sun (M-circle dot). The origin of their complex morphologies is poorly understood(1), although several mechanisms involving binary interaction have been proposed(2,3). In close binary systems, the orbital separation is short enough for the primary star to overfill its Roche lobe as the star expands during the asymptotic giant branch phase. The excess gas eventually forms a common envelope surrounding both stars. Drag forces then result in the envelope being ejected into a bipolar planetary nebula whose equator is coincident with the orbital plane of the system. Systems in which both stars have ejected their envelopes and are evolving towards the white dwarf stage are said to be double degenerate. Here we report that Henize 2-428 has a double-degenerate core with a combined mass of similar to 1.76M(circle dot), which is above the Chandrasekhar limit (the maximum mass of a stable white dwarf) of 1.4M(circle dot). This, together with its short orbital period (4.2 hours), suggests that the system should merge in 700 million years, triggering a type Ia supernova event. This supports the hypothesis of the double-degenerate, super-Chandrasekhar evolutionary pathway for the formation of type Ia supernovae(4).
C1 [Santander-Garcia, M.] Observ Astron Nacl, E-28803 Alcala De Henares, Spain.
   [Santander-Garcia, M.] CSIC, Inst Ciencia Mat Madrid, E-28049 Madrid, Spain.
   [Rodriguez-Gil, P.; Corradi, R. L. M.; Jones, D.] Inst Astrofis Canarias, E-38200 Tenerife, Spain.
   [Rodriguez-Gil, P.; Corradi, R. L. M.; Jones, D.] Univ La Laguna, Dept Astrofis, E-38205 Tenerife, Spain.
   [Miszalski, B.; Kotze, M. M.] South African Astron Observ, ZA-7935 Observatory, South Africa.
   [Miszalski, B.] Southern African Large Telescope Fdn, ZA-7935 Observatory, South Africa.
   [Boffin, H. M. J.] European So Observ, Santiago 19001, Chile.
   [Rubio-Diez, M. M.] INTA, CSIC, Ctr Astrobiol, E-28850 Torrejon De Ardoz, Spain.
C3 Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Ciencia de Materiales de Madrid (ICMM); Instituto de Astrofisica de Canarias; Universidad de la Laguna; National Research Foundation - South Africa; South African Astronomical Observatory; European Southern Observatory; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Centro de Astrobiologia (INTA)
RP Santander-García, M (corresponding author), Observ Astron Nacl, Apartado Correos 112, E-28803 Alcala De Henares, Spain.
EM m.santander@oan.es
FU Spanish MINECO [CSD2009-00038, AYA2012-35330, RYC-2010-05762, AYA 2012-38700]
NR 32
TC 70
Z9 76
U1 0
U2 7
PU NATURE PUBLISHING 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 5
PY 2015
VL 519
IS 7541
BP 63
EP U12
DI 10.1038/nature14124
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC4EQ
UT WOS:000350304000035
PM 25686608
DA 2026-03-09
ER

PT J
AU Wang, XL
   Cai, XD
   Su, ZE
   Chen, MC
   Wu, D
   Li, L
   Liu, NL
   Lu, CY
   Pan, JW
AF Wang, Xi-Lin
   Cai, Xin-Dong
   Su, Zu-En
   Chen, Ming-Cheng
   Wu, Dian
   Li, Li
   Liu, Nai-Le
   Lu, Chao-Yang
   Pan, Jian-Wei
TI Quantum teleportation of multiple degrees of freedom of a single photon
SO NATURE
LA English
DT Article
ID entanglement; state; computation; qubits
AB Quantum teleportation' provides a 'disembodied' way to transfer quantum states from one object to another at a distant location, assisted by previously shared entangled states and a classical communication channel. As well as being of fundamental interest, teleportation has been recognized as an important element in long-distance quantum communication', distributed quantum networks' and measurementbased quantum computation. There have been numerous demonstrations of teleportation in different physical systems such as photons's, atoms', ionsio,H, electrons' and superconducting circuits'3. All the previous experiments were limited to the teleportation of one degree of freedom only. However, a single quantum particle can naturally possess various degrees of freedom internal and external and with coherent coupling among them. A fundamental open challenge is to teleport multiple degrees of freedom simultaneously, which is necessary to describe a quantum particle fully and, therefore, to teleport it intact. Here we demonstrate quantum teleportation of the composite quantum states of a single photon encoded in both spin and orbital angular momentum. We use photon pairs entangled in both degrees of freedom (that is, hyper-entangled) as the quantum channel for teleportation, and develop a method to project and discriminate hyper-entangled Bell states by exploiting probabilistic quantum non-demolition measurement, which can be extended to more degrees of freedom. We verify the teleportation for both spin-orbit product states and hybrid entangled states, and achieve a teleportation fidelity ranging from 0.57 to 0.68, above the classical limit. Our work is a step towards the teleportation of more complex quantum systems, and demonstrates an increase in our technical control of scalable quantum technologies.
C1 [Wang, Xi-Lin; Cai, Xin-Dong; Su, Zu-En; Chen, Ming-Cheng; Wu, Dian; Li, Li; Liu, Nai-Le; Lu, Chao-Yang; Pan, Jian-Wei] Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Anhui, Peoples R China.
   [Wang, Xi-Lin; Cai, Xin-Dong; Su, Zu-En; Chen, Ming-Cheng; Wu, Dian; Li, Li; Liu, Nai-Le; Lu, Chao-Yang; Pan, Jian-Wei] Univ Sci & Technol China, Dept Modern Phys, Hefei 230026, Anhui, Peoples R China.
   [Wang, Xi-Lin; Cai, Xin-Dong; Su, Zu-En; Chen, Ming-Cheng; Wu, Dian; Li, Li; Liu, Nai-Le; Lu, Chao-Yang; Pan, Jian-Wei] Univ Sci & Technol China, CAS Ctr Excellence, Hefei 230026, Anhui, Peoples R China.
   [Wang, Xi-Lin; Cai, Xin-Dong; Su, Zu-En; Chen, Ming-Cheng; Wu, Dian; Li, Li; Liu, Nai-Le; Lu, Chao-Yang; Pan, Jian-Wei] Univ Sci & Technol China, Synerget Innovat Ctr Quantum Informat & Quantum P, Hefei 230026, Anhui, 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; CAS Center for Excellence in Quantum Information & Quantum Physics; Chinese Academy of Sciences; University of Science & Technology of China, CAS; CAS Center for Excellence in Quantum Information & Quantum Physics
RP Lu, CY (corresponding author), Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Anhui, Peoples R China.
EM cylu@ustc.edu.cn; pan@ustc.edu.cn
FU National Natural Science Foundation of China; Chinese Academy of Sciences; National Fundamental Research Program [2011CB921300]
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NR 30
TC 683
Z9 764
U1 7
U2 441
PU NATURE PUBLISHING 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 26
PY 2015
VL 518
IS 7540
BP 516
EP 519
DI 10.1038/nature14246
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC1JP
UT WOS:000350097300042
PM 25719668
DA 2026-03-09
ER

PT J
AU Zhang, C
   Spevak, W
   Zhang, Y
   Burton, EA
   Ma, Y
   Habets, G
   Zhang, JZ
   Lin, J
   Ewing, T
   Matusow, B
   Tsang, G
   Marimuthu, A
   Cho, H
   Wu, GX
   Wang, WR
   Fong, D
   Nguyen, H
   Shi, SY
   Womack, P
   Nespi, M
   Shellooe, R
   Carias, H
   Powell, B
   Light, E
   Sanftner, L
   Walters, J
   Tsai, J
   West, BL
   Visor, G
   Rezaei, H
   Lin, PS
   Nolop, K
   Ibrahim, PN
   Hirth, P
   Bollag, G
AF Zhang, Chao
   Spevak, Wayne
   Zhang, Ying
   Burton, Elizabeth A.
   Ma, Yan
   Habets, Gaston
   Zhang, Jiazhong
   Lin, Jack
   Ewing, Todd
   Matusow, Bernice
   Tsang, Garson
   Marimuthu, Adhirai
   Cho, Hanna
   Wu, Guoxian
   Wang, Weiru
   Fong, Daniel
   Hoa Nguyen
   Shi, Songyuan
   Womack, Patrick
   Nespi, Marika
   Shellooe, Rafe
   Carias, Heidi
   Powell, Ben
   Light, Emily
   Sanftner, Laura
   Walters, Jason
   Tsai, James
   West, Brian L.
   Visor, Gary
   Rezaei, Hamid
   Lin, Paul S.
   Nolop, Keith
   Ibrahim, Prabha N.
   Hirth, Peter
   Bollag, Gideon
TI RAF inhibitors that evade paradoxical MAPK pathway activation
SO NATURE
LA English
DT Article
ID selective inhibitor; metastatic melanoma; braf; vemurafenib; dabrafenib; resistance; mutations; survival; kinase; proliferation
AB Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling(1). Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma(2-5). However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers(6-9). Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation(10-12). Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.
C1 [Zhang, Chao; Spevak, Wayne; Zhang, Ying; Burton, Elizabeth A.; Ma, Yan; Habets, Gaston; Zhang, Jiazhong; Lin, Jack; Ewing, Todd; Matusow, Bernice; Tsang, Garson; Marimuthu, Adhirai; Cho, Hanna; Wu, Guoxian; Wang, Weiru; Fong, Daniel; Hoa Nguyen; Shi, Songyuan; Womack, Patrick; Nespi, Marika; Shellooe, Rafe; Carias, Heidi; Powell, Ben; Light, Emily; Sanftner, Laura; Walters, Jason; Tsai, James; West, Brian L.; Visor, Gary; Rezaei, Hamid; Lin, Paul S.; Nolop, Keith; Ibrahim, Prabha N.; Hirth, Peter; Bollag, Gideon] Plexxikon Inc, Berkeley, CA 94710 USA.
C3 Daiichi Sankyo Company Limited
RP Bollag, G (corresponding author), Plexxikon Inc, 91 Bolivar Dr, Berkeley, CA 94710 USA.
EM czhang@plexxikon.com; gbollag@plexxikon.com
NR 36
TC 302
Z9 376
U1 0
U2 109
PU NATURE PUBLISHING 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 22
PY 2015
VL 526
IS 7574
BP 583
EP U298
DI 10.1038/nature14982
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV1NX
UT WOS:000364026100052
PM 26466569
DA 2026-03-09
ER

PT J
AU Adam, RC
   Yang, H
   Rockowitz, S
   Larsen, SB
   Nikolova, M
   Oristian, DS
   Polak, L
   Kadaja, M
   Asare, A
   Zheng, DY
   Fuchs, E
AF Adam, Rene C.
   Yang, Hanseul
   Rockowitz, Shira
   Larsen, Samantha B.
   Nikolova, Maria
   Oristian, Daniel S.
   Polak, Lisa
   Kadaja, Meelis
   Asare, Amma
   Zheng, Deyou
   Fuchs, Elaine
TI Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice
SO NATURE
LA English
DT Article
ID identity genes; self-renewal; niche; skin; genome; differentiation; regeneration; inhibition
AB Adult stem cells occur in niches that balance self-renewal with lineage selection and progression during tissue homeostasis. Following injury, culture or transplantation, stem cells outside their niche often display fate flexibility(1-4). Here we show that super-enhancers(5) underlie the identity, lineage commitment and plasticity of adult stem cells in vivo. Using hair follicle as a model, we map the global chromatin domains of hair follicle stem cells and their committed progenitors in their native microenvironments. We show that super-enhancers and their dense clusters ('epicentres') of transcription factor binding sites undergo remodelling upon lineage progression. New fate is acquired by decommissioning old and establishing new super-enhancers and/or epicentres, an auto-regulatory process that abates one master regulator subset while enhancing another. We further show that when outside their niche, either in vitro or in wound-repair, hair follicle stem cells dynamically remodel super-enhancers in response to changes in their microenvironment. Intriguingly, some key super-enhancers shift epicentres, enabling their genes to remain active and maintain a transitional state in an ever-changing transcriptional landscape. Finally, we identify SOX9 as a crucial chromatin rheostat of hair follicle stem cell super-enhancers, and provide functional evidence that super-enhancers are dynamic, dense transcription-factor-binding platforms which are acutely sensitive to pioneer master regulators whose levels define not only spatial and temporal features of lineage-status but also stemness, plasticity in transitional states and differentiation.
C1 [Adam, Rene C.; Yang, Hanseul; Larsen, Samantha B.; Nikolova, Maria; Oristian, Daniel S.; Polak, Lisa; Kadaja, Meelis; Asare, Amma; Fuchs, Elaine] Rockefeller Univ, Howard Hughes Med Inst, Lab Mammalian Cell Biol & Dev, New York, NY 10065 USA.
   [Rockowitz, Shira; Zheng, Deyou] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA.
   [Zheng, Deyou] Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10461 USA.
   [Zheng, Deyou] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA.
C3 Rockefeller University; Howard Hughes Medical Institute; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University
RP Fuchs, E (corresponding author), Rockefeller Univ, Howard Hughes Med Inst, Lab Mammalian Cell Biol & Dev, New York, NY 10065 USA.
EM fuchslb@rockefeller.edu
FU Anderson Cancer Center Graduate Student Fellowship; National Institutes of Health [R01-AR31737, R21MH099452]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR031737] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007739, T32GM066699] Funding Source: NIH RePORTER
NR 37
TC 320
Z9 384
U1 3
U2 83
PU NATURE PUBLISHING 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 21
PY 2015
VL 521
IS 7552
BP 366
EP +
DI 10.1038/nature14289
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CI5RM
UT WOS:000354816500059
PM 25799994
DA 2026-03-09
ER

PT J
AU Mösta, P
   Ott, CD
   Radice, D
   Roberts, LF
   Schnetter, E
   Haas, R
AF Moesta, Philipp
   Ott, Christian D.
   Radice, David
   Roberts, Luke F.
   Schnetter, Erik
   Haas, Roland
TI A large-scale dynamo and magnetoturbulence in rapidly rotating core-collapse supernovae
SO NATURE
LA English
DT Article
ID gamma-ray bursts; magnetorotational instability; magnetic-fields; inverse cascade; massive stars; neutron-stars; simulations; explosions; turbulence; disks
AB Magnetohydrodynamic turbulence is important in many high-energy astrophysical systems, where instabilities can amplify the local magnetic field over very short timescales(1,2). Specifically, the magnetorotational instability and dynamo action(3-6) have been suggested as a mechanism for the growth of magnetar-strength magnetic fields (of 10(15) gauss and above) and for powering the explosion(7-10) of a rotating massive star(11,12). Such stars are candidate progenitors of type Ic-bl hypernovae(13,14), which make up all supernovae that are connected to long gamma-ray bursts(15,16). The magnetorotational instability has been studied with local high-resolution shearing-box simulations in three dimensions(17-19), and with global two-dimensional simulations(20), but it is not known whether turbulence driven by this instability can result in the creation of a large-scale, ordered and dynamically relevant field. Here we report results from global, three-dimensional, general-relativistic magnetohydrodynamic turbulence simulations. We show that hydromagnetic turbulence in rapidly rotating protoneutron stars produces an inverse cascade of energy. We find a large-scale, ordered toroidal field that is consistent with the formation of bipolar magnetorotationally driven outflows. Our results demonstrate that rapidly rotating massive stars are plausible progenitors for both type Ic-bl supernovae(13,21,22) and long gamma-ray bursts, and provide a viable mechanism for the formation of magnetars(23,24). Moreover, our findings suggest that rapidly rotating massive stars might lie behind potentially magnetar-powered superluminous supernovae(25,26).
C1 [Moesta, Philipp; Ott, Christian D.; Radice, David; Roberts, Luke F.] CALTECH, Walter Burke Inst Theoret Phys, TAPIR, Pasadena, CA 91125 USA.
   [Moesta, Philipp] Univ Calif Berkeley, Dept Astron, Berkeley, CA 94720 USA.
   [Schnetter, Erik] Perimeter Inst Theoret Phys, Waterloo, ON N2L 2Y5, Canada.
   [Schnetter, Erik] Univ Guelph, Dept Phys, Guelph, ON N1G 2W1, Canada.
   [Schnetter, Erik] Louisiana State Univ, Ctr Computat & Technol, Baton Rouge, LA 70803 USA.
   [Haas, Roland] Max Planck Inst Gravitat Phys, D-14476 Potsdam, Germany.
C3 California Institute of Technology; University of California System; University of California Berkeley; Perimeter Institute for Theoretical Physics; University of Guelph; Louisiana State University System; Louisiana State University; Max Planck Society
RP Mösta, P (corresponding author), CALTECH, Walter Burke Inst Theoret Phys, TAPIR, Mailcode 350-17, Pasadena, CA 91125 USA.
EM pmoesta@berkeley.edu
FU National Science Foundation (NSF) [AST-1212170, PHY-1151197, OCI-0905046]; NASA [PF5-160140, PF3-140114]; National Science and Engineering Research Council of Canada (NSERC); Sherman Fairchild Foundation; Division Of Astronomical Sciences; Direct For Mathematical & Physical Scien [1212170] Funding Source: National Science Foundation; Division Of Physics; Direct For Mathematical & Physical Scien [1212460] Funding Source: National Science Foundation; Division Of Physics; Direct For Mathematical & Physical Scien [1151197] Funding Source: National Science Foundation; Office of Advanced Cyberinfrastructure (OAC); Direct For Computer & Info Scie & Enginr [1440083] Funding Source: National Science Foundation; Office of Advanced Cyberinfrastructure (OAC); Direct For Computer & Info Scie & Enginr [0905046] Funding Source: National Science Foundation
NR 49
TC 240
Z9 270
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 17
PY 2015
VL 528
IS 7582
BP 376
EP +
DI 10.1038/nature15755
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CY8SM
UT WOS:000366678600047
PM 26618868
DA 2026-03-09
ER

PT J
AU Wu, ZX
   Curtin, WA
AF Wu, Zhaoxuan
   Curtin, W. A.
TI The origins of high hardening and low ductility in magnesium
SO NATURE
LA English
DT Article
ID transmission electron-microscopy; single-crystal magnesium; nonbasal slip systems; minimum energy paths; elastic band method; aluminum-alloys; automotive industry; room-temperature; saddle-points; hcp metals
AB Magnesium is a lightweight structural metal but it exhibits low ductility-connected with unusual, mechanistically unexplained, dislocation and plasticity phenomena-which makes it difficult to form and use in energy-saving lightweight structures. We employ long-time molecular dynamics simulations utilizing a density-functional-theory-validated interatomic potential, and reveal the fundamental origins of the previously unexplained phenomena. Here we show that the key < c+alpha > dislocation (where < c+alpha > indicates the magnitude and direction of slip) is metastable on easy-glide pyramidal II planes; we find that it undergoes a thermally activated, stress-dependent transition to one of three lower-energy, basal-dissociated immobile dislocation structures, which cannot contribute to plastic straining and that serve as strong obstacles to the motion of all other dislocations. This transition is intrinsic to magnesium, driven by reduction in dislocation energy and predicted to occur at very high frequency at room temperature, thus eliminating all major dislocation slip systems able to contribute to c-axis strain and leading to the high hardening and low ductility of magnesium. Enhanced ductility can thus be achieved by increasing the time and temperature at which the transition from the easy-glide metastable dislocation to the immobile basal-dissociated structures occurs. Our results provide the underlying insights needed to guide the design of ductile magnesium alloys.
C1 [Wu, Zhaoxuan; Curtin, W. A.] Ecole Polytech Fed Lausanne, Inst Engn Mech, CH-1015 Lausanne, Switzerland.
   [Wu, Zhaoxuan] Inst High Performance Comp, Singapore 138632, Singapore.
C3 Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Agency for Science Technology & Research (A*STAR); A*STAR - Institute of High Performance Computing (IHPC)
RP Curtin, WA (corresponding author), Ecole Polytech Fed Lausanne, Inst Engn Mech, CH-1015 Lausanne, Switzerland.
EM william.curtin@epfl.ch
FU Agency for Science, Technology and Research (A*STAR), Singapore; European Research Council, ERC [339081 - PreCoMet]
NR 37
TC 634
Z9 712
U1 18
U2 553
PU NATURE PUBLISHING 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 1
PY 2015
VL 526
IS 7571
BP 62
EP +
DI 10.1038/nature15364
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS5CY
UT WOS:000362095100035
PM 26390153
DA 2026-03-09
ER

PT J
AU Touma, JR
   Sridhar, S
AF Touma, Jihad R.
   Sridhar, S.
TI The disruption of multiplanet systems through resonance with a binary orbit
SO NATURE
LA English
DT Article
ID stellar multiplicity; planetary system; perturbations; evolution; origin; companions; migration
AB Most exoplanetary systems in binary stars are of S-type, and consist of one or more planets orbiting a primary star with a wide binary stellar companion(1,2). Planetary eccentricities and mutual inclinations can be large(3,4), perhaps forced gravitationally by the binary companion(4-6). Earlier work on single planet systems(5,7-10) appealed to the Kozai-Lidov instability(11,12) wherein a sufficiently inclined binary orbit excites large-amplitude oscillations in the planet's eccentricity and inclination. The instability, however, can be quenched by many agents that induce fast orbital precession, including mutual gravitational forces in a multiplanet system(5,13). Here we report that orbital precession, which inhibits Kozai-Lidov cycling in a multiplanet system, can become fast enough to resonate with the orbital motion of a distant binary companion. Resonant binary forcing results in dramatic outcomes ranging from the excitation of large planetary eccentricities and mutual inclinations to total disruption. Processes such as planetary migration(14,15) can bring an initially non-resonant system into resonance. As it does not require special physical or initial conditions, binary resonant driving is generic and may have altered the architecture of many multiplanet systems. It can also weaken the multiplanet occurrence rate in wide binaries, and affect planet formation in close binaries.
C1 [Touma, Jihad R.] Amer Univ Beirut, Dept Phys, Beirut 11072020, Lebanon.
   [Sridhar, S.] Raman Res Inst, Bangalore 560080, Karnataka, India.
C3 American University of Beirut; Department of Science & Technology (India); Raman Research Institute (RRI)
RP Touma, JR (corresponding author), Amer Univ Beirut, Dept Phys, POB 11-0236, Beirut 11072020, Lebanon.
EM jihad.touma@aub.edu.lb
NR 29
TC 15
Z9 19
U1 0
U2 13
PU NATURE PUBLISHING 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 27
PY 2015
VL 524
IS 7566
BP 439
EP 441
DI 10.1038/nature14873
PG 3
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP7LN
UT WOS:000360069300031
PM 26310763
DA 2026-03-09
ER

PT J
AU McGlade, C
   Ekins, P
AF McGlade, Christophe
   Ekins, Paul
TI The geographical distribution of fossil fuels unused when limiting global warming to 2 °C
SO NATURE
LA English
DT Article
ID oil; gas; emissions
AB Policy makers have generally agreed that the average global temperature rise caused by greenhouse gas emissions should not exceed 2 degrees C above the average global temperature of pre-industrial times(1). It has been estimated that to have at least a 50 per cent chance of keeping warming below 2 degrees C throughout the twenty-first century, the cumulative carbon emissions between 2011 and 2050 need to be limited to around 1,100 gigatonnes of carbon dioxide (Gt CO2)(2,3). However, the greenhouse gas emissions contained in present estimates of global fossil fuel reserves are around three times higher than this(2,4), and so the unabated use of all current fossil fuel reserves is incompatible with a warming limit of 2 degrees C. Here we use a single integrated assessment model that contains estimates of the quantities, locations and nature of the world's oil, gas and coal reserves and resources, and which is shown to be consistent with a wide variety of modelling approaches with different assumptions(5), to explore the implications of this emissions limit for fossil fuel production in different regions. Our results suggest that, globally, a third of oil reserves, half of gas reserves and over 80 per cent of current coal reserves should remain unused from 2010 to 2050 in order to meet the target of 2 degrees C. We show that development of resources in the Arctic and any increase in unconventional oil production are incommensurate with efforts to limit average global warming to 2 degrees C. Our results show that policy makers' instincts to exploit rapidly and completely their territorial fossil fuels are, in aggregate, inconsistent with their commitments to this temperature limit. Implementation of this policy commitment would also render unnecessary continued substantial expenditure on fossil fuel exploration, because any new discoveries could not lead to increased aggregate production.
C1 [McGlade, Christophe; Ekins, Paul] UCL, Inst Sustainable Resources, London WC1H 0NN, England.
C3 University of London; University College London
RP McGlade, C (corresponding author), UCL, Inst Sustainable Resources, Cent House,14 Upper Woburn Pl, London WC1H 0NN, England.
EM christophe.mcglade@ucl.ac.uk
FU UK Research Councils under Natural Environment Research Council [NE/G007748/1]; Engineering and Physical Sciences Research Council [EP/L024756/1] Funding Source: researchfish; Natural Environment Research Council [NE/G007748/1] Funding Source: researchfish; EPSRC [EP/L024756/1] Funding Source: UKRI; NERC [NE/G007748/1] Funding Source: UKRI
NR 51
TC 1323
Z9 1594
U1 13
U2 635
PU NATURE PUBLISHING 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 8
PY 2015
VL 517
IS 7533
BP 187
EP U143
DI 10.1038/nature14016
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600033
PM 25567285
DA 2026-03-09
ER

PT J
AU Kaminski, T
   Menten, KM
   Tylenda, R
   Hajduk, M
   Patel, NA
   Kraus, A
AF Kaminski, Tomasz
   Menten, Karl M.
   Tylenda, Romuald
   Hajduk, Marcin
   Patel, Nimesh A.
   Kraus, Alexander
TI Nuclear ashes and outflow in the eruptive star Nova Vul 1670
SO NATURE
LA English
DT Article
ID ck-vul; submillimeter; nebula; oldest; spectroscopy; millimeter; candidate; evolution; abundance; facility
AB CK Vulpeculae was observed in outburst in 1670-1672 (ref. 1), but no counterpart was seen until 1982, when a bipolar nebula was found at its location(1-3). Historically, CK Vul has been considered to be a nova (Nova Vul 1670), but its similarity to 'red transients', which are more luminous than classical novae and thought to be the results of stellar collisions(4), has re-opened the question of CK Vul's status5'6. Red transients cool to resemble late M-type stars, surrounded by circumstellar material rich in molecules and dust(7-9). No stellar source has been seen in CK Vul, though a radio continuum source was identified at the expansion centre of the nebula'. Here we report that CK Vul is surrounded by chemically rich molecular gas in the form of an outflow, as well as dust. The gas has peculiar isotopic ratios, revealing that CK Vul's composition was strongly enhanced by the nuclear ashes of hydrogen burning. The chemical composition cannot be reconciled with a nova or indeed any other known explosion. In addition, the mass of the surrounding gas is too large for a nova, though the conversion from observations of CO to a total mass is uncertain. We conclude that CK Vul is best explained as the remnant of a merger of two stars.
C1 [Kaminski, Tomasz] European So Observ, Santiago, Chile.
   [Kaminski, Tomasz; Menten, Karl M.; Kraus, Alexander] Max Planck Inst Radioastron, D-53121 Bonn, Germany.
   [Tylenda, Romuald; Hajduk, Marcin] N Copernicus Astron Ctr, Dept Astrophys, PL-87100 Torun, Poland.
   [Patel, Nimesh A.] Harvard Smithsonian Ctr Astrophys, Cambridge, MA 02138 USA.
C3 European Southern Observatory; Max Planck Society; Harvard University; Smithsonian Institution; Smithsonian Astrophysical Observatory
RP Kaminski, T (corresponding author), European So Observ, Alonso de Cordova 3107, Santiago, Chile.
EM tkaminsk@eso.org
NR 49
TC 49
Z9 52
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 APR 16
PY 2015
VL 520
IS 7547
BP 322
EP +
DI 10.1038/nature14257
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG0RI
UT WOS:000352974200032
PM 25799986
DA 2026-03-09
ER

PT J
AU Ran, FA
   Cong, L
   Yan, WX
   Scott, DA
   Gootenberg, JS
   Kriz, AJ
   Zetsche, B
   Shalem, O
   Wu, XB
   Makarova, KS
   Koonin, EV
   Sharp, PA
   Zhang, F
AF Ran, F. Ann
   Cong, Le
   Yan, Winston X.
   Scott, David A.
   Gootenberg, Jonathan S.
   Kriz, Andrea J.
   Zetsche, Bernd
   Shalem, Ophir
   Wu, Xuebing
   Makarova, Kira S.
   Koonin, Eugene V.
   Sharp, Phillip A.
   Zhang, Feng
TI In vivo genome editing using Staphylococcus aureus Cas9
SO NATURE
LA English
DT Article
ID off-target sites; guide rna; nuclease specificity; dna cleavage; crispr rna; gene; immunity; systems; endonuclease; sequence
AB The RNA-guided endonuclease Cas9 has emerged as a versatile genom-editing platform. However, the size of the commonly used Cas9 from Streptococcus pyogenes (SpCas9) limits its utility for basic research and therapeutic applications that use the highly versatileaderio-assolated virus (AAV) delivery vehicle. Here, we we characterize six smaller Cas9 ortholocgues and show that Cas9 from Staphylococcus aureus (SaCas9) can edit the genome with efficiencies similar to those of spcas9, while being more than 1 kilobase shorter. We packaged SaCas9 and its single guide RNA expression cassette into a single AAV vector and targeted the cholesterol regulatory gene Pcsk9 in the mouse liver. Within one week of injection we observed >40%. gene modification, accompanied by significant reductions in serum Pcsk9 and total cholesterol le; Is We further assess the genome -wide targeting specificity of SaCas9 and SpCas9 using BLESS, and demonstrate that SaCas9-mediated in vivo genome editing has the potential to be efficient and specific.
C1 [Ran, F. Ann; Cong, Le; Yan, Winston X.; Scott, David A.; Gootenberg, Jonathan S.; Zetsche, Bernd; Shalem, Ophir; Zhang, Feng] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Ran, F. Ann] Harvard Univ, Soc Fellows, Cambridge, MA 02138 USA.
   [Cong, Le; Kriz, Andrea J.; Sharp, Phillip A.] MIT, Dept Biol, Cambridge, MA 02139 USA.
   [Yan, Winston X.] Harvard Univ, Sch Med, Grad Program Biophys, Boston, MA 02115 USA.
   [Yan, Winston X.] Harvard Univ, Sch Med, Harvard MIT Div Hlth Sci & Technol, Boston, MA 02115 USA.
   [Scott, David A.; Zhang, Feng] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA.
   [Scott, David A.; Zhang, Feng] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA.
   [Gootenberg, Jonathan S.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA.
   [Wu, Xuebing; Sharp, Phillip A.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA.
   [Wu, Xuebing] MIT, Computat & Syst Biol Grad Program, Cambridge, MA 02139 USA.
   [Makarova, Kira S.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA.
   [Zhang, Feng] MIT, Dept Biol Engn, Cambridge, MA 02139 USA.
C3 Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Massachusetts Institute of Technology (MIT); Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Harvard University; Harvard Medical School; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); National Institutes of Health (NIH) - USA; NIH National Library of Medicine (NLM); Massachusetts Institute of Technology (MIT)
RP Zhang, F (corresponding author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
EM zhang@broadinstitute.org
FU National Institute of General Medical Sciences [T32GM007753]; Paul and Daisy Soros Fellowship; US Department of Energy Computational Science Graduate Fellowship; United States Public Health Service from the National Institutes of Health [RO1-GM34277, R01-CA133404]; United States Public Health Service from the National Cancer Institute [PO1-CA42063]; Cancer Center from the National Cancer Institute [P30-CA14051]; National Institutes of Health through NIMH [5DP1-MH100706]; National Institutes of Health through NIDDK [5R01DK097768-03]; Waterman Award from the National Science Foundation; Keck Foundation; New York Stem Cell Foundation; Damon Runyon Foundation; Searle Scholars Foundation; Merkin Foundation; Vallee Foundation; NIH core grant [5P30EY012196-17]; National Cancer Institute [P01CA042063, P30CA014051] Funding Source: NIH RePORTER; National Eye Institute [P30EY012196] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007753, R01GM034277, T32GM008313] Funding Source: NIH RePORTER
NR 50
TC 2128
Z9 2976
U1 24
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 9
PY 2015
VL 520
IS 7546
BP 186
EP U98
DI 10.1038/nature14299
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CF3NA
UT WOS:000352454600031
PM 25830891
DA 2026-03-09
ER

PT J
AU Wu, YW
   Hu, L
   Li, Z
   Deng, L
AF Wu, Yongwei
   Hu, Lin
   Li, Zhe
   Deng, Li
TI Catalytic asymmetric umpolung reactions of imines
SO NATURE
LA English
DT Article
ID enantioselective synthesis; alkylations; generation; amines
AB The carbon-nitrogen double bonds in imines are fundamentally important functional groups in organic chemistry. This is largely due to the fact that imines act as electrophiles towards carbon nucleophiles in reactions that form carbon-carbon bonds, thereby serving as one of the most widely used precursors for the formation of amines in both synthetic and biosynthetic settings(1-5). If the carbon atom of the imine could be rendered electron-rich, the imine could react as a nucleophile instead of as an electrophile. Such a reversal in the electronic characteristics of the imine functionality would facilitate the development of new chemical transformations that convert imines into amines via carbon-carbon bond-forming reactions with carbon electrophiles, thereby creating new opportunities for the efficient synthesis of amines. The development of asymmetric umpolung reactions of imines (in which the imines act as nucleophiles) remains uncharted territory, in spite of the far-reaching impact such reactions would have in organic synthesis. Here we report the discovery and development of new chiral phase-transfer catalysts that promote the highly efficient asymmetric umpolung reactions of imines with the carbon electrophile enals. These catalysts mediate the deprotonation of imines and direct the 2-azaallyl anions thus formed to react with enals in a highly chemoselective, regioselective, diastereoselective and enantioselective fashion. The reaction tolerates a broad range of imines and enals, and can be carried out in high yield with as little as 0.01 mole per cent catalyst with a moisture-and air-tolerant operational protocol. These umpolung reactions provide a conceptually new and practical approach to chiral amino compounds.
C1 [Wu, Yongwei; Hu, Lin; Li, Zhe; Deng, Li] Brandeis Univ, Dept Chem, Waltham, MA 02454 USA.
C3 Brandeis University
RP Deng, L (corresponding author), Brandeis Univ, Dept Chem, 415 South St, Waltham, MA 02454 USA.
EM deng@brandeis.edu
FU National Institute of General Medical Science (NIH) [GM-61591]
NR 30
TC 252
Z9 280
U1 3
U2 251
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 23
PY 2015
VL 523
IS 7561
BP 445
EP 450
DI 10.1038/nature14617
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN4DD
UT WOS:000358378900033
PM 26201597
DA 2026-03-09
ER

PT J
AU Jontof-Hutter, D
   Rowe, JF
   Lissauer, JJ
   Fabrycky, DC
   Ford, EB
AF Jontof-Hutter, Daniel
   Rowe, Jason F.
   Lissauer, Jack J.
   Fabrycky, Daniel C.
   Ford, Eric B.
TI The mass of the Mars-sized exoplanet Kepler-138 b from transit timing
SO NATURE
LA English
DT Article
ID low-density planets; sun-like star; 1st 16 months; differential evolution; candidates; system; orbits; radii; ii.; eccentricity
AB Extrasolar planets that pass in front of their host star (transit) cause a temporary decrease in the apparent brightness of the star, providing a direct measure of the planet's size and orbital period. In some systems with multiple transiting planets, the times of the transits are measurably affected by the gravitational interactions between neighbouring planets(1,2). In favourable cases, the departures from Keplerian orbits (that is, unaffected by gravitational effects) implied by the observed transit times permit the planetary masses to be measured, which is key to determining their bulk densities(3). Characterizing rocky planets is particularly difficult, because they are generally smaller and less massive than gaseous planets. Therefore, few exoplanets near the size of Earth have had their masses measured. Here we report the sizes and masses of three planets orbiting Kepler-138, a star much fainter and cooler than the Sun. We determine that the mass of the Mars-sized inner planet, Kepler-138 b, is 0.066(-0.037)(+0.059) Earth masses. Its density is 2.6(-1.5)(+2.4) grams per cubic centimetre. The middle and outer planets are both slightly larger than Earth. The middle planet's density (6.2(-3.4)(+5.8) grams per cubic centimetre) is similar to that of Earth, and the outer planet is less than half as dense at 2.1(-1.2)(+2.2) grams per cubic centimetre, implying that it contains a greater portion of low-density components such as water and hydrogen.
C1 [Jontof-Hutter, Daniel; Ford, Eric B.] Penn State Univ, Dept Astron, Davey Lab, University Pk, PA 16802 USA.
   [Jontof-Hutter, Daniel; Rowe, Jason F.; Lissauer, Jack J.] NASA, Ames Res Ctr, Moffett Field, CA 94035 USA.
   [Rowe, Jason F.] SETI Inst, Mountain View, CA 94043 USA.
   [Fabrycky, Daniel C.] Univ Chicago, Dept Astron & Astrophys, Chicago, IL 60637 USA.
C3 Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; National Aeronautics & Space Administration (NASA); NASA Ames Research Center; SETI Institute; University of Chicago
RP Jontof-Hutter, D (corresponding author), Penn State Univ, Dept Astron, Davey Lab, University Pk, PA 16802 USA.
EM dxj14@psu.edu
FU NASA Postdoctoral Program; Center for Exoplanets and Habitable Worlds; Pennsylvania State University; Eberly College of Science; Pennsylvania Space Grant Consortium; NASA [NNX14AB92G]; Kepler Participating Scientist Program award [NNX14AB87G]; NASA Kepler Participating Scientist Program award [NNX14AN76G]; NASA Exoplanet Research Program award [NNX15AE21G]; NASA [686556, NNX14AN76G, NNX14AB92G, 675549] Funding Source: Federal RePORTER
NR 56
TC 86
Z9 100
U1 0
U2 14
PU NATURE PUBLISHING 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 18
PY 2015
VL 522
IS 7556
BP 321
EP +
DI 10.1038/nature14494
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK7PU
UT WOS:000356425400048
PM 26085271
DA 2026-03-09
ER

PT J
AU Brienen, RJW
   Phillips, OL
   Feldpausch, TR
   Gloor, E
   Baker, TR
   Lloyd, J
   Lopez-Gonzalez, G
   Monteagudo-Mendoza, A
   Malhi, Y
   Lewis, SL
   Martinez, RV
   Alexiades, M
   Dávila, EA
   Alvarez-Loayza, P
   Andrade, A
   Aragao, LEOC
   Araujo-Murakami, A
   Arets, EJMM
   Arroyo, L
   Aymard, GA
   Bánki, OS
   Baraloto, C
   Barroso, J
   Bonal, D
   Boot, RGA
   Camargo, JLC
   Castilho, CV
   Chama, V
   Chao, KJ
   Chave, J
   Comiskey, JA
   Valverde, FC
   da Costa, L
   de Oliveira, EA
   Di Fiore, A
   Erwin, TL
   Fauset, S
   Forsthofer, M
   Galbraith, DR
   Grahame, ES
   Groot, N
   Hérault, B
   Higuchi, N
   Coronado, ENH
   Keeling, H
   Killeen, TJ
   Laurance, WF
   Laurance, S
   Licona, J
   Magnussen, WE
   Marimon, BS
   Marimon, BH
   Mendoza, C
   Neill, DA
   Nogueira, EM
   Núñez, P
   Camacho, NCP
   Parada, A
   Pardo-Molina, G
   Peacock, J
   Peña-Claros, M
   Pickavance, GC
   Pitman, NCA
   Poorter, L
   Prieto, A
   Quesada, CA
   Ramírez, F
   Ramírez-Angulo, H
   Restrepo, Z
   Roopsind, A
   Rudas, A
   Salomao, RP
   Schwarz, M
   Silva, N
   Silva-Espejo, JE
   Silveira, M
   Stropp, J
   Talbot, J
   ter Steege, H
   Teran-Aguilar, J
   Terborgh, J
   Thomas-Caesar, R
   Toledo, M
   Torello-Raventos, M
   Umetsu, RK
   Van der Heijden, GMF
   Van der Hout, P
   Vieira, ICG
   Vieira, SA
   Vilanova, E
   Vos, VA
   Zagt, RJ
AF Brienen, R. J. W.
   Phillips, O. L.
   Feldpausch, T. R.
   Gloor, E.
   Baker, T. R.
   Lloyd, J.
   Lopez-Gonzalez, G.
   Monteagudo-Mendoza, A.
   Malhi, Y.
   Lewis, S. L.
   Vasquez Martinez, R.
   Alexiades, M.
   Alvarez Davila, E.
   Alvarez-Loayza, P.
   Andrade, A.
   Aragao, L. E. O. C.
   Araujo-Murakami, A.
   Arets, E. J. M. M.
   Arroyo, L.
   Aymard C, G. A.
   Banki, O. S.
   Baraloto, C.
   Barroso, J.
   Bonal, D.
   Boot, R. G. A.
   Camargo, J. L. C.
   Castilho, C. V.
   Chama, V.
   Chao, K. J.
   Chave, J.
   Comiskey, J. A.
   Cornejo Valverde, F.
   da Costa, L.
   de Oliveira, E. A.
   Di Fiore, A.
   Erwin, T. L.
   Fauset, S.
   Forsthofer, M.
   Galbraith, D. R.
   Grahame, E. S.
   Groot, N.
   Herault, B.
   Higuchi, N.
   Coronado, E. N. Honorio
   Keeling, H.
   Killeen, T. J.
   Laurance, W. F.
   Laurance, S.
   Licona, J.
   Magnussen, W. E.
   Marimon, B. S.
   Marimon-Junior, B. H.
   Mendoza, C.
   Neill, D. A.
   Nogueira, E. M.
   Nunez, P.
   Pallqui Camacho, N. C.
   Parada, A.
   Pardo-Molina, G.
   Peacock, J.
   Pena-Claros, M.
   Pickavance, G. C.
   Pitman, N. C. A.
   Poorter, L.
   Prieto, A.
   Quesada, C. A.
   Ramirez, F.
   Ramirez-Angulo, H.
   Restrepo, Z.
   Roopsind, A.
   Rudas, A.
   Salomao, R. P.
   Schwarz, M.
   Silva, N.
   Silva-Espejo, J. E.
   Silveira, M.
   Stropp, J.
   Talbot, J.
   ter Steege, H.
   Teran-Aguilar, J.
   Terborgh, J.
   Thomas-Caesar, R.
   Toledo, M.
   Torello-Raventos, M.
   Umetsu, R. K.
   Van der Heijden, G. M. F.
   Van der Hout, P.
   Vieira, I. C. Guimaraes
   Vieira, S. A.
   Vilanova, E.
   Vos, V. A.
   Zagt, R. J.
TI Long-term decline of the Amazon carbon sink
SO NATURE
LA English
DT Article
ID tropical forest; experimental drought; wood productivity; tree mortality; turnover rates; sensitivity; growth; recruitment; disturbance; dynamics
AB Atmospheric carbon dioxide records indicate that the land surface has acted as a strong global carbon sink over recent decades(1,2), with a substantial fraction of this sink probably located in the tropics', particularly in the Amazon(4). Nevertheless, it is unclear how the terrestrial carbon sink will evolve as climate and atmospheric composition continue to change. Here we analyse the historical evolution of the biomass dynamics of the Amazon rainforest over three decades using a distributed network of 321 plots. While this analysis confirms that Amazon forests have acted as a long-term net biomass sink, we find a long-term decreasing trend of carbon accumulation. Rates of net increase in above-ground biomass declined by one-third during the past decade compared to the 1990s. This is a consequence of growth rate increases levelling off recently, while biomass mortality persistently increased throughout, leading to a shortening of carbon residence times. Potential drivers for the mortality increase include greater climate variability, and feedbacks of faster growth on mortality, resulting in shortened tree longevity(5). The observed decline of the Amazon sink diverges markedly from the recent increase in terrestrial carbon uptake at the global scale", and is contrary to expectations based on models(6).
C1 [Brienen, R. J. W.; Phillips, O. L.; Feldpausch, T. R.; Gloor, E.; Baker, T. R.; Lopez-Gonzalez, G.; Lewis, S. L.; Chao, K. J.; Fauset, S.; Galbraith, D. R.; Grahame, E. S.; Groot, N.; Coronado, E. N. Honorio; Keeling, H.; Peacock, J.; Pickavance, G. C.; Schwarz, M.; Talbot, J.] Univ Leeds, Sch Geog, Leeds LS2 9JT, W Yorkshire, England.
   [Feldpausch, T. R.; Aragao, L. E. O. C.] Univ Exeter, Coll Life & Environm Sci, Geog, Exeter EX4 4RJ, Devon, England.
   [Lloyd, J.] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, Ascot SL5 7PY, Berks, England.
   [Lloyd, J.] James Cook Univ, Sch Marine & Trop Biol, Cairns, Qld 4870, Australia.
   [Monteagudo-Mendoza, A.; Vasquez Martinez, R.] Prolongac Bolognesi Mze, Jardin Bot Missouri, Oxapampa, Pasco, Peru.
   [Malhi, Y.] Univ Oxford, Sch Geog & Environm, Environm Change Inst, Oxford OX1 3QK, England.
   [Lewis, S. L.] UCL, Dept Geog, London WC1E 6BT, England.
   [Alexiades, M.] Univ Kent, Sch Anthropol & Conservat, Canterbury CT1 3EH, Kent, England.
   [Alvarez Davila, E.; Restrepo, Z.] Jardin Bot Medellin, Serv Ecosistemicosy Cambio Climat, Medellin 050010, Colombia.
   [Alvarez-Loayza, P.; Pitman, N. C. A.; Terborgh, J.] Duke Univ, Ctr Trop Conservat, Durham, NC 27708 USA.
   [Andrade, A.; Camargo, J. L. C.; Higuchi, N.] INPA, Biol Dynam Forest Fragment Project, BR-69011970 Manaus, Amazonas, Brazil.
   [Andrade, A.; Camargo, J. L. C.; Higuchi, N.] STRI, BR-69011970 Manaus, Amazonas, Brazil.
   [Aragao, L. E. O. C.] Natl Inst Space Res INPE, BR-12227010 Sao Paulo, Brazil.
   [Araujo-Murakami, A.; Arroyo, L.; Parada, A.] Univ Autonoma Gabriel Rene Moreno, Museo Hist Nat Noel Kempff Mercado, Santa Cruz, Bolivia.
   [Arets, E. J. M. M.] Univ Wageningen & Res Ctr, Alterra, NL-6700 AA Wageningen, Netherlands.
   [Aymard C, G. A.] Herbario Univ PORT, Programa Cienclas Agro & Mar, UNELLEZ Guanare, Mesa De Cavacas 3350, Estado Portugue, Venezuela.
   [Banki, O. S.] Univ Amsterdam, Biodiversiteit Ecosyst Dynam, NL-1090 GE Amsterdam, Netherlands.
   [Baraloto, C.] INRA, UMR EcoFoG, F-97310 Kourou, French Guiana.
   [Baraloto, C.] Florida Int Univ, Dept Biol Sci, Int Ctr Trop Bot, Miami, FL 33199 USA.
   [Barroso, J.] Univ Fed Acre, Rio Branco, Brazil.
   [Bonal, D.] INRA, UMR Ecol & Ecophysiol Forestiere 1137, F-54280 Seichamps, France.
   [Boot, R. G. A.; Zagt, R. J.] Tropenbos Int, NL-6700 AE Wageningen, Netherlands.
   [Castilho, C. V.] Embrapa Roraima, BR-69301970 Bio Vista, RR, Brazil.
   [Chama, V.; Nunez, P.; Pallqui Camacho, N. C.; Silva-Espejo, J. E.] Univ Nacl San Antonio Abad Cusco, Cuzco, Peru.
   [Chao, K. J.] Natl Chung Hsing Univ, Coll Agr & Nat Resources, Int Master Program Agr, Taichung 40227, Taiwan.
   [Chave, J.] Univ Toulouse 3, CNRS, UMR Evolut & Divers Biol 5174, F-31062 Toulouse, France.
   [Comiskey, J. A.] Natl Pk Serv, Northeast Reg Inventory & Monitoring Program, Fredericksburg, VA 22405 USA.
   [Cornejo Valverde, F.] Andes toAmazon Biodivers Program, Madre De Dios, Peru.
   [da Costa, L.] Fed Univ Para, Ctr Geociencias, BR-66017970 Belem, Para, Brazil.
   [de Oliveira, E. A.; Forsthofer, M.; Marimon, B. S.; Marimon-Junior, B. H.; Umetsu, R. K.] Univ Estado Mato Grosso, BR-78690000 Nova Xavantina, MT, Brazil.
   [Di Fiore, A.] Univ Texas Austin, Dept Anthropol, Austin, TX 78712 USA.
   [Erwin, T. L.] Smithsonian Inst, Dept Entomol, Washington, DC 20013 USA.
   [Herault, B.] Cirad, UMR Ecol Forets Guyane, F-97310 Kourou, French Guiana.
   [Coronado, E. N. Honorio] Inst Invest Amazonia Peruana, Iquitos, Peru.
   [Killeen, T. J.] World Wildlife Fund, Washington, DC 20037 USA.
   [Laurance, W. F.; Laurance, S.] James Cook Univ, Ctr Trop Environm & Sustainabil Sci TESS, Cairns, Qld 4878, Australia.
   [Laurance, W. F.; Laurance, S.] James Cook Univ, Sch Marine & Environm Sci, Cairns, Qld 4878, Australia.
   [Licona, J.; Pena-Claros, M.; Toledo, M.] Inst Boliviano Invest Forestal, Santa Cruz 6201, Bolivia.
   [Magnussen, W. E.] Natl Inst Res Amazonia INPA, BR-69011970 Manaus, Amazonas, Brazil.
   [Mendoza, C.] FOMABO, Manejo Forestal Tierras Trop Bolivia, Sacta, Bolivia.
   [Mendoza, C.] UMSS, Escuela Ciencias Forestales ESFOR, Sacta, Bolivia.
   [Neill, D. A.] Univ Estatal Amazon, Fac Ingn Ambiental, Puyo, Pastaza, Ecuador.
   [Nogueira, E. M.; Quesada, C. A.] Natl Inst Res Amazonia INPA, BR-69080971 Manaus, Amazonas, Brazil.
   [Pardo-Molina, G.; Vos, V. A.] Univ Autonoma Beni, Riberalta, Beni, Bolivia.
   [Pena-Claros, M.; Poorter, L.] Wageningen Univ, Forest Ecol & Forest Management Grp, NL-6700 AA Wageningen, Netherlands.
   [Pitman, N. C. A.] Field Museum Nat Hist, Chicago, IL 60605 USA.
   [Prieto, A.; Ramirez, F.] Univ Nacl Amazonia Peruana, Iquitos, Loreto, Peru.
   [Ramirez-Angulo, H.; Vilanova, E.] Univ Los Andes, Inst Invest Desarrollo Forestal INDEFOR, Fac Cienclas Forestales & Ambientales, Merida 5101, Venezuela.
   [Roopsind, A.] Iwokrama Int Ctr Rainforest Conservat & Dev, Georgetown, Guyana.
   [Rudas, A.] Univ Nacl Colombia, Inst Ciencias Nat, Bogota 111321, Colombia.
   [Salomao, R. P.; Vieira, I. C. Guimaraes] Museu Paraense Emilio Goeldi, BR-66040170 Belem, Para, Brazil.
   [Silva, N.; Thomas-Caesar, R.] Univ Fed Rural Amazonia, BR-66077901 Belem, Para, Brazil.
   [Silveira, M.] Univ Fed Acre, Museu Univ, BR-69910900 Rio Branco, AC, Brazil.
   [Stropp, J.] Commiss European Communities, DG Joint Res Ctr, Inst Environm & Sustainabil, I-21010 Ispra, Italy.
   [ter Steege, H.] Nat Biodivers Ctr, NL-2300 RA Leiden, Netherlands.
   [ter Steege, H.] Univ Utrecht, Ecol & Biodivers Grp, NL-3508 TB Utrecht, Netherlands.
   [Teran-Aguilar, J.] Museo Hist Nat Alcide DOrbigny, Cochabamba, Bolivia.
   [Torello-Raventos, M.] James Cook Univ, Sch Earth & Environm Sci, Cairns, Qld 4870, Australia.
   [Torello-Raventos, M.] James Cook Univ, Ctr Trop Environm & Sustainabil Sci TESS, Cairns, Qld 4878, Australia.
   [Torello-Raventos, M.] James Cook Univ, Sch Marine & Trop Biol, Cairns, Qld 4878, Australia.
   [Van der Heijden, G. M. F.] Northumbria Univ, Sch Geog, Newcastle Upon Tyne NE1 8ST, Tyne & Wear, England.
   [Van der Heijden, G. M. F.] Univ Wisconsin, Milwaukee, WI 53202 USA.
   [Van der Heijden, G. M. F.] Smithsonian Trop Res Inst, Panama City, Panama.
   [Van der Hout, P.] Van der Hout Forestry Consulting, NL-3078 HP Rotterdam, Netherlands.
   [Vieira, S. A.] Univ Estadual Campinas, NEPAM, BR-13083867 Sao Paulo, Brazil.
   [Vos, V. A.] Ctr Invest & Promoc Campesinado, Reg Norte Amazon, Riberalta, Bolivia.
C3 University of Leeds; University of Exeter; Imperial College London; James Cook University; University of Oxford; University of London; University College London; University of Kent; Duke University; Institute Nacional de Pesquisas da Amazonia; Instituto Nacional de Pesquisas Espaciais (INPE); Wageningen University & Research; University of Amsterdam; INRAE; State University System of Florida; Florida International University; Universidade Federal do Acre (UFAC); INRAE; Universite de Lorraine; Empresa Brasileira de Pesquisa Agropecuaria (EMBRAPA); EMBRAPA Roraima; Universidad Nacional de San Antonio Abad del Cusco; National Chung Hsing University; Universite de Toulouse; Universite Federale Toulouse Midi-Pyrenees (ComUE); Universite Toulouse III - Paul Sabatier; Ecole Nationale Formation Agronomique (ENSFEA); Centre National de la Recherche Scientifique (CNRS); United States Department of the Interior; US National Park Service; Universidade Federal do Para; Universidade do Estado de Mato Grosso; University of Texas System; University of Texas Austin; Smithsonian Institution; Smithsonian National Museum of Natural History; CIRAD; World Wildlife Fund; James Cook University; James Cook University; Institute Nacional de Pesquisas da Amazonia; Universidad Mayor de San Simon; Institute Nacional de Pesquisas da Amazonia; Wageningen University & Research; Field Museum of Natural History (Chicago); Universidad Nacional de la Amazonia Peruana; University of Los Andes Venezuela; Universidad Nacional de Colombia; Museu Paraense Emilio Goeldi; Universidade Federal Rural da Amazonia (UFRA); European Commission Joint Research Centre; EC JRC ISPRA Site; Naturalis Biodiversity Center; Utrecht University; James Cook University; James Cook University; James Cook University; Northumbria University; University of Wisconsin System; University of Wisconsin Milwaukee; Smithsonian Institution; Smithsonian Tropical Research Institute; Universidade Estadual de Campinas
RP Brienen, RJW (corresponding author), Univ Leeds, Sch Geog, Leeds LS2 9JT, W Yorkshire, England.
EM r.brienen@leeds.ac.uk
FU Natural Environment Research Council [NE/B503384/1, NE/D01025X/1, NE/I02982X/1, NE/F005806/1, NE/D005590/1, NE/I028122/1]; Gordon and Betty Moore Foundation; EU Seventh Framework Programme [GEOCARBON-283080, AMAZALERT-282664]; NERC Research Fellowship [NE/I021160/1]; ERC Advanced Grant; Royal Society-Wolfson Research Merit Award; Investissement d'Avenir grants of the French ANR [CEBA: ANR-10-LABX-0025, TULIP: ANR-10-LABX-0041]; Conservation International; Missouri Botanical Garden; Smithsonian Institution; Wildlife Conservation Society; Natural Environment Research Council [NE/D005590/1, NE/M022021/1, NE/I021160/1, NE/D01025X/1, NER/A/S/2003/00609, NE/D010306/1, NE/F005806/1, NE/B504630/1, NE/I02982X/1, NE/F005776/1, NE/B503384/1, NE/I028122/1] Funding Source: researchfish; NERC [NE/M022021/1, NE/I028122/1, NE/I02982X/1, NE/D01025X/1, NE/F005806/1, NE/D005590/1, NE/F005776/1, NE/I021160/1, NE/D010306/1] Funding Source: UKRI
NR 45
TC 887
Z9 908
U1 24
U2 1036
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 19
PY 2015
VL 519
IS 7543
BP 344
EP +
DI 10.1038/nature14283
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD6AY
UT WOS:000351171900039
PM 25788097
DA 2026-03-09
ER

PT J
AU Sánchez-Lavega, A
   Muñoz, AG
   García-Melendo, E
   Pérez-Hoyos, S
   Gómez-Forrellad, JM
   Pellier, C
   Delcroix, M
   López-Valverde, MA
   González-Galindo, F
   Jaeschke, W
   Parker, D
   Phillips, J
   Peach, D
AF Sanchez-Lavega, A.
   Garcia Munoz, A.
   Garcia-Melendo, E.
   Perez-Hoyos, S.
   Gomez-Forrellad, J. M.
   Pellier, C.
   Delcroix, M.
   Lopez-Valverde, M. A.
   Gonzalez-Galindo, F.
   Jaeschke, W.
   Parker, D.
   Phillips, J.
   Peach, D.
TI An extremely high-altitude plume seen at Mars' morning terminator
SO NATURE
LA English
DT Article
ID clouds; mesosphere
AB The Martian limb.(that is, the observed 'edge' of the planet) represents a unique window into the complex atmospheric phenomena occurring there. Clouds of ice crystals (CO2 ice or H2O ice) have been observed numerous times by spacecraft and ground-based telescopes, showing that clouds are typically layered and always confined below an altitude of 100 kilometres; suspended dust has also been detected at altitudes up to 60 kilometres during major dust storms -6. Highly concentrated and localized patches of auroral emission controlled by magnetic field anomalies in the crust have been observed at an altitude of 130 kilometres'. Here we report the occurrence in March and April 2012 of two bright, extremely high-altitude plumes at the Martian terminator (the day-night boundary) at 200 to 250 kilometres or more above the surface, and thus well into the ionosphere and the exosphere'''. They were spotted at a longitude of about 1950 west, a latitude of about 45 (at Terra Cimmeria), extended about 500 to 1,000 kilometres in both the north-south and east-west directions, and lasted for about 10 days. The features exhibited day-to-day variability, and were seen at the morning terminator but not at the evening limb, which indicates rapid evolution in less than 10 hours and a cyclic behaviour. We used photometric measurements to explore two possible scenarios and investigate their nature. For particles reflecting solar radiation, clouds of CO2-ice or H2O-ice particles with an effective radius of 0.1 micrometres are favoured over dust. Alternatively, the plume could arise from auroral emission, of a brightness more than 1,000 times that of the Earth's aurora, over a region with a strong magnetic anomaly where aurorae have previously been detected'. Importantly, both explanations defy our current understanding of Mars' upper atmosphere.
C1 [Sanchez-Lavega, A.; Garcia-Melendo, E.; Perez-Hoyos, S.] Univ Basque Country, ETS Ingn, Dept Fis Aplicada 1, Bilbao 48013, Spain.
   [Sanchez-Lavega, A.; Perez-Hoyos, S.; Lopez-Valverde, M. A.; Gonzalez-Galindo, F.] Unidad Asociada Grp Ciencias Planetarias UPV EHU, Bilbao 48013, Spain.
   [Garcia Munoz, A.] Estec, European Space Agcy, NL-2201 AZ Noordwijk, Netherlands.
   [Garcia-Melendo, E.; Gomez-Forrellad, J. M.] Fundacio Observ Esteve Duran, Seva 08553, Barcelona, Spain.
   [Pellier, C.; Delcroix, M.] Soc Astron France, Commission Surfaces Planetaires, F-75016 Paris, France.
   [Lopez-Valverde, M. A.; Gonzalez-Galindo, F.] CSIC, Inst Astrofis Andalucia, E-18008 Granada, Spain.
   [Jaeschke, W.] Assoc Lunar & Planetary Observers, W Chester, PA 19380 USA.
   [Parker, D.] Assoc Lunar & Planetary Observers, Coral Gables, FL 33156 USA.
   [Phillips, J.] Assoc Lunar & Planetary Observers, Mt Pleasant, SC 29464 USA.
   [Peach, D.] British Astron Assoc, London W1J 0DU, England.
C3 University of Basque Country; University of Basque Country; European Space Agency; European Space Research & Technology Centre; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Astrofisica de Andalucia (IAA)
RP Sánchez-Lavega, A (corresponding author), Univ Basque Country, ETS Ingn, Dept Fis Aplicada 1, Alameda Urquijo S-N, Bilbao 48013, Spain.
EM agustin.sanchez@ehu.es
FU Spanish MINECO [AYA2012-36666]; FEDER, Grupos Gobierno Vasco [IT765-13]; UPV/EHU [UFI11/55]; Spanish MINECO through CONSOLIDER programme ASTROMOL [CSD2009-00038, AYA2011-30613-CO2-1]; CSIC by European Social Fund
NR 27
TC 25
Z9 27
U1 1
U2 26
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 26
PY 2015
VL 518
IS 7540
BP 525
EP 528
DI 10.1038/nature14162
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC1JP
UT WOS:000350097300044
PM 25686601
DA 2026-03-09
ER

PT J
AU Hsu, HW
   Postberg, F
   Sekine, Y
   Shibuya, T
   Kempf, S
   Horányi, M
   Juhász, A
   Altobelli, N
   Suzuki, K
   Masaki, Y
   Kuwatani, T
   Tachibana, S
   Sirono, S
   Moragas-Klostermeyer, G
   Srama, R
AF Hsu, Hsiang-Wen
   Postberg, Frank
   Sekine, Yasuhito
   Shibuya, Takazo
   Kempf, Sascha
   Horanyi, Mihaly
   Juhasz, Antal
   Altobelli, Nicolas
   Suzuki, Katsuhiko
   Masaki, Yuka
   Kuwatani, Tatsu
   Tachibana, Shogo
   Sirono, Sin-iti
   Moragas-Klostermeyer, Georg
   Srama, Ralf
TI Ongoing hydrothermal activities within Enceladus
SO NATURE
LA English
DT Article
ID saturns e-ring; nanocolloid formation; stream particles; dust particles; ionic-strength; silica; kinetics; evolution; systems; ice
AB Detection of sodium-salt-rich ice grains emitted from the plume of the Saturnian moon Enceladus suggests that the grains formed as frozen droplets from a liquid water reservoir that is, or has been, in contact with rock(1,2). Gravitational field measurements suggest a regional south polar subsurface ocean of about 10 kilometres thickness located beneath an ice crust 30 to 40 kilometres thick(3). These findings imply rock-water interactions in regions surrounding the core of Enceladus. The resulting chemical 'footprints' are expected to be preserved in the liquid and subsequently transported upwards to the near-surface plume sources, where they eventually would be ejected and could be measured by a spacecraft(4). Here we report an analysis of silicon-rich, nanometre-sized dust particles(5-8) (so-called stream particles) that stand out from the water-ice-dominated objects characteristic of Saturn. We interpret these grains as nanometre-sized SiO2 (silica) particles, initially embedded in icy grains emitted from Enceladus' subsurface waters and released by sputter erosion in Saturn's E ring. The composition and the limited size range (2 to 8 nanometres in radius) of stream particles indicate ongoing high-temperature (>90 degrees C) hydrothermal reactions associated with global-scale geothermal activity that quickly transports hydrothermal products from the ocean floor at a depth of at least 40 kilometres up to the plume of Enceladus.
C1 [Hsu, Hsiang-Wen; Kempf, Sascha; Horanyi, Mihaly; Juhasz, Antal] Univ Colorado, Atmospher & Space Phys Lab, Boulder, CO 80303 USA.
   [Postberg, Frank] Heidelberg Univ, Inst Geowissensch, D-69120 Heidelberg, Germany.
   [Postberg, Frank; Moragas-Klostermeyer, Georg; Srama, Ralf] Univ Stuttgart, Inst Raumfahrtsyst, D-70569 Stuttgart, Germany.
   [Sekine, Yasuhito] Univ Tokyo, Dept Complex Sci & Engn, Kashiwa, Chiba 2778561, Japan.
   [Shibuya, Takazo] JAMSTEC, Lab Ocean Earth Life Evolut Res, Yokosuka, Kanagawa 2370061, Japan.
   [Juhasz, Antal] Wigner RCP, Inst Particle & Nucl Phys, H-1121 Budapest, Hungary.
   [Altobelli, Nicolas] European Space Agcy, E-28691 Madrid, Spain.
   [Suzuki, Katsuhiko; Masaki, Yuka] JAMSTEC, Res & Dev Ctr Submarine Resources, Yokosuka, Kanagawa 2370061, Japan.
   [Kuwatani, Tatsu] Tohoku Univ, Grad Sch Environm Studies, Sendai, Miyagi 9808579, Japan.
   [Tachibana, Shogo] Hokkaido Univ, Dept Nat Hist Sci, Sapporo, Hokkaido 0600810, Japan.
   [Sirono, Sin-iti] Nagoya Univ, Grad Sch Environm Sci, Nagoya, Aichi 4648601, Japan.
C3 University of Colorado System; University of Colorado Boulder; Ruprecht Karls University Heidelberg; University of Stuttgart; University of Tokyo; Japan Agency for Marine-Earth Science & Technology (JAMSTEC); HUN-REN; HUN-REN Wigner Research Centre for Physics; Institute for Particle & Nuclear Physics - HAS; European Space Agency; Japan Agency for Marine-Earth Science & Technology (JAMSTEC); Tohoku University; Hokkaido University; Nagoya University
RP Hsu, HW (corresponding author), Univ Colorado, Atmospher & Space Phys Lab, Boulder, CO 80303 USA.
EM sean.hsu@lasp.colorado.edu
FU Ministry of Education, Culture, Sports, Science and Technology, Japan; Japan Society for the Promotion of Science; Astrobiology Program of the National Institutes of Natural Sciences, Japan; DLR [50 OH1103]; Grants-in-Aid for Scientific Research [23103003, 25108001, 25287140, 26707024, 25108002] Funding Source: KAKEN
NR 53
TC 422
Z9 472
U1 3
U2 197
PU NATURE PUBLISHING 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 12
PY 2015
VL 519
IS 7542
BP 207
EP +
DI 10.1038/nature14262
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500033
PM 25762281
DA 2026-03-09
ER

PT J
AU Gjoneska, E
   Pfenning, AR
   Mathys, H
   Quon, G
   Kundaje, A
   Tsai, LH
   Kellis, M
AF Gjoneska, Elizabeta
   Pfenning, Andreas R.
   Mathys, Hansruedi
   Quon, Gerald
   Kundaje, Anshul
   Tsai, Li-Huei
   Kellis, Manolis
TI Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease
SO NATURE
LA English
DT Article
ID differential expression; transcription factors; gene-expression; activation; discovery; microglia; elements; database; binding; encode
AB Alzheimer's disease (AD) is a severe(1) age-related neurodegenerative disorder characterized by accumulation of amyloid-beta plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated down-regulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune-cell-specific enhancer signatures as well as immune cell expression quantitative trait loci, while decreasing-level enhancer orthologues show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants, and implicate additional loci that do not reach genome-wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions.
C1 [Gjoneska, Elizabeta; Mathys, Hansruedi; Tsai, Li-Huei] MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, Cambridge, MA 02139 USA.
   [Gjoneska, Elizabeta; Pfenning, Andreas R.; Quon, Gerald; Kundaje, Anshul; Tsai, Li-Huei; Kellis, Manolis] Broad Inst Harvard Univ & Massachusetts Inst Tech, Cambridge, MA 02142 USA.
   [Pfenning, Andreas R.; Quon, Gerald; Kundaje, Anshul; Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA.
   [Kundaje, Anshul] Stanford Univ, Dept Genet, Dept Comp Sci, Stanford, CA 94305 USA.
C3 Massachusetts Institute of Technology (MIT); Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Massachusetts Institute of Technology (MIT); Stanford University
RP Tsai, LH (corresponding author), MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, E25-618, Cambridge, MA 02139 USA.
EM lhtsai@mit.edu; manoli@mit.edu
FU Belfer Neurodegeneration Consortium; NIH/NINDS/NIA [RO1NS078839]; Swiss National Science Foundation [P2BSP3_151885]; NIH/NHGRI [R01HG004037-07, RC1HG005334]; Direct For Biological Sciences; Div Of Biological Infrastructure [0644282] Funding Source: National Science Foundation; Swiss National Science Foundation (SNF) [P2BSP3_151885] Funding Source: Swiss National Science Foundation (SNF)
NR 57
TC 424
Z9 536
U1 1
U2 137
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 19
PY 2015
VL 518
IS 7539
BP 365
EP 369
DI 10.1038/nature14252
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400035
PM 25693568
DA 2026-03-09
ER

PT J
AU Haak, W
   Lazaridis, I
   Patterson, N
   Rohland, N
   Mallick, S
   Llamas, B
   Brandt, G
   Nordenfelt, S
   Harney, E
   Stewardson, K
   Fu, QM
   Mittnik, A
   Bánffy, E
   Economou, C
   Francken, M
   Friederich, S
   Pena, RG
   Hallgren, F
   Khartanovich, V
   Khokhlov, A
   Kunst, M
   Kuznetsov, P
   Meller, H
   Mochalov, O
   Moiseyev, V
   Nicklisch, N
   Pichler, SL
   Risch, R
   Guerra, MAR
   Roth, C
   Szécsényi-Nagy, A
   Wahl, J
   Meyer, M
   Krause, J
   Brown, D
   Anthony, D
   Cooper, A
   Alt, KW
   Reich, D
AF Haak, Wolfgang
   Lazaridis, Iosif
   Patterson, Nick
   Rohland, Nadin
   Mallick, Swapan
   Llamas, Bastien
   Brandt, Guido
   Nordenfelt, Susanne
   Harney, Eadaoin
   Stewardson, Kristin
   Fu, Qiaomei
   Mittnik, Alissa
   Banffy, Eszter
   Economou, Christos
   Francken, Michael
   Friederich, Susanne
   Pena, Rafael Garrido
   Hallgren, Fredrik
   Khartanovich, Valery
   Khokhlov, Aleksandr
   Kunst, Michael
   Kuznetsov, Pavel
   Meller, Harald
   Mochalov, Oleg
   Moiseyev, Vayacheslav
   Nicklisch, Nicole
   Pichler, Sandra L.
   Risch, Roberto
   Rojo Guerra, Manuel A.
   Roth, Christina
   Szecsenyi-Nagy, Anna
   Wahl, Joachim
   Meyer, Matthias
   Krause, Johannes
   Brown, Dorcas
   Anthony, David
   Cooper, Alan
   Alt, Kurt Werner
   Reich, David
TI Massive migration from the steppe was a source for Indo-European languages in Europe
SO NATURE
LA English
DT Article
ID ancient dna; admixture; history; diversity; farmers; genm
AB We generated genome-wide data from 69 Europeans who lived between 8,000-3,000 years ago by enriching ancient DNA libraries for a target set of almost 400,000 polymorphisms. Enrichment of these positions decreases the sequencing required for genome-wide ancient DNA analysis by a median of around 250-fold, allowing us to study an order of magnitude more individuals than previous studies(1-8) and to obtain new insights about the past. We show that the populations of Western and Far Eastern Europe followed opposite trajectories between 8,000-5,000 years ago. At the beginning of the Neolithic period in Europe, similar to 8,000-7,000 years ago, closely related groups of early farmers appeared in Germany, Hungary and Spain, different from indigenous hunter-gatherers, whereas Russia was inhabited by a distinctive population of hunter-gatherers with high affinity to a similar to 24,000-year-old Siberian(6). By similar to 6,000-5,000 years ago, farmers throughout much of Europe had more hunter-gatherer ancestry than their predecessors, but in Russia, the Yamnaya steppe herders of this time were descended not only from the preceding eastern European hunter-gatherers, but also from a population of Near Eastern ancestry. Western and Eastern Europe came into contact similar to 4,500 years ago, as the Late Neolithic Corded Ware people from Germany traced similar to 75% of their ancestry to the Yamnaya, documenting a massive migration into the heartland of Europe from its eastern periphery. This steppe ancestry persisted in all sampled central Europeans until at least similar to 3,000 years ago, and is ubiquitous in present-day Europeans. These results provide support for a steppe origin(9) of at least some of the Indo-European languages of Europe.
C1 [Haak, Wolfgang; Llamas, Bastien; Cooper, Alan] Univ Adelaide, Sch Earth & Environm Sci, Australian Ctr Ancient DNA, Adelaide, SA 5005, Australia.
   [Haak, Wolfgang; Llamas, Bastien; Cooper, Alan] Univ Adelaide, Inst Environm, Adelaide, SA 5005, Australia.
   [Lazaridis, Iosif; Rohland, Nadin; Mallick, Swapan; Nordenfelt, Susanne; Harney, Eadaoin; Stewardson, Kristin; Fu, Qiaomei; Reich, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
   [Lazaridis, Iosif; Patterson, Nick; Rohland, Nadin; Mallick, Swapan; Nordenfelt, Susanne; Harney, Eadaoin; Stewardson, Kristin; Fu, Qiaomei; Reich, David] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.
   [Mallick, Swapan; Harney, Eadaoin; Stewardson, Kristin; Reich, David] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA.
   [Brandt, Guido; Nicklisch, Nicole; Roth, Christina; Szecsenyi-Nagy, Anna; Alt, Kurt Werner] Johannes Gutenberg Univ Mainz, Inst Anthropol, D-55128 Mainz, Germany.
   [Fu, Qiaomei; Meyer, Matthias] Max Planck Inst Evolutionary Anthropol, D-04103 Leipzig, Germany.
   [Fu, Qiaomei] Chinese Acad Sci, IVPP, Key Lab Vertebrate Evolut & Human Origins, Beijing 100049, Peoples R China.
   [Mittnik, Alissa; Krause, Johannes] Univ Tubingen, Inst Archaeol Sci, D-72070 Tubingen, Germany.
   [Banffy, Eszter; Szecsenyi-Nagy, Anna] Hungarian Acad Sci, Inst Archaeol, Res Ctr Humanities, H-1014 Budapest, Hungary.
   [Banffy, Eszter] RGK, D-60325 Frankfurt, Germany.
   [Economou, Christos] Stockholm Univ, Archaeol Res Lab, S-11418 Stockholm, Sweden.
   [Francken, Michael; Krause, Johannes] Univ Tubingen, Senckenberg Ctr Human Evolut & Paleoenvironm, Dept Paleoanthropol, D-72070 Tubingen, Germany.
   [Francken, Michael; Krause, Johannes] Univ Tubingen, Senckenberg Ctr Human Evolut & Paleoenvironm, Dept Archaeogenet, D-72070 Tubingen, Germany.
   [Friederich, Susanne; Meller, Harald; Nicklisch, Nicole; Alt, Kurt Werner] Saxony Anhalt & State Museum Prehist, State Off Heritage Management & Archaeol, D-06114 Halle, Germany.
   [Pena, Rafael Garrido] Univ Autonoma Madrid, Fac Filosofia & Letras, Dept Prehist & Arqueol, E-28049 Madrid, Spain.
   [Hallgren, Fredrik] Cultural Heritage Fdn, S-72212 Vasteras, Sweden.
   [Khartanovich, Valery; Moiseyev, Vayacheslav] Peter Great Museum Anthropol & Ethnog Kunstkamera, St Petersburg 199034, Russia.
   [Khokhlov, Aleksandr; Kuznetsov, Pavel; Mochalov, Oleg] Volga State Acad Social Sci & Humanities, Samara 443099, Russia.
   [Kunst, Michael] Deutsch Archaeol Inst, Abt Madrid, E-28002 Madrid, Spain.
   [Nicklisch, Nicole; Alt, Kurt Werner] Danube Private Univ, A-3500 Krems, Austria.
   [Pichler, Sandra L.; Alt, Kurt Werner] Univ Basel, Inst Prehist & Archaeol Sci, CH-4003 Basel, Switzerland.
   [Risch, Roberto] Univ Autonoma Barcelona, Dept Prehist, E-08193 Barcelona, Spain.
   [Rojo Guerra, Manuel A.] Univ Valladolid, Dept Prehist & Arqueol, E-47002 Valladolid, Spain.
   [Wahl, Joachim] State Off Cultural Heritage Management Baden Wurt, D-78467 Constance, Germany.
   [Krause, Johannes] Max Planck Inst Sci Human Hist, D-07745 Jena, Germany.
   [Brown, Dorcas; Anthony, David] Hartwick Coll, Dept Anthropol, Oneonta, NY 13820 USA.
C3 Adelaide University; University of Adelaide; Adelaide University; University of Adelaide; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Johannes Gutenberg University of Mainz; Max Planck Society; Chinese Academy of Sciences; Institute of Vertebrate Paleontology & Paleoanthropology, CAS; Eberhard Karls University of Tubingen; Hungarian Academy of Sciences; Eotvos Lorand University; ELTE Research Centre for the Humanities; Institute of Archaeology - HAS; Stockholm University; Leibniz Association; Senckenberg Gesellschaft fur Naturforschung (SGN); Eberhard Karls University of Tubingen; Eberhard Karls University of Tubingen; Leibniz Association; Senckenberg Gesellschaft fur Naturforschung (SGN); Autonomous University of Madrid; Russian Academy of Sciences; The Kunstkamera; Samara State University of Social Sciences & Education; University of Basel; Autonomous University of Barcelona; Universidad de Valladolid
RP Reich, D (corresponding author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
EM reich@genetics.med.harvard.edu
FU Australian Research Council [DP130102158]; German Research Foundation [Al 287/7-1, 7-3, Al 287/10-1, Al 287/14-1, Me 3245/1-1, 1-3]; US National Science Foundation HOMINID grant [BCS-1032255]; US National Institutes of Health [GM100233]; Howard Hughes Medical Institute; National Human Genome Research Institute [R01HG006399] Funding Source: NIH RePORTER; Division Of Behavioral and Cognitive Sci; Direct For Social, Behav & Economic Scie [1032255] Funding Source: National Science Foundation
NR 30
TC 1282
Z9 1448
U1 10
U2 346
PU NATURE PUBLISHING 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 11
PY 2015
VL 522
IS 7555
BP 207
EP +
DI 10.1038/nature14317
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700037
PM 25731166
DA 2026-03-09
ER

PT J
AU Cai, N
   Bigdeli, TB
   Kretzschmar, W
   Li, YH
   Liang, JQ
   Song, L
   Hu, JC
   Li, QB
   Jin, W
   Hu, ZF
   Wang, GB
   Wang, LM
   Qian, PY
   Liu, Y
   Jiang, T
   Lu, Y
   Zhang, XQ
   Yin, Y
   Li, YR
   Xu, X
   Gao, JF
   Reimers, M
   Webb, T
   Riley, B
   Bacanu, S
   Peterson, RE
   Chen, YP
   Zhong, H
   Liu, ZR
   Wang, G
   Sun, J
   Sang, H
   Jiang, GQ
   Zhou, XY
   Li, Y
   Li, Y
   Zhang, W
   Wang, XY
   Fang, X
   Pan, RD
   Miao, GD
   Zhang, QW
   Hu, J
   Yu, FY
   Du, B
   Sang, WH
   Li, KQ
   Chen, GB
   Cai, M
   Yang, LJ
   Yang, DL
   Ha, BW
   Hong, XH
   Deng, H
   Li, GY
   Li, K
   Song, Y
   Gao, SG
   Zhang, JB
   Gan, ZY
   Meng, HQ
   Pan, JY
   Gao, CG
   Zhang, KR
   Sun, N
   Li, YH
   Niu, QH
   Zhang, YT
   Liu, TQ
   Hu, CM
   Zhang, Z
   Lv, LX
   Dong, JC
   Wang, XP
   Tao, M
   Wang, XM
   Xia, J
   Rong, H
   He, Q
   Liu, TB
   Huang, GP
   Mei, QY
   Shen, ZM
   Liu, Y
   Shen, JH
   Tian, T
   Liu, XJ
   Wu, WY
   Gu, DH
   Fu, GY
   Shi, JG
   Chen, YC
   Gan, XC
   Liu, LF
   Wang, LN
   Yang, FZ
   Cong, EZ
   Marchini, J
   Yang, HM
   Wang, J
   Shi, SX
   Mott, R
   Xu, Q
   Wang, J
   Kendler, KS
   Flint, J
AF Cai, Na
   Bigdeli, Tim B.
   Kretzschmar, Warren
   Li, Yihan
   Liang, Jieqin
   Song, Li
   Hu, Jingchu
   Li, Qibin
   Jin, Wei
   Hu, Zhenfei
   Wang, Guangbiao
   Wang, Linmao
   Qian, Puyi
   Liu, Yuan
   Jiang, Tao
   Lu, Yao
   Zhang, Xiuqing
   Yin, Ye
   Li, Yingrui
   Xu, Xun
   Gao, Jingfang
   Reimers, Mark
   Webb, Todd
   Riley, Brien
   Bacanu, Silviu
   Peterson, Roseann E.
   Chen, Yiping
   Zhong, Hui
   Liu, Zhengrong
   Wang, Gang
   Sun, Jing
   Sang, Hong
   Jiang, Guoqing
   Zhou, Xiaoyan
   Li, Yi
   Li, Yi
   Zhang, Wei
   Wang, Xueyi
   Fang, Xiang
   Pan, Runde
   Miao, Guodong
   Zhang, Qiwen
   Hu, Jian
   Yu, Fengyu
   Du, Bo
   Sang, Wenhua
   Li, Keqing
   Chen, Guibing
   Cai, Min
   Yang, Lijun
   Yang, Donglin
   Ha, Baowei
   Hong, Xiaohong
   Deng, Hong
   Li, Gongying
   Li, Kan
   Song, Yan
   Gao, Shugui
   Zhang, Jinbei
   Gan, Zhaoyu
   Meng, Huaqing
   Pan, Jiyang
   Gao, Chengge
   Zhang, Kerang
   Sun, Ning
   Li, Youhui
   Niu, Qihui
   Zhang, Yutang
   Liu, Tieqiao
   Hu, Chunmei
   Zhang, Zhen
   Lv, Luxian
   Dong, Jicheng
   Wang, Xiaoping
   Tao, Ming
   Wang, Xumei
   Xia, Jing
   Rong, Han
   He, Qiang
   Liu, Tiebang
   Huang, Guoping
   Mei, Qiyi
   Shen, Zhenming
   Liu, Ying
   Shen, Jianhua
   Tian, Tian
   Liu, Xiaojuan
   Wu, Wenyuan
   Gu, Danhua
   Fu, Guangyi
   Shi, Jianguo
   Chen, Yunchun
   Gan, Xiangchao
   Liu, Lanfen
   Wang, Lina
   Yang, Fuzhong
   Cong, Enzhao
   Marchini, Jonathan
   Yang, Huanming
   Wang, Jian
   Shi, Shenxun
   Mott, Richard
   Xu, Qi
   Wang, Jun
   Kendler, Kenneth S.
   Flint, Jonathan
TI Sparse whole-genome sequencing identifies two loci for major depressive disorder
SO NATURE
LA English
DT Article
ID linear mixed models; epidemiology; association; comorbidity; inference
AB Major depressive disorder (MDD), one of the most frequently encountered forms ofmental illness and a leading cause of disability worldwide(1), poses a major challenge to genetic analysis. To date, no robustly replicated genetic loci have been identified(2), despite analysis of more than 9,000 cases(3). Here, using low-coverage whole-genome sequencing of 5,303 Chinese women with recurrent MDD selected to reduce phenotypic heterogeneity, and 5,337 controls screened to exclude MDD, we identified, and subsequently replicated in an independent sample, two loci contributing to risk of MDD on chromosome 10: one near the SIRT1 gene (P = 2.53 x 10(-10)), the other in an intron of the LHPP gene (P = 6.45 x10(-12)). Analysis of 4,509 cases with a severe subtype of MDD, melancholia, yielded an increased genetic signal at the SIRT1 locus. We attribute our success to the recruitment of relatively homogeneous cases with severe illness.
C1 [Cai, Na; Kretzschmar, Warren; Li, Yihan; Fu, Guangyi; Marchini, Jonathan; Mott, Richard; Flint, Jonathan] Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England.
   [Bigdeli, Tim B.; Reimers, Mark; Webb, Todd; Riley, Brien; Bacanu, Silviu; Peterson, Roseann E.; Kendler, Kenneth S.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23298 USA.
   [Liang, Jieqin; Song, Li; Hu, Jingchu; Li, Qibin; Jin, Wei; Hu, Zhenfei; Wang, Guangbiao; Wang, Linmao; Qian, Puyi; Liu, Yuan; Jiang, Tao; Lu, Yao; Zhang, Xiuqing; Yin, Ye; Li, Yingrui; Xu, Xun; Yang, Huanming; Wang, Jian; Wang, Jun] BGI Shenzhen, Shenzhen 518083, Guangdong, Peoples R China.
   [Gao, Jingfang] Zhejiang Tradit Chinese Med Hosp, Hangzhou 310000, Zhejiang, Peoples R China.
   [Chen, Yiping] Univ Oxford, CTSU, Oxford OX3 7LF, England.
   [Zhong, Hui] Anhui Mental Hlth Ctr, Hefei 230000, Anhui, Peoples R China.
   [Liu, Zhengrong] Anshan Psychiat Rehabil Hosp, Anshan 114000, Liaoning, Peoples R China.
   [Wang, Gang] Capital Univ Med Sci, Beijing Anding Hosp, Beijing 100000, Peoples R China.
   [Sun, Jing] Nanjing Med Univ, Brain Hosp, Nanjing 210000, Jiangsu, Peoples R China.
   [Sang, Hong] Changchun Mental Hosp, Changchun 130000, Jilin, Peoples R China.
   [Jiang, Guoqing; Zhou, Xiaoyan] Chongqing Mental Hlth Ctr, Chongqing 404100, Peoples R China.
   [Li, Yi] Dalian 7 Hosp, Dalian 116000, Liaoning, Peoples R China.
   [Li, Yi] Wuhan Mental Hlth Ctr, Wuhan 430000, Hubei, Peoples R China.
   [Zhang, Wei] Daqing 3 Hosp Heilongjiang, Daqing 163000, Heilongjiang, Peoples R China.
   [Wang, Xueyi] Hebei Med Univ, Hosp 1, Shijiazhuang 50000, Hebei, Peoples R China.
   [Fang, Xiang] Fuzhou Psychiat Hosp, Fuzhou 350000, Fujian, Peoples R China.
   [Pan, Runde] Guangxi Longquanshan Hosp, Guangxi 545000, Zhuangzu, Peoples R China.
   [Miao, Guodong] Guangzhou Psychiat Hosp, Guangzhou Brain Hosp, Guangzhou 510000, Guangdong, Peoples R China.
   [Zhang, Qiwen] Hainan Anning Hosp, Haikou 570100, Hainan, Peoples R China.
   [Hu, Jian] Harbin Med Univ, Haerbin 150000, Heilongjiang, Peoples R China.
   [Yu, Fengyu] Harbin 1 Special Hosp, Haerbin 150000, Heilongjiang, Peoples R China.
   [Du, Bo; Sang, Wenhua; Li, Keqing] Hebei Mental Hlth Ctr, Baoding 71000, Hebei, Peoples R China.
   [Chen, Guibing] Huaian 3 Hosp, Huaian 223001, Jiangsu, Peoples R China.
   [Cai, Min] Huzhou 3 Hosp, Huzhou 313000, Zhejiang, Peoples R China.
   [Yang, Lijun] Jilin Brain Hosp, Siping 136000, Jilin, Peoples R China.
   [Yang, Donglin] Jining Psychiat Hosp, Jining 272000, Shandong, Peoples R China.
   [Ha, Baowei] Liaocheng 4 Hosp, Liaocheng 252000, Shandong, Peoples R China.
   [Hong, Xiaohong] Shantou Univ, Mental Hlth Ctr, Shantou 515000, Guangdong, Peoples R China.
   [Deng, Hong] Sichuan Univ, West China Hosp, Mental Hlth Ctr, Chengdu 610000, Sichuan, Peoples R China.
   [Li, Gongying] Jining Med Coll, Mental Hlth Inst, Jining 272000, Shandong, Peoples R China.
   [Li, Kan] Mental Hosp Jiangxi Prov, Nanchang 330000, Jiangxi, Peoples R China.
   [Song, Yan] Mudanjiang Psychiat Hosp Heilongjiang Prov, Mudanjiang 157000, Heilongjiang, Peoples R China.
   [Gao, Shugui] Ningbo Kang Ning Hosp, Ningbo 315000, Zhejiang, Peoples R China.
   [Zhang, Jinbei; Gan, Zhaoyu] Sun Yat Sen Univ, Hosp 3, Guangzhou 510630, Guangdong, Peoples R China.
   [Meng, Huaqing] ChongqingMed Univ, Hosp 1, Chongqing 400016, Peoples R China.
   [Pan, Jiyang] Jinan Univ, Hosp 1, Guangzhou 510000, Guangdong, Peoples R China.
   [Gao, Chengge] Xi An Jiao Tong Univ, Coll Med, Hosp 1, Xian, Shaan Xi, Peoples R China.
   [Zhang, Kerang; Sun, Ning] Shanxi Med Univ, Hosp 1, Taiyuan 30000, Shanxi, Peoples R China.
   [Li, Youhui; Niu, Qihui] Zhengzhou Univ, Hosp 1, Zhengzhou 450000, Henan, Peoples R China.
   [Zhang, Yutang] Lanzhou Univ, Hosp 2, Lanzhou 730000, Gansu, Peoples R China.
   [Liu, Tieqiao] Zhongnan Univ, Xiangya Hosp 2, Changsha 410000, Hunan, Peoples R China.
   [Hu, Chunmei] 3 Hosp Heilongjiang Prov, Beian 164000, Heilongjiang, Peoples R China.
   [Zhang, Zhen] Jiangsu Univ, Hosp 4, Zhenjiang 212000, Jiangsu, Peoples R China.
   [Lv, Luxian] Psychiat Hosp Henan Prov, Xinxiang 453000, Henan, Peoples R China.
   [Dong, Jicheng] Qingdao Mental Hlth Ctr, Qingdao 266000, Shandong, Peoples R China.
   [Wang, Xiaoping] Wuhan Univ, Renmin Hosp, Wuhan 430000, Hubei, Peoples R China.
   [Tao, Ming] Zhejiang Chinese Med Univ, Affiliated Hosp 2, Hangzhou 310000, Zhejiang, Peoples R China.
   [Wang, Xumei; Xia, Jing] China Med Univ, ShengJing Hosp, Shenyang 110001, Liaoning, Peoples R China.
   [Rong, Han] Kangning Hosp, Shenzhen Key Lab Psychol Healthcare, Shenzhen 518000, Guangdong, Peoples R China.
   [He, Qiang] Kanazawa Med Univ, Dept Gen Internal Med, Kahoku, Ishikawa 9200293, Japan.
   [Liu, Tiebang] Shenzhen Key Lab Psychol Healthcare, Shenzhen 518000, Guangdong, Peoples R China.
   [Liu, Tiebang] Shenzhen Kangning Hosp, Shenzhen 518000, Guangdong, Peoples R China.
   [Huang, Guoping] Sichuan Mental Hlth Ctr, Mianyang 621000, Sichuan, Peoples R China.
   [Mei, Qiyi] Suzhou Guangji Hosp, Suzhou 215000, Jiangsu, Peoples R China.
   [Shen, Zhenming] Tangshan 5 Hosp, Tangshan 63000, Hebei, Peoples R China.
   [Liu, Ying] ChinaMed Univ, Hosp 1, Shenyang 110001, Liaoning, Peoples R China.
   [Shen, Jianhua; Tian, Tian] Tianjin Anding Hosp, Tianjin 300000, Peoples R China.
   [Liu, Xiaojuan] Tianjin First Ctr Hosp, Tianjin 300000, Peoples R China.
   [Wu, Wenyuan] Tongji Univ Hosp, Shanghai 200000, Peoples R China.
   [Gu, Danhua] Weihai Mental Hlth Ctr, Weihai 264200, Shandong, Peoples R China.
   [Gu, Danhua] Weihai Mental Hlth Ctr, Weihai 264200, Shandong, Peoples R China.
   [Shi, Jianguo] Xian Mental Hlth Ctr, Xian 710000, Shaanxi, Peoples R China.
   [Chen, Yunchun] 4 Mil Med Univ, Xijing Hosp, Xian 710000, Shaanxi, Peoples R China.
   [Gan, Xiangchao] Max Planck Inst Plant Breeding Res, Dept Comparat Dev Genet, D-50829 Cologne, Germany.
   [Liu, Lanfen; Wang, Lina] Shandong Mental Hlth Ctr, Jinan 250000, Shandong, Peoples R China.
   [Yang, Fuzhong; Cong, Enzhao; Shi, Shenxun] Shanghai Jiao Tong Univ, Sch Med, Shanghai Mental Hlth Ctr, Shanghai 200030, Peoples R China.
   [Marchini, Jonathan] Univ Oxford, Dept Stat, Oxford OX1 3TG, England.
   [Shi, Shenxun] Fudan Univ, Huashan Hosp, Shanghai 200040, Peoples R China.
   [Xu, Qi] Chinese Acad Med Sci, Natl Lab Med Mol Biol, Inst Basic Med Sci, Beijing 10005, Peoples R China.
   [Xu, Qi] Chinese Acad Med Sci, Neurosci Ctr, Beijing 10005, Peoples R China.
   [Xu, Qi] Peking Union Med Coll, Beijing 10005, Peoples R China.
   [Wang, Jun] Univ Copenhagen, Dept Biol, DK-2200 Copenhagen, Denmark.
   [Wang, Jun] Macau Univ Sci & Technol, Taipa 999078, Macau, Peoples R China.
   [Wang, Jun] King Abdulaziz Univ, Princess Jawhara Ctr Excellence Res Hereditary Di, Jeddah 21589, Saudi Arabia.
   [Flint, Jonathan] East China Normal Univ, Shanghai 200062, Peoples R China.
C3 University of Oxford; Wellcome Centre for Human Genetics; Virginia Commonwealth University; Beijing Genomics Institute (BGI); Zhejiang Chinese Medical University; University of Oxford; Capital Medical University; Nanjing Medical University; Hebei Medical University; Harbin Medical University; Shantou University; Sichuan University; Jining Medical University; Sun Yat Sen University; Jinan University; Xi'an Jiaotong University; Shanxi Medical University; Zhengzhou University; Lanzhou University; Central South University; Jiangsu University; Wuhan University; Zhejiang Chinese Medical University; China Medical University; Kanazawa Medical University; Shenzhen Institute of Mental Health & Shenzhen Kangning Hospital; Tongji University; Air Force Medical University; Max Planck Society; Shanghai Jiao Tong University; University of Oxford; Fudan University; Chinese Academy of Medical Sciences - Peking Union Medical College; Chinese Academy of Medical Sciences - Peking Union Medical College; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; University of Copenhagen; Macau University of Science & Technology; King Abdulaziz University; East China Normal University
RP Cai, N (corresponding author), Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England.
FU Wellcome Trust [WT090532/Z/09/Z, WT083573/Z/07/Z, WT089269/Z/09/Z, WT097307]; NIH [MH-100549]; Brain and Behavior Research Foundation; Agency of Science, Technology and Research (A*STAR) Graduate Academy; ERC [617306]; 973 Program [2013CB531301]; NSFC [31430048, 31222031]; European Research Council (ERC) [617306] Funding Source: European Research Council (ERC)
NR 29
TC 674
Z9 771
U1 3
U2 446
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 30
PY 2015
VL 523
IS 7562
BP 588
EP +
DI 10.1038/nature14659
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN7ZL
UT WOS:000358655200044
PM 26176920
DA 2026-03-09
ER

PT J
AU Ehrenreich, D
   Bourrier, V
   Wheatley, PJ
   Etangs, ALD
   Hébrard, G
   Udry, S
   Bonfils, X
   Delfosse, X
   Désert, JM
   Sing, DK
   Vidal-Madjar, A
AF Ehrenreich, David
   Bourrier, Vincent
   Wheatley, Peter J.
   Etangs, Alain Lecavelier des
   Hebrard, Guillaume
   Udry, Stephane
   Bonfils, Xavier
   Delfosse, Xavier
   Desert, Jean-Michel
   Sing, David K.
   Vidal-Madjar, Alfred
TI A giant comet-like cloud of hydrogen escaping the warm Neptune-mass exoplanet GJ 436b
SO NATURE
LA English
DT Article
ID energetic neutral atoms; hubble-space-telescope; hd 209458b; transmission spectrum; extrasolar planets; atmospheric escape; stars; evaporation; evolution; radiation
AB Exoplanets orbiting close to their parent stars may lose some fraction of their atmospheres because of the extreme irradiation(1-6). Atmospheric mass loss primarily affects low-mass exoplanets, leading to the suggestion that hot rocky planets(7-9) might have begun as Neptune-like(10-16), but subsequently lost all of their atmospheres; however, no confident measurements have hitherto been available. The signature of this loss could be observed in the ultraviolet spectrum, when the planet and its escaping atmosphere transit the star, giving rise to deeper and longer transit signatures than in the optical spectrum(17). Here we report that in the ultraviolet the Neptune-mass exoplanet GJ 436b (also known as Gliese 436b) has transit depths of 56.3 +/- 63.5% (1 sigma), far beyond the 0.69% optical transit depth. The ultraviolet transits repeatedly start about two hours before, and end more than three hours after the approximately one hour optical transit, which is substantially different from one previous claim(6) (based on an inaccurate ephemeris). We infer from this that the planet is surrounded and trailed by a large exospheric cloud composed mainly of hydrogen atoms. We estimate a mass-loss rate in the range of about 10(8)-10(9) grams per second, which is far too small to deplete the atmosphere of a Neptune-like planet in the lifetime of the parent star, but would have been much greater in the past.
C1 [Ehrenreich, David; Bourrier, Vincent; Udry, Stephane] Observ Univ Geneve, CH-1290 Versoix, Switzerland.
   [Wheatley, Peter J.] Univ Warwick, Dept Phys, Coventry CV4 7AL, W Midlands, England.
   [Etangs, Alain Lecavelier des; Hebrard, Guillaume; Vidal-Madjar, Alfred] CNRS, UMR 7095, Inst Astrophys Paris, F-75014 Paris, France.
   [Etangs, Alain Lecavelier des; Hebrard, Guillaume; Vidal-Madjar, Alfred] Univ Paris 06, Sorbonne Univ, UMR 7095, Inst Astrophys Paris, F-75014 Paris, France.
   [Hebrard, Guillaume] CNRS, Observ Haute Provence, F-04870 St Michel lObservatoire, France.
   [Hebrard, Guillaume] OAMP, F-04870 St Michel lObservatoire, France.
   [Bonfils, Xavier; Delfosse, Xavier] Univ Grenoble Alpes, IPAG, F-38000 Grenoble, France.
   [Bonfils, Xavier; Delfosse, Xavier] CNRS, IPAG, F-38000 Grenoble, France.
   [Desert, Jean-Michel] Univ Colorado, Dept Astrophys & Planetary Sci, CASA, Boulder, CO 80309 USA.
   [Sing, David K.] Univ Exeter, Astrophys Grp, Sch Phys, Exeter EX4 4QL, Devon, England.
C3 University of Geneva; University of Warwick; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Sorbonne Universite; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Centre National de la Recherche Scientifique (CNRS); Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Institut de Planetologie et d'Astrophysique de Grenoble (IPAG); Institut de Planetologie et d'Astrophysique de Grenoble (IPAG); Centre National de la Recherche Scientifique (CNRS); University of Colorado System; University of Colorado Boulder; University of Exeter
RP Ehrenreich, D (corresponding author), Observ Univ Geneve, 51 Chemin Maillettes, CH-1290 Versoix, Switzerland.
EM david.ehrenreich@unige.ch
FU NASA [NAS 5-26555]; Swiss National Science Foundation (SNSF); CNES; French Agence Nationale de la Recherche (ANR) [ANR-12-BS05-0012]; Fondation Simone et Cino Del Duca; European Research Council (ERC) under ERC [337591-ExTrA];  [11817];  [12034];  [12965]; STFC [ST/L000733/1, ST/I001719/1] Funding Source: UKRI; Science and Technology Facilities Council [ST/L000733/1, ST/I001719/1] Funding Source: researchfish
NR 34
TC 402
Z9 444
U1 2
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 JUN 25
PY 2015
VL 522
IS 7557
BP 459
EP +
DI 10.1038/nature14501
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL2OC
UT WOS:000356782900045
PM 26108854
DA 2026-03-09
ER

PT J
AU Chen, ZS
   Shojaee, S
   Buchner, M
   Geng, HM
   Lee, J
   Klemm, L
   Titz, B
   Graeber, TG
   Park, E
   Tan, YX
   Satterthwaite, A
   Paietta, E
   Hunger, SP
   Willman, CL
   Melnick, A
   Loh, ML
   Jung, JU
   Coligan, JE
   Bolland, S
   Mak, TW
   Limnander, A
   Jumaa, H
   Reth, M
   Weiss, A
   Lowell, CA
   Müschen, M
AF Chen, Zhengshan
   Shojaee, Seyedmehdi
   Buchner, Maike
   Geng, Huimin
   Lee, JaeWoong
   Klemm, Lars
   Titz, Boern
   Graeber, Thomas G.
   Park, Eugene
   Tan, Ying Xim
   Satterthwaite, Anne
   Paietta, Elisabeth
   Hunger, Stephen P.
   Willman, Cheryl L.
   Melnick, Ari
   Loh, Mignon L.
   Jung, Jae U.
   Coligan, John E.
   Bolland, Silvia
   Mak, Tak W.
   Limnander, Andre
   Jumaa, Hassan
   Reth, Michael
   Weiss, Arthur
   Lowell, Clifford A.
   Mueschen, Markus
TI Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia
SO NATURE
LA English
DT Article
ID in-vivo; receptor; deletion; activation; motifs
AB B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum(for example, non-functional BCR)(1) or hyperactivation above maximum (for example, self-reactive BCR)(2,3) thresholds of signalling strength causes negative selection. In similar to 25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling(4,5). Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival(6). We tested the hypothesis that targeted hyperactivation-above a maximum threshold-will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR-ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1, Cd300a and Lair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7) and Inpp5d (ref. 8). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1)(9), we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL.
C1 [Chen, Zhengshan; Shojaee, Seyedmehdi; Buchner, Maike; Geng, Huimin; Lee, JaeWoong; Klemm, Lars; Park, Eugene; Lowell, Clifford A.; Mueschen, Markus] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA.
   [Titz, Boern; Graeber, Thomas G.] Univ Calif Los Angeles, Crump Inst Mol Imaging, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA.
   [Tan, Ying Xim; Weiss, Arthur] Univ Calif San Francisco, Howard Hughes Med Inst, Dept Med,Div Rheumatol, Rosalind Russell Ephraim P Engleman Med Res Ctr A, San Francisco, CA 94143 USA.
   [Satterthwaite, Anne] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA.
   [Paietta, Elisabeth] Albert Einstein Coll Med, Dept Med, Bronx, NY 10466 USA.
   [Hunger, Stephen P.] Childrens Hosp Philadelphia, Div Pediat Oncol, Philadelphia, PA 19104 USA.
   [Hunger, Stephen P.] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA.
   [Willman, Cheryl L.] Univ New Mexico, Ctr Canc, Albuquerque, NM 87102 USA.
   [Melnick, Ari] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA.
   [Melnick, Ari] Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10065 USA.
   [Loh, Mignon L.] Univ Calif San Francisco, Pediat Hematol Oncol, San Francisco, CA 94143 USA.
   [Jung, Jae U.] Univ So Calif, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA.
   [Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA.
   [Bolland, Silvia] NIAID, Autoimmun & Funct Genom Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA.
   [Mak, Tak W.] Univ Hlth Network, Campbell Family Inst Breast Canc Res, Toronto, ON M5G 2M9, Canada.
   [Limnander, Andre] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA.
   [Jumaa, Hassan] Univ Clin Ulm, Inst Immunol, D-89081 Ulm, Germany.
   [Reth, Michael] Univ Freiburg, BIOSS Ctr Biol Signalling Studies, D-79104 Freiburg, Germany.
   [Reth, Michael] Univ Freiburg, Fac Biol, D-79104 Freiburg, Germany.
   [Reth, Michael] MPI Immunbiol & Epigenet, D-79104 Freiburg, Germany.
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; Howard Hughes Medical Institute; University of Texas System; University of Texas Southwestern Medical Center; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of New Mexico; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; University of California System; University of California San Francisco; University of Southern California; 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 Toronto; University Health Network Toronto; University of California System; University of California San Francisco; Ulm University; University of Freiburg; University of Freiburg
RP Müschen, M (corresponding author), Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA.
EM markus.muschen@ucsf.edu
FU National Institutes of Health/National Cancer Institute [R01CA137060, R01CA139032, R01CA169458, R01CA172558, R01CA157644]; ECOG-ACRIN [CA180820, CA180794]; Leukemia and Lymphoma Society; California Institute for Regenerative Medicine [TR02-1816]; William Lawrence and Blanche Hughes Foundation; DFG [EXC294, TRR130, SFB746]; National Cancer Institute [R01CA157644, U10CA180794, U24CA196172, U10CA180886, U10CA180820] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [ZIAAI000912] Funding Source: NIH RePORTER; Cancer Research UK [18131] Funding Source: researchfish
NR 22
TC 120
Z9 148
U1 0
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 MAY 21
PY 2015
VL 521
IS 7552
BP 357
EP +
DI 10.1038/nature14231
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CI5RM
UT WOS:000354816500057
PM 25799995
DA 2026-03-09
ER

PT J
AU Strait, RT
   Posgai, MT
   Mahler, A
   Barasa, N
   Jacob, CO
   Köhl, J
   Ehlers, M
   Stringer, K
   Shanmukhappa, SK
   Witte, D
   Hossain, MM
   Khodoun, M
   Herr, AB
   Finkelman, FD
AF Strait, Richard T.
   Posgai, Monica T.
   Mahler, Ashley
   Barasa, Nathaniel
   Jacob, Chaim O.
   Koehl, Joerg
   Ehlers, Marc
   Stringer, Keith
   Shanmukhappa, Shiva Kumar
   Witte, David
   Hossain, Md Monir
   Khodoun, Marat
   Herr, Andrew B.
   Finkelman, Fred D.
TI IgG1 protects against renal disease in a mouse model of cryoglobulinaemia
SO NATURE
LA English
DT Article
ID fc-gamma-riib; class switch recombination; antiinflammatory activity; monoclonal-antibody; segmental flexibility; immune-responses; in-vivo; complement; inflammation; receptors
AB Immunoglobulins protect against disease to a considerable extent by activating complement and stimulatory immunoglobulin crystallizable fragment receptors (Ig FcRs), and aggregating microbial pathogens(1,2). Yet IgGI, the predominant murine serum Ig isotype, cannot activate complement by the classical pathway, binds more avidly to an inhibitory than to stimulatory FcRs, and has limited ability to aggregate pathogens(1-3). In these regards, it resembles human IgG4 (ref. 4). We hypothesized that limited ability to activate effector mechanisms might protect against immune complex immunopathology. Here we show that IgG 1 -deficient (gamma 1(-)) mice(5), immunized with a potent antigen, develop lethal renal disease soon after they begin to produce antigen-specific antibody, whereas similarly immunized wildtype mice remain healthy. Surprisingly, renal disease in this model is complement and FcR independent and results from immune complex precipitation in glomerular capillaries, as in some cryoglobulinaemic humans(6). IgG3, which self-associates to form large immune complexes(7,8), accounts for more than 97% of the mouse Ig in this cryoglobulin; furthermore, glomerular disease develops when mice are injected with IgG3 anti-trinitrophenyl (TNP) monoclonal antibody followed by a TNP-labelled protein. Renal disease is prevented in both active and passive immunization models by antigen-specific IgGI; other isotypes are less potent at preventing disease. These observations demonstrate the adaptive significance of Ig isotypes that poorly activate effector mechanisms, reveal an immune-complex-dependent, complement- and FcR-independent nephrotoxic mechanism, and suggest that isotypes that poorly activate effector mechanisms may be useful for inhibiting immune complex immunopathology.
C1 [Strait, Richard T.; Mahler, Ashley; Barasa, Nathaniel] Cincinnati Childrens Hosp Med Ctr, Div Emergency Med, Cincinnati, OH 45229 USA.
   [Strait, Richard T.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45267 USA.
   [Posgai, Monica T.; Herr, Andrew B.] Univ Cincinnati, Coll Med, Dept Mol Genet Biochem & Microbiol, Cincinnati, OH 45267 USA.
   [Jacob, Chaim O.] Univ So Calif, Sch Med, Dept Med, Los Angeles, CA 90033 USA.
   [Koehl, Joerg; Herr, Andrew B.; Finkelman, Fred D.] Cincinnati Childrens Hosp Med Ctr, Div Immunobiol, Cincinnati, OH 45229 USA.
   [Koehl, Joerg; Ehlers, Marc] Med Univ Lubeck, Inst Syst Inflammat Res, D-23538 Lubeck, Germany.
   [Stringer, Keith; Shanmukhappa, Shiva Kumar; Witte, David] Cincinnati Childrens Hosp Med Ctr, Div Pathol, Cincinnati, OH 45229 USA.
   [Hossain, Md Monir] Cincinnati Childrens Hosp Med Ctr, Div Biostat & Epidemiol, Cincinnati, OH 45229 USA.
   [Khodoun, Marat; Finkelman, Fred D.] Univ Cincinnati, Coll Med, Dept Med, Div Immunol Allergy & Rheumatol, Cincinnati, OH 45267 USA.
   [Finkelman, Fred D.] Cincinnati Vet Affairs Med Ctr, Med Serv, Cincinnati, OH 45220 USA.
C3 Cincinnati Children's Hospital Medical Center; University System of Ohio; University of Cincinnati; University System of Ohio; University of Cincinnati; University of Southern California; Cincinnati Children's Hospital Medical Center; University System of Ohio; University of Cincinnati; University of Lubeck; Cincinnati Children's Hospital Medical Center; Cincinnati Children's Hospital Medical Center; University System of Ohio; University of Cincinnati; US Department of Veterans Affairs; Veterans Health Administration (VHA); Cincinnati VA Medical Center
RP Finkelman, FD (corresponding author), Cincinnati Childrens Hosp Med Ctr, Div Immunobiol, Cincinnati, OH 45229 USA.
EM finkelfd@UCMAIL.UC.EDU
FU US Department of Veterans Affairs Merit Award; National Institutes of Health [R01 AI072040]; Cincinnati Children's Hospital; University of Cincinnati
NR 26
TC 57
Z9 69
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 JAN 22
PY 2015
VL 517
IS 7535
BP 501
EP +
DI 10.1038/nature13868
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AZ4MU
UT WOS:000348196500038
PM 25363774
DA 2026-03-09
ER

PT J
AU Khaminets, A
   Heinrich, T
   Mari, M
   Grumati, P
   Huebner, AK
   Akutsu, M
   Liebmann, L
   Stolz, A
   Nietzsche, S
   Koch, N
   Mauthe, M
   Katona, I
   Qualmann, B
   Weis, J
   Reggiori, F
   Kurth, I
   Hübner, CA
   Dikic, I
AF Khaminets, Aliaksandr
   Heinrich, Theresa
   Mari, Muriel
   Grumati, Paolo
   Huebner, Antje K.
   Akutsu, Masato
   Liebmann, Lutz
   Stolz, Alexandra
   Nietzsche, Sandor
   Koch, Nicole
   Mauthe, Mario
   Katona, Istvan
   Qualmann, Britta
   Weis, Joachim
   Reggiori, Fulvio
   Kurth, Ingo
   Huebner, Christian A.
   Dikic, Ivan
TI Regulation of endoplasmic reticulum turnover by selective autophagy
SO NATURE
LA English
DT Article
ID protein; degradation; phosphorylation; localization
AB The endoplasmic reticulum (ER) is the largest intracellular endomembrane system, enabling protein and lipid synthesis, ion homeostasis, quality control of newly synthesized proteins and organelle communication(1). Constant ER turnover and modulation is needed to meet different cellular requirements and autophagy has an important role in this process(2-8). However, its underlying regulatory mechanisms remain unexplained. Here we show that members of the FAM134 reticulon protein family are ER-resident receptors that bind to autophagy modifiers LC3 and GABARAP, and facilitate ER degradation by autophagy ('ER-phagy'). Downregulation of FAM134B protein in human cells causes an expansion of the ER, while FAM134B overexpression results in ER fragmentation and lysosomal degradation. Mutant FAM134B proteins that cause sensory neuropathy in humans(9) are unable to act as ER-phagy receptors. Consistently, disruption of Fam134b in mice causes expansion of the ER, inhibits ER turnover, sensitizes cells to stress-induced apoptotic cell death and leads to degeneration of sensory neurons. Therefore, selective ER-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover in mice and humans.
C1 [Khaminets, Aliaksandr; Grumati, Paolo; Stolz, Alexandra; Dikic, Ivan] Goethe Univ Frankfurt, Sch Med, Inst Biochem 2, D-60590 Frankfurt, Germany.
   [Heinrich, Theresa; Huebner, Antje K.; Liebmann, Lutz; Kurth, Ingo; Huebner, Christian A.] Univ Jena, Inst Human Genet, Jena Univ Hosp, D-07743 Jena, Germany.
   [Mari, Muriel; Mauthe, Mario; Reggiori, Fulvio] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Cell Biol, NL-3584 CX Utrecht, Netherlands.
   [Mari, Muriel; Reggiori, Fulvio] Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, NL-9713 AV Groningen, Netherlands.
   [Akutsu, Masato] Goethe Univ Frankfurt, Buchmann Inst Mol Life Sci, D-60438 Frankfurt, Germany.
   [Nietzsche, Sandor] Univ Jena, Jena Univ Hosp, Electron Microscopy Ctr, D-07743 Jena, Germany.
   [Koch, Nicole; Qualmann, Britta] Univ Jena, Jena Univ Hosp, Inst Biochem 1, D-07743 Jena, Germany.
   [Katona, Istvan; Weis, Joachim] RWTH Aachen Univ Hosp, Inst Neuropathol, D-52074 Aachen, Germany.
   [Dikic, Ivan] Univ Split, Sch Med, Inst Immunol, Mestrovicevo Setaliste B 21000, Split, Croatia.
C3 Goethe University Frankfurt; Friedrich Schiller University of Jena; Utrecht University; Utrecht University Medical Center; University of Groningen; Goethe University Frankfurt; Friedrich Schiller University of Jena; Friedrich Schiller University of Jena; RWTH Aachen University; RWTH Aachen University Hospital; University of Split
RP Dikic, I (corresponding author), Goethe Univ Frankfurt, Sch Med, Inst Biochem 2, Theodor Stern Kai 7, D-60590 Frankfurt, Germany.
EM Ingo.Kurth@med.uni-jena.de; Christian.Huebner@med.uni-jena.de; Ivan.Dikic@biochem2.de
FU Deutsche Forschungsgemeinschaft [DI 931/3-1, KU 1587/2-1, KU 1587/3-1, KU 1587/4-1, HU 800/5-1]; RTG [1715, HU 800/6-1, HU 800/7-1, QU116/6-2, RTG1715, WE1406/13-1]; Cluster of Excellence 'Macromolecular Complexes' of the Goethe University Frankfurt [EXC115]; LOEWE grant Ub-Net; LOEWE Centrum for Gene and Cell therapy Frankfurt; European Research Council/ERC [250241-LineUb]; ECHO [700.59.003]; ALW Open Program [821.02.017, 822.02.014]; DFG-NWO cooperation [DN82-303]; ZonMW VICI [016.130.606]; 7.FP, COFUND, Goethe International Postdoc Programme GO-IN [291776]
NR 38
TC 761
Z9 870
U1 7
U2 217
PU NATURE PUBLISHING 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 18
PY 2015
VL 522
IS 7556
BP 354
EP +
DI 10.1038/nature14498
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK7PU
UT WOS:000356425400056
PM 26040720
DA 2026-03-09
ER

PT J
AU Ong-Abdullah, M
   Ordway, JM
   Jiang, N
   Ooi, SE
   Kok, SY
   Sarpan, N
   Azimi, N
   Hashim, AT
   Ishak, Z
   Rosli, SK
   Malike, FA
   Abu Bakar, NA
   Marjuni, M
   Abdullah, N
   Yaakub, Z
   Amiruddin, MD
   Nookiah, R
   Singh, R
   Low, ETL
   Chan, KL
   Azizi, N
   Smith, SW
   Bacher, B
   Budiman, MA
   Van Brunt, A
   Wischmeyer, C
   Beil, M
   Hogan, M
   Lakey, N
   Lim, CC
   Arulandoo, X
   Wong, CK
   Choo, CN
   Wong, WC
   Kwan, YY
   Alwee, SSRS
   Sambanthamurthi, R
   Martienssen, RA
AF Ong-Abdullah, Meilina
   Ordway, Jared M.
   Jiang, Nan
   Ooi, Siew-Eng
   Kok, Sau-Yee
   Sarpan, Norashikin
   Azimi, Nuraziyan
   Hashim, Ahmad Tarmizi
   Ishak, Zamzuri
   Rosli, Samsul Kamal
   Malike, Fadila Ahmad
   Abu Bakar, Nor Azwani
   Marjuni, Marhalil
   Abdullah, Norziha
   Yaakub, Zulkifli
   Amiruddin, Mohd Din
   Nookiah, Rajanaidu
   Singh, Rajinder
   Low, Eng-Ti Leslie
   Chan, Kuang-Lim
   Azizi, Norazah
   Smith, Steven W.
   Bacher, Blaire
   Budiman, Muhammad A.
   Van Brunt, Andrew
   Wischmeyer, Corey
   Beil, Melissa
   Hogan, Michael
   Lakey, Nathan
   Lim, Chin-Ching
   Arulandoo, Xaviar
   Wong, Choo-Kien
   Choo, Chin-Nee
   Wong, Wei-Chee
   Kwan, Yen-Yen
   Alwee, Sharifah Shahrul Rabiah Syed
   Sambanthamurthi, Ravigadevi
   Martienssen, Robert A.
TI Loss of Karma transposon methylation underlies the mantled somaclonal variant of oil palm
SO NATURE
LA English
DT Article
ID elaeis-guineensis jacq.; mads box genes; epigenetic mutation; flower structure; arabidopsis; elements; genome; maize; retrotransposon; paramutation
AB Somaclonal variation arises in plants and animals when differentiated somatic cells are induced into a pluripotent state, but the resulting clones differ from each other and from their parents. In agriculture, somaclonal variation has hindered the micropropagation of elite hybrids and genetically modified crops, but the mechanism responsible remains unknown(1). The oil palm fruit 'mantled' abnormality is a somaclonal variant arising from tissue culture that drastically reduces yield, and has largely halted efforts to clone elite hybrids for oil production(2-4). Widely regarded as an epigenetic phenomenon(5), 'mantling' has defied explanation, but here we identify the MANTLED locus using epigenome-wide association studies of the African oil palm Elaeis guineensis. DNA hypomethylation of a LINE retrotransposon related to rice Karma, in the intron of the homeotic gene DEFICIENS, is common to all mantled clones and is associated with alternative splicing and premature termination. Dense methylation near the Karma splice site (termed the Good Karma epiallele) predicts normal fruit set, whereas hypomethylation (the Bad Karma epiallele) predicts homeotic transformation, parthenocarpy and marked loss of yield. Loss of Karma methylation and of small RNA in tissue culture contributes to the origin of mantled, while restoration in spontaneous revertants accounts for non-Mendelian inheritance. The ability to predict and cull mantling at the plantlet stage will facilitate the introduction of higher performing clones and optimize environmentally sensitive land resources.
C1 [Ong-Abdullah, Meilina; Ooi, Siew-Eng; Kok, Sau-Yee; Sarpan, Norashikin; Azimi, Nuraziyan; Hashim, Ahmad Tarmizi; Ishak, Zamzuri; Rosli, Samsul Kamal; Malike, Fadila Ahmad; Abu Bakar, Nor Azwani; Marjuni, Marhalil; Abdullah, Norziha; Yaakub, Zulkifli; Amiruddin, Mohd Din; Nookiah, Rajanaidu; Singh, Rajinder; Low, Eng-Ti Leslie; Chan, Kuang-Lim; Azizi, Norazah] Malaysian Palm Oil Board, Persiaran Inst, Kajang 43000, Selangor, Malaysia.
   [Ordway, Jared M.; Jiang, Nan; Smith, Steven W.; Bacher, Blaire; Budiman, Muhammad A.; Van Brunt, Andrew; Wischmeyer, Corey; Beil, Melissa; Hogan, Michael; Lakey, Nathan] Orion Genom, St Louis, MO 63108 USA.
   [Lim, Chin-Ching; Arulandoo, Xaviar] United Plantat Berhad, Teluk Intan 36009, Perak, Malaysia.
   [Wong, Choo-Kien; Choo, Chin-Nee; Wong, Wei-Chee] Appl Agr Resources Sdn Bhd, Petaling Jaya 47810, Selangor, Malaysia.
   [Kwan, Yen-Yen; Alwee, Sharifah Shahrul Rabiah Syed] Lengkuk Teknol, FELDA Global Ventures R&D Sdn Bhd, FELDA Biotechnol Ctr, Bandar Enstek 71760, Negeri Sembilan, Malaysia.
   [Martienssen, Robert A.] Cold Spring Harbor Lab, Howard Hughes Med Inst, Gordon & Betty Moore Fdn, Cold Spring Harbor, NY 11724 USA.
C3 Malaysian Palm Oil Board; Cold Spring Harbor Laboratory; Howard Hughes Medical Institute
RP Martienssen, RA (corresponding author), Cold Spring Harbor Lab, Howard Hughes Med Inst, Gordon & Betty Moore Fdn, Cold Spring Harbor, NY 11724 USA.
EM raviga@mpob.gov.my; martiens@cshl.edu
FU NIGMS NIH HHS [R01 GM067014] Funding Source: Medline
NR 40
TC 381
Z9 435
U1 3
U2 196
PU NATURE PUBLISHING 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 24
PY 2015
VL 525
IS 7570
BP 533
EP +
DI 10.1038/nature15365
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR8KI
UT WOS:000361599900053
PM 26352475
DA 2026-03-09
ER

PT J
AU Caskey, M
   Klein, F
   Lorenzi, JCC
   Seaman, MS
   West, AP
   Buckley, N
   Kremer, G
   Nogueira, L
   Braunschweig, M
   Scheid, JF
   Horwitz, JA
   Shimeliovich, I
   Ben-Avraham, S
   Witmer-Pack, M
   Platten, M
   Lehmann, C
   Burke, LA
   Hawthorne, T
   Gorelick, RJ
   Walker, BD
   Keler, T
   Gulick, RM
   Fätkenheuer, G
   Schlesinger, SJ
   Nussenzweig, MC
AF Caskey, Marina
   Klein, Florian
   Lorenzi, Julio C. C.
   Seaman, Michael S.
   West, Anthony P., Jr.
   Buckley, Noreen
   Kremer, Gisela
   Nogueira, Lilian
   Braunschweig, Malte
   Scheid, Johannes F.
   Horwitz, Joshua A.
   Shimeliovich, Irina
   Ben-Avraham, Sivan
   Witmer-Pack, Maggi
   Platten, Martin
   Lehmann, Clara
   Burke, Leah A.
   Hawthorne, Thomas
   Gorelick, Robert J.
   Walker, Bruce D.
   Keler, Tibor
   Gulick, Roy M.
   Faetkenheuer, Gerd
   Schlesinger, Sarah J.
   Nussenzweig, Michel C.
TI Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117
SO NATURE
LA English
DT Article
ID monoclonal-antibody; hiv-1 neutralization; genetic-determinants; passive transfer; in-vivo; therapy; virus; immunotherapy; vaccine; mice
AB HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned(1-3). However, recently developed single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1 (refs 4, 5). These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated(6-10). Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody(11), in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30mg kg(-1) infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8-2.5 log(10) and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure.
C1 [Caskey, Marina; Klein, Florian; Lorenzi, Julio C. C.; Buckley, Noreen; Nogueira, Lilian; Braunschweig, Malte; Scheid, Johannes F.; Horwitz, Joshua A.; Shimeliovich, Irina; Ben-Avraham, Sivan; Witmer-Pack, Maggi; Burke, Leah A.; Schlesinger, Sarah J.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA.
   [Seaman, Michael S.] Harvard Univ, Ctr Virol & Vaccine Res, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA.
   [West, Anthony P., Jr.] CALTECH, Div Biol, Pasadena, CA 91125 USA.
   [Kremer, Gisela; Platten, Martin; Lehmann, Clara; Faetkenheuer, Gerd] Univ Hosp Cologne, Dept Internal Med 1, D-50924 Cologne, Germany.
   [Kremer, Gisela] Univ Cologne, Clin Trials Ctr Cologne, ZKS Koln, D-50931 Cologne, Germany.
   [Braunschweig, Malte] Univ Freiburg, D-79085 Freiburg, Germany.
   [Platten, Martin; Lehmann, Clara; Faetkenheuer, Gerd] Partner Site Bonn Cologne, German Ctr Infect Res DZIF, Cologne, Germany.
   [Burke, Leah A.; Gulick, Roy M.] Cornell Univ, Div Infect Dis, Weill Med Coll, New York, NY 10065 USA.
   [Hawthorne, Thomas; Keler, Tibor] Celldex Therapeut Inc, Hampton, NJ 08827 USA.
   [Gorelick, Robert J.] Frederick Natl Lab Canc Res, Leidos Biomed Res, AIDS & Canc Virus Program, Frederick, MD 21702 USA.
   [Walker, Bruce D.] Massachusetts Gen Hosp, Radon Inst MGH MIT & Harvard, Howard Hughes Med Inst, Cambridge, MA 02139 USA.
   [Walker, Bruce D.] Harvard Univ, Sch Med, Cambridge, MA 02139 USA.
   [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA.
C3 Rockefeller University; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard Medical School; California Institute of Technology; University of Cologne; University of Cologne; University of Freiburg; University of Cologne; German Center for Infection Research; Cornell University; Weill Cornell Medicine; Celldex Therapeutics, Inc.; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Howard Hughes Medical Institute; Harvard University; Rockefeller University; Howard Hughes Medical Institute
RP Nussenzweig, MC (corresponding author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA.
EM nussen@rockefeller.edu
FU CNPq "Ciencia sem Fronteiras" Brazil [248676/2013-0]; Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) [OPP1033115, OPP1092074, OPP1040753, OPP1032144]; Cooperative Centers on Human Immunology from NIH [U19A1111825-01]; National Center for Advancing Translational Sciences (NCATS) [UL1 TR000043]; Robertson Foundation; NCI/NIH [HHSN261200800001E]; German Center for Infection Research (DZIF) [3BNC117]; Mark and Lisa Schwartz Foundation; CAVD [43307]; National Institute of Allergy and Infectious Diseases [U19AI111825] Funding Source: NIH RePORTER; Bill and Melinda Gates Foundation [OPP1033115, OPP1032144, OPP1040753] Funding Source: Bill and Melinda Gates Foundation
NR 40
TC 634
Z9 768
U1 0
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 JUN 25
PY 2015
VL 522
IS 7557
BP 487
EP +
DI 10.1038/nature14411
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL2OC
UT WOS:000356782900052
PM 25855300
DA 2026-03-09
ER

PT J
AU Zhao, L
   Oliver, E
   Maratou, K
   Atanur, SS
   Dubois, OD
   Cotroneo, E
   Chen, CN
   Wang, L
   Arce, C
   Chabosseau, PL
   Ponsa-Cobas, J
   Frid, MG
   Moyon, B
   Webster, Z
   Aldashev, A
   Ferrer, J
   Rutter, GA
   Stenmark, KR
   Aitman, TJ
   Wilkins, MR
AF Zhao, Lan
   Oliver, Eduardo
   Maratou, Klio
   Atanur, Santosh S.
   Dubois, Olivier D.
   Cotroneo, Emanuele
   Chen, Chien-Nien
   Wang, Lei
   Arce, Cristina
   Chabosseau, Pauline L.
   Ponsa-Cobas, Joan
   Frid, Maria G.
   Moyon, Benjamin
   Webster, Zoe
   Aldashev, Almaz
   Ferrer, Jorge
   Rutter, Guy A.
   Stenmark, Kurt R.
   Aitman, Timothy J.
   Wilkins, Martin R.
TI The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia
SO NATURE
LA English
DT Article
ID hypertension; expression; inhibition
AB The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension(1-3). We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.
C1 [Zhao, Lan; Oliver, Eduardo; Dubois, Olivier D.; Cotroneo, Emanuele; Chen, Chien-Nien; Wang, Lei; Arce, Cristina; Wilkins, Martin R.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Ctr Pharmacol & Therapeut, Div Expt Med, London W12 0NN, England.
   [Rutter, Guy A.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Sect Cell Biol & Funct Genom, Div Diabet Endocrinol & Metab, London W12 0NN, England.
   [Ponsa-Cobas, Joan; Ferrer, Jorge] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Fac Med, Sect Epigen & Dis,Dept Med, London W12 0NN, England.
   [Maratou, Klio; Atanur, Santosh S.; Chabosseau, Pauline L.; Aitman, Timothy J.] Hammersmith Hosp, Med Res Council Clin Sci Ctr, Physiol Genom & Med Grp, London W12 0NN, England.
   [Moyon, Benjamin; Webster, Zoe] Hammersmith Hosp, Med Res Council Clin Sci Ctr, Transgen & Embryon Stem Cell Lab, London W12 0NN, England.
   [Aldashev, Almaz] Inst Mol Biol & Med, Bishkek 720040, Kyrgyzstan.
   [Frid, Maria G.; Stenmark, Kurt R.] Univ Colorado, Dept Pediat & Med, Div Crit Care Med, Denver, CO 80045 USA.
   [Frid, Maria G.; Stenmark, Kurt R.] Univ Colorado, Cardiovasc Pulm Res Labs, Denver, CO 80045 USA.
C3 Imperial College London; Imperial College London; Imperial College London; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); Imperial College London; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); Imperial College London; Ministry of Health - Kyrgyzstan; University of Colorado System; University of Colorado Denver; University of Colorado System; University of Colorado Denver
RP Zhao, L (corresponding author), Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Ctr Pharmacol & Therapeut, Div Expt Med, London W12 0NN, England.
EM l.zhao@imperial.ac.uk
FU British Heart Foundation [PG/95170, PG/98018, PG/2000137, PG/04/035/16912, PG/12/61/29818, PG/10/59/28478, RG/10/16/28575]; Wellcome Trust [WT098424AIA]; MRC [MR/J0003042/1]; Royal Society; European Research Council [268880]; European Research Council (ERC) [268880] Funding Source: European Research Council (ERC); British Heart Foundation [PG/10/59/28478, RG/10/16/28575, PG/12/61/29818, PG/10/34/28338] Funding Source: researchfish; Medical Research Council [MR/K001981/1, MC_U120061454, MR/L02036X/1] Funding Source: researchfish; Wellcome Trust [101033/C/13/Z] Funding Source: researchfish; MRC [MR/K001981/1, MC_U120061454, MR/L02036X/1] Funding Source: UKRI
NR 34
TC 120
Z9 136
U1 0
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 AUG 20
PY 2015
VL 524
IS 7565
BP 356
EP U229
DI 10.1038/nature14620
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP2NN
UT WOS:000359714000037
PM 26258299
DA 2026-03-09
ER

PT J
AU Mastrobuono-Battisti, A
   Perets, HB
   Raymond, SN
AF Mastrobuono-Battisti, Alessandra
   Perets, Hagai B.
   Raymond, Sean N.
TI A primordial origin for the compositional similarity between the Earth and the Moon
SO NATURE
LA English
DT Article
ID giant impact; simulations; accretion; isotopes
AB Most of the properties of the Earth-Moon system can be explained by a collision between a planetary embryo (giant impactor) and the growing Earth late in the accretion process'. Simulations show that most of the material that eventually aggregates to form the Moon originates from the impactor(1,4,5). However, analysis of the terrestrial and lunar isotopic compositions show them to be highly similar(6-11). In contrast, the compositions of other Solar System bodies are significantly different from those of the Earth and Moon(12-14), suggesting that different Solar System bodies have distinct compositions. This challenges the giant impact scenario, because the Moon-forming impactor must then also be thought to have a composition different from that of the proto-Earth. Here we track the feeding zones of growing planets in a suite of simulations of planetary accretion(15), to measure the composition of Moon-forming impactors. We find that different planets formed in the same simulation have distinct compositions, but the compositions of giant impactors are statistically more similar to the planets they impact. A large fraction of planet-impactor pairs have almost identical compositions. Thus, the similarity in composition between the Earth and Moon could be a natural consequence of a late giant impact.
C1 [Mastrobuono-Battisti, Alessandra; Perets, Hagai B.] Technion Israel Inst Technol, Dept Phys, IL-32000 Haifa, Israel.
   [Raymond, Sean N.] CNRS, Lab Astrophys Bordeaux, UMR 5804, F-33270 Floirac, France.
   [Raymond, Sean N.] Univ Bordeaux, Lab Astrophys Bordeaux, UMR 5804, F-33270 Floirac, France.
C3 Technion Israel Institute of Technology; Universite de Bordeaux; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Universite de Bordeaux; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU)
RP Mastrobuono-Battisti, A (corresponding author), Technion Israel Inst Technol, Dept Phys, IL-32000 Haifa, Israel.
EM amastrobuono@physics.technion.ac.il; hperets@physics.technion.ac.il
FU BSF [2012384]; Minerva Center for Life under Extreme Planetary Conditions; ISF I-CORE [1829/12]; Marie Curie IRG [333644 'GRAND']; Agence Nationale pour la Recherche [ANR-13-BS05-0003-002]
NR 26
TC 61
Z9 72
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 APR 9
PY 2015
VL 520
IS 7546
BP 212
EP U165
DI 10.1038/nature14333
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CF3NA
UT WOS:000352454600037
PM 25855458
DA 2026-03-09
ER

PT J
AU Liu, WW
   Mazor, O
   Wilson, RI
AF Liu, Wendy W.
   Mazor, Ofer
   Wilson, Rachel I.
TI Thermosensory processing in the Drosophila brain
SO NATURE
LA English
DT Article
ID antennal lobe; central neurons; temperature; melanogaster; expression; avoidance; larval; tools
AB In Drosophila, just as in vertebrates, changes in external temperature are encoded by bidirectional opponent thermoreceptor cells: some cells are excited by warming and inhibited by cooling, whereas others are excited by cooling and inhibited by warming(1,2). The central circuits that process these signals are not understood. In Drosophila, a specific brain region receives input from thermoreceptor cells(2,3). Here we show that distinct genetically identified projection neurons (PNs) in this brain region are excited by cooling, warming, or both. The PNs excited by cooling receive mainly feed-forward excitation from cool thermoreceptors. In contrast, the PNs excited by warming ('warm-PNs') receive both excitation from warm thermoreceptors and crossover inhibition from cool thermoreceptors through inhibitory interneurons. Notably, this crossover inhibition elicits warming-evoked excitation, because warming suppresses tonic activity in cool thermoreceptors. This in turn disinhibits warm-PNs and sums with feed-forward excitation evoked by warming. Crossover inhibition could cancel non-thermal activity (noise) that is positively correlated among warm and cool thermoreceptor cells, while reinforcing thermal activity which is anti-correlated. Our results show how central circuits can combine signals from bidirectional opponent neurons to construct sensitive and robust neural codes.
C1 [Liu, Wendy W.; Mazor, Ofer; Wilson, Rachel I.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA.
   [Mazor, Ofer] Harvard Univ, Sch Med, Harvard NeuroDiscovery Ctr, Boston, MA 02115 USA.
C3 Harvard University; Harvard Medical School; Harvard University; Harvard Medical School
RP Wilson, RI (corresponding author), Harvard Univ, Sch Med, Dept Neurobiol, 220 Longwood Ave, Boston, MA 02115 USA.
EM rachel_wilson@hms.harvard.edu
FU NIH [R01 DC008174]; HHMI International Research Fellowship; MD-PhD Program at Harvard Medical School; National Eye Institute [P30EY012196] Funding Source: NIH RePORTER; National Institute on Deafness and Other Communication Disorders [R01DC008174] Funding Source: NIH RePORTER
NR 36
TC 74
Z9 95
U1 3
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 MAR 19
PY 2015
VL 519
IS 7543
BP 353
EP +
DI 10.1038/nature14170
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD6AY
UT WOS:000351171900041
PM 25739502
DA 2026-03-09
ER

PT J
AU Cargnello, M
   Johnston-Peck, AC
   Diroll, BT
   Wong, E
   Datta, B
   Damodhar, D
   Doan-Nguyen, VVT
   Herzing, AA
   Kagan, CR
   Murray, CB
AF Cargnello, Matteo
   Johnston-Peck, Aaron C.
   Diroll, Benjamin T.
   Wong, Eric
   Datta, Bianca
   Damodhar, Divij
   Doan-Nguyen, Vicky V. T.
   Herzing, Andrew A.
   Kagan, Cherie R.
   Murray, Christopher B.
TI Substitutional doping in nanocrystal superlattices
SO NATURE
LA English
DT Article
ID metal transition; conductivity; films
AB Doping is a process in which atomic impurities are intentionally added to a host material to modify its properties. It has had a revolutionary impact in altering or introducing electronic(1,2), magnetic(3,4), luminescent(5,6), and catalytic(7) properties for several applications, for example in semiconductors. Here we explore and demonstrate the extension of the concept of substitutional atomic doping to nanometre-scale crystal doping, in which one nanocrystal is used to replace another to form doped self-assembled superlattices. Towards this goal, we show that gold nanocrystals act as substitutional dopants in superlattices of cadmium selenide or lead selenide nanocrystals when the size of the gold nanocrystal is very close to that of the host. The gold nanocrystals occupy random positions in the superlattice and their density is readily and widely controllable, analogous to the case of atomic doping, but here through nanocrystal self-assembly. We also show that the electronic properties of the superlattices are highly tunable and strongly affected by the presence and density of the gold nanocrystal dopants. The conductivity of lead selenide films, for example, can be manipulated over at least six orders of magnitude by the addition of gold nanocrystals and is explained by a percolation model. As this process relies on the self-assembly of uniform nanocrystals, it can be generally applied to assemble a wide variety of nanocrystal-doped structures for electronic, optical, magnetic, and catalytic materials.
C1 [Cargnello, Matteo; Diroll, Benjamin T.; Kagan, Cherie R.; Murray, Christopher B.] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA.
   [Johnston-Peck, Aaron C.; Herzing, Andrew A.] NIST, Mat Measurement Lab, Gaithersburg, MD 20899 USA.
   [Wong, Eric] Univ Penn, Dept Phys, Philadelphia, PA 19104 USA.
   [Datta, Bianca; Damodhar, Divij; Doan-Nguyen, Vicky V. T.; Kagan, Cherie R.; Murray, Christopher B.] Univ Penn, Dept Mat Sci & Engn, Philadelphia, PA 19104 USA.
   [Kagan, Cherie R.] Univ Penn, Dept Elect & Syst Engn, Philadelphia, PA 19104 USA.
C3 University of Pennsylvania; National Institute of Standards & Technology (NIST) - USA; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania
RP Murray, CB (corresponding author), Univ Penn, Dept Chem, Philadelphia, PA 19104 USA.
EM cbmurray@sas.upenn.edu
FU Office of Naval Research MURI program [ONR-N00014-10-1-0942]; US Department of Energy Office of Basic Energy Sciences, Division of Materials Science and Engineering [DE-SC0002158]; National Research Council; US Department of Energy, Office of Basic Energy Sciences [DE-SC0012704]; Richard Perry University Professorship
NR 30
TC 187
Z9 232
U1 2
U2 358
PU NATURE PUBLISHING 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 27
PY 2015
VL 524
IS 7566
BP 450
EP +
DI 10.1038/nature14872
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP7LN
UT WOS:000360069300034
PM 26310766
DA 2026-03-09
ER

PT J
AU Wang, XX
   Ren, JS
   Gao, Q
   Hu, ZY
   Sun, Y
   Li, XM
   Rowlands, DJ
   Yin, WD
   Wang, JZ
   Stuart, DI
   Rao, ZH
   Fry, EE
AF Wang, Xiangxi
   Ren, Jingshan
   Gao, Qiang
   Hu, Zhongyu
   Sun, Yao
   Li, Xuemei
   Rowlands, David J.
   Yin, Weidong
   Wang, Junzhi
   Stuart, David I.
   Rao, Zihe
   Fry, Elizabeth E.
TI Hepatitis A virus and the origins of picornaviruses
SO NATURE
LA English
DT Article
ID capsid protein; crystal-structure; poliovirus; resolution; receptor; stability; model; site
AB Hepatitis A virus(HAV) remains enigmatic, despite 1.4 million cases worldwide annually(1). It differs radically from other picornaviruses, existing in an enveloped form(2) and being unusually stable, both genetically and physically(3), but has proved difficult to study. Here we report high-resolution X-ray structures for the mature virus and the empty particle. The structures of the two particles are indistinguishable, apart from some disorder on the inside of the empty particle. The full virus contains the small viral protein VP4, whereas the empty particle harbours only the uncleaved precursor, VP0. The smooth particle surface is devoid of depressions that might correspond to receptor-binding sites. Peptide scanning data extend the previously reported VP3 antigenic site4, while structure-based predictions(5) suggest further epitopes. HAV contains no pocket factor and can withstand remarkably high temperature and low pH, and empty particles are even more robust than full particles. The virus probably uncoats via a novel mechanism, being assembled differently to other picornaviruses. It utilizes a VP2 'domain swap' characteristic of insect picorna-like viruses(6,7), and structure-based phylogenetic analysis places HAV between typical picornaviruses and the insect viruses. The enigmatic properties of HAV may reflect its position as a link between 'modern' picornaviruses and the more 'primitive' precursor insect viruses; for instance, HAV retains the ability to move from cell-to-cell by transcytosis(8,9).
C1 [Wang, Xiangxi; Gao, Qiang; Sun, Yao; Li, Xuemei; Rao, Zihe] Chinese Acad Sci, Inst Biophys, Natl Lab Macromol, Beijing 100101, Peoples R China.
   [Ren, Jingshan; Stuart, David I.; Fry, Elizabeth E.] Univ Oxford, Div Struct Biol, Oxford OX3 7BN, England.
   [Gao, Qiang; Yin, Weidong] Sinovac Biotech Co Ltd, Beijing 100085, Peoples R China.
   [Hu, Zhongyu; Wang, Junzhi] Natl Inst Food & Drug Control, Beijing 100050, Peoples R China.
   [Rowlands, David J.] Univ Leeds, Inst Mol & Cellular Biol, Fac Biol Sci, Leeds LS2 9JT, W Yorkshire, England.
   [Rowlands, David J.] Univ Leeds, Astbury Ctr Struct Mol Biol, Fac Biol Sci, Leeds LS2 9JT, W Yorkshire, England.
   [Stuart, David I.] Diamond Light Sources, Didcot OX11 0DE, Oxon, England.
   [Rao, Zihe] Tsinghua Univ, Sch Med, Struct Biol Lab, Beijing 100084, Peoples R China.
   [Rao, Zihe] Nankai Univ, State Key Lab Med Chem Biol, Tianjin 300071, Peoples R China.
C3 Chinese Academy of Sciences; Institute of Biophysics, CAS; University of Oxford; National Institute of Food & Drug Control - China; University of Leeds; University of Leeds; Diamond Light Source; Tsinghua University; Nankai University
RP Stuart, DI (corresponding author), Univ Oxford, Div Struct Biol, Henry Wellcome Bldg Genomic Med, Oxford OX3 7BN, England.
EM wangjz@nicpbp.org.cn; dave@strubi.ox.ac.uk; raozh@xtal.tsinghua.edu.cn
FU Chinese Academy of Sciences [XDB08020200]; Ministry of Science and Technology 973 Project [2014CB542800]; National Major Project of Infectious Disease [2012ZX10004701]; National Science Foundation [81330036]; MRC [MR/N00065X/1, G19/3, G1000099] Funding Source: UKRI; STFC [ST/J001465/1] Funding Source: UKRI; Medical Research Council [G1100525, MR/N00065X/1, G19/3, G1000099] Funding Source: researchfish; Science and Technology Facilities Council [ST/J001465/1] Funding Source: researchfish
NR 39
TC 149
Z9 171
U1 0
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 JAN 1
PY 2015
VL 517
IS 7532
BP 85
EP U214
DI 10.1038/nature13806
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AX8SI
UT WOS:000347178400040
PM 25327248
DA 2026-03-09
ER

PT J
AU Hamilton, DP
   Skrutskie, MF
   Verbiscer, AJ
   Masci, FJ
AF Hamilton, Douglas P.
   Skrutskie, Michael F.
   Verbiscer, Anne J.
   Masci, Frank J.
TI Small particles dominate Saturn's Phoebe ring to surprisingly large distances
SO NATURE
LA English
DT Article
ID jupiters gossamer rings; radiation forces; dust; satellites; dynamics; galileo; fields; fate
AB Saturn's faint outermost ring, discovered in 2009 (ref. 1), is probably formed by particles ejected from the distant moon Phoebe(2,3). The ring was detected(1) between distances of 128 and 207 Saturn radii (R-S 5 60,330 kilometres) from the planet, with a full vertical extent of 40R(S), making it well over ten times larger than Saturn's hitherto largest known ring, the E ring. The total radial extent of the Phoebe ring could not, however, be determined at that time, nor could particle sizes be significantly constrained. Here we report infrared imaging of the entire ring, which extends from 100R(S) out to a surprisingly distant 270R(S). We model the orbital dynamics of ring particles launched from Phoebe, and construct theoretical power-law profiles of the particle size distribution. We find that very steep profiles fit the data best, and that elevated grain temperatures, arising because of the radiative inefficiency of the smallest grains, probably contribute to the steepness. By converting our constraint on particle sizes into a form that is independent of the uncertain size distribution, we determine that particles with radii greater than ten centimetres, whose orbits do not decay appreciably inward over 4.5 billion years, contribute at most about ten per cent to the cross-sectional area of the ring's dusty component.
C1 [Hamilton, Douglas P.] Univ Maryland, Dept Astron, College Pk, MD 20742 USA.
   [Skrutskie, Michael F.; Verbiscer, Anne J.] Univ Virginia, Dept Astron, Charlottesville, VA 22904 USA.
   [Masci, Frank J.] CALTECH, Ctr Infrared Proc & Anal, Pasadena, CA 91125 USA.
C3 University System of Maryland; University of Maryland College Park; University of Virginia; California Institute of Technology
RP Hamilton, DP (corresponding author), Univ Maryland, Dept Astron, College Pk, MD 20742 USA.
EM dphamil@umd.edu
FU National Aeronautics and Space Administration; NASA Outer Planets and Origins
NR 17
TC 18
Z9 19
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 JUN 11
PY 2015
VL 522
IS 7555
BP 185
EP +
DI 10.1038/nature14476
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700032
PM 26062508
DA 2026-03-09
ER

PT J
AU Wagenblast, E
   Soto, M
   Gutiérrez-Angel, S
   Hartl, CA
   Gable, AL
   Maceli, AR
   Erard, N
   Williams, AM
   Kim, SY
   Dickopf, S
   Harrell, JC
   Smith, AD
   Perou, CM
   Wilkinson, JE
   Hannon, GJ
   Knott, SRV
AF Wagenblast, Elvin
   Soto, Mar
   Gutierrez-Angel, Sara
   Hartl, Christina A.
   Gable, Annika L.
   Maceli, Ashley R.
   Erard, Nicolas
   Williams, Alissa M.
   Kim, Sun Y.
   Dickopf, Steffen
   Harrell, J. Chuck
   Smith, Andrew D.
   Perou, Charles M.
   Wilkinson, John E.
   Hannon, Gregory J.
   Knott, Simon R. V.
TI A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis
SO NATURE
LA English
DT Article
ID vasculogenic mimicry; genomic analysis; tumor; mammary; cells; survival; origins; brain; slpi
AB Cancer metastasis requires that primary tumour cells evolve the capacity to intravasate into the lymphatic system or vasculature, and extravasate into and colonize secondary sites(1). Others have demonstrated that individual cells within complex populations show heterogeneity in their capacity to form secondary lesions(2-5). Here we develop a polyclonal mouse model of breast tumour heterogeneity, and show that distinct clones within a mixed population display specialization, for example, dominating the primary tumour, contributing to metastatic populations, or showing tropism for entering the lymphatic or vasculature systems. We correlate these stable properties to distinct gene expression profiles. Those clones that efficiently enter the vasculature express two secreted proteins, Serpine2 and Slpi, which were necessary and sufficient to program these cells for vascular mimicry. Our data indicate that these proteins not only drive the formation of extravascular networks but also ensure their perfusion by acting as anticoagulants. We propose that vascular mimicry drives the ability of some breast tumour cells to contribute to distant metastases while simultaneously satisfying a critical need of the primary tumour to be fed by the vasculature. Enforced expression of SERPINE2 and SLPI in human breast cancer cell lines also programmed them for vascular mimicry, and SERPINE2 and SLPI were overexpressed preferentially in human patients that had lung-metastatic relapse. Thus, these two secreted proteins, and the phenotype they promote, may be broadly relevant as drivers of metastatic progression in human cancer.
C1 [Wagenblast, Elvin; Soto, Mar; Gutierrez-Angel, Sara; Hartl, Christina A.; Gable, Annika L.; Maceli, Ashley R.; Erard, Nicolas; Williams, Alissa M.; Kim, Sun Y.; Dickopf, Steffen; Hannon, Gregory J.; Knott, Simon R. V.] Cold Spring Harbor Lab, Howard Hughes Med Inst, Watson Sch Biol Sci, Cold Spring Harbor, NY 11724 USA.
   [Erard, Nicolas; Hannon, Gregory J.; Knott, Simon R. V.] Univ Cambridge, Li Ka Shing Ctr, CRUK Cambridge Inst, Cambridge CB2 0RE, England.
   [Harrell, J. Chuck; Perou, Charles M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Genet & Pathol, Chapel Hill, NC 27599 USA.
   [Smith, Andrew D.] Univ So Calif, Mol & Computat Biol, Los Angeles, CA 90089 USA.
   [Wilkinson, John E.] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA.
C3 Cold Spring Harbor Laboratory; Howard Hughes Medical Institute; CRUK Cambridge Institute; University of Cambridge; University of North Carolina; University of North Carolina Chapel Hill; University of Southern California; University of Michigan System; University of Michigan
RP Hannon, GJ (corresponding author), Cold Spring Harbor Lab, Howard Hughes Med Inst, Watson Sch Biol Sci, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA.
EM hannon@cshl.edu
FU Howard Hughes Medical Institute; NIH; Cancer Center [5P30CA045508]; Boehringer Ingelheim Fonds; NCI Breast SPORE program [P50-CA58223-09A1]; Breast Cancer Research Foundation; Triple Negative Breast Cancer Foundation; Hope Funds For Cancer Research; Div Of Biological Infrastructure; Direct For Biological Sciences [1156643] Funding Source: National Science Foundation; National Cancer Institute [P01CA013106, P30CA045508, P50CA058223] Funding Source: NIH RePORTER; Cancer Research UK [21143] Funding Source: researchfish
NR 26
TC 333
Z9 393
U1 2
U2 137
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 16
PY 2015
VL 520
IS 7547
BP 358
EP +
DI 10.1038/nature14403
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG0RI
UT WOS:000352974200041
PM 25855289
DA 2026-03-09
ER

PT J
AU Hite, RK
   Yuan, P
   Li, ZL
   Hsuing, YC
   Walz, T
   MacKinnon, R
AF Hite, Richard K.
   Yuan, Peng
   Li, Zongli
   Hsuing, Yichun
   Walz, Thomas
   MacKinnon, Roderick
TI Cryo-electron microscopy structure of the Slo2.2 Na+-activated K+ channel
SO NATURE
LA English
DT Article
ID migrating partial seizures; gated potassium channel; crystal-structure; cryo-em; sensory neurons; bk channels; angstrom resolution; kcnt1 mutation; gating ring; sodium
AB Na+-activated K+ channels are members of the Slo family of large conductance K+ channels that are widely expressed in the brain, where their opening regulates neuronal excitability. These channels fulfil a number of biological roles and have intriguing biophysical properties, including conductance levels that are ten times those of most other K+ channels and gating sensitivity to intracellular Na+. Here we present the structure of a complete Na+-activated K+ channel, chicken Slo2.2, in the Na+-free state, determined by cryo-electron microscopy at a nominal resolution of 4.5 angstroms. The channel is composed of a large cytoplasmic gating ring, in which resides the Na+-binding site and a transmembrane domain that closely resembles voltage-gated K+ channels. In the structure, the cytoplasmic domain adopts a closed conformation and the ion conduction pore is also closed. The structure reveals features that can explain the unusually high conductance of Slo channels and how contraction of the cytoplasmic gating ring closes the pore.
C1 [Hite, Richard K.; Yuan, Peng; Hsuing, Yichun; MacKinnon, Roderick] Rockefeller Univ, New York, NY 10065 USA.
   [Hite, Richard K.; Yuan, Peng; Hsuing, Yichun; MacKinnon, Roderick] Howard Hughes Med Inst, New York, NY 10065 USA.
   [Li, Zongli; Walz, Thomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA.
   [Li, Zongli; Walz, Thomas] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA.
C3 Rockefeller University; Howard Hughes Medical Institute; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Howard Hughes Medical Institute
RP MacKinnon, R (corresponding author), Rockefeller Univ, 1230 York Ave, New York, NY 10065 USA.
EM mackinn@rockefeller.edu
FU National Science Foundation [ACI-1053575];  [GM43949]; National Institute of General Medical Sciences [R01GM043949] Funding Source: NIH RePORTER
NR 72
TC 93
Z9 112
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 12
PY 2015
VL 527
IS 7577
BP 198
EP +
DI 10.1038/nature14958
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700037
PM 26436452
DA 2026-03-09
ER

PT J
AU Lee, HY
   Gao, XF
   Barrasa, MI
   Li, H
   Elmes, RR
   Peters, LL
   Lodish, HF
AF Lee, Hsiang-Ying
   Gao, Xiaofei
   Barrasa, M. Inmaculada
   Li, Hu
   Elmes, Russell R.
   Peters, Luanne L.
   Lodish, Harvey F.
TI PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal
SO NATURE
LA English
DT Article
ID diamond-blackfan anemia; transcription factors; erythropoiesis; identification; superfamily; deficiency; therapy; acid; gene; mice
AB Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production(1-9). Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells(10,11). Here we show that activation of the peroxisome proliferator-activated receptor alpha (PPAR-alpha) by the PPAR-alpha agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34(+) peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara(-/-) mice show no haematological difference from wild-typemice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-alpha agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-alpha alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid- treated BFU-E cells, PPAR-alpha co-occupies many chromatin sites with GR; when activated by PPAR-alpha agonists, additional PPAR-alpha is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-alpha agonists in stimulating self-renewal of early erythroid progenitor cells suggests that the clinically tested PPAR-alpha agonists we used may improve the efficacy of corticosteroids in treating Epo-resistant anaemias.
C1 [Lee, Hsiang-Ying; Gao, Xiaofei; Barrasa, M. Inmaculada; Elmes, Russell R.; Lodish, Harvey F.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA.
   [Li, Hu] Mayo Clin, Ctr Individualized Med, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA.
   [Peters, Luanne L.] Jackson Lab, Bar Harbor, ME 04609 USA.
   [Lodish, Harvey F.] MIT, Dept Biol, Cambridge, MA 02139 USA.
   [Lodish, Harvey F.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA.
C3 Massachusetts Institute of Technology (MIT); Whitehead Institute; Mayo Clinic; Jackson Laboratory; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT)
RP Lodish, HF (corresponding author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA.
EM lodish@wi.mit.edu
FU Defense Advanced Research Projects Agency [HR0011-14-2-0005]; Department of Defense/US Army Medical Research and Materiel Command [W81WH-12-1-0449]; National institutes of Health (NIH)/National Heart, Lung, and Blood Institute [2 P01 HL032262-25]; Diamond-Blackfan Anemia Foundation; Diamond Blackfan Anemia Canada; NIH [DK100692]; Leukemia and Lymphoma Society; National Cancer Institute [P30CA034196] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [P01HL032262] Funding Source: NIH RePORTER; Div Of Biological Infrastructure; Direct For Biological Sciences [1262049] Funding Source: National Science Foundation
NR 30
TC 120
Z9 154
U1 0
U2 54
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 25
PY 2015
VL 522
IS 7557
BP 474
EP +
DI 10.1038/nature14326
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL2OC
UT WOS:000356782900049
PM 25970251
DA 2026-03-09
ER

PT J
AU Buizert, C
   Adrian, B
   Ahn, J
   Albert, M
   Alley, RB
   Baggenstos, D
   Bauska, TK
   Bay, RC
   Bencivengo, BB
   Bentley, CR
   Brook, EJ
   Chellman, NJ
   Clow, GD
   Cole-Dai, J
   Conway, H
   Cravens, E
   Cuffey, KM
   Dunbar, NW
   Edwards, JS
   Fegyveresi, JM
   Ferris, DG
   Fitzpatrick, JJ
   Fudge, TJ
   Gibson, CJ
   Gkinis, V
   Goetz, JJ
   Gregory, S
   Hargreaves, GM
   Iverson, N
   Johnson, JA
   Jones, TR
   Kalk, ML
   Kippenhan, MJ
   Koffman, BG
   Kreutz, K
   Kuhl, TW
   Lebar, DA
   Lee, JE
   Marcott, SA
   Markle, BR
   Maselli, OJ
   McConnell, JR
   McGwire, KC
   Mitchell, LE
   Mortensen, NB
   Neff, PD
   Nishiizumi, K
   Nunn, RM
   Orsi, AJ
   Pasteris, DR
   Pedro, JB
   Pettit, EC
   Price, PB
   Priscu, JC
   Rhodes, RH
   Rosen, JL
   Schauer, AJ
   Schoenemann, SW
   Sendelbach, PJ
   Severinghaus, JP
   Shturmakov, AJ
   Sigl, M
   Slawny, KR
   Souney, JM
   Sowers, TA
   Spencer, MK
   Steig, EJ
   Taylor, KC
   Twickler, MS
   Vaughn, BH
   Voigt, DE
   Waddington, ED
   Welten, KC
   Wendricks, AW
   White, JWC
   Winstrup, M
   Wong, GJ
   Woodruff, TE
AF Buizert, Christo
   Adrian, Betty
   Ahn, Jinho
   Albert, Mary
   Alley, Richard B.
   Baggenstos, Daniel
   Bauska, Thomas K.
   Bay, Ryan C.
   Bencivengo, Brian B.
   Bentley, Charles R.
   Brook, Edward J.
   Chellman, Nathan J.
   Clow, Gary D.
   Cole-Dai, Jihong
   Conway, Howard
   Cravens, Eric
   Cuffey, Kurt M.
   Dunbar, Nelia W.
   Edwards, Jon S.
   Fegyveresi, John M.
   Ferris, Dave G.
   Fitzpatrick, Joan J.
   Fudge, T. J.
   Gibson, Chris J.
   Gkinis, Vasileios
   Goetz, Joshua J.
   Gregory, Stephanie
   Hargreaves, Geoffrey M.
   Iverson, Nels
   Johnson, Jay A.
   Jones, Tyler R.
   Kalk, Michael L.
   Kippenhan, Matthew J.
   Koffman, Bess G.
   Kreutz, Karl
   Kuhl, Tanner W.
   Lebar, Donald A.
   Lee, James E.
   Marcott, Shaun A.
   Markle, Bradley R.
   Maselli, Olivia J.
   McConnell, Joseph R.
   McGwire, Kenneth C.
   Mitchell, Logan E.
   Mortensen, Nicolai B.
   Neff, Peter D.
   Nishiizumi, Kunihiko
   Nunn, Richard M.
   Orsi, Anais J.
   Pasteris, Daniel R.
   Pedro, Joel B.
   Pettit, Erin C.
   Price, P. Buford
   Priscu, John C.
   Rhodes, Rachael H.
   Rosen, Julia L.
   Schauer, Andrew J.
   Schoenemann, Spruce W.
   Sendelbach, Paul J.
   Severinghaus, Jeffrey P.
   Shturmakov, Alexander J.
   Sigl, Michael
   Slawny, Kristina R.
   Souney, Joseph M.
   Sowers, Todd A.
   Spencer, Matthew K.
   Steig, Eric J.
   Taylor, Kendrick C.
   Twickler, Mark S.
   Vaughn, Bruce H.
   Voigt, Donald E.
   Waddington, Edwin D.
   Welten, Kees C.
   Wendricks, Anthony W.
   White, James W. C.
   Winstrup, Mai
   Wong, Gifford J.
   Woodruff, Thomas E.
TI Precise interpolar phasing of abrupt climate change during the last ice age
SO NATURE
LA English
DT Article
ID antarctic ice; chronology aicc2012; atmospheric co2; bipolar seesaw; core record; wais divide; polar ice; greenland; air; scale
AB The last glacial period exhibited abrupt Dansgaard-Oeschger climatic oscillations, evidence of which is preserved in a variety of Northern Hemisphere palaeodimate archives'. Ice cores show that Antarctica cooled during the warm phases of the Greenland Dansgaard-Oeschger cycle and vice versa''', suggesting an interhemispheric redistribution of heat through a mechanism called the bipolar seesaw(4-6). Variations in the Atlantic meridional overturning circulation (AMOC) strength are thought to have been important, but much uncertainty remains regarding the dynamics and trigger of these abrupt events'. Key information is contained in the relative phasing of hemispheric climate variations, yet the large, poorly constrained difference between gas age and ice age and the relatively low resolution of methane records from Antarctic ice cores have so far precluded methane-based synchronization at the required sub-centennial precision''''". Here we use a recently drilled high-accumulation Antarctic ice core to show that, on average, abrupt Greenland warming leads the corresponding Antarctic cooling onset by 218 +/- 92 years (2 sigma a) for DansgaardOeschger events, including the Bolling event; Greenland cooling leads the corresponding onset of Antarctic warming by 208 +/- 96 years. Our results demonstrate a north-to-south directionality of the abrupt climatic signal, which is propagated to the Southern Hemisphere high latitudes by oceanic rather than atmospheric processes. The similar interpolar phasing of warming and cooling transitions suggests that the transfer time of the climatic signal is independent of the AMOC background state. Our findings confirm a central role for ocean circulation in the bipolar seesaw and provide clear criteria for assessing hypotheses and model simulations of Dansgaard-Oeschger dynamics.
C1 [Buizert, Christo; Bauska, Thomas K.; Brook, Edward J.; Edwards, Jon S.; Kalk, Michael L.; Lee, James E.; Marcott, Shaun A.; Mitchell, Logan E.; Rhodes, Rachael H.; Rosen, Julia L.] Oregon State Univ, Coll Earth Ocean & Atmospher Sci, Corvallis, OR 97331 USA.
   [Adrian, Betty; Bencivengo, Brian B.; Hargreaves, Geoffrey M.; Nunn, Richard M.] US Geol Survey, Natl Ice Core Lab, Denver, CO 80225 USA.
   [Ahn, Jinho] Seoul Natl Univ, Sch Earth & Environm Sci, Seoul 151742, South Korea.
   [Albert, Mary; Gregory, Stephanie] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA.
   [Alley, Richard B.; Fegyveresi, John M.; Sowers, Todd A.; Voigt, Donald E.] Penn State Univ, Dept Geosci, University Pk, PA 16802 USA.
   [Baggenstos, Daniel; Orsi, Anais J.; Severinghaus, Jeffrey P.] Univ Calif San Diego, Scripps Inst Oceanog, La Jolla, CA 92093 USA.
   [Bay, Ryan C.; Price, P. Buford] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Bentley, Charles R.; Gibson, Chris J.; Goetz, Joshua J.; Johnson, Jay A.; Kuhl, Tanner W.; Lebar, Donald A.; Mortensen, Nicolai B.; Sendelbach, Paul J.; Shturmakov, Alexander J.; Slawny, Kristina R.; Wendricks, Anthony W.] Univ Wisconsin, Ice Drilling Design & Operat, Madison, WI 53706 USA.
   [Chellman, Nathan J.; Maselli, Olivia J.; McConnell, Joseph R.; McGwire, Kenneth C.; Pasteris, Daniel R.; Sigl, Michael; Taylor, Kendrick C.] Nevada Syst Higher Educ, Desert Res Inst, Reno, NV 89512 USA.
   [Clow, Gary D.] US Geol Survey, Boulder, CO 80309 USA.
   [Cole-Dai, Jihong; Ferris, Dave G.] S Dakota State Univ, Dept Chem & Biochem, Brookings, SD 57007 USA.
   [Conway, Howard; Fudge, T. J.; Markle, Bradley R.; Schauer, Andrew J.; Schoenemann, Spruce W.; Steig, Eric J.; Waddington, Edwin D.; Winstrup, Mai] Univ Washington, Dept Earth & Space Sci, Seattle, WA 98195 USA.
   [Cravens, Eric] ADC Management Serv, Lakewood, CO 80226 USA.
   [Cuffey, Kurt M.] Univ Calif Berkeley, Dept Geog, Berkeley, CA 94709 USA.
   [Dunbar, Nelia W.; Iverson, Nels] New Mexico Inst Min & Technol, Earth & Environm Sci Dept, Socorro, NM 87801 USA.
   [Fitzpatrick, Joan J.] US Geol Survey, Denver, CO 80225 USA.
   [Gkinis, Vasileios; Jones, Tyler R.; Vaughn, Bruce H.; White, James W. C.] Univ Colorado, Inst Arctic & Alpine Res, Boulder, CO 80309 USA.
   [Gkinis, Vasileios; Pedro, Joel B.; Winstrup, Mai] Univ Copenhagen, Ctr Ice & Climate, DK-2100 Copenhagen O, Denmark.
   [Kippenhan, Matthew J.] Antarctic Support Contract, Lockheed Martin US Antarctic Program, Centennial, CO 80112 USA.
   [Koffman, Bess G.] Columbia Univ, Lamont Doherty Earth Observ, Palisades, NY 10964 USA.
   [Kreutz, Karl] Univ Maine, Climate Change Inst, Orono, ME 04469 USA.
   [Kreutz, Karl] Univ Maine, Sch Earth & Climate Sci, Orono, ME 04469 USA.
   [Marcott, Shaun A.] Univ Wisconsin, Madison, WI 53706 USA.
   [Neff, Peter D.] Victoria Univ Wellington, Antarctic Res Ctr, Wellington 6012, New Zealand.
   [Nishiizumi, Kunihiko; Welten, Kees C.] Univ Calif Berkeley, Space Sci Lab, Berkeley, CA 94720 USA.
   [Orsi, Anais J.] Inst Pierre Simon Laplace, Lab Sci Climat & Environm, F-91191 Gif Sur Yvette, France.
   [Pedro, Joel B.] Univ Washington, Joint Inst Study Atmosphere & Oceans, Seattle, WA 98195 USA.
   [Pettit, Erin C.] Univ Alaska Fairbanks, Dept Geosci, Fairbanks, AK 99775 USA.
   [Priscu, John C.] Montana State Univ, Dept Land Resources & Environm Sci, Bozeman, MT 59717 USA.
   [Souney, Joseph M.; Twickler, Mark S.] Univ New Hampshire, Inst Study Earth Oceans & Space, Durham, NH 03824 USA.
   [Spencer, Matthew K.] Lake Super State Univ, Sch Phys Sci, Sault Sainte Marie, MI 49783 USA.
   [Wong, Gifford J.] Dartmouth Coll, Dept Earth Sci, Hanover, NH 03755 USA.
   [Woodruff, Thomas E.] Purdue Univ, PRIME Lab, W Lafayette, IN 47907 USA.
C3 Oregon State University; United States Department of the Interior; United States Geological Survey; Seoul National University (SNU); Dartmouth College; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; University of California System; University of California San Diego; Scripps Institution of Oceanography; University of California System; University of California Berkeley; University of Wisconsin System; University of Wisconsin Madison; Nevada System of Higher Education (NSHE); Desert Research Institute NSHE; United States Department of the Interior; United States Geological Survey; South Dakota State University; University of Washington; University of Washington Seattle; University of California System; University of California Berkeley; New Mexico Institute of Mining Technology; United States Department of the Interior; United States Geological Survey; University of Colorado System; University of Colorado Boulder; University of Copenhagen; Columbia University; University of Maine System; University of Maine Orono; University of Maine System; University of Maine Orono; University of Wisconsin System; University of Wisconsin Madison; Victoria University Wellington; University of California System; University of California Berkeley; Universite Paris Saclay; University of Washington; University of Washington Seattle; University of Alaska System; University of Alaska Fairbanks; Montana State University System; Montana State University Bozeman; University System Of New Hampshire; University of New Hampshire; Lake Superior State University; Dartmouth College; Purdue University System; Purdue University
RP Buizert, C (corresponding author), Oregon State Univ, Coll Earth Ocean & Atmospher Sci, Corvallis, OR 97331 USA.
EM buizertc@science.oregonstate.edu
FU US National Science foundation [0944078, 0841308, 1043528, 1142173, 1204172, 1142041, 1043518, 0839066, 0087345, 0944191, 0539232, 0537661, 1142069, 1142115, 0841135, 0839093, 1142166]; USGS Climate and Land Use Change Program; NOM Climate and Global Change Fellowship Program; illum Foundation; Joint Institute for the Study of the Atmosphere and Ocean; Korea Polar Research Institute [PE15010]; WAIS Divide Science Coordination Office at the Desert Research Institute of Nevada; Ice Drilling Program Office and Ice Drilling Design and Operations group for coring activities; NICL; Raytheon Polar Services for logistics support in Antarctica; 109th New York Air National Guard for airlift in Antarctica; The US National Science foundation [1142164, 1142178, 0538657, 1043500, 0944584, 1043313, 0537930, 1043092, 0230149, 0230396, 0440817, 0440819, 0944348, 0944266, 0839137, 0537593, 1043167]; Directorate For Geosciences; Division Of Polar Programs [0440819, 0944191, 0440817] Funding Source: National Science Foundation; Directorate For Geosciences; Division Of Polar Programs [0230396, 0230149] Funding Source: National Science Foundation; EPSCoR; Office Of The Director [1101245] Funding Source: National Science Foundation; Office of Polar Programs (OPP); Directorate For Geosciences [1443328, 1142115, 1142166, 1043518, 0944348, 1043092, 0944197] Funding Source: National Science Foundation; Office of Polar Programs (OPP); Directorate For Geosciences [1142173, 1043167, 1142041, 1142069, 1043528, 1043421, 1043508, 1142178] Funding Source: National Science Foundation; Office Of The Director; Office Of Internatl Science &Engineering [0968391] Funding Source: National Science Foundation; National Health and Medical Research Council (NHMRC) [1043092] Funding Source: National Health and Medical Research Council (NHMRC)
NR 69
TC 285
Z9 327
U1 9
U2 351
PU NATURE PUBLISHING 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 30
PY 2015
VL 520
IS 7549
BP 661
EP U169
DI 10.1038/nature14401
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700046
PM 25925479
DA 2026-03-09
ER

PT J
AU Wan, CH
   Borgeson, B
   Phanse, S
   Tu, F
   Drew, K
   Clark, G
   Xiong, XJ
   Kagan, O
   Kwan, J
   Bezginov, A
   Chessman, K
   Pal, S
   Cromar, G
   Papoulas, O
   Ni, ZY
   Boutz, DR
   Stoilova, S
   Havugimana, PC
   Guo, XH
   Malty, RH
   Sarov, M
   Greenblatt, J
   Babu, M
   Derry, WB
   Tillier, ER
   Wallingford, JB
   Parkinson, J
   Marcotte, EM
   Emili, A
AF Wan, Cuihong
   Borgeson, Blake
   Phanse, Sadhna
   Tu, Fan
   Drew, Kevin
   Clark, Greg
   Xiong, Xuejian
   Kagan, Olga
   Kwan, Julian
   Bezginov, Alexandr
   Chessman, Kyle
   Pal, Swati
   Cromar, Graham
   Papoulas, Ophelia
   Ni, Zuyao
   Boutz, Daniel R.
   Stoilova, Snejana
   Havugimana, Pierre C.
   Guo, Xinghua
   Malty, Ramy H.
   Sarov, Mihail
   Greenblatt, Jack
   Babu, Mohan
   Derry, W. Brent
   Tillier, Elisabeth R.
   Wallingford, John B.
   Parkinson, John
   Marcotte, Edward M.
   Emili, Andrew
TI Panorama of ancient metazoan macromolecular complexes
SO NATURE
LA English
DT Article
ID protein-interaction; interaction network; yeast; gene; interactome; map; resource; commd1; size; cell
AB Macromolecular complexes are essential to conserved biological processes, but their prevalence across animals is unclear. By combining extensive biochemical fractionation with quantitative mass spectrometry, here we directly examined the composition of soluble multiprotein complexes among diverse metazoan models. Using an integrative approach, we generated a draft conservation map consisting of more than one million putative high-confidence co-complex interactions for species with fully sequenced genomes that encompasses functional modules present broadly across all extant animals. Clustering reveals a spectrum of conservation, ranging from ancient eukaryotic assemblies that have probably served cellular housekeeping roles for at least one billion years, ancestral complexes that have accrued contemporary components, and rarer metazoan innovations linked to multicellularity. We validated these projections by independent co-fractionation experiments in evolutionarily distant species, affinity purification and functional analyses. The comprehensiveness, centrality and modularity of these reconstructed interactomes reflect their fundamental mechanistic importance and adaptive value to animal cell systems.
C1 [Wan, Cuihong; Phanse, Sadhna; Kagan, Olga; Kwan, Julian; Ni, Zuyao; Stoilova, Snejana; Havugimana, Pierre C.; Guo, Xinghua; Greenblatt, Jack; Emili, Andrew] Univ Toronto, Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada.
   [Wan, Cuihong; Borgeson, Blake; Tu, Fan; Drew, Kevin; Papoulas, Ophelia; Boutz, Daniel R.; Wallingford, John B.; Marcotte, Edward M.] Univ Texas Austin, Inst Cellular & Mol Biol, Ctr Syst & Synthet Biol, Austin, TX 78712 USA.
   [Clark, Greg; Bezginov, Alexandr; Tillier, Elisabeth R.] Dept Med Biophys, Toronto, ON M5G 1L7, Canada.
   [Xiong, Xuejian; Kwan, Julian; Chessman, Kyle; Cromar, Graham; Greenblatt, Jack; Derry, W. Brent; Parkinson, John; Emili, Andrew] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.
   [Xiong, Xuejian; Chessman, Kyle; Pal, Swati; Cromar, Graham; Derry, W. Brent; Parkinson, John] Hosp Sick Children, Toronto, ON M5G 1X8, Canada.
   [Malty, Ramy H.; Babu, Mohan] Univ Regina, Dept Biochem, Regina, SK S4S 0A2, Canada.
   [Sarov, Mihail] Max Planck Inst Mol Cell Biol & Genet, D-01307 Dresden, Germany.
   [Wallingford, John B.; Marcotte, Edward M.] Univ Texas Austin, Dept Mol Biosci, Austin, TX 78712 USA.
C3 University of Toronto; University of Texas System; University of Texas Austin; University of Toronto; University of Toronto; Hospital for Sick Children (SickKids); University of Regina; Max Planck Society; University of Texas System; University of Texas Austin
RP Marcotte, EM (corresponding author), Univ Texas Austin, Inst Cellular & Mol Biol, Ctr Syst & Synthet Biol, Austin, TX 78712 USA.
EM marcotte@icmb.utexas.edu; andrew.emili@utoronto.ca
FU CIHR; NSERC; ORF; CFI; Heart and Stroke; NIH [F32GM112495]; NIH; NSF; CPRIT; Welch Foundation [F-1515]; Direct For Biological Sciences [1237975] Funding Source: National Science Foundation; Division Of Integrative Organismal Systems [1237975] Funding Source: National Science Foundation
NR 48
TC 402
Z9 478
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 SEP 17
PY 2015
VL 525
IS 7569
BP 339
EP +
DI 10.1038/nature14877
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900035
PM 26344197
DA 2026-03-09
ER

PT J
AU Kovachy, T
   Asenbaum, P
   Overstreet, C
   Donnelly, CA
   Dickerson, SM
   Sugarbaker, A
   Hogan, JM
   Kasevich, MA
AF Kovachy, T.
   Asenbaum, P.
   Overstreet, C.
   Donnelly, C. A.
   Dickerson, S. M.
   Sugarbaker, A.
   Hogan, J. M.
   Kasevich, M. A.
TI Quantum superposition at the half-metre scale
SO NATURE
LA English
DT Article
ID choice gedanken experiment; atomic interferometry; light; time
AB The quantum superposition principle allows massive particles to be delocalized over distant positions. Though quantum mechanics has proved adept at describing the microscopic world, quantum superposition runs counter to intuitive conceptions of reality and locality when extended to the macroscopic scale(1), as exemplified by the thought experiment of Schrodinger's cat(2). Matter-wave interferometers(3), which split and recombine wave packets in order to observe interference, provide a way to probe the superposition principle on macroscopic scales(4) and explore the transition to classical physics(5). In such experiments, large wave-packet separation is impeded by the need for long interaction times and large momentum beam splitters, which cause susceptibility to dephasing and decoherence(1). Here we use light-pulse atom interferometry(6,7) to realize quantum interference with wave packets separated by up to 54 centimetres on a timescale of 1 second. These results push quantum superposition into a new macroscopic regime, demonstrating that quantum superposition remains possible at the distances and timescales of everyday life. The sub-nanokelvin temperatures of the atoms and a compensation of transverse optical forces enable a large separation while maintaining an interference contrast of 28 per cent. In addition to testing the superposition principle in a new regime, large quantum superposition states are vital to exploring gravity with atom interferometers in greater detail. We anticipate that these states could be used to increase sensitivity in tests of the equivalence principle(8-12), measure the gravitational Aharonov-Bohm effect(13), and eventually detect gravitational waves(14) and phase shifts associated with general relativity(12).
C1 [Kovachy, T.; Asenbaum, P.; Overstreet, C.; Donnelly, C. A.; Dickerson, S. M.; Sugarbaker, A.; Hogan, J. M.; Kasevich, M. A.] Stanford Univ, Dept Phys, Stanford, CA 94305 USA.
C3 Stanford University
RP Kasevich, MA (corresponding author), Stanford Univ, Dept Phys, Stanford, CA 94305 USA.
EM kasevich@stanford.edu
FU Fannie and John Hertz Foundation; NSF GRFP; Stanford Graduate Fellowship; NASA GSFC [NNX11AM31A]; NASA [142502, NNX11AM31A] Funding Source: Federal RePORTER
NR 44
TC 314
Z9 361
U1 3
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 DEC 24
PY 2015
VL 528
IS 7583
BP 530
EP +
DI 10.1038/nature16155
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900047
PM 26701053
DA 2026-03-09
ER

PT J
AU Rosa, A
   Chande, A
   Ziglio, S
   De Sanctis, V
   Bertorelli, R
   Goh, SL
   McCauley, SM
   Nowosielska, A
   Antonarakis, SE
   Luban, J
   Santoni, FA
   Pizzato, M
AF Rosa, Annachiara
   Chande, Ajit
   Ziglio, Serena
   De Sanctis, Veronica
   Bertorelli, Roberto
   Goh, Shih Lin
   McCauley, Sean M.
   Nowosielska, Anetta
   Antonarakis, Stylianos E.
   Luban, Jeremy
   Santoni, Federico Andrea
   Pizzato, Massimo
TI HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation
SO NATURE
LA English
DT Article
ID optimal viral infectivity; virus type-1 infectivity; cd4 down-regulation; t-cell-activation; immunodeficiency-virus; syncytium formation; glycosylated-gag; pore expansion; fusion; gene
AB HIV-1 Nef, a protein important for the development of AIDS, has well-characterized effects on host membrane trafficking and receptor downregulation. By an unidentified mechanism, Nef increases the intrinsic infectivity of HIV-1 virions in a host-cell-dependent manner. Here we identify the host transmembrane protein SERINC5, and to a lesser extent SERINC3, as a potent inhibitor of HIV-1 particle infectivity that is counteracted by Nef. SERINC5 localizes to the plasma membrane, where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. Nef redirects SERINC5 to a Rab7-positive endosomal compartment and thereby excludes it from HIV-1 particles. The ability to counteract SERINC5 was conserved in Nef encoded by diverse primate immunodeficiency viruses, as well as in the structurally unrelated glycosylated Gag from murine leukaemia virus. These examples of functional conservation and convergent evolution emphasize the fundamental importance of SERINC5 as a potent anti-retroviral factor.
C1 [Rosa, Annachiara; Chande, Ajit; Ziglio, Serena; Pizzato, Massimo] Univ Trent, Ctr Integrat Biol, I-38123 Trento, Italy.
   [De Sanctis, Veronica; Bertorelli, Roberto] Univ Trent, Lab Biomol Sequence & Struct Anal Hlth, NGS Facil, I-38123 Trento, Italy.
   [Goh, Shih Lin; McCauley, Sean M.; Nowosielska, Anetta; Luban, Jeremy] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA.
   [Antonarakis, Stylianos E.; Santoni, Federico Andrea] Univ Geneva, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland.
   [Antonarakis, Stylianos E.] IGE3 Inst Genet & Genom Geneva, CH-1211 Geneva, Switzerland.
C3 University of Trento; University of Trento; University of Massachusetts System; University of Massachusetts Worcester; University of Geneva
RP Pizzato, M (corresponding author), Univ Trent, Ctr Integrat Biol, I-38123 Trento, Italy.
EM massimo.pizzato@unitn.it
FU University of Trento; FP7 Marie Curie Career Integration grant [322130]; Caritro 'Ricerca Biomedica' grant [2013.0248]; National Institute of Health [DP1DA034990]; European Research Council [249968]
NR 50
TC 355
Z9 455
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 OCT 8
PY 2015
VL 526
IS 7572
BP 212
EP +
DI 10.1038/nature15399
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS9GV
UT WOS:000362399000038
PM 26416734
DA 2026-03-09
ER

PT J
AU Ghamari-Langroudi, M
   Digby, GJ
   Sebag, JA
   Millhauser, GL
   Palomino, R
   Matthews, R
   Gillyard, T
   Panaro, BL
   Tough, IR
   Cox, HM
   Denton, JS
   Cone, RD
AF Ghamari-Langroudi, Masoud
   Digby, Gregory J.
   Sebag, Julien A.
   Millhauser, Glenn L.
   Palomino, Rafael
   Matthews, Robert
   Gillyard, Taneisha
   Panaro, Brandon L.
   Tough, Iain R.
   Cox, Helen M.
   Denton, Jerod S.
   Cone, Roger D.
TI G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons
SO NATURE
LA English
DT Article
ID melanocortin-4 receptor; potassium channels; peptide yy; k+ channel; in-vitro; activation; vivo
AB The regulated release of anorexigenic alpha-melanocyte stimulating hormone (alpha-MSH) and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system has a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data show that alpha-MSH is an agonist that couples the receptor to the Gas signalling pathway(1), while AgRP binds competitively to block alpha-MSH binding(2) and blocks the constitutive activity mediated by the ligand-mimetic amino-terminal domain of the receptor(3). Here we show that, in mice, regulation of firing activity of neurons from the paraventricular nucleus of the hypothalamus (PVN) by alpha-MSH and AgRP can be mediated independently of G alpha(s) signalling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Furthermore, AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition of alpha-MSH binding. Consequently, Kir7.1 signalling appears to be central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signalling, including the gene dosage effect of MC4R4 and the sustained effects of AgRP on food intake(5).
C1 [Ghamari-Langroudi, Masoud; Digby, Gregory J.; Sebag, Julien A.; Matthews, Robert; Gillyard, Taneisha; Panaro, Brandon L.; Cone, Roger D.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Med Ctr, Nashville, TN 37232 USA.
   [Millhauser, Glenn L.; Palomino, Rafael] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA.
   [Gillyard, Taneisha] Meharry Med Coll, Dept Pharmacol, Nashville, TN 37208 USA.
   [Tough, Iain R.; Cox, Helen M.] Kings Coll London, Wolfson Ctr Age Related Dis, London SE1 1UL, England.
   [Denton, Jerod S.] Vanderbilt Univ, Med Ctr, Dept Anesthesiol, Nashville, TN 37232 USA.
   [Denton, Jerod S.] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA.
C3 Vanderbilt University; University of California System; University of California Santa Cruz; Meharry Medical College; University of London; King's College London; Vanderbilt University; Vanderbilt University
RP Ghamari-Langroudi, M (corresponding author), Vanderbilt Univ, Dept Mol Physiol & Biophys, Med Ctr, Nashville, TN 37232 USA.
EM masoud.ghamari-langroudi@vanderbilt.edu; roger.cone@vanderbilt.edu
FU NIH [RO1DK070332, 5R01 DK082884-03, R01DK064265]; Vanderbilt Diabetes Research and Training Center [DK020593]; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK020593] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R25GM059994] Funding Source: NIH RePORTER
NR 30
TC 147
Z9 189
U1 1
U2 35
PU NATURE PUBLISHING 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 2
PY 2015
VL 520
IS 7545
BP 94
EP U223
DI 10.1038/nature14051
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE7NE
UT WOS:000352027700044
PM 25600267
DA 2026-03-09
ER

PT J
AU Schutzius, TM
   Jung, S
   Maitra, T
   Graeber, G
   Köhme, M
   Poulikakos, D
AF Schutzius, Thomas M.
   Jung, Stefan
   Maitra, Tanmoy
   Graeber, Gustav
   Koehme, Moritz
   Poulikakos, Dimos
TI Spontaneous droplet trampolining on rigid superhydrophobic surfaces
SO NATURE
LA English
DT Article
ID extraordinary icephobicity; bouncing drop; contact time; water; condensation; physics; scale
AB Spontaneous removal of condensed matter from surfaces is exploited in nature and in a broad range of technologies to achieve self-cleaning(1,2), anti-icing(3-6) and condensation control(7,8). But despite much progress(5-7,9-14), our understanding of the phenomena leading to such behaviour remains incomplete, which makes it challenging to rationally design surfaces that benefit from its manifestation(15-18). Here we show that water droplets resting on superhydrophobic textured surfaces in a low-pressure environment can self-remove through sudden spontaneous levitation and subsequent trampoline-like bouncing behaviour, in which sequential collisions with the surface accelerate the droplets. These collisions have restitution coefficients (ratios of relative speeds after and before collision) greater than unity(19) despite complete rigidity of the surface, and thus seemingly violate the second law of thermodynamics. However, these restitution coefficients result from an overpressure beneath the droplet produced by fast droplet vaporization while substrate adhesion and surface texture restrict vapour flow. We also show that the high vaporization rates experienced by the droplets and the associated cooling can result in freezing from a supercooled state(20,21) that triggers a sudden increase in vaporization, which in turn boosts the levitation process. This effect can spontaneously remove surface icing by lifting away icy drops the moment they freeze. Although these observations are relevant only to systems in a low-pressure environment, they show how surface texturing can produce droplet-surface interactions that prohibit liquid and freezing water-droplet retention on surfaces.
C1 [Schutzius, Thomas M.; Jung, Stefan; Maitra, Tanmoy; Graeber, Gustav; Koehme, Moritz; Poulikakos, Dimos] ETH, Dept Mech & Proc Engn, Lab Thermodynam Emerging Technol, CH-8092 Zurich, Switzerland.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Poulikakos, D (corresponding author), ETH, Dept Mech & Proc Engn, Lab Thermodynam Emerging Technol, CH-8092 Zurich, Switzerland.
EM dpoulikakos@ethz.ch
FU Marie Curie Actions for People COFUND programme [FEL-14 13-1]; Swiss National Science Foundation [200021_135479]; Swiss National Science Foundation (SNF) [200021_135479] Funding Source: Swiss National Science Foundation (SNF)
NR 30
TC 419
Z9 462
U1 25
U2 919
PU NATURE PUBLISHING 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 5
PY 2015
VL 527
IS 7576
BP 82
EP 85
DI 10.1038/nature15738
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV4XV
UT WOS:000364270700047
PM 26536959
DA 2026-03-09
ER

PT J
AU Liu, Y
   Holmstrom, E
   Zhang, JW
   Yu, P
   Wang, JB
   Dyba, MA
   Chen, D
   Ying, JF
   Lockett, S
   Nesbitt, DJ
   Ferré-D'Amaré, AR
   Sousa, R
   Stagno, JR
   Wang, YX
AF Liu, Yu
   Holmstrom, Erik
   Zhang, Jinwei
   Yu, Ping
   Wang, Jinbu
   Dyba, Marzena A.
   Chen, De
   Ying, Jinfa
   Lockett, Stephen
   Nesbitt, David J.
   Ferre-D'Amare, Adrian R.
   Sousa, Rui
   Stagno, Jason R.
   Wang, Yun-Xing
TI Synthesis and applications of RNAs with position-selective labelling and mosaic composition
SO NATURE
LA English
DT Article
ID single-molecule; transcription initiation; messenger-rnas; dna templates; polymerase; riboswitch; stability; ligand; dissociation; specificity
AB Knowledge of the structure and dynamics of RNA molecules is critical to understanding their many biological functions. Furthermore, synthetic RNAs have applications as therapeutics and molecular sensors. Both research and technological applications of RNA would be dramatically enhanced by methods that enable incorporation of modified or labelled nucleotides into specifically designated positions or regions of RNA. However, the synthesis of tens of milligrams of such RNAs using existing methods has been impossible. Here we develop a hybrid solid-liquid phase transcription method and automated robotic platform for the synthesis of RNAs with position-selective labelling. We demonstrate its use by successfully preparing various isotope- or fluorescently labelled versions of the 71-nucleotide aptamer domain of an adenine riboswitch(1) for nuclear magnetic resonance spectroscopy or single-molecule Forster resonance energy transfer, respectively. Those RNAs includemolecules that were selectively isotope-labelled in specific loops, linkers, a helix, several discrete positions, or a single internal position, as well as RNA molecules that were fluorescently labelled in and near kissing loops. These selectively labelled RNAs have the same fold as those transcribed using conventional methods, but they greatly simplify the interpretation of NMR spectra. The single-position isotope-and fluorescently labelled RNA samples reveal multiple conformational states of the adenine riboswitch. Lastly, we describe a robotic platform- and the operation that automates this technology. Our selective labelling method may be useful for studying RNA structure and dynamics and for making RNA sensors for a variety of applications including cell-biological studies, substance detection(2), and disease diagnostics(3,4).
C1 [Liu, Yu; Wang, Jinbu; Stagno, Jason R.; Wang, Yun-Xing] NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA.
   [Holmstrom, Erik; Nesbitt, David J.] Univ Colorado, NIST, Joint Inst Lab Astrophys, Boulder, CO 80309 USA.
   [Holmstrom, Erik; Nesbitt, David J.] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA.
   [Zhang, Jinwei; Ferre-D'Amare, Adrian R.] NHLBI, Biochem & Biophys Ctr, Bethesda, MD 20892 USA.
   [Yu, Ping; Dyba, Marzena A.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Basic Sci Program, Struct Biophys Lab, Frederick, MD 21702 USA.
   [Chen, De; Lockett, Stephen] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Opt Microscopy & Anal Lab, Frederick, MD 21702 USA.
   [Ying, Jinfa] NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA.
   [Sousa, Rui] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); National Institute of Standards & Technology (NIST) - USA; University of Colorado System; University of Colorado Boulder; University of Colorado System; University of Colorado Boulder; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI); 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; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); University of Texas System; University of Texas at San Antonio
RP Wang, YX (corresponding author), NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA.
EM wangyunx@mail.nih.gov
FU National Cancer Institute, the National Institute of Diabetes, Digestive and Kidney Diseases, the National Heart, Lung and Blood Institute; Intramural Antiviral Target Program (IATAP) of the Office of the Director, National Institutes of Health; National Institutes of Health; National Cancer Institute [HHSN261200800001E]; National Science Foundation [CHE1266416, PHYS1125844]; National Institutes of Health Molecular Biophysics Training Program [T32 GM-065103]; W. M. Keck Foundation; National Institute of Standards and Technology; Direct For Mathematical & Physical Scien; Division Of Physics [1125844] Funding Source: National Science Foundation; National Cancer Institute [ZICBC011535] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM065103] Funding Source: NIH RePORTER
NR 45
TC 103
Z9 125
U1 1
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 JUN 18
PY 2015
VL 522
IS 7556
BP 368
EP +
DI 10.1038/nature14352
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK7PU
UT WOS:000356425400059
PM 25938715
DA 2026-03-09
ER

PT J
AU Kruijer, TS
   Kleine, T
   Fischer-Gödde, M
   Sprung, P
AF Kruijer, Thomas S.
   Kleine, Thorsten
   Fischer-Goedde, Mario
   Sprung, Peter
TI Lunar tungsten isotopic evidence for the late veneer
SO NATURE
LA English
DT Article
ID hf-w chronometry; siderophile element systematics; early mantle differentiation; core formation; osmium isotope; giant impact; moon; constraints; earth; accretion
AB According to the most widely accepted theory of lunar origin, a giant impact on the Earth led to the formation of the Moon, and also initiated the final stage of the formation of the Earth's core(1). Core formation should have removed the highly siderophile elements (HSE) from Earth's primitive mantle (that is, the bulk silicate Earth), yet HSE abundances are higher than expected(2). One explanation for this overabundance is that a 'late veneer' of primitive material was added to the bulk silicate Earth after the core formed(2). To test this hypothesis, tungsten isotopes are useful for two reasons: first, because the late veneer material had a different W-182/W-184 ratio to that of the bulk silicate Earth, and second, proportionally more material was added to the Earth than to the Moon(3). Thus, if a late veneer did occur, the bulk silicate Earth and the Moon must have different W-182/W-184 ratios. Moreover, the Moon-forming impact would also have created W-182 differences because the mantle and core material of the impactor with distinct W-182/W-184 would have mixed with the proto-Earth during the giant impact. However the W-182/W-184 of the Moon has not been determined precisely enough to identify signatures of a late veneer or the giant impact. Here, using more-precise measurement techniques, we show that the Moon exhibits a W-182 excess of 27 +/- 4 parts per million over the present-day bulk silicate Earth. This excess is consistent with the expected W-182 difference resulting from a late veneer with a total mass and composition inferred from HSE systematics(2). Thus, our data independently show that HSE abundances in the bulk silicate Earth were established after the giant impact and core formation, as predicted by the late veneer hypothesis. But, unexpectedly, we find that before the late veneer, no W-182 anomaly existed between the bulk silicate Earth and the Moon, even though one should have arisen through the giant impact. The origin of the homogeneous W-182 of the pre-late-veneer bulk silicate Earth and the Moon is enigmatic and constitutes a challenge to current models of lunar origin.
C1 [Kruijer, Thomas S.; Kleine, Thorsten; Fischer-Goedde, Mario; Sprung, Peter] Univ Munster, Inst Planetol, D-48149 Munster, Germany.
C3 University of Munster
RP Kruijer, TS (corresponding author), Univ Munster, Inst Planetol, Wilhelm Klemm Str 10, D-48149 Munster, Germany.
EM thomas.kruijer@wwu.de
NR 60
TC 141
Z9 156
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 APR 23
PY 2015
VL 520
IS 7548
BP 534
EP +
DI 10.1038/nature14360
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500041
PM 25855296
DA 2026-03-09
ER

PT J
AU van Bergeijk, P
   Adrian, M
   Hoogenraad, CC
   Kapitein, LC
AF van Bergeijk, Petra
   Adrian, Max
   Hoogenraad, Casper C.
   Kapitein, Lukas C.
TI Optogenetic control of organelle transport and positioning
SO NATURE
LA English
DT Article
ID ampa receptors; mitochondrial transport; axonal mitochondria; recycling endosm; dendritic spines; living cells; neurons; trafficking; growth; neurodegeneration
AB Proper positioning of organelles by cytoskeleton-based motor proteins underlies cellular events such as signalling, polarization and growth(1-8). For many organelles, however, the precise connection between position and function has remainedunclear, because strategies to control intracellular organelle positioning with spatiotemporal precision are lacking. Here we establish optical control of intracellular transport by using light-sensitive heterodimerization to recruit specific cytoskeletal motor proteins (kinesin, dynein or myosin) to selected cargoes. We demonstrate that the motility of peroxisomes, recycling endosomes and mitochondria can be locally and repeatedly induced or stopped, allowing rapid organelle repositioning. We applied this approach in primary rat hippocampal neurons to test how local positioning of recycling endosomes contributes to axon outgrowth and found that dynein-driven removal of endosomes from axonal growth cones reversibly suppressed axon growth, whereas kinesin-driven endosome enrichment enhanced growth. Our strategy for optogenetic control of organelle positioning will be widely applicable to explore site-specific organelle functions in different model systems.
C1 [van Bergeijk, Petra; Adrian, Max; Hoogenraad, Casper C.; Kapitein, Lukas C.] Univ Utrecht, Fac Sci, Dept Biol, NL-3584 CH Utrecht, Netherlands.
C3 Utrecht University
RP Hoogenraad, CC (corresponding author), Univ Utrecht, Fac Sci, Dept Biol, NL-3584 CH Utrecht, Netherlands.
EM c.hoogenraad@uu.nl; l.kapitein@uu.nl
FU Dutch Technology Foundation STW part of the Netherlands Organisation for Scientific Research (NWO); Foundation for Fundamental Research on Matter (FOM) part of the Netherlands Organisation for Scientific Research (NWO); NWO (NWO-ALW-VICI); NWO (NWO-ALW-VIDI); European Research Council (ERC starting grant)
NR 38
TC 228
Z9 290
U1 1
U2 109
PU NATURE PUBLISHING 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 5
PY 2015
VL 518
IS 7537
BP 111
EP +
DI 10.1038/nature14128
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7LE
UT WOS:000349098000042
PM 25561173
DA 2026-03-09
ER

PT J
AU Praetorius, SK
   Mix, AC
   Walczak, MH
   Wolhowe, MD
   Addison, JA
   Prahl, FG
AF Praetorius, S. K.
   Mix, A. C.
   Walczak, M. H.
   Wolhowe, M. D.
   Addison, J. A.
   Prahl, F. G.
TI North Pacific deglacial hypoxic events linked to abrupt ocean warming
SO NATURE
LA English
DT Article
ID santa-barbara basin; oxygen minimum zone; benthic foraminifera; organic-matter; nordic seas; water; surface; sediments; climate; temperature
AB Marine sediments from the North Pacific document two episodes of expansion and strengthening of the subsurface oxygen minimum zone (OMZ) accompanied by seafloor hypoxia during the last deglacial transition(1-4). The mechanisms driving this hypoxia remain under debate(1-11). We present a new high-resolution alkenone palaeotemperature reconstruction from the Gulf of Alaska that reveals two abrupt warming events of 4-5 degrees Celsius at the onset of the Bolling and Holocene intervals that coincide with sudden shifts to hypoxia at intermediate depths. The presence of diatomaceous laminations and hypoxia-tolerant benthic foraminiferal species, peaks in redox-sensitive trace metals(12,13), and enhanced N-15/N-14 ratio of organic matter(13), collectively suggest association with high export production. A decrease in O-18/O-16 values of benthic foraminifera accompanying the most severe deoxygenation event indicates subsurface warming of up to about 2 degrees Celsius. We infer that abrupt warming triggered expansion of the North Pacific OMZ through reduced oxygen solubility and increased marine productivity via physiological effects; following initiation of hypoxia, remobilization of iron from hypoxic sediments could have provided a positive feedback on ocean deoxygenation through increased nutrient utilization and carbon export. Such a biogeochemical amplification process implies high sensitivity of OMZ expansion to warming.
C1 [Praetorius, S. K.; Mix, A. C.; Walczak, M. H.; Wolhowe, M. D.; Prahl, F. G.] Oregon State Univ, Coll Earth Ocean & Atmospher Sci, Corvallis, OR 97331 USA.
   [Addison, J. A.] US Geol Survey, Menlo Pk, CA 94025 USA.
C3 Oregon State University; United States Department of the Interior; United States Geological Survey
RP Praetorius, SK (corresponding author), Carnegie Inst Sci, Dept Global Ecol, Stanford, CA 94305 USA.
EM spraetorius@carnegiescience.edu
FU NSF [AGS-0602395, OCE-1204204]; NSF; USGS Cimate and Land Use Change Research and Development Program; Volcano Science Center; Division Of Ocean Sciences; Directorate For Geosciences [1204204, 1502754, 1357529, 1502746] Funding Source: National Science Foundation
NR 68
TC 127
Z9 152
U1 2
U2 125
PU NATURE PUBLISHING 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 19
PY 2015
VL 527
IS 7578
BP 362
EP +
DI 10.1038/nature15753
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9ZN
UT WOS:000365356800053
PM 26581293
DA 2026-03-09
ER

PT J
AU Mattila, JP
   Shnyrova, AV
   Sundborger, AC
   Hortelano, ER
   Fuhrmans, M
   Neumann, S
   Müller, M
   Hinshaw, JE
   Schmid, SL
   Frolov, VA
AF Mattila, Juha-Pekka
   Shnyrova, Anna V.
   Sundborger, Anna C.
   Rodriguez Hortelano, Eva
   Fuhrmans, Marc
   Neumann, Sylvia
   Mueller, Marcus
   Hinshaw, Jenny E.
   Schmid, Sandra L.
   Frolov, Vadim A.
TI A hemi-fission intermediate links two mechanistically distinct stages of membrane fission
SO NATURE
LA English
DT Article
ID dependent conformational-changes; dissipative particle dynamics; crystal-structure; fusion; mechanics; gtpase; domain; simulations; bilayers; binding
AB Fusion and fission drive all vesicular transport. Although topologically opposite, these reactions pass through the same hemi-fusion/fission intermediate1,2, characterized by a 'stalk' in which only the outer membrane monolayers of the two compartments have merged to form a localized non-bilayer connection(1-3). Formation of the hemi-fission intermediate requires energy input from proteins catalysing membrane remodelling; however, the relationship between protein conformational rearrangements and hemi-fusion/fission remains obscure. Here we analysed how the GTPase cycle of human dynamin 1, the prototypical membrane fission catalyst(4-6), is directly coupled to membrane remodelling. We used intramolecular chemical crosslinking to stabilize dynamin in its GDP.AlF4--bound transition state. In the absence of GTP this conformer produced stable hemi-fission, but failed to progress to complete fission, even in the presence of GTP. Further analysis revealed that the pleckstrin homology domain (PHD) locked in its membrane-inserted state facilitated hemi-fission. A second mode of dynamin activity, fuelled by GTP hydrolysis, couples dynamin disassembly with cooperative diminishing of the PHD wedging, thus destabilizing the hemi-fission intermediate to complete fission. Molecular simulations corroborate the bimodal character of dynamin action and indicate radial and axial forces as dominant, although not independent, drivers of hemi-fission and fission transformations, respectively. Mirrored in the fusion reaction(7,8), the force bimodality might constitute a general paradigm for leakage-free membrane remodelling.
C1 [Mattila, Juha-Pekka; Schmid, Sandra L.] UT Southwestern Med Ctr, Dept Cell Biol, Dallas, TX 75201 USA.
   [Shnyrova, Anna V.; Rodriguez Hortelano, Eva; Frolov, Vadim A.] Univ Basque Country, Biophys Unit, CSIC, Leioa 48940, Spain.
   [Shnyrova, Anna V.; Rodriguez Hortelano, Eva; Frolov, Vadim A.] Univ Basque Country, Dept Biochem & Mol Biol, Leioa 48940, Spain.
   [Sundborger, Anna C.; Hinshaw, Jenny E.] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA.
   [Fuhrmans, Marc; Mueller, Marcus] Univ Gottingen, Inst Theoret Phys, D-37077 Gottingen, Germany.
   [Neumann, Sylvia] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA.
   [Frolov, Vadim A.] Basque Fdn Sci, IKERBASQUE, Bilbao 48011, Spain.
C3 University of Texas System; University of Texas Southwestern Medical Center; Consejo Superior de Investigaciones Cientificas (CSIC); University of Basque Country; CSIC - UPV EHU - Instituto Biofisika; University of Basque Country; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); University of Gottingen; Scripps Research Institute; Basque Foundation for Science
RP Schmid, SL (corresponding author), UT Southwestern Med Ctr, Dept Cell Biol, Dallas, TX 75201 USA.
EM jennyh@helix.nih.gov; sandra.schmid@utsouthwestern.edu; vadim.frolov@ehu.eus
FU National Institutes of Health [R01-GM42455]; Welch Foundation [I-1823]; Spanish Ministry of Economy and Competitiveness [BFU2012-34885]; Basque Government Program Etortek [IE12-332]; European FEDER; National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program; Volkswagen foundation; Academy of Finland;  [DFG-CRC803]; National Institute of Diabetes and Digestive and Kidney Diseases [ZIADK060100] Funding Source: NIH RePORTER
NR 39
TC 89
Z9 103
U1 0
U2 72
PU NATURE PUBLISHING 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 6
PY 2015
VL 524
IS 7563
BP 109
EP U243
DI 10.1038/nature14509
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO2QS
UT WOS:000359002300042
PM 26123023
DA 2026-03-09
ER

PT J
AU Benítez-Llambay, P
   Masset, F
   Koenigsberger, G
   Szulágyi, J
AF Benitez-Llambay, Pablo
   Masset, Frederic
   Koenigsberger, Gloria
   Szulagyi, Judit
TI Planet heating prevents inward migration of planetary cores
SO NATURE
LA English
DT Article
ID torque formula; super-earths; mass; disk; diffusion; accretion; gas
AB Planetary systems are born in the disks of gas, dust and rocky fragments that surround newly formed stars. Solid content assembles into ever-larger rocky fragments that eventually become planetary embryos. These then continue their growth by accreting leftover material in the disk. Concurrently, tidal effects in the disk cause a radial drift in the embryo orbits, a process known as migration(1-4). Fast inward migration is predicted by theory for embryos smaller than three to five Earth masses(5-7). With only inward migration, these embryos can only rarely become giant planets located at Earth's distance from the Sun and beyond(8,9), in contrast with observations(10). Here we report that asymmetries in the temperature rise associated with accreting infalling material(11,12) produce a force (which gives rise to an effect that we call 'heating torque') that counteracts inward migration. This provides a channel for the formation of giant planets(8) and also explains the strong planet-metallicity correlation found between the incidence of giant planets and the heavy-element abundance of the host stars(13,14).
C1 [Benitez-Llambay, Pablo] Univ Nacl Cordoba, IATE, Observ Astron, RA-5000 Cordoba, Argentina.
   [Masset, Frederic; Koenigsberger, Gloria] Univ Nacl Autonoma Mexico, Inst Ciencias Fis, Cuernavaca 62210, Morelos, Mexico.
   [Szulagyi, Judit] Univ Nice Sophia Antipolis, CNRS, Observ Cote Azur, Lab Lagrange, F-06304 Nice, France.
C3 National University of Cordoba; Universidad Nacional Autonoma de Mexico; Universite Cote d'Azur; Observatoire de la Cote d'Azur; Centre National de la Recherche Scientifique (CNRS)
RP Masset, F (corresponding author), Univ Nacl Autonoma Mexico, Inst Ciencias Fis, Ave Univ S-N, Cuernavaca 62210, Morelos, Mexico.
EM fmasset@cea.fr
FU CONICET; UNAM [PAPIIT IA101113, IN105313]; CONACyT [178377, 129343]; Capital Fund Management's J. P. Aguilar Grant
NR 26
TC 143
Z9 150
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 APR 2
PY 2015
VL 520
IS 7545
BP 63
EP U127
DI 10.1038/nature14277
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE7NE
UT WOS:000352027700036
PM 25832403
DA 2026-03-09
ER

PT J
AU Bencivenga, F
   Cucini, R
   Capotondi, F
   Battistoni, A
   Mincigrucci, R
   Giangrisostomi, E
   Gessini, A
   Manfredda, M
   Nikolov, IP
   Pedersoli, E
   Principi, E
   Svetina, C
   Parisse, P
   Casolari, F
   Danailov, MB
   Kiskinova, M
   Masciovecchio, C
AF Bencivenga, F.
   Cucini, R.
   Capotondi, F.
   Battistoni, A.
   Mincigrucci, R.
   Giangrisostomi, E.
   Gessini, A.
   Manfredda, M.
   Nikolov, I. P.
   Pedersoli, E.
   Principi, E.
   Svetina, C.
   Parisse, P.
   Casolari, F.
   Danailov, M. B.
   Kiskinova, M.
   Masciovecchio, C.
TI Four-wave mixing experiments with extreme ultraviolet transient gratings
SO NATURE
LA English
DT Article
ID free-electron laser; x-ray; coherent; spectroscopy; scattering; optics; pulses; phase
AB Four-wave mixing (FWM) processes, based on third-order nonlinear light-matter interactions, can combine ultrafast time resolution with energy and wavevector selectivity, and enable the exploration of dynamics inaccessible by linear methods(1-7). The coherent and multi-wave nature of the FWM approach has been crucial in the development of advanced technologies, such as silicon photonice, subwavelength imaging' and quantum communications(10). All these technologies operate at optical wavelengths, which limits the spatial resolution and does not allow the probing of excitations with energy in the electronvolt range. Extension to shorter wavelengths that is, the extreme ultraviolet and soft-X-ray ranges would allow the spatial resolution to be improved and the excitation energy range to be expanded, as well as enabling elemental selectivity to be achieved by exploiting core resonances(5-7,11-14). So far, FWM applications at such wavelengths have been prevented by the absence of coherent sources of sufficient brightness and of suitable experimental set-ups. Here we show how transient gratings, generated by the interference of coherent extreme-ultraviolet pulses delivered by the FERMI free-electron laser(15), can be used to stimulate FWM processes at suboptical wavelengths. Furthermore, we have demonstrated the possibility of observing the time evolution of the FWM signal, which shows the dynamics of coherent excitations as molecular vibrations. This result opens the way to FWM with nanometre spatial resolution and elemental selectivity, which, for example, would enable the investigation of charge-transfer dynamics(5-7). The theoretical possibility of realizing these applications has already stimulated ongoing developments of free-electron lasers(16-20): our results show that FWM at suboptical wavelengths is feasible, and we hope that they will enable advances in present and future photon sources.
C1 [Bencivenga, F.; Cucini, R.; Capotondi, F.; Battistoni, A.; Mincigrucci, R.; Giangrisostomi, E.; Gessini, A.; Manfredda, M.; Nikolov, I. P.; Pedersoli, E.; Principi, E.; Svetina, C.; Parisse, P.; Casolari, F.; Danailov, M. B.; Kiskinova, M.; Masciovecchio, C.] Elettra Sincrotrone Trieste, I-34012 Trieste, Italy.
   [Battistoni, A.; Giangrisostomi, E.; Svetina, C.] Univ Trieste, Dipartimento Fis, I-34127 Trieste, Italy.
   [Mincigrucci, R.] Univ Perugia, Dipartimento Fis & Geol, I-06123 Perugia, Italy.
C3 Elettra Sincrotrone Trieste; University of Trieste; University of Perugia
RP Bencivenga, F (corresponding author), Elettra Sincrotrone Trieste, Str Statale 14 Km 163,5 Area Sci Pk, I-34012 Trieste, Italy.
EM filippo.bencivenga@elettra.eu; claudio.masciovecchio@elettra.eu
FU Italian Ministry of University and Research [FIRB-RBAP045JF2, FIRB-RBAP06AWK3]; European Research Council [202804-TIMER]
CR Adams B, 2011, NAT PHYS, V7, P675, DOI 10.1038/nphys2056
   Allaria E, 2013, NAT COMMUN, V4, P0, DOI 10.1038/ncomms3476
   Allaria E, 2012, NEW J PHYS, V14, P0, DOI 10.1088/1367-2630/14/11/113009
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   ARMSTRONG JA, 1962, PHYS REV, V127, P1918, DOI 10.1103/PhysRev.127.1918
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   Bencivenga F, 2009, NUCL INSTRUM METH A, V606, P785, DOI 10.1016/j.nima.2009.05.147
   Bencivenga F, 2014, FARADAY DISCUSS, V171, P487, DOI 10.1039/c4fd00100a
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   Chen PY, 2011, NANO LETT, V11, P5514, DOI 10.1021/nl203354b
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NR 43
TC 204
Z9 229
U1 1
U2 156
PU NATURE PUBLISHING 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 9
PY 2015
VL 520
IS 7546
BP 205
EP U149
DI 10.1038/nature14341
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CF3NA
UT WOS:000352454600035
PM 25855456
DA 2026-03-09
ER

PT J
AU Lovelock, CE
   Cahoon, DR
   Friess, DA
   Guntenspergen, GR
   Krauss, KW
   Reef, R
   Rogers, K
   Saunders, ML
   Sidik, F
   Swales, A
   Saintilan, N
   Thuyen, LX
   Triet, T
AF Lovelock, Catherine E.
   Cahoon, Donald R.
   Friess, Daniel A.
   Guntenspergen, Glenn R.
   Krauss, Ken W.
   Reef, Ruth
   Rogers, Kerrylee
   Saunders, Megan L.
   Sidik, Frida
   Swales, Andrew
   Saintilan, Neil
   Thuyen, Le Xuan
   Triet, Tran
TI The vulnerability of Indo-Pacific mangrove forests to sea-level rise
SO NATURE
LA English
DT Article
ID northern australia; salt-marsh; sedimentation; evolution; elevation; impacts; adjust
AB Sea-level rise can threaten the long-term sustainability of coastal communities and valuable ecosystems such as coral reefs, salt marshes and mangroves(1,2). Mangrove forests have the capacity to keep pace with sea-level rise and to avoid inundation through vertical accretion of sediments, which allows them to maintain wetland soil elevations suitable for plant growth(3). The Indo-Pacific region holds most of the world's mangrove forests(4), but sediment delivery in this region is declining, owing to anthropogenic activities such as damming of rivers(5). This decline is of particular concern because the Indo-Pacific region is expected to have variable, but high, rates of future sea-level rise(6,7). Here we analyse recent trends in mangrove surface elevation changes across the Indo-Pacific region using data from a network of surface elevation table instruments(8-10). We find that sediment availability can enable mangrove forests to maintain rates of soil-surface elevation gain that match or exceed that of sea-level rise, but for 69 per cent of our study sites the current rate of sea-level rise exceeded the soil surface elevation gain. We also present a model based on our field data, which suggests that mangrove forests at sites with low tidal range and low sediment supply could be submerged as early as 2070.
C1 [Lovelock, Catherine E.; Reef, Ruth; Swales, Andrew] Univ Queensland, Sch Biol Sci, Brisbane, Qld 4072, Australia.
   [Lovelock, Catherine E.; Reef, Ruth; Saunders, Megan L.] Univ Queensland, Global Change Inst, Brisbane, Qld 4072, Australia.
   [Cahoon, Donald R.; Guntenspergen, Glenn R.] US Geol Survey, Patuxent Wildlife Res Ctr, Laurel, MD 20708 USA.
   [Friess, Daniel A.] Natl Univ Singapore, Dept Geog, Singapore 117570, Singapore.
   [Reef, Ruth] Univ Cambridge, Dept Geog, Cambridge Coastal Res Unit, Cambridge CB2 3EN, England.
   [Rogers, Kerrylee] Univ Wollongong, Sch Earth & Environm Sci, Wollongong, NSW 2522, Australia.
   [Sidik, Frida] Minist Marine Affairs & Fisheries, Inst Marine Res & Observat, Bali 82251, Indonesia.
   [Swales, Andrew] Natl Inst Water & Atmospher Res, Hamilton 3251, New Zealand.
   [Saintilan, Neil] Macquarie Univ, Dept Environm Sci, Sydney, NSW 2109, Australia.
   [Thuyen, Le Xuan; Triet, Tran] Vietnam Natl Univ, Univ Sci, Ho Chi Minh City, Vietnam.
C3 University of Queensland; University of Queensland; United States Department of the Interior; United States Geological Survey; National University of Singapore; University of Cambridge; University of Wollongong; Ministry of Marine Affairs and Fisheries; Earth Sciences New Zealand; National Institute of Water & Atmospheric Research (NIWA) - New Zealand; Macquarie University; Vietnam National University Ho Chi Minh City (VNUHCM) System
RP Lovelock, CE (corresponding author), Univ Queensland, Sch Biol Sci, Brisbane, Qld 4072, Australia.
EM c.lovelock@uq.edu.au
FU Australian Research Council [FS100100024]; US Geological Survey Climate and Land Use Research and Development Program; Australian Research Council [FS100100024] Funding Source: Australian Research Council
NR 38
TC 671
Z9 771
U1 33
U2 764
PU NATURE PUBLISHING 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 22
PY 2015
VL 526
IS 7574
BP 559
EP U217
DI 10.1038/nature15538
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV1NX
UT WOS:000364026100047
PM 26466567
DA 2026-03-09
ER

PT J
AU Scott, N
   Prigge, M
   Yizhar, O
   Kimchi, T
AF Scott, Niv
   Prigge, Matthias
   Yizhar, Ofer
   Kimchi, Tali
TI A sexually dimorphic hypothalamic circuit controls maternal care and oxytocin secretion
SO NATURE
LA English
DT Article
ID dopaminergic-neurons; parental behavior; sex-differences; expression; organization; kisspeptin; beta; mice
AB It is commonly assumed, but has rarely been demonstrated(1,2), that sex differences in behaviour arise from sexual dimorphism in the underlying neural circuits(3,4). Parental care is a complex stereotypic behaviour towards offspring that is shared by numerous species(5). Mice display profound sex differences in offspring-directed behaviours. At their first encounter, virgin females behave maternally towards alien pups while males will usually ignore the pups or attack them(6-9). Here we show that tyrosine hydroxylase (TH)-expressing neurons in the anteroventral periventricular nucleus (AVPV) of the mouse hypothalamus are more numerous in mothers than in virgin females and males, and govern parental behaviours in a sex-specific manner. In females, ablating the AVPV TH+ neurons impairs maternal behaviour whereas optogenetic stimulation or increased TH expression in these cells enhancematernal care. In males, however, this same neuronal cluster has no effect on parental care but rather suppresses intermale aggression. Furthermore, optogenetic activation or increased TH expression in the AVPV TH+ neurons of female mice increases circulating oxytocin, whereas their ablation reduces oxytocin levels. Finally, we show that AVPV TH+ neurons relay a monosynaptic input to oxytocin-expressing neurons in the paraventricular nucleus. Our findings uncover a previously unknown role for this neuronal population in the control of maternal care and oxytocin secretion, and provide evidence for a causal relationship between sexual dimorphism in the adult brain and sex differences in parental behaviour.
C1 [Scott, Niv; Prigge, Matthias; Yizhar, Ofer; Kimchi, Tali] Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel.
C3 Weizmann Institute of Science
RP Yizhar, O; Kimchi, T (corresponding author), Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel.
EM ofer.yizhar@weizmann.ac.il; tali.kimchi@weizmann.ac.il
FU Clore Center for Biological Physics; Minerva postdoctoral fellowship; Minerva Foundation [711131]; Women's Health Research Center; Gruber Foundation [720667]; ISF [1324/15, 1351/12]; Jenna and Julia Birnbach Career Development Chair; Marie Curie CIG [321919]; ERC StG [337637]; Nollman Career Development Chair; European Research Council (ERC) [337637] Funding Source: European Research Council (ERC)
NR 36
TC 195
Z9 233
U1 0
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 SEP 24
PY 2015
VL 525
IS 7570
BP 519
EP +
DI 10.1038/nature15378
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA VC0SK
UT WOS:000427190300001
PM 26375004
DA 2026-03-09
ER

PT J
AU Krinner, S
   Stadler, D
   Husmann, D
   Brantut, JP
   Esslinger, T
AF Krinner, Sebastian
   Stadler, David
   Husmann, Dominik
   Brantut, Jean-Philippe
   Esslinger, Tilman
TI Observation of quantized conductance in neutral matter
SO NATURE
LA English
DT Article
ID point contacts; quantum; resistance; transport; drop
AB In transport experiments, the quantum nature of matter becomes directly evident when changes in conductance occur only in discrete steps(1), with a size determined solely by Planck's constant h. Observations of quantized steps in electrical conductance(2,3) have provided important insights into the physics of mesoscopic systems(4) and have allowed the development of quantum electronic devices(5). Even though quantized conductance should not rely on the presence of electric charges, it has never been observed for neutral, massive particles(6). In its most fundamental form, it requires a quantum-degenerate Fermi gas, a ballistic and adiabatic transport channel, and a constriction with dimensions comparable to the Fermi wavelength. Here we report the observation of quantized conductance in the transport of neutral atoms driven by a chemical potential bias. The atoms are in an ultra-ballistic regime, where their mean free path exceeds not only the size of the transport channel, but also the size of the entire system, including the atom reservoirs. We use high-resolution lithography to shape light potentials that realize either a quantum point contact or a quantum wire for atoms. These constrictions are imprinted on a quasi-two-dimensional ballistic channel connecting the reservoirs(7). By varying either a gate potential or the transverse confinement of the constrictions, we observe distinct plateaux in the atom conductance. The conductance in the first plateau is found to be equal to the universal conductance quantum, 1/h. We use Landauer's formula to model our results and find good agreement for low gate potentials, with all parameters determined a priori. Our experiment lets us investigate quantum conductors with wide control not only over the channel geometry, but also over the reservoir properties, such as interaction strength, size and thermalization rate.
C1 [Krinner, Sebastian; Stadler, David; Husmann, Dominik; Brantut, Jean-Philippe; Esslinger, Tilman] ETH, Inst Quantum Elect, CH-8093 Zurich, Switzerland.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Brantut, JP (corresponding author), ETH, Inst Quantum Elect, CH-8093 Zurich, Switzerland.
EM brantutj@phys.ethz.ch
FU SNF
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NR 42
TC 190
Z9 205
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 JAN 1
PY 2015
VL 517
IS 7532
BP 64
EP U148
DI 10.1038/nature14049
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AX8SI
UT WOS:000347178400035
PM 25557712
DA 2026-03-09
ER

PT J
AU Lo, HY
   Kienzler, D
   de Clercq, L
   Marinelli, M
   Negnevitsky, V
   Keitch, BC
   Home, JP
AF Lo, Hsiang-Yu
   Kienzler, Daniel
   de Clercq, Ludwig
   Marinelli, Matteo
   Negnevitsky, Vlad
   Keitch, Ben C.
   Home, Jonathan P.
TI Spin-motion entanglement and state diagnosis with squeezed oscillator wavepackets
SO NATURE
LA English
DT Article
ID quantum; superposition
AB Mesoscopic superpositions of distinguishable coherent states provide an analogue of the 'Schrodinger's cat' thought experiment(1,2). For mechanical oscillators these have primarily been realized using coherent wavepackets, for which the distinguishability arises as a result of the spatial separation of the superposed states(3-5). Here we demonstrate superpositions composed of squeezed wavepackets, which we generate by applying an internal-state-dependent force to a single trapped ion initialized in a squeezed vacuum state with nine decibel reduction in the quadrature variance. This allows us to characterize the initial squeezed wavepacket by monitoring the onset of spin-motion entanglement, and to verify the evolution of the number states of the oscillator as a function of the duration of the force. In both cases we observe clear differences between displacements aligned with the squeezed and anti-squeezed axes. We observe coherent revivals when inverting the state-dependent force after separating the wavepackets by more than 19 times the ground-state root mean squared extent, which corresponds to 56 times the root mean squared extent of the squeezed wavepacket along the displacement direction. Aside from their fundamental nature, these states may be useful for quantum metrology(6) or quantum information processing with continuous variables(7-9).
C1 [Lo, Hsiang-Yu; Kienzler, Daniel; de Clercq, Ludwig; Marinelli, Matteo; Negnevitsky, Vlad; Keitch, Ben C.; Home, Jonathan P.] ETH, Inst Quantum Elect, CH-8093 Zurich, Switzerland.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Lo, HY (corresponding author), ETH, Inst Quantum Elect, Otto Stern Weg 1, CH-8093 Zurich, Switzerland.
EM hylo@phys.ethz.ch; jhome@phys.ethz.ch
FU Swiss National Science Foundation [200021 134776]; National Centre of Competence in Research for Quantum Science and Technology (QSIT); Swiss National Science Foundation (SNF) [200021_134776] Funding Source: Swiss National Science Foundation (SNF)
NR 29
TC 80
Z9 83
U1 2
U2 24
PU NATURE PUBLISHING 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 21
PY 2015
VL 521
IS 7552
BP 336
EP +
DI 10.1038/nature14458
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CI5RM
UT WOS:000354816500052
PM 25993964
DA 2026-03-09
ER

PT J
AU Schaff, F
   Bech, M
   Zaslansky, P
   Jud, C
   Liebi, M
   Guizar-Sicairos, M
   Pfeiffer, F
AF Schaff, Florian
   Bech, Martin
   Zaslansky, Paul
   Jud, Christoph
   Liebi, Marianne
   Guizar-Sicairos, Manuel
   Pfeiffer, Franz
TI Six-dimensional real and reciprocal space small-angle X-ray scattering tomography
SO NATURE
LA English
DT Article
ID computed-tomography; collagen orientation; bone; myelin; saxs; nanostructure; composite; dentin; brain
AB When used in combination with raster scanning, small-angle X-ray scattering (SAXS) has proven to be a valuable imaging technique of the nanoscale(1), for example of bone, teeth and brain matter(2-5). Although two-dimensional projection imaging has been used to characterize various materials successfully, its three-dimensional extension, SAXS computed tomography, poses substantial challenges, which have yet to be overcome. Previous work(6-11) using SAXS computed tomography was unable to preserve oriented SAXS signals during reconstruction. Here we present a solution to this problem and obtain a complete SAXS computed tomography, which preserves oriented scattering information. By introducing virtual tomography axes, we take advantage of the two-dimensional SAXS information recorded on an area detector and use it to reconstruct the full three-dimensional scattering distribution in reciprocal space for each voxel of the three-dimensional object in real space. The presented method could be of interest for a combined six-dimensional real and reciprocal space characterization of mesoscopic materials with hierarchically structured features with length scales ranging from a few nanometres to a few millimetres-for example, biomaterials such as bone or teeth, or functional materials such as fuel-cell or battery components.
C1 [Schaff, Florian; Jud, Christoph; Pfeiffer, Franz] Tech Univ Munich, Lehrstuhl Biomed Phys, Dept Phys, D-85748 Garching, Germany.
   [Schaff, Florian; Jud, Christoph; Pfeiffer, Franz] Tech Univ Munich, Inst Med Tech, D-85748 Garching, Germany.
   [Bech, Martin] Lund Univ, Dept Med Radiat Phys, Clin Sci, S-22185 Lund, Sweden.
   [Zaslansky, Paul] Charite, Julius Wolff Inst, D-13353 Berlin, Germany.
   [Liebi, Marianne; Guizar-Sicairos, Manuel] Paul Scherrer Inst, CH-5232 Villigen, Switzerland.
   [Pfeiffer, Franz] Tech Univ Munich, Klinikum Rechts Isar, Inst Diagnost & Interventionelle Radiol, D-81675 Munich, Germany.
C3 Technical University of Munich; Technical University of Munich; Lund University; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute; Technical University of Munich
RP Schaff, F (corresponding author), Tech Univ Munich, Lehrstuhl Biomed Phys, Dept Phys, D-85748 Garching, Germany.
EM florian.schaff@tum.de; martin.bech@med.lu.se; franz.pfeiffer@tum.de
FU DFG Cluster of Excellence Munich-Centre for Advanced Photonics (MAP); DFG Gottfried Wilhelm Leibniz program; DFG (German Research Foundation) [SPP1420]; TUM Graduate School; TUM Institute for Advanced Studies (TUM-IAS)
NR 26
TC 159
Z9 176
U1 5
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 NOV 19
PY 2015
VL 527
IS 7578
BP 353
EP +
DI 10.1038/nature16060
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9ZN
UT WOS:000365356800051
PM 26581292
DA 2026-03-09
ER

PT J
AU Barker, S
   Chen, J
   Gong, X
   Jonkers, L
   Knorr, G
   Thornalley, D
AF Barker, Stephen
   Chen, James
   Gong, Xun
   Jonkers, Lukas
   Knorr, Gregor
   Thornalley, David
TI Icebergs not the trigger for North Atlantic cold events
SO NATURE
LA English
DT Article
ID last glacial period; deep-water; climate variability; ice-sheet; chronology aicc2012; heinrich events; antarctic ice; ocean; circulation; sea
AB Abrupt climate change is a ubiquitous feature of the Late Pleistocene epoch'. In particular, the sequence of Dansgaard Oeschger events (repeated transitions between warm interstadial and cold stadial conditions), as recorded by ice cores in Greenland', are thought to be linked to changes in the mode of overturning circulation in the Atlantic Ocean'. Moreover, the observed correspondence between North Atlantic cold events and increased iceberg calving and dispersal from ice sheets surrounding the North Atlantic' has inspired many ocean and climate modelling studies that make use of freshwater forcing scenarios to simulate abrupt change across the North Atlantic region and beyond'. On the other hand, previous studies(4,8) identified an apparent lag between North Atlantic cooling events and the appearance of ice-rafted debris over the last glacial cycle, leading to the hypothesis that iceberg discharge may be a consequence of stadial conditions rather than the cause(4,9-11). Here we further establish this relationship and demonstrate a systematic delay between pronounced surface cooling and the arrival of ice-rafted debris at a site southwest of Iceland over the past four glacial cycles, implying that in general icebergs arrived too late to have triggered cooling. Instead we suggest that on the basis of our comparisons of ice-rafted debris and polar planktonic foraminifera abrupt transitions to stadial conditions should be considered as a nonlinear response to more gradual cooling across the North Atlantic. Although the freshwater derived from melting icebergs may provide a positive feedback for enhancing and or prolonging stadial conditions(10,11), it does not trigger northern stadial events.
C1 [Barker, Stephen; Chen, James; Gong, Xun; Jonkers, Lukas] Cardiff Univ, Sch Earth & Ocean Sci, Cardiff CF10 3AT, S Glam, Wales.
   [Knorr, Gregor] Alfred Wegener Inst, Helmholtz Ctr Polar & Marine Res, D-27570 Bremerhaven, Germany.
   [Thornalley, David] UCL, Dept Geog, London WC1E 6BT, England.
   [Thornalley, David] Woods Hole Oceanog Inst, Woods Hole, MA 02543 USA.
C3 Cardiff University; Helmholtz Association; Alfred Wegener Institute, Helmholtz Centre for Polar & Marine Research; University of London; University College London; Woods Hole Oceanographic Institution
RP Barker, S (corresponding author), Cardiff Univ, Sch Earth & Ocean Sci, Cardiff CF10 3AT, S Glam, Wales.
EM barkers3@cf.ac.uk
FU Philip Leverhulme Prize; Corner Science and Education Foundation (GCCF3); UK Natural Environment Research Council (NERC) [NE/L006405/1, NE/J008133/1]; 'Helmholtz Climate Initiative REKLIM' (Regional Climate Change); Helmholtz Association of German research centres (HGF); climate change consortium of Wales; Natural Environment Research Council [NE/J008133/1, NE/L006405/1] Funding Source: researchfish; NERC [NE/J008133/1, NE/L006405/1] Funding Source: UKRI
NR 63
TC 204
Z9 230
U1 5
U2 136
PU NATURE PUBLISHING 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 16
PY 2015
VL 520
IS 7547
BP 333
EP +
DI 10.1038/nature14330
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG0RI
UT WOS:000352974200035
PM 25877202
DA 2026-03-09
ER

PT J
AU Dietl, A
   Ferousi, C
   Maalcke, WJ
   Menzel, A
   de Vries, S
   Keltjens, JT
   Jetten, MSM
   Kartal, B
   Barends, TRM
AF Dietl, Andreas
   Ferousi, Christina
   Maalcke, Wouter J.
   Menzel, Andreas
   de Vries, Simon
   Keltjens, Jan T.
   Jetten, Mike S. M.
   Kartal, Boran
   Barends, Thomas R. M.
TI The inner workings of the hydrazine synthase multiprotein complex
SO NATURE
LA English
DT Article
ID cytochrome-c peroxidase; anammox bacterium; crystal-structure; structural basis; system; ligand
AB Anaerobic ammonium oxidation (anammox) has a major role in the Earth's nitrogen cycle(1,2) and is used in energy-efficient waste-water treatment(3). This bacterial process combines nitrite and ammonium to form dinitrogen (N-2) gas, and has been estimated to synthesize up to 50% of the dinitrogen gas emitted into our atmosphere from the oceans(2). Strikingly, the anammox process relies on the highly unusual, extremely reactive intermediate hydrazine(4), a compound also used as a rocket fuel because of its high reducing power. So far, the enzymatic mechanism by which hydrazine is synthesized is unknown. Here we report the 2.7 angstrom resolution crystal structure, as well as biophysical and spectroscopic studies, of a hydrazine synthase multiprotein complex isolated from the anammox organism Kuenenia stuttgartiensis. The structure shows an elongated dimer of heterotrimers, each of which has two unique c-type haem-containing active sites, as well as an interaction point for a redox partner. Furthermore, a system of tunnels connects these active sites. The crystal structure implies a two-step mechanism for hydrazine synthesis: a three-electron reduction of nitric oxide to hydroxylamine at the active site of the gamma-subunit and its subsequent condensation with ammonia, yielding hydrazine in the active centre of the alpha-subunit. Our results provide the first, to our knowledge, detailed structural insight into the mechanism of biological hydrazine synthesis, which is of major significance for our understanding of the conversion of nitrogenous compounds in nature.
C1 [Dietl, Andreas; Barends, Thomas R. M.] Max Planck Inst Med Res, Dept Biomol Mech, Jahnstr 29, D-69120 Heidelberg, Germany.
   [Ferousi, Christina; Maalcke, Wouter J.; Keltjens, Jan T.; Jetten, Mike S. M.; Kartal, Boran] Radboud Univ Nijmegen, Inst Water & Wetland Res, Dept Microbiol, NL-6525 AJ Nijmegen, Netherlands.
   [Menzel, Andreas] Paul Scherrer Inst, Swiss Light Source, CH-5232 Villigen, Switzerland.
   [de Vries, Simon; Jetten, Mike S. M.] Delft Univ Technol, Dept Biotechnol, Delft, Netherlands.
   [Kartal, Boran] Univ Ghent, Microbiol Lab, Dept Biochem & Microbiol, B-9000 Ghent, Belgium.
C3 Max Planck Society; Radboud University Nijmegen; Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute; Delft University of Technology; Ghent University
RP Barends, TRM (corresponding author), Max Planck Inst Med Res, Dept Biomol Mech, Jahnstr 29, D-69120 Heidelberg, Germany.
EM kartal@science.ru.nl; Thomas.Barends@mpimf-heidelberg.mpg.de
FU Netherlands Organization for Scientific Research [863.11.003, 142.16.1201]; European Research Council [ERC232937]; Spinoza Prize; NIGMS [P41-GM103311]; Max Planck Society
NR 32
TC 153
Z9 187
U1 11
U2 367
PU NATURE PUBLISHING 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 19
PY 2015
VL 527
IS 7578
BP 404
EP +
DI 10.1038/nature15517
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9ZN
UT WOS:000365356800060
PM 26479033
DA 2026-03-09
ER

PT J
AU Levy, A
   Goren, MG
   Yosef, I
   Auster, O
   Manor, M
   Amitai, G
   Edgar, R
   Qimron, U
   Sorek, R
AF Levy, Asaf
   Goren, Moran G.
   Yosef, Ido
   Auster, Oren
   Manor, Miriam
   Amitai, Gil
   Edgar, Rotem
   Qimron, Udi
   Sorek, Rotem
TI CRISPR adaptation biases explain preference for acquisition of foreign DNA
SO NATURE
LA English
DT Article
ID adaptive immune-systems; escherichia-coli; homologous recombination; spacer acquisition; recbcd enzyme; cas system; replication; prokaryotes; plasmids; bacteria
AB CRISPR-Cas (clustered, regularly interspaced short palindromic repeats coupled with CRISPR-associated proteins) is a bacterial immunity system that protects against invading phages or plasmids. In the process of CRISPR adaptation, short pieces of DNA ('spacers') are acquired from foreign elements and integrated into the CRISPR array. So far, it has remained a mystery how spacers are preferentially acquired from the foreign DNA while the self chromosome is avoided. Here we show that spacer acquisition is replication-dependent, and that DNA breaks formed at stalled replication forks promote spacer acquisition. Chromosomal hotspots of spacer acquisition were confined by Chi sites, which are sequence octamers highly enriched on the bacterial chromosome, suggesting that these sites limit spacer acquisition from self DNA. We further show that the avoidance of self is mediated by the RecBCD double-stranded DNA break repair complex. Our results suggest that, in Escherichia coli, acquisition of new spacers largely depends on RecBCD-mediated processing of double-stranded DNA breaks occurring primarily at replication forks, and that the preference for foreign DNA is achieved through the higher density of Chi sites on the self chromosome, in combination with the higher number of forks on the foreign DNA. This model explains the strong preference to acquire spacers both from high copy plasmids and from phages.
C1 [Levy, Asaf; Amitai, Gil; Sorek, Rotem] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel.
   [Goren, Moran G.; Yosef, Ido; Auster, Oren; Manor, Miriam; Edgar, Rotem; Qimron, Udi] Tel Aviv Univ, Sackler Sch Med, Dep Clin Microbiol & Immunol, IL-69978 Tel Aviv, Israel.
C3 Weizmann Institute of Science; Tel Aviv University; Sackler Faculty of Medicine
RP Qimron, U (corresponding author), Tel Aviv Univ, Sackler Sch Med, Dep Clin Microbiol & Immunol, IL-69978 Tel Aviv, Israel.
EM ehudq@post.tau.ac.il; rotem.sorek@weizmann.ac.il
FU Israel Science Foundation [1303/12, 1796, 268/14]; European Research Council [260432, 336079]; Human Frontier Science Program [RGP0011/2013]; Abisch-Frenkel foundation; Pasteur-Weizmann Council; Minerva Foundation; Deutsch-Israelische Projektkooperation grant from the Deutsche Forschungsgemeinschaft; Israeli Ministry of Health [9988-3]; Azrieli Foundation; European Research Council (ERC) [260432, 336079] Funding Source: European Research Council (ERC)
NR 37
TC 317
Z9 398
U1 2
U2 120
PU NATURE PUBLISHING 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 23
PY 2015
VL 520
IS 7548
BP 505
EP +
DI 10.1038/nature14302
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500035
PM 25874675
DA 2026-03-09
ER

PT J
AU Ling, LL
   Schneider, T
   Peoples, AJ
   Spoering, AL
   Engels, I
   Conlon, BP
   Mueller, A
   Schäberle, TF
   Hughes, DE
   Epstein, S
   Jones, M
   Lazarides, L
   Steadman, VA
   Cohen, DR
   Felix, CR
   Fetterman, KA
   Millett, WP
   Nitti, AG
   Zullo, AM
   Chen, C
   Lewis, K
AF Ling, Losee L.
   Schneider, Tanja
   Peoples, Aaron J.
   Spoering, Amy L.
   Engels, Ina
   Conlon, Brian P.
   Mueller, Anna
   Schaeberle, Till F.
   Hughes, Dallas E.
   Epstein, Slava
   Jones, Michael
   Lazarides, Linos
   Steadman, Victoria A.
   Cohen, Douglas R.
   Felix, Cintia R.
   Fetterman, K. Ashley
   Millett, William P.
   Nitti, Anthony G.
   Zullo, Ashley M.
   Chen, Chao
   Lewis, Kim
TI A new antibiotic kills pathogens without detectable resistance
SO NATURE
LA English
DT Article
ID cell-wall biosynthesis; peptidoglycan precursor; vancomycin-resistance; peptide; identification; transporter; metabolism; organisms; proteins; encodes
AB Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.
C1 [Ling, Losee L.; Peoples, Aaron J.; Spoering, Amy L.; Hughes, Dallas E.; Cohen, Douglas R.; Felix, Cintia R.; Fetterman, K. Ashley; Millett, William P.; Nitti, Anthony G.; Zullo, Ashley M.] NovoBiot Pharmaceut, Cambridge, MA 02138 USA.
   [Schneider, Tanja; Engels, Ina; Mueller, Anna] Univ Bonn, Immunol & Parasitol Pharmaceut Microbiol Sect, Inst Med Microbiol, D-53115 Bonn, Germany.
   [Schneider, Tanja; Engels, Ina; Mueller, Anna; Schaeberle, Till F.] German Ctr Infect Res DZIF, D-53115 Bonn, Germany.
   [Conlon, Brian P.; Chen, Chao; Lewis, Kim] Northeastern Univ, Dept Biol, Antimicrobial Discovery Ctr, Boston, MA 02115 USA.
   [Schaeberle, Till F.] Univ Bonn, Inst Pharmaceut Biol, D-53115 Bonn, Germany.
   [Epstein, Slava] Northeastern Univ, Dept Biol, Boston, MA 02115 USA.
   [Jones, Michael; Lazarides, Linos; Steadman, Victoria A.] Selcia, Ongar CM5 0GS, Essex, England.
C3 University of Bonn; German Center for Infection Research; Northeastern University; University of Bonn; Northeastern University
RP Lewis, K (corresponding author), Northeastern Univ, Dept Biol, Antimicrobial Discovery Ctr, Boston, MA 02115 USA.
EM k.lewis@neu.edu
FU NIH [T-R01 AI085585, AI085612]; Charles A. King Trust; German Research Foundation (DFG) [SCHN1284/1-2]; German Center for Infection Research (DZIF)
NR 50
TC 1923
Z9 2384
U1 30
U2 3152
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 22
PY 2015
VL 517
IS 7535
BP 455
EP +
DI 10.1038/nature14098
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AZ4MU
UT WOS:000348196500028
PM 25561178
DA 2026-03-09
ER

PT J
AU Gaudelli, NM
   Long, DH
   Townsend, CA
AF Gaudelli, Nicole M.
   Long, Darcie H.
   Townsend, Craig A.
TI β-Lactam formation by a non-ribosomal peptide synthetase during antibiotic biosynthesis
SO NATURE
LA English
DT Article
ID condensation domains; nocardicin; specificity; enzymes
AB Non-ribosomal peptide synthetases are giant enzymes composed of modules that house repeated sets of functional domains, which select, activate and couple amino acids drawn from a pool of nearly 500 potential building blocks(1). The structurally and stereochemically diverse peptides generated in this manner underlie the biosynthesis of a large sector of natural products. Many of their derived metabolites are bioactive such as the antibiotics vancomycin, bacitracin, daptomycin and the beta-lactam-containing penicillins, cephalosporins andnocardicins. Penicillins and cephalosporins are synthesized from a classically derived non-ribosomal peptide synthetase tripeptide (from delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase)(2). Here we report an unprecedented non-ribosomal peptide synthetase activity that both assembles a serine-containing peptide and mediates its cyclization to the critical beta-lactamring of the nocardicin family of antibiotics. A histidine-rich condensation domain, which typically performs peptide bond formation during product assembly, also synthesizes the embedded four-membered ring. We propose a mechanism, and describe supporting experiments, that is distinct from the pathways that have evolved to the three other beta-lactam antibiotic families: penicillin/cephalosporins, clavams and carbapenems. These findings raise the possibility that beta-lactam rings can be regio- and stereospecifically integrated into engineered peptides for application as, for example, targeted protease inactivators(3,4).
C1 [Gaudelli, Nicole M.; Long, Darcie H.; Townsend, Craig A.] Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA.
C3 Johns Hopkins University
RP Townsend, CA (corresponding author), Johns Hopkins Univ, Dept Chem, Charles & 34Th St, Baltimore, MD 21218 USA.
EM ctownsend@jhu.edu
FU National Institutes of Health [AI014937]; National Institute of Allergy and Infectious Diseases [R01AI121072] Funding Source: NIH RePORTER
NR 35
TC 93
Z9 119
U1 1
U2 100
PU NATURE PUBLISHING 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 16
PY 2015
VL 520
IS 7547
BP 383
EP +
DI 10.1038/nature14100
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG0RI
UT WOS:000352974200046
PM 25624104
DA 2026-03-09
ER

PT J
AU Lafkas, D
   Shelton, A
   Chiu, C
   Boenig, GD
   Chen, YM
   Stawicki, SS
   Siltanen, C
   Reichelt, M
   Zhou, MJ
   Wu, XM
   Eastham-Anderson, J
   Moore, H
   Roose-Girma, M
   Chinn, Y
   Hang, JQ
   Warming, S
   Egen, J
   Lee, WP
   Austin, C
   Wu, Y
   Payandeh, J
   Lowe, JB
   Siebel, CW
AF Lafkas, Daniel
   Shelton, Amy
   Chiu, Cecilia
   Boenig, Gladys de Leon
   Chen, Yongmei
   Stawicki, Scott S.
   Siltanen, Christian
   Reichelt, Mike
   Zhou, Meijuan
   Wu, Xiumin
   Eastham-Anderson, Jeffrey
   Moore, Heather
   Roose-Girma, Meron
   Chinn, Yvonne
   Hang, Julie Q.
   Warming, Soren
   Egen, Jackson
   Lee, Wyne P.
   Austin, Cary
   Wu, Yan
   Payandeh, Jian
   Lowe, John B.
   Siebel, Christian W.
TI Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung
SO NATURE
LA English
DT Article
ID stem-cells; clara cells; mouse model; airway; repair; regeneration; maintenance; mechanisms; receptors; system
AB Prevailing dogma holds that cell-cell communication through Notch ligands and receptors determines binary cell fate decisions during progenitor cell divisions, with differentiated lineages remaining fixed(1). Mucociliary clearance(2,3) in mammalian respiratory airways depends on secretory cells (club and goblet) and ciliated cells to produce and transport mucus. During development or repair, the closely related Jagged ligands (JAG1 and JAG2) induce Notch signalling to determine the fate of these lineages as they descend from a common proliferating progenitor(4-8). In contrast to such situations in which cell fate decisions are made in rapidly dividing populations(9,10), cells of the homeostatic adult airway epithelium are long-lived(11-13), and little is known about the role of active Notch signalling under such conditions. To disrupt Jagged signalling acutely in adult mammals, here we generate antibody antagonists that selectively target each Jagged paralogue, and determine a crystal structure that explains selectivity. We show that acute Jagged blockade induces a rapid and near-complete loss of club cells, with a concomitant gain in ciliated cells, under homeostatic conditions without increased cell death or division. Fate analyses demonstrate a direct conversion of club cells to ciliated cells without proliferation, meeting a conservative definition of direct transdifferentiation(14). Jagged inhibition also reversed goblet cell metaplasia in a preclinical asthma model, providing a therapeutic foundation(15). Our discovery that Jagged antagonism relieves a blockade of cell-to-cell conversion unveils unexpected plasticity, and establishes a model for Notch regulation of transdifferentiation.
C1 [Lafkas, Daniel; Shelton, Amy; Siltanen, Christian; Siebel, Christian W.] Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA.
   [Chiu, Cecilia; Chen, Yongmei; Stawicki, Scott S.; Wu, Yan] Genentech Inc, Dept Antibody Engn, San Francisco, CA 94080 USA.
   [Boenig, Gladys de Leon; Payandeh, Jian] Genentech Inc, Dept Biol Struct, San Francisco, CA 94080 USA.
   [Reichelt, Mike; Eastham-Anderson, Jeffrey; Austin, Cary; Lowe, John B.] Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA.
   [Zhou, Meijuan; Wu, Xiumin; Lee, Wyne P.] Genentech Inc, Dept Translat Immunol, San Francisco, CA 94080 USA.
   [Moore, Heather; Egen, Jackson] Genentech Inc, Dept Discovery Immunol, San Francisco, CA 94080 USA.
   [Roose-Girma, Meron; Warming, Soren] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA.
   [Chinn, Yvonne; Hang, Julie Q.] Genentech Inc, Dept Prot Chem, 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; Genentech; Roche Holding USA; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech
RP Siebel, CW (corresponding author), Genentech Inc, Dept Discovery Oncol, 1 DNA Way, San Francisco, CA 94080 USA.
EM csiebel@gene.com
NR 44
TC 184
Z9 216
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 DEC 3
PY 2015
VL 528
IS 7580
BP 127
EP +
DI 10.1038/nature15715
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000062
PM 26580007
DA 2026-03-09
ER

PT J
AU Gewin, V
AF Gewin, Virginia
TI OUTREACH Speak up for science
SO NATURE
LA English
DT Article
NR 5
TC 7
Z9 7
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 JAN 8
PY 2015
VL 517
IS 7533
BP 231
EP 233
DI 10.1038/nj7533-231a
PG 3
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600043
PM 25767845
DA 2026-03-09
ER

PT J
AU Hayashi, MT
   Cesare, AJ
   Rivera, T
   Karlseder, J
AF Hayashi, Makoto T.
   Cesare, Anthony J.
   Rivera, Teresa
   Karlseder, Jan
TI Cell death during crisis is mediated by mitotic telomere deprotection
SO NATURE
LA English
DT Article
ID spindle-assembly checkpoint; dna-damage response; dysfunctional telomeres; atm; senescence; immortalization; crispr-cas9; activation; inhibitor; trf2
AB Tumour formation is blocked by two barriers: replicative senescence and crisis(1). Senescence is triggered by short telomeres and is bypassed by disruption of tumour-suppressive pathways. After senescence bypass, cells undergo crisis, during which almost all of the cells in the population die. Cells that escape crisis harbour unstable genomes and other parameters of transformation. The mechanism of cell death during crisis remains unexplained. Here we show that human cells in crisis undergo spontaneous mitotic arrest, resulting in death during mitosis or in the following cell cycle. This phenotype is induced by loss of p53 function, and is suppressed by telomerase overexpression. Telomere fusions triggered mitotic arrest in p53-compromised non-crisis cells, indicating that such fusions are the underlying cause of cell death. Exacerbation of mitotic telomere deprotection by partial TRF2 (also known as TERF2) knockdown(2) increased the ratio of cells that died duringmitotic arrest and sensitized cancer cells to mitotic poisons. We propose a crisis pathway wherein chromosome fusions induce mitotic arrest, resulting in mitotic telomere deprotection and cell death, thereby eliminating precancerous cells from the population.
C1 [Hayashi, Makoto T.; Cesare, Anthony J.; Rivera, Teresa; Karlseder, Jan] Salk Inst Biol Studies, Mol & Cell Biol Dept, La Jolla, CA 92037 USA.
   [Hayashi, Makoto T.] Kyoto Univ, Dept Gene Mech, Grad Sch Biostudies, Hakubi Ctr Adv Res,Sakyo Ku, Kyoto 6068501, Japan.
   [Cesare, Anthony J.] Univ Sydney, Childrens Med Res Inst, Westmead, NSW 2145, Australia.
C3 Salk Institute; Kyoto University; University of Sydney; Children's Medical Research Institute - Australia
RP Karlseder, J (corresponding author), Salk Inst Biol Studies, Mol & Cell Biol Dept, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA.
EM karlseder@salk.edu
FU Human Frontier Science Program; Japan Society for the Promotion of Science; NIH NRSA [5T32CA009370]; Glenn Center for Research on Aging; CIRM [TG2-01158]; Salk Institute Cancer Center Core Grant [P30CA014195]; NIH [R01GM087476, R01CA174942]; Donald and Darlene Shiley Chair; Highland Street Foundation; Fritz B. Burns Foundation; Emerald Foundation; National Cancer Institute [P30CA014195, T32CA009370] Funding Source: NIH RePORTER
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NR 30
TC 99
Z9 120
U1 2
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 25
PY 2015
VL 522
IS 7557
BP 492
EP +
DI 10.1038/nature14513
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL2OC
UT WOS:000356782900053
PM 26108857
DA 2026-03-09
ER

PT J
AU Banks, AS
   McAllister, FE
   Camporez, JPG
   Zushin, PJH
   Jurczak, MJ
   Laznik-Bogoslavski, D
   Shulman, GI
   Gygi, SP
   Spiegelman, BM
AF Banks, Alexander S.
   McAllister, Fiona E.
   Camporez, Joao Paulo G.
   Zushin, Peter-James H.
   Jurczak, Michael J.
   Laznik-Bogoslavski, Dina
   Shulman, Gerald I.
   Gygi, Steven P.
   Spiegelman, Bruce M.
TI An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ
SO NATURE
LA English
DT Article
ID cyclin-dependent kinase-5; activated protein-kinase; insulin sensitivity; mass-spectrometry; mek inhibition; phosphorylation; modulation; glucose; obese; cdk5
AB Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPAR gamma (peroxisome proliferator-activated receptor gamma) at serine 273 by cydin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues(1). Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPAR gamma, such as the thiazolidinediones and PPAR gamma partial agonists or non-agonists(2). For a better understanding of the importance of this obesity-linked PPAR gamma phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPAR gamma phosphorylation at serine 273 and worsened insulin resistance. Unbiased proteomic studies show that extracellular signal-regulated kinase (ERK) kinases are activated in these knockout animals. Here we show that ERK directly phosphorylates serine 273 of PPAR gamma in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ ERK kinase (MEK). Importantly, pharmacological inhibition of MEK and ERK markedly improves insulin resistance in both obese wildtype and ob/ob mice, and also completely reverses the deleterious effects of the Cdk5 ablation. These data show that an ERK/Cdk5 axis controls PPAR gamma function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes.
C1 [Banks, Alexander S.; Zushin, Peter-James H.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA.
   [Banks, Alexander S.; Zushin, Peter-James H.] Harvard Univ, Sch Med, Boston, MA 02115 USA.
   [McAllister, Fiona E.; Gygi, Steven P.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA.
   [Camporez, Joao Paulo G.; Jurczak, Michael J.; Shulman, Gerald I.] Yale Univ, Sch Med, Yale Mouse Metab Phenotyping Ctr, New Haven, CT 06510 USA.
   [Camporez, Joao Paulo G.; Jurczak, Michael J.; Shulman, Gerald I.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA.
   [Camporez, Joao Paulo G.; Jurczak, Michael J.; Shulman, Gerald I.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA.
   [Laznik-Bogoslavski, Dina; Spiegelman, Bruce M.] Dana Farber Canc Inst, Boston, MA 02115 USA.
C3 Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Yale University; Yale University; Yale University; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute
RP Banks, AS (corresponding author), Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, 75 Francis St, Boston, MA 02115 USA.
EM abanks@research.bwh.harvard.edu; bruce_spiegelman@dfci.harvard.edu
FU National Institutes of Health (NIH) [DK31405, DK93638]; Harvard University Milton Fund; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK034854] Funding Source: NIH RePORTER
NR 44
TC 256
Z9 289
U1 1
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 JAN 15
PY 2015
VL 517
IS 7534
BP 391
EP U581
DI 10.1038/nature13887
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300051
PM 25409143
DA 2026-03-09
ER

PT J
AU Hsu, TYT
   Simon, LM
   Neill, NJ
   Marcotte, R
   Sayad, A
   Bland, CS
   Echeverria, GV
   Sun, TT
   Kurley, SJ
   Tyagi, S
   Karlin, KL
   Dominguez-Vidaña, R
   Hartman, JD
   Renwick, A
   Scorsone, K
   Bernardi, RJ
   Skinner, SO
   Jain, A
   Orellana, M
   Lagisetti, C
   Golding, I
   Jung, SY
   Neilson, JR
   Zhang, XHF
   Cooper, TA
   Webb, TR
   Neel, BG
   Shaw, CA
   Westbrook, TF
AF Hsu, Tiffany Y. -T.
   Simon, Lukas M.
   Neill, Nicholas J.
   Marcotte, Richard
   Sayad, Azin
   Bland, Christopher S.
   Echeverria, Gloria V.
   Sun, Tingting
   Kurley, Sarah J.
   Tyagi, Siddhartha
   Karlin, Kristen L.
   Dominguez-Vidana, Rocio
   Hartman, Jessica D.
   Renwick, Alexander
   Scorsone, Kathleen
   Bernardi, Ronald J.
   Skinner, Samuel O.
   Jain, Antrix
   Orellana, Mayra
   Lagisetti, Chandraiah
   Golding, Ido
   Jung, Sung Y.
   Neilson, Joel R.
   Zhang, Xiang H-F.
   Cooper, Thomas A.
   Webb, Thomas R.
   Neel, Benjamin G.
   Shaw, Chad A.
   Westbrook, Thomas F.
TI The spliceosome is a therapeutic vulnerability in MYC-driven cancer
SO NATURE
LA English
DT Article
ID c-myc; breast-cancer; gene; protein; cells; transcription; principles; initiation; growth
AB MYC (also known as c-MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its protumorigenic functions have been attributed to its ability to regulate gene expression programs(1-3). Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts(4-7). While such increases in RNA and protein production may endow cancer cells with pro-tumour hallmarks, this increase in synthesis may also generate new or heightened burden on MYC-driven cancer cells to process these macromolecules properly(8). Here we discover that the spliceosome is a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene in human mammary epithelial cells, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (such as SF3B1 and U2AF1) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total precursor messenger RNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Notably, genetic or pharmacological inhibition of the spliceosome in vivo impairs survival, tumorigenicity and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.
C1 [Hsu, Tiffany Y. -T.; Neill, Nicholas J.; Bland, Christopher S.; Sun, Tingting; Kurley, Sarah J.; Tyagi, Siddhartha; Karlin, Kristen L.; Dominguez-Vidana, Rocio; Skinner, Samuel O.; Jain, Antrix; Orellana, Mayra; Golding, Ido; Westbrook, Thomas F.] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA.
   [Hsu, Tiffany Y. -T.; Dominguez-Vidana, Rocio; Neilson, Joel R.; Westbrook, Thomas F.] Baylor Coll Med, Interdept Program Mol & Biomed Sci, Houston, TX 77030 USA.
   [Hsu, Tiffany Y. -T.] Baylor Coll Med, Med Scientist Training Program, Houston, TX 77030 USA.
   [Hsu, Tiffany Y. -T.; Simon, Lukas M.; Neill, Nicholas J.; Bland, Christopher S.; Sun, Tingting; Kurley, Sarah J.; Tyagi, Siddhartha; Karlin, Kristen L.; Dominguez-Vidana, Rocio; Hartman, Jessica D.; Renwick, Alexander; Orellana, Mayra; Shaw, Chad A.; Westbrook, Thomas F.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.
   [Marcotte, Richard; Sayad, Azin] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2C4, Canada.
   [Echeverria, Gloria V.; Neilson, Joel R.; Cooper, Thomas A.] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA.
   [Echeverria, Gloria V.; Cooper, Thomas A.] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA.
   [Echeverria, Gloria V.; Cooper, Thomas A.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.
   [Scorsone, Kathleen; Bernardi, Ronald J.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA.
   [Skinner, Samuel O.; Golding, Ido] Univ Illinois, Dept Phys, Urbana, IL 61801 USA.
   [Lagisetti, Chandraiah] SRI Int, Ctr Chem Biol, Biosci Div, Menlo Pk, CA 94025 USA.
   [Zhang, Xiang H-F.] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA.
   [Neel, Benjamin G.] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 2J7, Canada.
C3 Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; University of Illinois System; University of Illinois Urbana-Champaign; SRI International; Baylor College of Medicine; University of Toronto
RP Westbrook, TF (corresponding author), Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA.
EM thomasw@bcm.edu
FU NIH [NCI 1F30CA180447, 1R01CA178039-01, U54-CA149196]; CPRIT [RP101499, RP120583]; Gillson Longenbaugh Foundation; Alex's Lemonade Stand Foundation; Susan G. Komen for the Cure [KG090355]; DOD Breast Cancer Research Program [BC120604];  [NCI P30CA125123]; Division Of Physics; Direct For Mathematical & Physical Scien [1147498] Funding Source: National Science Foundation; National Cancer Institute [P30CA125123] Funding Source: NIH RePORTER; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR060733] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R25GM056929] Funding Source: NIH RePORTER; CDMRP [BC120604, 542284] Funding Source: Federal RePORTER
NR 39
TC 400
Z9 484
U1 2
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 SEP 17
PY 2015
VL 525
IS 7569
BP 384
EP +
DI 10.1038/nature14985
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900045
PM 26331541
DA 2026-03-09
ER

PT J
AU Gerya, TV
   Stern, RJ
   Baes, M
   Sobolev, SV
   Whattam, SA
AF Gerya, T. V.
   Stern, R. J.
   Baes, M.
   Sobolev, S. V.
   Whattam, S. A.
TI Plate tectonics on the Earth triggered by plume-induced subduction initiation
SO NATURE
LA English
DT Article
ID mantle plumes; melt; crust; origin; geodynamics; emplacement; extraction; basalt; models; growth
AB Scientific theories of how subduction and plate tectonics began on Earth-and what the tectonic structure of Earth was before this-remain enigmatic and contentious(1). Understanding viable scenarios for the onset of subduction and plate tectonics(2,3) is hampered by the fact that subduction initiation processes must have been markedly different before the onset of global plate tectonics because most present-day subduction initiation mechanisms require acting plate forces and existing zones of lithospheric weakness, which are both consequences of plate tectonics(4). However, plume-induced subduction initiation(5-9) could have started the first subduction zone without the help of plate tectonics. Here, we test this mechanism using high-resolution three-dimensional numerical thermomechanical modelling. We demonstrate that three key physical factors combine to trigger self-sustained subduction: (1) a strong, negatively buoyant oceanic lithosphere; (2) focused magmatic weakening and thinning of lithosphere above the plume; and (3) lubrication of the slab interface by hydrated crust. We also show that plume-induced subduction could only have been feasible in the hotter early Earth for old oceanic plates. In contrast, younger plates favoured episodic lithospheric drips rather than self-sustained subduction and global plate tectonics.
C1 [Gerya, T. V.] ETH, Dept Earth Sci, CH-8092 Zurich, Switzerland.
   [Stern, R. J.] Univ Texas Dallas, Geosci Dept, Richardson, TX 75083 USA.
   [Baes, M.; Sobolev, S. V.] GFZ German Res Ctr Geosci, D-14473 Potsdam, Germany.
   [Sobolev, S. V.] Univ Potsdam, Inst Earth & Environm Sci, D-14476 Potsdam, Germany.
   [Whattam, S. A.] Korea Univ, Dept Earth & Environm Sci, Seoul 136701, South Korea.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Texas System; University of Texas Dallas; Helmholtz Association; GFZ Helmholtz Centre for Geosciences; University of Potsdam; Korea University
RP Gerya, TV (corresponding author), ETH, Dept Earth Sci, Sonneggstr 5, CH-8092 Zurich, Switzerland.
EM taras.gerya@erdw.ethz.ch
FU ERC ITN project ZIP; SNF project Swiss-AlpArray; SNF [200021_149252]; ETH [ETH-37_11-2]; SNF short scientific visits program; Swiss National Science Foundation (SNF) [200021_149252] Funding Source: Swiss National Science Foundation (SNF)
NR 60
TC 345
Z9 398
U1 15
U2 337
PU NATURE PUBLISHING 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 12
PY 2015
VL 527
IS 7577
BP 221
EP +
DI 10.1038/nature15752
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700042
PM 26560300
DA 2026-03-09
ER

PT J
AU Eckert, D
   Jauzac, M
   HuanYuan, S
   Kneib, JP
   Erben, T
   Israel, H
   Jullo, E
   Klein, M
   Massey, R
   Richard, J
   Tchernin, C
AF Eckert, Dominique
   Jauzac, Mathilde
   HuanYuan, Shan
   Kneib, Jean-Paul
   Erben, Thomas
   Israel, Holger
   Jullo, Eric
   Klein, Matthias
   Massey, Richard
   Richard, Johan
   Tchernin, Celine
TI Warm-hot baryons comprise 5-10 per cent of filaments in the cosmic web
SO NATURE
LA English
DT Article
ID hubble-frontier-fields; large-scale filament; intergalactic medium; galaxy clusters; chandra view; dark-matter; abell 2744; catalog; merger; gas
AB Observations of the cosmic microwave background indicate that baryons account for 5 per cent of the Universe's total energy content(1). In the local Universe, the census of all observed baryons falls short of this estimate by a factor of two(2,3). Cosmological simulations indicate that the missing baryons have not condensed into virialized haloes, but reside throughout the filaments of the cosmic web (where matter density is larger than average) as a low-density plasma at temperatures of 10(5)-10(7) kelvin, known as the warm-hot intergalactic medium(3-6). There have been previous claims of the detection of warm-hot baryons along the line of sight to distant blazars(7-10) and of hot gas between interacting clusters(11-14). These observations were, however, unable to trace the large-scale filamentary structure, or to estimate the total amount of warm-hot baryons in a representative volume of the Universe. Here we report X-ray observations of filamentary structures of gas at 10(7) kelvin associated with the galaxy cluster Abell 2744. Previous observations of this cluster15 were unable to resolve and remove coincidental X-ray point sources. After subtracting these, we find hot gas structures that are coherent over scales of 8 megaparsecs. The filaments coincide with over-densities of galaxies and dark matter, with 5-10 per cent of their mass in baryonic gas. This gas has been heated up by the cluster's gravitational pull and is now feeding its core. Our findings strengthen evidence for a picture of the Universe in which a large fraction of the missing baryons reside in the filaments of the cosmic web.
C1 [Eckert, Dominique; Tchernin, Celine] Univ Geneva, Dept Astron, CH-1290 Versoix, Switzerland.
   [Eckert, Dominique] INAF IASF Milano, I-20133 Milan, Italy.
   [Jauzac, Mathilde; Israel, Holger; Massey, Richard] Univ Durham, Dept Phys, Inst Computat Cosmol, Durham DH1 3LE, England.
   [Jauzac, Mathilde] Univ KwaZulu Natal, Sch Math Sci, Astrophys & Cosmol Res Unit, ZA-4041 Durban, South Africa.
   [HuanYuan, Shan; Kneib, Jean-Paul] Observ Sauverny, Ecole Polytech Fed Lausanne, Astrophys Lab, CH-1290 Versoix, Switzerland.
   [Kneib, Jean-Paul; Jullo, Eric] Aix Marseille Univ, CNRS, UMR 7326, LAM, F-13388 Marseille, France.
   [Erben, Thomas; Klein, Matthias] Argelander Inst Astron, D-53121 Bonn, Germany.
   [Richard, Johan] Univ Lyon 1, CRAL, Observ Lyon, F-69561 St Genis Laval, France.
C3 University of Geneva; Istituto Nazionale Astrofisica (INAF); Durham University; University of Kwazulu Natal; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Aix-Marseille Universite; University of Bonn; Universite Lyon 1
RP Eckert, D (corresponding author), Univ Geneva, Dept Astron, Chemin Ecogia 16, CH-1290 Versoix, Switzerland.
EM Dominique.Eckert@unige.ch
FU ESA Member States; NASA; UK Science and Technology Facilities Council [ST/L00075X/1, ST/H005234/1]; Leverhulme trust [PLP-2011-003]; Royal Society; ERC advanced grant LIDA; CNRS; Marie Curie International Incoming Fellowship within the 7th European Community Framework Programme; NSFC of China [11103011]; Deutsche Forschungsgemeinschaft through the Transregional Collaborative Research Centre [TR 33]; CNES; ERC starting grant CALENDS; STFC [ST/H005234/1, ST/L00075X/1] Funding Source: UKRI; Science and Technology Facilities Council [ST/L00075X/1, ST/H005234/1] Funding Source: researchfish
NR 54
TC 158
Z9 165
U1 0
U2 11
PU NATURE PUBLISHING 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 3
PY 2015
VL 528
IS 7580
BP 105
EP +
DI 10.1038/nature16058
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000056
PM 26632589
DA 2026-03-09
ER

PT J
AU Zhen, B
   Hsu, CW
   Igarashi, Y
   Lu, L
   Kaminer, I
   Pick, A
   Chua, SL
   Joannopoulos, JD
   Soljacic, M
AF Zhen, Bo
   Hsu, Chia Wei
   Igarashi, Yuichi
   Lu, Ling
   Kaminer, Ido
   Pick, Adi
   Chua, Song-Liang
   Joannopoulos, John D.
   Soljacic, Marin
TI Spawning rings of exceptional points out of Dirac cones
SO NATURE
LA English
DT Article
ID parity-time symmetry; microcavity; physics; lasers
AB The Dirac cone underlies many unique electronic properties of graphene(1) and topological insulators, and its band structure-two conical bands touching at a single point-has also been realized for photons in waveguide arrays(2), atoms in optical lattices(3), and through accidental degeneracy(4,5). Deformation of the Dirac cone often reveals intriguing properties; an example is the quantum Hall effect, where a constant magnetic field breaks the Dirac cone into isolated Landau levels. A seemingly unrelated phenomenon is the exceptional point(6,7), also known as the parity-time symmetry breaking point(8-11), where two resonances coincide in both their positions and widths. Exceptional points lead to counter-intuitive phenomena such as loss-induced transparency(12), unidirectional transmission or reflection(11,13,14), and lasers with reversed pump dependence(15) or single-mode operation(16,17). Dirac cones and exceptional points are connected: it was theoretically suggested that certain non-Hermitian perturbations can deform a Dirac cone and spawn a ring of exceptional points(18-20). Here we experimentally demonstrate such an 'exceptional ring' in a photonic crystal slab. Angle-resolved reflection measurements of the photonic crystal slab reveal that the peaks of reflectivity follow the conical band structure of a Dirac cone resulting from accidental degeneracy, whereas the complex eigenvalues of the system are deformed into a two-dimensional flat band enclosed by an exceptional ring. This deformation arises from the dissimilar radiation rates of dipole and quadrupole resonances, which play a role analogous to the loss and gain in parity-time symmetric systems. Our results indicate that the radiation existing in any open system can fundamentally alter its physical properties in ways previously expected only in the presence of material loss and gain.
C1 [Zhen, Bo; Hsu, Chia Wei; Igarashi, Yuichi; Lu, Ling; Kaminer, Ido; Pick, Adi; Joannopoulos, John D.; Soljacic, Marin] MIT, Elect Res Lab, Cambridge, MA 02139 USA.
   [Hsu, Chia Wei] Yale Univ, Dept Appl Phys, New Haven, CT 06520 USA.
   [Igarashi, Yuichi] NEC Corp Ltd, Smart Energy Res Labs, Tsukuba, Ibaraki 3058501, Japan.
   [Pick, Adi] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.
   [Chua, Song-Liang] DSO Natl Labs, Singapore 118230, Singapore.
C3 Massachusetts Institute of Technology (MIT); Yale University; NEC Corporation; Harvard University
RP Zhen, B (corresponding author), MIT, Elect Res Lab, Cambridge, MA 02139 USA.
EM bozhen@mit.edu; chiawei.hsu@yale.edu
FU Army Research Office through Institute for Soldier Nanotechnologies [W911NF-07-D0004, W911NF-13-D-0001]; S3TEC, an Energy Frontier Research Center - US Department of Energy [DE-SC0001299]; Materials Research Science and Engineering Center of the National Science Foundation [DMR-1419807]; Marie Curie grant [328853-MC-BSiCS]
NR 30
TC 749
Z9 822
U1 20
U2 447
PU NATURE PUBLISHING 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 17
PY 2015
VL 525
IS 7569
BP 354
EP 358
DI 10.1038/nature14889
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900038
PM 26352476
DA 2026-03-09
ER

PT J
AU Schulz, R
   Hilchenbach, M
   Langevin, Y
   Kissel, J
   Silen, J
   Briois, C
   Engrand, C
   Hornung, K
   Baklouti, D
   Bardyn, A
   Cottin, H
   Fischer, H
   Fray, N
   Godard, M
   Lehto, H
   Le Roy, L
   Merouane, S
   Orthous-Daunay, FR
   Paquette, J
   Rynö, J
   Siljeström, S
   Stenzel, O
   Thirkell, L
   Varmuza, K
   Zaprudin, B
AF Schulz, Rita
   Hilchenbach, Martin
   Langevin, Yves
   Kissel, Jochen
   Silen, Johan
   Briois, Christelle
   Engrand, Cecile
   Hornung, Klaus
   Baklouti, Donia
   Bardyn, Anais
   Cottin, Herve
   Fischer, Henning
   Fray, Nicolas
   Godard, Marie
   Lehto, Harry
   Le Roy, Lena
   Merouane, Sihane
   Orthous-Daunay, Francois-Regis
   Paquette, John
   Ryno, Jouni
   Siljestrom, Sandra
   Stenzel, Oliver
   Thirkell, Laurent
   Varmuza, Kurt
   Zaprudin, Boris
TI Comet 67P/Churyumov-Gerasimenko sheds dust coat accumulated over the past four years
SO NATURE
LA English
DT Article
ID solar-system; deep impact; water ice; particles; cosima
AB Comets are composed of dust and frozen gases. The ices are mixed with the refractory material either as an icy conglomerate(1), or as an aggregate of pre-solar grains (grains that existed prior to the formation of the Solar System), mantled by an ice layer(2,3). The presence of water-ice grains in periodic comets is now well established(4-6). Modelling of infrared spectra obtained about ten kilometres from the nucleus of comet Hartley 2 suggests that larger dust particles are being physically decoupled from fine-grained water-ice particles that may be aggregates(7), which supports the icy-conglomerate model. It is known that comets build up crusts of dust that are subsequently shed as they approach perihelion(8-10). Micrometre-sized interplanetary dust particles collected in the Earth's stratosphere and certain micrometeorites are assumed to be of cometary origin(11-13). Here we report that grains collected from the Jupiter-family comet 67P/Churyumov-Gerasimenko come from a dusty crust that quenches the material outflow activity at the comet surface(14). The larger grains (exceeding 50 micrometres across) are fluffy (with porosity over 50 per cent), and many shattered when collected on the target plate, suggesting that they are agglomerates of entities in the size range of interplanetary dust particles. Their surfaces are generally rich in sodium, which explains the high sodium abundance in cometary meteoroids(15). The particles collected to date therefore probably represent parent material of interplanetary dust particles. This argues against comet dust being composed of a silicate core mantled by organic refractory material and then by a mixture of water-dominated ices(2,3). At its previous recurrence (orbital period 6.5 years), the comet's dust production doubled when it was between 2.7 and 2.5 astronomical units from the Sun(14), indicating that this was when the nucleus shed its mantle. Once the mantle is shed, unprocessed material starts to supply the developing coma, radically changing its dust component, which then also contains icy grains, as detected during encounters with other comets closer to the Sun(4,5).
C1 [Schulz, Rita] European Space Agcy, Sci Support Off, Keplerlaan 1,Postbus 299, NL-2200 AG Noordwijk, Netherlands.
   [Hilchenbach, Martin; Kissel, Jochen; Fischer, Henning; Merouane, Sihane; Paquette, John; Stenzel, Oliver] Max Planck Inst Sonnensyst Forsch, D-37077 Gottingen, Germany.
   [Langevin, Yves; Baklouti, Donia] Univ Paris Sud, CNRS, Inst Astrophys Spatiale, F-91405 Orsay, France.
   [Silen, Johan; Ryno, Jouni] Finnish Meteorol Inst, Observat Serv, FI-00560 Helsinki, Finland.
   [Briois, Christelle; Bardyn, Anais; Thirkell, Laurent] Univ Orleans, CNRS, Lab Phys & Chim Environm & Espace LPC2E, F-45071 Orleans, France.
   [Engrand, Cecile; Godard, Marie] Univ Paris Sud, CNRS, IN2P3, Ctr Sci Nucl & Sci Mat,UMR8609, F-91405 Orsay, France.
   [Hornung, Klaus] Univ Bundeswehr, D-85577 Neubiberg, Germany.
   [Bardyn, Anais; Cottin, Herve; Fray, Nicolas] Univ Paris Est Creteil, LISA, CNRS, UMR 7583, F-94000 Creteil, France.
   [Lehto, Harry; Zaprudin, Boris] Univ Paris Diderot, Inst Pierre Simon Laplace, F-94000 Creteil, France.
   [Le Roy, Lena] Univ Turku, Dept Phys & Astron, Tuorla Observ Vaisantie, Piikkio 21500, Finland.
   [Orthous-Daunay, Francois-Regis] Univ Bern, CSH, CH-3012 Bern, Switzerland.
   [Siljestrom, Sandra] Univ Grenoble Alpes, CNRS, Inst Planetol & Astrophys Grenoble, F-38000 Grenoble, France.
   [Varmuza, Kurt] SP Tech Res Inst Sweden, Dept Chem Mat & Surfaces, S-50115 Boras, Sweden.
   Vienna Univ Technol, Inst Stat & Wahrscheinlichkeitstheorie, A-1040 Vienna, Austria.
C3 Max Planck Society; Universite Paris Saclay; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); Finnish Meteorological Institute; Centre National de la Recherche Scientifique (CNRS); Universite de Orleans; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Universite Paris Saclay; Bundeswehr University Munich; Universite Paris-Est-Creteil-Val-de-Marne (UPEC); Universite Paris Cite; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Universite Paris Cite; Universite Paris Saclay; University of Turku; University of Bern; Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Centre National de la Recherche Scientifique (CNRS); Institut de Planetologie et d'Astrophysique de Grenoble (IPAG); SP Technical Research Institute of Sweden; Technische Universitat Wien
RP Schulz, R (corresponding author), European Space Agcy, Sci Support Off, Keplerlaan 1,Postbus 299, NL-2200 AG Noordwijk, Netherlands.
EM rita.schulz@esa.int
FU national funding agencies of Germany (DLR) [50QP1302]; national funding agencies of France (CNES); national funding agencies of Austria; national funding agencies of Finland; ESA Technical Directorate; Swedish National Space Board [121/11]; Austrian Science Fund (FWF) [P26871] Funding Source: Austrian Science Fund (FWF); Swedish National Space Agency (SNSA) [121/11, 121/11] Funding Source: Swedish National Space Agency (SNSA)
NR 30
TC 144
Z9 154
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 FEB 12
PY 2015
VL 518
IS 7538
BP 216
EP 218
DI 10.1038/nature14159
PG 3
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300034
PM 25624103
DA 2026-03-09
ER

PT J
AU Eisenstein, M
AF Eisenstein, Michael
TI Seeking answers amid a toxic debate
SO NATURE
LA English
DT Article
ID field
NR 11
TC 0
Z9 0
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 MAY 21
PY 2015
VL 521
IS 7552
BP S52
EP S55
DI 
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA DF8BJ
UT WOS:000371581600001
DA 2026-03-09
ER

PT J
AU Koch, M
   Varela, L
   Kim, JG
   Kim, JD
   Hernández-Nuño, F
   Simonds, SE
   Castorena, CM
   Vianna, CR
   Elmquist, JK
   Morozov, YM
   Rakic, P
   Bechmann, I
   Cowley, MA
   Szigeti-Buck, K
   Dietrich, MO
   Gao, XB
   Diano, S
   Horvath, TL
AF Koch, Marco
   Varela, Luis
   Kim, Jae Geun
   Kim, Jung Dae
   Hernandez-Nuno, Francisco
   Simonds, Stephanie E.
   Castorena, Carlos M.
   Vianna, Claudia R.
   Elmquist, Joel K.
   Morozov, Yury M.
   Rakic, Pasko
   Bechmann, Ingo
   Cowley, Michael A.
   Szigeti-Buck, Klara
   Dietrich, Marcelo O.
   Gao, Xiao-Bing
   Diano, Sabrina
   Horvath, Tamas L.
TI Hypothalamic POMC neurons promote cannabinoid-induced feeding
SO NATURE
LA English
DT Article
ID uncoupling protein-2; food-intake; mitochondrial dynamics; endocannabinoid system; neuropeptide-y; neuroendocrine; nucleus; obesity; localization; circuits
AB Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for the central regulation of food intake. Here we test whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB1R activity increases feeding, and notably, CB1R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide alpha-melanocyte-stimulating hormone, and the opioid peptide beta-endorphin. CB1R activation selectively increases beta-endorphin but not alpha-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids.
C1 [Koch, Marco; Varela, Luis; Kim, Jae Geun; Kim, Jung Dae; Hernandez-Nuno, Francisco; Szigeti-Buck, Klara; Dietrich, Marcelo O.; Gao, Xiao-Bing; Diano, Sabrina; Horvath, Tamas L.] Yale Univ, Sch Med, Sect Comparat Med, Program Integrat Cell Signaling & Neurobiol Metab, New Haven, CT 06520 USA.
   [Koch, Marco; Bechmann, Ingo] Univ Leipzig, Inst Anat, D-04103 Leipzig, Germany.
   [Kim, Jung Dae; Diano, Sabrina; Horvath, Tamas L.] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT 06520 USA.
   [Simonds, Stephanie E.; Cowley, Michael A.] Monash Univ, Dept Physiol, Obes & Diabet Inst, Clayton, Vic 3800, Australia.
   [Castorena, Carlos M.; Vianna, Claudia R.; Elmquist, Joel K.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Endocrinol & Metab, Dallas, TX 75390 USA.
   [Morozov, Yury M.; Rakic, Pasko; Dietrich, Marcelo O.; Diano, Sabrina; Horvath, Tamas L.] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06520 USA.
   [Rakic, Pasko; Horvath, Tamas L.] Yale Univ, Sch Med, Kavli Inst Neurosci, New Haven, CT 06520 USA.
C3 Yale University; Leipzig University; Yale University; Monash University; University of Texas System; University of Texas Southwestern Medical Center; Yale University; Yale University
RP Horvath, TL (corresponding author), Yale Univ, Sch Med, Sect Comparat Med, Program Integrat Cell Signaling & Neurobiol Metab, 333 Cedar St, New Haven, CT 06520 USA.
EM tamas.horvath@yale.edu
FU US National Institutes of Health [DP1 DK098058, R01 DK097566, R01 AG040236, P01 NS062686]; American Diabetes Association; Klarmann Family Foundation; Helmholtz Society (ICEMED); Deutsche Forschungsgemeinschaft [SFB 1052/1]
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NR 54
TC 323
Z9 365
U1 3
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 MAR 5
PY 2015
VL 519
IS 7541
BP 45
EP U72
DI 10.1038/nature14260
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC4EQ
UT WOS:000350304000032
PM 25707796
DA 2026-03-09
ER

PT J
AU Mnih, V
   Kavukcuoglu, K
   Silver, D
   Rusu, AA
   Veness, J
   Bellemare, MG
   Graves, A
   Riedmiller, M
   Fidjeland, AK
   Ostrovski, G
   Petersen, S
   Beattie, C
   Sadik, A
   Antonoglou, I
   King, H
   Kumaran, D
   Wierstra, D
   Legg, S
   Hassabis, D
AF Mnih, Volodymyr
   Kavukcuoglu, Koray
   Silver, David
   Rusu, Andrei A.
   Veness, Joel
   Bellemare, Marc G.
   Graves, Alex
   Riedmiller, Martin
   Fidjeland, Andreas K.
   Ostrovski, Georg
   Petersen, Stig
   Beattie, Charles
   Sadik, Amir
   Antonoglou, Ioannis
   King, Helen
   Kumaran, Dharshan
   Wierstra, Daan
   Legg, Shane
   Hassabis, Demis
TI Human-level control through deep reinforcement learning
SO NATURE
LA English
DT Article
ID recognition
AB The theory of reinforcement learning provides a normative account', deeply rooted in psychological' and neuroscientifie perspectives on animal behaviour, of how agents may optimize their control of an environment. To use reinforcement learning successfully in situations approaching real-world complexity, however, agents are confronted with a difficult task: they must derive efficient representations of the environment from high-dimensional sensory inputs, and use these to generalize past experience to new situations. Remarkably, humans and other animals seem to solve this problem through a harmonious combination of reinforcement learning and hierarchical sensory processing systems4'5, the former evidenced by a wealth of neural data revealing notable parallels between the phasic signals emitted by dopaminergic neurons and temporal difference reinforcement learning algorithms'. While reinforcement learning agents have achieved some successes in a variety of domains", their applicability has previously been limited to domains in which useful features can be handcrafted, or to domains with fully observed, low-dimensional state spaces. Here we use recent advances in training deep neural networks'" to develop a novel artificial agent, termed a deep Q-network, that can learn successful policies directly from high-dimensional sensory inputs using end-to-end reinforcement learning. We tested this agent on the challenging domain of classic Atari 2600 games". We demonstrate that the deep Q-network agent, receiving only the pixels and the game score as inputs, was able to surpass the performance of all previous algorithms and achieve a level comparable to that of a professional human games tester across a set of 49 games, using the same algorithm, network architecture and hyperparameters. This work bridges the divide between high-dimensional sensory inputs and actions, resulting in the first artificial agent that is capable of learning to excel at a diverse array of challenging tasks.
C1 [Mnih, Volodymyr; Kavukcuoglu, Koray; Silver, David; Rusu, Andrei A.; Veness, Joel; Bellemare, Marc G.; Graves, Alex; Riedmiller, Martin; Fidjeland, Andreas K.; Ostrovski, Georg; Petersen, Stig; Beattie, Charles; Sadik, Amir; Antonoglou, Ioannis; King, Helen; Kumaran, Dharshan; Wierstra, Daan; Legg, Shane; Hassabis, Demis] Google DeepMind, London EC4A 3TW, England.
C3 Alphabet Inc.; DeepMind; Google Incorporated
RP Kavukcuoglu, K (corresponding author), Google DeepMind, 5 New St Sq, London EC4A 3TW, England.
EM demishassabis@google.com
NR 30
TC 20806
Z9 24610
U1 383
U2 5556
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 26
PY 2015
VL 518
IS 7540
BP 529
EP 533
DI 10.1038/nature14236
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC1JP
UT WOS:000350097300045
PM 25719670
DA 2026-03-09
ER

PT J
AU Dewar, JM
   Budzowska, M
   Walter, JC
AF Dewar, James M.
   Budzowska, Magda
   Walter, Johannes C.
TI The mechanism of DNA replication termination in vertebrates
SO NATURE
LA English
DT Article
ID topoisomerase-ii; cross-link; simian-virus-40 dna; mcm2-7 helicase; t-antigen; association; chromatin; complex; cdc45; gins
AB Eukaryotic DNA replication terminates when replisomes from adjacent replication origins converge. Termination involves local completion of DNA synthesis, decatenation of daughter molecules and replisome disassembly. Termination has been difficult to study because termination events are generally asynchronous and sequence nonspecific. To overcome these challenges, we paused converging replisomes with a site-specific barrier in Xenopus egg extracts. Upon removal of the barrier, forks underwent synchronous and site-specific termination, allowing mechanistic dissection of this process. We show that DNA synthesis does not slow detectably as forks approach each other, and that leading strands pass each other unhindered before undergoing ligation to downstream lagging strands. Dissociation of the replicative CMG helicase (comprising CDC45, MCM2-7 and GINS) occurs only after the final ligation step, and is not required for completion of DNA synthesis, strongly suggesting that converging CMGs pass one another and dissociate from double-stranded DNA. This termination mechanism allows rapid completion of DNA synthesis while avoiding premature replisome disassembly.
C1 [Dewar, James M.; Budzowska, Magda; Walter, Johannes C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.
   [Walter, Johannes C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Howard Hughes Med Inst, Boston, MA 02115 USA.
C3 Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Harvard University; Harvard Medical School
RP Walter, JC (corresponding author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.
EM johannes_walter@hms.harvard.edu
FU NIH [GM62267, GM80676]
NR 50
TC 121
Z9 154
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 SEP 17
PY 2015
VL 525
IS 7569
BP 345
EP +
DI 10.1038/nature14887
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900036
PM 26322582
DA 2026-03-09
ER

PT J
AU Wang, JH
   Cao, JL
   Dickson, AL
   Poss, KD
AF Wang, Jinhu
   Cao, Jingli
   Dickson, Amy L.
   Poss, Kenneth D.
TI Epicardial regeneration is guided by cardiac outflow tract and Hedgehog signalling
SO NATURE
LA English
DT Article
ID zebrafish heart regeneration; motor-neuron induction; sonic-hedgehog; in-vivo; transcription factors; floor plate; cells; injury; cardiomyocytes; notochord
AB In response to cardiac damage, a mesothelial tissue layer enveloping the heart called the epicardium is activated to proliferate and accumulate at the injury site. Recent studies have implicated the epicardium in multiple aspects of cardiac repair: as a source of paracrine signals for cardiomyocyte survival or proliferation; a supply of perivascular cells and possibly other cell types such as cardiomyocytes; and as a mediator of inflammation1-9. However, the biology and dynamism of the adult epicardium is poorly understood. To investigate this, we created a transgenic line to ablate the epicardial cell population in adult zebrafish. Here we find that genetic depletion of the epicardium after myocardial loss inhibits cardiomyocyte proliferation and delays muscle regeneration. The epicardium vigorously regenerates after its ablation, through proliferation and migration of spared epicardial cells as a sheet to cover the exposed ventricular surface in a wave from the chamber base towards its apex. By reconstituting epicardial regeneration ex vivo, we show that extirpation of the bulbous arteriosus-a distinct, smooth-muscle-rich tissue structure that distributes outflow from the ventricle-prevents epicardial regeneration. Conversely, experimental repositioning of the bulbous arteriosus by tissue recombination initiates epicardial regeneration and can govern its direction. Hedgehog (Hh) ligand is expressed in the bulbous arteriosus, and treatment with a Hh signalling antagonist arrests epicardial regeneration and blunts the epicardial response to muscle injury. Transplantation of Sonic hedgehog (Shh)-soaked beads at the ventricular base stimulates epicardial regeneration after bulbous arteriosus removal, indicating that Hh signalling can substitute for the influence of the outflow tract. Thus, the ventricular epicardium has pronounced regenerative capacity, regulated by the neighbouring cardiac outflow tract and Hh signalling. These findings extend our understanding of tissue interactions during regeneration and have implications for mobilizing epicardial cells for therapeutic heart repair.
C1 [Wang, Jinhu; Cao, Jingli; Dickson, Amy L.; Poss, Kenneth D.] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA.
   [Wang, Jinhu; Cao, Jingli; Dickson, Amy L.; Poss, Kenneth D.] Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC 27710 USA.
C3 Duke University; Duke University; Howard Hughes Medical Institute
RP Poss, KD (corresponding author), Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA.
EM kenneth.poss@duke.edu
FU American Heart Association; National Institutes of Health [HL081674]; American Federation for Aging Research
NR 29
TC 163
Z9 195
U1 0
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 JUN 11
PY 2015
VL 522
IS 7555
BP 226
EP +
DI 10.1038/nature14325
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700041
PM 25938716
DA 2026-03-09
ER

PT J
AU Wei, J
   Tong, L
AF Wei, Jia
   Tong, Liang
TI Crystal structure of the 500-kDa yeast acetyl-CoA carboxylase holoenzyme dimer
SO NATURE
LA English
DT Article
ID bacterial biotin carboxylase; fatty-acid synthesis; carboxyltransferase domain; pyruvate-carboxylase; coenzyme; dimerization; inhibition; insights; subunit; complex
AB Acetyl-CoA carboxylase (ACC) has crucial roles in fatty acid metabolism and is an attractive target for drug discovery against diabetes, cancer and other diseases(1-6). Saccharomyces cerevisiae ACC (ScACC) is crucial for the production of very-long-chain fatty acids and the maintenance of the nuclear envelope(7,8). ACC contains biotin carboxylase (BC) and carboxyltransferase (CT) activities, and its biotin is linked covalently to the biotin carboxyl carrier protein (BCCP). Most eukaryotic ACCs are 250-kilodalton (kDa), multi-domain enzymes and function as homodimers and higher oligomers. They contain a unique, 80-kDa central region that shares no homology with other proteins. Although the structures of the BC, CT and BCCP domains and other biotin-dependent carboxylase holoenzymes are known(1,9-14), there is currently no structural information on the ACC holoenzyme. Here we report the crystal structure of the full-length, 500-kDa holoenzyme dimer of ScACC. The structure is remarkably different from that of the other biotin-dependent carboxylases. The central region contains five domains and is important for positioning the BC and CT domains for catalysis. The structure unexpectedly reveals a dimer of the BC domain and extensive conformational differences compared to the structure of the BC domain alone, which is a monomer. These structural changes reveal why the BC domain alone is catalytically inactive and define the molecular mechanism for the inhibition of eukaryotic ACC by the natural product soraphen A(15,16) and by phosphorylation of a Ser residue just before the BC domain core in mammalian ACC. The BC and CT active sites are separated by 80 angstrom, and the entire BCCP domain must translocate during catalysis.
C1 [Wei, Jia; Tong, Liang] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA.
C3 Columbia University
RP Tong, L (corresponding author), Columbia Univ, Dept Biol Sci, New York, NY 10027 USA.
EM ltong@columbia.edu
FU NIH [S100D012018, R01DK067238]
NR 30
TC 71
Z9 87
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 OCT 29
PY 2015
VL 526
IS 7575
BP 723
EP 727
DI 10.1038/nature15375
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CU8ZH
UT WOS:000363832100053
PM 26458104
DA 2026-03-09
ER

PT J
AU Rossi, A
   Kontarakis, Z
   Gerri, C
   Nolte, H
   Hölper, S
   Krüger, M
   Stainier, DYR
AF Rossi, Andrea
   Kontarakis, Zacharias
   Gerri, Claudia
   Nolte, Hendrik
   Hoelper, Soraya
   Krueger, Marcus
   Stainier, Didier Y. R.
TI Genetic compensation induced by deleterious mutations but not gene knockdowns
SO NATURE
LA English
DT Article
ID egfl7; identification; elastogenesis; expression; phenotypes; knockout; talen
AB Cells sense their environment and adapt to it by fine-tuning their transcriptome. Wired into this network of gene expression control are mechanisms to compensate for gene dosage. The increasing use of reverse genetics in zebrafish, and other model systems, has revealed profound differences between the phenotypes caused by genetic mutations and those caused by gene knockdowns at many loci(1-3), an observation previously reported in mouse and Arabidopsis(4-7). To identify the reasons underlying the phenotypic differences between mutants and knockdowns, we generated mutations in zebrafish egfl7, an endothelial extracellular matrix gene of therapeutic interest, as well as in vegfaa. Here we show that egfl7 mutants do not show any obvious phenotypes while animals injected with egfl7 morpholino (morphants) exhibit severe vascular defects. We further observe that egfl7 mutants are less sensitive than their wild-type siblings to Egfl7 knockdown, arguing against residual protein function in the mutants or significant off-target effects of the morpholinos when used at a moderate dose. Comparing egfl7 mutant and morphant proteomes and transcriptomes, we identify a set of proteins and genes that are upregulated in mutants but not in morphants. Among them are extracellular matrix genes that can rescue egfl7 morphants, indicating that they could be compensating for the loss of Egfl7 function in the phenotypically wild-type egfl7 mutants. Moreover, egfl7 CRISPR interference, which obstructs transcript elongation and causes severe vascular defects, does not cause the upregulation of these genes. Similarly, vegfaa mutants but not morphants show an upregulation of vegfab. Taken together, these data reveal the activation of a compensatory network to buffer against deleterious mutations, which was not observed after translational or transcriptional knockdown.
C1 [Rossi, Andrea; Kontarakis, Zacharias; Gerri, Claudia; Nolte, Hendrik; Hoelper, Soraya; Krueger, Marcus; Stainier, Didier Y. R.] Max Planck Inst Heart & Lung Res, D-61231 Bad Nauheim, Germany.
C3 Max Planck Society
RP Stainier, DYR (corresponding author), Max Planck Inst Heart & Lung Res, D-61231 Bad Nauheim, Germany.
EM didier.stainier@mpi-bn.mpg.de
FU Max Planck Society; Packard foundation; EMBO
NR 29
TC 966
Z9 1220
U1 6
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 AUG 13
PY 2015
VL 524
IS 7564
BP 230
EP +
DI 10.1038/nature14580
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900034
PM 26168398
DA 2026-03-09
ER

PT J
AU Kaufman, AM
   Lester, BJ
   Foss-Feig, M
   Wall, ML
   Rey, AM
   Regal, CA
AF Kaufman, A. M.
   Lester, B. J.
   Foss-Feig, M.
   Wall, M. L.
   Rey, A. M.
   Regal, C. A.
TI Entangling two transportable neutral atoms via local spin exchange
SO NATURE
LA English
DT Article
ID optical lattice; ultracold atoms; entanglement; information; trap; ions
AB To advance quantum information science, physical systems are sought that meet the stringent requirements for creating and preserving quantum entanglement. In atomic physics, robust two-qubit entanglement is typically achieved by strong, long-range interactions in the form of either Coulomb interactions between ions or dipolar interactions between Rydberg atoms(1-4). Although such interactions allow fast quantum gates, the interacting atoms must overcome the associated coupling to the environment and crosstalk among qubits(5-)8. Local interactions, such as those requiring substantial wavefunction overlap, can alleviate these detrimental effects; however, such interactions present a new challenge: to distribute entanglement, qubits must be transported, merged for interaction, and then isolated for storage and subsequent operations. Here we show how, using a mobile optical tweezer, it is possible to prepare and locally entangle two ultracold neutral atoms, and then separate them while preserving their entanglement(9-11). Ground-state neutral atom experiments have measured dynamics consistent with spin entanglement(10,12,13), and have detected entanglement with macroscopic observables(14,15); we are now able to demonstrate position-resolved two-particle coherence via application of a local gradient and parity measurements'. This new entanglement-verification protocol could be applied to arbitrary spin-entangled states of spatially separated atoms(16,17). The local entangling operation is achieved via spin-exchange interactions(9-11), and quantum tunnelling is used to combine and separate atoms. These techniques provide a framework for dynamically entangling remote qubits via local operations within a large-scale quantum register.
C1 [Kaufman, A. M.; Lester, B. J.; Wall, M. L.; Rey, A. M.; Regal, C. A.] NIST, JILA, Boulder, CO 80309 USA.
   [Kaufman, A. M.; Lester, B. J.; Wall, M. L.; Rey, A. M.; Regal, C. A.] Univ Colorado, Boulder, CO 80309 USA.
   [Kaufman, A. M.; Lester, B. J.; Rey, A. M.; Regal, C. A.] Univ Colorado, Dept Phys, Boulder, CO 80309 USA.
   [Foss-Feig, M.] Joint Quantum Inst, Gaithersburg, MD 20899 USA.
   [Foss-Feig, M.] NIST, Gaithersburg, MD 20899 USA.
C3 National Institute of Standards & Technology (NIST) - USA; University of Colorado System; University of Colorado Boulder; University of Colorado System; University of Colorado Boulder; National Institute of Standards & Technology (NIST) - USA
RP Regal, CA (corresponding author), NIST, JILA, Boulder, CO 80309 USA.
EM regal@colorado.edu
FU David and Lucile Packard Foundation; National Science Foundation [1125844]; Clare Boothe Luce Foundation; NSF-PIF; ARO; ARO-DARPA-OLE; AFOSR; NRC postdoctoral fellowship program; Direct For Mathematical & Physical Scien; Division Of Physics [1125844] Funding Source: National Science Foundation
NR 34
TC 123
Z9 148
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 NOV 12
PY 2015
VL 527
IS 7577
BP 208
EP +
DI 10.1038/nature16073
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700039
PM 26524533
DA 2026-03-09
ER

PT J
AU Jolma, A
   Yin, YM
   Nitta, KR
   Dave, K
   Popov, A
   Taipale, M
   Enge, M
   Kivioja, T
   Morgunova, E
   Taipale, J
AF Jolma, Arttu
   Yin, Yimeng
   Nitta, Kazuhiro R.
   Dave, Kashyap
   Popov, Alexander
   Taipale, Minna
   Enge, Martin
   Kivioja, Teemu
   Morgunova, Ekaterina
   Taipale, Jussi
TI DNA-dependent formation of transcription factor pairs alters their binding specificity
SO NATURE
LA English
DT Article
ID gene-expression; cooperative binding; protein; domain; complex; genome; sites; ets; recognition; enhancers
AB Gene expression is regulated by transcription factors (TFs), proteins that recognize short DNA sequence motifs(1-3). Such sequences are very common in the human genome, and an important determinant of the specificity of gene expression is the cooperative binding of multiple TFs to closely located motifs(4-6). However, interactions between DNA-bound TFs have not been systematically characterized. To identify TF pairs that bind cooperatively to DNA, and to characterize their spacing and orientation preferences, we have performed consecutive affinity-purification systematic evolution of ligands by exponential enrichment (CAP-SELEX) analysis of 9,400 TF-TF-DNA interactions. This analysis revealed 315 TF-TF interactions recognizing 618 heterodimeric motifs, most of which have not been previously described. The observed cooperativity occurred promiscuously between TFs from diverse structural families. Structural analysis of the TF pairs, including a novel crystal structure of MEIS1 and DLX3 bound to their identified recognition site, revealed that the interactions between the TFs were predominantly mediated by DNA. Most TF pair sites identified involved a large overlap between individual TF recognition motifs, and resulted in recognition of composite sites that were markedly different from the individual TF's motifs. Together, our results indicate that the DNA molecule commonly plays an active role in cooperative interactions that define the gene regulatory lexicon.
C1 [Jolma, Arttu; Yin, Yimeng; Nitta, Kazuhiro R.; Dave, Kashyap; Taipale, Minna; Enge, Martin; Morgunova, Ekaterina; Taipale, Jussi] Karolinska Inst, Dept Biosci & Nutr, SE-14183 Stockholm, Sweden.
   [Popov, Alexander] European Synchrotron Radiat Facil, F-38043 Grenoble, France.
   [Kivioja, Teemu; Taipale, Jussi] Univ Helsinki, Genome Scale Biol Program, FI-00014 Helsinki, Finland.
C3 Karolinska Institutet; European Synchrotron Radiation Facility (ESRF); University of Helsinki
RP Taipale, J (corresponding author), Karolinska Inst, Dept Biosci & Nutr, SE-14183 Stockholm, Sweden.
EM jussi.taipale@ki.se
FU Finnish Academy CoE in Cancer Genetics; Center for Innovative Medicine; Knut and Alice Wallenberg Foundation; Goran Gustafsson Foundation; Vetenskapsradet
NR 74
TC 406
Z9 520
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 NOV 19
PY 2015
VL 527
IS 7578
BP 384
EP +
DI 10.1038/nature15518
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9ZN
UT WOS:000365356800058
PM 26550823
DA 2026-03-09
ER

PT J
AU Altshuler, DM
   Durbin, RM
   Abecasis, GR
   Bentley, DR
   Chakravarti, A
   Clark, AG
   Donnelly, P
   Eichler, EE
   Flicek, P
   Gabriel, SB
   Gibbs, RA
   Green, ED
   Hurles, ME
   Knoppers, BM
   Korbel, JO
   Lander, ES
   Lee, C
   Lehrach, H
   Mardis, ER
   Marth, GT
   McVean, GA
   Nickerson, DA
   Wang, J
   Wilson, RK
   Boerwinkle, E
   Doddapaneni, H
   Han, Y
   Korchina, V
   Kovar, C
   Lee, S
   Muzny, D
   Reid, JG
   Zhu, YM
   Chang, YQ
   Feng, Q
   Fang, XD
   Guo, XS
   Jian, M
   Jiang, H
   Jin, X
   Lan, TM
   Li, GQ
   Li, JX
   Li, YR
   Liu, SM
   Liu, X
   Lu, Y
   Ma, XD
   Tang, MF
   Wang, B
   Wang, GB
   Wu, HL
   Wu, RH
   Xu, X
   Yin, Y
   Zhang, DD
   Zhang, WW
   Zhao, J
   Zhao, MR
   Zheng, XL
   Lander, ES
   Altshuler, DM
   Gabriel, SB
   Gupta, N
   Gharani, N
   Toji, LH
   Gerry, NP
   Resch, AM
   Flicek, P
   Barker, J
   Clarke, L
   Gil, L
   Hunt, SE
   Kelman, G
   Kulesha, E
   Leinonen, R
   McLaren, WM
   Radhakrishnan, R
   Roa, A
   Smirnov, D
   Smith, RE
   Streeter, I
   Thormann, A
   Toneva, I
   Vaughan, B
   Zheng-Bradley, X
   Bentley, DR
   Grocock, R
   Humphray, S
   James, T
   Kingsbury, Z
   Lehrach, H
   Sudbrak, R
   Albrecht, MW
   Amstislavskiy, VS
   Borodina, TA
   Lienhard, M
   Mertes, F
   Sultan, M
   Timmermann, B
   Yaspo, ML
   Mardis, ER
   Wilson, RK
   Fulton, L
   Fulton, R
   Sherry, ST
   Ananiev, V
   Belaia, Z
   Beloslyudtsev, D
   Bouk, N
   Chen, C
   Church, D
   Cohen, R
   Cook, C
   Garner, J
   Hefferon, T
   Kimelman, M
   Liu, CL
   Lopez, J
   Meric, P
   O'Sullivan, C
   Ostapchuk, Y
   Phan, L
   Ponomarov, S
   Schneider, V
   Shekhtman, E
   Sirotkin, K
   Slotta, D
   Zhang, H
   McVean, GA
   Durbin, RM
   Balasubramaniam, S
   Burton, J
   Danecek, P
   Keane, TM
   Kolb-Kokocinski, A
   McCarthy, S
   Stalker, J
   Quail, M
   Schmidt, JP
   Davies, CJ
   Gollub, J
   Webster, T
   Wong, B
   Zhan, YP
   Auton, A
   Campbell, CL
   Kong, Y
   Marcketta, A
   Yu, FL
   Antunes, L
   Bainbridge, M
   Muzny, D
   Sabo, A
   Huang, ZY
   Coin, LJM
   Fang, L
   Guo, XS
   Jin, X
   Li, GQ
   Li, QB
   Li, YR
   Li, ZY
   Lin, HX
   Liu, BH
   Luo, RB
   Shao, HJ
   Xie, YL
   Ye, C
   Yu, C
   Zhang, F
   Zheng, HC
   Zhu, HM
   Alkan, C
   Dal, E
   Kahveci, F
   Marth, GT
   Garrison, EP
   Kural, D
   Lee, WP
   Leong, WF
   Stromberg, M
   Ward, AN
   Wu, JT
   Zhang, MY
   Daly, MJ
   DePristo, MA
   Handsaker, RE
   Altshuler, DM
   Banks, E
   Bhatia, G
   del Angel, G
   Gabriel, SB
   Genovese, G
   Gupta, N
   Li, H
   Kashin, S
   Lander, ES
   McCarroll, SA
   Nemesh, JC
   Poplin, RE
   Yoon, SC
   Lihm, J
   Makarov, V
   Clark, AG
   Gottipati, S
   Keinan, A
   Rodriguez-Flores, JL
   Korbel, JO
   Rausch, T
   Fritz, MH
   Stuetz, AM
   Flicek, P
   Beal, K
   Clarke, L
   Datta, A
   Herrero, J
   McLaren, WM
   Ritchie, GRS
   Smith, RE
   Zerbino, D
   Zheng-Bradley, X
   Sabeti, PC
   Shlyakhter, I
   Schaffner, SF
   Vitti, J
   Cooper, DN
   Ball, EV
   Stenson, PD
   Bentley, DR
   Barnes, B
   Bauer, M
   Cheetham, RK
   Cox, A
   Eberle, M
   Humphray, S
   Kahn, S
   Murray, L
   Peden, J
   Shaw, R
   Kenny, EE
   Batzer, MA
   Konkel, MK
   Walker, JA
   MacArthur, DG
   Lek, M
   Sudbrak, R
   Amstislavskiy, VS
   Herwig, R
   Mardis, ER
   Ding, L
   Koboldt, DC
   Larson, D
   Ye, K
   Gravel, S
   Swaroop, A
   Chew, E
   Lappalainen, T
   Erlich, Y
   Gymrek, M
   Willems, TF
   Simpson, JT
   Shriver, MD
   Rosenfeld, JA
   Bustamante, CD
   Montgomery, SB
   De La Vega, FM
   Byrnes, JK
   Carroll, AW
   DeGorter, MK
   Lacroute, P
   Maples, BK
   Martin, AR
   Moreno-Estrada, A
   Shringarpure, SS
   Zakharia, F
   Halperin, E
   Baran, Y
   Lee, C
   Cerveira, E
   Hwang, J
   Malhotra, A
   Plewczynski, D
   Radew, K
   Romanovitch, M
   Zhang, CS
   Hyland, FCL
   Craig, DW
   Christoforides, A
   Homer, N
   Izatt, T
   Kurdoglu, AA
   Sinari, SA
   Squire, K
   Sherry, ST
   Xiao, CL
   Sebat, J
   Antaki, D
   Gujral, M
   Noor, A
   Ye, K
   Burchard, EG
   Hernandez, RD
   Gignoux, CR
   Haussler, D
   Katzman, SJ
   Kent, WJ
   Howie, B
   Ruiz-Linares, A
   Dermitzakis, ET
   Devine, SE
   Goncalo, RA
   Kang, HM
   Kidd, JM
   Blackwell, T
   Caron, S
   Chen, W
   Emery, S
   Fritsche, L
   Fuchsberger, C
   Jun, G
   Li, BS
   Lyons, R
   Scheller, C
   Sidore, C
   Song, SY
   Sliwerska, E
   Taliun, D
   Tan, A
   Welch, R
   Wing, MK
   Zhan, XW
   Awadalla, P
   Hodgkinson, A
   Li, Y
   Shi, XH
   Quitadamo, A
   Lunter, G
   McVean, GA
   Marchini, JL
   Myers, S
   Churchhouse, C
   Delaneau, O
   Gupta-Hinch, A
   Kretzschmar, W
   Iqbal, Z
   Mathieson, I
   Menelaou, A
   Rimmer, A
   Xifara, DK
   Oleksyk, TK
   Fu, YX
   Liu, XM
   Xiong, MM
   Jorde, L
   Witherspoon, D
   Xing, JC
   Eichler, EE
   Browning, BL
   Browning, SR
   Hormozdiari, F
   Sudmant, PH
   Khurana, E
   Durbin, RM
   Hurles, ME
   Tyler-Smith, C
   Albers, CA
   Ayub, Q
   Balasubramaniam, S
   Chen, Y
   Colonna, V
   Danecek, P
   Jostins, L
   Keane, TM
   McCarthy, S
   Walter, K
   Xue, YL
   Gerstein, MB
   Abyzov, A
   Balasubramanian, S
   Chen, JM
   Clarke, D
   Fu, Y
   Harmanci, AO
   Jin, M
   Lee, D
   Liu, J
   Mu, XJ
   Zhang, J
   Zhang, Y
   Li, YR
   Luo, RB
   Zhu, HM
   Alkan, C
   Dal, E
   Kahveci, F
   Marth, GT
   Garrison, EP
   Kural, D
   Lee, WP
   Ward, AN
   Wu, JT
   Zhang, MY
   McCarroll, SA
   Handsaker, RE
   Altshuler, DM
   Banks, E
   Del Angel, G
   Genovese, G
   Hartl, C
   Li, H
   Kashin, S
   Nemesh, JC
   Shakir, K
   Yoon, SC
   Lihm, J
   Makarov, V
   Degenhardt, J
   Korbel, JO
   Fritz, MH
   Meiers, S
   Raeder, B
   Rausch, T
   Stuetz, AM
   Flicek, P
   Casale, FP
   Clarke, L
   Smith, RE
   Stegle, O
   Zheng-Bradley, X
   Bentley, DR
   Barnes, B
   Cheetham, RK
   Eberle, M
   Humphray, S
   Kahn, S
   Murray, L
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   Lee, Charles
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   Radew, Kamen
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   Zhang, Chengsheng
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   Kent, W. James
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   Dermitzakis, Emmanouil T.
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   Kang, Hyun Min
   Kidd, Jeffrey M.
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   Gupta-Hinch, Anjali
   Kretzschmar, Warren
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   Mathieson, Iain
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   Liu, Xiaoming
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   Witherspoon, David
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   Eichler, Evan E.
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   Sudmant, Peter H.
   Khurana, Ekta
   Durbin, Richard M.
   Hurles, Matthew E.
   Tyler-Smith, Chris
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   Balasubramaniam, Senduran
   Chen, Yuan
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   Danecek, Petr
   Jostins, Luke
   Keane, Thomas M.
   McCarthy, Shane
   Walter, Klaudia
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   Balasubramanian, Suganthi
   Chen, Jieming
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   Jin, Mike
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   Liu, Jeremy
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   Zhang, Yan
   Li, Yingrui
   Luo, Ruibang
   Zhu, Hongmei
   Alkan, Can
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   Marth, Gabor T.
   Garrison, Erik P.
   Kural, Deniz
   Lee, Wan-Ping
   Ward, Alistair N.
   Wu, Jiantao
   Zhang, Mengyao
   McCarroll, Steven A.
   Handsaker, Robert E.
   Altshuler, David M.
   Banks, Eric
   Del Angel, Guillermo
   Genovese, Giulio
   Hartl, Chris
   Li, Heng
   Kashin, Seva
   Nemesh, James C.
   Shakir, Khalid
   Yoon, Seungtai C.
   Lihm, Jayon
   Makarov, Vladimir
   Degenhardt, Jeremiah
   Korbel, Jan O.
   Fritz, Markus H.
   Meiers, Sascha
   Raeder, Benjamin
   Rausch, Tobias
   Stuetz, Adrian M.
   Flicek, Paul
   Casale, Francesco Paolo
   Clarke, Laura
   Smith, Richard E.
   Stegle, Oliver
   Zheng-Bradley, Xiangqun
   Bentley, David R.
   Barnes, Bret
   Cheetham, R. Keira
   Eberle, Michael
   Humphray, Sean
   Kahn, Scott
   Murray, Lisa
   Shaw, Richard
   Lameijer, Eric-Wubbo
   Batzer, Mark A.
   Konkel, Miriam K.
   Walker, Jerilyn A.
   Ding, Li
   Hall, Ira
   Ye, Kai
   Lacroute, Phil
   Lee, Charles
   Cerveira, Eliza
   Malhotra, Ankit
   Hwang, Jaeho
   Plewczynski, Dariusz
   Radew, Kamen
   Romanovitch, Mallory
   Zhang, Chengsheng
   Craig, David W.
   Homer, Nils
   Church, Deanna
   Xiao, Chunlin
   Sebat, Jonathan
   Antaki, Danny
   Bafna, Vineet
   Michaelson, Jacob
   Ye, Kenny
   Devine, Scott E.
   Gardner, Eugene J.
   Abecasis, Goncalo R.
   Kidd, Jeffrey M.
   Mills, Ryan E.
   Dayama, Gargi
   Emery, Sarah
   Jun, Goo
   Shi, Xinghua
   Quitadamo, Andrew
   Lunter, Gerton
   McVean, Gil A.
   Chen, Ken
   Fan, Xian
   Chong, Zechen
   Chen, Tenghui
   Witherspoon, David
   Xing, Jinchuan
   Eichler, Evan E.
   Chaisson, Mark J.
   Hormozdiari, Fereydoun
   Huddleston, John
   Malig, Maika
   Nelson, Bradley J.
   Sudmant, Peter H.
   Parrish, Nicholas F.
   Khurana, Ekta
   Hurles, Matthew E.
   Blackburne, Ben
   Lindsay, Sarah J.
   Ning, Zemin
   Walter, Klaudia
   Zhang, Yujun
   Gerstein, Mark B.
   Abyzov, Alexej
   Chen, Jieming
   Clarke, Declan
   Lam, Hugo
   Mu, Xinmeng Jasmine
   Sisu, Cristina
   Zhang, Jing
   Zhang, Yan
   Yu, Fuli
   Bainbridge, Matthew
   Challis, Danny
   Evani, Uday S.
   Kovar, Christie
   Lu, James
   Muzny, Donna
   Nagaswamy, Uma
   Reid, Jeffrey G.
   Sabo, Aniko
   Yu, Jin
   Guo, Xiaosen
   Li, Wangshen
   Li, Yingrui
   Wu, Renhua
   Marth, Gabor T.
   Garrison, Erik P.
   Leong, Wen Fung
   Ward, Alistair N.
   del Angel, Guillermo
   DePristo, Mark A.
   Gabriel, Stacey B.
   Gupta, Namrata
   Hartl, Chris
   Poplin, Ryan E.
   Clark, Andrew G.
   Rodriguez-Flores, Juan L.
   Flicek, Paul
   Clarke, Laura
   Smith, Richard E.
   Zheng-Bradley, Xiangqun
   MacArthur, Daniel G.
   Mardis, Elaine R.
   Fulton, Robert
   Koboldt, Daniel C.
   Gravel, Simon
   Bustamante, Carlos D.
   Craig, David W.
   Christoforides, Alexis
   Homer, Nils
   Izatt, Tyler
   Sherry, Stephen T.
   Xiao, Chunlin
   Dermitzakis, Emmanouil T.
   Abecasis, Gonalo R.
   Kang, Hyun Min
   McVean, Gil A.
   Gerstein, Mark B.
   Balasubramanian, Suganthi
   Habegger, Lukas
   Yu, Haiyuan
   Flicek, Paul
   Clarke, Laura
   Cunningham, Fiona
   Dunham, Ian
   Zerbino, Daniel
   Zheng-Bradley, Xiangqun
   Lage, Kasper
   Jespersen, Jakob Berg
   Horn, Heiko
   Montgomery, Stephen B.
   DeGorter, Marianne K.
   Khurana, Ekta
   Tyler-Smith, Chris
   Chen, Yuan
   Colonna, Vincenza
   Xue, Yali
   Gerstein, Mark B.
   Balasubramanian, Suganthi
   Fu, Yao
   Kim, Donghoon
   Auton, Adam
   Marcketta, Anthony
   Desalle, Rob
   Narechania, Apurva
   Sayres, Melissa A. Wilson
   Garrison, Erik P.
   Handsaker, Robert E.
   Kashin, Seva
   McCarroll, Steven A.
   Rodriguez-Flores, Juan L.
   Flicek, Paul
   Clarke, Laura
   Zheng-Bradley, Xiangqun
   Erlich, Yaniv
   Gymrek, Melissa
   Willems, Thomas Frederick
   Bustamante, Carlos D.
   Mendez, Fernando L.
   Poznik, G. David
   Underhill, Peter A.
   Lee, Charles
   Cerveira, Eliza
   Malhotra, Ankit
   Romanovitch, Mallory
   Zhang, Chengsheng
   Abecasis, Goncalo R.
   Coin, Lachlan
   Shao, Haojing
   Mittelman, David
   Tyler-Smith, Chris
   Ayub, Qasim
   Banerjee, Ruby
   Cerezo, Maria
   Chen, Yuan
   Fitzgerald, ThomasW.
   Louzada, Sandra
   Massaia, Andrea
   McCarthy, Shane
   Ritchie, Graham R.
   Xue, Yali
   Yang, Fengtang
   Kovar, Christie
   Kalra, Divya
   Hale, Walker
   Muzny, Donna
   Reid, Jeffrey G.
   Dan, Xu
   Guo, Xiaosen
   Li, Guoqing
   Li, Yingrui
   Ye, Chen
   Zheng, Xiaole
   Altshuler, David M.
   Flicek, Paul
   Clarke, Laura
   Zheng-Bradley, Xiangqun
   Bentley, David R.
   Cox, Anthony
   Humphray, Sean
   Kahn, Scott
   Sudbrak, Ralf
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TI A global reference for human genetic variation
SO NATURE
LA English
DT Article
ID genome-wide association; complement factor-h; macular degeneration; mutation; variant; susceptibility; loc387715; common; rare
AB The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.
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   [Tishkoff, Sarah] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA.
   [Via, Marc] Univ Barcelona, Dept Psychiat & Clin Psychobiol, Barcelona 08035, Spain.
   [Via, Marc] Univ Barcelona, Inst Brain Cognit & Behav IR3C, Barcelona 08035, Spain.
   [Bodmer, Walter] Univ Oxford, John Radcliffe Hosp, Canc & Immunogenet Lab, Oxford OX3 9DS, England.
   [Bedoya, Gabriel] Univ Antioquia, Inst Biol, Lab Mol Genet, Medellin, Colombia.
   [Gao, Yang] Peking Univ, Shenzhen Hosp, Shenzhen 518036, Peoples R China.
   [Chu, Jiayou] Chinese Acad Med Sci, Inst Med Biol, Kunming 650118, Peoples R China.
   [Chu, Jiayou] Peking Union Med Coll, Kunming 650118, Peoples R China.
   [Garcia-Montero, Andres; Orfao, Alberto] Univ Salamanca, Inst Biomed Res Salamanca IBSAL, Ctr Invest Canc IBMCC CSIC USAL, Inst Biol Mol & Celular Canc, Salamanca 37007, Spain.
   [Garcia-Montero, Andres; Orfao, Alberto] Univ Salamanca, Natl DNA Bank Carlos 3, Salamanca 37007, Spain.
   [Dutil, Julie] Ponce Hlth Sci Univ, Ponce Res Inst, Ponce, PR 00716 USA.
   [Hennis, Anselm] Univ W Indies, Res Inst Trop Med, Chron Dis Res Ctr, Mona, Jamaica.
   [Hennis, Anselm; Watson, Harold] Univ W Indies, Fac Med Sci, Mona, Jamaica.
   [McKenzie, Colin] Univ W Indies, Res Inst Trop Med, Trop Metab Res Unit, Mona, Jamaica.
   [Qadri, Firdausi; LaRocque, Regina] Int Ctr Diarrhoeal Dis Res, Dhaka, Bangladesh.
   [Deng, Xiaoyan] Xishuangbanna Hlth Sch, Xishuangbanna 666100, Peoples R China.
   [Asogun, Danny] Irrua Specialist Teaching Hosp, Edo, Edo State, Nigeria.
   [Folarin, Onikepe; Happi, Christian; Omoniwa, Omonwunmi] Redeemers Univ, Ede, Ogun State, Nigeria.
   [Happi, Christian; Omoniwa, Omonwunmi] Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA.
   [Jallow, Muminatou; Joof, Fatoumatta Sisay; Corrah, Tumani; Rockett, Kirk; Kwiatkowski, Dominic] MRC Unit, Banjul, Gambia.
   [Kooner, Jaspal] Univ London Imperial Coll Sci Technol & Med, NHLI, Hammersmith Hosp, London SW7 2AZ, England.
   [Tran Tinh Hien; Dunstan, Sarah J.; Nguyen Thuy Hang] Univ Oxford, Clin Res Unit, Ctr Trop Med, Ho Chi Minh City, Vietnam.
   [Dunstan, Sarah J.] Univ Melbourne, Peter Doherty Inst Infect & Immun, Melbourne, Vic 3000, Australia.
   [Fonnie, Richard; Kanneh, Lansana; Grant, Donald S.] Kenema Govt Hosp, Minist Hlth & Sanitat, Kenema, Sierra Leone.
   [Garry, Robert; Moses, Lina; Schieffelin, John; Grant, Donald S.] Tulane Univ, Hlth Sci Ctr, New Orleans, LA 70118 USA.
   [Gallo, Carla; Poletti, Giovanni] Univ Peruana Cayetano Heredia, Fac Ciencias & Filosofia, Lab Invest & Desarrollo, Lima, Peru.
   [Saleheen, Danish; Rasheed, Asif] Ctr Noncommunicable Dis, Karachi, Pakistan.
   [Saleheen, Danish] Univ Penn, Perelman Sch Med, Dept Epidemiol & Biostat, Philadelphia, PA 19104 USA.
   [Brook, Lisa D.; Felsenfeld, Adaml.; McEwen, Jean E.; Vaydylevich, Yekaterina; Schloss, Jeffery A.; Brooks, Lisa D.] NHGRI, US Natl Inst Hlth, Bethesda, MD 20892 USA.
   [Duncanson, Audrey; Dunn, Michael] Wellcome Trust Res Labs, London NW1 2BE, England.
   [Yang, Huanming] James D Watson Inst Genome Sci, Hangzhou 310008, Zhejiang, Peoples R China.
C3 Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; University of Michigan System; University of Michigan; Vertex Pharmaceuticals; Wellcome Trust Sanger Institute; Illumina; Johns Hopkins University; Cornell University; University of Oxford; Wellcome Centre for Human Genetics; University of Oxford; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Howard Hughes Medical Institute; European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Baylor College of Medicine; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI); McGill University; European Molecular Biology Laboratory (EMBL); Jackson Laboratory; Ewha Womans University; Max Planck Society; Washington University (WUSTL); Utah System of Higher Education; University of Utah; Utah System of Higher Education; University of Utah; Affymetrix; National Institutes of Health (NIH) - USA; Beijing Genomics Institute (BGI); University of Copenhagen; King Abdulaziz University; Macau University of Science & Technology; University of Hong Kong; University of Hong Kong; Coriell Institute for Medical Research; Maastricht University; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI); Ihsan Dogramaci Bilkent University; Kansas State University; Illumina; Harvard University; Cold Spring Harbor Laboratory; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Cornell University; Cornell University; Weill Cornell Medicine; European Molecular Biology Laboratory (EMBL); University of London; University College London; Harvard University; Harvard University; Harvard University; Cardiff University; Icahn School of Medicine at Mount Sinai; Louisiana State University System; Louisiana State University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; McGill University; National Institutes of Health (NIH) - USA; NIH National Eye Institute (NEI); Columbia University; Columbia University; Harvard University; Harvard University; Harvard Medical School; Massachusetts Institute of Technology (MIT); Whitehead Institute; Ontario Institute for Cancer Research; University of Toronto; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Rutgers University System; Rutgers University New Brunswick; Rutgers University Biomedical & Health Sciences; Rutgers Cancer Institute of New Jersey; Stanford University; Stanford University; CINVESTAV - Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional; Tel Aviv University; Tel Aviv University; Thermo Fisher Scientific; Translational Genomics Research Institute; Thermo Fisher Scientific; 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 San Diego; University of California System; University of California San Diego; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva 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; University of California System; University of California San Francisco; University of California System; University of California Santa Cruz; Howard Hughes Medical Institute; University of Chicago; University of London; University College London; University of Geneva; University of Geneva; Swiss Institute of Bioinformatics; University System of Maryland; University of Maryland Baltimore; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Texas System; University of Texas Health Science Center Houston; Vanderbilt University; University of Michigan System; University of Michigan; Consiglio Nazionale delle Ricerche (CNR); Istituto di Ricerca Genetica e Biomedica (IRGB-CNR); University of Sassari; University of Texas System; University of Texas Southwestern Medical Center; Universite de Montreal; Centre Hospitalier Universitaire Sainte-Justine; University of North Carolina; University of North Carolina Charlotte; Utrecht University; Utrecht University Medical Center; University of Puerto Rico; University of Puerto Rico Mayaguez; Utah System of Higher Education; University of Utah; Rutgers University System; Rutgers University New Brunswick; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Cornell University; Weill Cornell Medicine; Radboud University Nijmegen; Radboud University Nijmegen; Radboud University Nijmegen; Consiglio Nazionale delle Ricerche (CNR); Istituto di Genetica e Biofisica Adriano Buzzati-Traverso (IGB-CNR); Yale University; Yale University; Yale University; Mayo Clinic; Yale University; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; University of California System; University of California San Diego; University of California System; University of California San Diego; University of Texas System; UTMD Anderson Cancer Center; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Technical University of Denmark; American Museum of Natural History (AMNH); American Museum of Natural History (AMNH); Arizona State University; Arizona State University-Tempe; Stanford University; University of Queensland; Johns Hopkins University; State University of New York (SUNY) System; Stony Brook University; University of Oxford; University of Oxford; Johns Hopkins University; University of Wisconsin System; University of Wisconsin Madison; The Morgridge Institute for Research, Inc.; University of Wisconsin System; University of Wisconsin Madison; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI); Duke University; University of Pennsylvania; University of Barcelona; University of Barcelona; University of Oxford; Universidad de Antioquia; Peking University; Chinese Academy of Medical Sciences - Peking Union Medical College; Institute of Medical Biology - CAMS; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; University of Salamanca; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC-USAL - Instituto de Biologia Molecular y Celular del Cancer de Salamanca (IBMCC); University of Salamanca; Ponce Health Sciences University; University West Indies Mona Jamaica; University West Indies Mona Jamaica; University West Indies Mona Jamaica; International Centre for Diarrhoeal Disease Research (ICDDR); Redeemers University; Harvard University; Harvard T.H. Chan School of Public Health; University of London; London School of Hygiene & Tropical Medicine; Imperial College London; University of Oxford; University of Melbourne; Peter Doherty Institute; Kenema Government Hospital; Ministry of Health & Sanitation Sierra Leone; Tulane University; Universidad Peruana Cayetano Heredia; University of Pennsylvania; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI)
RP Auton, A (corresponding author), Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA.
EM goncalo@umich.edu; adam.auton@gmail.com
FU Wellcome Trust [090532/Z/09/Z, 095552/Z/11/Z, WT098051, WT095908, WT109497, WT086084/Z/08/Z, WT100956/Z/13/Z, WT097307, WT0855322/Z/08/Z, WT090770/Z/09/Z, 089276/Z.09/Z]; Medical Research Council UK [G0801823]; UK Biotechnology and Biological Sciences Research Council [BB/I02593X/1, BB/I021213/1]; British Heart Foundation; Monument Trust; European Molecular Biology Laboratory; European Research Council [617306]; Chinese 863 Program [2012AA02A201]; National Basic Research program of China 973 program [2011CB809201, 2011CB809202, 2011CB809203]; Natural Science Foundation of China [31161130357]; Shenzhen Municipal Government of China [ZYC201105170397A]; Canadian Institutes of Health Research [136855]; Canada Research Chair; Le Fonds de Recherche du Quebec-Sante (FRQS); Genome Quebec; Ontario Ministry of Research and Innovation - Ontario Institute for Cancer Research Investigator Award; Quebec Ministry of Economic Development, Innovation, and Exports [PSR-SIIRI-195]; German Federal Ministry of Education and Research (BMBF) [0315428A, 01GS08201]; Max Planck Society; BMBF-EPITREAT [0316190A]; German Research Foundation (Deutsche Forschungsgemeinschaft) [KO4037/1-1]; Beatriu de Pinos Program [2006 BP-A 10144, 2009 BP-B 00274]; Spanish National Institute for Health Research [PRB2 IPT13/0001-ISCIII-SGEFI/FEDER]; Ewha Womans University; Japan Society for the Promotion of Science [PE13075]; Louis Jeantet Foundation; Marie Curie Actions Career Integration grant [303772]; Swiss National Science Foundation [31003A_130342]; NCCR "Frontiers in Genetics"; University of Geneva; US National Institutes of Health National Center for Biotechnology Information; Harvard Medical School Eleanor and Miles Shore Fellowship; Lundbeck Foundation [R170-2014-1039]; NIJ [2014-DN-BX-K089]; Mary Beryl Patch Turnbull Scholar Program; NSF Graduate Research Fellowship [DGE-1147470]; Simons Foundation SFARI [SF51]; Sloan Foundation;  [U54HG3067];  [U54HG3273];  [U01HG5211];  [U54HG3079];  [R01HG2898];  [R01HG2385];  [RC2HG5552];  [U01HG6513];  [U01HG5214];  [U01HG5715];  [U01HG5718];  [U01HG5728];  [U41HG7635];  [U41HG7497];  [R01HG4960];  [R01HG5701];  [R01HG5214];  [R01HG6855];  [R01HG7068];  [R01HG7644];  [DP2OD6514];  [DP5OD9154];  [R01CA166661];  [R01CA172652];  [P01GM99568];  [R01GM59290];  [R01GM104390];  [T32GM7790];  [R01HL87699];  [R01HL104608];  [T32HL94284];  [HHSN268201100040C];  [HHSN272201000025C]; Swiss National Science Foundation (SNF) [31003A_130342] Funding Source: Swiss National Science Foundation (SNF); National Cancer Institute [P30CA016672] Funding Source: NIH RePORTER; National Eye Institute [ZIAEY000546] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [R01HL104608] Funding Source: NIH RePORTER; National Human Genome Research Institute [U41HG002371, R01HG006855, R01HG002385, R01HG005701] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK075787] Funding Source: NIH RePORTER; Biotechnology and Biological Sciences Research Council [BB/I021213/1, BB/I02593X/1] Funding Source: researchfish; Lundbeck Foundation [R170-2014-1039] Funding Source: researchfish; Medical Research Council [G0801823] Funding Source: researchfish; Wellcome Trust [095552/Z/11/Z] Funding Source: researchfish; BBSRC [BB/I021213/1, BB/I02593X/1] Funding Source: UKRI; MRC [G0801823] Funding Source: UKRI; European Research Council (ERC) [617306] Funding Source: European Research Council (ERC)
NR 38
TC 10664
Z9 12106
U1 41
U2 368
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 1
PY 2015
VL 526
IS 7571
BP 68
EP +
DI 10.1038/nature15393
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS5CY
UT WOS:000362095100036
PM 26432245
DA 2026-03-09
ER

PT J
AU Amari, T
   Luciani, JF
   Aly, JJ
AF Amari, Tahar
   Luciani, Jean-Francois
   Aly, Jean-Jacques
TI Small-scale dynamo magnetism as the driver for heating the solar atmosphere
SO NATURE
LA English
DT Article
ID quiet sun magnetism; transition region; coronal closure; simulations; convection; spicules; fields; flux; photosphere; plasma
AB The long-standing problem of how the solar atmosphere is heated has been addressed by many theoretical studies, which have stressed the relevance of two specific mechanisms, involving magnetic reconnection and waves, as well as the necessity of treating the chromosphere and corona together(1-7). But a fully consistent model has not yet been constructed and debate continues, in particular about the possibility of coronal plasma being heated by energetic phenomena observed in the chromosphere(2,3,8-11). Here we report modelling of the heating of the quiet Sun, in which magnetic fields are generated by a subphotospheric fluid dynamo intrinsically connected to granulation. We find that the fields expand into the chromosphere, where plasma is heated at the rate required to match observations (4,500 watts per square metre) by small-scale eruptions that release magnetic energy and drive sonic motions. Some energetic eruptions can even reach heights of 10 million metres above the surface of the Sun, thereby affecting the very low corona. Extending the model by also taking into account the vertical weak network magnetic field allows for the existence of a mechanism able to heat the corona above, while leaving unchanged the physics of chromospheric eruptions. Such a mechanism rests on the eventual dissipation of Alfven waves generated inside the chromosphere and that carry upwards the required energy flux of 300 watts per square metre. The model shows a topologically complex magnetic field of 160 gauss on the Sun's surface, agreeing with inferences obtained from spectropolarimetric observations(12-14), chromospheric features (contributing only weakly to the coronal heating) that can be identified with observed spicules(9) and blinkers(10,11), and vortices that may be possibly associated with observed solar tornadoes(8).
C1 [Amari, Tahar; Luciani, Jean-Francois] Ecole Polytech, Ctr Phys Theor, CNRS, F-91128 Palaiseau, France.
   [Aly, Jean-Jacques] Univ Paris 07, Ctr Etud Saclay, AIM Unite Mixte Rech CEA CNRS, UMR 7158, F-91191 Gif Sur Yvette, France.
C3 Institut Polytechnique de Paris; Ecole Polytechnique; Centre National de la Recherche Scientifique (CNRS); CEA; Centre National de la Recherche Scientifique (CNRS); Universite Paris Cite; Universite Paris Saclay; CNRS - National Institute for Earth Sciences & Astronomy (INSU)
RP Amari, T (corresponding author), Ecole Polytech, Ctr Phys Theor, CNRS, F-91128 Palaiseau, France.
EM tahar.amari@polytechnique.edu
FU Centre National d'Etudes Spatiales (CNES)
NR 49
TC 40
Z9 41
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 JUN 11
PY 2015
VL 522
IS 7555
BP 188
EP +
DI 10.1038/nature14478
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700033
PM 26062509
DA 2026-03-09
ER

PT J
AU Schnupf, P
   Gaboriau-Routhiau, V
   Gros, M
   Friedman, R
   Moya-Nilges, M
   Nigro, G
   Cerf-Bensussan, N
   Sansonetti, PJ
AF Schnupf, Pamela
   Gaboriau-Routhiau, Valerie
   Gros, Marine
   Friedman, Robin
   Moya-Nilges, Maryse
   Nigro, Giulia
   Cerf-Bensussan, Nadine
   Sansonetti, Philippe J.
TI Growth and host interaction of mouse segmented filamentous bacteria in vitro
SO NATURE
LA English
DT Article
ID gut; genome; mice; maturation; responses
AB The gut microbiota plays a crucial role in the maturation of the intestinal mucosal immune system of its host(1,2). Within the thousand bacterial species present in the intestine, the symbiont segmented filamentous bacterium(SFB) is unique in its ability to potently stimulate the post-natal maturation of the B-and T-cell compartments and induce a striking increase in the small-intestinal Th17 responses(3-5). Unlike other commensals, SFB intimately attaches to absorptive epithelial cells in the ileum and cells overlying Peyer's patches(6,7). This colonization does not result in pathology; rather, it protects the host from pathogens(4). Yet, little is known about the SFB-host interaction that underlies the important immunostimulatory properties of SFB, because SFB have resisted in vitro culturing for more than 50 years. Here we grow mouse SFB outside their host in an SFB-host cell co-culturing system. Single-celled SFB isolated from mono-colonized mice undergo filamentation, segmentation, and differentiation to release viable infectious particles, the intracellular offspring, which can colonize mice to induce signature immune responses. In vitro, intracellular offspring can attach to mouse and human host cells and recruit actin. In addition, SFB can potently stimulate the upregulation of host innate defence genes, inflammatory cytokines, and chemokines. In vitro culturing thereby mimics the in vivo niche, provides new insights into SFB growth requirements and their immunostimulatory potential, and makes possible the investigation of the complex developmental stages of SFB and the detailed dissection of the unique SFB-host interaction at the cellular and molecular levels.
C1 [Schnupf, Pamela; Friedman, Robin; Nigro, Giulia; Sansonetti, Philippe J.] Inst Pasteur, Unite Pathogenie Microbienne Mol, F-75724 Paris 15, France.
   [Schnupf, Pamela; Friedman, Robin; Nigro, Giulia; Sansonetti, Philippe J.] Inst Pasteur, INSERM, Unit U786, F-75724 Paris 15, France.
   [Schnupf, Pamela; Gaboriau-Routhiau, Valerie; Cerf-Bensussan, Nadine] Inst Imagine, INSERM, UMR1163, Lab Intestinal Immun, F-75015 Paris, France.
   [Gaboriau-Routhiau, Valerie] INRA, Micalis UMR1319, F-78350 Jouy En Josas, France.
   [Gaboriau-Routhiau, Valerie; Gros, Marine; Cerf-Bensussan, Nadine] Univ Paris 05, Sorbonne Paris Cite, F-75015 Paris, France.
   [Gaboriau-Routhiau, Valerie; Gros, Marine; Cerf-Bensussan, Nadine] Inst Imagine, F-75015 Paris, France.
   [Gros, Marine] Ecole Normale Super Lyon, Dept Biol, F-69007 Lyon, France.
   [Moya-Nilges, Maryse] Inst Pasteur, Imagopole, Ultrastruct Microscopy Platform, F-75724 Paris 15, France.
   [Sansonetti, Philippe J.] Coll France, Microbiol & Malad Infect, F-75005 Paris, France.
C3 Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Institut National de la Sante et de la Recherche Medicale (Inserm); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Universite Paris Saclay; INRAE; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Ecole Normale Superieure de Lyon (ENS de LYON); Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Universite PSL; College de France
RP Sansonetti, PJ (corresponding author), Inst Pasteur, Unite Pathogenie Microbienne Mol, 25-28 Rue Dr Roux, F-75724 Paris 15, France.
EM nadine.cerf-bensussan@inserm.fr; psanson@pasteur.fr
FU INSERM, Institut Pasteur, College de France; INRA; Investissement d'Avenir [ANR-10-IAHU-01]; LabEX IBEID;  [TORNADO-FP7-KBBE-2007-2A-222720];  [ANR-2010-BLAN1317];  [ERC-2009-AG-232798-HOMEOPITH];  [ERC-2013-AdG-339579-DECRYPT];  [ERC-2013-AdG-339407-IMMUNOBIOTA]
NR 27
TC 130
Z9 170
U1 0
U2 84
PU NATURE PUBLISHING 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 2
PY 2015
VL 520
IS 7545
BP 99
EP U231
DI 10.1038/nature14027
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE7NE
UT WOS:000352027700045
PM 25600271
DA 2026-03-09
ER

PT J
AU Ma, CD
   Wang, CX
   Acevedo-Vélez, C
   Gellman, SH
   Abbott, NL
AF Ma, C. Derek
   Wang, Chenxuan
   Acevedo-Velez, Claribel
   Gellman, Samuel H.
   Abbott, Nicholas L.
TI Modulation of hydrophobic interactions by proximally immobilized ions
SO NATURE
LA English
DT Article
ID chemical force microscopy; self-assembled monolayers; beta-peptides; intermolecular interactions; surfaces; water; spectroscopy; interfaces; signature; hydration
AB The structure of water near non-polar molecular fragments or surfaces mediates the hydrophobic interactions that underlie a broad range of interfacial, colloidal and biophysical phenomena(1-4),. Substantial progress over the past decade has improved our understanding of hydrophobic interactions in simple model systems(1,5-10), but most biologically and technologically relevant structures contain non-polar domains in close proximity to polar and charged functional groups. Theories and simulations exploring such nanometre-scale chemical heterogeneity find it can have an important effect(8,10-12), but the influence of this heterogeneity on hydrophobic interactions has not been tested experimentally. Here we report chemical force microscopy measurements on alkyl-functionalized surfaces that reveal a dramatic change in the surfaces' hydrophobic interaction strengths on coimmobilization of amine or guanidine groups. Protonation of amine groups doubles the strength of hydrophobic interactions, and guanidinium groups eliminate measurable hydrophobic interactions in all pH ranges investigated. We see these divergent effects of proximally immobilized cations also in single-molecule measurements on conformationally stable beta-peptides with non-polar subunits located one nanometre from either amine- or guanidine-bearing subunits. Our results demonstrate the importance of nanometre-scale chemical heterogeneity, with hydrophobicity not an intrinsic property of any given non-polar domain but strongly modulated by functional groups located as far away as one nanometre. The judicious placing of charged groups near hydrophobic domains thus provides a strategy for tuning hydrophobic driving forces to optimize molecular recognition or self-assembly processes.
C1 [Ma, C. Derek; Wang, Chenxuan; Acevedo-Velez, Claribel; Abbott, Nicholas L.] Univ Wisconsin, Dept Chem & Biol Engn, Madison, WI 53706 USA.
   [Wang, Chenxuan; Gellman, Samuel H.] 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 Gellman, SH (corresponding author), Univ Wisconsin, Dept Chem, 1101 Univ Ave, Madison, WI 53706 USA.
EM gellman@chem.wisc.edu; abbott@engr.wisc.edu
FU Wisconsin Nanoscale Science and Engineering Center (NSF grant) [DMR-0832760]; Wisconsin Materials Research Science and Engineering Center (NSF grant) [DMR-1121288]; Division Of Materials Research; Direct For Mathematical & Physical Scien [0832760] Funding Source: National Science Foundation
NR 43
TC 172
Z9 214
U1 2
U2 302
PU NATURE PUBLISHING 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 15
PY 2015
VL 517
IS 7534
BP 347
EP U443
DI 10.1038/nature14018
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300041
PM 25592540
DA 2026-03-09
ER

PT J
AU Walter, D
   Lier, A
   Geiselhart, A
   Thalheimer, FB
   Huntscha, S
   Sobotta, MC
   Moehrle, B
   Brocks, D
   Bayindir, I
   Kaschutnig, P
   Muedder, K
   Klein, C
   Jauch, A
   Schroeder, T
   Geiger, H
   Dick, TP
   Holland-Letz, T
   Schmezer, P
   Lane, SW
   Rieger, MA
   Essers, MAG
   Williams, DA
   Trumpp, A
   Milsom, MD
AF Walter, Dagmar
   Lier, Amelie
   Geiselhart, Anja
   Thalheimer, Frederic B.
   Huntscha, Sina
   Sobotta, Mirko C.
   Moehrle, Bettina
   Brocks, David
   Bayindir, Irem
   Kaschutnig, Paul
   Muedder, Katja
   Klein, Corinna
   Jauch, Anna
   Schroeder, Timm
   Geiger, Hartmut
   Dick, Tobias P.
   Holland-Letz, Tim
   Schmezer, Peter
   Lane, Steven W.
   Rieger, Michael A.
   Essers, Marieke A. G.
   Williams, David A.
   Trumpp, Andreas
   Milsom, Michael D.
TI Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells
SO NATURE
LA English
DT Article
ID targeted disruption; quiescence; cytokines; defects; growth; alpha; blood
AB Haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood cells. The accumulation of DNA damage in HSCs is a hallmark of ageing and is probably a major contributing factor in age-related tissue degeneration and malignant transformation'. A number of accelerated ageing syndromes are associated with defective DNA repair and genomic instability, including the most common inherited bone marrow failure syndrome, Fanconi anaemia'''. However, the physiological source of DNA damage in HSCs from both normal and diseased individuals remains unclear. Here we show in mice that DNA damage is a direct consequence of inducing HSCs to exit their homeostatic quiescent state in response to conditions that model physiological stress, such as infection or chronic blood loss. Repeated activation of HSCs out of their dormant state provoked the attrition of normal HSCs and, in the case of mice with a nonfunctional Fanconi anaemia DNA repair pathway, led to a complete collapse of the haematopoietic system, which phenocopied the highly penetrant bone marrow failure seen in Fanconi anaemia patients. Our findings establish a novel link between physiological stress and DNA damage in normal HSCs and provide a mechanistic explanation for the universal accumulation of DNA damage in HSCs during ageing and the accelerated failure of the haematopoietic system in Fanconi anaemia patients.
C1 [Walter, Dagmar; Lier, Amelie; Huntscha, Sina; Klein, Corinna; Essers, Marieke A. G.; Trumpp, Andreas; Milsom, Michael D.] Heidelberg Inst Stem Cell Technol & Expt Med gGmb, D-69120 Heidelberg, Germany.
   [Geiselhart, Anja; Brocks, David; Bayindir, Irem; Kaschutnig, Paul; Milsom, Michael D.] Deutsch Krebsforschungszentrum DKFZ, Div Stem Cells & Canc, Expt Hematol Grp, D-69120 Heidelberg, Germany.
   [Thalheimer, Frederic B.; Rieger, Michael A.] Goethe Univ Frankfurt, LOEWE Ctr Cell & Gene Therapy, D-60595 Frankfurt, Germany.
   [Thalheimer, Frederic B.; Rieger, Michael A.] Goethe Univ Frankfurt, Dept Hematol Oncol, D-60595 Frankfurt, Germany.
   [Sobotta, Mirko C.; Dick, Tobias P.] DKFZ ZMBH Alliance, Deutsch Krebsforschungszentrum DKFZ, Div Redox Regulat, D-69120 Heidelberg, Germany.
   [Moehrle, Bettina; Geiger, Hartmut] Univ Ulm, Inst Mol Med Stem Cells & Aging, D-89081 Ulm, Germany.
   [Muedder, Katja; Trumpp, Andreas] Deutsch Krebsforschungszentrum DKFZ, Div Stem Cells & Canc, D-69120 Heidelberg, Germany.
   [Jauch, Anna] Heidelberg Univ, Inst Human Genet, D-69120 Heidelberg, Germany.
   [Schroeder, Timm] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, CH-4058 Basel, Switzerland.
   [Geiger, Hartmut] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA.
   [Holland-Letz, Tim] Deutsch Krebsforschungszentrum DKFZ, Div Biostat, D-69120 Heidelberg, Germany.
   [Schmezer, Peter] Deutsch Krebsforschungszentrum DKFZ, Div Epigen & Canc Risk Factors, D-69120 Heidelberg, Germany.
   [Lane, Steven W.] Univ Queensland, QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia.
   [Essers, Marieke A. G.] Deutsch Krebsforschungszentrum DKFZ, Div Stem Cells & Canc, Hematopoiet Stem Cells & Stress Grp, D-69120 Heidelberg, Germany.
   [Williams, David A.] Boston Childrens Hosp, Boston, MA 02115 USA.
   [Williams, David A.] Dana Farber Canc Inst, Boston, MA 02115 USA.
   [Williams, David A.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA.
   [Williams, David A.] Harvard Univ, Sch Med, Boston, MA 02115 USA.
C3 Helmholtz Association; German Cancer Research Center (DKFZ); Goethe University Frankfurt; Goethe University Frankfurt; Helmholtz Association; German Cancer Research Center (DKFZ); Ulm University; Helmholtz Association; German Cancer Research Center (DKFZ); Ruprecht Karls University Heidelberg; Swiss Federal Institutes of Technology Domain; ETH Zurich; Cincinnati Children's Hospital Medical Center; Helmholtz Association; German Cancer Research Center (DKFZ); Helmholtz Association; German Cancer Research Center (DKFZ); University of Queensland; QIMR Berghofer Medical Research Institute; Helmholtz Association; German Cancer Research Center (DKFZ); Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University; Harvard Medical School
RP Milsom, MD (corresponding author), Heidelberg Inst Stem Cell Technol & Expt Med gGmb, D-69120 Heidelberg, Germany.
EM m.milsom@hi-stem.de
FU Animal Laboratory Services Deutsches Krebsforschungszentrum (DKFZ) core facility; BioRN Leading-Edge Cluster "Cell-Based and Molecular Medicine" - German Federal Ministry of Education and Research; Dietmar Hopp Foundation; LOEWE Center for Cell and Gene Therapy Frankfurt, Hessisches Ministerium fur Wissenschaft und Kunst [III L 4-518/17.004]; Deutsche Forschungsgemeinschaft [SFB873]; Helmholtz International Graduate School; Leukemia Foundation of Australia; Cure Cancer Australia Foundation; National Health and Medical Research Foundation of Australia
NR 32
TC 510
Z9 580
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 APR 23
PY 2015
VL 520
IS 7548
BP 549
EP +
DI 10.1038/nature14131
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500045
PM 25707806
DA 2026-03-09
ER

PT J
AU Diao, JJ
   Liu, R
   Rong, YG
   Zhao, ML
   Zhang, J
   Lai, Y
   Zhou, QJ
   Wilz, LM
   Li, JX
   Vivona, S
   Pfuetzner, RA
   Brunger, AT
   Zhong, Q
AF Diao, Jiajie
   Liu, Rong
   Rong, Yueguang
   Zhao, Minglei
   Zhang, Jing
   Lai, Ying
   Zhou, Qiangjun
   Wilz, Livia M.
   Li, Jianxu
   Vivona, Sandro
   Pfuetzner, Richard A.
   Brunger, Axel T.
   Zhong, Qing
TI ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes
SO NATURE
LA English
DT Article
ID snare complex; in-vitro; beclin 1; proteins; curvature; yeast; rubicon; system; form
AB Autophagy, an important catabolic pathway implicated in a broad spectrum of human diseases, begins by forming double membrane autophagosomes that engulf cytosolic cargo and ends by fusing autophagosomes with lysosomes for degradation(1,2). Membrane fusion activity is required for early biogenesis of autophagosomes and late degradation in lysosomes(3-7). However, the key regulatory mechanisms of autophagic membrane tethering and fusion remain largely unknown. Here we report that ATG14 (also known as bedin-1-associated autophagy-related key regulator (Barkor) or ATG14L), an essential autophagy-specific regulator of the class III phosphatidylinositol 3-kinase complex(8-11), promotes membrane tethering of protein-free liposomes, and enhances hemifusion and full fusion of proteoliposomes reconstituted with the target (t)-SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) syntaxin 17 (STX17) and SNAP29, and the vesicle (v)-SNARE VAMP8 (vesicle-associated membrane protein 8). ATG14 binds to the SNARE core domain of STX17 through its coiled-coil domain, and stabilizes the STX17-SNAP29 binary t-SNARE complex on autophagosomes. The STX17 binding, membrane tethering and fusion-enhancing activities of ATG14 require its homo-oligomerization by cysteine repeats. In ATG14 homo-oligomerization-defective cells, autophagosomes still efficiently form but their fusion with endolysosomes is blocked. Recombinant ATG14 homo-oligomerization mutants also completely lose their ability to promote membrane tethering and to enhance SNARE-mediated fusion in vitro. Taken together, our data suggest an autophagy-specific membrane fusion mechanism in which oligomeric ATG14 directly binds to STX17-SNAP29 binary t-SNARE complex on autophagosomes and primes it for VAMP8 interaction to promote autophagosome-endolysosome fusion.
C1 [Diao, Jiajie; Zhao, Minglei; Lai, Ying; Zhou, Qiangjun; Vivona, Sandro; Pfuetzner, Richard A.; Brunger, Axel T.] Stanford Univ, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
   [Diao, Jiajie; Zhao, Minglei; Lai, Ying; Zhou, Qiangjun; Vivona, Sandro; Pfuetzner, Richard A.; Brunger, Axel T.] Stanford Univ, Dept Biol Struct, Stanford, CA 94305 USA.
   [Diao, Jiajie; Zhao, Minglei; Lai, Ying; Zhou, Qiangjun; Vivona, Sandro; Pfuetzner, Richard A.; Brunger, Axel T.] Stanford Univ, Dept Photon Sci, Stanford, CA 94305 USA.
   [Diao, Jiajie; Zhao, Minglei; Lai, Ying; Zhou, Qiangjun; Vivona, Sandro; Pfuetzner, Richard A.; Brunger, Axel T.] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA.
   [Diao, Jiajie; Zhao, Minglei; Lai, Ying; Zhou, Qiangjun; Vivona, Sandro; Pfuetzner, Richard A.; Brunger, Axel T.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Liu, Rong; Rong, Yueguang; Zhang, Jing; Zhong, Qing] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Ctr Autophagy Res, Dallas, TX 75390 USA.
   [Liu, Rong; Rong, Yueguang; Zhang, Jing; Zhong, Qing] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA.
   [Liu, Rong] China Agr Univ, Coll Food Sci & Nutr Engn, Beijing 100083, Peoples R China.
   [Wilz, Livia M.; Li, Jianxu] Univ Calif Berkeley, Dept Mol & Cell Biol, Div Biochem Biophys & Struct Biol, Berkeley, CA 94720 USA.
C3 Stanford University; Stanford University; Stanford University; Stanford University; Howard Hughes Medical Institute; Stanford University; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; China Agricultural University; University of California System; University of California Berkeley
RP Zhong, Q (corresponding author), Univ Texas SW Med Ctr Dallas, Dept Internal Med, Ctr Autophagy Res, Dallas, TX 75390 USA.
EM qing.zhong@utsouthwestern.edu
FU National Institutes of Health (NIH) [P41 GM103403]; Welch Foundation [1-1864]; Cancer Prevention & Research Institute of Texas [RP140320]; American Cancer Society [RSG-11-274-01-CCG]; NIH [CA133228, R37-MH63105]; China Scholarship Council; National Cancer Institute of the NIH [5P30CA142543]; National Cancer Institute [P30CA142543] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007232] Funding Source: NIH RePORTER; National Institute of Mental Health [R01MH063105] Funding Source: NIH RePORTER
NR 39
TC 475
Z9 566
U1 4
U2 183
PU NATURE PUBLISHING 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 23
PY 2015
VL 520
IS 7548
BP 563
EP +
DI 10.1038/nature14147
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500048
PM 25686604
DA 2026-03-09
ER

PT J
AU Do-Monte, FH
   Quiñones-Laracuente, K
   Quirk, GJ
AF Do-Monte, Fabricio H.
   Quinones-Laracuente, Kelvin
   Quirk, Gregory J.
TI A temporal shift in the circuits mediating retrieval of fear memory
SO NATURE
LA English
DT Article
ID paraventricular thalamic nucleus; ventromedial prefrontal cortex; basolateral amygdala; conditioned fear; projections; rat; extinction; cortices; consolidation; hippocampus
AB Fear memories allow animals to avoid danger, thereby increasing their chances of survival. Fear memories can be retrieved long after learning(1,2), but little is known about how retrieval circuits change with time(3,4). Here we show that the dorsal midline thalamus of rats is required for the retrieval of auditory conditioned fear at late (24 hours, 7 days, 28 days), but not early (0.5 hours, 6 hours) time points after learning. Consistent with this, the paraventricular nucleus of the thalamus (PVT), a subregion of the dorsal midline thalamus, showed increased c-Fos expression only at late time points, indicating that the PVT is gradually recruited for fear retrieval. Accordingly, the conditioned tone responses of PVTneurons increased with time after training. The prelimbic (PL) prefrontal cortex, which is necessary for fear retrieval(5-7), sends dense projections to the PVT8. Retrieval at late time points activated PL neurons projecting to the PVT, and optogenetic silencing of these projections impaired retrieval at late, but not early, time points. In contrast, silencing of PL inputs to the basolateral amygdala impaired retrieval at early, but not late, time points, indicating a time-dependent shift in retrieval circuits. Retrieval at late time points also activated PVT neurons projecting to the central nucleus of the amygdala, and silencing these projections at late, but not early, time points induced a persistent attenuation of fear. Thus, the PVT may act as a crucial thalamic node recruited into cortico-amygdalar networks for retrieval and maintenance of long-term fear memories.
C1 [Do-Monte, Fabricio H.; Quinones-Laracuente, Kelvin; Quirk, Gregory J.] Univ Puerto Rico, Dept Psychiat, Sch Med, San Juan, PR 00936 USA.
   [Do-Monte, Fabricio H.; Quinones-Laracuente, Kelvin; Quirk, Gregory J.] Univ Puerto Rico, Dept Anat & Neurobiol, Sch Med, San Juan, PR 00936 USA.
C3 University of Puerto Rico; University of Puerto Rico Medical Sciences Campus; University of Puerto Rico; University of Puerto Rico Medical Sciences Campus
RP Do-Monte, FH (corresponding author), Univ Puerto Rico, Dept Psychiat, Sch Med, POB 365067, San Juan, PR 00936 USA.
EM fabriciodomonte@gmail.com
FU NIH [R01-MH058883, P50-MH086400]; University of Puerto Rico President's Office; MBRS-RISE Program [R25-GM061838]; NSF [DBI-0115825]; RCMI [8G12-MD007600]; National Institute of General Medical Sciences [R25GM061838] Funding Source: NIH RePORTER; National Institute of Mental Health [R01MH058883] Funding Source: NIH RePORTER
NR 30
TC 373
Z9 457
U1 4
U2 125
PU NATURE PUBLISHING 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 26
PY 2015
VL 519
IS 7544
BP 460
EP +
DI 10.1038/nature14030
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE1WF
UT WOS:000351602800054
PM 25600268
DA 2026-03-09
ER

PT J
AU Penzo, MA
   Robert, V
   Tucciarone, J
   De Bundel, D
   Wang, MH
   Van Aelst, L
   Darvas, M
   Parada, LF
   Palmiter, RD
   He, M
   Huang, ZJ
   Li, B
AF Penzo, Mario A.
   Robert, Vincent
   Tucciarone, Jason
   De Bundel, Dimitri
   Wang, Minghui
   Van Aelst, Linda
   Darvas, Martin
   Parada, Luis F.
   Palmiter, Richard D.
   He, Miao
   Huang, Z. Josh
   Li, Bo
TI The paraventricular thalamus controls a central amygdala fear circuit
SO NATURE
LA English
DT Article
ID conditional deletion; neurotrophic factor; nucleus; projections; expression; protein; midline; stress; orexin
AB Appropriate responses to an imminent threat brace us for adversities. The ability to sense and predict threatening or stressful events is essential for such adaptive behaviour. In the mammalian brain, one putative stress sensor is the paraventricular nucleus of the thalamus (PVT), an area that is readily activated by both physical and psychological stressors(1-3). However, the role of the PVT in the establishment of adaptive behavioural responses remains unclear. Here we show in mice that the PVT regulates fear processing in the lateral division of the central amygdala (CeL), a structure that orchestrates fear learning and expression(4,5). Selective inactivation of CeL-projecting PVT neurons prevented fear conditioning, an effect that can be accounted for by an impairment in fear-conditioning-induced synaptic potentiation onto somatostatin-expressing (SOM+) CeL neurons, which has previously been shown to store fear memory(6). Consistently, we found that PVT neurons preferentially innervate SOM+ neurons in the CeL, and stimulation of PVT afferents facilitated SOM+ neuron activity and promoted intra-CeL inhibition, two processes that are critical for fear learning and expression(5,6). Notably, PVT modulation of SOM+ CeL neurons was mediated by activation of the brain-derived neurotrophic factor (BDNF) receptor tropomysin-related kinase B (TrkB). As a result, selective deletion of either Bdnf in the PVT or Trkb in SOM+ CeL neurons impaired fear conditioning, while infusion of BDNF into the CeL enhanced fear learning and elicited unconditioned fear responses. Our results demonstrate that the PVT-CeL pathway constitutes a novel circuit essential for both the establishment of fear memory and the expression of fear responses, and uncover mechanisms linking stress detection in PVT with the emergence of adaptive behaviour.
C1 [Penzo, Mario A.; Robert, Vincent; Tucciarone, Jason; Wang, Minghui; Van Aelst, Linda; Huang, Z. Josh; Li, Bo] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA.
   [Robert, Vincent] Ecole Normale Super, F-94230 Cachan, France.
   [Tucciarone, Jason] SUNY Stony Brook, Med Scientist Training Program, Stony Brook, NY 11790 USA.
   [Tucciarone, Jason] SUNY Stony Brook, Program Neurosci, Stony Brook, NY 11790 USA.
   [De Bundel, Dimitri] INSERM, CNRS, Inst Genom Fonct, UMR 5203,U661, F-34090 Montpellier, France.
   [Darvas, Martin] Univ Washington, Dept Pathol, Seattle, WA 98104 USA.
   [Parada, Luis F.] Univ Texas SW Med Ctr Dallas, Dept Dev Biol, Dallas, TX 75390 USA.
   [Palmiter, Richard D.] Univ Washington, Howard Hughes Med Inst, Dept Biochem, Seattle, WA 98195 USA.
   [He, Miao] Fudan Univ, Inst Brain Sci, Shanghai 200032, Peoples R China.
   [He, Miao] Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China.
C3 Cold Spring Harbor Laboratory; Universite Paris Saclay; State University of New York (SUNY) System; Stony Brook University; State University of New York (SUNY) System; Stony Brook University; Universite de Montpellier; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); University of Washington; University of Washington Seattle; University of Texas System; University of Texas Southwestern Medical Center; University of Washington; University of Washington Seattle; Howard Hughes Medical Institute; Fudan University; Fudan University
RP Penzo, MA (corresponding author), Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA.
EM mpenzo@cshl.edu; bli@cshl.edu
FU National Institutes of Health (NIH); Dana Foundation; NARSAD; Louis Feil Trust; Stanley Family Foundation; Harvey L. Karp Discovery Award; National Institute of Mental Health [R01MH101214, R01MH094705] Funding Source: NIH RePORTER
NR 26
TC 378
Z9 461
U1 4
U2 166
PU NATURE PUBLISHING 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 26
PY 2015
VL 519
IS 7544
BP 455
EP +
DI 10.1038/nature13978
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE1WF
UT WOS:000351602800053
PM 25600269
DA 2026-03-09
ER

PT J
AU Wu, DL
   Potluri, N
   Lu, JP
   Kim, YC
   Rastinejad, F
AF Wu, Dalei
   Potluri, Nalini
   Lu, Jingping
   Kim, Youngchang
   Rastinejad, Fraydoon
TI Structural integration in hypoxia-inducible factors
SO NATURE
LA English
DT Article
ID pas-b domain; ligand-binding; transcription factor; cancer biology; dimerization; proteins; heterodimerization; identification; hif-2-alpha; recognition
AB The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-alpha and ARNT (also called HIF-1 beta) subunits. Here we describe crystal structures for each of mouse HIF-2 alpha-ARNT and HIF-1 alpha-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2 alpha-ARNT and HIF-1 alpha-ARNT, wherein ARNT spirals around the outside of each HIF-alpha subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-alpha mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.
C1 [Wu, Dalei; Potluri, Nalini; Lu, Jingping; Rastinejad, Fraydoon] Sanford Burnham Prebys Med Discovery Inst, Metab Dis Program, Orlando, FL 32827 USA.
   [Kim, Youngchang] Argonne Natl Lab, Biosci Div, Struct Biol Ctr, Argonne, IL 60439 USA.
C3 Sanford Burnham Prebys Medical Discovery Institute; United States Department of Energy (DOE); Argonne National Laboratory
RP Rastinejad, F (corresponding author), Sanford Burnham Prebys Med Discovery Inst, Metab Dis Program, Orlando, FL 32827 USA.
EM frastinejad@sbpdiscovery.org
NR 64
TC 277
Z9 332
U1 2
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 AUG 20
PY 2015
VL 524
IS 7565
BP 303
EP +
DI 10.1038/nature14883
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP2NN
UT WOS:000359714000026
PM 26245371
DA 2026-03-09
ER

PT J
AU Mohammed, H
   Russell, IA
   Stark, R
   Rueda, OM
   Hickey, TE
   Tarulli, GA
   Serandour, AAA
   Birrell, SN
   Bruna, A
   Saadi, A
   Menon, S
   Hadfield, J
   Pugh, M
   Raj, GV
   Brown, GD
   D'Santos, C
   Robinson, JLL
   Silva, G
   Launchbury, R
   Perou, CM
   Stingl, J
   Caldas, C
   Tilley, WD
   Carroll, JS
AF Mohammed, Hisham
   Russell, I. Alasdair
   Stark, Rory
   Rueda, Oscar M.
   Hickey, Theresa E.
   Tarulli, Gerard A.
   Serandour, Aurelien A. A.
   Birrell, Stephen N.
   Bruna, Alejandra
   Saadi, Amel
   Menon, Suraj
   Hadfield, James
   Pugh, Michelle
   Raj, Ganesh V.
   Brown, Gordon D.
   D'Santos, Clive
   Robinson, Jessica L. L.
   Silva, Grace
   Launchbury, Rosalind
   Perou, Charles M.
   Stingl, John
   Caldas, Carlos
   Tilley, Wayne D.
   Carroll, Jason S.
TI Progesterone receptor modulates ERα action in breast cancer
SO NATURE
LA English
DT Article
ID estrogen-receptor; synthetic progestin; mechanism; therapy; reveals; acetate; cells; women; trial; gene
AB Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-alpha (ER alpha) function and breast cancer prognosis. Here we show that PR is not merely an ER alpha-induced gene target, but is also an ER alpha-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ER alpha to direct ER alpha chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ER alpha(+) cell line xenografts and primary ER alpha(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ER alpha antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ER alpha(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ER alpha chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.
C1 [Mohammed, Hisham; Russell, I. Alasdair; Stark, Rory; Rueda, Oscar M.; Serandour, Aurelien A. A.; Bruna, Alejandra; Saadi, Amel; Menon, Suraj; Hadfield, James; Pugh, Michelle; Brown, Gordon D.; D'Santos, Clive; Robinson, Jessica L. L.; Launchbury, Rosalind; Stingl, John; Caldas, Carlos; Carroll, Jason S.] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England.
   [Hickey, Theresa E.; Tarulli, Gerard A.; Birrell, Stephen N.; Tilley, Wayne D.] Univ Adelaide, Dame Roma Mitchell Canc Res Labs, Adelaide, SA 5005, Australia.
   [Hickey, Theresa E.; Tarulli, Gerard A.; Birrell, Stephen N.; Tilley, Wayne D.] Univ Adelaide, Sch Med, Adelaide Prostate Canc Res Ctr, Adelaide, SA 5005, Australia.
   [Raj, Ganesh V.] Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA.
   [Silva, Grace; Perou, Charles M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA.
   [Caldas, Carlos] Cambridge Univ Hosp NHS Fdn Trust, Addenbrookes Hosp, Cambridge Breast Unit, Cambridge CB2 2QQ, England.
   [Caldas, Carlos] NIHR Cambridge Biomed Res Ctr, Cambridge CB2 2QQ, England.
   [Caldas, Carlos] Cambridge Expt Canc Med Ctr, Cambridge CB2 0RE, England.
C3 Cancer Research UK; University of Cambridge; CRUK Cambridge Institute; Adelaide University; University of Adelaide; Adelaide University; University of Adelaide; University of Texas System; University of Texas Southwestern Medical Center; University of North Carolina; University of North Carolina Chapel Hill; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; University of Cambridge; University of Cambridge
RP Carroll, JS (corresponding author), Univ Cambridge, Canc Res UK Cambridge Inst, Robinson Way, Cambridge CB2 0RE, England.
EM wayne.tilley@adelaide.edu.au; jason.carroll@cruk.cam.ac.uk
FU University of Cambridge; Cancer Research UK; Hutchison Whampoa Limited; National Cancer Institute of National Institutes of Health [5P30CA142543]; Department of Defense [W81XWH-12-1-0288-03]; National Health and Medical Research Council of Australia [1008349, 1084416]; Cancer Australia [627229]; US Department of Defense Breast Cancer Research Program (BCRP) [W81XWH-11-1-0592]; Royal Adelaide Hospital Research Foundation; ERC; EMBO Young investigator award; Cancer Research UK [20411, 16942, 22310] Funding Source: researchfish; National Institute for Health Research [NF-SI-0611-10154] Funding Source: researchfish; National Health and Medical Research Council (NHMRC) [1008349] Funding Source: National Health and Medical Research Council (NHMRC); National Cancer Institute [P30CA142543] Funding Source: NIH RePORTER
NR 31
TC 523
Z9 637
U1 5
U2 148
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 16
PY 2015
VL 523
IS 7560
BP 313
EP +
DI 10.1038/nature14583
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM8KY
UT WOS:000357950900034
PM 26153859
DA 2026-03-09
ER

PT J
AU Konermann, S
   Brigham, MD
   Trevino, AE
   Joung, J
   Abudayyeh, OO
   Barcena, C
   Hsu, PD
   Habib, N
   Gootenberg, JS
   Nishimasu, H
   Nureki, O
   Zhang, F
AF Konermann, Silvana
   Brigham, Mark D.
   Trevino, Alexandro E.
   Joung, Julia
   Abudayyeh, Omar O.
   Barcena, Clea
   Hsu, Patrick D.
   Habib, Naomi
   Gootenberg, Jonathan S.
   Nishimasu, Hiroshi
   Nureki, Osamu
   Zhang, Feng
TI Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex
SO NATURE
LA English
DT Article
ID protein-coupled receptors; human-cells; raf inhibition; target dna; rna; resistance; cancer; melanoma; cas9; pathway
AB Systematic interrogation of gene function requires the ability to perturb gene expression in a robust and generalizable manner. Here we describe structure-guided engineering of a CRISPR-Cas9 complex to mediate efficient transcriptional activation at endogenous genomic loci. We used these engineered Cas9 activation complexes to investigate single-guide RNA (sgRNA) targeting rules for effective transcriptional activation, to demonstrate multiplexed activation of ten genes simultaneously, and to upregulate long intergenic non-coding RNA (lincRNA) transcripts. We also synthesized a library consisting of 70,290 guides targeting all human RefSeq coding isoforms to screen for genes that, upon activation, confer resistance to a BRAF inhibitor. The top hits included genes previously shown to be able to confer resistance, and novel candidates were validated using individual sgRNA and complementary DNA overexpression. A gene expression signature based on the top screening hits correlated with markers of BRAF inhibitor resistance in cell lines and patient-derived samples. These results collectively demonstrate the potential of Cas9-based activators as a powerful genetic perturbation technology.
C1 [Konermann, Silvana; Brigham, Mark D.; Trevino, Alexandro E.; Joung, Julia; Abudayyeh, Omar O.; Barcena, Clea; Hsu, Patrick D.; Habib, Naomi; Gootenberg, Jonathan S.; Zhang, Feng] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Konermann, Silvana; Brigham, Mark D.; Trevino, Alexandro E.; Abudayyeh, Omar O.; Barcena, Clea; Hsu, Patrick D.; Gootenberg, Jonathan S.; Zhang, Feng] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA.
   [Konermann, Silvana; Brigham, Mark D.; Trevino, Alexandro E.; Abudayyeh, Omar O.; Barcena, Clea; Hsu, Patrick D.; Gootenberg, Jonathan S.; Zhang, Feng] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA.
   [Konermann, Silvana; Brigham, Mark D.; Trevino, Alexandro E.; Joung, Julia; Abudayyeh, Omar O.; Barcena, Clea; Hsu, Patrick D.; Gootenberg, Jonathan S.; Zhang, Feng] MIT, Dept Biol Engn, Cambridge, MA 02139 USA.
   [Gootenberg, Jonathan S.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA.
   [Nishimasu, Hiroshi; Nureki, Osamu] Univ Tokyo, Grad Sch Sci, Dept Biol Sci, Tokyo 1130032, Japan.
   [Nishimasu, Hiroshi] JST, Tokyo 1130032, Japan.
C3 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; University of Tokyo; Japan Science & Technology Agency (JST)
RP Zhang, F (corresponding author), Broad Inst MIT & Harvard, 75 Ames St, Cambridge, MA 02142 USA.
EM zhang@broadinstitute.org
FU NSF Graduate Research Fellowship; D.O.E. Computational Science Graduate Fellowship; PRESTO from JST; JSPS; CREST program; JST; NIMH [DP1-MH100706]; NINDS [R01-N507312401]; NSF; Keck, Searle Scholars; Klingenstein Foundation; Vallee Foundation; Simons Foundation; Bob Metcalfe; Grants-in-Aid for Scientific Research [26291010] Funding Source: KAKEN
NR 51
TC 2149
Z9 2919
U1 19
U2 965
PU NATURE PUBLISHING 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 29
PY 2015
VL 517
IS 7536
BP 583
EP U332
DI 10.1038/nature14136
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA2ZL
UT WOS:000348775000036
PM 25494202
DA 2026-03-09
ER

PT J
AU Pfender, S
   Kuznetsov, V
   Pasternak, M
   Tischer, T
   Santhanam, B
   Schuh, M
AF Pfender, Sybille
   Kuznetsov, Vitaliy
   Pasternak, Michal
   Tischer, Thomas
   Santhanam, Balaji
   Schuh, Melina
TI Live imaging RNAi screen reveals genes essential for meiosis in mammalian oocytes
SO NATURE
LA English
DT Article
ID nuclear-envelope breakdown; enclosed mouse oocytes; greatwall kinase; in-vitro; aneuploidy; cells; fertilization; kinetochores; insights; anaphase
AB During fertilization, an egg and a sperm fuse to form a new embryo. Eggs develop from oocytes in a process called meiosis. Meiosis inhuman oocytes is highly error-prone(1,2), and defective eggs are the leading cause of pregnancy loss and several genetic disorders such as Down's syndrome(3-5). Which genes safeguard accurate progression through meiosis is largely unclear. Here we develop high-content phenotypic screening methods for the systematic identification of mammalian meiotic genes. We targeted 774 genes by RNA interference within follicle-enclosed mouse oocytes to block protein expression from an early stage of oocyte development onwards. We then analysed the function of several genes simultaneously by high-resolution imaging of chromosomes and microtubules in live oocytes and scored each oocyte quantitatively for 50 phenotypes, generating a comprehensive resource of meiotic gene function. The screen generated an unprecedented annotated data set of meiotic progression in 2,241 mammalian oocytes, which allowed us to analyse systematically which defects are linked to abnormal chromosome segregation during meiosis, identifying progression into anaphase with misaligned chromosomes as well as defects in spindle organization as risk factors. This study demonstrates how high-content screens can be performed in oocytes, and allows systematic studies of meiosis in mammals.
C1 [Pfender, Sybille; Kuznetsov, Vitaliy; Pasternak, Michal; Tischer, Thomas; Santhanam, Balaji; Schuh, Melina] MRC, Mol Biol Lab, Cambridge CB2 0QH, England.
C3 MRC Laboratory Molecular Biology
RP Schuh, M (corresponding author), MRC, Mol Biol Lab, Francis Crick Ave,Cambridge Biomed Campus, Cambridge CB2 0QH, England.
EM mschuh@mrc-lmb.cam.ac.uk
FU Boehringer-Ingelheim Fonds; EMBO [ALTF700-2014]; European Research Council [337415]; European Community [241548]; MRC [MC_U105192711, MC_U105185859] Funding Source: UKRI; Medical Research Council [MC_U105192711, MC_U105185859, 1274326] Funding Source: researchfish; European Research Council (ERC) [337415] Funding Source: European Research Council (ERC)
NR 30
TC 71
Z9 75
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 13
PY 2015
VL 524
IS 7564
BP 239
EP +
DI 10.1038/nature14568
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900036
PM 26147080
DA 2026-03-09
ER

PT J
AU Liu, JF
   Bai, Y
   Wang, S
   Justham, S
   Lu, YJ
   Gu, WM
   Liu, QZ
   Di Stefano, R
   Guo, JC
   Cabrera-Lavers, A
   Alvarez, P
   Cao, Y
   Kulkarni, S
AF Liu, Ji-Feng
   Bai, Yu
   Wang, Song
   Justham, Stephen
   Lu, You-Jun
   Gu, Wei-Min
   Liu, Qing-Zhong
   Di Stefano, Rosanne
   Guo, Jin-Cheng
   Cabrera-Lavers, Antonio
   Alvarez, Pedro
   Cao, Yi
   Kulkarni, Shri
TI Relativistic baryonic jets from an ultraluminous supersoft X-ray source
SO NATURE
LA English
DT Article
ID discovery; novae; disks
AB The formation of relativistic jets by an accreting compact object is one of the fundamental mysteries of astrophysics. Although the theory is poorly understood, observations of relativistic jets from systems known as microquasars (compact binary stars)(1,2) have led to a well established phenomenology(3,4). Relativistic jets are not expected to be produced by sources with soft or supersoft X-ray spectra, although two such systems are known to produce relatively low-velocity bipolar outflows(5,6). Here we report the optical spectra of an ultraluminous supersoft X-ray source (ULS7,8) in the nearby galaxy M81 (M81 ULS-1; refs 9, 10). Unexpectedly, the spectra show blueshifted, broad H alpha emission lines, characteristic of baryonic jets with relativistic speeds. These time-variable emission lines have projected velocities of about 17 per cent of the speed of light, and seem to be similar to those from the prototype microquasar SS 433 (refs 11, 12). Such relativistic jets are not expected to be launched from white dwarfs(13), and an origin from a black hole or a neutron star is hard to reconcile with the persistence of M81 ULS-1's soft X-rays(10). Thus the unexpected presence of relativistic jets in a ULS challenges canonical theories of jet formation(3,4), but might be explained by a long-speculated, supercritically accreting black hole with optically thick outflows(14-20).
C1 [Liu, Ji-Feng; Bai, Yu; Wang, Song; Justham, Stephen; Lu, You-Jun; Guo, Jin-Cheng] Chinese Acad Sci, Natl Astron Observ, Key Lab Opt Astron, Beijing 100012, Peoples R China.
   [Liu, Ji-Feng; Justham, Stephen; Lu, You-Jun] Univ Chinese Acad Sci, Coll Astron & Space Sci, Beijing 100049, Peoples R China.
   [Gu, Wei-Min] Xiamen Univ, Dept Astron, Xiamen 361005, Fujian Province, Peoples R China.
   [Liu, Qing-Zhong] Chinese Acad Sci, Purple Mt Observ, Key Lab Dark Matter & Space Astron, Nanjing 210008, Jiangsu, Peoples R China.
   [Di Stefano, Rosanne] Harvard Smithsonian Ctr Astrophys, Cambridge, MA 02138 USA.
   [Cabrera-Lavers, Antonio; Alvarez, Pedro] Inst Astrofis Canarias, E-38200 San Cristobal la Laguna, Tenerife, Spain.
   [Cabrera-Lavers, Antonio; Alvarez, Pedro] Univ La Laguna, Dept Astrofis, E-38205 San Cristobal la Laguna, Tenerife, Spain.
   [Cao, Yi; Kulkarni, Shri] CALTECH, Dept Astron, Pasadena, CA 91125 USA.
C3 Chinese Academy of Sciences; National Astronomical Observatory, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Xiamen University; Chinese Academy of Sciences; Nanjing Institute of Astronomical Optics & Technology, NAOC, CAS; Purple Mountain Observatory, CAS; Smithsonian Astrophysical Observatory; Smithsonian Institution; Harvard University; Instituto de Astrofisica de Canarias; Universidad de la Laguna; California Institute of Technology
RP Liu, JF (corresponding author), Chinese Acad Sci, Natl Astron Observ, Key Lab Opt Astron, 20A Datun Rd, Beijing 100012, Peoples R China.
EM jfliu@nao.cas.cn
FU Chinese Academy of Sciences [XDB09000000]; 973 Program [2014CB845705]; National Science Foundation of China [NSFC-11333004/11425313]; W.M. Keck Foundation
NR 32
TC 35
Z9 37
U1 0
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 DEC 3
PY 2015
VL 528
IS 7580
BP 108
EP +
DI 10.1038/nature15751
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000057
PM 26605521
DA 2026-03-09
ER

PT J
AU Lopes, R
   Imanaliev, A
   Aspect, A
   Cheneau, M
   Boiron, D
   Westbrook, CI
AF Lopes, R.
   Imanaliev, A.
   Aspect, A.
   Cheneau, M.
   Boiron, D.
   Westbrook, C. I.
TI Atomic Hong-Ou-Mandel experiment
SO NATURE
LA English
DT Article
ID quantum interference; photons; indistinguishability; interferometry; entanglement; violation; optics
AB Two-particle interference is a fundamental feature of quantum mechanics, and is even less intuitive than wave-particle duality for a single particle. In this duality, classical concepts-wave or particle-are still referred to, and interference happens in ordinary space-time. On the other hand, two-particle interference takes place in a mathematical space that has no classical counterpart. Entanglement lies at the heart of this interference, as it does in the fundamental tests of quantum mechanics involving the violation of Bell's inequalities(1-4). The Hong, Ou and Mandel experiment(5) is a conceptually simpler situation, in which the interference between two-photon amplitudes also leads to behaviour impossible to describe using a simple classical model. Here we report the realization of the Hong, Ou and Mandel experiment using atoms instead of photons. We create a source that emits pairs of atoms, and cause one atom of each pair to enter one of the two input channels of a beam-splitter, and the other atom to enter the other input channel. When the atoms are spatially overlapped so that the two inputs are indistinguishable, the atoms always emerge together in one of the output channels. This result opens the way to testing Bell's inequalities involving mechanical observables of massive particles, such as momentum, using methods inspired by quantum optics(6,7), and to testing theories of the quantum-to-classical transition(8-11). Our work also demonstrates a new way to benchmark non-classical atom sources(12,13) that may be of interest for quantum information processing(14) and quantum simulation(15).
C1 [Lopes, R.; Imanaliev, A.; Aspect, A.; Cheneau, M.; Boiron, D.; Westbrook, C. I.] Univ Paris Sud, CNRS, Grad Sch, Lab Charles Fabry,Inst Opt, 2 Ave Augustin Fresnel, F-91127 Palaiseau, France.
C3 Institut Polytechnique de Paris; Ecole Polytechnique; Universite Paris Saclay; Centre National de la Recherche Scientifique (CNRS)
RP Lopes, R (corresponding author), Univ Paris Sud, CNRS, Grad Sch, Lab Charles Fabry,Inst Opt, 2 Ave Augustin Fresnel, F-91127 Palaiseau, France.
EM raphael.lopes@institutoptique.fr; marc.cheneau@institutoptique.fr
FU IFRAF; Triangle de la Physique; Labex PALM; ANR (PROQUP, QEAGE); FCT [SFRH/BD/74352/2010]; ESF; POPH/QREN; EU; EU (ERC) [267775]; EU (QUANTATOP); EU (Marie Curie) [CIG 618760]; EU (CORENT); European Research Council (ERC) [267775] Funding Source: European Research Council (ERC); Fundação para a Ciência e a Tecnologia [SFRH/BD/74352/2010] Funding Source: FCT
NR 36
TC 156
Z9 173
U1 0
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 APR 2
PY 2015
VL 520
IS 7545
BP 66
EP +
DI 10.1038/nature14331
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE7NE
UT WOS:000352027700037
PM 25832404
DA 2026-03-09
ER

PT J
AU Fu, Q
   Hajdinjak, M
   Moldovan, OT
   Constantin, S
   Mallick, S
   Skoglund, P
   Patterson, N
   Rohland, N
   Lazaridis, I
   Nickel, B
   Viola, B
   Prüfer, K
   Meyer, M
   Kelso, J
   Reich, D
   Pääbo, S
AF Fu, Qiaomei
   Hajdinjak, Mateja
   Moldovan, Oana Teodora
   Constantin, Silviu
   Mallick, Swapan
   Skoglund, Pontus
   Patterson, Nick
   Rohland, Nadin
   Lazaridis, Iosif
   Nickel, Birgit
   Viola, Bence
   Pruefer, Kay
   Meyer, Matthias
   Kelso, Janet
   Reich, David
   Paeaebo, Svante
TI An early modern human from Romania with a recent Neanderthal ancestor
SO NATURE
LA English
DT Article
ID genome sequence; ancient; dna; cave; admixture; origins; history; systems; europe
AB Neanderthals are thought to have disappeared in Europe approximately 39,000-41,000 years ago but they have contributed 1-3% of the DNA of present-day people in Eurasia(1). Here we analyse DNA from a 37,000-42,000-year-old(2) modern human from Pestera cu Oase, Romania. Although the specimen contains small amounts of human DNA, we use an enrichment strategy to isolate sites that are informative about its relationship to Neanderthals and present-day humans. We find that on the order of 6-9% of the genome of the Oase individual is derived from Neanderthals, more than any other modern human sequenced to date. Three chromosomal segments of Neanderthal ancestry are over 50 centimorgans in size, indicating that this individual had a Neanderthal ancestor as recently as four to six generations back. However, the Oase individual does not share more alleles with later Europeans than with East Asians, suggesting that the Oase population did not contribute substantially to later humans in Europe.
C1 [Fu, Qiaomei] Chinese Acad Sci, IVPP, Key Lab Vertebrate Evolut & Human Origins, Beijing 100044, Peoples R China.
   [Fu, Qiaomei; Mallick, Swapan; Skoglund, Pontus; Rohland, Nadin; Lazaridis, Iosif; Reich, David] Harvard Univ, Dept Genet, Sch Med, Boston, MA 02115 USA.
   [Fu, Qiaomei; Hajdinjak, Mateja; Nickel, Birgit; Viola, Bence; Pruefer, Kay; Meyer, Matthias; Kelso, Janet; Paeaebo, Svante] Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, D-04103 Leipzig, Germany.
   [Moldovan, Oana Teodora] Emil Racovita Inst Speleol, Cluj Branch, Cluj Napoca 400006, Romania.
   [Constantin, Silviu] Emil Racovita Inst Speleol, Dept Geospeleol & Paleontol, Bucharest 010986 12, Romania.
   [Mallick, Swapan; Patterson, Nick; Reich, David] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Mallick, Swapan; Viola, Bence] Max Planck Inst Evolutionary Anthropol, Dept Human Evolut, D-04103 Leipzig, Germany.
   [Viola, Bence] Univ Toronto, Dept Anthropol, Toronto, ON M5S 2S2, Canada.
   [Reich, David] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA USA.
C3 Chinese Academy of Sciences; Institute of Vertebrate Paleontology & Paleoanthropology, CAS; Harvard University; Harvard Medical School; Max Planck Society; Romanian Academy; Emil Racovita Institute of Speleology; Emil Racovita Institute of Speleology; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Max Planck Society; University of Toronto; Harvard University; Harvard Medical School; Howard Hughes Medical Institute
RP Reich, D (corresponding author), Harvard Univ, Dept Genet, Sch Med, Boston, MA 02115 USA.
EM reich@genetics.med.harvard.edu; paabo@eva.mpg.de
FU Chinese Academy of Sciences [XDA05130202]; Special Foundation of the President of the Chinese Academy of Sciences; Romanian National Research Council [PCCE 31/2010]; US National Science Foundation HOMINID [BCS-1032255]; US National Institutes of Health [GM100233]; Howard Hughes Medical Institute; Presidential Innovation Fund of the Max Planck Society; Direct For Social, Behav & Economic Scie; Division Of Behavioral and Cognitive Sci [1032255] Funding Source: National Science Foundation
NR 41
TC 532
Z9 620
U1 1
U2 329
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 13
PY 2015
VL 524
IS 7564
BP 216
EP +
DI 10.1038/nature14558
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900031
PM 26098372
DA 2026-03-09
ER

PT J
AU Zhang, K
   Donnelly, CJ
   Haeusler, AR
   Grima, JC
   Machamer, JB
   Steinwald, P
   Daley, EL
   Miller, SJ
   Cunningham, KM
   Vidensky, S
   Gupta, S
   Thomas, MA
   Hong, I
   Chiu, SL
   Huganir, RL
   Ostrow, LW
   Matunis, MJ
   Wang, JO
   Sattler, R
   Lloyd, TE
   Rothstein, JD
AF Zhang, Ke
   Donnelly, Christopher J.
   Haeusler, Aaron R.
   Grima, Jonathan C.
   Machamer, James B.
   Steinwald, Peter
   Daley, Elizabeth L.
   Miller, Sean J.
   Cunningham, Kathleen M.
   Vidensky, Svetlana
   Gupta, Saksham
   Thomas, Michael A.
   Hong, Ingie
   Chiu, Shu-Ling
   Huganir, Richard L.
   Ostrow, Lyle W.
   Matunis, Michael J.
   Wang, Jiou
   Sattler, Rita
   Lloyd, Thomas E.
   Rothstein, Jeffrey D.
TI The C9orf72 repeat expansion disrupts nucleocytoplasmic transport
SO NATURE
LA English
DT Article
ID nuclear import; segregation distortion; ggggcc repeat; drosophila; mutations; tdp-43; gene; als; neurodegeneration; proteins
AB The hexanucleotide repeat expansion (HRE) GGGGCC (G(4)C(2)) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G(4)C(2) RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30G(4)C(2) repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.
C1 [Zhang, Ke; Machamer, James B.; Cunningham, Kathleen M.; Gupta, Saksham; Ostrow, Lyle W.; Lloyd, Thomas E.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21205 USA.
   [Donnelly, Christopher J.; Grima, Jonathan C.; Daley, Elizabeth L.; Miller, Sean J.; Vidensky, Svetlana; Thomas, Michael A.; Sattler, Rita; Rothstein, Jeffrey D.] Johns Hopkins Univ, Sch Med, Brain Sci Inst, Baltimore, MD 21205 USA.
   [Haeusler, Aaron R.; Steinwald, Peter; Matunis, Michael J.; Wang, Jiou] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Biochem & Mol Biol, Baltimore, MD 21205 USA.
   [Grima, Jonathan C.; Hong, Ingie; Chiu, Shu-Ling; Huganir, Richard L.; Lloyd, Thomas E.; Rothstein, Jeffrey D.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA.
C3 Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins Bloomberg School of Public Health; Johns Hopkins University
RP Rothstein, JD (corresponding author), Johns Hopkins Univ, Sch Med, Brain Sci Inst, Baltimore, MD 21205 USA.
EM tlloyd4@jhmi.edu; jrothstein@jhmi.edu
FU NIH [R01NS085207, NS091046, R01 NS082563, R01 NS074324, NS089616, CA009110]; Brain Science Institute; Robert Packard Center for ALS Research at Johns Hopkins; Muscular Dystrophy Association; Alzheimer's Drug Discovery Foundation; Judith and Jean Pape Adams Charitable Foundation; Alzheimer's Disease Research Center - Johns Hopkins; Maryland TEDCO; Target ALS Springboard Fellowship; William and Ella Owens Foundation; ALS Association; NIH K99 award [NS091486]; National Science Foundation Graduate Research Fellowship; Thomas Shortman Training Fund Graduate Scholarship; National Cancer Institute [T32CA009110] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM060980] Funding Source: NIH RePORTER; National Institute on Aging; National Institute of Neurological Disorders and Stroke [R01NS074324, R01NS089616] Funding Source: NIH RePORTER; NIH Office of the Director; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke; National Institute of General Medical Sciences [P40OD018537] Funding Source: NIH RePORTER
NR 47
TC 788
Z9 942
U1 1
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 SEP 3
PY 2015
VL 525
IS 7567
BP 56
EP +
DI 10.1038/nature14973
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100024
PM 26308891
DA 2026-03-09
ER

PT J
AU Luu, TT
   Garg, M
   Kruchinin, SY
   Moulet, A
   Hassan, MT
   Goulielmakis, E
AF Luu, T. T.
   Garg, M.
   Kruchinin, S. Yu.
   Moulet, A.
   Hassan, M. Th.
   Goulielmakis, E.
TI Extreme ultraviolet high-harmonic spectroscopy of solids
SO NATURE
LA English
DT Article
ID attosecond control; generation; dynamics; field
AB Extreme ultraviolet (EUV) high-harmonic radiation(1,2) emerging from laser-driven atoms, molecules or plasmas underlies powerful attosecond spectroscopy techniques(3-5) and provides insight into fundamental structural and dynamic properties of matter(6,7). The advancement of these spectroscopy techniques to study strong-field electron dynamics in condensed matter calls for the generation and manipulation of EUV radiation in bulk solids, but this capability has remained beyond the reach of optical sciences. Recent experiments(8,9) and theoretical predictions(10-12) paved the way to strong-field physics in solids by demonstrating the generation and optical control of deep ultraviolet radiation(8) in bulk semiconductors, driven by femtosecond mid-infrared fields or the coherent up-conversion of terahertz fields to multi-octave spectra in the mid-infrared and optical frequencies(9). Here we demonstrate that thin films of SiO2 exposed to intense, few-cycle to sub-cycle pulses give rise to wideband coherent EUV radiation extending in energy to about 40 electronvolts. Our study indicates the association of the emitted EUV radiation with intraband currents of multi-petahertz frequency, induced in the lowest conduction band of SiO2. To demonstrate the applicability of high-harmonic spectroscopy to solids, we exploit the EUV spectra to gain access to fine details of the energy dispersion profile of the conduction band that are as yet inaccessible by photoemission spectroscopy in wide-bandgap dielectrics. In addition, we use the EUV spectra to trace the attosecond control of the intraband electron motion induced by synthesized optical transients. Our work advances light-wave electronics(5,13-15) in condensed matter into the realm of multi-petahertz frequencies and their attosecond control, and marks the advent of solid-state EUV photonics.
C1 [Luu, T. T.; Garg, M.; Kruchinin, S. Yu.; Moulet, A.; Hassan, M. Th.; Goulielmakis, E.] Max Planck Inst Quantum Opt, D-85748 Garching, Germany.
C3 Max Planck Society
RP Goulielmakis, E (corresponding author), Max Planck Inst Quantum Opt, Hans Kopfermann Str 1, D-85748 Garching, Germany.
EM elgo@mpq.mpg.de
FU European Research Council [Attoelectronics-258501]; Deutsche Forschungsgemeinschaft Cluster of Excellence: Munich Centre for Advanced Photonics; Max Planck Society; European Research Training Network ATTOFEL
NR 29
TC 758
Z9 821
U1 12
U2 497
PU NATURE PUBLISHING 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 28
PY 2015
VL 521
IS 7553
BP 498
EP 502
DI 10.1038/nature14456
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ2AN
UT WOS:000355286600038
PM 26017451
DA 2026-03-09
ER

PT J
AU Allegretti, M
   Klusch, N
   Mills, DJ
   Vonck, J
   Kühlbrandt, W
   Davies, KM
AF Allegretti, Matteo
   Klusch, Niklas
   Mills, Deryck J.
   Vonck, Janet
   Kuehlbrandt, Werner
   Davies, Karen M.
TI Horizontal membrane-intrinsic α-helices in the stator a-subunit of an F-type ATP synthase
SO NATURE
LA English
DT Article
ID essential arginine residue; c-ring; f0f1-atp synthase; polytomella sp; resolution; substitution; transport; complex; model; polar
AB ATP, the universal energy currency of cells, is produced by F-type ATP synthases, which are ancient, membrane-bound nanomachines. F-type ATP synthases use the energy of a transmembrane electrochemical gradient to generate ATP by rotary catalysis. Protons moving across the membrane drive a rotor ring composed of 8-15 c-subunits(1). A central stalk transmits the rotation of the c-ring to the catalytic F-1 head, where a series of conformational changes results in ATP synthesis(2). A key unresolved question in this fundamental process is how protons pass through the membrane to drive ATP production. Mitochondrial ATP synthases form V-shaped homodimers in cristae membranes(3). Here we report the structure of a native and active mitochondrial ATP synthase dimer, determined by single-particle electron cryomicroscopy at 6.2 angstrom resolution. Our structure shows four long, horizontal membrane-intrinsic alpha-helices in the a-subunit, arranged in two hairpins at an angle of approximately 70 degrees relative to the c-ring helices. It has been proposed that a strictly conserved membrane-embedded arginine in the a-subunit couples proton translocation to c-ring rotation(4). A fit of the conserved carboxy-terminal a-subunit sequence places the conserved arginine next to a proton-binding c-subunit glutamate. The map shows a slanting solvent-accessible channel that extends from the mitochondrial matrix to the conserved arginine. Another hydrophilic cavity on the lumenal membrane surface defines a direct route for the protons to an essential histidine-glutamate pair(5). Our results provide unique new insights into the structure and function of rotary ATP synthases and explain how ATP production is coupled to proton translocation.
C1 [Allegretti, Matteo; Klusch, Niklas; Mills, Deryck J.; Vonck, Janet; Kuehlbrandt, Werner; Davies, Karen M.] Max Planck Inst Biophys, Dept Struct Biol, D-60438 Frankfurt, Germany.
C3 Max Planck Society
RP Kühlbrandt, W (corresponding author), Max Planck Inst Biophys, Dept Struct Biol, Max von Laue Str 3, D-60438 Frankfurt, Germany.
EM werner.kuehlbrandt@biophys.mpg.de; karen.davies@biophys.mpg.de
FU Max Planck Society; Deutsche Forschungsgemeinschaft Cluster of Excellence Frankfurt 'Macromolecular Complexes'
NR 45
TC 209
Z9 227
U1 3
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 MAY 14
PY 2015
VL 521
IS 7551
BP 237
EP +
DI 10.1038/nature14185
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH9SY
UT WOS:000354377800062
PM 25707805
DA 2026-03-09
ER

PT J
AU Bedford, T
   Riley, S
   Barr, IG
   Broor, S
   Chadha, M
   Cox, NJ
   Daniels, RS
   Gunasekaran, CP
   Hurt, AC
   Kelso, A
   Klimov, A
   Lewis, NS
   Li, XY
   McCauley, JW
   Odagiri, T
   Potdar, V
   Rambaut, A
   Shu, YL
   Skepner, E
   Smith, DJ
   Suchard, MA
   Tashiro, M
   Wang, DY
   Xu, XY
   Lemey, P
   Russell, CA
AF Bedford, Trevor
   Riley, Steven
   Barr, Ian G.
   Broor, Shobha
   Chadha, Mandeep
   Cox, Nancy J.
   Daniels, Rodney S.
   Gunasekaran, C. Palani
   Hurt, Aeron C.
   Kelso, Anne
   Klimov, Alexander
   Lewis, Nicola S.
   Li, Xiyan
   McCauley, John W.
   Odagiri, Takato
   Potdar, Varsha
   Rambaut, Andrew
   Shu, Yuelong
   Skepner, Eugene
   Smith, Derek J.
   Suchard, Marc A.
   Tashiro, Masato
   Wang, Dayan
   Xu, Xiyan
   Lemey, Philippe
   Russell, Colin A.
TI Global circulation patterns of seasonal influenza viruses vary with antigenic drift
SO NATURE
LA English
DT Article
ID dynamics; epidemiology; selection; network; spread; sites; waves
AB Understanding the spatiotemporal patterns of emergence and circulation of new human seasonal influenza virus variants is a key scientific and public health challenge. The global circulation patterns of influenza A/H3N2 viruses are well characterized(1-7), but the patterns of A/H1N1 and B viruses have remained largely unexplored. Here we show that the global circulation patterns of A/H1N1 (up to 2009), B/Victoria, and B/Yamagata viruses differ substantially from those of A/H3N2 viruses, on the basis of analyses of 9,604 haemagglutinin sequences of human seasonal influenza viruses from 2000 to 2012. Whereas genetic variants of A/H3N2 viruses did not persist locally between epidemics and were reseeded from East and Southeast Asia, genetic variants of A/H1N1 and B viruses persisted across several seasons and exhibited complex global dynamics with East and Southeast Asia playing a limited role in disseminating new variants. The less frequent global movement of influenza A/H1N1 and B viruses coincided with slower rates of antigenic evolution, lower ages of infection, and smaller, less frequent epidemics compared to A/H3N2 viruses. Detailed epidemic models support differences in age of infection, combined with the less frequent travel of children, as probable drivers of the differences in the patterns of global circulation, suggesting a complex interaction between virus evolution, epidemiology, and human behaviour.
C1 [Bedford, Trevor] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA.
   [Riley, Steven] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Infect Dis Epidemiol, MRC Ctr Outbreak Anal & Modelling, London SW7 2AZ, England.
   [Riley, Steven; Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA.
   [Barr, Ian G.; Hurt, Aeron C.; Kelso, Anne] WHO, Collaborating Ctr Reference & Res Influenza, Melbourne, Vic 3000, Australia.
   [Broor, Shobha] SGT Med Coll Hosp & Res Inst, Gurgaon 122505, Haryana, India.
   [Chadha, Mandeep; Potdar, Varsha] Natl Inst Virol, Pune 411001, Maharashtra, India.
   [Cox, Nancy J.; Klimov, Alexander; Xu, Xiyan] Ctr Dis Control & Prevent, WHO Collaborating Ctr Reference & Res Influenza, Atlanta, GA 30329 USA.
   [Daniels, Rodney S.; McCauley, John W.] Natl Inst Med Res, MRC, WHO Collaborating Ctr Reference & Res Influenza, London NW7 1AA, England.
   [Gunasekaran, C. Palani] King Inst Prevent Med & Res, Madras 600032, Tamil Nadu, India.
   [Hurt, Aeron C.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Parkville, Vic 3010, Australia.
   [Lewis, Nicola S.; Skepner, Eugene; Smith, Derek J.] Univ Cambridge, Dept Zool, Cambridge CB2 3EJ, England.
   [Li, Xiyan; Shu, Yuelong; Wang, Dayan] China CDC, WHO Collaborating Ctr Reference & Res Influenza, Natl Inst Viral Dis Control & Prevent, Beijing 102206, Peoples R China.
   [Odagiri, Takato; Tashiro, Masato] Natl Inst Infect Dis, WHO Collaborating Ctr Reference & Res Influenza, Tokyo 2080011, Japan.
   [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH9 3JT, Midlothian, Scotland.
   [Rambaut, Andrew] Univ Edinburgh, Ctr Immunol Infect & Evolut, Edinburgh EH9 3FL, Midlothian, Scotland.
   [Smith, Derek J.] Erasmus MC, Dept Virosci, NL-3015 Rotterdam, Netherlands.
   [Suchard, Marc A.] Univ Calif Los Angeles, Dept Biostat, Fielding Sch Publ Hlth, 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.
   [Lemey, Philippe] KU Leuven Univ Leuven, Rega Inst, Dept Microbiol & Immunol, B-3000 Leuven, Belgium.
   [Russell, Colin A.] Univ Cambridge, Dept Vet Med, Cambridge CB3 0ES, England.
C3 Fred Hutchinson Cancer Center; Imperial College London; National Institutes of Health (NIH) - USA; NIH Fogarty International Center (FIC); World Health Organization; World Health Organization (WHO) Australia; Indian Council of Medical Research (ICMR); ICMR - National Institute of Virology (NIV); Centers for Disease Control & Prevention - USA; MRC National Institute for Medical Research; University of Melbourne; University of Cambridge; Chinese Center for Disease Control & Prevention; National Institute for Viral Disease Control & Prevention, Chinese Center for Disease Control & Prevention; Japan Institute for Health Security (JIHS); National Institute of Infectious Diseases (NIID); University of Edinburgh; University of Edinburgh; Erasmus University Rotterdam; Erasmus MC; 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; KU Leuven; University of Cambridge
RP Russell, CA (corresponding author), Univ Cambridge, Dept Vet Med, Cambridge CB3 0ES, England.
EM car44@cam.ac.uk
FU Newton International Fellowship from the Royal Society; National Institutes of Health (NIH) [U54 GM111274]; Medical Research Council (UK) [MR/J008761/1]; Wellcome Trust (UK) [093488/Z/10/Z]; Fogarty International Centre (USA) [R01 TW008246-01]; Department of Homeland Security (USA, RAPIDD program); National Institute of General Medical Sciences (USA) [MIDAS U01 GM110721-01]; National Institute for Health Research (UK, Health Protection Research Unit); Australian Government Department of Health; US Department of Health and Human Services; National Science Foundation DMS [1264153]; NIH [R01 AI 107034]; EU [278433-PREDEMICS]; ERC [260864]; Royal Society;  [U117512723]; Medical Research Council [MR/J008761/1, MC_U117585868, MR/K010174/1B, MC_U117512723, MR/K010174/1] Funding Source: researchfish; National Institute for Health Research [HPRU-2012-10080] Funding Source: researchfish; The Francis Crick Institute [10030] Funding Source: researchfish; Direct For Mathematical & Physical Scien; Division Of Mathematical Sciences [1264153] Funding Source: National Science Foundation; MRC [MC_U117512723, MC_U117585868, MR/J008761/1, MR/K010174/1] Funding Source: UKRI
NR 38
TC 400
Z9 510
U1 6
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 JUL 9
PY 2015
VL 523
IS 7559
BP 217
EP U206
DI 10.1038/nature14460
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM4ZO
UT WOS:000357695900036
PM 26053121
DA 2026-03-09
ER

PT J
AU Bao, J
   Bawendi, MG
AF Bao, Jie
   Bawendi, Moungi G.
TI A colloidal quantum dot spectrometer
SO NATURE
LA English
DT Article
ID cdse; nanocrystals; resolution; light; regression; design; filter; model; size
AB Spectroscopy is carried out in almost every field of science, whenever light interacts with matter(1). Although sophisticated instruments with impressive performance characteristics are available, much effort continues to be invested in the development of miniaturized, cheap and easy-to-use systems(1-13). Current microspectrometer designs mostly use interference filters(2-5) and interferometric optics(3) that limit their photon efficiency, resolution and spectral range(2,3). Here we show that many of these limitations can be overcome by replacing interferometric optics with a two-dimensional absorptive filter array composed of colloidal quantum dots(14-17). Instead of measuring different bands of a spectrum individually after introducing temporal or spatial separations with gratings or interference-based narrow-band filters, a colloidal quantum dot spectrometer measures a light spectrum based on the wavelength multiplexing principle(18): multiple spectral bands are encoded and detected simultaneously with one filter and one detector(9-12), respectively, with the array format allowing the process to be efficiently repeated many times using different filters with different encoding so that sufficient information is obtained to enable computational reconstruction of the target spectrum. We illustrate the performance of such a quantum dot microspectrometer, made from 195 different types of quantum dots with absorption features that cover a spectral range of 300 nanometres, by measuring shifts in spectral peak positions as small as one nanometre. Given this performance, demonstrable avenues for further improvement, the ease with which quantum dots can be processed and integrated, and their numerous finely tuneable bandgaps that cover a broad spectral range, we expect that quantum dot micro-spectrometers will be useful in applications where minimizing size, weight, cost and complexity of the spectrometer are critical.
C1 [Bao, Jie] Tsinghua Univ, Dept Elect Engn, Beijing 100084, Peoples R China.
   [Bao, Jie; Bawendi, Moungi G.] MIT, Dept Chem, Cambridge, MA 02139 USA.
   [Bao, Jie] CALTECH, Dept Phys, Pasadena, CA 91125 USA.
C3 Tsinghua University; Massachusetts Institute of Technology (MIT); California Institute of Technology
RP Bao, J (corresponding author), Tsinghua Univ, Dept Elect Engn, Beijing 100084, Peoples R China.
EM bao@tsinghua.edu.cn
FU ARO through the Institute for Soldier Nanotechnologies [W911NF-07-D-0004]; Tsinghua University; Division of Physics, Mathematics and Astronomy at the California Institute of Technology
NR 38
TC 613
Z9 728
U1 36
U2 921
PU NATURE PUBLISHING 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 2
PY 2015
VL 523
IS 7558
BP 67
EP +
DI 10.1038/nature14576
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL7RN
UT WOS:000357169500032
PM 26135449
DA 2026-03-09
ER

PT J
AU Westcott, PMK
   Halliwill, KD
   To, MD
   Rashid, M
   Rust, AG
   Keane, TM
   Delrosario, R
   Jen, KY
   Gurley, KE
   Kemp, CJ
   Fredlund, E
   Quigley, DA
   Adams, DJ
   Balmain, A
AF Westcott, Peter M. K.
   Halliwill, Kyle D.
   To, Minh D.
   Rashid, Mamunur
   Rust, Alistair G.
   Keane, Thomas M.
   Delrosario, Reyno
   Jen, Kuang-Yu
   Gurley, Kay E.
   Kemp, Christopher J.
   Fredlund, Erik
   Quigley, David A.
   Adams, David J.
   Balmain, Allan
TI The mutational landscapes of genetic and chemical models of Kras-driven lung cancer
SO NATURE
LA English
DT Article
ID sequencing data; k-ras; point mutations; expression; genome; mouse; signatures; carcinoma; mtus1; cell
AB Next-generation sequencing of human tumours has refined our understanding of the mutational processes operative in cancer initiation and progression, yet major questions remain regarding the factors that induce driver mutations and the processes that shape mutation selection during tumorigenesis. Here we performed whole-exome sequencing on adenomas from three mouse models of non-small-cell lung cancer, which were induced either by exposure to carcinogens (methyl-nitrosourea (MNU) and urethane) or by genetic activation of Kras (Kras(LA2)). Although the MNU-induced tumours carried exactly the same initiating mutation in Kras as seen in the Kras(LA2) model (G12D), MNU tumours had an average of 192 non-synonymous, somatic single-nucleotide variants, compared with only six in tumours from the Kras(LA2) model. By contrast, the Kras(LA2) tumours exhibited a significantly higher level of aneuploidy and copy number alterations compared with the carcinogen-induced tumours, suggesting that carcinogen-induced and genetically engineered models lead to tumour development through different routes. The wild-type allele of Kras has been shown to act as a tumour suppressor inmouse models of non-small-cell lung cancer. We demonstrate that urethane-induced tumours from wild-type mice carry mostly (94%) Kras Q61R mutations, whereas those from Kras heterozygous animals carry mostly (92%) KrasQ61L mutations, indicating a major role for germ-line Kras status in mutation selection during initiation. The exome wide mutation spectra incarcinogen-induced tumours overwhelmingly display signatures of the initiating carcinogen, while adenocarcinomas acquire additional C > T mutations at CpG sites. These data provide a basis for understanding results from human tumour genome sequencing, which has identified two broad categories of tumours based on the relative frequency of single-nucleotide variations and copy number alterations(1), and underline the importance of carcinogen models for understanding the complex mutation spectra seen in human cancers.
C1 [Westcott, Peter M. K.; Halliwill, Kyle D.; To, Minh D.; Delrosario, Reyno; Quigley, David A.; Balmain, Allan] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.
   [Westcott, Peter M. K.; Halliwill, Kyle D.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 USA.
   [Rashid, Mamunur; Rust, Alistair G.; Keane, Thomas M.; Adams, David J.] Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England.
   [Jen, Kuang-Yu] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA.
   [Gurley, Kay E.; Kemp, Christopher J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA.
   [Fredlund, Erik] Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17121 Stockholm, Sweden.
   [Balmain, Allan] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA.
C3 University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of California System; University of California San Francisco; Wellcome Trust Sanger Institute; University of California System; University of California San Francisco; Fred Hutchinson Cancer Center; Karolinska Institutet; University of California System; University of California San Francisco
RP Balmain, A (corresponding author), Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.
EM abalmain@cc.ucsf.edu
FU National Cancer Institute (NCI) [R01 CA111834, U01 CA84244, U01 CA141455, U01 CA176287]; Bonnie Addario Foundation; National Institutes of Health (NIH) [T32 GM007175]; National Science Foundation GRFP award; NCI F31 NRSA award; NIH [T32 GM007175]; Cancer Research UK; Wellcome Trust; Cancer Research UK [13031] Funding Source: researchfish
NR 42
TC 277
Z9 328
U1 1
U2 72
PU NATURE PUBLISHING 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 22
PY 2015
VL 517
IS 7535
BP 489
EP +
DI 10.1038/nature13898
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AZ4MU
UT WOS:000348196500035
PM 25363767
DA 2026-03-09
ER

PT J
AU Ackerman, LKG
   Lovell, MM
   Weix, DJ
AF Ackerman, Laura K. G.
   Lovell, Matthew M.
   Weix, Daniel J.
TI Multimetallic catalysed cross-coupling of aryl bromides with aryl triflates
SO NATURE
LA English
DT Article
ID unactivated arenes; halides; transition; iodoarenes; arylation; biaryls; cobalt
AB The advent of transition-metal catalysed strategies for forming new carbon-carbon bonds has revolutionized the field of organic chemistry, enabling the efficient synthesis of ligands, materials, and biologically active molecules(1-3). In cases where a single metal fails to promote a selective or efficient transformation, the synergistic cooperation(4) of two distinct catalysts-multimetallic catalysis-can be used instead. Many important reactions rely on multimetallic catalysis(5-10), such as the Wacker oxidation of olefins(6-8) and the Sonogashira coupling of alkynes with aryl halides(9,10), but this approach has largely been limited to the use of metals with distinct reactivities, with only one metal catalyst undergoing oxidative addition(11,12). Here, we demonstrate that cooperativity between two group 10 metal catalysts-(bipyridine)nickel and (1,3-bis(diphenylphosphino) propane) palladiumenables a general cross-Ullmann reaction (the cross-coupling of two different aryl electrophiles)(13-15). Our method couples aryl bromides with aryl triflates directly, eliminating the use of arylmetal reagents and avoiding the challenge of differentiating between multiple carbon-hydrogen bonds that is required for direct arylation methods(16,17). Selectivity can be achieved without an excess of either substrate and originates from the orthogonal reactivity of the two catalysts and the relative stability of the two arylmetal intermediates. While (1,3-bis(diphenylphosphino) propane) palladium reacts preferentially with aryl triflates to afford a persistent intermediate, (bipyridine) nickel reacts preferentially with aryl bromides to form a transient, reactive intermediate. Although each catalyst forms less than 5 per cent cross-coupled product in isolation, together they are able to achieve a yield of up to 94 per cent. Our results reveal a new method for the synthesis of biaryls, heteroaryls, and dienes, as well as a general mechanism for the selective transfer of ligands between two metal catalysts. We anticipate that this reaction will simplify the synthesis of pharmaceuticals, many of which are currently made with pre-formed organometallic reagents(1-3), and lead to the discovery of new multimetallic reactions.
C1 [Ackerman, Laura K. G.; Lovell, Matthew M.; Weix, Daniel J.] Univ Rochester, Dept Chem, Rochester, NY 14627 USA.
C3 University of Rochester
RP Weix, DJ (corresponding author), Univ Rochester, Dept Chem, Rochester, NY 14627 USA.
EM daniel.weix@rochester.edu
FU NIH [R01 GM097243]; NSF [NSF DGE-1419118]; Elon Huntington Hooker Fellowship (Univ. Rochester); National Institute of General Medical Sciences [R01GM097243] Funding Source: NIH RePORTER
NR 30
TC 284
Z9 316
U1 5
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 AUG 27
PY 2015
VL 524
IS 7566
BP 454
EP +
DI 10.1038/nature14676
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP7LN
UT WOS:000360069300035
PM 26280337
DA 2026-03-09
ER

PT J
AU Hatfield-Dodds, S
   Schandl, H
   Adams, PD
   Baynes, TM
   Brinsmead, TS
   Bryan, BA
   Chiew, FHS
   Graham, PW
   Grundy, M
   Harwood, T
   McCallum, R
   McCrea, R
   McKellar, LE
   Newth, D
   Nolan, M
   Prosser, I
   Wonhas, A
AF Hatfield-Dodds, Steve
   Schandl, Heinz
   Adams, Philip D.
   Baynes, Timothy M.
   Brinsmead, Thomas S.
   Bryan, Brett A.
   Chiew, Francis H. S.
   Graham, Paul W.
   Grundy, Mike
   Harwood, Tom
   McCallum, Rebecca
   McCrea, Rod
   McKellar, Lisa E.
   Newth, David
   Nolan, Martin
   Prosser, Ian
   Wonhas, Alex
TI Australia is 'free to choose' economic growth and falling environmental pressures
SO NATURE
LA English
DT Article
ID greenhouse-gas emissions; biodiversity; benefits; capacity; land
AB Over two centuries of economic growth have put undeniable pressure on the ecological systems that underpin human well-being. While it is agreed that these pressures are increasing, views divide on how they may be alleviated. Some suggest technological advances will automatically keep us from transgressing key environmental thresholds; others that policy reform can reconcile economic and ecological goals; while a third school argues that only a fundamental shift in societal values can keep human demands within the Earth's ecological limits. Here we use novel integrated analysis of the energy-water-food nexus, rural land use (including biodiversity), material flows and climate change to explore whether mounting ecological pressures in Australia can be reversed, while the population grows and living standards improve. We show that, in the right circumstances, economic and environmental outcomes can be decoupled. Although economic growth is strong across all scenarios, environmental performance varies widely: pressures are projected to more than double, stabilize or fall markedly by 2050. However, we find no evidence that decoupling will occur automatically. Nor do we find that a shift in societal values is required. Rather, extensions of current policies that mobilize technology and incentivize reduced pressure account for the majority of differences in environmental performance. Our results show that Australia can make great progress towards sustainable prosperity, if it chooses to do so.
C1 [Hatfield-Dodds, Steve; Schandl, Heinz; Chiew, Francis H. S.; Harwood, Tom; McCallum, Rebecca; Prosser, Ian] CSIRO, Black Mt Labs, Acton, ACT 2601, Australia.
   [Adams, Philip D.] Victoria Univ, Melbourne, Vic 3000, Australia.
   [Baynes, Timothy M.; Wonhas, Alex] CSIRO, N Ryde, NSW 2113, Australia.
   [Brinsmead, Thomas S.; Graham, Paul W.] CSIRO, Energy Ctr, Mayfield West, NSW 2304, Australia.
   [Bryan, Brett A.] CSIRO, Urrbrae, SA 5064, Australia.
   [Grundy, Mike] CSIRO, Queensland Biosci Precinct, St Lucia, Qld 4067, Australia.
   [McCrea, Rod; McKellar, Lisa E.] CSIRO, Ecosci Precinct, Dutton Park, Qld 4102, Australia.
   [Newth, David] CSIRO, Yarralumla Labs, Yarralumla, ACT 2601, Australia.
C3 Commonwealth Scientific & Industrial Research Organisation (CSIRO); Victoria University; Commonwealth Scientific & Industrial Research Organisation (CSIRO); Commonwealth Scientific & Industrial Research Organisation (CSIRO); CSIRO Energy; Commonwealth Scientific & Industrial Research Organisation (CSIRO); Commonwealth Scientific & Industrial Research Organisation (CSIRO); Commonwealth Scientific & Industrial Research Organisation (CSIRO); Commonwealth Scientific & Industrial Research Organisation (CSIRO)
RP Hatfield-Dodds, S (corresponding author), CSIRO, Black Mt Labs, Acton, ACT 2601, Australia.
EM Steve.Hatfield-Dodds@csiro.au
FU CSIRO Land and Water; CSIRO Energy; CSIRO Agriculture; CSIRO Oceans and Atmosphere
NR 48
TC 136
Z9 156
U1 3
U2 209
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 5
PY 2015
VL 527
IS 7576
BP 49
EP 53
DI 10.1038/nature16065
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV4XV
UT WOS:000364270700040
PM 26536956
DA 2026-03-09
ER

PT J
AU Denkov, N
   Tcholakova, S
   Lesov, I
   Cholakova, D
   Smoukov, SK
AF Denkov, Nikolai
   Tcholakova, Slavka
   Lesov, Ivan
   Cholakova, Diana
   Smoukov, Stoyan K.
TI Self-shaping of oil droplets via the formation of intermediate rotator phases upon cooling
SO NATURE
LA English
DT Article
ID liquid-crystal; design; microfluidics; fabrication; nanofibers; nucleation
AB Revealing the chemical and physical mechanisms underlying symmetry breaking and shape transformations is key to understanding morphogenesis(1). If we are to synthesize artificial structures with similar control and complexity to biological systems, we need energy-and material-efficient bottom-up processes to create building blocks of various shapes that can further assemble into hierarchical structures. Lithographic top-down processing(2) allows a high level of structural control in microparticle production but at the expense of limited productivity. Conversely, bottom-up particle syntheses(3-8) have higher material and energy efficiency, but are more limited in the shapes achievable. Linear hydrocarbons are known to pass through a series of metastable plastic rotator phases before freezing(9,10). Here we show that by using appropriate cooling protocols, we can harness these phase transitions to control the deformation of liquid hydrocarbon droplets and then freeze them into solid particles, permanently preserving their shape. Upon cooling, the droplets spontaneously break their shape symmetry several times, morphing through a series of complex regular shapes owing to the internal phase-transition processes. In this way we produce particles including micrometre-sized octahedra, various polygonal platelets, O-shapes, and fibres of submicrometre diameter, which can be selectively frozen into the corresponding solid particles. This mechanism offers insights into achieving complex morphogenesis from a system with a minimal number of molecular components.
C1 [Denkov, Nikolai; Tcholakova, Slavka; Lesov, Ivan; Cholakova, Diana] Univ Sofia, Fac Chem & Pharm, Dept Chem & Pharmaceut Engn, Sofia 1164, Bulgaria.
   [Smoukov, Stoyan K.] Univ Cambridge, Dept Mat Sci & Met, Act & Intelligent Mat Lab, Cambridge CB3 0FS, England.
C3 University of Sofia; University of Cambridge
RP Smoukov, SK (corresponding author), Univ Cambridge, Dept Mat Sci & Met, Act & Intelligent Mat Lab, Cambridge CB3 0FS, England.
EM sks46@cam.ac.uk
FU European Research Council (ERC) [280078]; European Commission [286205]
NR 28
TC 139
Z9 159
U1 1
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 DEC 17
PY 2015
VL 528
IS 7582
BP 392
EP +
DI 10.1038/nature16189
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CY8SM
UT WOS:000366678600051
PM 26649824
DA 2026-03-09
ER

PT J
AU Ramirez, S
   Liu, X
   MacDonald, CJ
   Moffa, A
   Zhou, J
   Redondo, RL
   Tonegawa, S
AF Ramirez, Steve
   Liu, Xu
   MacDonald, Christopher J.
   Moffa, Anthony
   Zhou, Joanne
   Redondo, Roger L.
   Tonegawa, Susumu
TI Activating positive memory engrams suppresses depression-like behaviour
SO NATURE
LA English
DT Article
ID nucleus-accumbens; hippocampal neurogenesis; optogenetic stimulation; prefrontal cortex; major depression; reward circuitry; stress; mechanisms; amygdala; disorders
AB Stress is considered a potent environmental risk factor for many behavioural abnormalities, including anxiety and mood disorders(1,2). Animal models can exhibit limited but quantifiable behavioural impairments resulting from chronic stress, including deficits in motivation, abnormal responses to behavioural challenges, and anhedonia(3-5). The hippocampus is thought to negatively regulate the stress response and to mediate various cognitive and mnemonic aspects of stress-induced impairments(2,3,5), although the neuronal underpinnings sufficient to support behavioural improvements are largely unknown. Here we acutely rescue stress-induced depression-related behaviours in mice by optogenetically reactivating dentate gyrus cells that were previously active during a positive experience. A brain-wide histological investigation, coupled with pharmacological and projection-specific optogenetic blockade experiments, identified glutamatergic activity in the hippocampus-amygdala-nucleus-accumbens pathway as a candidate circuit supporting the acute rescue. Finally, chronically reactivating hippocampal cells associated with a positive memory resulted in the rescue of stress-induced behavioural impairments and neurogenesis at time points beyond the light stimulation. Together, our data suggest that activating positive memories artificially is sufficient to suppress depression-like behaviours and point to dentate gyrus engram cells as potential therapeutic nodes for intervening with maladaptive behavioural states.
C1 [Ramirez, Steve; MacDonald, Christopher J.; Moffa, Anthony; Zhou, Joanne; Redondo, Roger L.; Tonegawa, Susumu] MIT, Dept Biol, Picower Inst Learning & Memory, RIKEN MIT Ctr Neural Circuit Genet, Cambridge, MA 02139 USA.
   [Ramirez, Steve; MacDonald, Christopher J.; Moffa, Anthony; Zhou, Joanne; Redondo, Roger L.; Tonegawa, Susumu] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA.
   [Redondo, Roger L.] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA.
C3 Massachusetts Institute of Technology (MIT); RIKEN; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Howard Hughes Medical Institute
RP Tonegawa, S (corresponding author), MIT, Dept Biol, Picower Inst Learning & Memory, RIKEN MIT Ctr Neural Circuit Genet, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
EM tonegawa@mit.edu
FU RIKEN Brain Science Institute; Howard Hughes Medical Institute
NR 32
TC 260
Z9 335
U1 0
U2 196
PU NATURE PUBLISHING 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 18
PY 2015
VL 522
IS 7556
BP 335
EP +
DI 10.1038/nature14514
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK7PU
UT WOS:000356425400052
PM 26085274
DA 2026-03-09
ER

PT J
AU Bleichert, F
   Botchan, MR
   Berger, JM
AF Bleichert, Franziska
   Botchan, Michael R.
   Berger, James M.
TI Crystal structure of the eukaryotic origin recognition complex
SO NATURE
LA English
DT Article
ID dna-replication; conformational-changes; orc6 protein; atp-hydrolysis; binding; sequence; domain; clamp; initiators; homology
AB Initiation of cellular DNA replication is tightly controlled to sustain genomic integrity. In eukaryotes, the heterohexameric origin recognition complex (ORC) is essential for coordinating replication onset. Here we describe the crystal structure of Drosophila ORC at 3.5 angstrom resolution, showing that the 270 kiloclalton initiator core complex comprises a two-layered notched ring in which a collar of winged-helix domains from the Orcl-5 subunits sits atop a layer of AAA+ (ATPases associated with a variety of cellular activities) folds. Although canonical inter-AAA+ domain interactions exist between four of the six ORC subunits, unanticipated features are also evident. These include highly interdigitated domain-swapping interactions between the winged-helix folds and AAA+ modules of neighbouring protomers, and a quasi-spiral arrange. ment of DNA binding elements that circumnavigate an approximately 20 A wide channel in the centre of the complex. Comparative analyses indicate that ORC encircles DNA, using its winged-helix domain face to engage the mini-chromosome maintenance 2-7 (MCM2-7) complex during replicative helicase loading; however, an observed out-of-plane rotation of more than 900 for the Orc1 AAA+ domain disrupts interactions with catalytic amino acids in Orc4, narrowing and sealing off entry into the central channel. Prima facie, our data indicate that Drosophila ORC can switch between active and autoinhibited conformations, suggesting a novel means for cell cycle and/or developmental control of ORC functions.
C1 [Bleichert, Franziska; Berger, James M.] Johns Hopkins Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA.
   [Botchan, Michael R.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
C3 Johns Hopkins University; Johns Hopkins Medicine; University of California System; University of California Berkeley
RP Berger, JM (corresponding author), Johns Hopkins Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA.
EM mbotchan@berkeley.edu; jberge29@jhmi.edu
FU National Institutes of Health [GM071747, CA R37-30490]; UC Berkeley Miller Institute for Basic Research in Science
NR 68
TC 104
Z9 125
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 MAR 19
PY 2015
VL 519
IS 7543
BP 321
EP +
DI 10.1038/nature14239
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD6AY
UT WOS:000351171900034
PM 25762138
DA 2026-03-09
ER

PT J
AU Pittelkow, CM
   Liang, XQ
   Linquist, BA
   van Groenigen, KJ
   Lee, J
   Lundy, ME
   van Gestel, N
   Six, J
   Venterea, RT
   van Kessel, C
AF Pittelkow, Cameron M.
   Liang, Xinqiang
   Linquist, Bruce A.
   van Groenigen, Kees Jan
   Lee, Juhwan
   Lundy, Mark E.
   van Gestel, Natasja
   Six, Johan
   Venterea, Rodney T.
   van Kessel, Chris
TI Productivity limits and potentials of the principles of conservation agriculture
SO NATURE
LA English
DT Article
ID food security; metaanalysis; africa; impact; maize; yield
AB One of the primary challenges of our time is to feed a growing and more demanding world population with reduced external inputs and minimal environmental impacts, all under more variable and extreme climate conditions in the future(1-4). Conservation agriculture represents a set of three crop management principles that has received strong international support to help address this challenge(5,6), with recent conservation agriculture efforts focusing on smallholder farming systems in sub-Saharan Africa and South Asia(7). However, conservation agriculture is highly debated, with respect to both its effects on crop yields(8-10) and its applicability in different farming contexts(7,11-13). Here we conduct a global meta-analysis using 5,463 paired yield observations from 610 studies to compare no-till, the original and central concept of conservation agriculture, with conventional tillage practices across 48 crops and 63 countries. Overall, our results show that no-till reduces yields, yet this response is variable and under certain conditions no-till can produce equivalent or greater yields than conventional tillage. Importantly, when no-till is combined with the other two conservation agriculture principles of residue retention and crop rotation, its negative impacts are minimized. Moreover, no-till in combination with the other two principles significantly increases rainfed crop productivity in dry climates, suggesting that it may become an important climate-change adaptation strategy for ever-drier regions of the world. However, any expansion of conservation agriculture should be done with caution in these areas, as implementation of the other two principles is often challenging in resource-poor and vulnerable smallholder farming systems, thereby increasing the likelihood of yield losses rather than gains. Although farming systems are multifunctional, and environmental and socio-economic factors need to be considered(14-16), our analysis indicates that the potential contribution of no-till to the sustainable intensification of agriculture is more limited than often assumed.
C1 [Pittelkow, Cameron M.; Linquist, Bruce A.; Lundy, Mark E.; van Kessel, Chris] Univ Calif Davis, Dept Plant Sci, Davis, CA 95616 USA.
   [Liang, Xinqiang] Zhejiang Univ, Coll Environm & Resource Sci, Hangzhou 310058, Zhejiang, Peoples R China.
   [van Groenigen, Kees Jan; van Gestel, Natasja] No Arizona Univ, Ctr Ecosyst Sci & Soc, Flagstaff, AZ 86011 USA.
   [Lee, Juhwan; Six, Johan] ETH, Dept Environm Syst Sci, Swiss Fed Inst Technol, CH-8092 Zurich, Switzerland.
   [Venterea, Rodney T.] ARS, USDA, Soil & Water Management Unit, St Paul, MN 55108 USA.
   [Venterea, Rodney T.] Univ Minnesota, Dept Soil Water & Climate, St Paul, MN 55108 USA.
C3 University of California System; University of California Davis; Zhejiang University; Northern Arizona University; Swiss Federal Institutes of Technology Domain; ETH Zurich; United States Department of Agriculture (USDA); University of Minnesota System; University of Minnesota Twin Cities
RP Pittelkow, CM (corresponding author), Univ Illinois, Dept Crop Sci, Urbana, IL 61801 USA.
EM cmpitt@illinois.edu
FU National Key Science and Technology Project of China [2014ZX07101-012]
NR 31
TC 1189
Z9 1359
U1 68
U2 1577
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 15
PY 2015
VL 517
IS 7534
BP 365
EP U482
DI 10.1038/nature13809
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300045
PM 25337882
DA 2026-03-09
ER

PT J
AU Carmi, Y
   Spitzer, MH
   Linde, IL
   Burt, BM
   Prestwood, TR
   Perlman, N
   Davidson, MG
   Kenkel, JA
   Segal, E
   Pusapati, GV
   Bhattacharya, N
   Engleman, EG
AF Carmi, Yaron
   Spitzer, Matthew H.
   Linde, Ian L.
   Burt, Bryan M.
   Prestwood, Tyler R.
   Perlman, Nicola
   Davidson, Matthew G.
   Kenkel, Justin A.
   Segal, Ehud
   Pusapati, Ganesh V.
   Bhattacharya, Nupur
   Engleman, Edgar G.
TI Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity
SO NATURE
LA English
DT Article
ID minor histocompatibility antigens; chronic inflammation; metastatic melanoma; pancreatic-cancer; tumor-regression; antibody; host; immunoglobulin; immunotherapy; receptors
AB Whereas cancers grow within host tissues and evade host immunity through immune-editing and immunosuppression(1-5), tumours are rarely transmissible between individuals. Much like transplanted allogeneic organs, allogeneic tumours are reliably rejected by host T cells, even when the tumour and host share the same major histocompatibility complex alleles, the most potent determinants of transplant rejection(6-10). How such tumour-eradicating immunity is initiated remains unknown, although elucidating this process could provide the basis for inducing similar responses against naturally arising tumours. Here we find that allogeneic tumour rejection is initiated in mice by naturally occurring tumour-binding IgG antibodies, which enable dendritic cells (DCs) to internalize tumour antigens and subsequently activate tumour-reactive T cells. We exploited this mechanism to treat autologous and autochthonous tumours successfully. Either systemic administration of DCs loaded with allogeneic-IgG-coated tumour cells or intratumoral injection of allogeneic IgG in combination with DC stimuli induced potent T-cell-mediated antitumour immune responses, resulting in tumour eradication in mouse models of melanoma, pancreas, lung and breast cancer. Moreover, this strategy led to eradication of distant tumours and metastases, as well as the injected primary tumours. To assess the clinical relevance of these findings, we studied antibodies and cells from patients with lung cancer. T cells from these patients responded vigorously to autologous tumour antigens after culture with allogeneic-IgG-loaded DCs, recapitulating our findings in mice. These results reveal that tumour-binding allogeneic IgG can induce powerful antitumour immunity that can be exploited for cancer immunotherapy.
C1 [Carmi, Yaron; Spitzer, Matthew H.; Linde, Ian L.; Prestwood, Tyler R.; Perlman, Nicola; Davidson, Matthew G.; Kenkel, Justin A.; Segal, Ehud; Bhattacharya, Nupur; Engleman, Edgar G.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA.
   [Spitzer, Matthew H.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Palo Alto, CA 94305 USA.
   [Burt, Bryan M.] Stanford Univ, Sch Med, Dept Cardiothorac Surg, Palo Alto, CA 94305 USA.
   [Pusapati, Ganesh V.] Stanford Univ, Sch Med, Dept Biochem, Palo Alto, CA 94305 USA.
C3 Stanford University; Stanford University; Stanford University; Stanford University
RP Engleman, EG (corresponding author), Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA.
EM ycarmi76@stanford.edu; edengleman@stanford.edu
FU NIH [U01 CA141468, 5T32AI007290-27]; NIH NRSA [F31CA189331]; Smith Stanford Graduate Fellowship; National Cancer Institute [P30CA124435] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [T32AI007290] Funding Source: NIH RePORTER
NR 31
TC 193
Z9 239
U1 2
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 MAY 7
PY 2015
VL 521
IS 7550
BP 99
EP U254
DI 10.1038/nature14424
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH4YS
UT WOS:000354040900041
PM 25924063
DA 2026-03-09
ER

PT J
AU Fong, CY
   Gilan, O
   Lam, EYN
   Rubin, AF
   Ftouni, S
   Tyler, D
   Stanley, K
   Sinha, D
   Yeh, P
   Morison, J
   Giotopoulos, G
   Lugo, D
   Jeffrey, P
   Lee, SCW
   Carpenter, C
   Gregory, R
   Ramsay, RG
   Lane, SW
   Abdel-Wahab, O
   Kouzarides, T
   Johnstone, RW
   Dawson, SJ
   Huntly, BJP
   Prinjha, RK
   Papenfuss, AT
   Dawson, MA
AF Fong, Chun Yew
   Gilan, Omer
   Lam, Enid Y. N.
   Rubin, Alan F.
   Ftouni, Sarah
   Tyler, Dean
   Stanley, Kym
   Sinha, Devbarna
   Yeh, Paul
   Morison, Jessica
   Giotopoulos, George
   Lugo, Dave
   Jeffrey, Philip
   Lee, Stanley Chun-Wei
   Carpenter, Christopher
   Gregory, Richard
   Ramsay, Robert G.
   Lane, Steven W.
   Abdel-Wahab, Omar
   Kouzarides, Tony
   Johnstone, Ricky W.
   Dawson, Sarah-Jane
   Huntly, Brian J. P.
   Prinjha, Rab K.
   Papenfuss, Anthony T.
   Dawson, Mark A.
TI BET inhibitor resistance emerges from leukaemia stem cells
SO NATURE
LA English
DT Article
ID selective-inhibition; drug-resistance; cancer; mutations; mechanism; discovery; chromatin; accurate; program
AB Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a newtherapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks(1,2). Early clinical trials have shown promise, especially in acute myeloid leukaemia(3), and therefore the evaluation of resistance mechanismsis crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is notmediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increasedWnt/beta-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies.
C1 [Fong, Chun Yew; Gilan, Omer; Lam, Enid Y. N.; Ftouni, Sarah; Tyler, Dean; Stanley, Kym; Sinha, Devbarna; Yeh, Paul; Ramsay, Robert G.; Johnstone, Ricky W.; Dawson, Sarah-Jane; Papenfuss, Anthony T.; Dawson, Mark A.] Peter MacCallum Canc Ctr, Canc Res Div, East Melbourne, Vic 3002, Australia.
   [Fong, Chun Yew; Gilan, Omer; Tyler, Dean; Yeh, Paul; Ramsay, Robert G.; Johnstone, Ricky W.; Dawson, Sarah-Jane; Papenfuss, Anthony T.; Dawson, Mark A.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, East Melbourne, Vic 3002, Australia.
   [Fong, Chun Yew; Yeh, Paul; Dawson, Mark A.] Peter MacCallum Canc Ctr, Dept Haematol, East Melbourne, Vic 3002, Australia.
   [Rubin, Alan F.; Papenfuss, Anthony T.] Walter & Eliza Hall Inst Med Res, Bioinformat Div, Parkville, Vic 3052, Australia.
   [Rubin, Alan F.; Papenfuss, Anthony T.] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia.
   [Morison, Jessica; Giotopoulos, George; Huntly, Brian J. P.] Cambridge Inst Med Res, Dept Haematol, Cambridge CB2 OXY, England.
   [Morison, Jessica; Giotopoulos, George; Huntly, Brian J. P.] Wellcome Trust MRC Stem Cell Inst, Cambridge CB2 0XY, England.
   [Lugo, Dave; Jeffrey, Philip; Gregory, Richard; Prinjha, Rab K.] GlaxoSmithKline, Epinova DPU, Immunoinflammat Ctr Excellence Drug Discovery, Med Res Ctr, Stevenage SG1 2NY, Herts, England.
   [Lee, Stanley Chun-Wei; Abdel-Wahab, Omar] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA.
   [Carpenter, Christopher] GlaxoSmithKline, Canc Epigenet DPU, Oncol R&D, Collegeville, PA 19426 USA.
   [Lane, Steven W.] Univ Queensland, QIMR Berghofer Med Res Inst, Brisbane, Qld 4029, Australia.
   [Kouzarides, Tony] Gurdon Inst, Cambridge CB2 1QN, England.
   [Kouzarides, Tony] Dept Pathol, Cambridge CB2 1QN, England.
C3 Peter Maccallum Cancer Center; University of Melbourne; Peter Maccallum Cancer Center; Peter Maccallum Cancer Center; Walter & Eliza Hall Institute; University of Melbourne; GlaxoSmithKline; Glaxosmithkline United Kingdom; Memorial Sloan Kettering Cancer Center; GlaxoSmithKline; Glaxosmithkline USA; QIMR Berghofer Medical Research Institute; University of Queensland
RP Dawson, MA (corresponding author), Peter MacCallum Canc Ctr, Canc Res Div, East Melbourne, Vic 3002, Australia.
EM mark.dawson@petermac.org
FU Leukaemia Foundation Australia; Haematology Society of Australia; Haematology Society of New Zealand; Royal Australasian College of Physicians; Victorian Comprehensive Cancer Centre; National Cancer Institute [P30CA008748, P30CA006516] Funding Source: NIH RePORTER; Cancer Research UK [17001] Funding Source: researchfish; Medical Research Council [MR/M010392/1] Funding Source: researchfish; The Francis Crick Institute; Cancer Research UK [10827] Funding Source: researchfish; MRC [MR/M010392/1] Funding Source: UKRI
NR 42
TC 466
Z9 532
U1 0
U2 133
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 24
PY 2015
VL 525
IS 7570
BP 538
EP +
DI 10.1038/nature14888
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR8KI
UT WOS:000361599900054
PM 26367796
DA 2026-03-09
ER

PT J
AU Crowther, TW
   Glick, HB
   Covey, KR
   Bettigole, C
   Maynard, DS
   Thomas, SM
   Smith, JR
   Hintler, G
   Duguid, MC
   Amatulli, G
   Tuanmu, MN
   Jetz, W
   Salas, C
   Stam, C
   Piotto, D
   Tavani, R
   Green, S
   Bruce, G
   Williams, SJ
   Wiser, SK
   Huber, MO
   Hengeveld, GM
   Nabuurs, GJ
   Tikhonova, E
   Borchardt, P
   Li, CF
   Powrie, LW
   Fischer, M
   Hemp, A
   Homeier, J
   Cho, P
   Vibrans, AC
   Umunay, PM
   Piao, SL
   Rowe, CW
   Ashton, MS
   Crane, PR
   Bradford, MA
AF Crowther, T. W.
   Glick, H. B.
   Covey, K. R.
   Bettigole, C.
   Maynard, D. S.
   Thomas, S. M.
   Smith, J. R.
   Hintler, G.
   Duguid, M. C.
   Amatulli, G.
   Tuanmu, M. -N.
   Jetz, W.
   Salas, C.
   Stam, C.
   Piotto, D.
   Tavani, R.
   Green, S.
   Bruce, G.
   Williams, S. J.
   Wiser, S. K.
   Huber, M. O.
   Hengeveld, G. M.
   Nabuurs, G. -J.
   Tikhonova, E.
   Borchardt, P.
   Li, C. -F.
   Powrie, L. W.
   Fischer, M.
   Hemp, A.
   Homeier, J.
   Cho, P.
   Vibrans, A. C.
   Umunay, P. M.
   Piao, S. L.
   Rowe, C. W.
   Ashton, M. S.
   Crane, P. R.
   Bradford, M. A.
TI Mapping tree density at a global scale
SO NATURE
LA English
DT Article
ID climate-change; forest; biomass; hyperdominance; map
AB The global extent and distribution of forest trees is central to our understanding of the terrestrial biosphere. We provide the first spatially continuous map of forest tree density at a global scale. This map reveals that the global number of trees is approximately 3.04 trillion, an order of magnitude higher than the previous estimate. Of these trees, approximately 1.39 trillion exist in tropical and subtropical forests, with 0.74 trillion in boreal regions and 0.61 trillion in temperate regions. Biome-level trends in tree density demonstrate the importance of climate and topography in controlling local tree densities at finer scales, as well as the overwhelming effect of humans across most of the world. Based on our projected tree densities, we estimate that over 15 billion trees are cut down each year, and the global number of trees has fallen by approximately 46% since the start of human civilization.
C1 [Crowther, T. W.; Glick, H. B.; Covey, K. R.; Bettigole, C.; Maynard, D. S.; Smith, J. R.; Hintler, G.; Duguid, M. C.; Jetz, W.; Umunay, P. M.; Rowe, C. W.; Ashton, M. S.; Crane, P. R.; Bradford, M. A.] Yale Univ, Sch Forestry & Environm Studies, New Haven, CT 06511 USA.
   [Thomas, S. M.] Univ Helsinki, Dept Environm Sci, FIN-00014 Helsinki, Finland.
   [Amatulli, G.; Tuanmu, M. -N.; Jetz, W.] Yale Univ, Dept Ecol & Evolutionary Biol, New Haven, CT 06511 USA.
   [Jetz, W.] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, Ascot SL5 7PY, Berks, England.
   [Salas, C.] Univ La Frontera, Dept Ciencias Forestales, Temuco 4811230, Chile.
   [Stam, C.] RedCastle Resources, Salt Lake City, UT 84103 USA.
   [Piotto, D.] Univ Fed Sul Bahia, BR-45613204 Ferradas, Itabuna, Brazil.
   [Tavani, R.] Food & Agr Org United Nat, Forestry Dept, I-00153 Rome, Italy.
   [Green, S.; Bruce, G.] Operat Wallacea, Spilbsy PE23 4EX, Leics, England.
   [Green, S.] Univ Kent, DICE, SAC, Canterbury ME4 4AG, Kent, England.
   [Williams, S. J.] CEA, URA 2210, CNRS, Mol Imaging Res Ctr MIRCen, F-91401 Orsay, France.
   [Wiser, S. K.] Landcare Res, Lincoln 7640, New Zealand.
   [Huber, M. O.] Snowand Landscape Res, Swiss Fed Inst Forest, WSL, CH-8903 Birmensdorf, Switzerland.
   [Hengeveld, G. M.; Nabuurs, G. -J.] Univ Wageningen & Res Ctr, Environm Sci Grp, NL-6708 PB Wageningen, Netherlands.
   [Tikhonova, E.] Ctr Forest Ecol & Prod RAS, Moscow 117997, Russia.
   [Borchardt, P.] Univ Hamburg, Inst Geog, CEN Ctr Earth Syst Res & Sustainabil, D-20146 Hamburg, Germany.
   [Li, C. -F.] Masaryk Univ, Dept Bot & Zool, Brno 61137, Czech Republic.
   [Powrie, L. W.] South African Natl Biodivers Inst, Kirstenbosch Res Ctr, ZA-7735 Claremont, South Africa.
   [Fischer, M.] Univ Bern, Inst Plant Sci, Bot Garden, CH-3013 Bern, Switzerland.
   [Fischer, M.] Univ Bern, Oeschger Ctr Climate Change Res, CH-3013 Bern, Switzerland.
   [Fischer, M.] Biodivers & Climate Res Ctr BIK F, Senckenberg Gesell Nat Forsch, D-60325 Frankfurt, Germany.
   [Hemp, A.] Univ Bayreuth, Dept Plant Systemat, D-95447 Bayreuth, Germany.
   [Homeier, J.] Univ Gottingen, Albrecht von Haller Inst Plant Sci, D-37073 Gottingen, Germany.
   [Cho, P.] Univ Lancaster, Trop Ecol Res Grp, Lancaster Environm Ctr, Lancaster LA1 4YQ, England.
   [Vibrans, A. C.] Univ Reg Blumenau, Dept Engn Florestal, BR-89030000 Blumenau, SC, Brazil.
   [Piao, S. L.] Peking Univ, Sinofrench Inst Earth Syst Sci, Coll Urban & Environm Sci, Beijing 100871, Peoples R China.
C3 Yale University; University of Helsinki; Yale University; Imperial College London; Universidad de La Frontera; Universidade Federal do Sul da Bahia; Food & Agriculture Organization of the United Nations (FAO); University of Kent; CEA; Centre National de la Recherche Scientifique (CNRS); Landcare Research - New Zealand; Swiss Federal Institutes of Technology Domain; Swiss Federal Institute for Forest, Snow & Landscape Research; Wageningen University & Research; University of Hamburg; Masaryk University; South African National Biodiversity Institute; University of Bern; University of Bern; Leibniz Association; Senckenberg Gesellschaft fur Naturforschung (SGN); Senckenberg Biodiversitat & Klima- Forschungszentrum (BiK-F); University of Bayreuth; University of Gottingen; Lancaster University; Universidade Regional de Blumenau (FURB); Peking University
RP Crowther, TW (corresponding author), Yale Univ, Sch Forestry & Environm Studies, New Haven, CT 06511 USA.
EM thomas.crowther11@gmail.com
FU Yale Climate and Energy Institute; British Ecological Society; Chilean research grants FONDECYT [1151495]; National Science Foundation; Center for Tropical Forest Science; Smithsonian Tropical Research Institute; John D. and Catherine T. MacArthur Foundation; Mellon Foundation; Small World Institute Fund; Ucross High Plains Stewardship Initiative
NR 36
TC 665
Z9 790
U1 20
U2 725
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 10
PY 2015
VL 525
IS 7568
BP 201
EP +
DI 10.1038/nature14967
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400028
PM 26331545
DA 2026-03-09
ER

PT J
AU Morone, F
   Makse, HA
AF Morone, Flaviano
   Makse, Hernan A.
TI Influence maximization in complex networks through optimal percolation
SO NATURE
LA English
DT Article
AB The whole frame of interconnections in complex networks hinges on a specific set of structural nodes, much smaller than the total size, which, if activated, would cause the spread of information to the whole network(1), or, if immunized, would prevent the diffusion of a large scale epidemic(2,3). Localizing this optimal, that is, minimal, set of structural nodes, called influencers, is one of the most important problems in network science(4,5). Despite the vast use of heuristic strategies to identify influential spreaders(6-14), the problem remains unsolved. Here we map the problem onto optimal percolation in random networks to identify the minimal set of influencers, which arises by minimizing the energy of a many-body system, where the form of the interactions is fixed by the non-backtracking matrix(15) of the network. Big data analyses reveal that the set of optimal influencers is much smaller than the one predicted by previous heuristic centralities. Remarkably, a large number of previously neglected weakly connected nodes emerges among the optimal influencers. These are topologically tagged as low-degree nodes surrounded by hierarchical coronas of hubs, and are uncovered only through the optimal collective interplay of all the influencers in the network. The present theoretical framework may hold a larger degree of universality, being applicable to other hard optimization problems exhibiting a continuous transition from a known phase(16).
C1 [Morone, Flaviano; Makse, Hernan A.] CUNY City Coll, Levich Inst, New York, NY 10031 USA.
   [Morone, Flaviano; Makse, Hernan A.] CUNY City Coll, Dept Phys, New York, NY 10031 USA.
C3 City University of New York (CUNY) System; City College of New York (CUNY); City University of New York (CUNY) System; City College of New York (CUNY)
RP Makse, HA (corresponding author), CUNY City Coll, Levich Inst, New York, NY 10031 USA.
EM hmakse@lev.ccny.cuny.edu
FU NIH-NIGMS [1R21GM107641]; NSF-PoLS [PHY-1305476]; ARL; Direct For Computer & Info Scie & Enginr; Div Of Information & Intelligent Systems [1515022] Funding Source: National Science Foundation; Direct For Mathematical & Physical Scien; Division Of Physics [1305476] Funding Source: National Science Foundation
NR 30
TC 973
Z9 1092
U1 14
U2 519
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 6
PY 2015
VL 524
IS 7563
BP 65
EP U122
DI 10.1038/nature14604
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO2QS
UT WOS:000359002300032
PM 26131931
DA 2026-03-09
ER

PT J
AU Lindemans, CA
   Calafiore, M
   Mertelsmann, AM
   O'Connor, MH
   Dudakov, JA
   Jenq, RR
   Velardi, E
   Young, LF
   Smith, OM
   Lawrence, G
   Ivanov, JA
   Fu, YY
   Takashima, S
   Hua, GQ
   Martin, ML
   O'Rourke, KP
   Lo, YH
   Mokry, M
   Romera-Hernandez, M
   Cupedo, T
   Dow, LE
   Nieuwenhuis, EE
   Shroyer, NF
   Liu, C
   Kolesnick, R
   van den Brink, MRM
   Hanash, AM
AF Lindemans, Caroline A.
   Calafiore, Marco
   Mertelsmann, Anna M.
   O'Connor, Margaret H.
   Dudakov, Jarrod A.
   Jenq, Robert R.
   Velardi, Enrico
   Young, Lauren F.
   Smith, Odette M.
   Lawrence, Gillian
   Ivanov, Juliet A.
   Fu, Ya-Yuan
   Takashima, Shuichiro
   Hua, Guoqiang
   Martin, Maria L.
   O'Rourke, Kevin P.
   Lo, Yuan-Hung
   Mokry, Michal
   Romera-Hernandez, Monica
   Cupedo, Tom
   Dow, Lukas E.
   Nieuwenhuis, Edward E.
   Shroyer, Noah F.
   Liu, Chen
   Kolesnick, Richard
   van den Brink, Marcel R. M.
   Hanash, Alan M.
TI Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration
SO NATURE
LA English
DT Article
ID versus-host-disease; bone-marrow-transplantation; innate lymphoid-cells; in-vitro; t-cell; inflammation; expression; niche; lgr5; induction
AB Epithelial regeneration is critical for barrier maintenance and organ function after intestinal injury. The intestinal stem cell (ISC) niche provides Wnt, Notch and epidermal growth factor (EGF) signals supporting Lgr5(+) crypt base columnar ISCs for normal epithelial maintenance(1,2). However, little is known about the regulation of the ISC compartment after tissue damage. Using ex vivo organoid cultures, here we show that innate lymphoid cells (ILCs), potent producers of interleukin-22 (IL-22) after intestinal injury(3,4), increase the growth of mouse small intestine organoids in an IL-22-dependent fashion. Recombinant IL-22 directly targeted ISCs, augmenting the growth of both mouse and human intestinal organoids, increasing proliferation and promoting ISC expansion. IL-22 induced STAT3 phosphorylation in Lgr5(+) ISCs, and STAT3 was crucial for both organoid formation and IL-22-mediated regeneration. Treatment with IL-22 in vivo after mouse allogeneic bone marrow transplantation enhanced the recovery of ISCs, increased epithelial regeneration and reduced intestinal pathology and mortality from graft-versus-host disease. ATOH1-deficient organoid culture demonstrated that IL-22 induced epithelial regeneration independently of the Paneth cell niche. Our findings reveal a fundamental mechanism by which the immune system is able to support the intestinal epithelium, activating ISCs to promote regeneration.
C1 [Lindemans, Caroline A.; Calafiore, Marco; Mertelsmann, Anna M.; O'Connor, Margaret H.; Jenq, Robert R.; Lawrence, Gillian; Ivanov, Juliet A.; Fu, Ya-Yuan; Takashima, Shuichiro; van den Brink, Marcel R. M.; Hanash, Alan M.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA.
   [Lindemans, Caroline A.; Mokry, Michal; Nieuwenhuis, Edward E.] Univ Med Ctr Utrecht, Dept Pediat, NL-3508 AB Utrecht, Netherlands.
   [Dudakov, Jarrod A.; Velardi, Enrico; Young, Lauren F.; Smith, Odette M.; van den Brink, Marcel R. M.] Mem Sloan Kettering Canc Ctr, Dept Immunol, New York, NY 10065 USA.
   [Dudakov, Jarrod A.] Monash Univ, Dept Anat & Dev Biol, Clayton, Vic 3800, Australia.
   [Jenq, Robert R.; Dow, Lukas E.] Weill Cornell Med, Dept Med, New York, NY 10021 USA.
   [Hua, Guoqiang] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10065 USA.
   [Hua, Guoqiang; Martin, Maria L.; Kolesnick, Richard] Mem Sloan Kettering Canc Ctr, Dept Mol Pharmacol, New York, NY 10065 USA.
   [O'Rourke, Kevin P.] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA.
   [Lo, Yuan-Hung; Shroyer, Noah F.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA.
   [Romera-Hernandez, Monica; Cupedo, Tom] Erasmus Univ, Med Ctr, Dept Hematol, NL-3000 CA Rotterdam, Netherlands.
   [Liu, Chen] Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL 32610 USA.
C3 Memorial Sloan Kettering Cancer Center; Utrecht University; Utrecht University Medical Center; Memorial Sloan Kettering Cancer Center; Monash University; Cornell University; Weill Cornell Medicine; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Baylor College of Medicine; Erasmus University Rotterdam; Erasmus MC; State University System of Florida; University of Florida
RP Hanash, AM (corresponding author), Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA.
EM hanasha@mskcc.org
FU National Institutes of Health [K08-HL115355, R01-HL125571, R01-HL069929, R01-AI100288, R01-AI080455, R01-AI101406, P01-CA023766/Project 4, K99-CA176376, P30-CA008748]; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200900059C]; European Union [GC220918]; Experimental Therapeutics Center of MSKCC; Lymphoma Foundation; Alex's Lemonade Stand; Geoffrey Beene Cancer Research Center at MSKCC; Susan and Peter Solomon Divisional Genomics Program; MSKCC Cycle for Survival; Lucille Castori Center for Microbes, Inflammation Cancer; Innovational Research Incentives Scheme Vidi grant from the Netherlands Organization for Scientific Research (Zon-MW) [91710377]; People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7 under REA [289720]; Bio Medical Exchange Program of the Deutscher Akademischer Austauschdienst; Dutch Cancer Society [2013-5883]; mobility grant from the University Medical Center Utrecht; C.J. Martin fellowship from the Australian National Health and Medical Research Council; Scholar Award from the American Society of Hematology; Mechtild Harf Research Grant from the DKMS Foundation for Giving Life; New Investigator Award from the American Society for Blood and Marrow Transplantation; Amy Strelzer Manasevit Research Program; National Cancer Institute [P30CA008748, P01CA023766] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [U19AI116497] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007739] Funding Source: NIH RePORTER
NR 39
TC 904
Z9 1034
U1 14
U2 315
PU NATURE PUBLISHING 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 24
PY 2015
VL 528
IS 7583
BP 560
EP +
DI 10.1038/nature16460
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900054
PM 26649819
DA 2026-03-09
ER

PT J
AU Schulte, CHH
   Hansom, J
   Jones, AE
   Matthiesen, C
   Le Gall, C
   Atature, M
AF Schulte, Carsten H. H.
   Hansom, Jack
   Jones, Alex E.
   Matthiesen, Clemens
   Le Gall, Claire
   Atature, Mete
TI Quadrature squeezed photons from a two-level system
SO NATURE
LA English
DT Article
ID resonance fluorescence; quantum-dot; states; noise; generation; device; light
AB Resonance fluorescence arises from the interaction of an optical field with a two-level system, and has played a fundamental role in the development of quantum optics and its applications. Despite its conceptual simplicity, it entails a wide range of intriguing phenomena, such as the Mollow-triplet emission spectrum(1), photon antibunching(2) and coherent photon emission(3). One fundamental aspect of resonance fluorescence-squeezing in the form of reduced quantum fluctuations in the single photon stream from an atom in free space-was predicted more than 30 years ago(4). However, the requirement to operate in the weak excitation regime, together with the combination of modest oscillator strength of atoms and low collection efficiencies, has continued to necessitate stringent experimental conditions for the observation of squeezing with atoms. Attempts to circumvent these issues had to sacrifice antibunching, owing to either stimulated forward scattering from atomic ensembles(5,6) or multi-photon transitions inside optical cavities(7,8). Here, we use an artificial atom with a large optical dipole enabling 100-fold improvement of the photon detection rate over the natural atom counterpart(9) and reach the necessary conditions for the observation of quadrature squeezing in single resonance-fluorescence photons. By implementing phase-dependent homodyne intensity-correlation detection(9-11), we demonstrate that the electric field quadrature variance of resonance fluorescence is three per cent below the fundamental limit set by vacuum fluctuations, while the photon statistics remain antibunched. The presence of squeezing and antibunching simultaneously is a fully non-classical outcome of the wave-particle duality of photons.
C1 [Schulte, Carsten H. H.; Hansom, Jack; Jones, Alex E.; Matthiesen, Clemens; Le Gall, Claire; Atature, Mete] Univ Cambridge, Cavendish Lab, JJ Thomson Ave, Cambridge CB3 0HE, England.
C3 University of Cambridge
RP Atature, M (corresponding author), Univ Cambridge, Cavendish Lab, JJ Thomson Ave, Cambridge CB3 0HE, England.
EM ma424@cam.ac.uk
FU University of Cambridge; European Research Council ERC [617985]; EU-FP7 Marie Curie Initial Training Network [S3NANO]; Clare College Cambridge; European Research Council (ERC) [617985] Funding Source: European Research Council (ERC)
NR 30
TC 106
Z9 114
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 SEP 10
PY 2015
VL 525
IS 7568
BP 222
EP +
DI 10.1038/nature14868
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400032
PM 26322581
DA 2026-03-09
ER

PT J
AU Bondy-Denomy, J
   Garcia, B
   Strum, S
   Du, MJ
   Rollins, MF
   Hidalgo-Reyes, Y
   Wiedenheft, B
   Maxwell, KL
   Davidson, AR
AF Bondy-Denomy, Joseph
   Garcia, Bianca
   Strum, Scott
   Du, Mingjian
   Rollins, MaryClare F.
   Hidalgo-Reyes, Yurima
   Wiedenheft, Blake
   Maxwell, Karen L.
   Davidson, Alan R.
TI Multiple mechanisms for CRISPR-Cas inhibition by anti-CRISPR proteins
SO NATURE
LA English
DT Article
ID guided surveillance complex; crystal-structure; immune-system; rna; dna; recognition; resistance; sequence; cascade
AB The battle for survival between bacteria and the viruses that infect them (phages) has led to the evolution of many bacterial defence systems and phage-encoded antagonists of these systems. Clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR-associated (cas) genes comprise an adaptive immune system that is one of the most widespread means by which bacteria defend themselves against phages(1-3). We identified the first examples of proteins produced by phages that inhibit a CRISPR-Cas system(4). Here we performed biochemical and in vivo investigations of three of these anti-CRISPR proteins, and show that each inhibits CRISPR-Cas activity through a distinct mechanism. Two block the DNA-binding activity of the CRISPR-Cas complex, yet do this by interacting with different protein subunits, and using steric or non-steric modes of inhibition. The third anti-CRISPR protein operates by binding to the Cas3 helicase-nuclease and preventing its recruitment to the DNA-bound CRISPR-Cas complex. In vivo, this anti-CRISPR can convert the CRISPR-Cas system into a transcriptional repressor, providing the first example-to our knowledge-of modulation of CRISPR-Cas activity by a protein interactor. The diverse sequences and mechanisms of action of these anti-CRISPR proteins imply an independent evolution, and foreshadow the existence of other means by which proteins may alter CRISPR-Cas function.
C1 [Bondy-Denomy, Joseph; Garcia, Bianca; Du, Mingjian; Hidalgo-Reyes, Yurima; Davidson, Alan R.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada.
   [Strum, Scott; Davidson, Alan R.] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada.
   [Rollins, MaryClare F.; Wiedenheft, Blake] Montana State Univ, Dept Microbiol & Immunol, Bozeman, MT 59717 USA.
   [Maxwell, Karen L.] Univ Toronto, Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada.
C3 University of Toronto; University of Toronto; Montana State University System; Montana State University Bozeman; University of Toronto
RP Davidson, AR (corresponding author), Univ Toronto, Dept Mol Genet, 100 Coll St, Toronto, ON M5S 1A8, Canada.
EM karen.maxwell@utoronto.ca; alan.davidson@utoronto.ca
FU Canadian Institutes of Health Research (CIHR) [MOP-130482, MOP-136845]; CIHR Canada Graduate Scholarship Doctoral Award; Ontario Graduate Scholarship award; National Institutes of Health [R01GM108888, P20GM103500]; National Science Foundation EPSCoR [EPS-110134]; M.J. Murdock Charitable Trust; Montana State University Agricultural Experimental Station
NR 21
TC 273
Z9 357
U1 3
U2 353
PU NATURE PUBLISHING 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 1
PY 2015
VL 526
IS 7571
BP 136
EP +
DI 10.1038/nature15254
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS5CY
UT WOS:000362095100049
PM 26416740
DA 2026-03-09
ER

PT J
AU Bai, YH
   McCoy, JG
   Levin, EJ
   Sobrado, P
   Rajashankar, KR
   Fox, BG
   Zhou, M
AF Bai, Yonghong
   McCoy, Jason G.
   Levin, Elena J.
   Sobrado, Pablo
   Rajashankar, Kanagalaghatta R.
   Fox, Brian G.
   Zhou, Ming
TI X-ray structure of a mammalian stearoyl-CoA desaturase
SO NATURE
LA English
DT Article
ID fatty-acid desaturation; coenzyme-a desaturase; substrate-specificity; crystal-structure; diiron proteins; ribonucleotide reductase; saccharomyces-cerevisiae; mechanism; enzyme; identification
AB Stearoyl-CoA desaturase (SCD) is conserved in all eukaryotes and introduces the first double bond into saturated fatty acyl-CoAs1-4. Because the monounsaturated products of SCD are key precursors of membrane phospholipids, cholesterol esters and triglycerides, SCD is pivotal in fatty acid metabolism. Humans have two SCD homologues (SCD1 and SCD5), while mice have four (SCD1-SCD4). SCD1-deficient mice do not become obese or diabetic when fed a high-fat diet because of improved lipid metabolic profiles and insulin sensitivity(5,6). Thus, SCD1 is a pharmacological target in the treatment of obesity, diabetes and other metabolic diseases(7). SCD1 is an integral membrane protein located in the endoplasmic reticulum, and catalyses the formation of a cis-double bond between the ninth and tenth carbons of stearoyl-or palmitoyl-CoA(8,9). The reaction requires molecular oxygen, which is activated by a di-iron centre, and cytochrome b(5), which regenerates the di-iron centre(10). To understand better the structural basis of these characteristics of SCD function, here we crystallize and solve the structure of mouse SCD1 bound to stearoyl-CoA at 2.6 angstrom resolution. The structure shows a novel fold comprising four transmembrane helices capped by a cytosolic domain, and a plausible pathway for lateral substrate access and product egress. The acyl chain of the bound stearoyl-CoA is enclosed in a tunnel buried in the cytosolic domain, and the geometry of the tunnel and the conformation of the bound acyl chain provide a structural basis for the regioselectivity and stereospecificity of the desaturation reaction. The dimetal centre is coordinated by a unique spacial arrangement of nine conserved histidine residues that implies a potentially novel mechanism for oxygen activation. The structure also illustrates a possible route for electron transfer from cytochrome b5 to the di-iron centre.
C1 [Bai, Yonghong; McCoy, Jason G.; Levin, Elena J.; Zhou, Ming] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA.
   [Sobrado, Pablo; Fox, Brian G.] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA.
   [Rajashankar, Kanagalaghatta R.] Cornell Univ, Argonne Natl Lab, NE CAT, Argonne, IL 60439 USA.
   [Rajashankar, Kanagalaghatta R.] Cornell Univ, Argonne Natl Lab, Dept Chem & Chem Biol, Argonne, IL 60439 USA.
C3 Baylor College of Medicine; University of Wisconsin System; University of Wisconsin Madison; United States Department of Energy (DOE); Argonne National Laboratory; Cornell University; Cornell University; United States Department of Energy (DOE); Argonne National Laboratory
RP Zhou, M (corresponding author), Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA.
EM bgfox@biochem.wisc.edu; mzhou@bcm.edu
FU US National Institutes of Health [R01DK088057, R01GM098878, R01HL086392, U54GM095315, U54GM094584, R01GM050853]; American Heart Association [12EIA8850017]; Cancer Prevention and Research Institute of Texas [R12MZ]; National Institute of General Medical Sciences [P41GM103403]; American Heart Association (AHA) [12EIA8850017] Funding Source: American Heart Association (AHA)
NR 49
TC 200
Z9 239
U1 0
U2 107
PU NATURE PUBLISHING 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 13
PY 2015
VL 524
IS 7564
BP 252
EP +
DI 10.1038/nature14549
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900039
PM 26098370
DA 2026-03-09
ER

PT J
AU Bahng, JH
   Yeom, B
   Wang, YC
   Tung, SO
   Hoff, JD
   Kotov, N
AF Bahng, Joong Hwan
   Yeom, Bongjun
   Wang, Yichun
   Tung, Siu On
   Hoff, J. Damon
   Kotov, Nicholas
TI Anomalous dispersions of 'hedgehog' particles
SO NATURE
LA English
DT Article
ID surface; water; air; nanoparticles; interface
AB Hydrophobic particles in water and hydrophilic particles in oil aggregate, but can form colloidal dispersions if their surfaces are chemically camouflaged with surfactants, organic tethers, adsorbed polymers or other particles that impart affinity for the solvent and increase interparticle repulsion(1,2). A different strategy for modulating the interaction between a solid and a liquid uses surface corrugation, which gives rise to unique wetting behaviour(3-5). Here we show that this topographical effect can also be used to disperse particles in a wide range of solvents without recourse to chemicals to camouflage the particles' surfaces: we produce micrometre-sized particles that are coated with stiff, nanoscale spikes and exhibit long-term colloidal stability in both hydrophilic and hydrophobic media. We find that these 'hedgehog' particles do not interpenetrate each other with their spikes, which markedly decreases the contact area between the particles and, therefore, the attractive forces between them. The trapping of air in aqueous dispersions, solvent autoionization at highly developed interfaces, and long-range electrostatic repulsion in organic media also contribute to the colloidal stability of our particles. The unusual dispersion behaviour of our hedgehog particles, overturning the notion that like dissolves like, might help to mitigate adverse environmental effects of the use of surfactants and volatile organic solvents, and deepens our understanding of interparticle interactions and nanoscale colloidal chemistry.
C1 [Bahng, Joong Hwan; Wang, Yichun; Kotov, Nicholas] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA.
   [Yeom, Bongjun; Kotov, Nicholas] Univ Michigan, Dept Chem Engn, Ann Arbor, MI 48109 USA.
   [Tung, Siu On; Kotov, Nicholas] Univ Michigan, Macromol Sci & Engn Program, Ann Arbor, MI 48109 USA.
   [Hoff, J. Damon] Single Mol Anal Real Time SMART Ctr, Ann Arbor, MI 48109 USA.
   [Kotov, Nicholas] Univ Michigan, Dept Mat Sci & Engn, Ann Arbor, MI 48109 USA.
   [Kotov, Nicholas] Univ Michigan, Biointerfaces Inst, Ann Arbor, MI 48109 USA.
C3 University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan
RP Kotov, N (corresponding author), Univ Michigan, Dept Biomed Engn, 1107 Carl A Gerstacker Bldg,2200 Bonisteel Blvd, Ann Arbor, MI 48109 USA.
EM kotov@umich.edu
FU Center for Solar and Thermal Energy Conversion, an Energy Frontier Research Center - US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-SC0000957]; US NSF [ECS-0601345, CBET 0933384, CBET 0932823, CBET 1036672]; US Department of Defense [W911NF-10-1-0518, MURI W911NF-12-1-0407]; Directorate For Engineering; Div Of Civil, Mechanical, & Manufact Inn [1463474] Funding Source: National Science Foundation; Division Of Materials Research; Direct For Mathematical & Physical Scien [1411014] Funding Source: National Science Foundation
NR 29
TC 134
Z9 152
U1 1
U2 301
PU NATURE PUBLISHING 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 29
PY 2015
VL 517
IS 7536
BP 596
EP 599
DI 10.1038/nature14092
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA2ZL
UT WOS:000348775000039
PM 25631447
DA 2026-03-09
ER

PT J
AU Perez, K
   Hailey, CJ
   Bauer, FE
   Krivonos, RA
   Mori, K
   Baganoff, FK
   Barrière, NM
   Boggs, SE
   Christensen, FE
   Craig, WW
   Grefenstette, BW
   Grindlay, JE
   Harrison, FA
   Hong, J
   Madsen, KK
   Nynka, M
   Stern, D
   Tomsick, JA
   Wik, DR
   Zhang, S
   Zhang, WW
   Zoglauer, A
AF Perez, Kerstin
   Hailey, Charles J.
   Bauer, Franz E.
   Krivonos, Roman A.
   Mori, Kaya
   Baganoff, Frederick K.
   Barriere, Nicolas M.
   Boggs, Steven E.
   Christensen, Finn E.
   Craig, William W.
   Grefenstette, Brian W.
   Grindlay, Jonathan E.
   Harrison, Fiona A.
   Hong, Jaesub
   Madsen, Kristin K.
   Nynka, Melania
   Stern, Daniel
   Tomsick, John A.
   Wik, Daniel R.
   Zhang, Shuo
   Zhang, William W.
   Zoglauer, Andreas
TI Extended hard-X-ray emission in the inner few parsecs of the Galaxy
SO NATURE
LA English
DT Article
ID xmm-newton observations; black-hole; candidate; sgr; variability; luminosity; spectra; flux
AB The Galactic Centre hosts a puzzling stellar population in its inner few parsecs, with a high abundance of surprisingly young, relatively massive stars bound within the deep potential well of the central supermassive black hole, Sagittarius A* (ref. 1). Previous studies suggest that the population of objects emitting soft X-rays (less than 10 kiloelectronvolts) within the surrounding hundreds of parsecs, as well as the population responsible for unresolved X-ray emission extending along the Galactic plane, is dominated by accreting white dwarf systems'. Observations of diffuse hardX-ray (more than 10 kiloelectronvolts) emission in the inner 10 parsecs, however, have been hampered by the limited spatial resolution of previous instruments. Here we report the presence of a distinct hard-X-ray component within the central 4 X 8 parsecs, as revealed by subarcminute-resolution images in the 20-40 kiloelectronvolt range. This emission is more sharply peaked towards the Galactic Centre than is the surface brightness of the soft-X-ray population'. This could indicate a significantly more massive population of accreting white dwarfs, large populations of lowmass X-ray binaries or millisecond pulsars, or particle outflows interacting with the surrounding radiation field, dense molecular material or magnetic fields. However, all these interpretations pose significant challenges to our understanding of stellar evolution, binary formation, and cosmic-ray production in the Galactic Centre.
C1 [Perez, Kerstin; Hailey, Charles J.; Mori, Kaya; Nynka, Melania; Zhang, Shuo] Columbia Univ, Columbia Astrophys Lab, New York, NY 10027 USA.
   [Perez, Kerstin] Haverford Coll, Haverford, PA 19041 USA.
   [Bauer, Franz E.] Pontificia Univ Catolica Chile, Fac Fis, Inst Astrofis, Santiago 22, Chile.
   [Bauer, Franz E.] Millennium Inst Astrophys, Santiago 7820436, Chile.
   [Bauer, Franz E.] Space Sci Inst, Boulder, CO 80301 USA.
   [Krivonos, Roman A.; Barriere, Nicolas M.; Boggs, Steven E.; Craig, William W.; Tomsick, John A.; Zoglauer, Andreas] Univ Calif Berkeley, Space Sci Lab, Berkeley, CA 94720 USA.
   [Baganoff, Frederick K.] MIT, Kavli Inst Astrophys & Space Res, Cambridge, MA 02139 USA.
   [Christensen, Finn E.] Tech Univ Denmark, Natl Space Inst, DTU Space, DK-2800 Lyngby, Denmark.
   [Craig, William W.] Lawrence Livermore Natl Lab, Livermore, CA 94551 USA.
   [Grefenstette, Brian W.; Harrison, Fiona A.; Madsen, Kristin K.] CALTECH, Cahill Ctr Astron & Astrophys, Pasadena, CA 91125 USA.
   [Grindlay, Jonathan E.; Hong, Jaesub] Harvard Smithsonian Ctr Astrophys, Cambridge, MA 02138 USA.
   [Stern, Daniel] CALTECH, Jet Prop Lab, Pasadena, CA 91109 USA.
   [Wik, Daniel R.; Zhang, William W.] NASA, Goddard Space Flight Ctr, Greenbelt, MD 20771 USA.
C3 Columbia University; Haverford College; Pontificia Universidad Catolica de Chile; University of California System; University of California Berkeley; Massachusetts Institute of Technology (MIT); Technical University of Denmark; United States Department of Energy (DOE); Lawrence Livermore National Laboratory; California Institute of Technology; Harvard University; Smithsonian Institution; Smithsonian Astrophysical Observatory; California Institute of Technology; National Aeronautics & Space Administration (NASA); NASA Jet Propulsion Laboratory (JPL); National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center
RP Perez, K (corresponding author), Columbia Univ, Columbia Astrophys Lab, 550 West 120th St,Room 1027, New York, NY 10027 USA.
EM kperez1@haverford.edu
FU NASA [NNG08FD60C]; Basal-CATA [PFB-06/2007]; CONICYT-Chile [FONDECYT 1141218, EMBIGGEN Anillo ACT1101]; Iniciativa Cientifica Milenio del Ministerio de Economia, Fomento y Turismo [IC120009]
NR 46
TC 61
Z9 71
U1 0
U2 14
PU NATURE PUBLISHING 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 30
PY 2015
VL 520
IS 7549
BP 646
EP U138
DI 10.1038/nature14353
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700043
PM 25925477
DA 2026-03-09
ER

PT J
AU Prum, RO
   Berv, JS
   Dornburg, A
   Field, DJ
   Townsend, JP
   Lemmon, EM
   Lemmon, AR
AF Prum, Richard O.
   Berv, Jacob S.
   Dornburg, Alex
   Field, Daniel J.
   Townsend, Jeffrey P.
   Lemmon, Emily Moriarty
   Lemmon, Alan R.
TI A comprehensive phylogeny of birds (Aves) using targeted next-generation DNA sequencing
SO NATURE
LA English
DT Article
ID species divergence times; relaxed phylogenetics; molecular evolution; tree; rates; diversification; substitution; calibrations; nucleotide; selection
AB Although reconstruction of the phylogeny of living birds has progressed tremendously in the last decade, the evolutionary history of Neoaves-a clade that encompasses nearly all living bird species-remains the greatest unresolved challenge in dinosaur systematics. Here we investigate avian phylogeny with an unprecedented scale of data: >390,000 bases of genomic sequence data from each of 198 species of living birds, representing all major avian lineages, and two crocodilian outgroups. Sequence data were collected using anchored hybrid enrichment, yielding 259 nuclear loci with an average length of 1,523 bases for a total data set of over 7.8x10(7) bases. Bayesian and maximum likelihood analyses yielded highly supported and nearly identical phylogenetic trees for all major avian lineages. Five major clades form successive sister groups to the rest of Neoaves: (1) a clade including nightjars, other caprimulgiforms, swifts, and hummingbirds; (2) a clade uniting cuckoos, bustards, and turacos with pigeons, mesites, and sandgrouse; (3) cranes and their relatives; (4) a comprehensive waterbird clade, including all diving, wading, and shorebirds; and (5) a comprehensive landbird clade with the enigmatic hoatzin (Opisthocomus hoazin) as the sister group to the rest. Neither of the two main, recently proposed Neoavian clades-Columbea and Passerea(1)-were supported as monophyletic. The results of our divergence time analyses are congruent with the palaeontological record, supporting a major radiation of crown birds in the wake of the Cretaceous-Palaeogene (K-Pg) mass extinction.
C1 [Prum, Richard O.; Dornburg, Alex; Townsend, Jeffrey P.] Yale Univ, Dept Ecol & Evolutionary Biol, New Haven, CT 06520 USA.
   [Prum, Richard O.; Dornburg, Alex; Field, Daniel J.] Yale Univ, Peabody Museum Nat Hist, New Haven, CT 06520 USA.
   [Berv, Jacob S.] Cornell Univ, Fuller Evolutionary Biol Program, Dept Ecol & Evolutionary Biol, Ithaca, NY 14853 USA.
   [Berv, Jacob S.] Cornell Lab Ornithol, Ithaca, NY 14853 USA.
   [Dornburg, Alex] North Carolina Museum Nat Sci, Raleigh, NC 27601 USA.
   [Field, Daniel J.] Yale Univ, Dept Geol & Geophys, New Haven, CT 06520 USA.
   [Townsend, Jeffrey P.] Yale Univ, Dept Biostat, New Haven, CT 06520 USA.
   [Townsend, Jeffrey P.] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
   [Lemmon, Emily Moriarty] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA.
   [Lemmon, Alan R.] Florida State Univ, Dept Comp Sci, Tallahassee, FL 32306 USA.
C3 Yale University; Yale University; Cornell University; Cornell University; Yale University; Yale University; Yale University; State University System of Florida; Florida State University; State University System of Florida; Florida State University
RP Prum, RO (corresponding author), Yale Univ, Dept Ecol & Evolutionary Biol, New Haven, CT 06520 USA.
EM richard.prum@yale.edu; jsb439@cornell.edu
FU Yale University; NSF; NIH; Division Of Environmental Biology; Direct For Biological Sciences [1120516] Funding Source: National Science Foundation
NR 79
TC 1298
Z9 1497
U1 10
U2 687
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 22
PY 2015
VL 526
IS 7574
BP 569
EP U247
DI 10.1038/nature15697
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV1NX
UT WOS:000364026100049
PM 26444237
DA 2026-03-09
ER

PT J
AU Hanks, TD
   Kopec, CD
   Brunton, BW
   Duan, CA
   Erlich, JC
   Brody, CD
AF Hanks, Timothy D.
   Kopec, Charles D.
   Brunton, Bingni W.
   Duan, Chunyu A.
   Erlich, Jeffrey C.
   Brody, Carlos D.
TI Distinct relationships of parietal and prefrontal cortices to evidence accumulation
SO NATURE
LA English
DT Article
ID perceptual decision-making; neural basis; eye field; cortex; rat; neurons; macaque; motion; monkey; area
AB Gradual accumulation of evidence is thought to be fundamental for decision-making, and its neural correlates have been found in several brain regions'. Here we develop a generalizable method to measure tuning curves that specify the relationship between neural responses and mentally accumulated evidence, and apply it to distinguish the encoding of decision variables in posterior parietal cortex and prefrontal cortex (frontal orienting fields, FOF). We recorded the firing rates of neurons in posterior parietal cortex and FOF from rats performing a perceptual decision-making task. Classical analyses uncovered correlates of accumulating evidence, similar to previous observations in primates and also similar across the two regions. However, tuning curve assays revealed that while the posterior parietal cortex encodes a graded value of the accumulating evidence, the FOF has a more categorical encoding that indicates, throughout the trial, the decision provisionally favoured by the evidence accumulated so far. Contrary to current views(3,5,7,9), this suggests that premotor activity in the frontal cortex does not have a role in the accumulation process, but instead has a more categorical function, such as transforming accumulated evidence into a discrete choice. To probe causally the role of FOF activity, we optogenetically silenced it during different time points of the trial. Consistent with a role in committing to a categorical choice at the end of the evidence accumulation process, but not consistent with a role during the accumulation itself, a behavioural effect was observed only when FOF silencing occurred at the end of the perceptual stimulus. Our results place important constraints on the circuit logic of brain regions involved in decision-making.
C1 [Hanks, Timothy D.; Kopec, Charles D.; Brunton, Bingni W.; Duan, Chunyu A.; Erlich, Jeffrey C.; Brody, Carlos D.] Princeton Univ, Princeton Neurosci Inst, Princeton, NJ 08544 USA.
   [Hanks, Timothy D.; Kopec, Charles D.; Brunton, Bingni W.; Duan, Chunyu A.; Erlich, Jeffrey C.; Brody, Carlos D.] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA.
   [Brunton, Bingni W.] Univ Washington, Dept Biol, Seattle, WA 98105 USA.
   [Brunton, Bingni W.] Univ Washington, Dept Appl Math, Seattle, WA 98105 USA.
   [Erlich, Jeffrey C.] NYU Shanghai, NYU ECNU Inst Brain & Cognit Sci, Shanghai 200122, Peoples R China.
   [Brody, Carlos D.] Princeton Univ, Howard Hughes Med Inst, Princeton, NJ 08544 USA.
C3 Princeton University; Princeton University; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; New York University; NYU Shanghai; Princeton University; Howard Hughes Medical Institute
RP Brody, CD (corresponding author), Princeton Univ, Princeton Neurosci Inst, Princeton, NJ 08544 USA.
EM brody@princeton.edu
FU National Institutes of Health (NIH) [F32MH098572]; Howard Hughes Medical Institute; NIH [T32MH065214]; National Institute on Drug Abuse; National Institute of Mental Health [T32MH065214] Funding Source: NIH RePORTER
NR 26
TC 333
Z9 389
U1 1
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 APR 9
PY 2015
VL 520
IS 7546
BP 220
EP U195
DI 10.1038/nature14066
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CF3NA
UT WOS:000352454600039
PM 25600270
DA 2026-03-09
ER

PT J
AU High, AA
   Devlin, RC
   Dibos, A
   Polking, M
   Wild, DS
   Perczel, J
   de Leon, NP
   Lukin, MD
   Park, H
AF High, Alexander A.
   Devlin, Robert C.
   Dibos, Alan
   Polking, Mark
   Wild, Dominik S.
   Perczel, Janos
   de Leon, Nathalie P.
   Lukin, Mikhail D.
   Park, Hongkun
TI Visible-frequency hyperbolic metasurface
SO NATURE
LA English
DT Article
ID negative refraction; metamaterials; silver; excitation; index; modes
AB Metamaterials are artificial optical media composed of subwavelength metallic and dielectric building blocks that feature optical phenomena not present in naturally occurring materials(1-7). Although they can serve as the basis for unique optical devices that mould the flow of light in unconventional ways, three-dimensional metamaterials suffer from extreme propagation losses(8,9). Two-dimensional metamaterials (metasurfaces) such as hyperbolic metasurfaces for propagating surface plasmon polaritons(10,11) have the potential to alleviate this problem. Because the surface plasmon polaritons are guided at a metal-dielectric interface (rather than passing through metallic components), these hyperbolic metasurfaces have been predicted to suffer much lower propagation loss while still exhibiting optical phenomena akin to those in three-dimensional metamaterials. Moreover, because of their planar nature, these devices enable the construction of integrated metamaterial circuits as well as easy coupling with other optoelectronic elements. Here we report the experimental realization of a visible-frequency hyperbolic metasurface using single-crystal silver nanostructures defined by lithographic and etching techniques. The resulting devices display the characteristic properties of metamaterials, such as negative refraction(1-5) and diffraction-free propagation(6,7), with device performance greatly exceeding those of previous demonstrations. Moreover, hyperbolic metasurfaces exhibit strong, dispersion-dependent spin-orbit coupling, enabling polarization-and wavelength-dependent routeing of surface plasmon polaritons and two-dimensional chiral optical components(12-15). These results open the door to realizing integrated optical meta-circuits, with wide-ranging applications in areas from imaging and sensing to quantum optics and quantum information science.
C1 [High, Alexander A.; Polking, Mark; de Leon, Nathalie P.; Park, Hongkun] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA.
   [High, Alexander A.; Wild, Dominik S.; Perczel, Janos; de Leon, Nathalie P.; Lukin, Mikhail D.; Park, Hongkun] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.
   [Devlin, Robert C.; Dibos, Alan] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA.
   [Perczel, Janos] MIT, Dept Phys, Cambridge, MA 02139 USA.
C3 Harvard University; Harvard University; Harvard University; Massachusetts Institute of Technology (MIT)
RP Park, H (corresponding author), Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA.
EM lukin@physics.harvard.edu; hongkun_park@harvard.edu
FU ONR-MURI [FA9550-12-1-0024]; NSF-AMO [PHY-0969816]; NSF-CUA [PHY-1125846]; DARPA SPARQC [W31P4Q-12-1-0017]; Direct For Mathematical & Physical Scien; Division Of Physics [1125846] Funding Source: National Science Foundation; Directorate For Engineering; Div Of Electrical, Commun & Cyber Sys [1541959] Funding Source: National Science Foundation; Division Of Physics; Direct For Mathematical & Physical Scien [0969816] Funding Source: National Science Foundation
NR 30
TC 514
Z9 580
U1 41
U2 1039
PU NATURE PUBLISHING 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 11
PY 2015
VL 522
IS 7555
BP 192
EP 196
DI 10.1038/nature14477
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700034
PM 26062510
DA 2026-03-09
ER

PT J
AU Brunette, TJ
   Parmeggiani, F
   Huang, PS
   Bhabha, G
   Ekiert, DC
   Tsutakawa, SE
   Hura, GL
   Tainer, JA
   Baker, D
AF Brunette, T. J.
   Parmeggiani, Fabio
   Huang, Po-Ssu
   Bhabha, Gira
   Ekiert, Damian C.
   Tsutakawa, Susan E.
   Hura, Greg L.
   Tainer, John A.
   Baker, David
TI Exploring the repeat protein universe through computational protein design
SO NATURE
LA English
DT Article
ID x-ray-scattering; software; architecture; generation; resolution; stability; sequence; database; scaffold; binders
AB A central question in protein evolution is the extent to which naturally occurring proteins sample the space of folded structures accessible to the polypeptide chain. Repeat proteins composed of multiple tandem copies of a modular structure unit(1) are widespread in nature and have critical roles in molecular recognition, signalling, and other essential biological processes(2). Naturally occurring repeat proteins have been re-engineered for molecular recognition and modular scaffolding applications(3-5). Here we use computational protein design to investigate the space of folded structures that can be generated by tandem repeating a simple helix-loop-helix-loop structural motif. Eighty-three designs with sequences unrelated to known repeat proteins were experimentally characterized. Of these, 53 are monomeric and stable at 95 degrees C, and 43 have solution X-ray scattering spectra consistent with the design models. Crystal structures of 15 designs spanning a broad range of curvatures are in close agreement with the design models with root mean square deviations ranging from 0.7 to 2.5 angstrom. Our results show that existing repeat proteins occupy only a small fraction of the possible repeat protein sequence and structure space and that it is possible to design novel repeat proteins with precisely specified geometries, opening up a wide array of new possibilities for biomolecular engineering.
C1 [Brunette, T. J.; Parmeggiani, Fabio; Huang, Po-Ssu; Baker, David] Univ Washington, Dept Biochem, Seattle, WA 98195 USA.
   [Brunette, T. J.; Parmeggiani, Fabio; Huang, Po-Ssu; Baker, David] Univ Washington, Inst Prot Design, Seattle, WA 98195 USA.
   [Bhabha, Gira] UCSF, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA.
   [Ekiert, Damian C.] UCSF, Dept Microbiol & Immunol, San Francisco, CA 94158 USA.
   [Tsutakawa, Susan E.; Hura, Greg L.; Tainer, John A.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging, Berkeley, CA 94720 USA.
   [Hura, Greg L.] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA.
   [Tainer, John A.] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA.
   [Baker, David] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA.
C3 University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of California System; University of California San Francisco; University of California System; University of California San Francisco; 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 Santa Cruz; University of Texas System; UTMD Anderson Cancer Center; University of Washington; University of Washington Seattle; Howard Hughes Medical Institute
RP Baker, D (corresponding author), Univ Washington, Dept Biochem, Seattle, WA 98195 USA.
EM dabaker@uw.edu
FU National Science Foundation (NSF) [MCB-1445201, CHE-1332907]; Defense Threat Reduction Agency (DTRA); Air Force Office of Scientific Research (AFOSR) [FA950-12-10112]; Howard Hughes Medical Institute [HHMI-027779]; Swiss National Science Foundation Postdoc Fellowship [PBZHP3-125470]; Human Frontier Science Program Long-Term Fellowship [LT000070/2009-L]; National Institutes of Health grant MINOS (Macromolecular Insights on Nucleic Acids Optimized by Scattering) [GM105404]; United States Department of Energy program Integrated Diffraction Analysis Technologies (IDAT); Damon Runyon Cancer Research Foundation [DRG-2140-12]; Merck fellowship of the Damon Runyon Cancer Research Foundation [DRG-2136-12]; NIH [K99GM112982]; Robert A. Welch Distinguished Chair in Chemistry; Office of Science, Office of Basic Energy Sciences, of the US Department of Energy [DE-AC02-05CH11231]; UC Office of the President, Multicampus Research Programs and Initiatives [MR-15-338599]; Sandler Foundation; National Institutes of Health; National Institute of General Medical Sciences; Howard Hughes Medical Institute; Swiss National Science Foundation (SNF) [PBZHP3-125470] Funding Source: Swiss National Science Foundation (SNF); Div Of Molecular and Cellular Bioscience; Direct For Biological Sciences [1445201] Funding Source: National Science Foundation
NR 47
TC 199
Z9 257
U1 1
U2 149
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 24
PY 2015
VL 528
IS 7583
BP 580
EP +
DI 10.1038/nature16162
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900058
PM 26675729
DA 2026-03-09
ER

PT J
AU Miniati, F
   Beresnyak, A
AF Miniati, Francesco
   Beresnyak, Andrey
TI Self-similar energetics in large clusters of galaxies
SO NATURE
LA English
DT Article
ID large-scale structure; seed magnetic-fields; turbulent motions; rotation measures; power spectrum; adaptive mesh; shock-waves; refinement; generation; statistics
AB Massive galaxy clusters are filled with a hot, turbulent and magnetized intra-cluster medium. Still forming under the action of gravitational instability, they grow in mass by accretion of supersonic flows. These flows partially dissipate into heat through a complex network of large-scale shocks(1), while residual transonic (near-sonic) flows create giant turbulent eddies and cascades(2,3). Turbulence heats the intra-cluster medium(4) and also amplifies magnetic energy by way of dynamo action(5-8). However, the pattern regulating the transformation of gravitational energy into kinetic, thermal, turbulent and magnetic energies remains unknown. Here we report that the energy components of the intra-cluster medium are ordered according to a permanent hierarchy, in which the ratio of thermal to turbulent to magnetic energy densities remains virtually unaltered throughout the cluster's history, despite evolution of each individual component and the drive towards equipartition of the turbulent dynamo. This result revolves around the approximately constant efficiency of turbulence generation from the gravitational energy that is freed during mass accretion, revealed by our computational model of cosmological structure formation(3,9). The permanent character of this hierarchy reflects yet another type of self-similarity in cosmology(10-13), while its structure, consistent with current data(14-18), encodes information about the efficiency of turbulent heating and dynamo action.
C1 [Miniati, Francesco] ETH, Dept Phys, CH-8093 Zurich, Switzerland.
   [Beresnyak, Andrey] KTH Royal Inst Technol, Nordita, SE-10691 Stockholm, Sweden.
   [Beresnyak, Andrey] Stockholm Univ, SE-10691 Stockholm, Sweden.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich; Royal Institute of Technology; Nordic Institute for Theoretical Physics; Stockholm University
RP Miniati, F (corresponding author), ETH, Dept Phys, Wolfgang Pauli Str 27, CH-8093 Zurich, Switzerland.
EM fm@phys.ethz.ch
FU Swiss National Supercomputing Center (CSCS) [S419, S506]
NR 36
TC 63
Z9 69
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 JUL 2
PY 2015
VL 523
IS 7558
BP 59
EP +
DI 10.1038/nature14552
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL7RN
UT WOS:000357169500030
PM 26135447
DA 2026-03-09
ER

PT J
AU Stanley, DA
   Garratt, MPD
   Wickens, JB
   Wickens, VJ
   Potts, SG
   Raine, NE
AF Stanley, Dara A.
   Garratt, Michael P. D.
   Wickens, Jennifer B.
   Wickens, Victoria J.
   Potts, Simon G.
   Raine, Nigel E.
TI Neonicotinoid pesticide exposure impairs crop pollination services provided by bumblebees
SO NATURE
LA English
DT Article
ID potential exposure; fruit-quality; apple; pollen; bees; insecticides; success; traits
AB Recent concern over global pollinator declines has led to considerable research on the effects of pesticides on bees(1-5). Although pesticides are typically not encountered at lethal levels in the field, there is growing evidence indicating that exposure to field-realistic levels can have sublethal effects on bees, affecting their foraging behaviour(1,6,7), homing ability(8,9) and reproductive success(2,5). Bees are essential for the pollination of a wide variety of crops and the majority of wild flowering plants(10-12), but until now research on pesticide effects has been limited to direct effects on bees themselves and not on the pollination services they provide. Here we show the first evidence to our knowledge that pesticide exposure can reduce the pollination services bumblebees deliver to apples, a crop of global economic importance. Bumblebee colonies exposed to a neonicotinoid pesticide provided lower visitation rates to apple trees and collected pollen less often. Most importantly, these pesticide-exposed colonies produced apples containing fewer seeds, demonstrating a reduced delivery of pollination services. Our results also indicate that reduced pollination service delivery is not due to pesticide-induced changes in individual bee behaviour, but most likely due to effects at the colony level. These findings show that pesticide exposure can impair the ability of bees to provide pollination services, with important implications for both the sustained delivery of stable crop yields and the functioning of natural ecosystems.
C1 [Stanley, Dara A.; Raine, Nigel E.] Royal Holloway Univ London, Sch Biol Sci, Egham TW20 0EX, Surrey, England.
   [Garratt, Michael P. D.; Wickens, Jennifer B.; Wickens, Victoria J.; Potts, Simon G.] Univ Reading, Sch Agr Policy & Dev, Ctr Agri Environm Res, Reading RG6 6AR, Berks, England.
   [Raine, Nigel E.] Univ Guelph, Sch Environm Sci, Guelph, ON N1G 2W1, Canada.
C3 University of London; Royal Holloway University London; University of Reading; University of Guelph
RP Stanley, DA (corresponding author), Royal Holloway Univ London, Sch Biol Sci, Egham TW20 0EX, Surrey, England.
EM darastanley@gmail.com; nraine@uoguelph.ca
FU UK Insect Pollinators Initiative [BB/I000178/1, BB/1000348/1]; Living with Environmental Change programme; Biotechnology and Biological Sciences Research Council (BBSRC); Wellcome Trust; Scottish Government; Department for Environment, Food and Rural Affairs (Defra); Natural Environment Research Council (NERC); Rebanks Family Chair in Pollinator Conservation by The W. Garfield Weston Foundation; BBSRC [BB/I000178/1, BB/I000348/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/I000348/1, BB/I000178/1] Funding Source: researchfish
NR 42
TC 282
Z9 338
U1 13
U2 564
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 24
PY 2015
VL 528
IS 7583
BP 548
EP +
DI 10.1038/nature16167
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900051
PM 26580009
DA 2026-03-09
ER

PT J
AU Sheffield, MEJ
   Dombeck, DA
AF Sheffield, Mark E. J.
   Dombeck, Daniel A.
TI Calcium transient prevalence across the dendritic arbour predicts place field properties
SO NATURE
LA English
DT Article
ID neurons in-vivo; ca1 pyramidal neurons; cellular resolution; basal dendrites; neural activity; virtual navigation; spikes; dynamics; spines; cells
AB Establishing the hippocampal cellular ensemble that represents an animal's environment involves the emergence and disappearance of place fields in specific CA1 pyramidal neurons(1-4), and the acquisition of different spatial firing properties across the active population(5). While such firing flexibility and diversity have been linked to spatial memory, attention and task performance(6,7), the cellular and network origin of these place cell features is unknown. Basic integrate-and-fire models of place firing propose that such features result solely from varying inputs to place cells(8,9), but recent studies(3,10) suggest instead that place cells themselves may play an active role through regenerative dendritic events. However, owing to the difficulty of performing functional recordings from place cell dendrites, no direct evidence of regenerative dendritic events exists, leaving any possible connection to place coding unknown. Using multi-plane two-photon calcium imaging of CA1 place cell somata, axons and dendrites in mice navigating a virtual environment, here we show that regenerative dendritic events do exist in place cells of behaving mice, and, surprisingly, their prevalence throughout the arbour is highly spatiotemporally variable. Furthermore, we show that the prevalence of such events predicts the spatial precision and persistence or disappearance of place fields. This suggests that the dynamics of spiking throughout the dendritic arbour may play a key role in forming the hippocampal representation of space.
C1 [Sheffield, Mark E. J.; Dombeck, Daniel A.] Northwestern Univ, Dept Neurobiol, Evanston, IL 60208 USA.
C3 Northwestern University
RP Dombeck, DA (corresponding author), Northwestern Univ, Dept Neurobiol, Evanston, IL 60208 USA.
EM d-dombeck@northwestern.edu
FU Klingenstein Foundation; Whitehall Foundation; Chicago Biomedical Consortium; Searle Funds at The Chicago Community Trust; Northwestern University; National Institutes of Health [1R01MH101297]; National Institute of Mental Health [R01MH101297] Funding Source: NIH RePORTER
NR 48
TC 185
Z9 228
U1 1
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 JAN 8
PY 2015
VL 517
IS 7533
BP 200
EP U191
DI 10.1038/nature13871
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600036
PM 25363782
DA 2026-03-09
ER

PT J
AU Duff, MO
   Olson, S
   Wei, XT
   Garrett, SC
   Osman, A
   Bolisetty, M
   Plocik, A
   Celniker, SE
   Graveley, BR
AF Duff, Michael O.
   Olson, Sara
   Wei, Xintao
   Garrett, Sandra C.
   Osman, Ahmad
   Bolisetty, Mohan
   Plocik, Alex
   Celniker, Susan E.
   Graveley, Brenton R.
TI Genome-wide identification of zero nucleotide recursive splicing in Drosophila
SO NATURE
LA English
DT Article
ID in-vivo; generation; junctions; introns
AB Recursive splicing is a process in which large introns are removed in multiple steps by re-splicing at ratchet points-5' splice sites recreated after splicing(1). Recursive splicing was first identified in the Drosophila Ultrabithorax (Ubx) gene(1) and only three additional Drosophila genes have since been experimentally shown to undergo recursive splicing(2,3). Here we identify 197 zero nucleotide exon ratchet points in 130 introns of 115 Drosophila genes from total RNA sequencing data generated from developmental time points, dissected tissues and cultured cells. The sequential nature of recursive splicing was confirmed by identification of lariat introns generated by splicing to and from the ratchet points. We also show that recursive splicing is a constitutive process, that depletion of U2AF inhibits recursive splicing, and that the sequence and function of ratchet points are evolutionarily conserved in Drosophila. Finally, we identify four recursively spliced human genes, one of which is also recursively spliced in Drosophila. Together, these results indicate that recursive splicing is commonly used in Drosophila, occurs in humans, and provides insight into the mechanisms by which some large introns are removed.
C1 [Duff, Michael O.; Olson, Sara; Wei, Xintao; Garrett, Sandra C.; Osman, Ahmad; Bolisetty, Mohan; Plocik, Alex; Graveley, Brenton R.] Univ Connecticut, Ctr Hlth, Inst Syst Genom, Dept Genet & Genome Sci, Farmington, CT 06030 USA.
   [Celniker, Susan E.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Dept Genome Dynam, Berkeley, CA 94720 USA.
C3 University of Connecticut; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; University of California System; University of California Berkeley
RP Graveley, BR (corresponding author), Univ Connecticut, Ctr Hlth, Inst Syst Genom, Dept Genet & Genome Sci, Farmington, CT 06030 USA.
EM graveley@uchc.edu
FU NHGRI [U54HG006994, R01GM095296]
NR 18
TC 162
Z9 197
U1 0
U2 24
PU NATURE PUBLISHING 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 21
PY 2015
VL 521
IS 7552
BP 376
EP +
DI 10.1038/nature14475
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CI5RM
UT WOS:000354816500061
PM 25970244
DA 2026-03-09
ER

PT J
AU Rebsamen, M
   Pochini, L
   Stasyk, T
   de Araújo, MEG
   Galluccio, M
   Kandasamy, RK
   Snijder, B
   Fauster, A
   Rudashevskaya, EL
   Bruckner, M
   Scorzoni, S
   Filipek, PA
   Huber, KVM
   Bigenzahn, JW
   Heinz, LX
   Kraft, C
   Bennett, KL
   Indiveri, C
   Huber, LA
   Superti-Furga, G
AF Rebsamen, Manuele
   Pochini, Lorena
   Stasyk, Taras
   de Araujo, Mariana E. G.
   Galluccio, Michele
   Kandasamy, Richard K.
   Snijder, Berend
   Fauster, Astrid
   Rudashevskaya, Elena L.
   Bruckner, Manuela
   Scorzoni, Stefania
   Filipek, Przemyslaw A.
   Huber, Kilian V. M.
   Bigenzahn, Johannes W.
   Heinz, Leonhard X.
   Kraft, Claudine
   Bennett, Keiryn L.
   Indiveri, Cesare
   Huber, Lukas A.
   Superti-Furga, Giulio
TI SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1
SO NATURE
LA English
DT Article
ID mass-spectrometry data; rag gtpases; membrane transporters; proteomic analysis; tumor-suppressor; protein-complex; mechanism; identification; strategy; ragulator
AB Cell growth and proliferation are tightly linked to nutrient availability. The mechanistic target of rapamycin complex 1 (mTORC1) integrates the presence of growth factors, energy levels, glucose and amino acids to modulate metabolic status and cellular responses(1-3). mTORC1 is activated at the surface of lysosomes by the RAG GTPases and the Ragulator complex through a not fully understood mechanism monitoring amino acid availability in the lysosomal lumen and involving the vacuolar H1-ATPase(4-8). Here we describe the uncharacterized human member 9 of the solute carrier family 38 (SLC38A9) as a lysosomal membrane-resident protein competent in amino acid transport. Extensive functional proteomic analysis established SLC38A9 as an integral part of the Ragulator-RAG GTPases machinery. Gain of SLC38A9 function rendered cells resistant to amino acid withdrawal, whereas loss of SLC38A9 expression impaired amino-acid-induced mTORC1 activation. Thus SLC38A9 is a physical and functional component of the amino acid sensing machinery that controls the activation of mTOR.
C1 [Rebsamen, Manuele; Kandasamy, Richard K.; Snijder, Berend; Fauster, Astrid; Rudashevskaya, Elena L.; Bruckner, Manuela; Scorzoni, Stefania; Huber, Kilian V. M.; Bigenzahn, Johannes W.; Heinz, Leonhard X.; Bennett, Keiryn L.; Superti-Furga, Giulio] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria.
   [Pochini, Lorena; Galluccio, Michele; Indiveri, Cesare] Univ Calabria, Dept DiBEST Biol Ecol & Earth Sci, I-87036 Arcavacata Di Rende, Italy.
   [Stasyk, Taras; de Araujo, Mariana E. G.; Filipek, Przemyslaw A.; Huber, Lukas A.] Med Univ Innsbruck, Div Cell Biol, Bioctr, A-6020 Innsbruck, Austria.
   [Kraft, Claudine] Univ Vienna, Max F Perutz Labs, A-1030 Vienna, Austria.
C3 Austrian Academy of Sciences; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences; University of Calabria; Medical University of Innsbruck; University of Vienna; Vienna Biocenter (VBC); Max F. Perutz Laboratories (MFPL)
RP Superti-Furga, G (corresponding author), Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria.
EM gsuperti@cemm.oeaw.ac.at
FU Austrian Academy of Sciences; ERC [i-FIVE 250179]; EMBO [ALTF 1346-2011, IEF 301663, ALTF 314-2012]; Swiss NSF [P300P3_147897]; Vienna Science and Technology Fund [WWTF VRG10-001]; Austrian Science Fund [FWF P 25522-B20, MCBO/SFB021]; Italian Ministry of Instruction University and Research, PON-ricerca e competitivita [PON01_00937]; Austrian Federal Ministry for Science and Research; Austrian Science Fund (FWF) [P 25522] Funding Source: researchfish; Austrian Science Fund (FWF) [P25522] Funding Source: Austrian Science Fund (FWF); Swiss National Science Foundation (SNF) [P300P3_147897] Funding Source: Swiss National Science Foundation (SNF)
NR 40
TC 548
Z9 665
U1 1
U2 172
PU NATURE PUBLISHING 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 26
PY 2015
VL 519
IS 7544
BP 477
EP +
DI 10.1038/nature14107
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE1WF
UT WOS:000351602800057
PM 25561175
DA 2026-03-09
ER

PT J
AU Deng, K
   Pertea, M
   Rongvaux, A
   Wang, LY
   Durand, CM
   Ghiaur, G
   Lai, J
   McHugh, HL
   Hao, HP
   Zhang, H
   Margolick, JB
   Gurer, C
   Murphy, AJ
   Valenzuela, DM
   Yancopoulos, GD
   Deeks, SG
   Strowig, T
   Kumar, P
   Siliciano, JD
   Salzberg, SL
   Flavell, RA
   Shan, L
   Siliciano, RF
AF Deng, Kai
   Pertea, Mihaela
   Rongvaux, Anthony
   Wang, Leyao
   Durand, Christine M.
   Ghiaur, Gabriel
   Lai, Jun
   McHugh, Holly L.
   Hao, Haiping
   Zhang, Hao
   Margolick, Joseph B.
   Gurer, Cagan
   Murphy, Andrew J.
   Valenzuela, David M.
   Yancopoulos, George D.
   Deeks, Steven G.
   Strowig, Till
   Kumar, Priti
   Siliciano, Janet D.
   Salzberg, Steven L.
   Flavell, Richard A.
   Shan, Liang
   Siliciano, Robert F.
TI Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations
SO NATURE
LA English
DT Article
ID viral reservoir; viremia; immunodominance; stability
AB Despite antiretroviral therapy (ART), human immunodeficiency virus (HIV)-1 persists in a stable latent reservoir(1,2), primarily in resting memory CD4(+) T cells(3,4). This reservoir presents a major barrier to the cure of HIV-1 infection. To purge the reservoir, pharmacological reactivation of latent HIV-1 has been proposed(5) and tested both in vitro and in vivo(6-8). A key remaining question is whether virusspecific immune mechanisms, including cytotoxic T lymphocytes (CTLs), can clear infected cells in ART-treated patients after latency is reversed. Here we show that there is a striking all or none pattern for CTL escape mutations in HIV-1 Gag epitopes. Unless ART is started early, the vast majority (>98%) of latent viruses carry CTL escape mutations that render infected cells insensitive to CTLs directed at common epitopes. To solve this problem, we identified CTLs that could recognize epitopes from latent HIV-1 that were unmutated in every chronically infected patient tested. Upon stimulation, these CTLs eliminated target cells infected with autologous virus derived from the latent reservoir, both in vitro and in patient-derived humanized mice. The predominance of CTL-resistant viruses in the latent reservoir poses a major challenge to viral eradication. Our results demonstrate that chronically infected patients retain abroad-spectrum viral-specific CTL response and that appropriate boosting of this response may be required for the elimination of the latent reservoir.
C1 [Deng, Kai; Pertea, Mihaela; Durand, Christine M.; Lai, Jun; McHugh, Holly L.; Siliciano, Janet D.; Siliciano, Robert F.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA.
   [Pertea, Mihaela; Salzberg, Steven L.] Johns Hopkins Univ, Sch Med, Ctr Computat Biol, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA.
   [Rongvaux, Anthony; Strowig, Till; Flavell, Richard A.; Shan, Liang] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06510 USA.
   [Wang, Leyao] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT 06510 USA.
   [Ghiaur, Gabriel] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA.
   [Hao, Haiping] Johns Hopkins Univ, Sch Med, Deep Sequencing & Microarray Core, Baltimore, MD 21205 USA.
   [Zhang, Hao; Margolick, Joseph B.] Johns Hopkins Univ, Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA.
   [Gurer, Cagan; Murphy, Andrew J.; Valenzuela, David M.; Yancopoulos, George D.] Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA.
   [Deeks, Steven G.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94110 USA.
   [Kumar, Priti] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA.
   [Salzberg, Steven L.] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA.
   [Flavell, Richard A.] Howard Hughes Med Inst, New Haven, CT 06510 USA.
   [Siliciano, Robert F.] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA.
C3 Johns Hopkins University; Johns Hopkins University; Yale University; Yale University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Regeneron; University of California System; University of California San Francisco; Yale University; Johns Hopkins University; Howard Hughes Medical Institute; Howard Hughes Medical Institute; Johns Hopkins University
RP Flavell, RA (corresponding author), Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06510 USA.
EM richard.flavell@yale.edu; liang.shan@yale.edu; rsiliciano@jhmi.edu
FU Howard Hughes Medical Institute; Martin Delaney CARE; DARE Collaboratories (NIH grants) [AI096113, 1U19AI096109]; ARCH E Collaborative Research Grant from the Foundation for AIDS Research [amFAR 108165-50-RGRL]; Johns Hopkins Center for AIDS Research [P30AI094189]; NIH [43222, T32 AI07019]; Bill and Melinda Gates Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Heart Lung and Blood Institute; National Institute of Dental and Craniofacial Research [P30AI027763] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [T32HL007525] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [T32AI007019] Funding Source: NIH RePORTER; National Institute of Nursing Research; National Institute of Diabetes and Digestive and Kidney Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Dental and Craniofacial Research; National Cancer Institute; National Institute of Allergy and Infectious Diseases; National Institute on Aging; National Institute on Minority Health and Health Disparities; National Heart Lung and Blood Institute [P30AI094189] Funding Source: NIH RePORTER; National Institute of Nursing Research; National Institute on Drug Abuse; National Cancer Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; National Institute on Aging; National Institute on Minority Health and Health Disparities [P30AI027763] Funding Source: NIH RePORTER
NR 34
TC 436
Z9 517
U1 6
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 JAN 15
PY 2015
VL 517
IS 7534
BP 381
EP U544
DI 10.1038/nature14053
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300049
PM 25561180
DA 2026-03-09
ER

PT J
AU Dunsmoor, JE
   Murty, VP
   Davachi, L
   Phelps, EA
AF Dunsmoor, Joseph E.
   Murty, Vishnu P.
   Davachi, Lila
   Phelps, Elizabeth A.
TI Emotional learning selectively and retroactively strengthens memories for related events
SO NATURE
LA English
DT Article
ID long-term-memory; arousal; retention; fear
AB Neurobiological models of long-term memory propose a mechanism by which initially weak memories are strengthened through subsequent activation that engages common neural pathways minutes to hours later(1). This synaptic tag-and-capture model has been hypothesized to explain how inconsequential information is selectively consolidated following salient experiences. Behavioural evidence for tag-and-capture is provided by rodent studies in which weak early memories are strengthened by future behavioural training(2,3). Whether a process of behavioural tagging occurs in humans to transform weak episodic memories into stable long-term memories is unknown. Here we show, in humans, that information is selectively consolidated if conceptually related information, putatively represented in a common neural substrate, is made salient through an emotional learning experience. Memory for neutral objects was selectively enhanced if other objects from the same category were paired with shock. Retroactive enhancements as a result of emotional learning were observed following a period of consolidation, but were not observed in an immediate memory test or for items strongly encoded before fear conditioning. These findings provide new evidence for a generalized retroactive memory enhancement, whereby inconsequential information can be retroactively credited as relevant, and therefore selectively remembered, if conceptually related information acquires salience in the future.
C1 [Dunsmoor, Joseph E.; Murty, Vishnu P.; Davachi, Lila; Phelps, Elizabeth A.] NYU, Dept Psychol, New York, NY 10003 USA.
   [Dunsmoor, Joseph E.; Murty, Vishnu P.; Davachi, Lila; Phelps, Elizabeth A.] NYU, Ctr Neural Sci, New York, NY 10003 USA.
   [Phelps, Elizabeth A.] Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA.
C3 New York University; New York University; Nathan Kline Institute for Psychiatric Research
RP Davachi, L (corresponding author), NYU, Dept Psychol, 6 Washington Pl, New York, NY 10003 USA.
EM lila.davachi@nyu.edu; liz.phelps@nyu.edu
FU NIH [RO1 MH097085, R01 MH047692, F31 DA036361]; NIMH Training Award in Systems and Integrative Neuroscience [T32 MH019524]; National Institute of Mental Health [R01MH074692, T32MH019524] Funding Source: NIH RePORTER
NR 25
TC 228
Z9 267
U1 2
U2 102
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 16
PY 2015
VL 520
IS 7547
BP 345
EP +
DI 10.1038/nature14106
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG0RI
UT WOS:000352974200038
PM 25607357
DA 2026-03-09
ER

PT J
AU Lehar, SM
   Pillow, T
   Xu, M
   Staben, L
   Kajihara, KK
   Andlen, RV
   DePalatis, L
   Raab, H
   Hazenbos, WL
   Morisaki, JH
   Kim, J
   Park, S
   Darwish, M
   Lee, BC
   Hernandez, H
   Loyet, KM
   Lupardus, P
   Fong, RN
   Yan, DH
   Halouni, CC
   Luis, E
   Khalfin, Y
   Plise, E
   Heong, JC
   Lyssikatos, JP
   Strandh, M
   Koefoed, K
   Andersen, PS
   Flygare, JA
   Tan, MW
   Brown, EJ
   Ariathasan, SM
AF Lehar, Sophie M.
   Pillow, Thomas
   Xu, Min
   Staben, Leanna
   Kajihara, Kimberly K.
   Andlen, Richard V.
   DePalatis, Laura
   Raab, Helga
   Hazenbos, Wouter L.
   Morisaki, J. Hiroshi
   Kim, Janice
   Park, Summer
   Darwish, Martine
   Lee, Byoung-Chul
   Hernandez, Hilda
   Loyet, Kelly M.
   Lupardus, Patrick
   Fong, Rina
   Yan, Donghong
   Halouni, Cecile C.
   Luis, Elizabeth
   Khalfin, Yana
   Plise, Emile
   Heong, Jonathan C.
   Lyssikatos, Joseph P.
   Strandh, Magnus
   Koefoed, Klaus
   Andersen, Peter S.
   Flygare, John A.
   Tan, Man Wah
   Brown, Eric J.
   Ariathasan, Sanjeev M.
TI Novel antibody-antibiotic conjugate eliminates intracellular S. aureus
SO NATURE
LA English
DT Article
ID staphylococcus-aureus; bacteremia; internalization; phagocytosis; persisters; predictors; rifampicin; recurrent; survival; model
AB Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S. aureus within host cells may provide a reservoir relatively protected from antibiotics, thus enabling long-term colonization of the host and explaining clinical failures and relapses after antibiotic therapy. Here we confirm that intracellular reservoirs of S. aureus in mice comprise a virulent subset of bacteria that can establish infection even in the presence of vancomycin, and we introduce a novel therapeutic that effectively kills intracellular S. aureus. This antibody-antibiotic conjugate consists of an anti-S. aureus antibody conjugated to a highly efficacious antibiotic that is activated only after it is released in the proteolytic environment of the phagolysosome. The antibody-antibiotic conjugate is superior to vancomycin for treatment of bacteraemia and provides direct evidence that intracellular S. aureus represents an important component of invasive infections.
C1 [Lehar, Sophie M.; Kajihara, Kimberly K.; Hazenbos, Wouter L.; Morisaki, J. Hiroshi; Tan, Man Wah; Brown, Eric J.; Ariathasan, Sanjeev M.] Genentech Inc, Dept Infect Dis, San Francisco, CA 94080 USA.
   [Pillow, Thomas; Staben, Leanna; Lyssikatos, Joseph P.; Flygare, John A.] Genentech Inc, Dept Med Chem, San Francisco, CA 94080 USA.
   [Xu, Min; Kim, Janice; Park, Summer; Yan, Donghong] Genentech Inc, Translat Immunol Dept, San Francisco, CA 94080 USA.
   [Andlen, Richard V.; DePalatis, Laura; Raab, Helga; Darwish, Martine; Lee, Byoung-Chul; Luis, Elizabeth] Genentech Inc, Dept Prot Chem, San Francisco, CA 94080 USA.
   [Hernandez, Hilda; Loyet, Kelly M.; Khalfin, Yana] Genentech Inc, Biochem & Cellular Pharmacol Dept, San Francisco, CA 94080 USA.
   [Lupardus, Patrick; Fong, Rina] Genentech Inc, Dept Biol Struct, San Francisco, CA 94080 USA.
   [Halouni, Cecile C.] Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA.
   [Plise, Emile; Heong, Jonathan C.] Genentech Inc, Drug Metab & Pharmacokinet Dept, San Francisco, CA 94080 USA.
   [Strandh, Magnus; Koefoed, Klaus; Andersen, Peter S.] Symphogen AS, DK-2750 Ballerup, Denmark.
C3 Roche Holding; Roche Holding USA; Genentech; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech; Symphogen
RP Brown, EJ (corresponding author), Genentech Inc, Dept Infect Dis, San Francisco, CA 94080 USA.
EM brown.eric@gene.com; sanj@gene.com
FU DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
NR 45
TC 698
Z9 798
U1 9
U2 492
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 19
PY 2015
VL 527
IS 7578
BP 323
EP +
DI 10.1038/nature16057
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9ZN
UT WOS:000365356800045
PM 26536114
DA 2026-03-09
ER

PT J
AU Medley, GF
   Hollingsworth, TD
   Olliaro, PL
   Adams, ER
AF Medley, Graham F.
   Hollingsworth, T. Deirdre
   Olliaro, Piero L.
   Adams, Emily R.
TI Health-seeking behaviour, diagnostics and transmission dynamics in the control of visceral leishmaniasis in the Indian subcontinent
SO NATURE
LA English
DT Article
ID elimination; metaanalysis; management; outbreak; bihar; nepal
AB Countries in the Indian subcontinent have committed to reducing the incidence of kala-azar, a clinical manifestation of visceral leishmaniasis, to below 1 in 10,000 by 2020. We address the role of timing of use and accuracy of diagnostics in kala-azar control and elimination. We use empirical data on health-seeking behaviour and health-system performance from the Indian state of Bihar, Bangladesh and Nepal to parameterize a mathematical model. Diagnosis of cases is key to case management, control and surveillance. Treatment of cases prevents onward transmission, and we show that the differences in time to diagnosis in these three settings explain the observed differences in incidence. Shortening the time from health-care seeking to diagnosis is likely to lead to dramatic reductions in incidence in Bihar, bringing the incidence down to the levels seen in Bangladesh and Nepal. The results emphasize the importance of maintaining population and health-system awareness, particularly as transmission and disease incidence decline. We explore the possibility of diagnosing patients before the onset of clinical kala-azar (before 14 days fever), and show that this could have a marked impact on incidence, even for a moderately sensitive test. However, limited specificity (that results in false positives) is a major barrier to such a strategy. Diagnostic tests of high specificity used at an early stage of active infection, even if sensitivity is only moderate, could have a key role in the control of kala-azar, and prevent its resurgence when paired with the passive health-care system and tests of high sensitivity, such as the test for rK39 antibody response.
C1 [Medley, Graham F.] Univ London London Sch Hyg & Trop Med, Global Hlth & Dev, London WC1E 7HT, England.
   [Hollingsworth, T. Deirdre; Adams, Emily R.] Univ Warwick, Sch Life Sci, WIDER, Coventry CV4 7AL, W Midlands, England.
   [Hollingsworth, T. Deirdre] Univ Warwick, Warwick Math Inst, Coventry CV4 7AL, W Midlands, England.
   [Olliaro, Piero L.] WHO, WHO Special Programme Res & Training Trop Dis TDR, World Bank, UNICEF,UNDP, CH-1211 Geneva, Switzerland.
   [Olliaro, Piero L.] Univ Oxford, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford OX3 7FZ, England.
   [Adams, Emily R.] Univ Liverpool, Liverpool Sch Trop Med, Dept Parasitol, Res Ctr Drugs & Diagnost, Liverpool L3 5QA, Merseyside, England.
C3 University of London; London School of Hygiene & Tropical Medicine; University of Warwick; University of Warwick; World Health Organization; The World Bank; University of Oxford; Liverpool School of Tropical Medicine; University of Liverpool
RP Adams, ER (corresponding author), Univ Warwick, Sch Life Sci, WIDER, Coventry CV4 7AL, W Midlands, England.
EM emily.adams@lstmed.ac.uk
FU Bill and Melinda Gates Foundation through the Diagnostics Modelling Consortium based at Imperial College; NTD Modelling Consortium by the Bill and Melinda Gates Foundation; Task Force for Global Health
NR 22
TC 60
Z9 67
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 DEC 3
PY 2015
VL 528
IS 7580
BP S102
EP S108
DI 10.1038/nature16042
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000017
PM 26633763
DA 2026-03-09
ER

PT J
AU Guo, X
   Wang, L
   Li, J
   Ding, ZY
   Xiao, JX
   Yin, XT
   He, S
   Shi, P
   Dong, LP
   Li, GH
   Tian, CL
   Wang, JW
   Cong, Y
   Xu, YH
AF Guo, Xue
   Wang, Ling
   Li, Jie
   Ding, Zhanyu
   Xiao, Jianxiong
   Yin, Xiaotong
   He, Shuang
   Shi, Pan
   Dong, Liping
   Li, Guohong
   Tian, Changlin
   Wang, Jiawei
   Cong, Yao
   Xu, Yanhui
TI Structural insight into autoinhibition and histone H3-induced activation of DNMT3A
SO NATURE
LA English
DT Article
ID de-novo methylation; dna methylation; patterns; expression; methyltransferases; software; domain; model; h3
AB DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance(1-5). Mammalian genomic DNA methylation is established during embryogenesis by de novo DNA methyltransferases, DNMT3A and DNMT3B(6-8), and the methylation patterns vary with developmental stages and cell types(9-12). DNAmethyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a(13). Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation(14). The ATRX-DNMT3-DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0)(15-17). The histone H3 tail stimulates the enzymatic activity of Dnmt3a in vitro(17,18), whereas the molecular mechanism remains elusive. Here we show that DNMT3A exists in an autoinhibitory form and that the histone H3 tail stimulates its activity in a DNMT3L-independent manner. We determine the crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 angstrom resolution, respectively. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalyticdomain (CD) through blocking its DNA-binding affinity. HistoneH3(but not H3K4me3) disrupts ADD-CD interaction, induces a large movement of the ADD domain, and thus releases the autoinhibition of DNMT3A. The finding adds another layer of regulation of DNA methylation to ensure that the enzyme is mainly activated at proper targeting loci when unmethylated H3K4 is present, and strongly supports a negative correlation between H3K4me3 and DNA methylation across the mammalian genome(9,10,19,20). Our study provides a new insight into an unexpected autoinhibition and histone H3-induced activation of the de novo DNA methyltransferase after its initial genomic positioning.
C1 [Guo, Xue; Wang, Ling; Li, Jie; Xiao, Jianxiong; Yin, Xiaotong; He, Shuang; Xu, Yanhui] Fudan Univ, Shanghai Med Coll, Inst Biomed Sci, Shanghai Canc Ctr, Shanghai 200032, Peoples R China.
   [Guo, Xue; Wang, Ling; Xu, Yanhui] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China.
   [Ding, Zhanyu; Cong, Yao] Chinese Acad Sci, Shanghai Inst Biol Sci, Natl Ctr Prot Sci Shanghai, State Key Lab Mol Biol,Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China.
   [Shi, Pan; Tian, Changlin] Chinese Acad Sci, High Magnet Field Lab, Hefei 230031, Peoples R China.
   [Shi, Pan; Tian, Changlin] Univ Sci & Technol China, Natl Lab Phys Sci Microscale, Hefei 230026, Peoples R China.
   [Shi, Pan; Tian, Changlin] Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Peoples R China.
   [Dong, Liping; Li, Guohong] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China.
   [Dong, Liping] Univ Chinese Acad Sci, Beijing 100049, Peoples R China.
   [Wang, Jiawei] Tsinghua Univ, Sch Life Sci, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100084, Peoples R China.
C3 Fudan University; Fudan University; Chinese Academy of Sciences; Center for Excellence in Molecular Cell Science, CAS; Chinese Academy of Sciences; Hefei Institutes of Physical Science, 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; Institute of Biophysics, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Tsinghua University
RP Xu, YH (corresponding author), Fudan Univ, Shanghai Med Coll, Inst Biomed Sci, Shanghai Canc Ctr, Shanghai 200032, Peoples R China.
EM xuyh@fudan.edu.cn
FU National Basic Research Program of China [2011CB965300, 2009CB918600, 2013CB910401]; National Science & Technology Major Project 'Key New Drug Creation and Manufacturing Program' of China [2014ZX09507-002, 2011ZX09506-001]; National Natural Science Foundation of China [31270779, 91419301, 31030019, U1432242, 31270771, 31222016, 31300685, U1332138]; Basic Research Project of Shanghai Science and Technology Commission [12JC1402700, 13JC1406300]; Fok Ying Tung Education Foundation [20090071220012]; Chinese Academy of Sciences Pilot Strategic Science and Technology Projects B [XDB08030201, XDB08030302]
NR 43
TC 280
Z9 349
U1 2
U2 181
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 29
PY 2015
VL 517
IS 7536
BP 640
EP U281
DI 10.1038/nature13899
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA2ZL
UT WOS:000348775000049
PM 25383530
DA 2026-03-09
ER

PT J
AU Schmoller, KM
   Turner, JJ
   Koivomägi, M
   Skotheim, JM
AF Schmoller, Kurt M.
   Turner, J. J.
   Koivomaegi, M.
   Skotheim, Jan M.
TI Dilution of the cell cycle inhibitor Whi5 controls budding-yeast cell size
SO NATURE
LA English
DT Article
ID saccharomyces-cerevisiae; g(1) cyclin; cln3; growth; transcription; cdk; g1; division; genes; phosphorylation
AB Cell size fundamentally affects all biosynthetic processes by determining the scale of organelles and influencing surface transport(1,2). Although extensive studies have identified many mutations affecting cell size, the molecular mechanisms underlying size control have remained elusive(3). In the budding yeast Saccharomyces cere-visiae, size control occurs in G1 phase before Start, the point of irreversible commitment to cell division(4,5). It was previously thought that activity of the G1 cyclin Cln3 increased with cell size to trigger Start by initiating the inhibition of the transcriptional inhibitor Whi5 (refs 6-8). Here we show that although Cln3 concentration does modulate the rate at which cells pass Start, its synthesis increases in proportion to cell size so that its total concentration is nearly constant during pre-Start G1. Rather than increasing Cln3 activity, we identify decreasing Whi5 activity-due to the dilution of Whi5 by cell growth-as a molecular mechanism through which cell size controls proliferation. Whi5 is synthesized in S/G2/M phases of the cell cycle in a largely size-independent manner. This results in smaller daughter cells being born with higher Whi5 concentrations that extend their pre-Start G1 phase. Thus, at its most fundamental level, size control in budding yeast results from the differential scaling of Cln3 and Whi5 synthesis rates with cell size. More generally, our work shows that differential size-dependency of protein synthesis can provide an elegant mechanism to coordinate cellular functions with growth.
C1 [Schmoller, Kurt M.; Turner, J. J.; Koivomaegi, M.; Skotheim, Jan M.] Stanford Univ, Dept Biol, Stanford, CA 94305 USA.
C3 Stanford University
RP Skotheim, JM (corresponding author), Stanford Univ, Dept Biol, Stanford, CA 94305 USA.
EM skotheim@stanford.edu
FU Burroughs Wellcome Fund (CASI); National Science Foundation (CAREER); National Institutes of Health [GM007276]; Human Frontier Science Program; National Institute of General Medical Sciences [T32GM007276] Funding Source: NIH RePORTER
NR 37
TC 223
Z9 287
U1 0
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 OCT 8
PY 2015
VL 526
IS 7572
BP 268
EP +
DI 10.1038/nature14908
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS9GV
UT WOS:000362399000050
PM 26390151
DA 2026-03-09
ER

PT J
AU Kim, MS
   Lapkouski, M
   Yang, W
   Gellert, M
AF Kim, Min-Sung
   Lapkouski, Mikalai
   Yang, Wei
   Gellert, Martin
TI Crystal structure of the V(D)J recombinase RAG1-RAG2
SO NATURE
LA English
DT Article
ID dna hairpin formation; amino-acid-residues; single active-site; mutational analysis; binding domain; rag2 proteins; complex; transposition; cleavage; rag1/2
AB V(D)J recombination in the vertebrate immune system generates a highly diverse population of immunoglobulins and T-cell receptors by combinatorial joining of segments of coding DNA. The RAG1-RAG2 protein complex initiates this site-specific recombination by cutting DNA at specific sites flanking the coding segments. Here we report the crystal structure of the mouse RAG1-RAG2 complex at 3.2A resolution. The 230-kilodalton RAG1-RAG2 heterotetramer is 'Y-shaped', with the amino-terminal domains of the two RAG1 chains forming an intertwined stalk. Each RAG1-RAG2 heterodimer composes one arm of the 'Y', with the active site in the middle and RAG2 at its tip. The RAG1-RAG2 structure rationalizes more than 60 mutations identified in immunodeficient patients, as well as a large body of genetic and biochemical data. The architectural similarity between RAG1 and the hairpin-forming transposases Hermes and Tn5 suggests the evolutionary conservation of these DNA rearrangements.
C1 [Kim, Min-Sung; Lapkouski, Mikalai; Yang, Wei; Gellert, Martin] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
RP Yang, W (corresponding author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA.
EM wei.yang@nih.gov; gellert@helix.nih.gov
FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases [ZIADK036147, ZIADK036167] Funding Source: NIH RePORTER
NR 45
TC 128
Z9 147
U1 4
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 FEB 26
PY 2015
VL 518
IS 7540
BP 507
EP 511
DI 10.1038/nature14174
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC1JP
UT WOS:000350097300040
PM 25707801
DA 2026-03-09
ER

PT J
AU Linari, M
   Brunello, E
   Reconditi, M
   Fusi, L
   Caremani, M
   Narayanan, T
   Piazzesi, G
   Lombardi, V
   Irving, M
AF Linari, Marco
   Brunello, Elisabetta
   Reconditi, Massimo
   Fusi, Luca
   Caremani, Marco
   Narayanan, Theyencheri
   Piazzesi, Gabriella
   Lombardi, Vincenzo
   Irving, Malcolm
TI Force generation by skeletal muscle is controlled by mechanosensing in myosin filaments
SO NATURE
LA English
DT Article
ID x-ray-diffraction; sarcomere-length dependence; vertebrate striated-muscle; structural-changes; thick-filament; cross-bridges; active force; fibers; contraction; frog
AB Contraction of both skeletal muscle and the heart is thought to be controlled by a calcium-dependent structural change in the actin-containing thin filaments, which permits the binding of myosin motors from the neighbouring thick filaments to drive filament sliding(1-3). Here we show by synchrotron small-angle X-ray diffraction of frog (Rana temporaria) single skeletal muscle cells that, although the well-known thin-filament mechanism is sufficient for regulation of muscle shortening against low load, force generation against high load requires a second permissive step linked to a change in the structure of the thick filament. The resting (switched 'OFF') structure of the thick filament is characterized by helical tracks of myosin motors on the filament surface and a short backbone periodicity(2,4,5). This OFF structure is almost completely preserved during low-load shortening, which is driven by a small fraction of constitutively active (switched 'ON') myosin motors outside thick-filament control. At higher load, these motors generate sufficient thick-filament stress to trigger the transition to its long-periodicity ON structure, unlocking the major population of motors required for high-load contraction. This concept of the thick filament as a regulatory mechanosensor provides a novel explanation for the dynamic and energetic properties of skeletal muscle. A similar mechanism probably operates in the heart.
C1 [Linari, Marco; Brunello, Elisabetta; Reconditi, Massimo; Caremani, Marco; Piazzesi, Gabriella; Lombardi, Vincenzo] Univ Florence, Dept Biol, Physiol Lab, I-50019 Florence, Italy.
   [Linari, Marco; Reconditi, Massimo] UdR Firenze, Consorzio Nazl Interuniv Sci Fis Mat, I-50019 Florence, Italy.
   [Fusi, Luca; Irving, Malcolm] Kings Coll London, Randall Div, London SE1 1UL, England.
   [Fusi, Luca; Irving, Malcolm] Kings Coll London, BHF Ctr Res Excellence, London SE1 1UL, England.
   [Narayanan, Theyencheri] European Synchrotron Radiat Facil, F-38043 Grenoble, France.
C3 University of Florence; University of London; King's College London; University of London; King's College London; European Synchrotron Radiation Facility (ESRF)
RP Lombardi, V (corresponding author), Univ Florence, Dept Biol, Physiol Lab, I-50019 Florence, Italy.
EM vincenzo.lombardi@unifi.it
FU Ente Cassa di Risparmio di Firenze [2010.1402]; FIRB-Futuro in Ricerca project [RBFR08JAMZ]; MIUR-PRIN project (Italy) [2010R8JK2X]; MRC (UK); ESRF; MRC [G0601065] Funding Source: UKRI; Medical Research Council [G0601065] Funding Source: researchfish
NR 25
TC 251
Z9 290
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 DEC 10
PY 2015
VL 528
IS 7581
BP 276
EP +
DI 10.1038/nature15727
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX9VH
UT WOS:000366053300044
PM 26560032
DA 2026-03-09
ER

PT J
AU Brestoff, JR
   Kim, BS
   Saenz, SA
   Stine, RR
   Monticelli, LA
   Sonnenberg, GF
   Thome, JJ
   Farber, DL
   Lutfy, K
   Seale, P
   Artis, D
AF Brestoff, Jonathan R.
   Kim, Brian S.
   Saenz, Steven A.
   Stine, Rachel R.
   Monticelli, Laurel A.
   Sonnenberg, Gregory F.
   Thome, Joseph J.
   Farber, Donna L.
   Lutfy, Kabirullah
   Seale, Patrick
   Artis, David
TI Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity
SO NATURE
LA English
DT Article
ID type-2; fat; eosinophils; brown; homeostasis; expression; ablation; glucose; unique; ucp1
AB Obesity is an increasingly prevalent disease regulated by genetic and environmental factors. Emerging studies indicate that immune cells, including monocytes, granulocytes and lymphocytes, regulate metabolic homeostasis and are dysregulated in obesity(1,2). Group 2 innate lymphoid cells (ILC2s) can regulate adaptive immunity(3,4) and eosinophil and alternatively activated macrophage responses(5), and were recently identified in murine white adipose tissue (WAT)(5) where they may act to limit the development of obesity(6). However, ILC2s have not been identified inhuman adipose tissue, and the mechanisms by which ILC2s regulate metabolic homeostasis remain unknown. Here we identify ILC2s in human WAT and demonstrate that decreased ILC2 responses in WAT are a conserved characteristic of obesity in humans and mice. Interleukin (IL)-33 was found to be critical for the maintenance of ILC2s in WAT and in limiting adiposity in mice by increasing caloric expenditure. This was associated with recruitment of uncoupling protein 1 (UCP1)(+) beige adipocytes in WAT, a process known as beiging or browning that regulates caloric expenditure(7-9). IL-33-induced beiging was dependent on ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was sufficient to drive beiging independently of the adaptive immune system, eosinophils or IL-4 receptor signalling. We found that ILC2s produce methionine-enkephalin peptides that can act directly on adipocytes to upregulate Ucp1 expression in vitro and that promote beiging in vivo. Collectively, these studies indicate that, in addition to responding to infection or tissue damage, ILC2s can regulate adipose function and metabolic homeostasis in part via production of enkephalin peptides that elicit beiging.
C1 [Brestoff, Jonathan R.; Monticelli, Laurel A.; Sonnenberg, Gregory F.; Artis, David] Cornell Univ, Weill Cornell Med Coll, Dept Microbiol & Immunol, Jill Roberts Inst Res IBD,Joan & Sanford I Weill, New York, NY 10021 USA.
   [Brestoff, Jonathan R.; Kim, Brian S.; Saenz, Steven A.; Monticelli, Laurel A.; Artis, David] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA.
   [Brestoff, Jonathan R.; Kim, Brian S.; Saenz, Steven A.; Monticelli, Laurel A.; Artis, David] Univ Penn, Inst Immunol, Perelman Sch Med, Philadelphia, PA 19104 USA.
   [Stine, Rachel R.; Seale, Patrick] Univ Penn, Perelman Sch Med, Dept Cell & Dev Biol, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA.
   [Thome, Joseph J.; Farber, Donna L.] Columbia Univ, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 10032 USA.
   [Thome, Joseph J.; Farber, Donna L.] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA.
   [Farber, Donna L.] Columbia Univ, Med Ctr, Dept Surg, New York, NY 10032 USA.
   [Lutfy, Kabirullah] Western Univ Hlth Sci, Coll Pharm, Dept Pharmaceut Sci, Pomona, CA 91766 USA.
C3 Cornell University; Weill Cornell Medicine; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; Columbia University; Columbia University; Columbia University; Western University of Health Sciences
RP Artis, D (corresponding author), Cornell Univ, Weill Cornell Med Coll, Dept Microbiol & Immunol, Jill Roberts Inst Res IBD,Joan & Sanford I Weill, New York, NY 10021 USA.
EM dartis@med.cornell.edu
FU National Institutes of Health [AI061570, AI074878, AI095466, AI095608, AI102942, AI097333]; Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Disease Award; Crohn's & Colitis Foundation of America; NIH [F30-AI112023, T32-AI060516, T32-AI007532, KL2-RR024132, DP5OD012116, P01AI06697, F31AG047003, DP2OD007288]; Searle Scholars Award; Penn Diabetes Endocrine Research Center [P30DK19525]; NCI Comprehensive Cancer Center Support Grant [2-P30 CA016520]; NIH/NIDDK P30 Center for Molecular Studies in Digestive and Liver Diseases [P30-DK050306]; National Cancer Institute [P30CA016520] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [R01AI095466, P01AI106697, U01AI095608, T32AI007532] Funding Source: NIH RePORTER; National Institute of Arthritis and Musculoskeletal and Skin Diseases [T32AR007465] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK019525, P30DK050306] Funding Source: NIH RePORTER
NR 34
TC 780
Z9 909
U1 3
U2 234
PU NATURE PUBLISHING 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 12
PY 2015
VL 519
IS 7542
BP 242
EP +
DI 10.1038/nature14115
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500041
PM 25533952
DA 2026-03-09
ER

PT J
AU Pineda, JE
   Offner, SSR
   Parker, RJ
   Arce, HG
   Goodman, AA
   Caselli, P
   Fuller, GA
   Bourke, TL
   Corder, SA
AF Pineda, Jaime E.
   Offner, Stella S. R.
   Parker, Richard J.
   Arce, Hector G.
   Goodman, Alyssa A.
   Caselli, Paola
   Fuller, Gary A.
   Bourke, Tyler L.
   Corder, Stuartt A.
TI The formation of a quadruple star system with wide separation
SO NATURE
LA English
DT Article
ID stellar multiplicity; protostellar outflow; embedded protostars; molecular clouds; mass function; binary stars; dense cores; large array; evolution; fragmentation
AB The initial multiplicity of stellar systems is highly uncertain. A number of mechanisms have been proposed to explain the origin of binary and multiple star systems, including core fragmentation, disk fragmentation and stellar capture(1-3). Observations show that protostellar and pre-main-sequence multiplicity is higher than the multiplicity found in field stars(4-7), which suggests that dynamical interactions occur early, splitting up multiple systems and modifying the initial stellar separations(8,9). Without direct, high-resolution observations of forming systems, however, it is difficult to determine the true initial multiplicity and the dominant binary formation mechanism. Here we report observations of a wide-separation (greater than 1,000 astronomical units) quadruple system composed of a young protostar and three gravitationally bound dense gas condensations. These condensations are the result of fragmentation of dense gas filaments, and each condensation is expected to forma star on a time-scale of 40,000 years. We determine that the closest pair will form a bound binary, while the quadruple stellar system itself is bound but unstable on timescales of 500,000 years (comparable to the lifetime of the embedded protostellar phase(10)). These observations suggest that filament fragmentation on length scales of about 5,000 astronomical units offers a viable pathway to the formation of multiple systems.
C1 [Pineda, Jaime E.] ETH, Inst Astron, CH-8093 Zurich, Switzerland.
   [Offner, Stella S. R.; Arce, Hector G.] Yale Univ, Dept Astron, New Haven, CT 06520 USA.
   [Offner, Stella S. R.] Univ Massachusetts, Dept Astron, Amherst, MA 01003 USA.
   [Parker, Richard J.] Liverpool John Moores Univ, Astrophys Res Inst, Liverpool L3 5RF, Merseyside, England.
   [Goodman, Alyssa A.; Bourke, Tyler L.] Harvard Smithsonian Ctr Astrophys, Cambridge, MA 02138 USA.
   [Caselli, Paola] Max Planck Inst Extraterr Phys MPE, D-85741 Garching, Germany.
   [Fuller, Gary A.] Univ Manchester, Sch Phys & Astron, Jodrell Bank Ctr Astrophys, UK ARC Node, Manchester M13 9PL, Lancs, England.
   [Bourke, Tyler L.] Jodrell Bank Observ, SKA Org, Macclesfield SK11 9DL, Cheshire, England.
   [Corder, Stuartt A.] Joint ALMA Observ, Santiago, Chile.
   [Corder, Stuartt A.] Natl Radio Astron Observ, Charlottesville, VA 22903 USA.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich; Yale University; University of Massachusetts System; University of Massachusetts Amherst; Liverpool John Moores University; Smithsonian Institution; Harvard University; Smithsonian Astrophysical Observatory; Max Planck Society; University of Manchester; Jodrell Bank Centre for Astrophysics; University of Manchester; Jodrell Bank Centre for Astrophysics; National Radio Astronomy Observatory (NRAO)
RP Pineda, JE (corresponding author), ETH, Inst Astron, Wolfgang Pauli Str 27, CH-8093 Zurich, Switzerland.
EM jpineda@mpe.mpg.de
FU Swiss National Science Foundation [CRSII2_141880]; NSF CAREER award [AST-0845619]; NSF [AST-0908159]; ERC [PALs 320620]; NASA [NNX09AB89G, 51311.01, NAS 5-26555]; Space Telescope Science Institute; Royal Astronomical Society; Canada Foundation for Innovation; Swiss National Science Foundation (SNF) [CRSII2_141880] Funding Source: Swiss National Science Foundation (SNF); STFC [ST/L000768/1] Funding Source: UKRI; NASA [120872, NNX09AB89G] Funding Source: Federal RePORTER; Science and Technology Facilities Council [ST/L000768/1] Funding Source: researchfish
NR 30
TC 103
Z9 109
U1 0
U2 6
PU NATURE PUBLISHING 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 12
PY 2015
VL 518
IS 7538
BP 213
EP U447
DI 10.1038/nature14166
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300033
PM 25673415
DA 2026-03-09
ER

PT J
AU Mire, CE
   Matassov, D
   Geisbert, JB
   Latham, TE
   Agans, KN
   Xu, R
   Ota-Setlik, A
   Egan, MA
   Fenton, KA
   Clarke, DK
   Eldridge, JH
   Geisbert, TW
AF Mire, Chad E.
   Matassov, Demetrius
   Geisbert, Joan B.
   Latham, Theresa E.
   Agans, Krystle N.
   Xu, Rong
   Ota-Setlik, Ayuko
   Egan, Michael A.
   Fenton, Karla A.
   Clarke, David K.
   Eldridge, John H.
   Geisbert, Thomas W.
TI Single-dose attenuated Vesiculovax vaccines protect primates against Ebola Makona virus
SO NATURE
LA English
DT Article
ID stomatitis-virus; neurovirulence; immunogenicity; vectors
AB The family Filoviridae contains three genera, Ebolavirus, Marburgvirus, and Cuevavirusl. Some members of the genus, including Zaire ebolavirus (ZEBOV), can cause lethal haemorrhagic fever in humans. During 2014 an unprecedented ZEBOV outbreak occurred in West Africa and is still ongoing, resulting in over 10,000 deaths, and causing global concern of uncontrolled disease. To meet this challenge a rapid-acting vaccine is needed. Many vaccine approaches have shown promise in being able to protect nonhuman primates against ZEBOV2. In response to the current ZEBOV outbreak several of these vaccines have been fast tracked for human use. However, it is not known whether any of these vaccines can provide protection against the new outbreak Makona strain of ZEBOV. One of these approaches is a first-generation recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing the ZEBOV glycoprotein (GP) (rVSV/ZEBOV). To address safety concerns associated with this vector, we developed two candidate, further-attenuated rVSV/ZEBOV vaccines. Both attenuated vaccines produced an approximately tenfold lower vaccine-associated viraemia compared to the first-generation vaccine and both provided complete, single-dose protection of macaques from lethal challenge with the Makona outbreak strain of ZEBOV.
C1 [Mire, Chad E.; Geisbert, Joan B.; Agans, Krystle N.; Fenton, Karla A.; Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA.
   [Mire, Chad E.; Geisbert, Joan B.; Agans, Krystle N.; Fenton, Karla A.; Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA.
   [Matassov, Demetrius; Latham, Theresa E.; Clarke, David K.; Eldridge, John H.] Profectus BioSci Inc, Dept Virol & Vaccine Vectors, Tarrytown, NY 10591 USA.
   [Xu, Rong; Ota-Setlik, Ayuko; Egan, Michael A.; Eldridge, John H.] Profectus BioSci Inc, Dept Immunol, Tarrytown, NY 10591 USA.
C3 University of Texas System; University of Texas Medical Branch Galveston; University of Texas System; University of Texas Medical Branch Galveston
RP Geisbert, TW (corresponding author), Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA.
EM twgeisbe@utmb.edu
FU Department of Microbiology and Immunology at UTMB; Department of Health and Human Services, National Institutes of Health [R01AI09881701]
NR 21
TC 77
Z9 88
U1 0
U2 24
PU NATURE PUBLISHING 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 30
PY 2015
VL 520
IS 7549
BP 688
EP U253
DI 10.1038/nature14428
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700052
PM 25853476
DA 2026-03-09
ER

PT J
AU Schumacher, MA
   Balani, P
   Min, JK
   Chinnam, NB
   Hansen, S
   Vulic, M
   Lewis, K
   Brennan, RG
AF Schumacher, Maria A.
   Balani, Pooja
   Min, Jungki
   Chinnam, Naga Babu
   Hansen, Sonja
   Vulic, Marin
   Lewis, Kim
   Brennan, Richard G.
TI HipBA-promoter structures reveal the basis of heritable multidrug tolerance
SO NATURE
LA English
DT Article
ID escherichia-coli k-12; persister cells; affects lethality; affects frequency; protein-dna; inhibition; mechanisms; peptidoglycan; strains; operon
AB Multidrug tolerance is largely responsible for chronic infections and caused by a small population of dormant cells called persisters. Selection for survival in the presence of antibiotics produced the first genetic link to multidrug tolerance: a mutant in the Escherichia coli hipA locus. HipA encodes a serine-protein kinase, the multidrug tolerance activity of which is neutralized by binding to the transcriptional regulator HipB and hipBA promoter. The physiological role of HipA in multidrug tolerance, however, has been unclear. Here we show that wild-type HipA contributes to persister formation and that high-persister hipA mutants cause multidrug tolerance in urinary tract infections. Perplexingly, high-persister mutations map to the N-subdomain-1 of HipA far from its active site. Structures of higher-order HipA-HipB-promoter complexes reveal HipA forms dimers in these assemblies via N-subdomain-1 interactions that occlude their active sites. High-persistence mutations, therefore, diminish HipA-HipA dimerization, thereby unleashing HipA to effect multidrug tolerance. Thus, our studies reveal the mechanistic basis of heritable, clinically relevant antibiotic tolerance.
C1 [Schumacher, Maria A.; Min, Jungki; Chinnam, Naga Babu; Brennan, Richard G.] Duke Univ, Sch Med, Dept Biochem, Durham, NC 27710 USA.
   [Balani, Pooja; Hansen, Sonja; Vulic, Marin; Lewis, Kim] Northeastern Univ, Dept Biol, Antimicrobial Discovery Ctr, Boston, MA 02115 USA.
C3 Duke University; Northeastern University
RP Schumacher, MA (corresponding author), Duke Univ, Sch Med, Dept Biochem, Durham, NC 27710 USA.
EM maria.schumacher@duke.edu; k.lewis@neu.edu; Richard.brennan@duke.edu
FU NIAID-GSCID; MD Anderson Trust; Welch Foundation [G-0040]; Duke University School of Medicine; National Institutes of Health [T-R01 AI085585, R01GM061162]; Army Research Office [W911NF-09-1-0278]
NR 44
TC 188
Z9 242
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 AUG 6
PY 2015
VL 524
IS 7563
BP 59
EP U108
DI 10.1038/nature14662
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO2QS
UT WOS:000359002300031
PM 26222023
DA 2026-03-09
ER

PT J
AU Neumann, B
   Coakley, S
   Giordano-Santini, R
   Linton, C
   Lee, ES
   Nakagawa, A
   Xue, D
   Hilliard, MA
AF Neumann, Brent
   Coakley, Sean
   Giordano-Santini, Rosina
   Linton, Casey
   Lee, Eui Seung
   Nakagawa, Akihisa
   Xue, Ding
   Hilliard, Massimo A.
TI EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway
SO NATURE
LA English
DT Article
ID cell corpse engulfment; caenorhabditis-elegans; c-elegans; sensory neurons; fusogen eff-1; receptor; phosphatidylserine; phagocytosis; migration; jmjd6
AB Functional regeneration after nervous system injury requires transected axons to reconnect with their original target tissue. Axonal fusion, a spontaneous regenerative mechanism identified in several species, provides an efficient means of achieving target reconnection as a regrowing axon is able to contact and fuse with its own separated axon fragment, thereby re-establishing the original axonal tract(1-7). Here we report a molecular characterization of this process in Caenorhabditis elegans, revealing dynamic changes in the subcellular localization of the EFF-1 fusogen after axotomy, and establishing phosphatidylserine (PS) and the PS receptor (PSR-1) as critical components for axonal fusion. PSR-1 functions cell-autonomously in the regrowing neuron and, instead of acting in its canonical signalling pathway(8), acts in a parallel phagocytic pathway that includes the transthyretin protein TTR-52, as well as CED-7, NRF-5 and CED-6 (refs 9-12). We show that TTR-52 binds to PS exposed on the injured axon, and can restore fusion several hours after injury. We propose that PS functions as a 'save-me' signal for the distal fragment, allowing conserved apoptotic cell clearance molecules to function in reestablishing axonal integrity during regeneration of the nervous system.
C1 [Neumann, Brent; Coakley, Sean; Giordano-Santini, Rosina; Linton, Casey; Hilliard, Massimo A.] Univ Queensland, Queensland Brain Inst, CJCADR, Brisbane, Qld 4072, Australia.
   [Lee, Eui Seung; Nakagawa, Akihisa; Xue, Ding] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA.
C3 University of Queensland; University of Colorado System; University of Colorado Boulder
RP Hilliard, MA (corresponding author), Univ Queensland, Queensland Brain Inst, CJCADR, Brisbane, Qld 4072, Australia.
EM m.hilliard@uq.edu.au
FU NIH Office of Research Infrastructure Programs [P40 OD010440]; International C. elegans Gene Knockout Consortium; NHMRC [631634, 1068871]; NIH [R01 NS060129, GM059083, GM079097, GM088241]; ARC Future Fellowship [FT110100097]; HFSPO Fellowship [LT000762/2012]; Australian Postgraduate Award; University of Queensland Research Scholarship; ARC LIEF [LE130100078]; Australian Research Council [FT110100097] Funding Source: Australian Research Council; National Health and Medical Research Council (NHMRC) [631634, 1068871] Funding Source: National Health and Medical Research Council (NHMRC); National Health and Medical Research Council of Australia [1068871] Funding Source: NHMRC; National Institute of General Medical Sciences; NIH Office of the Director [P40OD010440] Funding Source: NIH RePORTER
NR 35
TC 103
Z9 133
U1 0
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 JAN 8
PY 2015
VL 517
IS 7533
BP 219
EP U259
DI 10.1038/nature14102
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600040
PM 25567286
DA 2026-03-09
ER

PT J
AU Li, Q
   Chen, L
   Gadinski, MR
   Zhang, SH
   Zhang, GZ
   Li, HY
   Haque, A
   Chen, LQ
   Jackson, TN
   Wang, Q
AF Li, Qi
   Chen, Lei
   Gadinski, Matthew R.
   Zhang, Shihai
   Zhang, Guangzu
   Li, Haoyu
   Haque, Aman
   Chen, Long-Qing
   Jackson, Thomas N.
   Wang, Qing
TI Flexible high-temperature dielectric materials from polymer nanocomposites
SO NATURE
LA English
DT Article
ID energy-storage; electronics; capacitors; ceramics; density; films
AB Dielectric materials, which store energy electrostatically, are ubiquitous in advanced electronics and electric power systems(1-8). Compared to their ceramic counterparts, polymer dielectrics have higher breakdown strengths and greater reliability(1-3,9), are scalable, lightweight and can be shaped into intricate configurations, and are therefore an ideal choice for many power electronics, power conditioning, and pulsed power applications(1,9,10). However, polymer dielectrics are limited to relatively low working temperatures, and thus fail to meet the rising demand for electricity under the extreme conditions present in applications such as hybrid and electric vehicles, aerospace power electronics, and underground oil and gas exploration(11-13). Here we describe crosslinked polymer nanocomposites that contain boron nitride nanosheets, the dielectric properties of which are stable over a broad temperature and frequency range. The nanocomposites have outstanding high-voltage capacitive energy storage capabilities at record temperatures (a Weibull breakdown strength of 403 megavolts per metre and a discharged energy density of 1.8 joules per cubic centimetre at 250 degrees Celsius). Their electrical conduction is several orders of magnitude lower than that of existing polymers and their high operating temperatures are attributed to greatly improved thermal conductivity, owing to the presence of the boron nitride nanosheets, which improve heat dissipation compared to pristine polymers (which are inherently susceptible to thermal runaway). Moreover, the polymer nanocomposites are lightweight, photopatternable and mechanically flexible, and have been demonstrated to preserve excellent dielectric and capacitive performance after intensive bending cycles. These findings enable broader applications of organic materials in high-temperature electronics and energy storage devices.
C1 [Li, Qi; Chen, Lei; Gadinski, Matthew R.; Zhang, Guangzu; Chen, Long-Qing; Wang, Qing] Penn State Univ, Dept Mat Sci & Engn, University Pk, PA 16802 USA.
   [Zhang, Shihai] PolyK Technol, State Coll, PA 16802 USA.
   [Li, Haoyu; Jackson, Thomas N.] Penn State Univ, Dept Elect Engn, University Pk, PA 16802 USA.
   [Haque, Aman] Penn State Univ, Dept Mech & Nucl Engn, University Pk, PA 16802 USA.
C3 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; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park
RP Wang, Q (corresponding author), Penn State Univ, Dept Mat Sci & Engn, University Pk, PA 16802 USA.
EM wang@matse.psu.edu
FU US Office of Naval Research [N00014-11-1-0342]; Air Force Office of Scientific Research [FA9550-14-1-0264]; Dow Chemical Corporation
NR 30
TC 1894
Z9 2020
U1 62
U2 2108
PU NATURE PUBLISHING 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 30
PY 2015
VL 523
IS 7562
BP 576
EP +
DI 10.1038/nature14647
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN7ZL
UT WOS:000358655200041
PM 26223625
DA 2026-03-09
ER

PT J
AU Metzger, BPH
   Yuan, DC
   Gruber, JD
   Duveau, F
   Wittkopp, PJ
AF Metzger, Brian P. H.
   Yuan, David C.
   Gruber, Jonathan D.
   Duveau, Fabien
   Wittkopp, Patricia J.
TI Selection on noise constrains variation in a eukaryotic promoter
SO NATURE
LA English
DT Article
ID saccharomyces-cerevisiae; gene-expression; bioconductor package; regulatory elements; sequence; cis; mutation; dissection; evolution; enhancers
AB Genetic variation segregating within a species reflects the combined activities of mutation, selection, and genetic drift. In the absence of selection, polymorphisms are expected to be a randomsubset of new mutations; thus, comparing the effects of polymorphisms and new mutations provides a test for selection(1-4). When evidence of selection exists, such comparisons can identify properties of mutations that are most likely to persist in natural populations(2). Here we investigate how mutation and selection have shaped variation in a cis-regulatory sequence controlling gene expression by empirically determining the effects of polymorphisms segregating in the TDH3 promoter among 85 strains of Saccharomyces cerevisiae and comparing their effects to a distribution of mutational effects defined by 236 point mutations in the same promoter. Surprisingly, we find that selection on expression noise (that is, variability in expression among genetically identical cells(5)) appears to have had a greater impact on sequence variation in the TDH3 promoter than selection on mean expression level. This is not necessarily because variation in expression noise impacts fitness more than variation in mean expression level, but rather because of differences in the distributions of mutational effects for these two phenotypes. This study shows how systematically examining the effects of new mutations can enrich our understanding of evolutionary mechanisms. It also provides rare empirical evidence of selection acting on expression noise.
C1 [Metzger, Brian P. H.; Gruber, Jonathan D.; Duveau, Fabien; Wittkopp, Patricia J.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA.
   [Yuan, David C.; Wittkopp, Patricia J.] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA.
C3 University of Michigan System; University of Michigan; University of Michigan System; University of Michigan
RP Wittkopp, PJ (corresponding author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA.
EM wittkopp@umich.edu
FU March of Dimes [5-FY07-181]; Alfred P. Sloan Research Foundation; National Science Foundation [MCB-1021398]; National Institutes of Health [1R01 GM108826]; University of Michigan; University of Michigan Rackham Graduate School, Ecology and Evolutionary Biology Department; National Institutes of Health Genome Sciences training grant [T32 HG000040]; National Institutes of Health Genetics training grant [T32 GM007544]; National Institutes of Health National Research Service Award (NRSA) postdoctoral fellowship [1 F32 GM083513-0]; European Molecular Biology Organization postdoctoral fellowship [EMBO ALTF 1114-2012]; National Human Genome Research Institute [T32HG000040] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007544] Funding Source: NIH RePORTER
NR 46
TC 107
Z9 124
U1 0
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 MAY 21
PY 2015
VL 521
IS 7552
BP 344
EP +
DI 10.1038/nature14244
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CI5RM
UT WOS:000354816500054
PM 25778704
DA 2026-03-09
ER

PT J
AU Spellman, T
   Rigotti, M
   Ahmari, SE
   Fusi, S
   Gogos, JA
   Gordon, JA
AF Spellman, Timothy
   Rigotti, Mattia
   Ahmari, Susanne E.
   Fusi, Stefano
   Gogos, Joseph A.
   Gordon, Joshua A.
TI Hippocampal-prefrontal input supports spatial encoding in working memory
SO NATURE
LA English
DT Article
ID ventral hippocampus; theta-oscillations; dorsal hippocampus; population code; cortex; rats; performance; lesions; task; representations
AB Spatial working memory, the caching of behaviourally relevant spatial cues on a timescale of seconds, is a fundamental constituent of cognition. Although the prefrontal cortex and hippocampus are known to contribute jointly to successful spatial working memory, the anatomical pathway and temporal window for the interaction of these structures critical to spatial working memory has not yet been established. Here we find that direct hippocampal-prefrontal afferents are critical for encoding, but not for maintenance or retrieval, of spatial cues in mice. These cues are represented by the activity of individual prefrontal units in a manner that is dependent on hippocampal input only during the cue-encoding phase of a spatial working memory task. Successful encoding of these cues appears to be mediated by gamma-frequency synchrony between the two structures. These findings indicate a critical role for the direct hippocampal-prefrontal afferent pathway in the continuous updating of task-related spatial information during spatial working memory.
C1 [Spellman, Timothy; Gogos, Joseph A.] Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY 10032 USA.
   [Rigotti, Mattia; Fusi, Stefano; Gogos, Joseph A.] Columbia Univ, Dept Neurosci, New York, NY 10032 USA.
   [Rigotti, Mattia] IBM Corp, TJ Watson Res Ctr, Yorktown Hts, NY 10598 USA.
   [Rigotti, Mattia] Columbia Univ, Italian Acad Adv Studies Amer, New York, NY 10032 USA.
   [Ahmari, Susanne E.] Univ Pittsburgh, Dept Psychiat, Translat Neurosci Program, Pittsburgh, PA 15219 USA.
   [Ahmari, Susanne E.] Univ Pittsburgh, Ctr Neurosci, Pittsburgh, PA 15261 USA.
   [Ahmari, Susanne E.] Univ Pittsburgh, Ctr Neural Basis Cognit, Pittsburgh, PA 15261 USA.
   [Fusi, Stefano] Columbia Univ, Kavli Inst Brain Sci, New York, NY 10032 USA.
   [Gordon, Joshua A.] Columbia Univ, Dept Psychiat, New York, NY 10032 USA.
   [Gordon, Joshua A.] New York State Psychiat Inst & Hosp, Div Integrat Neurosci, New York, NY 10032 USA.
C3 Columbia University; Columbia University; International Business Machines (IBM); IBM USA; Columbia University; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Columbia University; Columbia University; New York State Psychiatry Institute
RP Gordon, JA (corresponding author), Columbia Univ, Dept Psychiat, 1051 Riverside Dr, New York, NY 10032 USA.
EM jg343@columbia.edu
FU National Institutes of Health [MH096274, MH081968]; Hope for Depression Research Foundation; International Mental Health Research Organization; Gatsby Charitable Foundation; Swartz Foundation; National Institute of Mental Health [R01MH096274] Funding Source: NIH RePORTER
NR 49
TC 513
Z9 654
U1 12
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 JUN 18
PY 2015
VL 522
IS 7556
BP 309
EP +
DI 10.1038/nature14445
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK7PU
UT WOS:000356425400046
PM 26053122
DA 2026-03-09
ER

PT J
AU Yoneda, H
   Inubushi, Y
   Nagamine, K
   Michine, Y
   Ohashi, H
   Yumoto, H
   Yamauchi, K
   Mimura, H
   Kitamura, H
   Katayama, T
   Ishikawa, T
   Yabashi, M
AF Yoneda, Hitoki
   Inubushi, Yuichi
   Nagamine, Kazunori
   Michine, Yurina
   Ohashi, Haruhiko
   Yumoto, Hirokatsu
   Yamauchi, Kazuto
   Mimura, Hidekazu
   Kitamura, Hikaru
   Katayama, Tetsuo
   Ishikawa, Tetsuya
   Yabashi, Makina
TI Atomic inner-shell laser at 1.5-angstrom wavelength pumped by an X-ray free-electron laser
SO NATURE
LA English
DT Article
ID emission; plasma; absorption
AB Since the invention of the first lasers in the visible-light region, research has aimed to produce short-wavelength lasers that generate coherent X-rays(1,2); the shorter the wavelength, the better the imaging resolution of the laser and the shorter the pulse duration, leading to better temporal resolution in probe measurements. Recently, free-electron lasers based on self-amplified spontaneous emission(3,4) have made it possible to generate a hard-X-ray laser (that is, the photon energy is of the order of ten kiloelectronvolts) in anngstrom-wavelength regime(5,6), enabling advances in fields from ultrafast X-ray spectrosopy to X-ray quantum optics. An atomic laser based on neon atoms and pumped by a soft-X-ray (that is, a photon energy of less than one kiloelectronvolt) free-electron laser has been achieved at a wavelength of 14 nanometres7. Here, we use a copper target and report a hard-X-ray inner-shell atomic laser operating at a wavelength of 1.5 angstroms. X-ray free-electron laser pulses with an intensity of about 10(19) watts per square centimetre(7,8) tuned to the copper K-absorption edge produced sufficient population inversion to generate strong amplified spontaneous emission on the copper Ka lines. Furthermore, we operated the X-ray free-electron laser source in a two-colour mode(9), with one colour tuned for pumping and the other for the seed (starting) light for the laser.
C1 [Yoneda, Hitoki; Nagamine, Kazunori; Michine, Yurina] Univ Electrocommun, Inst Laser Sci, Chofu, Tokyo 1828585, Japan.
   [Yoneda, Hitoki; Inubushi, Yuichi; Ohashi, Haruhiko; Yamauchi, Kazuto; Mimura, Hidekazu; Ishikawa, Tetsuya; Yabashi, Makina] RIKEN SPring 8 Ctr, Sayo, Hyogo 6795148, Japan.
   [Inubushi, Yuichi; Ohashi, Haruhiko; Yumoto, Hirokatsu; Katayama, Tetsuo] Japan Synchrotron Radiat Res Inst JASRI, Sayo, Hyogo 6795198, Japan.
   [Yamauchi, Kazuto] Osaka Univ, Grad Sch Engn, Suita, Osaka 5650871, Japan.
   [Mimura, Hidekazu] Univ Tokyo, Dept Precis Engn, Bunkyo Ku, Tokyo 1138656, Japan.
   [Kitamura, Hikaru] Kyoto Univ, Dept Phys, Sakyo Ku, Kyoto 6068502, Japan.
C3 University of Electro-Communications - Japan; RIKEN; Japan Synchrotron Radiation Research Institute; University of Osaka; University of Tokyo; Kyoto University
RP Yoneda, H (corresponding author), Univ Electrocommun, Inst Laser Sci, Chofu, Tokyo 1828585, Japan.
EM yoneda@ils.uec.ac.jp
FU Photon Frontier Network Program; Global COE Program 'Center of Excellence for Atomically Controlled Fabrication Technology' from the Ministry of Education, Sports, Culture, Science and Technology, Japan (MEXT);  [2012B8014];  [2013A8013];  [2013B8020];  [2014A8008];  [25247093];  [23226004]; Grants-in-Aid for Scientific Research [25247093, 23226004] Funding Source: KAKEN
NR 28
TC 136
Z9 156
U1 2
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 AUG 27
PY 2015
VL 524
IS 7566
BP 446
EP +
DI 10.1038/nature14894
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP7LN
UT WOS:000360069300033
PM 26310765
DA 2026-03-09
ER

PT J
AU Weber, F
   Chung, S
   Beier, KT
   Xu, M
   Luo, LQ
   Dan, Y
AF Weber, Franz
   Chung, Shinjae
   Beier, Kevin T.
   Xu, Min
   Luo, Liqun
   Dan, Yang
TI Control of REM sleep by ventral medulla GABAergic neurons
SO NATURE
LA English
DT Article
ID locus-coeruleus neurons; reticular-formation; paradoxical sleep; muscle tone; c-fos; cat; nucleus; localization; transections; lesions
AB Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with vivid dreams(1-3). Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation(2), and the neural circuits in the pons have since been studied extensively(4-8). The medulla also contains neurons that are active during REM sleep(9-13), but whether they play a causal role in REM sleep generation remains unclear. Here we show that a GABAergic (gamma-aminobutyric-acidreleasing) pathway originating from the ventral medulla powerfully promotes REM sleep in mice. Optogenetic activation of ventral medulla GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects. Optrode recordings from channelrhodopsin-2-tagged ventral medulla GABAergic neurons showed that they were most active during REM sleep (REMmax), and during wakefulness they were preferentially active during eating and grooming. Furthermore, dual retrograde tracing showed that the rostral projections to the pons and midbrain and caudal projections to the spinal cord originate from separate ventral medulla neuron populations. Activating the rostral GABAergic projections was sufficient for both the induction and maintenance of REM sleep, which are probably mediated in part by inhibition of REM suppressing GABAergic neurons in the ventrolateral periaqueductal grey. These results identify a key component of the pontomedullary network controlling REM sleep. The capability to induce REM sleep on command may offer a powerful tool for investigating its functions.
C1 [Weber, Franz; Chung, Shinjae; Xu, Min; Dan, Yang] Univ Calif Berkeley, Howard Hughes Med Inst, Helen Wills Neurosci Inst, Div Neurobiol,Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
   [Beier, Kevin T.; Luo, Liqun] Stanford Univ, Howard Hughes Med Inst, Dept Biol, Stanford, CA 94305 USA.
C3 University of California System; University of California Berkeley; Howard Hughes Medical Institute; Howard Hughes Medical Institute; Stanford University
RP Dan, Y (corresponding author), Univ Calif Berkeley, Howard Hughes Med Inst, Helen Wills Neurosci Inst, Div Neurobiol,Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
EM ydan@berkeley.edu
FU EMBO; Human Frontier Science Program
NR 34
TC 225
Z9 276
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 OCT 15
PY 2015
VL 526
IS 7573
BP 435
EP +
DI 10.1038/nature14979
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200052
PM 26444238
DA 2026-03-09
ER

PT J
AU Kimura, W
   Xiao, F
   Canseco, DC
   Muralidhar, S
   Thet, S
   Zhang, HM
   Abderrahman, Y
   Chen, R
   Garcia, JA
   Shelton, JM
   Richardson, JA
   Ashour, AM
   Asaithamby, A
   Liang, HQ
   Xing, C
   Lu, ZG
   Zhang, CC
   Sadek, HA
AF Kimura, Wataru
   Xiao, Feng
   Canseco, Diana C.
   Muralidhar, Shalini
   Thet, SuWannee
   Zhang, Helen M.
   Abderrahman, Yezan
   Chen, Rui
   Garcia, Joseph A.
   Shelton, John M.
   Richardson, James A.
   Ashour, Abdelrahman M.
   Asaithamby, Aroumougame
   Liang, Hanquan
   Xing, Chao
   Lu, Zhigang
   Zhang, Cheng Cheng
   Sadek, Hesham A.
TI Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart
SO NATURE
LA English
DT Article
ID hematopoietic stem-cells; hif-alpha; rna-seq; renewal; proliferation; hydroxylation; regeneration
AB Although the adult mammalian heart is incapable of meaningful functional recovery following substantial cardiomyocyte loss, it is now clear that modest cardiomyocyte turnover occurs in adult mouse and human hearts(1,2), mediated primarily by proliferation of pre-existing cardiomyocytes(3-5). However, fate mapping of these cycling cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers(6). In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia-inducible factor 1 alpha (Hif-1 alpha) subunit is critical for their maintenance and function(7-10). Here we report fate mapping of hypoxic cells and their progenies by generating a transgenic mouse expressing a chimaeric protein in which the oxygen-dependent degradation (ODD) domain of Hif-1 alpha is fused to the tamoxifen-inducible CreERT2 recombinase. In mice bearing the creERT2-ODD transgene driven by either the ubiquitous CAG promoter or the cardiomyocyte-specific a myosin heavy chain promoter, we identify a rare population of hypoxic cardiomyocytes that display characteristics of proliferative neonatal cardiomyocytes, such as smaller size, mononucleation and lower oxidative DNA damage. Notably, these hypoxic cardiomyocytes contributed widely to new cardiomyocyte formation in the adult heart. These results indicate that hypoxia signalling is an important hallmark of cycling cardiomyocytes, and suggest that hypoxia fate mapping can be a powerful tool for identifying cycling cells in adult mammals.
C1 [Kimura, Wataru; Xiao, Feng; Canseco, Diana C.; Muralidhar, Shalini; Thet, SuWannee; Abderrahman, Yezan; Chen, Rui; Garcia, Joseph A.; Shelton, John M.; Ashour, Abdelrahman M.; Sadek, Hesham A.] Univ Texas SW Med Ctr Dallas, Div Cardiol, Dept Internal Med, Dallas, TX 75390 USA.
   [Kimura, Wataru] Univ Tsukuba, Tsukuba Adv Res Alliance, Life Sci Ctr, Tsukuba, Ibaraki 3058577, Japan.
   [Zhang, Helen M.; Lu, Zhigang; Zhang, Cheng Cheng] Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA.
   [Zhang, Helen M.; Lu, Zhigang; Zhang, Cheng Cheng] Univ Texas SW Med Ctr Dallas, Dept Dev Biol, Dallas, TX 75390 USA.
   [Garcia, Joseph A.] VA North Texas Hlth Care Syst, Dept Med, Dallas, TX 75216 USA.
   [Richardson, James A.] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA.
   [Richardson, James A.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA.
   [Asaithamby, Aroumougame] Univ Texas SW Med Ctr Dallas, Dept Radiat Oncol, Dallas, TX 75390 USA.
   [Liang, Hanquan; Xing, Chao] Univ Texas SW Med Ctr Dallas, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA.
   [Sadek, Hesham A.] Univ Texas SW 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 Tsukuba; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA North Texas Health Care System; 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 Texas System; University of Texas Southwestern Medical Center
RP Sadek, HA (corresponding author), Univ Texas SW Med Ctr Dallas, Div Cardiol, Dept Internal Med, Dallas, TX 75390 USA.
EM hesham.sadek@utsouthwestern.edu
FU NHLBI NIH HHS [R01 HL108104, R01 HL115275] Funding Source: Medline; BLRD VA [I01 BX000446] Funding Source: Medline
NR 29
TC 260
Z9 317
U1 0
U2 71
PU NATURE PUBLISHING 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 9
PY 2015
VL 523
IS 7559
BP 226
EP U243
DI 10.1038/nature14582
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM4ZO
UT WOS:000357695900038
PM 26098368
DA 2026-03-09
ER

PT J
AU Tsankov, AM
   Gu, HC
   Akopian, V
   Ziller, MJ
   Donaghey, J
   Amit, I
   Gnirke, A
   Meissner, A
AF Tsankov, Alexander M.
   Gu, Hongcang
   Akopian, Veronika
   Ziller, Michael J.
   Donaghey, Julie
   Amit, Ido
   Gnirke, Andreas
   Meissner, Alexander
TI Transcription factor binding dynamics during human ES cell differentiation
SO NATURE
LA English
DT Article
ID embryonic stem-cells; dna methylation; chip-seq; epigenomic analysis; regulatory network; super-enhancers; regions; genome; state; specification
AB Pluripotent stem cells provide a powerful system to dissect the underlying molecular dynamics la ell fate changes during mammalian development. Here we report the integrative analysis of genome-wide binding data for 38 transcription factors with extensive epigenume and transcriptional data across the differentiation of human embryonic stem cells to the three germ layers. We describe core regulatory dynamics and show the lineage-specific behaviour of selected factors. In addition to the orchestrated remodelling of the chromatin landscape, we find that the binding of several transcription factors is strongly associated with. specific loss of DNA methylation in one germ layer, and in many cases a reciprocal gain in the other layers. Taken together, our work shows context-dependent rewiring of transcription factor binding, downstream signalling effectors, and the epigenome during human embryonic stem cell differentiation.
C1 [Tsankov, Alexander M.; Gu, Hongcang; Ziller, Michael J.; Donaghey, Julie; Amit, Ido; Gnirke, Andreas; Meissner, Alexander] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Tsankov, Alexander M.; Akopian, Veronika; Ziller, Michael J.; Donaghey, Julie; Meissner, Alexander] Harvard Stem Cell Inst, Cambridge, MA 02138 USA.
   [Tsankov, Alexander M.; Akopian, Veronika; Ziller, Michael J.; Donaghey, Julie; Meissner, Alexander] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.
   [Amit, Ido] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel.
C3 Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University; Weizmann Institute of Science
RP Meissner, A (corresponding author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
EM alexander_meissner@harvard.edu
FU NIH [U01ES017155]; NIGMS [P01GM099117]; NHGRI [P50HG006193]; New York Stem Cell Foundation; NIH Ruth L. Kirschstein NRSA fellowship [5F32DK095537]; National Institute of General Medical Sciences [P01GM099117] Funding Source: NIH RePORTER
NR 48
TC 273
Z9 354
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 FEB 19
PY 2015
VL 518
IS 7539
BP 344
EP 349
DI 10.1038/nature14233
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400031
PM 25693565
DA 2026-03-09
ER

PT J
AU Ito, HT
   Zhang, SJ
   Witter, MP
   Moser, EI
   Moser, MB
AF Ito, Hiroshi T.
   Zhang, Sheng-Jia
   Witter, Menno P.
   Moser, Edvard I.
   Moser, May-Britt
TI A prefrontal-thalamo-hippocampal circuit for goal-directed spatial navigation
SO NATURE
LA English
DT Article
ID nucleus-reuniens-thalami; sequential-context; grid cells; memory; cortex; parietal; neurons; rat; representation; modulation
AB Spatial navigation requires information about the relationship between current and future positions. The activity of hippocampal neurons appears to reflect such a relationship, representing not only instantaneous position but also the path towards a goal location. However, how the hippocampus obtains information about goal direction is poorly understood. Here we report a prefrontal-thalamic neural circuit that is required for hippocampal representation of routes or trajectories through the environment. Trajectory-dependent firing was observed in medial prefrontal cortex, the nucleus reuniens of the thalamus, and the CA1 region of the hippocampus in rats. Lesioning or optogenetic silencing of the nucleus reuniens substantially reduced trajectory-dependent CA1 firing. Trajectory-dependent activity was almost absent in CA3, which does not receive nucleus reuniens input. The data suggest that projections from medial prefrontal cortex, via the nucleus reuniens, are crucial for representation of the future path during goal-directed behaviour and point to the thalamus as a key node in networks for long-range communication between cortical regions involved in navigation.
C1 [Ito, Hiroshi T.; Zhang, Sheng-Jia; Witter, Menno P.; Moser, Edvard I.; Moser, May-Britt] Norwegian Univ Sci & Technol, MTFS, Kavli Inst Syst Neurosci, N-7491 Trondheim, Norway.
   [Ito, Hiroshi T.; Zhang, Sheng-Jia; Witter, Menno P.; Moser, Edvard I.; Moser, May-Britt] Norwegian Univ Sci & Technol, MTFS, Ctr Neural Computat, N-7491 Trondheim, Norway.
C3 Norwegian University of Science & Technology (NTNU); Norwegian University of Science & Technology (NTNU)
RP Ito, HT (corresponding author), Norwegian Univ Sci & Technol, MTFS, Kavli Inst Syst Neurosci, Olav Kyrres Gate 9, N-7491 Trondheim, Norway.
EM hiroshi.ito@ntnu.no; may-britt.moser@ntnu.no
FU European Research Council [232608, 268598]; Kavli Foundation; Centre of Excellence scheme of the Research Council of Norway (Centre for the Biology of Memory); Centre of Excellence scheme of the Research Council of Norway (Centre for Neural Computation); European Research Council (ERC) [268598, 232608] Funding Source: European Research Council (ERC)
NR 51
TC 324
Z9 423
U1 5
U2 135
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 4
PY 2015
VL 522
IS 7554
BP 50
EP U82
DI 10.1038/nature14396
PG 25
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ5QP
UT WOS:000355543400027
PM 26017312
DA 2026-03-09
ER

PT J
AU Van Roy, P
   Daley, AC
   Briggs, DEG
AF Van Roy, Peter
   Daley, Allison C.
   Briggs, Derek E. G.
TI Anomalocaridid trunk limb homology revealed by a giant filter-feeder with paired flaps
SO NATURE
LA English
DT Article
ID burgess shale; appendages; morphology; evolution; opabinia; affinity; brain
AB Exceptionally preserved fossils from the Palaeozoic era provide crucial insights into arthropod evolution, with recent discoveries bringing phylogeny and character homology into sharp focus(1-4). Integral to such studies are anomalocaridids, a clade of stem arthropods whose remarkable morphology illuminates early arthropod relationships(5,6) and Cambrian ecology(7-9). Although recent work has focused on the anomalocaridid head(6-10), the nature of their trunk has been debated widely(5,11-18). Here we describe new anomalocaridid(17) specimens from the Early Ordovician Fezouata Biota of Morocco(19), which not only show well-preserved head appendages providing key ecological data, but also elucidate the nature of anomalocaridid trunk flaps, resolving their homology with arthropod trunk limbs. The new material shows that each trunk segment bears a separate dorsal and ventral pair of flaps, with a series of setal blades attached at the base of the dorsal flaps. Comparisons with other stem lineage arthropods(16,20-22) indicate that anomalocaridid ventral flaps are homologous with lobopodous walking limbs and the endopod of the euarthropod biramous limb, whereas the dorsal flaps and associated setal blades are homologous with the flaps of gilled lobopodians (for example, Kerygmachela kierkegaardi, Pambdelurion whittingtoni) and exites of the 'Cambrian biramous limb'(23). This evidence shows that anomalocaridids represent a stage before the fusion of exite and endopod into the 'Cambrian biramous limb'(5,16,23), confirming their basal placement in the euarthropod stem(4-6), rather than in the arthropod crown(24) or with cycloneuralian worms(14). Unlike other anomalocaridids, the Fezouata taxon combines head appendages convergently(9) adapted for filter-feeding with an unprecedented body length exceeding 2 m, indicating a new direction in the feeding ecology of the clade. The evolution of giant filter-feeding anomalocaridids may reflect the establishment of highly developed planktic ecosystems during the Great Ordovician Biodiversification Event(25).
C1 [Van Roy, Peter; Briggs, Derek E. G.] Yale Univ, Dept Geol & Geophys, New Haven, CT 06520 USA.
   [Van Roy, Peter] Univ Ghent, Dept Geol & Soil Sci, Res Unit Palaeontol, B-9000 Ghent, Belgium.
   [Daley, Allison C.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England.
   [Daley, Allison C.] Oxford Univ Museum Nat Hist, Oxford OX1 3PW, England.
   [Briggs, Derek E. G.] Yale Univ, Yale Peabody Museum Nat Hist, New Haven, CT 06520 USA.
C3 Yale University; Ghent University; University of Oxford; University of Oxford; Yale University
RP Van Roy, P (corresponding author), Yale Univ, Dept Geol & Geophys, POB 208109, New Haven, CT 06520 USA.
EM peter.vanroy@yale.edu
FU Biology Commission of the Research Foundation - Flanders (FWO); Swedish Research Council (Vetenskapsradet); Oxford University Museum of Natural History; National Science Foundation [EAR-1053247]; Division of Invertebrate Paleontology, YPM; Directorate For Geosciences; Division Of Earth Sciences [1053247] Funding Source: National Science Foundation
NR 30
TC 146
Z9 155
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 JUN 4
PY 2015
VL 522
IS 7554
BP 77
EP U178
DI 10.1038/nature14256
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ5QP
UT WOS:000355543400032
PM 25762145
DA 2026-03-09
ER

PT J
AU Buffie, CG
   Bucci, V
   Stein, RR
   McKenney, PT
   Ling, LL
   Gobourne, A
   No, D
   Liu, H
   Kinnebrew, M
   Viale, A
   Littmann, E
   van den Brink, MRM
   Jenq, RR
   Taur, Y
   Sander, C
   Cross, JR
   Toussaint, NC
   Xavier, JB
   Pamer, EG
AF Buffie, Charlie G.
   Bucci, Vanni
   Stein, Richard R.
   McKenney, Peter T.
   Ling, Lilan
   Gobourne, Asia
   No, Daniel
   Liu, Hui
   Kinnebrew, Melissa
   Viale, Agnes
   Littmann, Eric
   van den Brink, Marcel R. M.
   Jenq, Robert R.
   Taur, Ying
   Sander, Chris
   Cross, Justin R.
   Toussaint, Nora C.
   Xavier, Joao B.
   Pamer, Eric G.
TI Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile
SO NATURE
LA English
DT Article
ID intestinal microbiota; metabolism; domination; phylogeny; scindens; proposal; salts; mice
AB The gastrointestinal tracts of mammals are colonized by hundreds of microbial species that contribute to health, including colonization resistance against intestinal pathogens(1). Many antibiotics destroy intestinal microbial communities and increase susceptibility to intestinal pathogens(2). Among these, Clostridium difficile, a major cause of antibiotic-induced diarrhoea, greatly increases morbidity and mortality in hospitalized patients(3). Which intestinal bacteria provide resistance to C. difficile infection and their in vivo inhibitory mechanisms remain unclear. Here we correlate loss of specific bacterial taxa with development of infection, by treating mice with different antibiotics that result in distinct microbiota changes and lead to varied susceptibility to C. difficile. Mathematical modelling augmented by analyses of the microbiota of hospitalized patients identifies resistance-associated bacteria common to mice and humans. Using these platforms, we determine that Clostridium scindens, a bile acid 7 alpha-dehydroxylating intestinal bacterium, is associated with resistance to C. difficile infection and, upon administration, enhances resistance to infection in a secondary bile acid dependent fashion. Using a workflow involving mouse models, clinical studies, metagenomic analyses, and mathematical modelling, we identify a probiotic candidate that corrects a clinically relevant microbiome deficiency. These findings have implications for the rational design of targeted antimicrobials as well as microbiome-based diagnostics and therapeutics for individuals at risk of C. difficile infection.
C1 [Buffie, Charlie G.; McKenney, Peter T.; Kinnebrew, Melissa; Taur, Ying; Pamer, Eric G.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA.
   [Buffie, Charlie G.; McKenney, Peter T.; Ling, Lilan; Gobourne, Asia; No, Daniel; Kinnebrew, Melissa; Littmann, Eric; Taur, Ying; Toussaint, Nora C.; Xavier, Joao B.; Pamer, Eric G.] Mem Sloan Kettering Canc Ctr, Lucille Castori Ctr Microbes Inflammat & Canc, New York, NY 10065 USA.
   [Bucci, Vanni; Stein, Richard R.; Sander, Chris; Toussaint, Nora C.; Xavier, Joao B.] Sloan Kettering Inst, Computat Biol Program, New York, NY 10065 USA.
   [Bucci, Vanni] Univ Massachusetts Dartmouth, Dept Biol, N Dartmouth, MA 02747 USA.
   [Liu, Hui; Cross, Justin R.] Sloan Kettering Inst, Donald B & Catherine C Marron Canc Metab Ctr, New York, NY 10065 USA.
   [Viale, Agnes] Sloan Kettering Inst, Genom Core Lab, New York, NY 10065 USA.
   [van den Brink, Marcel R. M.; Jenq, Robert R.] Mem Sloan Kettering Canc Ctr, Dept Med, Bone Marrow Transplant Serv, New York, NY 10065 USA.
   [van den Brink, Marcel R. M.; Pamer, Eric G.] Sloan Kettering Inst, Immunol Program, New York, NY 10065 USA.
C3 Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; University of Massachusetts System; University Massachusetts Dartmouth; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center
RP Pamer, EG (corresponding author), Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA.
EM pamere@mskcc.org
FU US National Institutes of Health (NIH) [RO1 AI42135, AI95706]; Tow Foundation; NIH Office of the Director [DP2OD008440]; NCI [U54 CA148967]; Lucille Castori Center for Microbes, Inflammation, and Cancer; Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH [T32GM07739]; National Cancer Institute [P30CA008748, P01CA023766, T32CA009149] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007739] Funding Source: NIH RePORTER
NR 40
TC 1422
Z9 1801
U1 9
U2 477
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 8
PY 2015
VL 517
IS 7533
BP 205
EP U207
DI 10.1038/nature13828
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600037
PM 25337874
DA 2026-03-09
ER

PT J
AU Durst, R
   Sauls, K
   Peal, DS
   deVlaming, A
   Toomer, K
   Leyne, M
   Salani, M
   Talkowski, ME
   Brand, H
   Perrocheau, M
   Simpson, C
   Jett, C
   Stone, MR
   Charles, F
   Chiang, C
   Lynch, SN
   Bouatia-Naji, N
   Delling, FN
   Freed, LA
   Tribouilloy, C
   Le Tourneau, T
   LeMarec, H
   Fernandez-Friera, L
   Solis, J
   Trujillano, D
   Ossowski, S
   Estivill, X
   Dina, C
   Bruneval, P
   Chester, A
   Schott, JJ
   Irvine, KD
   Mao, YP
   Wessels, A
   Motiwala, T
   Puceat, M
   Tsukasaki, Y
   Menick, DR
   Kasiganesan, H
   Nie, XJ
   Broome, AM
   Williams, K
   Johnson, A
   Markwald, RR
   Jeunemaitre, X
   Hagege, A
   Levine, RA
   Milan, DJ
   Norris, RA
   Slaugenhaupt, SA
AF Durst, Ronen
   Sauls, Kimberly
   Peal, David S.
   deVlaming, Annemarieke
   Toomer, Katelynn
   Leyne, Maire
   Salani, Monica
   Talkowski, Michael E.
   Brand, Harrison
   Perrocheau, Maelle
   Simpson, Charles
   Jett, Christopher
   Stone, Matthew R.
   Charles, Florie
   Chiang, Colby
   Lynch, Stacey N.
   Bouatia-Naji, Nabila
   Delling, Francesca N.
   Freed, Lisa A.
   Tribouilloy, Christophe
   Le Tourneau, Thierry
   LeMarec, Herve
   Fernandez-Friera, Leticia
   Solis, Jorge
   Trujillano, Daniel
   Ossowski, Stephan
   Estivill, Xavier
   Dina, Christian
   Bruneval, Patrick
   Chester, Adrian
   Schott, Jean-Jacques
   Irvine, Kenneth D.
   Mao, Yaopan
   Wessels, Andy
   Motiwala, Tahirali
   Puceat, Michel
   Tsukasaki, Yoshikazu
   Menick, Donald R.
   Kasiganesan, Harinath
   Nie, Xingju
   Broome, Ann-Marie
   Williams, Katherine
   Johnson, Amanda
   Markwald, Roger R.
   Jeunemaitre, Xavier
   Hagege, Albert
   Levine, Robert A.
   Milan, David J.
   Norris, Russell A.
   Slaugenhaupt, Susan A.
TI Mutations in DCHS1 cause mitral valve prolapse
SO NATURE
LA English
DT Article
ID echocardiographic evidence; filamin-a; expression; gene; quantification; identification; regurgitation; locus; fat
AB Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals(1-3). It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery(4,5). Despite a clear heritable component, the genetic aetiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds), that segregates with MVP in the family. Morpholino knockdown of the zebrafish homologue dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 messenger RNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1(+/-) mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs, as well as in Dchs1(+/-) mouse MVICs, result in altered migration and cellular patterning, supporting these processes as aetiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease.
C1 [Durst, Ronen; Leyne, Maire; Salani, Monica; Talkowski, Michael E.; Brand, Harrison; Simpson, Charles; Jett, Christopher; Stone, Matthew R.; Charles, Florie; Chiang, Colby; Milan, David J.; Slaugenhaupt, Susan A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res,Res Inst, Boston, MA 02114 USA.
   [Durst, Ronen; Leyne, Maire; Salani, Monica; Talkowski, Michael E.; Brand, Harrison; Simpson, Charles; Jett, Christopher; Stone, Matthew R.; Charles, Florie; Chiang, Colby; Milan, David J.; Slaugenhaupt, Susan A.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02114 USA.
   [Durst, Ronen] Hadassah Hebrew Univ, Med Ctr, Div Cardiol, Jerusalem, Israel.
   [Sauls, Kimberly; deVlaming, Annemarieke; Toomer, Katelynn; Wessels, Andy; Motiwala, Tahirali; Williams, Katherine; Johnson, Amanda; Markwald, Roger R.; Norris, Russell A.] Med Univ S Carolina, Childrens Res Inst, Cardiovasc Dev Biol Ctr, Dept Regenerat Med & Cell Biol,Dept Med, Charleston, SC 29425 USA.
   [Peal, David S.; Lynch, Stacey N.; Milan, David J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr,Cardiol Div, Boston, MA 02114 USA.
   [Talkowski, Michael E.; Brand, Harrison] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.
   [Perrocheau, Maelle; Bouatia-Naji, Nabila; Jeunemaitre, Xavier; Hagege, Albert] Paris Cardiovasc Res Ctr, INSERM, UMR 970, F-75015 Paris, France.
   [Bouatia-Naji, Nabila; Jeunemaitre, Xavier; Hagege, Albert; Levine, Robert A.] Univ Paris 05, Sorbonne Paris Cite, Fac Med, F-75006 Paris, France.
   [Delling, Francesca N.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med,Cardiovasc Div, Boston, MA 02215 USA.
   [Freed, Lisa A.] Yale Univ, Sch Med, Heart & Vasc Ctr, Yale New Haven Hosp, New Haven, CT 06510 USA.
   [Tribouilloy, Christophe] Univ Hosp Amiens, Dept Cardiol, F-80000 Amiens, France.
   [Tribouilloy, Christophe] Jules Verne Univ Picardie, U 1088, INSERM, F-80000 Amiens, France.
   [Le Tourneau, Thierry; LeMarec, Herve; Dina, Christian; Schott, Jean-Jacques] INSERM, U1087, F-44007 Nantes, France.
   [Le Tourneau, Thierry; LeMarec, Herve; Dina, Christian; Schott, Jean-Jacques] Univ Hosp, Inst Thorax, F-44007 Nantes, France.
   [Fernandez-Friera, Leticia; Solis, Jorge] Ctr Nacl Invest Cardiovasc Carlos III CNIC, Madrid 28029, Spain.
   [Fernandez-Friera, Leticia; Solis, Jorge] Hosp Univ Monteprincipe, Madrid 28660, Spain.
   [Trujillano, Daniel; Estivill, Xavier] Ctr Genom Regulat, Genet Causes Dis Grp, Barcelona 08003, Catalonia, Spain.
   [Trujillano, Daniel; Ossowski, Stephan; Estivill, Xavier] UPF, Barcelona 08002, Catalonia, Spain.
   [Trujillano, Daniel; Estivill, Xavier] Hosp del Mar Med Res Inst IMIM, Barcelona 08003, Catalonia, Spain.
   [Trujillano, Daniel; Estivill, Xavier] CIBER Epidemiol & Publ Hlth CIBERESP, Barcelona 08036, Catalonia, Spain.
   [Ossowski, Stephan] CRG, Genom & Epigen Variat Dis Grp, Barcelona 08003, Catalonia, Spain.
   [Dina, Christian; Schott, Jean-Jacques] CNRS, UMR 6291, F-44007 Nantes, France.
   [Dina, Christian; Schott, Jean-Jacques] Univ Nantes, F-44322 Nantes, France.
   [Dina, Christian; Schott, Jean-Jacques] CHU Nantes, Serv Cardiol, Inst Thorax, F-44093 Nantes, France.
   [Bruneval, Patrick] Hop Europe Georges Pompidou, Serv Anat Pathol, F-75015 Paris, France.
   [Chester, Adrian] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Heart Sci Ctr, London SW7 2AZ, England.
   [Irvine, Kenneth D.; Mao, Yaopan] Rutgers State Univ, Waksman Inst, Howard Hughes Med Inst, Piscataway, NJ 08854 USA.
   [Irvine, Kenneth D.; Mao, Yaopan] Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA.
   [Puceat, Michel] Aix Marseille Univ, Med Sch La Timone, Team Physiopathol Cardiac Dev, INSERM,UMR S910, F-13885 Marseille, France.
   [Tsukasaki, Yoshikazu] Univ Texas Hlth Ctr Tyler Northeast Tyler, Dept Cellular & Mol Biol, Tyler, TX 75708 USA.
   [Menick, Donald R.; Kasiganesan, Harinath] Med Univ S Carolina, Div Cardiol, Dept Med, Gazes Cardiac Res Inst, Charleston, SC 29425 USA.
   [Nie, Xingju; Broome, Ann-Marie] Med Univ S Carolina, Dept Radiol & Radiol Sci, Charleston, SC 29425 USA.
   [Jeunemaitre, Xavier] Hop Europeen Georges Pompidou, AP HP, AP HP, F-75015 Paris, France.
   [Hagege, Albert] Hop Europeen Georges Pompidou, AP HP, Dept Cardiol, F-75015 Paris, France.
   [Levine, Robert A.] Harvard Univ, Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Div Cardiol, Boston, MA 02114 USA.
C3 Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Hebrew University of Jerusalem; Hadassah University Medical Center; Medical University of South Carolina; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Universite Paris Cite; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Yale University; Universite de Picardie Jules Verne (UPJV); CHU Amiens; Universite de Picardie Jules Verne (UPJV); Institut National de la Sante et de la Recherche Medicale (Inserm); Institut National de la Sante et de la Recherche Medicale (Inserm); Institut National de la Sante et de la Recherche Medicale (Inserm); Nantes Universite; CHU de Nantes; Centro Nacional de Investigaciones Cardiovasculares (CNIC); Barcelona Institute of Science & Technology; Pompeu Fabra University; Centre de Regulacio Genomica (CRG); Pompeu Fabra University; Hospital del Mar Research Institute; Hospital del Mar; CIBER - Centro de Investigacion Biomedica en Red; CIBERESP; Barcelona Institute of Science & Technology; Pompeu Fabra University; Centre de Regulacio Genomica (CRG); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Nantes Universite; Institut National de la Sante et de la Recherche Medicale (Inserm); Nantes Universite; CHU de Nantes; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Europeen Georges-Pompidou - APHP; Imperial College London; Howard Hughes Medical Institute; Rutgers University System; Rutgers University New Brunswick; Rutgers University System; Rutgers University New Brunswick; Aix-Marseille Universite; Institut National de la Sante et de la Recherche Medicale (Inserm); Medical University of South Carolina; Medical University of South Carolina; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Europeen Georges-Pompidou - APHP; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Europeen Georges-Pompidou - APHP; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital
RP Slaugenhaupt, SA (corresponding author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res,Res Inst, Boston, MA 02114 USA.
EM norrisra@musc.edu; slaugenhaupt@chgr.mgh.harvard.edu
FU Fondation Leducq (Paris, France) Mitral Transatlantic Network of Excellence grant [07CVD04]; Innovation in Clinical Research award of the Doris Duke Charitable Foundation; Aetna Quality Care Research Fund; National Heart Lung and Blood Institute Resequencing and Genotyping (RSG) Service; National Institutes of Health from the Extramural Research Facilities Program of the National Center for Research Resources [C06 RR018823]; French Society of Cardiology; National Heart Lung and Blood Institute [R01HL122906-01, R01-HL33756, COBRE 1P30 GM103342, 8P20 GM103444-07, R01-HL109004, R01-HL127692, RO1-HL095696]; VA Merit Review [BX002327]; National Institute of Mental Health [R00-MH095867]; Hassenfeld Scholar Program; March of Dimes; M.G.H. Scholars Program; American Heart Association [09GRNT2060075, 11SDG5270006, 2261354, 15GRNT25080052]; National Science Foundation [EPS-0903795]; NHLBI [K24 HL67434, R01HL72265, R01HL109506]; Ellison Foundation, Boston, MA; Howard Hughes Medical Institute; American Heart Association (AHA) [11SDG5270006, 09GRNT2060075, 15GRNT25080052] Funding Source: American Heart Association (AHA); National Heart Lung and Blood Institute [T32HL007208, T32HL007260, R01HL122906] Funding Source: NIH RePORTER
NR 40
TC 153
Z9 177
U1 2
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 SEP 3
PY 2015
VL 525
IS 7567
BP 109
EP +
DI 10.1038/nature14670
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100035
PM 26258302
DA 2026-03-09
ER

PT J
AU Sharma, A
   Hartwig, JF
AF Sharma, Ankit
   Hartwig, John F.
TI Metal-catalysed azidation of tertiary C-H bonds suitable for late-stage functionalization
SO NATURE
LA English
DT Article
ID community-acquired pneumonia; amination; complex; chemistry; oxidation; nitrogen; alkane; azithromycin; activation; molecules
AB Many enzymes oxidize unactivated aliphatic C-H bonds selectively to form alcohols; however, biological systems do not possess enzymes that catalyse the analogous aminations of C-H bonds(1,2). The absence of such enzymes limits the discovery of potential medicinal candidates because nitrogen-containing groups are crucial to the biological activity of therapeutic agents and clinically useful natural products. In one prominent example illustrating the importance of incorporating nitrogen-based functionality, the conversion of the ketone of erythromycin to the -N(Me)CH2- group in azithromycin leads to a compound that can be dosed once daily with a shorter treatment time(3,4). For such reasons, synthetic chemists have sought catalysts that directly convert C-H bonds to C-N bonds. Most currently used catalysts for C-H bond amination are ill suited to the intermolecular functionalization of complex molecules because they require excess substrate or directing groups, harsh reaction conditions, weak or acidic C-H bonds, or reagents containing specialized groups on the nitrogen atom(5-14). Among C-H bond amination reactions, those forming a C-N bond at a tertiary alkyl group would be particularly valuable, because this linkage is difficult to form from ketones or alcohols that might be created in a biosynthetic pathway by oxidation(15). Here we report a mild, selective, iron-catalysed azidation of tertiary C-H bonds that occurs without excess of the valuable substrate. The reaction tolerates aqueous environments and is suitable for the functionalization of complex structures in the late stages of a multistep synthesis. Moreover, this azidation makes it possible to install a range of nitrogen-based functional groups, including those from Huisgen 'click' cycloadditions and the Staudinger ligation(16-19). We anticipate that these reactions will create opportunities to modify natural products, their precursors and their derivatives to produce analogues that contain different polarity and charge as a result of nitrogen-containing groups. It could also be used to help identify targets of biologically active molecules by creating a point of attachment for example, to fluorescent tags or 'handles' for affinity chromatography-directly on complex molecular structures.
C1 [Sharma, Ankit; Hartwig, John F.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
C3 University of California System; University of California Berkeley
RP Hartwig, JF (corresponding author), Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
EM jhartwig@berkeley.edu
FU US NIH [4R37GM055382, S10-RR027172]; Swiss National Science Foundation (SNSF [PBGEP2_145544]; US NIH; Swiss National Science Foundation (SNF) [PBGEP2_145544] Funding Source: Swiss National Science Foundation (SNF)
NR 30
TC 369
Z9 435
U1 4
U2 378
PU NATURE PUBLISHING 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 29
PY 2015
VL 517
IS 7536
BP 600
EP 604
DI 10.1038/nature14127
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA2ZL
UT WOS:000348775000040
PM 25631448
DA 2026-03-09
ER

PT J
AU Boucrot, E
   Ferreira, APA
   Almeida-Souza, L
   Debard, S
   Vallis, Y
   Howard, G
   Bertot, L
   Sauvonnet, N
   McMahon, HT
AF Boucrot, Emmanuel
   Ferreira, Antonio P. A.
   Almeida-Souza, Leonardo
   Debard, Sylvain
   Vallis, Yvonne
   Howard, Gillian
   Bertot, Laetitia
   Sauvonnet, Nathalie
   McMahon, Harvey T.
TI Endophilin marks and controls a clathrin-independent endocytic pathway
SO NATURE
LA English
DT Article
ID receptor-mediated endocytosis; synaptic vesicle endocytosis; coated pit formation; tumor-suppressor; binding partners; down-regulation; bar domains; dynamin; cells; proteins
AB Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. Here we show in mammalian cells that endophilin marks and controls a fast-acting tubulovesicular endocytic pathway that is independent of AP2 and clathrin, activated upon ligand binding to cargo receptors, inhibited by inhibitors of dynamin, Rac, phosphatidylinositol-3-OH kinase, PAK1 and actin polymerization, and activated upon Cdc42 inhibition. This pathway is prominent at the leading edges of cells where phosphatidylinositol-3,4-bisphosphate-produced by the dephosphorylation of phosphatidylinositol-3,4,5-triphosphate by SHIP1 and SHIP2-recruits lamellipodin, which in turn engages endophilin. This pathway mediates the ligand-triggered uptake of several G-protein-coupled receptors such as alpha(2a)- and beta(1)-adrenergic, dopaminergic D3 and D4 receptors and muscarinic acetylcholine receptor 4, the receptor tyrosine kinases EGFR, HGFR, VEGFR, PDGFR, NGFR and IGF1R, as well as interleukin-2 receptor. We call this new endocytic route fast endophilin-mediated endocytosis (FEME).
C1 [Boucrot, Emmanuel; Almeida-Souza, Leonardo; Vallis, Yvonne; Howard, Gillian; McMahon, Harvey T.] MRC Lab Mol Biol, Cambridge CB2 0QH, England.
   [Boucrot, Emmanuel; Ferreira, Antonio P. A.; Debard, Sylvain] UCL, Inst Struct & Mol Biol, London WC1E 6BT, England.
   [Boucrot, Emmanuel; Ferreira, Antonio P. A.; Debard, Sylvain] Birkbeck Coll, London WC1E 6BT, England.
   [Debard, Sylvain] Ecole Normale Super, Dept Biol, F-94235 Cachan, France.
   [Bertot, Laetitia; Sauvonnet, Nathalie] Inst Pasteur, Unite Pathogenie Mol Microbienne, F-75724 Paris 15, France.
C3 MRC Laboratory Molecular Biology; University of London; University College London; Birkbeck University London; University of London; Birkbeck University London; Universite Paris Saclay; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris
RP McMahon, HT (corresponding author), MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England.
EM e.boucrot@ucl.ac.uk; hmm@mrc-lmb.cam.ac.uk
FU Medical Research Council UK [U105178805]; Royal Society [RG120481]; Fundacao para a Ciencia e Tecnologia; Marie Curie Actions; Biotechnology and Biological Sciences Research Council [BB/I018921/1] Funding Source: researchfish; Medical Research Council [MC_U105178795] Funding Source: researchfish; BBSRC [BB/I018921/1] Funding Source: UKRI; MRC [MC_U105178795] Funding Source: UKRI
NR 62
TC 425
Z9 499
U1 3
U2 177
PU NATURE PUBLISHING 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 22
PY 2015
VL 517
IS 7535
BP 460
EP +
DI 10.1038/nature14067
PG 29
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AZ4MU
UT WOS:000348196500029
PM 25517094
DA 2026-03-09
ER

PT J
AU Kropff, E
   Carmichael, JE
   Moser, MB
   Moser, EI
AF Kropff, Emilio
   Carmichael, James E.
   Moser, May-Britt
   Moser, Edvard I.
TI Speed cells in the medial entorhinal cortex
SO NATURE
LA English
DT Article
ID geometric borders; path-integration; place cells; grid cells; representation; interference; position; theta; model; oscillations
AB Grid cells in the medial entorhinal cortex have spatial firing fields that repeat periodically in a hexagonal pattern. When animals move, activity is translated between grid cells in accordance with the animal's displacement in the environment. For this translation to occur, grid cells must have continuous access to information about instantaneous running speed. However, a powerful entorhinal speed signal has not been identified. Here we show that running speed is represented in the firing rate of a ubiquitous but functionally dedicated population of entorhinal neurons distinct from other cell populations of the local circuit, such as grid, head-direction and border cells. These 'speed cells' are characterized by a context-invariant positive, linear response to running speed, and share with grid cells a prospective bias of 50-80ms. Our observations point to speed cells as a key component of the dynamic representation of self-location in the medial entorhinal cortex.
C1 [Kropff, Emilio; Carmichael, James E.; Moser, May-Britt; Moser, Edvard I.] Norwegian Univ Sci & Technol, Kavli Inst Syst Neurosci, MTFS, N-7491 Trondheim, Norway.
   [Kropff, Emilio; Carmichael, James E.; Moser, May-Britt; Moser, Edvard I.] Norwegian Univ Sci & Technol, Ctr Neural Computat, MTFS, N-7491 Trondheim, Norway.
   [Kropff, Emilio] Consejo Nacl Invest Cient & Tecn, Leloir Inst, IIBBA, RA-1033 Buenos Aires, DF, Argentina.
C3 Norwegian University of Science & Technology (NTNU); Norwegian University of Science & Technology (NTNU); Leloir Institute; Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET)
RP Kropff, E (corresponding author), Norwegian Univ Sci & Technol, Kavli Inst Syst Neurosci, MTFS, Olav Kyrres Gate 9, N-7491 Trondheim, Norway.
EM ekropff@leloir.org.ar; edvard.moser@ntnu.no
FU European Research Council [232608, 338865]; European Commission [600725]; FP7 collaborative project [200873]; Kavli Foundation; Louis-Jeantet Prize for Medicine; Centre of Excellence scheme of the Research Council of Norway (Centre for the Biology of Memory and Centre for Neural Computation); Ministry of Science of Argentina [PICT 2012-0548]; European Research Council (ERC) [232608, 338865] Funding Source: European Research Council (ERC)
NR 33
TC 448
Z9 582
U1 4
U2 121
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 23
PY 2015
VL 523
IS 7561
BP 419
EP U78
DI 10.1038/nature14622
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN4DD
UT WOS:000358378900028
PM 26176924
DA 2026-03-09
ER

PT J
AU Samanta, J
   Grund, EM
   Silva, HM
   Lafaille, JJ
   Fishell, G
   Salzer, JL
AF Samanta, Jayshree
   Grund, Ethan M.
   Silva, Hernandez M.
   Lafaille, Juan J.
   Fishell, Gord
   Salzer, James L.
TI Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination
SO NATURE
LA English
DT Article
ID sonic hedgehog; multiple-sclerosis; subventricular zone; discrete populations; precursor cells; spinal-cord; cns; demyelination; progenitors; myelin
AB Enhancing repair of myelin is an important but still elusive therapeutic goal in many neurological disorders(1). In multiple sclerosis, an inflammatory demyelinating disease, endogenous remyelination does occur but is frequently insufficient to restore function. Both parenchymal oligodendrocyte progenitor cells and endogenous adult neural stem cells resident within the subventricular zone are known sources of remyelinating cells(2). Here we characterize the contribution to remyelination of a subset of adult neural stem cells, identified by their expression of Gli1, a transcriptional effector of the sonic hedgehog pathway. We show that these cells are recruited from the subventricular zone to populate demyelinated lesions in the forebrain but never enter healthy, white matter tracts. Unexpectedly, recruitment of this pool of neural stem cells, and their differentiation into oligodendrocytes, is significantly enhanced by genetic or pharmacological inhibition of Gli1. Importantly, complete inhibition of canonical hedgehog signalling was ineffective, indicating that the role of Gli1 both in augmenting hedgehog signalling and in retarding myelination is specialized. Indeed, inhibition of Gli1 improves the functional outcome in a relapsing/remitting model of experimental autoimmune encephalomyelitis and is neuroprotective. Thus, endogenous neural stem cells can be mobilized for the repair of demyelinated lesions by inhibiting Gli1, identifying a new therapeutic avenue for the treatment of demyelinating disorders.
C1 [Samanta, Jayshree; Grund, Ethan M.; Fishell, Gord; Salzer, James L.] NYU, Sch Med, Dept Neurosci & Physiol, Inst Neurosci, New York, NY 10016 USA.
   [Silva, Hernandez M.; Lafaille, Juan J.] NYU, Sch Med, Kimmel Ctr Biol & Med, Skirball Inst, New York, NY 10016 USA.
C3 New York University; New York University
RP Samanta, J (corresponding author), NYU, Sch Med, Dept Neurosci & Physiol, Inst Neurosci, New York, NY 10016 USA.
EM jayshree.samanta@nyumc.org; james.salzer@nyumc.org
FU New York State Department of Health Stem Cell Board; National Multiple Sclerosis Society
NR 32
TC 136
Z9 158
U1 0
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 OCT 15
PY 2015
VL 526
IS 7573
BP 448
EP +
DI 10.1038/nature14957
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200055
PM 26416758
DA 2026-03-09
ER

PT J
AU Guo, P
   Shin, J
   Greenaway, AG
   Min, JG
   Su, J
   Choi, HJ
   Liu, LF
   Cox, PA
   Hong, SB
   Wright, PA
   Zou, XD
AF Guo, Peng
   Shin, Jiho
   Greenaway, Alex G.
   Min, Jung Gi
   Su, Jie
   Choi, Hyun June
   Liu, Leifeng
   Cox, Paul A.
   Hong, Suk Bong
   Wright, Paul A.
   Zou, Xiaodong
TI A zeolite family with expanding structural complexity and embedded isoreticular structures
SO NATURE
LA English
DT Article
ID diffraction; design; frameworks; co2
AB The prediction and synthesis of new crystal structures enable the targeted preparation of materials with desired properties. Among porous solids, this has been achieved for metal-organic frameworks(1-3), but not for the more widely applicable zeolites(4,5), where new materials are usually discovered using exploratory synthesis. Although millions of hypothetical zeolite structures have been proposed(6,7), not enough is known about their synthesis mechanism to allow any given structure to be prepared. Here we present an approach that combines structure solution with structure prediction, and inspires the targeted synthesis of new super-complex zeolites. We used electron diffraction to identify a family of related structures and to discover the structural 'coding' within them. This allowed us to determine the complex, and previously unknown, structure of zeolite ZSM-25 (ref. 8), which has the largest unit-cell volume of all known zeolites (91,554 cubic angstroms) and demonstrates selective CO2 adsorption. By extending our method, we were able to predict other members of a family of increasingly complex, but structurally related, zeolites and to synthesize two more-complex zeolites in the family, PST-20 and PST-25, with much larger cell volumes (166,988 and 275,178 cubic angstroms, respectively) and similar selective adsorption properties. Members of this family have the same symmetry, but an expanding unit cell, and are related by hitherto unrecognized structural principles; we call these family members embedded isoreticular zeolite structures.
C1 [Guo, Peng; Su, Jie; Liu, Leifeng; Zou, Xiaodong] Stockholm Univ, Inorgan & Struct Chem, Dept Mat & Environm Chem, SE-10691 Stockholm, Sweden.
   [Guo, Peng; Su, Jie; Liu, Leifeng; Zou, Xiaodong] Stockholm Univ, Berzelii Ctr EXSELENT Porous Mat, SE-10691 Stockholm, Sweden.
   [Shin, Jiho; Min, Jung Gi; Choi, Hyun June; Hong, Suk Bong] POSTECH, Ctr Ordered Nanoporous Mat Synth, Sch Environm Sci & Engn, Pohang 790784, South Korea.
   [Greenaway, Alex G.; Wright, Paul A.] Univ St Andrews, EaStCHEM Sch Chem, St Andrews KY16 9ST, Fife, Scotland.
   [Cox, Paul A.] Univ Portsmouth, Sch Pharm & Biomed Sci, Portsmouth PO1 2DT, Hants, England.
C3 Stockholm University; Stockholm University; Pohang University of Science & Technology (POSTECH); University of St Andrews; University of Portsmouth
RP Hong, SB (corresponding author), POSTECH, Ctr Ordered Nanoporous Mat Synth, Sch Environm Sci & Engn, Pohang 790784, South Korea.
EM sbhong@postech.ac.kr; paw2@st-andrews.ac.uk; xzou@mmk.su.se
FU Swedish Research Council (VR); Swedish Governmental Agency for Innovation Systems (VINNOVA); Rontgen-Angstrom Cluster through the project grant MATsynCELL; Knut and Alice Wallenberg Foundation through the project grant 3DEM-NATUR; NCRI [2012R1A3A-2048833]; BK 21-plus programmes through the National Research Foundation of Korea; UK EPSRC [EP/J02077X/1]; Knut and Alice Wallenberg Foundation; Engineering and Physical Sciences Research Council [EP/J02077X/1] Funding Source: researchfish; EPSRC [EP/J02077X/1] Funding Source: UKRI
NR 41
TC 176
Z9 191
U1 6
U2 471
PU NATURE PUBLISHING 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 6
PY 2015
VL 524
IS 7563
BP 74
EP U143
DI 10.1038/nature14575
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO2QS
UT WOS:000359002300034
PM 26176918
DA 2026-03-09
ER

PT J
AU Lamichhaney, S
   Berglund, J
   Almén, MS
   Maqbool, K
   Grabherr, M
   Martinez-Barrio, A
   Promerova, M
   Rubin, CJ
   Wang, C
   Zamani, N
   Grant, BR
   Grant, PR
   Webster, MT
   Andersson, L
AF Lamichhaney, Sangeet
   Berglund, Jonas
   Almen, Markus Sallman
   Maqbool, Khurram
   Grabherr, Manfred
   Martinez-Barrio, Alvaro
   Promerova, Marta
   Rubin, Carl-Johan
   Wang, Chao
   Zamani, Neda
   Grant, B. Rosemary
   Grant, Peter R.
   Webster, Matthew T.
   Andersson, Leif
TI Evolution of Darwin's finches and their beaks revealed by genome sequencing
SO NATURE
LA English
DT Article
ID frontonasal dysplasia; geospiza-difficilis; adaptive radiation; speciation; galapagos; alignment; gene; association; populations; morphology
AB Darwin's finches, inhabiting the Galapagos archipelago and Cocos Island, constitute an iconic model for studies of speciation and adaptive evolution. Here we report the results of whole-genome re-sequencing of 120 individuals representing all of the Darwin's finch species and two close relatives' Phylogenetic analysis reveals important discrepancies with the phenotype-based taxonomy. We find extensive evidence for interspecific gene flow throughout the radiation. Hybridization has given rise to species of mixed ancestry. A 240 kilobase haplotype encompassing the ALX1 gene that encodes a transcription factor affecting craniofacial. development is strongly associated with beak shape diversity across Darwin's finch species as well as within the medium ground finch (Geospiza fortis) a species that has undergone rapid evolution of beak shape in response to environmental changes. The ALX1 haplotype has contributed to diversification of beak shapes among the Darwin's finches and thereby, to an expanded utilization of food resources.
C1 [Lamichhaney, Sangeet; Berglund, Jonas; Almen, Markus Sallman; Grabherr, Manfred; Martinez-Barrio, Alvaro; Promerova, Marta; Rubin, Carl-Johan; Wang, Chao; Zamani, Neda; Webster, Matthew T.; Andersson, Leif] Uppsala Univ, Dept Med Biochem & Microbiol, SE-75123 Uppsala, Sweden.
   [Maqbool, Khurram; Andersson, Leif] Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden.
   [Zamani, Neda] Umea Univ, Dept Plant Physiol, SE-90187 Umea, Sweden.
   [Grant, B. Rosemary; Grant, Peter R.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA.
   [Andersson, Leif] Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.
C3 Uppsala University; Swedish University of Agricultural Sciences; Umea University; Princeton University; Texas A&M University System; Texas A&M University College Station
RP Andersson, L (corresponding author), Uppsala Univ, Dept Med Biochem & Microbiol, SE-75123 Uppsala, Sweden.
EM leif.andersson@imbim.uu.se
FU National Science Foundation (USA); Knut and Alice Wallenberg Foundation; Uppsala University and Hospital, SciLifeLab; Swedish Research Council [80576801, 70374401]
NR 59
TC 696
Z9 839
U1 24
U2 987
PU NATURE PUBLISHING 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 19
PY 2015
VL 518
IS 7539
BP 371
EP 375
DI 10.1038/nature14181
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400036
PM 25686609
DA 2026-03-09
ER

PT J
AU Schulkey, CE
   Regmi, SD
   Magnan, RA
   Danzo, MT
   Luther, H
   Hutchinson, AK
   Panzer, AA
   Grady, MM
   Wilson, DB
   Jay, PY
AF Schulkey, Claire E.
   Regmi, Suk D.
   Magnan, Rachel A.
   Danzo, Megan T.
   Luther, Herman
   Hutchinson, Alayna K.
   Panzer, Adam A.
   Grady, Mary M.
   Wilson, David B.
   Jay, Patrick Y.
TI The maternal-age-associated risk of congenital heart disease is modifiable
SO NATURE
LA English
DT Article
ID chromosome substitution strains; cardiovascular defects; birth-defects; malformations; mice; epidemiology; population; metabolome; mutations; council
AB Maternal age is a risk factor for congenital heart disease even in the absence of any chromosomal abnormality in the newborn(1-7). Whether the basis of this risk resides with the mother or oocyte is unknown. The impact of maternal age on congenital heart disease can be modelled in mouse pups that harbour a mutation of the cardiac transcription factor gene Nkx2-5 (ref. 8). Here, reciprocal ovarian transplants between young and old mothers establish a maternal basis for the age-associated risk in mice. A high-fat diet does not accelerate the effect of maternal ageing, so hyperglycaemia and obesity do not simply explain the mechanism. The age-associated risk varies with the mother's strain background, making it a quantitative genetic trait. Most remarkably, voluntary exercise, whether begun by mothers at a young age or later in life, can mitigate the risk when they are older. Thus, even when the offspring carry a causal mutation, an intervention aimed at the mother can meaningfully reduce their risk of congenital heart disease.
C1 [Schulkey, Claire E.; Regmi, Suk D.; Magnan, Rachel A.; Danzo, Megan T.; Luther, Herman; Hutchinson, Alayna K.; Panzer, Adam A.; Grady, Mary M.; Wilson, David B.; Jay, Patrick Y.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA.
   [Wilson, David B.] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA.
   [Jay, Patrick Y.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA.
C3 Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL)
RP Jay, PY (corresponding author), Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA.
EM jay_p@kids.wustl.edu
FU Ruth L. Kirschstein National Research Service Award from the Developmental Cardiology and Pulmonary Training Program (National Institutes ofHealth (NIH)) [T32HL007873]; Children's Discovery Institute of Washington University; St Louis Children's Hospital, the Children's Heart Foundation; NIH [R01 HL105857, P30 DK52574, P30 DK020579]; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK020579, P30DK052574] Funding Source: NIH RePORTER
NR 27
TC 69
Z9 81
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 APR 9
PY 2015
VL 520
IS 7546
BP 230
EP U225
DI 10.1038/nature14361
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CF3NA
UT WOS:000352454600041
PM 25830876
DA 2026-03-09
ER

PT J
AU Wang, LF
   Zhou, Y
   Xu, L
   Xiao, R
   Lu, XY
   Chen, L
   Chong, J
   Li, HR
   He, C
   Fu, XD
   Wang, D
AF Wang, Lanfeng
   Zhou, Yu
   Xu, Liang
   Xiao, Rui
   Lu, Xingyu
   Chen, Liang
   Chong, Jenny
   Li, Hairi
   He, Chuan
   Fu, Xiang-Dong
   Wang, Dong
TI Molecular basis for 5-carboxycytosine recognition by RNA polymerase II elongation complex
SO NATURE
LA English
DT Article
ID structural basis; dna methylation; substrate-specificity; tet proteins; transcription; 5-formylcytosine; 5-carboxylcytosine; 5-methylcytosine; reveals; mechanism
AB DNA methylation at selective cytosine residues (5-methylcytosine (5mC)) and their removal by TET-mediated DNA demethylation are critical for setting up pluripotent states in early embryonic development(1,2). TET enzymes successively convert 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), with 5fC and 5caC subject to removal by thymine DNA glycosylase (TDG) in conjunction with base excision repair(1-6). Early reports indicate that 5fC and 5caC could be stably detected on enhancers, promoters and gene bodies, with distinct effects on gene expression, but the mechanisms have remained elusive(7,8). Here we determined the X-ray crystal structure of yeast elongating RNA polymerase II (Pol II) in complex with a DNA template containing oxidized 5mCs, revealing specific hydrogen bonds between the 5-carboxyl group of 5caC and the conserved epi-DNA recognition loop in the polymerase. This causes a positional shift for incoming nucleoside 5'-triphosphate (NTP), thus compromising nucleotide addition. To test the implication of this structural insight in vivo, we determined the global effect of increased 5fC/5caC levels on transcription, finding that such DNA modifications indeed retarded Pol II elongation on gene bodies. These results demonstrate the functional impact of oxidized 5mCs on gene expression and suggest a novel role for Pol II as a specific and direct epigenetic sensor during transcription elongation.
C1 [Wang, Lanfeng; Xu, Liang; Chong, Jenny; Wang, Dong] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA.
   [Zhou, Yu; Xiao, Rui; Chen, Liang; Li, Hairi; Fu, Xiang-Dong] Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA.
   [Lu, Xingyu; He, Chuan] Univ Chicago, Dept Chem, Dept Biochem & Mol Biol, Chicago, IL 60637 USA.
   [Lu, Xingyu; He, Chuan] Univ Chicago, Inst Biophys Dynam, Howard Hughes Med Inst, Chicago, IL 60637 USA.
C3 University of California System; University of California San Diego; University of California System; University of California San Diego; University of Chicago; Howard Hughes Medical Institute; University of Chicago
RP Wang, D (corresponding author), Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, 9500 Gilman Dr, La Jolla, CA 92093 USA.
EM xdfu@ucsd.edu; dongwang@ucsd.edu
FU National Institutes of Health (NIH) [GM102362]; Kimmel Scholars award from the Sidney Kimmel Foundation for Cancer Research; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego; NIH [HG006827, GM052872, HG004659]; Howard Hughes Medical Institute; National Human Genome Research Institute [R01HG004659, R01HG006827] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM102362] Funding Source: NIH RePORTER
NR 38
TC 129
Z9 153
U1 1
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 JUL 30
PY 2015
VL 523
IS 7562
BP 621
EP +
DI 10.1038/nature14482
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN7ZL
UT WOS:000358655200051
PM 26123024
DA 2026-03-09
ER

PT J
AU Mbengue, A
   Bhattacharjee, S
   Pandharkar, T
   Liu, HN
   Estiu, G
   Stahelin, RV
   Rizk, SS
   Njimoh, DL
   Ryan, Y
   Chotivanich, K
   Nguon, C
   Ghorbal, M
   Lopez-Rubio, JJ
   Pfrender, M
   Emrich, S
   Mohandas, N
   Dondorp, AM
   Wiest, O
   Haldar, K
AF Mbengue, Alassane
   Bhattacharjee, Souvik
   Pandharkar, Trupti
   Liu, Haining
   Estiu, Guillermina
   Stahelin, Robert V.
   Rizk, Shahir S.
   Njimoh, Dieudonne L.
   Ryan, Yana
   Chotivanich, Kesinee
   Nguon, Chea
   Ghorbal, Mehdi
   Lopez-Rubio, Jose-Juan
   Pfrender, Michael
   Emrich, Scott
   Mohandas, Narla
   Dondorp, Arjen M.
   Wiest, Olaf
   Haldar, Kasturi
TI A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria
SO NATURE
LA English
DT Article
ID protein; ubiquitin; dynamics; artesunate; accuracy; well
AB Artemisinins are the cornerstone of anti-malarial drugs'. Emergence and spread of resistance to them' raises risk of wiping out recent gains achieved in reducing worldwide malaria burden and threatens future malaria control and elimination on a global level. Genome-wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance'''. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinosito1-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase, as well as its lipid product phosphatidylinosito1-3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signalling in which transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination.
C1 [Mbengue, Alassane; Bhattacharjee, Souvik; Pandharkar, Trupti; Liu, Haining; Estiu, Guillermina; Stahelin, Robert V.; Rizk, Shahir S.; Njimoh, Dieudonne L.; Ryan, Yana; Wiest, Olaf; Haldar, Kasturi] Univ Notre Dame, Boler Parseghian Ctr Rare & Neglected Dis, Notre Dame, IN 46556 USA.
   [Mbengue, Alassane; Bhattacharjee, Souvik; Pandharkar, Trupti; Rizk, Shahir S.; Njimoh, Dieudonne L.; Ryan, Yana; Pfrender, Michael; Haldar, Kasturi] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA.
   [Liu, Haining; Estiu, Guillermina; Stahelin, Robert V.; Wiest, Olaf] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA.
   [Stahelin, Robert V.] Indiana Univ Sch Med, Dept Biochem & Mol Biol, South Bend, IN 46617 USA.
   [Njimoh, Dieudonne L.] Univ Buea, Fac Sci, Dept Biochem & Mol Biol, Buea, Southwest Regio, Cameroon.
   [Chotivanich, Kesinee; Dondorp, Arjen M.] Mahidol Univ, Fac Trop Med, Bangkok 10400, Thailand.
   [Nguon, Chea] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh 12302, Cambodia.
   [Ghorbal, Mehdi; Lopez-Rubio, Jose-Juan] Univ Montpellier 1&2 MiVEGEC, CNRS 5290, IRD 224, Montpellier, France.
   [Emrich, Scott] Univ Notre Dame, Dept Comp Sci & Engn, Notre Dame, IN 46556 USA.
   [Mohandas, Narla] New York Blood Ctr, New York, NY 10032 USA.
   [Dondorp, Arjen M.] Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford OX3 7BN, England.
   [Wiest, Olaf] Peking Univ, Shenzhen Grad Sch, Lab Chem Genom, Lab Computat Chem & Drug Design, Shenzhen 518055, Peoples R China.
C3 University of Notre Dame; University of Notre Dame; University of Notre Dame; Indiana University System; Indiana University South Bend; Mahidol University; National Center Parasitology, Entomology & Malaria Control; Institut de Recherche pour le Developpement (IRD); Universite de Montpellier; University of Notre Dame; New York Blood Center; University of Oxford; Peking University; Peking University Shenzhen Graduate School (PKU Shenzhen)
RP Haldar, K (corresponding author), Univ Notre Dame, Boler Parseghian Ctr Rare & Neglected Dis, Notre Dame, IN 46556 USA.
EM khaldar@nd.edu
FU NIH [HL069630, AI039071, HL078826, AI081077, DK26263]; Notre Dame International
NR 47
TC 439
Z9 539
U1 4
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 APR 30
PY 2015
VL 520
IS 7549
BP 683
EP U246
DI 10.1038/nature14412
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700051
PM 25874676
DA 2026-03-09
ER

PT J
AU Thi, EP
   Mire, CE
   Lee, ACH
   Geisbert, JB
   Zhou, JZ
   Agans, KN
   Snead, NM
   Deer, DJ
   Barnard, TR
   Fenton, KA
   MacLachlan, I
   Geisbert, TW
AF Thi, Emily P.
   Mire, Chad E.
   Lee, Amy C. H.
   Geisbert, Joan B.
   Zhou, Joy Z.
   Agans, Krystle N.
   Snead, Nicholas M.
   Deer, Daniel J.
   Barnard, Trisha R.
   Fenton, Karla A.
   MacLachlan, Ian
   Geisbert, Thomas W.
TI Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primates
SO NATURE
LA English
DT Article
ID hepatitis-c virus; hairpin rnas; disease; mice
AB The current outbreak of Ebola virus in West Africa is unprecedented, causing more cases and fatalities than all previous outbreaks combined, and has yet to be controlled(1). Several post-exposure interventions have been employed under compassionate use to treat patients repatriated to Europe and the United States(2). However, the in vivo efficacy of these interventions against the new outbreak strain of Ebola virus is unknown. Here we show that lipid-nanoparticle-encapsulated short interfering RNAs (siRNAs) rapidly adapted to target the Makona outbreak strain of Ebola virus are able to protect 100% of rhesus monkeys against lethal challenge when treatment was initiated at 3 days after exposure while animals were viraemic and clinically ill. Although all infected animals showed evidence of advanced disease including abnormal haematology, blood chemistry and coagulopathy, siRNA-treated animals had milder clinical features and fully recovered, while the untreated control animals succumbed to the disease. These results represent the first, to our knowledge, successful demonstration of therapeutic anti-Ebola virus efficacy against the new outbreak strain in nonhuman primates and highlight the rapid development of lipid-nanoparticle-delivered siRNA as a countermeasure against this highly lethal human disease.
C1 [Thi, Emily P.; Lee, Amy C. H.; Zhou, Joy Z.; Snead, Nicholas M.; Barnard, Trisha R.; MacLachlan, Ian] Tekmira Pharmaceut, Burnaby, BC V5J 5J8, Canada.
   [Mire, Chad E.; Geisbert, Joan B.; Agans, Krystle N.; Deer, Daniel J.; Fenton, Karla A.; Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77550 USA.
   [Mire, Chad E.; Geisbert, Joan B.; Agans, Krystle N.; Deer, Daniel J.; Fenton, Karla A.; Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77550 USA.
C3 University of Texas System; University of Texas Medical Branch Galveston; University of Texas System; University of Texas Medical Branch Galveston
RP Geisbert, TW (corresponding author), Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77550 USA.
EM twgeisbe@utmb.edu
FU Department of Health and Human Services, National Institutes of Health [U19AI109711]
NR 21
TC 209
Z9 242
U1 1
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 MAY 21
PY 2015
VL 521
IS 7552
BP 362
EP +
DI 10.1038/nature14442
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CI5RM
UT WOS:000354816500058
PM 25901685
DA 2026-03-09
ER

PT J
AU Wu, J
   Okamura, D
   Li, M
   Suzuki, K
   Luo, CY
   Ma, L
   He, YP
   Li, ZW
   Benner, C
   Tamura, I
   Krause, MN
   Nery, JR
   Du, TT
   Zhang, ZZ
   Hishida, T
   Takahashi, Y
   Aizawa, E
   Kim, NY
   Lajara, J
   Guillen, P
   Campistol, JM
   Esteban, CR
   Ross, PJ
   Saghatelian, A
   Ren, B
   Ecker, JR
   Belmonte, JCI
AF Wu, Jun
   Okamura, Daiji
   Li, Mo
   Suzuki, Keiichiro
   Luo, Chongyuan
   Ma, Li
   He, Yupeng
   Li, Zhongwei
   Benner, Chris
   Tamura, Isao
   Krause, Marie N.
   Nery, Joseph R.
   Du, Tingting
   Zhang, Zhuzhu
   Hishida, Tomoaki
   Takahashi, Yuta
   Aizawa, Emi
   Kim, Na Young
   Lajara, Jeronimo
   Guillen, Pedro
   Campistol, Josep M.
   Esteban, Concepcion Rodriguez
   Ross, Pablo J.
   Saghatelian, Alan
   Ren, Bing
   Ecker, Joseph R.
   Belmonte, Juan Carlos Izpisua
TI An alternative pluripotent state confers interspecies chimaeric competency
SO NATURE
LA English
DT Article
ID embryonic stem-cells; primitive streak; mouse embryos; homologous recombination; regulatory regions; self-renewal; culture; embryogenesis; specification; transcription
AB Pluripotency, the ability to generate any cell type of the body, is an evanescent attribute of embryonic cells. Transitory pluripotent cells can be captured at different time points during embryogenesis and maintained as embryonic stem cells or epiblast stem cells in culture. Since ontogenesis is a dynamic process in both space and time, it seems counterintuitive that these two temporal states represent the full spectrum of organismal pluripotency. Here we show that by modulating culture parameters, a stem-cell type with unique spatial characteristics and distinct molecular and functional features, designated as region-selective pluripotent stem cells (rsPSCs), can be efficiently obtained from mouse embryos and primate pluripotent stem cells, including humans. The ease of culturing and editing the genome of human rsPSCs offers advantages for regenerative medicine applications. The unique ability of human rsPSCs to generate post-implantation interspecies chimaeric embryos may facilitate our understanding of early human development and evolution.
C1 [Wu, Jun; Okamura, Daiji; Li, Mo; Suzuki, Keiichiro; Ma, Li; Li, Zhongwei; Tamura, Isao; Krause, Marie N.; Hishida, Tomoaki; Takahashi, Yuta; Aizawa, Emi; Kim, Na Young; Esteban, Concepcion Rodriguez; Belmonte, Juan Carlos Izpisua] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA.
   [Luo, Chongyuan; Ecker, Joseph R.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA.
   [Luo, Chongyuan; He, Yupeng; Nery, Joseph R.; Zhang, Zhuzhu; Ecker, Joseph R.] Salk Inst Biol Studies, Genom Anal Lab, La Jolla, CA 92037 USA.
   [Benner, Chris] Salk Inst Biol Studies, Integrated Genom, La Jolla, CA 92037 USA.
   [Du, Tingting; Ren, Bing] Univ Calif San Diego, Ludwig Inst Canc Res, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA.
   [Hishida, Tomoaki] Univ Tsukuba, Tsukuba Adv Res Alliance, Life Sci Ctr, Tsukuba, Ibaraki 3058577, Japan.
   [Lajara, Jeronimo; Guillen, Pedro] Univ Catolica, Med, Guadalupe 30107, Spain.
   [Guillen, Pedro] Fdn Pedro Guillen, Clin Cemtro, Madrid 28035, Spain.
   [Campistol, Josep M.] Hosp Clin Barcelona, E-08036 Barcelona, Spain.
   [Ross, Pablo J.] Univ Calif Davis, Davis, CA 95616 USA.
   [Saghatelian, Alan] Salk Inst Biol Studies, Peptide Biol Lab, La Jolla, CA 92037 USA.
C3 Salk Institute; Salk Institute; Howard Hughes Medical Institute; Salk Institute; Salk Institute; Ludwig Institute for Cancer Research; University of California System; University of California San Diego; University of Tsukuba; Universidad Catolica de Valencia San Vicente Martir; University of Barcelona; Hospital Clinic de Barcelona; University of California System; University of California Davis; Salk Institute
RP Belmonte, JCI (corresponding author), Salk Inst Biol Studies, Gene Express Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA.
EM belmonte@salk.edu
FU California Institute for Regenerative Medicine Training Grant; UCAM; Fundacion Pedro Guillen; G. Harold and Leila Y. Mathers Charitable Foundation; Leona M. and Harry B. Helmsley Charitable Trust; Moxie Foundation
NR 57
TC 199
Z9 235
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 MAY 21
PY 2015
VL 521
IS 7552
BP 316
EP +
DI 10.1038/nature14413
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CI5RM
UT WOS:000354816500048
PM 25945737
DA 2026-03-09
ER

PT J
AU Spitale, JN
   Hurford, TA
   Rhoden, AR
   Berkson, EE
   Platts, SS
AF Spitale, Joseph N.
   Hurford, Terry A.
   Rhoden, Alyssa R.
   Berkson, Emily E.
   Platts, Symeon S.
TI Curtain eruptions from Enceladus' south-polar terrain
SO NATURE
LA English
DT Article
ID jets
AB Observations of the south pole of the Saturnian moon Enceladus revealed large rifts in the south-polar terrain, informally called 'tiger stripes', named Alexandria, Baghdad, Cairo and Damascus Sulci. These fractures have been shown to be the sources of the observed jets of water vapour and icy particles(1-4) and to exhibit higher temperatures than the surrounding terrain(5,6). Subsequent observations have focused on obtaining close-up imaging of this region to better characterize these emissions. Recent work(7) examined those newer data sets and used triangulation of discrete jets3 to produce maps of jetting activity at various times. Here we show that much of the eruptive activity can be explained by broad, curtain-like eruptions. Optical illusions in the curtain eruptions resulting from a combination of viewing direction and local fracture geometry produce image features that were probably misinterpreted previously as discrete jets. We present maps of the total emission along the fractures, rather than just the jet-like component, for five times during an approximately one-year period in 2009 and 2010. An accurate picture of the style, timing and spatial distribution of the south-polar eruptions is crucial to evaluating theories for the mec(h)anism controlling the eruptions.
C1 [Spitale, Joseph N.] Planetary Sci Inst, Tucson, AZ 85719 USA.
   [Hurford, Terry A.] NASA, Goddard Space Flight Ctr, Greenbelt, MD 20771 USA.
   [Rhoden, Alyssa R.] Johns Hopkins Univ, Appl Phys Lab, Laurel, MD 20723 USA.
   [Berkson, Emily E.] Rochester Inst Technol, Rochester, NY 14623 USA.
   [Platts, Symeon S.] Univ Arizona, Film & Televis Dept, Tucson, AZ 85721 USA.
C3 National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center; Johns Hopkins University; Johns Hopkins University Applied Physics Laboratory; Rochester Institute of Technology; University of Arizona
RP Spitale, JN (corresponding author), Planetary Sci Inst, 1700 East Ft Lowell Rd,Suite 106, Tucson, AZ 85719 USA.
EM jnspitale@psi.edu
FU Cassini Data Analysis and Participating Scientists Program [NNX13AG45G]
NR 7
TC 55
Z9 66
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 MAY 7
PY 2015
VL 521
IS 7550
BP 57
EP U368
DI 10.1038/nature14368
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH4YS
UT WOS:000354040900031
PM 25951283
DA 2026-03-09
ER

PT J
AU von Appen, A
   Kosinski, J
   Sparks, L
   Ori, A
   DiGuilio, AL
   Vollmer, B
   Mackmull, MT
   Banterle, N
   Parca, L
   Kastritis, P
   Buczak, K
   Mosalaganti, S
   Hagen, W
   Andres-Pons, A
   Lemke, EA
   Bork, P
   Antonin, W
   Glavy, JS
   Bui, KH
   Beck, M
AF von Appen, Alexander
   Kosinski, Jan
   Sparks, Lenore
   Ori, Alessandro
   DiGuilio, Amanda L.
   Vollmer, Benjamin
   Mackmull, Marie-Therese
   Banterle, Niccolo
   Parca, Luca
   Kastritis, Panagiotis
   Buczak, Katarzyna
   Mosalaganti, Shyamal
   Hagen, Wim
   Andres-Pons, Amparo
   Lemke, Edward A.
   Bork, Peer
   Antonin, Wolfram
   Glavy, Joseph S.
   Bui, Khanh Huy
   Beck, Martin
TI In situ structural analysis of the human nuclear pore complex
SO NATURE
LA English
DT Article
ID protein-structure; architecture; reveals; phosphorylation; stoichiometry; tomography; prediction; module
AB Nuclear pore complexes are fundamental components of all eukaryotic cells that mediate nucleocytoplasmic exchange. Determining their 110-megadalton structure imposes a formidable challenge and requires in situ structural biology approaches. Of approximately 30 nucleoporins (Nups), 15 are structured and form the Y and innerring complexes. These two major scaffolding modules assemble in multiple copies into an eight-fold rotationally symmetric structure that fuses the inner and outer nuclear membranes to forma central channel of similar to 60 nm in diameter(1). The scaffold is decorated with transport-channel Nups that often contain phenylalanine-repeat sequences and mediate the interaction with cargo complexes. Although the architectural arrangement of parts of the Y complex has been elucidated, it is unclear how exactly it oligomerizes in situ. Here we combine cryo-electron tomography with mass spectrometry, biochemical analysis, perturbation experiments and structural modelling to generate, to our knowledge, the most comprehensive architectural model of the human nuclear pore complex to date. Our data suggest previously unknown protein interfaces across Y complexes and to inner-ring complex members. We show that the transport-channel Nup358 (also known as Ranbp2) has a previously unanticipated role in Y-complex oligomerization. Our findings blur the established boundaries between scaffold and transport-channel Nups. We conclude that, similar to coated vesicles, several copies of the same structural building block-although compositionally identical-engage in different local sets of interactions and conformations.
C1 [von Appen, Alexander; Kosinski, Jan; Sparks, Lenore; Ori, Alessandro; Mackmull, Marie-Therese; Banterle, Niccolo; Parca, Luca; Kastritis, Panagiotis; Buczak, Katarzyna; Mosalaganti, Shyamal; Hagen, Wim; Andres-Pons, Amparo; Lemke, Edward A.; Bork, Peer; Bui, Khanh Huy; Beck, Martin] European Mol Biol Lab, Struct & Computat Biol Unit, D-69117 Heidelberg, Germany.
   [DiGuilio, Amanda L.; Glavy, Joseph S.] Stevens Inst Technol, Dept Chem Chem Biol & Biomed Engn, Hoboken, NJ 07030 USA.
   [Vollmer, Benjamin; Antonin, Wolfram] Max Planck Gesell, Friedrich Miescher Lab, D-72076 Tubingen, Germany.
   [Bui, Khanh Huy] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ H3A 0C7, Canada.
C3 European Molecular Biology Laboratory (EMBL); Stevens Institute of Technology; Eberhard Karls University of Tubingen; Max Planck Society; McGill University
RP Bui, KH (corresponding author), European Mol Biol Lab, Struct & Computat Biol Unit, D-69117 Heidelberg, Germany.
EM huy.bui@mcgill.ca; martin.beck@embl.de
FU EMBL's mechanical workshop; Electron Microscopy and Proteomics Core Facilities; Centre for Statistical Data Analysis; Swiss National Science Foundation; European Molecular Biology Organization; Marie Curie Actions; Alexander von Humboldt Foundation; Robert Crooks Stanley Fellowship at the Stevens Institute of Technology; National Institute on Aging (NIA) [1R21AG047433-01]; EMBL Interdisciplinary Postdoc Programme under Marie Curie COFUND Actions; Ignition Grant Initiative from Stevens Institute of Technology; NIA [1R21AG047433-01]; EMBL; European Research Council [309271-NPCAtlas]
NR 43
TC 316
Z9 355
U1 1
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 1
PY 2015
VL 526
IS 7571
BP 140
EP +
DI 10.1038/nature15381
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS5CY
UT WOS:000362095100050
PM 26416747
DA 2026-03-09
ER

PT J
AU Duggin, IG
   Aylett, CHS
   Walsh, JC
   Michie, KA
   Wang, Q
   Turnbull, L
   Dawson, EM
   Harry, EJ
   Whitchurch, CB
   Amos, LA
   Löwe, J
AF Duggin, Iain G.
   Aylett, Christopher H. S.
   Walsh, James C.
   Michie, Katharine A.
   Wang, Qing
   Turnbull, Lynne
   Dawson, Emma M.
   Harry, Elizabeth J.
   Whitchurch, Cynthia B.
   Amos, Linda A.
   Loewe, Jan
TI CetZ tubulin-like proteins control archaeal cell shape
SO NATURE
LA English
DT Article
ID haloferax-volcanii; ftsz; evolution; sequence; visualization; halobacterium; refinement; bacteria; homolog; domains
AB Tubulin is a major component of the eukaryotic cytoskeleton, controlling cell shape, structure and dynamics, whereas its bacterial homologue FtsZ establishes the cytokinetic ring that constricts during cell division(1,2). How such different roles of tubulin and FtsZ evolved is unknown. Studying Archaea may provide clues as these organisms share characteristics with Eukarya and Bacteria(3). Here we report the structure and function of proteins from a distinct family related to tubulin and FtsZ, named CetZ, which co-exists with FtsZ in many archaea. CetZ X-ray crystal structures showed the FtsZ/tubulin superfamily fold, and one crystal form contained sheets of protofilaments, suggesting a structural role. However, inactivation of CetZ proteins in Haloferax volcanii did not affect cell division. Instead, CetZ1 was required for differentiation of the irregular plate-shaped cells into a rod-shaped cell type that was essential for normal swimming motility. CetZ1 formed dynamic cytoskeletal structures in vivo, relating to its capacity to remodel the cell envelope and direct rod formation. CetZ2 was also implicated in H. volcanii cell shape control. Our findings expand the known roles of the FtsZ/tubulin superfamily to include archaeal cell shape dynamics, suggesting that a cytoskeletal role might predate eukaryotic cell evolution, and they support the premise that a major function of the microbial rod shape is to facilitate swimming.
C1 [Duggin, Iain G.; Aylett, Christopher H. S.; Michie, Katharine A.; Wang, Qing; Amos, Linda A.; Loewe, Jan] MRC, Mol Biol Lab, Cambridge CB2 0QH, England.
   [Duggin, Iain G.; Walsh, James C.; Turnbull, Lynne; Dawson, Emma M.; Harry, Elizabeth J.; Whitchurch, Cynthia B.] Univ Technol Sydney, Ithree Inst, Sydney, NSW 2007, Australia.
   [Walsh, James C.] Univ New S Wales, Sch Phys, Sydney, NSW 2052, Australia.
C3 MRC Laboratory Molecular Biology; University of Technology Sydney; University of New South Wales Sydney
RP Duggin, IG (corresponding author), MRC, Mol Biol Lab, Francis Crick Ave, Cambridge CB2 0QH, England.
EM Iain.Duggin@uts.edu.au
FU Medical Research Council, UK [U105184326]; University of Technology Sydney, Australia; NHMRC, Australia [SRF 571905]; Medical Research Council [MC_U105184326] Funding Source: researchfish; MRC [MC_U105184326] Funding Source: UKRI
NR 53
TC 116
Z9 147
U1 0
U2 61
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 19
PY 2015
VL 519
IS 7543
BP 362
EP +
DI 10.1038/nature13983
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD6AY
UT WOS:000351171900043
PM 25533961
DA 2026-03-09
ER

PT J
AU Li, HB
   Yuen, KH
   Otto, F
   Leung, PK
   Sridharan, TK
   Zhang, QZ
   Liu, HY
   Tang, YW
   Qiu, KP
AF Li, Hua-bai
   Yuen, Ka Ho
   Otto, Frank
   Leung, Po Kin
   Sridharan, T. K.
   Zhang, Qizhou
   Liu, Hauyu
   Tang, Ya-Wen
   Qiu, Keping
TI Self-similar fragmentation regulated by magnetic fields in a region forming massive stars
SO NATURE
LA English
DT Article
ID ngc 6334 i; submillimeter polarization; zeeman observations; filamentary clouds; molecular clouds; collapse; dust; dimensions; kinematics; strengths
AB Most molecular clouds are filamentary or elongated(1-3). For those forming low-mass stars (<8 solar masses), the competition between self-gravity and turbulent pressure along the dynamically dominant intercloud magnetic field (10 to 100 parsecs) shapes the clouds to be elongated either perpendicularly(4) or parallel(5) to the fields. A recent study(6) also suggested that on the scales of 0.1 to 0.01 parsecs, such fields are dynamically important within cloud cores forming massive stars (>8 solar masses). But whether the core fieldmorphologies are inherited from the intercloud medium or governed by cloud turbulence is unknown, as is the effect of magnetic fields on cloud fragmentation at scales of 10 to 0.1 parsecs(7-9). Here we report magnetic-field maps inferred from polarimetric observations of NGC6334, a region forming massive stars, on the 100 to 0.01 parsec scale. NGC6334 hosts young star-forming sites(10-12) where fields are not severely affected by stellar feedback, and their directions do not change much over the entire scale range. This means that the fields are dynamically important. The ordered fields lead to a self-similar gas fragmentation: at all scales, there exist elongated gas structures nearly perpendicular to the fields. Many gas elongations have density peaks near the ends, which symmetrically pinch the fields. The field strength is proportional to the 0.4th power of the density, which is an indication of anisotropic gas contractions along the field. We conclude that magnetic fields have a crucial role in the fragmentation of NGC6334.
C1 [Li, Hua-bai; Yuen, Ka Ho; Otto, Frank; Leung, Po Kin] Chinese Univ Hong Kong, Dept Phys, Shatin, Hong Kong, Peoples R China.
   [Sridharan, T. K.; Zhang, Qizhou] Harvard Smithsonian Ctr Astrophys, Cambridge, MA 02138 USA.
   [Liu, Hauyu; Tang, Ya-Wen] Natl Taiwan Univ, Acad Sinica, Inst Astron & Astrophys, Taipei 10617, Taiwan.
   [Qiu, Keping] Nanjing Univ, Sch Astron & Space Sci, Nanjing 210093, Jiangsu, Peoples R China.
C3 Chinese University of Hong Kong; Smithsonian Institution; Smithsonian Astrophysical Observatory; Harvard University; National Taiwan University; Academia Sinica - Taiwan; Nanjing University
RP Li, HB (corresponding author), Chinese Univ Hong Kong, Dept Phys, Shatin, Hong Kong, Peoples R China.
EM hbli@phy.cuhk.edu.hk
FU Hong Kong Research Grants Council [ECS 24300314]; CUHK; Deutsche Forschungsgemeinschaft priority programme 1573 [46]; Smithsonian Institution; Academia Sinica
NR 48
TC 106
Z9 116
U1 0
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 23
PY 2015
VL 520
IS 7548
BP 518
EP +
DI 10.1038/nature14291
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500037
PM 25822792
DA 2026-03-09
ER

PT J
AU Senyilmaz, D
   Virtue, S
   Xu, XJ
   Tan, CY
   Griffin, JL
   Miller, AK
   Vidal-Puig, A
   Teleman, AA
AF Senyilmaz, Deniz
   Virtue, Sam
   Xu, Xiaojun
   Tan, Chong Yew
   Griffin, Julian L.
   Miller, Aubry K.
   Vidal-Puig, Antonio
   Teleman, Aurelio A.
TI Regulation of mitochondrial morphology and function by stearoylation of TFR1
SO NATURE
LA English
DT Article
ID mitofusin 2; parkinsons-disease; drosophila; phosphorylation; dynamics; acid; dysfunction; apoptosis; mutants; stress
AB Mitochondria are involved in a variety of cellular functions, including ATP production, amino acid and lipid biogenesis and breakdown, signalling and apoptosis(1-3). Mitochondrial dysfunction has been linked to neurodegenerative diseases, cancer and ageing(4). Although transcriptional mechanisms that regulate mitochondrial abundance are known(5), comparatively little is known about how mitochondrial function is regulated. Here we identify the metabolite stearic acid (C18:0) and human transferrin receptor 1 (TFR1; also known as TFRC) as mitochondrial regulators. We elucidate a signalling pathway whereby C18:0 stearoylates TFR1, thereby inhibiting its activation of JNK signalling. This leads to reduced ubiquitination of mitofusin via HUWE1, thereby promoting mitochondrial fusion and function. We find that animal cells are poised to respond to both increases and decreases in C18:0 levels, with increased C18:0 dietary intake boosting mitochondrial fusion in vivo. Intriguingly, dietary C18:0 supplementation can counteract the mitochondrial dysfunction caused by genetic defects such as loss of the Parkinson's disease genes Pink or Parkin in Drosophila. This work identifies the metabolite C18:0 as a signalling molecule regulating mitochondrial function in response to diet.
C1 [Senyilmaz, Deniz; Xu, Xiaojun; Miller, Aubry K.; Teleman, Aurelio A.] German Canc Res Ctr, D-69120 Heidelberg, Germany.
   [Virtue, Sam; Tan, Chong Yew; Vidal-Puig, Antonio] Univ Cambridge, Metab Res Labs, Wellcome Trust MRC Inst Metab Sci, Cambridge CB2 0QQ, England.
   [Griffin, Julian L.] Dept Biochem, Cambridge CB2 1GA, England.
   [Vidal-Puig, Antonio] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, Cambs, England.
C3 Helmholtz Association; German Cancer Research Center (DKFZ); University of Cambridge; Wellcome Trust Sanger Institute
RP Teleman, AA (corresponding author), German Canc Res Ctr, D-69120 Heidelberg, Germany.
EM a.teleman@dkfz.de
FU Deutsche Forschungsgemeinschaft (DFG) [SFB1118]; Helmholtz Portfolio Topic 'Metabolic Dysfunction'; European Research Council [260602]; Biotechnology and Biological Sciences Research Council; Medical Research Council; British Heart Foundation; BBSRC [BB/H013539/2, BB/J009865/1, BB/H002731/1] Funding Source: UKRI; MRC [MC_UU_12012/2, G0802051, MC_PC_13030, MC_UP_A090_1006, G0400192] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/J009865/1, BB/H013539/2, BB/H002731/1] Funding Source: researchfish; British Heart Foundation [PG/12/53/29714, RG/12/13/29853] Funding Source: researchfish; Medical Research Council [MC_UU_12012/2, G0400192, MC_UU_12012/5/B, G0802051, MC_PC_13030, MC_UP_A090_1006] Funding Source: researchfish; European Research Council (ERC) [260602] Funding Source: European Research Council (ERC)
NR 30
TC 202
Z9 229
U1 5
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 SEP 3
PY 2015
VL 525
IS 7567
BP 124
EP +
DI 10.1038/nature14601
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100038
PM 26214738
DA 2026-03-09
ER

PT J
AU Dou, ZX
   Xu, CY
   Donahue, G
   Shimi, T
   Pan, JA
   Zhu, JJ
   Ivanov, A
   Capelll, BC
   Drake, AM
   Shah, PP
   Catanzaro, JM
   Ricketts, MD
   Lamark, T
   Adam, SA
   Marmorstein, R
   Zong, WX
   Johansen, T
   Goldman, RD
   Adams, PD
   Berger, SL
AF Dou, Zhixun
   Xu, Caiyue
   Donahue, Greg
   Shimi, Takeshi
   Pan, Ji-An
   Zhu, Jiajun
   Ivanov, Andrejs
   Capelll, Brian C.
   Drake, Adam M.
   Shah, Parisha P.
   Catanzaro, Joseph M.
   Ricketts, M. Daniel
   Lamark, Trond
   Adam, Stephen A.
   Marmorstein, Ronen
   Zong, Wei-Xing
   Johansen, Terje
   Goldman, Robert D.
   Adams, Peter D.
   Berger, Shelley L.
TI Autophagy mediates degradation of nuclear lamina
SO NATURE
LA English
DT Article
ID b1; senescence; chromatin; proteins; p53; pathogenesis; organization; expression; domains; atg5
AB Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents and is associated with human diseases(1-3). Although extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known about the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery(4-6), is present in the nucleus and directly interacts with the nuclear lamina protein lamin B1, and binds to lamin-associated domains on chromatin. This LC3-lamin B1 interaction does not downregulate lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated RAS. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers lamin B1 to the lysosome. Inhibiting autophagy or the LC3-lamin B1 interaction prevents activated RAS-induced lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Our study suggests that this new function of autophagy acts as a guarding mechanism protecting cells from tumorigenesis.
C1 [Dou, Zhixun; Xu, Caiyue; Donahue, Greg; Zhu, Jiajun; Capelll, Brian C.; Drake, Adam M.; Shah, Parisha P.; Berger, Shelley L.] Univ Penn, Perelman Sch Med, Dept Cell & Dev Biol, Epigenet Program, Philadelphia, PA 19104 USA.
   [Shimi, Takeshi; Adam, Stephen A.; Goldman, Robert D.] Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA.
   [Pan, Ji-An; Catanzaro, Joseph M.; Zong, Wei-Xing] SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA.
   [Ivanov, Andrejs; Adams, Peter D.] Univ Glasgow, Inst Canc Sci, Glasgow G61 1BD, Lanark, Scotland.
   [Ivanov, Andrejs; Adams, Peter D.] Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland.
   [Ricketts, M. Daniel; Marmorstein, Ronen] Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA.
   [Lamark, Trond; Johansen, Terje] Arctic Univ Norway, Univ Tromso, Inst Med Biol, Mol Canc Res Grp, N-9037 Tromso, Norway.
   [Marmorstein, Ronen] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA.
   [Marmorstein, Ronen] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA.
C3 University of Pennsylvania; Northwestern University; Feinberg School of Medicine; State University of New York (SUNY) System; Stony Brook University; University of Glasgow; Beatson Institute; University of Pennsylvania; UiT The Arctic University of Tromso; University of Pennsylvania; University of Pennsylvania
RP Berger, SL (corresponding author), Univ Penn, Perelman Sch Med, Dept Cell & Dev Biol, Epigenet Program, Philadelphia, PA 19104 USA.
EM bergers@upenn.edu
FU Leukemia & Lymphoma Society; Dermatology Foundation; Melanoma Research Foundation; American Skin Association; NIA [P01AG031862]; NIH [R01 CA078831]; Progeria Research Foundation;  [R01 GM106023]; Cancer Research UK [22311] Funding Source: researchfish; National Cancer Institute [R01CA078831, P30CA060553, R01CA129536] Funding Source: NIH RePORTER; National Institute of Arthritis and Musculoskeletal and Skin Diseases [T32AR007465] Funding Source: NIH RePORTER; National Institute on Aging [P01AG031862] Funding Source: NIH RePORTER
NR 30
TC 525
Z9 598
U1 2
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 5
PY 2015
VL 527
IS 7576
BP 105
EP 109
DI 10.1038/nature15548
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV4XV
UT WOS:000364270700052
PM 26524528
DA 2026-03-09
ER

PT J
AU Oehlers, SH
   Cronan, MR
   Scott, NR
   Thomas, MI
   Okuda, KS
   Walton, EM
   Beerman, RW
   Crosier, PS
   Tobin, DM
AF Oehlers, Stefan H.
   Cronan, Mark R.
   Scott, Ninecia R.
   Thomas, Monica I.
   Okuda, Kazuhide S.
   Walton, Eric M.
   Beerman, Rebecca W.
   Crosier, Philip S.
   Tobin, David M.
TI Interception of host angiogenic signalling limits mycobacterial growth
SO NATURE
LA English
DT Article
ID zebrafish; granuloma; metronidazole; tuberculosis; infection; tumor; vegf; macrophage; inhibitor; tissue
AB Pathogenic mycobacteria induce the formation of complex cellular aggregates called granulomas that are the hallmark of tuberculosis(1,2). Here we examine the development and consequences of vascularization of the tuberculous granuloma in the zebrafish-Mycobacterium marinum infection model, which is characterized by organized granulomas with necrotic cores that bear striking resemblance to those of human tuberculosis(2). Using intravital microscopy in the transparent larval zebrafish, we show that granuloma formation is intimately associated with angiogenesis. The initiation of angiogenesis in turn coincides with the generation of local hypoxia and transcriptional induction of the canonical pro-angiogenic molecule Vegfaa. Pharmacological inhibition of the Vegf pathway suppresses granuloma-associated angiogenesis, reduces infection burden and limits dissemination. Moreover, anti-angiogenic therapies synergize with the first-line anti-tubercular antibiotic rifampicin, as well as with the antibiotic metronidazole, which targets hypoxic bacterial populations(3). Our data indicate that mycobacteria induce granuloma-associated angiogenesis, which promotes mycobacterial growth and increases spread of infection to new tissue sites. We propose the use of anti-angiogenic agents, now being used in cancer regimens, as a host-targeting tuberculosis therapy, particularly in extensively drug-resistant disease for which current antibiotic regimens are largely ineffective.
C1 [Oehlers, Stefan H.; Cronan, Mark R.; Scott, Ninecia R.; Thomas, Monica I.; Walton, Eric M.; Beerman, Rebecca W.; Tobin, David M.] Duke Univ, Dept Mol Genet & Microbiol, Med Ctr, Ctr Microbial Pathogenesis, Durham, NC 27710 USA.
   [Okuda, Kazuhide S.; Crosier, Philip S.] Univ Auckland, Dept Mol Med & Pathol, Auckland 1023, New Zealand.
C3 Duke University; University of Auckland
RP Tobin, DM (corresponding author), Duke Univ, Dept Mol Genet & Microbiol, Med Ctr, Ctr Microbial Pathogenesis, Durham, NC 27710 USA.
EM david.tobin@duke.edu
FU Australian National Health and Medical Research Council CJ Martin Early Career Fellowship; American Cancer Society Postdoctoral Fellowship [PF-13-223-01-MPC]; Duke Summer Research Opportunities Program; Malaysian Ministry of Science and Technology and Innovation scholarship; New Zealand Ministry of Science and Innovation [UOAX0813]; Duke University Center for AIDS Research (CFAR); National Institutes of Health (NIH) [5P30 AI064518]; Mallinckrodt Scholar Award; Searle Scholar Award; Vallee Foundation Young Investigator Award; NIH Director's New Innovator Award [1DP2-OD008614]; National Institute on Minority Health and Health Disparities; National Institute on Aging; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart Lung and Blood Institute; National Cancer Institute; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; National Institute of Nursing Research; National Institute of Dental and Craniofacial Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development [P30AI064518] Funding Source: NIH RePORTER
NR 38
TC 217
Z9 253
U1 3
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 JAN 29
PY 2015
VL 517
IS 7536
BP 612
EP U178
DI 10.1038/nature13967
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA2ZL
UT WOS:000348775000043
PM 25470057
DA 2026-03-09
ER

PT J
AU Parker, IM
   Saunders, M
   Bontrager, M
   Weitz, AP
   Hendricks, R
   Magarey, R
   Suiter, K
   Gilbert, GS
AF Parker, Ingrid M.
   Saunders, Megan
   Bontrager, Megan
   Weitz, Andrew P.
   Hendricks, Rebecca
   Magarey, Roger
   Suiter, Karl
   Gilbert, Gregory S.
TI Phylogenetic structure and host abundance drive disease pressure in communities
SO NATURE
LA English
DT Article
ID infectious-diseases; tropical forest; plant-disease; biodiversity; pathogens; ecology; herbivores; emergence; escape; signal
AB Pathogens play an important part in shaping the structure and dynamics of natural communities, because species are not affected by them equally(1,2). A shared goal of ecology and epidemiology is to predict when a species is most vulnerable to disease. A leading hypothesis asserts that the impact of disease should increase with host abundance, producing a 'rare-species advantage'(3-5). However, the impact of a pathogen may be decoupled from host abundance, because most pathogens infect more than one species, leading to pathogen spillover onto closely related species(6,7). Here we show that the phylogenetic and ecological structure of the surrounding community can be important predictors of disease pressure. We found that the amount of tissue lost to disease increased with the relative abundance of a species across a grassland plant community, and that this rare-species advantage had an additional phylogenetic component: disease pressure was stronger on species with many close relatives. We used a global model of pathogen sharing as a function of relatedness between hosts, which provided a robust predictor of relative disease pressure at the local scale. In our grassland, the total amount of disease was most accurately explained not by the abundance of the focal host alone, but by the abundance of all species in the community weighted by their phylogenetic distance to the host. Furthermore, the model strongly predicted observed disease pressure for 44 novel host species we introduced experimentally to our study site, providing evidence for a mechanism to explain why phylogenetically rare species are more likely to become invasive when introduced(8,9). Our results demonstrate how the phylogenetic and ecological structure of communities can have a key role in disease dynamics, with implications for the maintenance of biodiversity, biotic resistance against introduced weeds, and the success of managed plants in agriculture and forestry.
C1 [Parker, Ingrid M.; Bontrager, Megan; Weitz, Andrew P.] Univ Calif Santa Cruz, Dept Ecol & Evolutionary Biol, Santa Cruz, CA 95064 USA.
   [Parker, Ingrid M.; Gilbert, Gregory S.] Smithsonian Trop Res Inst, Balboa, Panama.
   [Saunders, Megan; Hendricks, Rebecca; Gilbert, Gregory S.] Univ Calif Santa Cruz, Dept Environm Studies, Santa Cruz, CA 95064 USA.
   [Magarey, Roger; Suiter, Karl] N Carolina State Univ, Ctr Integrated Pest Management, Raleigh, NC 27606 USA.
C3 University of California System; University of California Santa Cruz; Smithsonian Institution; Smithsonian Tropical Research Institute; University of California System; University of California Santa Cruz; North Carolina State University
RP Parker, IM (corresponding author), Univ Calif Santa Cruz, Dept Ecol & Evolutionary Biol, Santa Cruz, CA 95064 USA.
EM imparker@ucsc.edu
FU National Science Foundation [DEB-0842059, DEB-1136626]; G.S.G. [14-8130-1472-CA]; US Department of Agriculture APHIS-PPQ-CPHST PERAL [14-8130-1472-CA]; Direct For Biological Sciences; Division Of Environmental Biology [1136626] Funding Source: National Science Foundation
NR 37
TC 264
Z9 318
U1 7
U2 289
PU NATURE PUBLISHING 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 23
PY 2015
VL 520
IS 7548
BP 542
EP +
DI 10.1038/nature14372
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500043
PM 25903634
DA 2026-03-09
ER

PT J
AU Akiyama, T
   Gibson, MC
AF Akiyama, Takuya
   Gibson, Matthew C.
TI Decapentaplegic and growth control in the developing Drosophila wing
SO NATURE
LA English
DT Article
ID morphogen gradient formation; gene-expression; bmp activity; dpp; protein; range; size; proliferation; hedgehog
AB As a central model for morphogen action during animal development, the bone morphogenetic protein 2/4 (BMP2/4)-like ligand Decapentaplegic (Dpp) is proposed to form a long-range signalling gradient that directs both growth and pattern formation during Drosophila wing disc development(1-6). While the patterning role of Dpp secreted from a stripe of cells along the anterior-posterior compartmental boundary is well established(1,2,6), the mechanism by which a Dpp gradient directs uniform cell proliferation remains controversial and poorly understood(7-13). Here, to determine the precise spatiotemporal requirements for Dpp during wing disc development, we use CRISPR-Cas9-mediated genome editing to generate a flippase recognition target (FRT)-dependent conditional null allele. By genetically removing Dpp from its endogenous stripe domain, we confirm the requirement of Dpp for the activation of a downstream phospho-Mothers against dpp (p-Mad) gradient and the regulation of the patterning targets spalt (sal), optomotor blind (omb; also known as bifid) and brinker (brk). Surprisingly, however, third-instar wing blade primordia devoid of compartmental dpp expression maintain relatively normal rates of cell proliferation and exhibit only mild defects in growth. These results indicate that during the latter half of larval development, the Dpp morphogen gradient emanating from the anterior-posterior compartment boundary is not directly required for wing disc growth.
C1 [Akiyama, Takuya; Gibson, Matthew C.] Stowers Inst Med Res, Kansas City, MO 64110 USA.
   [Gibson, Matthew C.] Univ Kansas, Sch Med, Dept Anat & Cell Biol, Kansas City, KS 66160 USA.
C3 Stowers Institute for Medical Research; University of Kansas; University of Kansas Medical Center
RP Gibson, MC (corresponding author), Stowers Inst Med Res, Kansas City, MO 64110 USA.
EM MG2@stowers.org
FU Stowers Institute for Medical Research
NR 45
TC 78
Z9 89
U1 1
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 NOV 19
PY 2015
VL 527
IS 7578
BP 375
EP +
DI 10.1038/nature15730
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9ZN
UT WOS:000365356800056
PM 26550824
DA 2026-03-09
ER

PT J
AU Feist, A
   Echternkamp, KE
   Schauss, J
   Yalunin, SV
   Schäfer, S
   Ropers, C
AF Feist, Armin
   Echternkamp, Katharina E.
   Schauss, Jakob
   Yalunin, Sergey V.
   Schaefer, Sascha
   Ropers, Claus
TI Quantum coherent optical phase modulation in an ultrafast transmission electron microscope
SO NATURE
LA English
DT Article
ID light; diffraction; photoemission; fields; pulses
AB Coherent manipulation of quantum systems with light is expected to be a cornerstone of future information and communication technology, including quantum computation and cryptography(1). The transfer of an optical phase onto a quantum wavefunction is a defining aspect of coherent interactions and forms the basis of quantum state preparation, synchronization and metrology. Light-phase-modulated electron states near atoms and molecules are essential for the techniques of attosecond science, including the generation of extreme-ultraviolet pulses and orbital tomography(2,3). In contrast, the quantum-coherent phase-modulation of energetic free-electron beams has not been demonstrated, although it promises direct access to ultrafast imaging and spectroscopy with tailored electron pulses on the attosecond scale. Here we demonstrate the coherent quantum state manipulation of free-electron populations in an electron microscope beam. We employ the interaction of ultrashort electron pulses with optical nearfields(4-9) to induce Rabi oscillations in the populations of electron momentum states, observed as a function of the optical driving field. Excellent agreement with the scaling of an equal-Rabi multi-level quantum ladder is obtained(10), representing the observation of a light-driven 'quantum walk'(5) coherently reshaping electron density in momentum space(11). We note that, after the interaction, the optically generated superposition of momentum states evolves into a train of attosecond electron pulses. Our results reveal the potential of quantum control for the precision structuring of electron densities, with possible applications ranging from ultrafast electron spectroscopy and microscopy to accelerator science and free-electron lasers.
C1 [Feist, Armin; Echternkamp, Katharina E.; Schauss, Jakob; Yalunin, Sergey V.; Schaefer, Sascha; Ropers, Claus] Univ Gottingen, Inst Phys 4, Solids & Nanostruct, D-37077 Gottingen, Germany.
C3 University of Gottingen
RP Schäfer, S (corresponding author), Univ Gottingen, Inst Phys 4, Solids & Nanostruct, D-37077 Gottingen, Germany.
EM schaefer@ph4.physik.uni-goettingen.de; cropers@gwdg.de
FU Deutsche Forschungsgemeinschaft [DFG-SFB 1073]; VolkswagenStiftung; Lower Saxony Ministry of Science and Culture
NR 42
TC 476
Z9 521
U1 7
U2 389
PU NATURE PUBLISHING 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 14
PY 2015
VL 521
IS 7551
BP 200
EP +
DI 10.1038/nature14463
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH9SY
UT WOS:000354377800054
PM 25971512
DA 2026-03-09
ER

PT J
AU Algara-Siller, G
   Lehtinen, O
   Wang, FC
   Nair, RR
   Kaiser, U
   Wu, HA
   Geim, AK
   Grigorieva, IV
AF Algara-Siller, G.
   Lehtinen, O.
   Wang, F. C.
   Nair, R. R.
   Kaiser, U.
   Wu, H. A.
   Geim, A. K.
   Grigorieva, I. V.
TI Square ice in graphene nanocapillaries
SO NATURE
LA English
DT Article
ID electron-microscopy; phase-transitions; carbon nanotubes; radiation-damage; water-structure; ordered water; graphite; interfaces; dynamics; growth
AB Bulk water exists in many forms, including liquid, vapour and numerous crystalline and amorphous phases of ice, with hexagonal ice being responsible for the fascinating variety of snowflakes(1,2). Much less noticeable but equally ubiquitous is water adsorbed at interfaces and confined in microscopic pores. Such low-dimensional water determines aspects of various phenomena in materials science, geology, biology, tribology and nanotechnology(3-8). Theory suggests many possible phases for adsorbed and confined water(9-17), but it has proved challenging to assess its crystal structure experimentally(17-23). Here we report high-resolution electron microscopy imaging of water locked between two graphene sheets, an archetypal example of hydrophobic confinement. The observations show that the nanoconfined water at room temperature forms 'square ice'-a phase having symmetry qualitatively different from the conventional tetrahedral geometry of hydrogen bonding between water molecules. Square ice has a high packing density with a lattice constant of 2.83 angstrom and can assemble in bilayer and trilayer crystallites. Molecular dynamics simulations indicate that square ice should be present inside hydrophobic nano-channels independently of their exact atomic nature.
C1 [Algara-Siller, G.; Lehtinen, O.; Kaiser, U.] Univ Ulm, Grp Electron Microscopy Mat Sci, Cent Facil Electron Microscopy, D-89081 Ulm, Germany.
   [Wang, F. C.; Wu, H. A.] Univ Sci & Technol China, Chinese Acad Sci, Key Lab Mech Behav & Design Mat, Dept Modern Mech, Hefei 230027, Anhui, Peoples R China.
   [Nair, R. R.; Geim, A. K.; Grigorieva, I. V.] Univ Manchester, Sch Phys & Astron, Manchester M13 9PL, Lancs, England.
C3 Ulm University; Chinese Academy of Sciences; University of Science & Technology of China, CAS; University of Manchester
RP Grigorieva, IV (corresponding author), Univ Manchester, Sch Phys & Astron, Manchester M13 9PL, Lancs, England.
EM ute.kaiser@uni-ulm.de; wuha@ustc.edu.cn; irina.grigorieva@manchester.ac.uk
FU DFG (Germany); European Research Council; EU Graphene Flagship; National Natural Science Foundation of China; Ministry of Science, Research and Arts of Baden-Wuerttemberg (Germany); Office of Naval Research; Air Force Office of Scientific Research; Anhui Provincial Natural Science Foundation (China); Finnish Cultural Foundation; Fundamental Research Funds for the Central Universities of China; EPSRC [EP/K005014/1, EP/G035954/1] Funding Source: UKRI; Engineering and Physical Sciences Research Council [EP/K005014/1, EP/G035954/1] Funding Source: researchfish
NR 49
TC 678
Z9 757
U1 29
U2 1239
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 26
PY 2015
VL 519
IS 7544
BP 443
EP +
DI 10.1038/nature14295
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE1WF
UT WOS:000351602800050
PM 25810206
DA 2026-03-09
ER

PT J
AU Kopp, T
   Riedl, E
   Bangert, C
   Bowman, EP
   Greisenegger, E
   Horowitz, A
   Kittler, H
   Blumenschein, WM
   McClanahan, TK
   Marbury, T
   Zachariae, C
   Xu, DL
   Hou, XS
   Mehta, A
   Zandvliet, AS
   Montgomery, D
   van Aarle, F
   Khalilieh, S
AF Kopp, Tamara
   Riedl, Elisabeth
   Bangert, Christine
   Bowman, Edward P.
   Greisenegger, Elli
   Horowitz, Ann
   Kittler, Harald
   Blumenschein, Wendy M.
   McClanahan, Terrill K.
   Marbury, Thomas
   Zachariae, Claus
   Xu, Danlin
   Hou, Xiaoli Shirley
   Mehta, Anish
   Zandvliet, Anthe S.
   Montgomery, Diana
   van Aarle, Frank
   Khalilieh, Sauzanne
TI Clinical improvement in psoriasis with specific targeting of interleukin-23
SO NATURE
LA English
DT Article
ID dendritic cells; monoclonal-antibody; atopic-dermatitis; double-blind; expression; pathogenesis; ustekinumab; vulgaris; safety; skin
AB Psoriasis is a chronic inflammatory skin disorder that affects approximately 2-3% of the population worldwide and has severe effects on patients' physical and psychological well-being(1-3). The discovery that psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused on the interleukin (IL)-12/23p40 subunit shared by IL-12 and IL-23. Evidence suggests that specific inhibition of IL-23 would result in improvement in psoriasis. Here we evaluate tildrakizumab, a monoclonal antibody that targets the IL-23p19 subunit, in a three-part, randomized, placebo-controlled, sequential, rising multiple-dose phase I study in patients with moderate-to-severe psoriasis to provide clinical proof that specific targeting of IL-23p19 results in symptomatic improvement of disease severity in human subjects. A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg kg(-1) groups by day 196. In part 2, 10 out of 15 subjects in the 3 mg kg(-1) group and 13 out of 14 subjects in the 10 mg kg(-1) group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate-to-severe psoriasis patients as demonstrated by improvements in PASI scores and histological samples.
C1 [Kopp, Tamara; Bangert, Christine; Greisenegger, Elli] Univ Vienna, Sch Med, Dept Dermatol, Div Immunol Allergy & Infect Dis, A-1090 Vienna, Austria.
   [Kopp, Tamara] Juvenis Med Ctr, A-1010 Vienna, Austria.
   [Riedl, Elisabeth; Kittler, Harald] Univ Vienna, Sch Med, Dept Dermatol, Div Gen Dermatol, A-1090 Vienna, Austria.
   [Bowman, Edward P.; Horowitz, Ann; Blumenschein, Wendy M.; McClanahan, Terrill K.; Xu, Danlin; Hou, Xiaoli Shirley; Mehta, Anish; Zandvliet, Anthe S.; Montgomery, Diana; van Aarle, Frank; Khalilieh, Sauzanne] Merck & Co Inc, Whitehouse Stn, NJ 08889 USA.
   [Marbury, Thomas] Orlando Clin Res Ctr, Orlando, FL 32809 USA.
   [Zachariae, Claus] Univ Copenhagen, Gentofte Hosp, Dept Dermatoallergol, DK-2900 Hellerup, Denmark.
C3 University of Vienna; University of Vienna; Merck & Company; Merck & Company USA; University of Copenhagen; Herlev & Gentofte Hospital
RP Khalilieh, S (corresponding author), Merck & Co Inc, Whitehouse Stn, NJ 08889 USA.
EM sauzanne.khalilieh@merck.com
FU Merck Co., Inc.
NR 33
TC 186
Z9 211
U1 0
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 MAY 14
PY 2015
VL 521
IS 7551
BP 222
EP +
DI 10.1038/nature14175
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH9SY
UT WOS:000354377800059
PM 25754330
DA 2026-03-09
ER

PT J
AU Vafabakhsh, R
   Levitz, J
   Isacoff, EY
AF Vafabakhsh, Reza
   Levitz, Joshua
   Isacoff, Ehud Y.
TI Conformational dynamics of a class C G-protein-coupled receptor
SO NATURE
LA English
DT Article
ID metabotropic glutamate receptors; ligand-induced rearrangement; single-molecule fret; structural basis; activation; trajectory; pharmacology; domain; state
AB G-protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors in eukaryotes. Crystal structures have provided insight into GPCR interactions with ligands and G proteins(1,2), but our understanding of the conformational dynamics of activation is incomplete. Metabotropic glutamate receptors (mGluRs) are dimeric class C GPCRs that modulate neuronal excitability, synaptic plasticity, and serve as drug targets for neurological disorders(3,4). A 'clamshell' ligand-binding domain (LBD), which contains the ligand-binding site, is coupled to the transmembrane domain via a cysteine-rich domain, and LBD closure seems to be the first step in activation(5,6). Crystal structures of isolated mGluR LBD dimers led to the suggestion that activation also involves a reorientation of the dimer interface from a 'relaxed' to an 'active' state(7,8), but the relationship between ligand binding, LBD closure and dimer interface rearrangement in activation remains unclear. Here we use single-molecule fluorescence resonance energy transfer to probe the activation mechanism of full-length mammalian group II mGluRs. We show that the LBDs interconvert between three conformations: resting, activated and a short-lived intermediate state. Orthosteric agonists induce transitions between these conformational states, with efficacy determined by occupancy of the active conformation. Unlike mGluR2, mGluR3 displays basal dynamics, which are Ca2+-dependent and lead to basal protein activation. Our results support a general mechanism for the activation of mGluRs in which agonist binding induces closure of the LBDs, followed by dimer interface reorientation. Our experimental strategy should be widely applicable to study conformational dynamics in GPCRs and other membrane proteins.
C1 [Vafabakhsh, Reza; Levitz, Joshua; Isacoff, Ehud Y.] Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA.
   [Isacoff, Ehud Y.] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA.
   [Isacoff, Ehud Y.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Phys Biosci Div, 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; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory
RP Isacoff, EY (corresponding author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA.
EM ehud@berkeley.edu
FU National Institutes of Health Nanomedicine Development Center for the Optical Control of Biological Function [2PN2EY018241]; National Science Foundation (EAGER) [IOS-1451027]; Direct For Biological Sciences [1451027] Funding Source: National Science Foundation; Division Of Integrative Organismal Systems [1451027] Funding Source: National Science Foundation
NR 32
TC 147
Z9 171
U1 0
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 AUG 27
PY 2015
VL 524
IS 7566
BP 497
EP +
DI 10.1038/nature14679
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA DF8BT
UT WOS:000371582600001
PM 26258295
DA 2026-03-09
ER

PT J
AU Soluyanov, AA
   Gresch, D
   Wang, ZJ
   Wu, QS
   Troyer, M
   Dai, X
   Bernevig, BA
AF Soluyanov, Alexey A.
   Gresch, Dominik
   Wang, Zhijun
   Wu, QuanSheng
   Troyer, Matthias
   Dai, Xi
   Bernevig, B. Andrei
TI Type-II Weyl semimetals
SO NATURE
LA English
DT Article
ID fermion semimetal
AB Fermions-elementary particles such as electrons-are classified as Dirac, Majorana or Weyl. Majorana and Weyl fermions had not been observed experimentally until the recent discovery of condensed matter systems such as topological superconductors and semimetals, in which they arise as low-energy excitations(1-6). Here we propose the existence of a previously overlooked type of Weyl fermion that emerges at the boundary between electron and hole pockets in a new phase of matter. This particle was missed by Weyl(7) because it breaks the stringent Lorentz symmetry in high-energy physics. Lorentz invariance, however, is not present in condensed matter physics, and by generalizing the Dirac equation, we find the new type of Weyl fermion. In particular, whereas Weyl semimetals-materials hosting Weyl fermions-were previously thought to have standard Weyl points with a point-like Fermi surface (which we refer to as type-I), we discover a type-II Weyl point, which is still a protected crossing, but appears at the contact of electron and hole pockets in type-II Weyl semimetals. We predict that WTe2 is an example of a topological semimetal hosting the new particle as a low-energy excitation around such a type-II Weyl point. The existence of type-II Weyl points in WTe2 means that many of its physical properties are very different to those of standard Weyl semimetals with point-like Fermi surfaces.
C1 [Soluyanov, Alexey A.; Gresch, Dominik; Wu, QuanSheng; Troyer, Matthias] Swiss Fed Inst Technol, Theoret Phys & Stn Zurich Q, CH-8093 Zurich, Switzerland.
   [Wang, Zhijun; Bernevig, B. Andrei] Princeton Univ, Dept Phys, Princeton, NJ 08544 USA.
   [Dai, Xi] Chinese Acad Sci, Inst Phys, Beijing 100190, Peoples R China.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich; Princeton University; Chinese Academy of Sciences; Institute of Physics, CAS
RP Soluyanov, AA (corresponding author), Swiss Fed Inst Technol, Theoret Phys & Stn Zurich Q, CH-8093 Zurich, Switzerland.
EM soluyanov@itp.phys.ethz.ch
FU Microsoft Research; Swiss National Science Foundation through the National Competence Center in Research MARVEL; European Research Council through ERC Advanced Grant SIMCOFE; ARO MURI [W911NF-12-1-0461]; NSF CAREER [DMR-0952428]; NSF MRSEC [DMR-0819860]; Packard Foundation; Keck grant; National Natural Science Foundation of China; 973 program of China [2011CBA00108, 2013CB921700]; Chinese Academy of Sciences [XDB07020100];  [ONR-N00014-11-1-0635]; Division Of Materials Research; Direct For Mathematical & Physical Scien [0952428] Funding Source: National Science Foundation
NR 23
TC 2191
Z9 2432
U1 21
U2 1226
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 495
EP 498
DI 10.1038/nature15768
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500043
PM 26607545
DA 2026-03-09
ER

PT J
AU Wang, DS
   Cai, CG
   Dong, XB
   Yu, QC
   Zhang, XO
   Yang, L
   Zeng, YA
AF Wang, Daisong
   Cai, Cheguo
   Dong, Xiaobing
   Yu, Qing Cissy
   Zhang, Xiao-Ou
   Yang, Li
   Zeng, Yi Arial
TI Identification of multipotent mammary stemcells by protein C receptor expression
SO NATURE
LA English
DT Article
ID stem-cells; wnt proteins; gland; lineages; mouse; basal; gene
AB The mammary gland is composed of multiple types of epithelial cells, which are generated by mammary stem cells (MaSCs) residing at the top of the hierarchy(1,2). However, the existence of these multi-potent MaSCs remains controversial and the nature of such cells is unknown(3,4). Here we demonstrate that protein C receptor (Procr), a novel Wnt target in the mammary gland, marks a unique population of multipotent mouse MaSCs. Procr-positive cells localize to the basal layer, exhibit epithelial-to-mesenchymal transition characteristics, and express low levels of basal keratins. Procr-expressing cells have a high regenerative capacity in transplantation assays and differentiate into all lineages of the mammary epithelium by lineage tracing. These results define a novel multipotent mammary stem cell population that could be important in the initiation of breast cancer.
C1 [Wang, Daisong; Cai, Cheguo; Dong, Xiaobing; Yu, Qing Cissy; Zeng, Yi Arial] Chinese Acad Sci, State Key Lab Cell Biol, Inst Biochem & Cell Biol, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China.
   [Zhang, Xiao-Ou; Yang, Li] Chinese Acad Sci, Key Lab Computat Biol, CAS MPG Partner Inst Computat Biol, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China.
C3 Chinese Academy of Sciences; Center for Excellence in Molecular Cell Science, CAS; Chinese Academy of Sciences; Max Planck Society
RP Zeng, YA (corresponding author), Chinese Acad Sci, State Key Lab Cell Biol, Inst Biochem & Cell Biol, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China.
EM yzeng@sibcb.ac.cn
NR 27
TC 273
Z9 332
U1 2
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 JAN 1
PY 2015
VL 517
IS 7532
BP 81
EP U201
DI 10.1038/nature13851
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AX8SI
UT WOS:000347178400039
PM 25327250
DA 2026-03-09
ER

PT J
AU Cuskin, F
   Lowe, EC
   Temple, MJ
   Zhu, YP
   Cameron, EA
   Pudlo, NA
   Porter, NT
   Urs, K
   Thompson, AJ
   Cartmell, A
   Rogowski, A
   Hamilton, BS
   Chen, R
   Tolbert, TJ
   Piens, K
   Bracke, D
   Vervecken, W
   Hakki, Z
   Speciale, G
   Munoz-Munoz, JL
   Day, A
   Peña, MJ
   McLean, R
   Suits, MD
   Boraston, AB
   Atherly, T
   Ziemer, CJ
   Williams, SJ
   Davies, GJ
   Abbott, DW
   Martens, EC
   Gilbert, HJ
AF Cuskin, Fiona
   Lowe, Elisabeth C.
   Temple, Max J.
   Zhu, Yanping
   Cameron, Elizabeth A.
   Pudlo, Nicholas A.
   Porter, Nathan T.
   Urs, Karthik
   Thompson, Andrew J.
   Cartmell, Alan
   Rogowski, Artur
   Hamilton, Brian S.
   Chen, Rui
   Tolbert, Thomas J.
   Piens, Kathleen
   Bracke, Debby
   Vervecken, Wouter
   Hakki, Zalihe
   Speciale, Gaetano
   Munoz-Munoz, Jose L.
   Day, Andrew
   Pena, Maria J.
   McLean, Richard
   Suits, Michael D.
   Boraston, Alisdair B.
   Atherly, Todd
   Ziemer, Cherie J.
   Williams, Spencer J.
   Davies, Gideon J.
   Abbott, D. Wade
   Martens, Eric C.
   Gilbert, Harry J.
TI Human gut Bacteroidetes can utilize yeast mannan through a selfish mechanism
SO NATURE
LA English
DT Article
ID carbohydrate-active enzymes; polysaccharide utilization; bacteria; catabolism; microbiota; insights; complex; family; starch
AB Yeasts, which have been a component of the human diet for at least 7,000 years, possess an elaborate cell wall alpha-mannan. The influence of yeast mannan on the ecology of the human microbiota is unknown. Here we show that yeast alpha-mannan is a viable food source for the Gram-negative bacterium Bacteroides thetaiotaomicron, a dominant member of the microbiota. Detailed biochemical analysis and targeted gene disruption studies support a model whereby limited cleavage of alpha-mannan on the surface generates large oligosaccharides that are subsequently depolymerized to mannose by the action of periplasmic enzymes. Co-culturing studies showed that metabolism of yeast mannan by B. thetaiotaomicron presents a 'selfish' model for the catabolism of this difficult to breakdown polysaccharide. Genomic comparison with B. thetaiotaomicron in conjunction with cell culture studies show that a cohort of highly successful members of the microbiota has evolved to consume sterically-restricted yeast glycans, an adaptation that may reflect the incorporation of eukaryotic microorganisms into the human diet.
C1 [Cuskin, Fiona; Lowe, Elisabeth C.; Temple, Max J.; Zhu, Yanping; Rogowski, Artur; Munoz-Munoz, Jose L.; Day, Andrew; Gilbert, Harry J.] Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
   [Cuskin, Fiona; Zhu, Yanping; Pena, Maria J.; Abbott, D. Wade; Gilbert, Harry J.] Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA.
   [Cameron, Elizabeth A.; Pudlo, Nicholas A.; Porter, Nathan T.; Urs, Karthik; Martens, Eric C.] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA.
   [Thompson, Andrew J.; Davies, Gideon J.] Univ York, Dept Chem, York YO10 5DD, N Yorkshire, England.
   [Cartmell, Alan; Hakki, Zalihe; Speciale, Gaetano; Williams, Spencer J.] Univ Melbourne, Sch Chem, Parkville, Vic 3010, Australia.
   [Cartmell, Alan; Hakki, Zalihe; Speciale, Gaetano; Williams, Spencer J.] Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Parkville, Vic 3010, Australia.
   [Hamilton, Brian S.] Indiana Univ, Interdisciplinary Biochem Grad Program, Bloomington, IN 47405 USA.
   [Chen, Rui] Indiana Univ, Dept Chem, Bloomington, IN 47405 USA.
   [Tolbert, Thomas J.] Univ Kansas, Sch Pharm, Dept Pharmaceut Chem, Lawrence, KS 66047 USA.
   [Piens, Kathleen; Bracke, Debby; Vervecken, Wouter] Oxyrane, B-9052 Ghent, Belgium.
   [McLean, Richard; Abbott, D. Wade] Agr & Agrifood Canada, Lethbridge Res Ctr, Lethbridge, AB T1J 4B1, Canada.
   [Suits, Michael D.; Boraston, Alisdair B.] Univ Victoria, Victoria, BC V8P 5C2, Canada.
   [Atherly, Todd; Ziemer, Cherie J.] ARS, USDA, Natl Lab Agr & Environm, Ames, IA 50011 USA.
C3 Newcastle University - UK; University System of Georgia; University of Georgia; University of Michigan System; University of Michigan; University of York - UK; University of Melbourne; University of Melbourne; Indiana University System; Indiana University Bloomington; Indiana University System; Indiana University Bloomington; University of Kansas; Agriculture & Agri Food Canada; University of Victoria; United States Department of Agriculture (USDA); USDA Agricultural Research Service
RP Abbott, DW (corresponding author), Univ Georgia, Complex Carbohydrate Res Ctr, 315 Riverbend Rd, Athens, GA 30602 USA.
EM wade.abbott@agr.gc.ca; emartens@umich.edu
FU European Research Council [322820]; Wellcome Trust [WT097907AIA]; BBSRC [BB/G016127/1]; US Department of Energy (DOE) Bioenergy Research Center (BESC) - Office of Biological and Environmental Research in the DOE Office of Science; National Institutes of Health [GM090080]; University of Michigan Medical School Host Microbiome Initiative; Agriculture and Agri-Food Canada; AgriFlex [2510]; Canadian Institute of Health Research operating grant [MOP-68913]; Australian Research Council; Mizutani Foundation; BBSRC [BB/G016127/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/G016127/1] Funding Source: researchfish; National Institute of General Medical Sciences [T32GM007544] Funding Source: NIH RePORTER
NR 42
TC 439
Z9 510
U1 13
U2 341
PU NATURE PUBLISHING 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 8
PY 2015
VL 517
IS 7533
BP 165
EP U86
DI 10.1038/nature13995
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600028
PM 25567280
DA 2026-03-09
ER

PT J
AU Campbell, EK
   Holz, M
   Gerlich, D
   Maier, JP
AF Campbell, E. K.
   Holz, M.
   Gerlich, D.
   Maier, J. P.
TI Laboratory confirmation of C60+ as the carrier of two diffuse interstellar bands
SO NATURE
LA English
DT Article
ID electronic-spectra; argon matrices; clouds; spectroscopy; features
AB The diffuse interstellar bands are absorption lines seen towards reddened stars(1). None of the molecules responsible for these bands have been conclusively identified(2). Two bands at 9,632 (a) over circle ngstroms and 9,577 (a) over circle ngstroms were reported in 1994, and were suggested to arise from C-60(+) molecules (ref. 3), on the basis of the proximity of these wavelengths to the absorption bands of C-60(+) measured in a neon matrix(4). Confirmation of this assignment requires the gas-phase spectrum of C-60(+). Here we report laboratory spectroscopy of C-60(+) in the gas phase, cooled to 5.8 kelvin. The absorption spectrum hasmaxima at 9,632.7 +/- 0.1 (a) over circle ngstroms and 9,577.5 +/- 0.1 (a) over circle ngstroms, and the full widths at half-maximum of these bands are 2.2 +/- 0.2 (a) over circle ngstroms and 2.5 +/- 0.2 (a) over circle ngstroms, respectively. We conclude that we have positively identified the diffuse interstellar bands at 9,632 (a) over circle ngstroms and 9,577 (a) over circle ngstroms as arising from C-60(+) in the interstellarmedium.
C1 [Campbell, E. K.; Holz, M.; Maier, J. P.] Univ Basel, Dept Chem, CH-4056 Basel, Switzerland.
   [Gerlich, D.] Tech Univ Chemnitz, Dept Phys, D-09107 Chemnitz, Germany.
C3 University of Basel; Technische Universitat Chemnitz
RP Maier, JP (corresponding author), Univ Basel, Dept Chem, Klingelbergstr 80, CH-4056 Basel, Switzerland.
EM j.p.maier@unibas.ch
FU European Research Council [ERC-AdG-ElecSpecIons: 246998]
NR 24
TC 526
Z9 566
U1 4
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 16
PY 2015
VL 523
IS 7560
BP 322
EP +
DI 10.1038/nature14566
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM8KY
UT WOS:000357950900036
PM 26178962
DA 2026-03-09
ER

PT J
AU Piskounova, E
   Agathocleous, M
   Murphy, MM
   Hu, ZP
   Huddlestun, SE
   Zhao, ZY
   Leitch, AM
   Johnson, TM
   DeBerardinis, RJ
   Morrison, SJ
AF Piskounova, Elena
   Agathocleous, Michalis
   Murphy, Malea M.
   Hu, Zeping
   Huddlestun, Sara E.
   Zhao, Zhiyu
   Leitch, A. Marilyn
   Johnson, Timothy M.
   DeBerardinis, Ralph J.
   Morrison, Sean J.
TI Oxidative stress inhibits distant metastasis by human melanoma cells
SO NATURE
LA English
DT Article
ID breast-tumor cells; cancer-cells; cardiovascular-disease; antioxidants; metabolism; lung; prevention; mortality; dormancy; survival
AB Solid cancer cells commonly enter the blood and disseminate systemically, but are highly inefficient at forming distant metastases for poorly understood reasons. Here we studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NOD-SCID-Il2rg(-/-) (NSG) mice. We show that melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficiently metastasizing melanomas. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumours. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence on NADPH-generating enzymes in the folate pathway. Antioxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumours in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo.
C1 [Piskounova, Elena; Agathocleous, Michalis; Murphy, Malea M.; Hu, Zeping; Huddlestun, Sara E.; Zhao, Zhiyu; DeBerardinis, Ralph J.; Morrison, Sean J.] Univ Texas SW Med Ctr Dallas, Childrens Res Inst, Dallas, TX 75390 USA.
   [Piskounova, Elena; Agathocleous, Michalis; Murphy, Malea M.; Hu, Zeping; Huddlestun, Sara E.; Zhao, Zhiyu; DeBerardinis, Ralph J.; Morrison, Sean J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA.
   [Leitch, A. Marilyn] Univ Texas SW Med Ctr Dallas, Dept Surg, Dallas, TX 75390 USA.
   [Johnson, Timothy M.] Univ Michigan, Dept Dermatol, Ann Arbor, MI 48109 USA.
   [Morrison, Sean J.] Univ Texas SW 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; University of Michigan System; University of Michigan; Howard Hughes Medical Institute; University of Texas System; University of Texas Southwestern Medical Center
RP Morrison, SJ (corresponding author), Univ Texas SW Med Ctr Dallas, Childrens Res Inst, Dallas, TX 75390 USA.
EM sean.morrison@utsouthwestern.edu
FU Howard Hughes Medical Institute Funding Source: Medline; NCI NIH HHS [P30 CA142543, K99 CA201228] Funding Source: Medline; National Cancer Institute [P30CA142543] Funding Source: NIH RePORTER
NR 49
TC 1001
Z9 1153
U1 1
U2 293
PU NATURE PUBLISHING 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 12
PY 2015
VL 527
IS 7577
BP 186
EP +
DI 10.1038/nature15726
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700035
PM 26466563
DA 2026-03-09
ER

PT J
AU Wang, DW
   Gouhier, TC
   Menge, BA
   Ganguly, AR
AF Wang, Daiwei
   Gouhier, Tarik C.
   Menge, Bruce A.
   Ganguly, Auroop R.
TI Intensification and spatial homogenization of coastal upwelling under climate change
SO NATURE
LA English
DT Article
ID california current; future; trends; ecosystem; pacific; impacts; north
AB The timing and strength of wind-driven coastal upwelling along the eastern margins of major ocean basins regulate the productivity of critical fisheries and marine ecosystems by bringing deep and nutrient-rich waters to the sunlit surface, where photosynthesis can occur(1-3). How coastal upwelling regimes might change in a warming climate is therefore a question of vital importance(4,5). Although enhanced land-ocean differential heating due to greenhouse warming has been proposed to intensify coastal upwelling by strengthening alongshore winds', analyses of observations and previous climate models have provided little consensus on historical and projected trends in coastal upwelling(7-13). Here we show that there are strong and consistent changes in the timing, intensity and spatial heterogeneity of coastal upwelling in response to future warming in most Eastern Boundary Upwelling Systems (EBUSs). An ensemble of climate models shows that by the end of the twenty-first century the upwelling season will start earlier, end later and become more intense at high but not low latitudes. This projected increase in upwelling intensity and duration at high latitudes will result in a substantial reduction of the existing latitudinal variation in coastal upwelling. These patterns are consistent across three of the four EBUSs (Canary, Benguela and Humboldt, but not California). The lack of upwelling intensification and greater uncertainty associated with the California EBUS may reflect regional controls associated with the atmospheric response to climate change. Given the strong linkages between upwelling and marine ecosystems(14,15), the projected changes in the intensity, timing and spatial structure of coastal upwelling may influence the geographical distribution of marine biodiversity.
C1 [Wang, Daiwei; Ganguly, Auroop R.] Northeastern Univ, Dept Civil & Environm Engn, Sustainabil & Data Sci Lab, Boston, MA 02115 USA.
   [Gouhier, Tarik C.] Northeastern Univ, Ctr Marine Sci, Dept Marine & Environm Sci, Nahant, MA 01908 USA.
   [Menge, Bruce A.] Oregon State Univ, Dept Integrat Biol, Corvallis, OR 97331 USA.
C3 Northeastern University; Northeastern University; Oregon State University
RP Wang, DW (corresponding author), Northeastern Univ, Dept Civil & Environm Engn, Sustainabil & Data Sci Lab, Boston, MA 02115 USA.
EM dw2116@gmail.com
FU Northeastern University's Interdisciplinary Research Program; US National Science Foundation's Expeditions in Computing program [1029711]; Directorate For Geosciences; Division Of Ocean Sciences [1061233] Funding Source: National Science Foundation; Div Of Information & Intelligent Systems; Direct For Computer & Info Scie & Enginr [1029711] Funding Source: National Science Foundation
NR 41
TC 347
Z9 405
U1 8
U2 284
PU NATURE PUBLISHING 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 19
PY 2015
VL 518
IS 7539
BP 390
EP 394
DI 10.1038/nature14235
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400040
PM 25693571
DA 2026-03-09
ER

PT J
AU Mitchell, EG
   Kenchington, CG
   Liu, AG
   Matthews, JJ
   Butterfield, NJ
AF Mitchell, Emily G.
   Kenchington, Charlotte G.
   Liu, Alexander G.
   Matthews, Jack J.
   Butterfield, Nicholas J.
TI Reconstructing the reproductive mode of an Ediacaran macro-organism
SO NATURE
LA English
DT Article
ID point pattern-analysis; mistaken point; spatial structure; spore dispersal; seed dispersal; newfoundland; community; dynamics; insights; fossils
AB Enigmatic macrofossils of late Ediacaran age (580-541 million years ago) provide the oldest known record of diverse complex organisms on Earth, lying between the microbially dominated ecosystems of the Proterozoic and the Cambrian emergence of the modern biosphere(1). Among the oldest and most enigmatic of these macrofossils are the Rangeomorpha, a group characterized by modular, self-similar branching and a sessile benthic habit(2-4). Localized occurrences of large in situ fossilized rangeomorph populations allow fundamental aspects of their biology to be resolved using spatial point process techniques(5). Here we use such techniques to identify recurrent clustering patterns in the rangeomorph Fractofusus, revealing a complex life history of multigenerational, stolon-like asexual reproduction, interspersed with dispersal by waterborne propagules. Ecologically, such a habit would have allowed both for the rapid colonization of a localized area and for transport to new, previously uncolonized areas. The capacity of Fractofusus to derive adult morphology by two distinct reproductive modes documents the sophistication of its underlying developmental biology.
C1 [Mitchell, Emily G.; Kenchington, Charlotte G.; Butterfield, Nicholas J.] Univ Cambridge, Dept Earth Sci, Cambridge CB2 3EQ, England.
   [Kenchington, Charlotte G.] British Geol Survey, Nottingham NG12 5GG, England.
   [Liu, Alexander G.] Univ Bristol, Sch Earth Sci, Bristol BS8 1TQ, Avon, England.
   [Matthews, Jack J.] Univ Oxford, Dept Earth Sci, Oxford OX1 3AN, England.
C3 University of Cambridge; UK Research & Innovation (UKRI); Natural Environment Research Council (NERC); NERC British Geological Survey; University of Bristol; University of Oxford
RP Mitchell, EG (corresponding author), Univ Cambridge, Dept Earth Sci, Downing St, Cambridge CB2 3EQ, England.
EM ek338@cam.ac.uk
FU Natural Environment Research Council [NE/I005927/1, NE/J5000045/1, NE/L011409/1, NE/G523539/1]; Cambridge Philosophical Society; NERC [NE/I005927/1, NE/L011409/1, bgs05002] Funding Source: UKRI; Natural Environment Research Council [NE/I005927/1, bgs05002, NE/L011409/1, 1095099] Funding Source: researchfish
NR 55
TC 95
Z9 102
U1 0
U2 43
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 20
PY 2015
VL 524
IS 7565
BP 343
EP +
DI 10.1038/nature14646
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP2NN
UT WOS:000359714000034
PM 26237408
DA 2026-03-09
ER

PT J
AU Wilson, DJ
   Sudhir, V
   Piro, N
   Schilling, R
   Ghadimi, A
   Kippenberg, TJ
AF Wilson, D. J.
   Sudhir, V.
   Piro, N.
   Schilling, R.
   Ghadimi, A.
   Kippenberg, T. J.
TI Measurement-based control of a mechanical oscillator at its thermal decoherence rate
SO NATURE
LA English
DT Article
ID back-action; quantum; feedback; motion; noise
AB In real-time quantum feedback protocols(1,2), the record of a continuous measurement is used to stabilize a desired quantum state. Recent years have seen successful applications of these protocols in a variety of well-isolated micro-systems, including microwave photons(3) and superconducting qubits(4). However, stabilizing the quantum state of a tangibly massive object, such as a mechanical oscillator, remains very challenging: the main obstacle is environmental decoherence, which places stringent requirements on the timescale in which the state must be measured. Here we describe a position sensor that is capable of resolving the zero-point motion of a solid-state, 4.3-megahertz nanomechanical oscillator in the timescale of its thermal decoherence, a basic requirement for real-time (Markovian) quantum feedback control tasks, such as ground-state preparation. The sensor is based on evanescent optomechanical coupling to a high-Q microcavity(5), and achieves an imprecision four orders of magnitude below that at the standard quantum limit for a weak continuous position measurement(6)-a 100-fold improvement over previous reports(7-9)-while maintaining an imprecision-back-action product that is within a factor of five of the Heisenberg uncertainty limit. As a demonstration of its utility, we use the measurement as an error signal with which to feedback cool the oscillator. Using radiation pressure as an actuator, the oscillator is cold damped(10) with high efficiency: from a cryogenic-bath temperature of 4.4 kelvin to an effective value of 1.1 +/- 0.1 millikelvin, corresponding to a mean phonon number of 5.3 +/- 0.6 (that is, a ground-state probability of 16 per cent). Our results set a new benchmark for the performance of a linear position sensor, and signal the emergence of mechanical oscillators as practical subjects for measurement-based quantum control.
C1 [Wilson, D. J.; Sudhir, V.; Piro, N.; Schilling, R.; Ghadimi, A.; Kippenberg, T. J.] Ecole Polytech Fed Lausanne, Inst Condensed Matter Phys, CH-1015 Lausanne, Switzerland.
C3 Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne
RP Kippenberg, TJ (corresponding author), Ecole Polytech Fed Lausanne, Inst Condensed Matter Phys, CH-1015 Lausanne, Switzerland.
EM tobias.kippenberg@epfl.ch
FU ERC Advanced Grant (QuREM); DARPA/MTO ORCHID programme; Marie Curie Initial Training Network 'Cavity Quantum Optomechanics' (cQOM); Swiss National Science Foundation - NCCR of Quantum Engineering (QSIT); European Commission [303029, 331985]
NR 30
TC 276
Z9 305
U1 5
U2 149
PU NATURE PUBLISHING 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 20
PY 2015
VL 524
IS 7565
BP 325
EP 329
DI 10.1038/nature14672
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP2NN
UT WOS:000359714000030
PM 26258303
DA 2026-03-09
ER

PT J
AU Xue, SF
   Tian, SQ
   Fujii, K
   Kladwang, W
   Das, R
   Barna, M
AF Xue, Shifeng
   Tian, Siqi
   Fujii, Kotaro
   Kladwang, Wipapat
   Das, Rhiju
   Barna, Maria
TI RNA regulons in Hox 5′ UTRs confer ribosome specificity to gene regulation
SO NATURE
LA English
DT Article
ID cap-dependent translation; entry site; messenger-rna; specialized ribosm; mediated translation; robust analysis; initiation; secondary; shape; expression
AB Emerging evidence suggests that the ribosome has a regulatory function in directing how the genome is translated in time and space. However, how this regulation is encoded in the messenger RNA sequence remains largely unknown. Here we uncover unique RNA regulons embedded in homeobox (Hox) 5' untranslated regions (UTRs) that confer ribosome-mediated control of gene expression. These structured RNA elements, resembling viral internal ribosome entry sites (IRESs), are found in subsets of Hox mRNAs. They facilitate ribosome recruitment and require the ribosomal protein RPL38 for their activity. Despite numerous layers of Hox gene regulation, these IRES elements are essential for converting Hox transcripts into proteins to pattern the mammalian body plan. This specialized mode of IRES-dependent translation is enabled by an additional regulatory element that we term the translation inhibitory element (TIE), which blocks cap-dependent translation of transcripts. Together, these data uncover a new paradigm for ribosome-mediated control of gene expression and organismal development.
C1 [Xue, Shifeng; Fujii, Kotaro; Barna, Maria] Stanford Univ, Dept Dev Biol, Stanford, CA 94305 USA.
   [Xue, Shifeng; Fujii, Kotaro; Barna, Maria] Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
   [Xue, Shifeng] Univ Calif San Francisco, Tetrad Grad Program, San Francisco, CA 94158 USA.
   [Tian, Siqi; Kladwang, Wipapat; Das, Rhiju] Stanford Univ, Dept Biochem, Stanford, CA 94305 USA.
   [Das, Rhiju] Stanford Univ, Dept Phys, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; University of California System; University of California San Francisco; Stanford University; Stanford University
RP Barna, M (corresponding author), Stanford Univ, Dept Dev Biol, Stanford, CA 94305 USA.
EM mbarna@stanford.edu
FU Agency of Science, Technology and Research of Singapore; Stanford Graduate Fellowship; Human Frontier Science Program Fellowship [NIH R01 GM102519]
NR 59
TC 241
Z9 302
U1 0
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 JAN 1
PY 2015
VL 517
IS 7532
BP 33
EP U55
DI 10.1038/nature14010
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AX8SI
UT WOS:000347178400029
PM 25409156
DA 2026-03-09
ER

PT J
AU Jiang, L
   Kon, N
   Li, TY
   Wang, SJ
   Su, T
   Hibshoosh, H
   Baer, R
   Gu, W
AF Jiang, Le
   Kon, Ning
   Li, Tongyuan
   Wang, Shang-Jui
   Su, Tao
   Hibshoosh, Hanina
   Baer, Richard
   Gu, Wei
TI Ferroptosis as a p53-mediated activity during tumour suppression
SO NATURE
LA English
DT Article
ID cell-death; cystine/glutamate antiporter; p53-inducible regulator; metabolic-regulation; embryonic lethality; mdm2-deficient mice; reactive oxygen; system x(c)(-); p53 function; cancer
AB Although p53-mediated cell-cycle arrest, senescence and apoptosis serve as critical barriers to cancer development, emerging evidence suggests that the metabolic activities of p53 are also important. Here we show that p53 inhibits cystine uptake and sensitizes cells to ferroptosis, a non-apoptotic form of cell death, by repressing expression of SLC7A11, a key component of the cystine/glutamate antiporter. Notably, p53(3KR), an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence and apoptosis, fully retains the ability to regulate SLC7A11 expression and induce ferroptosis upon reactive oxygen species (ROS)-induced stress. Analysis of mutant mice shows that these non-canonical p53 activities contribute to embryonic development and the lethality associated with loss of Mdm2. Moreover, SLC7A11 is highly expressed in human tumours, and its overexpression inhibits ROS-induced ferroptosis and abrogates p53(3KR)-mediated tumour growth suppression in xenograft models. Our findings uncover a new mode of tumour suppression based on p53 regulation of cystine metabolism, ROS responses and ferroptosis.
C1 [Jiang, Le; Kon, Ning; Li, Tongyuan; Wang, Shang-Jui; Baer, Richard; Gu, Wei] Columbia Univ Coll Phys & Surg, Inst Canc Genet, New York, NY 10032 USA.
   [Su, Tao; Hibshoosh, Hanina; Baer, Richard; Gu, Wei] Columbia Univ Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY 10032 USA.
   [Su, Tao; Hibshoosh, Hanina; Baer, Richard; Gu, Wei] Columbia Univ Coll Phys & Surg, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA.
C3 Columbia University; Columbia University; Columbia University
RP Gu, W (corresponding author), Columbia Univ Coll Phys & Surg, Inst Canc Genet, 1130 St Nicholas Ave, New York, NY 10032 USA.
EM wg8@columbia.edu
FU National Cancer Institute of the National Institutes of Health [5R01CA172023, 5RO1CA166294, 5RO1CA169246, 5RO1CA085533, 2P01CA080058]; National Cancer Institute [2P01CA097403]; NIH cancer biology training grant [T32-CA09503]; National Cancer Institute [R01CA085533] Funding Source: NIH RePORTER
NR 40
TC 2789
Z9 3138
U1 44
U2 1102
PU NATURE PUBLISHING 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 2
PY 2015
VL 520
IS 7545
BP 57
EP +
DI 10.1038/nature14344
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE7NE
UT WOS:000352027700035
PM 25799988
DA 2026-03-09
ER

PT J
AU Gennaris, A
   Ezraty, B
   Henry, C
   Agrebi, R
   Vergnes, A
   Oheix, E
   Bos, J
   Leverrier, P
   Espinosa, L
   Szewczyk, J
   Vertommen, D
   Iranzo, O
   Collet, JF
   Barras, F
AF Gennaris, Alexandra
   Ezraty, Benjamin
   Henry, Camille
   Agrebi, Rym
   Vergnes, Alexandra
   Oheix, Emmanuel
   Bos, Julia
   Leverrier, Pauline
   Espinosa, Leon
   Szewczyk, Joanna
   Vertommen, Didier
   Iranzo, Olga
   Collet, Jean-Francois
   Barras, Frederic
TI Repairing oxidized proteins in the bacterial envelope using respiratory chain electrons
SO NATURE
LA English
DT Article
ID methionine sulfoxide reductases; genes; roles; identification; performance; chaperones; catalysis; software; reveals; target
AB The reactive species of oxygen and chlorine damage cellular components, potentially leading to cell death. In proteins, the sulfur-containing amino acid methionine is converted to methionine sulfoxide, which can cause a loss of biological activity. To rescue proteins with methionine sulfoxide residues, living cells express methionine sulfoxide reductases (Msrs) in most subcellular compartments, including the cytosol, mitochondria and chloroplasts(1-3). Here we report the identification of an enzymatic system, MsrPQ, repairing proteins containing methionine sulfoxide in the bacterial cell envelope, a compartment particularly exposed to the reactive species of oxygen and chlorine generated by the host defence mechanisms. MsrP, a molybdo-enzyme, and MsrQ, a haem-binding membrane protein, are widely conserved throughout Gram-negative bacteria, including major human pathogens. MsrPQ synthesis is induced by hypochlorous acid, a powerful antimicrobial released by neutrophils. Consistently, MsrPQ is essential for the maintenance of envelope integrity under bleach stress, rescuing a wide series of structurally unrelated periplasmic proteins from methionine oxidation, including the primary periplasmic chaperone SurA. For this activity, MsrPQ uses electrons from the respiratory chain, which represents a novel mechanism to import reducing equivalents into the bacterial cell envelope. A remarkable feature of MsrPQ is its capacity to reduce both rectus (R-) and sinister (S-) diastereoisomers of methionine sulfoxide, making this oxidoreductase complex functionally different from previously identified Msrs. The discovery that a large class of bacteria contain a single, non-stereospecific enzymatic complex fully protecting methionine residues from oxidation should prompt a search for similar systems in eukaryotic subcellular oxidizing compartments, including the endoplasmic reticulum.
C1 [Gennaris, Alexandra; Agrebi, Rym; Leverrier, Pauline; Szewczyk, Joanna; Collet, Jean-Francois] WELBIO, B-1200 Brussels, Belgium.
   [Gennaris, Alexandra; Agrebi, Rym; Leverrier, Pauline; Szewczyk, Joanna; Vertommen, Didier; Collet, Jean-Francois] Catholic Univ Louvain, Duve Inst, B-1200 Brussels, Belgium.
   [Gennaris, Alexandra; Agrebi, Rym; Leverrier, Pauline; Szewczyk, Joanna; Collet, Jean-Francois] Brussels Ctr Redox Biol, B-1200 Brussels, Belgium.
   [Ezraty, Benjamin; Henry, Camille; Vergnes, Alexandra; Bos, Julia; Espinosa, Leon; Barras, Frederic] Aix Marseille Univ, CNRS, Lab Chim Bacterienne, UMR 7283,Inst Microbiol Mediterranee, F-13009 Marseille, France.
   [Oheix, Emmanuel; Iranzo, Olga] Aix Marseille Univ, Cent Marseille, CNRS, iSm2,UMR 7313, F-13397 Marseille, France.
C3 WELBIO; Universite Catholique Louvain; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Aix-Marseille Universite; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Chemistry (INC); Aix-Marseille Universite
RP Collet, JF (corresponding author), WELBIO, Ave Hippocrate 75, B-1200 Brussels, Belgium.
EM jfcollet@uclouvain.be; barras@imm.cnrs.fr
FU Indo-French Center for the Promotion of Advanced Research CEFIPRA [5105-2]; Fonds Maurange, Fondation Roi Baudouin; FRS-FNRS; European Research Council [282335-Sulfenic]; Centre National de la Recherche Scientifique (CNRS); Fondation pour la Recherche Medicale (FRM); Aix-Marseille Universite
NR 49
TC 124
Z9 145
U1 2
U2 84
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 17
PY 2015
VL 528
IS 7582
BP 409
EP +
DI 10.1038/nature15764
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CY8SM
UT WOS:000366678600055
PM 26641313
DA 2026-03-09
ER

PT J
AU Payne, KAP
   Quezada, CP
   Fisher, K
   Dunstan, MS
   Collins, FA
   Sjuts, H
   Levy, C
   Hay, S
   Rigby, SEJ
   Leys, D
AF Payne, Karl A. P.
   Quezada, Carolina P.
   Fisher, Karl
   Dunstan, Mark S.
   Collins, Fraser A.
   Sjuts, Hanno
   Levy, Colin
   Hay, Sam
   Rigby, Stephen E. J.
   Leys, David
TI Reductive dehalogenase structure suggests a mechanism for B12-dependent dehalogenation
SO NATURE
LA English
DT Article
ID molecular characterization; halorespiration; cob(ii)alamin; enzyme
AB Organohalide chemistry underpins many industrial and agricultural processes, and a large proportion of environmental pollutants are organohalides(1). Nevertheless, organohalide chemistry is not exclusively of anthropogenic origin, with natural abiotic and biological processes contributing to the global halide cycle(2,3). Reductive dehalogenases are responsible for biological dehalogenation in organohalide respiring bacteria(4,5), with substrates including polychlorinated biphenyls or dioxins(6,7). Reductive dehalogenases form a distinct subfamily of cobalamin (B12)-dependent enzymes that are usuallymembrane associated and oxygen sensitive, hindering detailed studies(8-12). Here we report the characterization of a soluble, oxygen-tolerant reductive dehalogenase and, by combining structure determination with EPR (electron paramagnetic resonance) spectroscopy and simulation, show that a direct interaction between the cobalamin cobalt and the substrate halogen underpins catalysis. In contrast to the carbon-cobalt bond chemistry catalysed by the other cobalamin-dependent subfamilies(13), we propose that reductive dehalogenases achieve reduction of the organohalide substrate via halogen-cobalt bond formation. This presents a new model in both organohalide and cobalamin (bio) chemistry that will guide future exploitation of these enzymes in bioremediation or biocatalysis.
C1 [Payne, Karl A. P.; Quezada, Carolina P.; Fisher, Karl; Dunstan, Mark S.; Collins, Fraser A.; Sjuts, Hanno; Levy, Colin; Hay, Sam; Rigby, Stephen E. J.; Leys, David] Univ Manchester, Manchester Inst Biotechnol, Manchester M1 7DN, Lancs, England.
C3 University of Manchester
RP Leys, D (corresponding author), Univ Manchester, Manchester Inst Biotechnol, 131 Princess St, Manchester M1 7DN, Lancs, England.
EM david.leys@manchester.ac.uk
FU ERC grant [DEHALORES206080]; CONICYT Chile; BBSRC [BB/H021523/1, BB/E013007/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/C00521X/1, BB/E013007/1, BB/H021523/1, 1338042, 1626769] Funding Source: researchfish
NR 34
TC 239
Z9 285
U1 12
U2 387
PU NATURE PUBLISHING 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 22
PY 2015
VL 517
IS 7535
BP 513
EP +
DI 10.1038/nature13901
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AZ4MU
UT WOS:000348196500041
PM 25327251
DA 2026-03-09
ER

PT J
AU Lee, JS
   Hnilova, M
   Maes, M
   Lin, YCL
   Putarjunan, A
   Han, SK
   Avila, J
   Torii, KU
AF Lee, Jin Suk
   Hnilova, Marketa
   Maes, Michal
   Lin, Ya-Chen Lisa
   Putarjunan, Aarthi
   Han, Soon-Ki
   Avila, Julian
   Torii, Keiko U.
TI Competitive binding of antagonistic peptides fine-tunes stomatal patterning
SO NATURE
LA English
DT Article
ID asymmetric cell-division; secretory peptide; arabidopsis; kinase; density; protein; differentiation; activation; stomagen; organ
AB During development, cells interpret complex and often conflicting signals to make optimal decisions. Plant stomata, the cellular interface between a plant and the atmosphere, develop according to positional cues, which include a family of secreted peptides called epidermal patterning factors (EPFs). How these signalling peptides orchestrate pattern formation at a molecular level remains unclear. Here we report in Arabidopsis that Stomagen (also called EPF-LIKE9) peptide, which promotes stomatal development, requires ERECTA (ER)-family receptor kinases and interferes with the inhibition of stomatal development by the EPIDERMAL PATTERNING FACTOR 2 (EPF2)-ER module. Both EPF2 and Stomagen directly bind to ER and its co-receptor TOO MANY MOUTHS. Stomagen peptide competitively replaced EPF2 binding to ER. Furthermore, application of EPF2, but not Stomagen, elicited rapid phosphorylation of downstream signalling components in vivo. Our findings demonstrate how a plant receptor agonist and antagonist define inhibitory and inductive cues to fine-tune tissue patterning on the plant epidermis.
C1 [Lee, Jin Suk; Lin, Ya-Chen Lisa; Han, Soon-Ki; Avila, Julian; Torii, Keiko U.] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA.
   [Lee, Jin Suk; Maes, Michal; Lin, Ya-Chen Lisa; Putarjunan, Aarthi; Han, Soon-Ki; Avila, Julian; Torii, Keiko U.] Univ Washington, Dept Biol, Seattle, WA 98195 USA.
   [Hnilova, Marketa] Univ Washington, Dept Mat Sci & Engn, Seattle, WA 98195 USA.
C3 Howard Hughes Medical Institute; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle
RP Torii, KU (corresponding author), Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA.
EM ktorii@u.washingotn.edu
FU Howard Hughes Medical Institute Funding Source: Medline; Grants-in-Aid for Scientific Research [26113507] Funding Source: KAKEN
NR 33
TC 238
Z9 275
U1 1
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 JUN 25
PY 2015
VL 522
IS 7557
BP 435
EP +
DI 10.1038/nature14561
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL2OC
UT WOS:000356782900041
PM 26083750
DA 2026-03-09
ER

PT J
AU Tao, YY
   Cheung, LS
   Li, S
   Eom, JS
   Chen, LQ
   Xu, Y
   Perry, K
   Frommer, WB
   Feng, L
AF Tao, Yuyong
   Cheung, Lily S.
   Li, Shuo
   Eom, Joon-Seob
   Chen, Li-Qing
   Xu, Yan
   Perry, Kay
   Frommer, Wolf B.
   Feng, Liang
TI Structure of a eukaryotic SWEET transporter in a homotrimeric complex
SO NATURE
LA English
DT Article
ID sugar transporter; crystal-structure; protein; bacterial; oligomerization; nutrition; mechanism
AB Eukaryotes rely on efficient distribution of energy and carbon skeletons between organs in the form of sugars. Glucose in animals and sucrose in plants serve as the dominant distribution forms. Cellular sugar uptake and release require vesicular and/or plasma membrane transport proteins. Humans and plants use proteins from three superfamilies for sugar translocation: the major facilitator superfamily (MFS), the sodium solute symporter family (SSF; only in the animal kingdom), and SWEETs1-5. SWEETs carry mono-and disaccharides(6) across vacuolar or plasma membranes. Plant SWEETs play key roles in sugar translocation between compartments, cells, and organs, notably in nectar secretion(7), phloem loading for long distance translocation(8), pollen nutrition(9), and seed filling(10). Plant SWEETs cause pathogen susceptibility possibly by sugar leakage from infected cells(3,11,12). The vacuolar Arabidopsis thaliana AtSWEET2 sequesters sugars in root vacuoles; loss-of-function mutants show increased susceptibility to Pythium infection(13). Here we show that its orthologue, the vacuolar glucose transporter OsSWEET2b from rice (Oryza sativa), consists of an asymmetrical pair of triple-helix bundles, connected by an inversion linker transmembrane helix (TM4) to create the translocation pathway. Structural and biochemical analyses show OsSWEET2b in an apparent inward (cytosolic) open state forming homomeric trimers. TM4 tightly interacts with the first triple-helix bundle within a protomer and mediates key contacts among protomers. Structure-guided mutagenesis of the close paralogue SWEET1 from Arabidopsis identified key residues in substrate translocation and protomer crosstalk. Insights into the structure-function relationship of SWEETs are valuable for understanding the transport mechanism of eukaryotic SWEETs and may be useful for engineering sugar flux.
C1 [Tao, Yuyong; Li, Shuo; Xu, Yan; Feng, Liang] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
   [Cheung, Lily S.; Eom, Joon-Seob; Chen, Li-Qing; Frommer, Wolf B.] Carnegie Inst Sci, Dept Plant Biol, Stanford, CA 94305 USA.
   [Li, Shuo] Sichuan Univ, Coll Life Sci, Ctr Growth Metab & Aging, Key Lab Bioresource & Ecoenvironm,Minist Educ, Chengdu 610014, Peoples R China.
   [Perry, Kay] Cornell Univ, Argonne Natl Lab, NE CAT, Argonne, IL 60439 USA.
   [Perry, Kay] Cornell Univ, Argonne Natl Lab, Dept Chem & Chem Biol, Argonne, IL 60439 USA.
C3 Stanford University; Carnegie Institution for Science; Sichuan University; United States Department of Energy (DOE); Argonne National Laboratory; Cornell University; United States Department of Energy (DOE); Argonne National Laboratory; Cornell University
RP Feng, L (corresponding author), Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, 279 Campus Dr, Stanford, CA 94305 USA.
EM liangf@stanford.edu
FU Stanford University; Harold and Leila Y. Mathers Charitable Foundation; Alfred P. Sloan Foundation; Division of Chemical Sciences, Geosciences and Biosciences, Office of Basic Energy Sciences at the US Department of Energy [DOE DE-FG02-04ER15542]; National Science Foundation [IOS-1258018]; National Science Foundation Postdoctoral Research Fellowship in Biology [1401855]; National Natural Science Foundation of China [31300618]; National Institute of General Medical Sciences (NIH) [P41 GM103403]; US DOE [DE-AC02-06CH11357]; National Institute of General Medical Sciences [R01GM117108] Funding Source: NIH RePORTER; Division Of Integrative Organismal Systems; Direct For Biological Sciences [1401855] Funding Source: National Science Foundation
NR 48
TC 164
Z9 190
U1 9
U2 226
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 12
PY 2015
VL 527
IS 7577
BP 259
EP +
DI 10.1038/nature15391
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700050
PM 26479032
DA 2026-03-09
ER

PT J
AU Zhao, QF
   Wang, M
   Xu, DX
   Zhang, QL
   Liu, W
AF Zhao, Qunfei
   Wang, Min
   Xu, Dongxiao
   Zhang, Qinglin
   Liu, Wen
TI Metabolic coupling of two small-molecule thiols programs the biosynthesis of lincomycin A
SO NATURE
LA English
DT Article
ID gene-cluster; mycothiol; intermediate; bacillithiol; mechanisms; proteins; enzymes; sulfur; octose
AB Low-molecular-mass thiols in organisms are well known for their redox-relevant role in protection against various endogenous and exogenous stresses(1-3). In eukaryotes and Gram-negative bacteria, the primary thiol is glutathione (GSH), a cysteinyl-containing tripeptide. In contrast, mycothiol(MSH), a cysteinyl pseudo-disaccharide, is dominant in Gram-positive actinobacteria, including antibiotic-producing actinomycetes and pathogenic mycobacteria. MSH is equivalent to GSH, either as a cofactor or as a substrate, in numerous biochemical processes(4), most of which have not been characterized, largely due to the dearth of information concerning MSH-dependent proteins. Actinomycetes are able to produce another thiol, ergothioneine (EGT), a histidine betaine derivative that is widely assimilated by plants and animals for variable physiological activities(5). The involvement of EGT in enzymatic reactions, however, lacks any precedent. Here we report that the unprecedented coupling of two bacterial thiols, MSH and EGT, has a constructive role in the biosynthesis of lincomycin A, a sulfur-containing lincosamide (C8 sugar) antibiotic that has been widely used for half a century to treat Gram-positive bacterial infections(6-9). EGT acts as a carrier to template the molecular assembly, and MSH is the sulfur donor for lincomycin maturation after thiol exchange. These thiols function through two unusual S-glycosylations that program lincosamide transfer, activation and modification, providing the first paradigm for EGT-associated biochemical processes and for the poorly understood MSH-dependent biotransformations, a newly described model that is potentially common in the incorporation of sulfur, an element essential for life and ubiquitous in living systems.
C1 [Zhao, Qunfei; Wang, Min; Xu, Dongxiao; Liu, Wen] Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bioorgan & Nat Prod Chem, Shanghai 200032, Peoples R China.
   [Zhang, Qinglin; Liu, Wen] Huzhou Ctr Biosynthet Innovat, Huzhou 313000, Peoples R China.
C3 Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS
RP Liu, W (corresponding author), Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bioorgan & Nat Prod Chem, 345 Lingling Rd, Shanghai 200032, Peoples R China.
EM wliu@mail.sioc.ac.cn
FU NSFC [81302674, 31430005, 91213303, 21472231, 91413101]; STCSM [14JC1407700, 13XD1404500]; MST of China [2012AA02A706]
NR 35
TC 114
Z9 139
U1 2
U2 204
PU NATURE PUBLISHING 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 5
PY 2015
VL 518
IS 7537
BP 115
EP +
DI 10.1038/nature14137
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7LE
UT WOS:000349098000043
PM 25607359
DA 2026-03-09
ER

PT J
AU Phillips, A
   Shroufi, A
   Vojnov, L
   Cohn, J
   Roberts, T
   Ellman, T
   Bonner, K
   Rousseau, C
   Garnett, G
   Cambiano, V
   Nakagawa, F
   Ford, D
   Bansi-Matharu, L
   Miners, A
   Lundgren, JD
   Eaton, JW
   Parkes-Ratanshi, R
   Katz, Z
   Maman, D
   Ford, N
   Vitoria, M
   Doherty, M
   Dowdy, D
   Nichols, B
   Murtagh, M
   Wareham, M
   Palamountain, KM
   Musanhu, CC
   Stevens, W
   Katzenstein, D
   Ciaranello, A
   Barnabas, R
   Braithwaite, RS
   Bendavid, E
   Nathoo, KJ
   van de Vijver, D
   Wilson, DP
   Holmes, C
   Bershteyn, A
   Walker, S
   Raizes, E
   Jani, I
   Nelson, LJ
   Peeling, R
   Terris-Prestholt, F
   Murungu, J
   Mutasa-Apollo, T
   Hallett, TB
   Revill, P
AF Phillips, Andrew
   Shroufi, Amir
   Vojnov, Lara
   Cohn, Jennifer
   Roberts, Teri
   Ellman, Tom
   Bonner, Kimberly
   Rousseau, Christine
   Garnett, Geoff
   Cambiano, Valentina
   Nakagawa, Fumiyo
   Ford, Deborah
   Bansi-Matharu, Loveleen
   Miners, Alec
   Lundgren, Jens D.
   Eaton, Jeffrey W.
   Parkes-Ratanshi, Rosalind
   Katz, Zachary
   Maman, David
   Ford, Nathan
   Vitoria, Marco
   Doherty, Meg
   Dowdy, David
   Nichols, Brooke
   Murtagh, Maurine
   Wareham, Meghan
   Palamountain, Kara M.
   Musanhu, Christine Chakanyuka
   Stevens, Wendy
   Katzenstein, David
   Ciaranello, Andrea
   Barnabas, Ruanne
   Braithwaite, R. Scott
   Bendavid, Eran
   Nathoo, Kusum J.
   van de Vijver, David
   Wilson, David P.
   Holmes, Charles
   Bershteyn, Anna
   Walker, Simon
   Raizes, Elliot
   Jani, Ilesh
   Nelson, Lisa J.
   Peeling, Rosanna
   Terris-Prestholt, Fern
   Murungu, Joseph
   Mutasa-Apollo, Tsitsi
   Hallett, Timothy B.
   Revill, Paul
TI Sustainable HIV treatment in Africa through viral-load-informed differentiated care
SO NATURE
LA English
DT Article
ID dried blood spots; cd4 cell count; 1st-line antiretroviral therapy; stratall anrs 12110/esther; resource-limited settings; cost-effectiveness; drug-resistance; outcm; quantification; implementation
AB There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.
C1 [Phillips, Andrew; Cambiano, Valentina; Nakagawa, Fumiyo; Bansi-Matharu, Loveleen] UCL, Dept Infect & Populat Hlth, London NW3 2PF, England.
   [Shroufi, Amir; Ellman, Tom; Maman, David] Medecinssans Frontieres MSF SA, SAMU, ZA-7700 Cape Town, South Africa.
   [Vojnov, Lara; Katz, Zachary; Wareham, Meghan] Clinton Hlth Access Initiat, Boston, MA 02127 USA.
   [Cohn, Jennifer; Roberts, Teri] Med Sans Frontieres, Access Campaign, CH-1202 Geneva, Switzerland.
   [Bonner, Kimberly] Med Sans Frontieres, CH-1211 Geneva 21, Switzerland.
   [Rousseau, Christine; Garnett, Geoff] Bill & Melinda Gates Fdn, Seattle, WA 98199 USA.
   [Ford, Deborah] UCL, Inst Clin Trials & Methodol, MRC Clin Trials Unit, London WC2B 6NH, England.
   [Miners, Alec] London Sch Hyg & Trop Med, Hlth Serv Res & Policy, London WC1H 9SY, England.
   [Lundgren, Jens D.] Univ Copenhagen, Rigshosp, Dept Infect Dis, CHIP, DK-92100 Copenhagen, Denmark.
   [Eaton, Jeffrey W.; Hallett, Timothy B.] Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis Epidemiol, London W2 1PG, England.
   [Parkes-Ratanshi, Rosalind] Makerere Univ, Coll Hlth Sci, IDI, Kampala, Uganda.
   [Ford, Nathan; Vitoria, Marco; Doherty, Meg] WHO, HIV AIDS & Global Hepatitis Programme, CH-1211 Geneva, Switzerland.
   [Dowdy, David] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA.
   [Nichols, Brooke; van de Vijver, David] Erasmus MC, Dept Virosci, NL-3000 CA Rotterdam, Netherlands.
   [Murtagh, Maurine] Univ London London Sch Hyg & Trop Med, Int Diagnost Ctr, London WC1E 7HT, England.
   [Palamountain, Kara M.] Northwestern Univ, Kellogg Sch Management, Evanston, IL 60208 USA.
   [Musanhu, Christine Chakanyuka] WHO Country Off, Harare, Zimbabwe.
   [Stevens, Wendy] Univ Witwatersrand, Dept Mol Med & Haematol, ZA-2050 Johannesburg, South Africa.
   [Katzenstein, David] Stanford Univ, Med Ctr, Div Infect Dis, Stanford, CA 94305 USA.
   [Ciaranello, Andrea] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA.
   [Barnabas, Ruanne] Univ Washington, Med Global Hlth & Epidemiol, Seattle, WA 98104 USA.
   [Braithwaite, R. Scott] NYU, Sch Med, Dept Populat Hlth, New York, NY 10016 USA.
   [Bendavid, Eran] Stanford Univ, Dept Med, Div Gen Med Disciplines, Stanford, CA 94305 USA.
   [Nathoo, Kusum J.] Univ Zimbabwe, Coll Hlth Sci, Dept Paediat & Child Hlth, Harare, Zimbabwe.
   [Wilson, David P.] Univ New S Wales, Sydney, NSW 2052, Australia.
   [Holmes, Charles] Ctr Infect Dis Res Zambia, Lusaka, Zambia.
   [Bershteyn, Anna] Inst Dis Modeling, Bellevue, WA 98005 USA.
   [Walker, Simon; Revill, Paul] Univ York, Ctr Hlth Econ, York YO10 5DD, N Yorkshire, England.
   [Raizes, Elliot] CDC, Care & Treatment Branch, Ctr Global Hlth, Div Global HIV AIDS GAP, Atlanta, GA 30333 USA.
   [Jani, Ilesh] Minist Hlth, INS, Maputo, Mozambique.
   [Nelson, Lisa J.] US Dept State, Off US Global AIDS Coordinator & Hlth Diplomacy S, Washington, DC 20520 USA.
   [Peeling, Rosanna] London Sch Hyg & Trop Med, Dept Clin Res, London WC1E 7HT, England.
   [Terris-Prestholt, Fern] London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London WC1H 9SH, England.
   [Murungu, Joseph; Mutasa-Apollo, Tsitsi] Minist Hlth & Child Care, Harare, Zimbabwe.
C3 University of London; University College London; Doctors Without Borders; Doctors Without Borders; Bill & Melinda Gates Foundation; University of London; University College London; Medical Research Council Clinical Trials Unit; University of London; London School of Hygiene & Tropical Medicine; University of Copenhagen; Rigshospitalet; Imperial College London; Makerere University; World Health Organization; Johns Hopkins University; Johns Hopkins Bloomberg School of Public Health; Erasmus University Rotterdam; Erasmus MC; University of London; London School of Hygiene & Tropical Medicine; Northwestern University; University of Witwatersrand; Stanford University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; University of Washington; University of Washington Seattle; New York University; Stanford University; University of Zimbabwe; University of New South Wales Sydney; University of York - UK; Centers for Disease Control & Prevention - USA; CDC Center for Global Health (CGH); University of London; London School of Hygiene & Tropical Medicine; University of London; London School of Hygiene & Tropical Medicine
RP Phillips, A (corresponding author), UCL, Dept Infect & Populat Hlth, Rowland Hill St, London NW3 2PF, England.
EM andrew.phillips@ucl.ac.uk
FU HIV Modelling Consortium; Bill and Melinda Gates Foundation; World Health Organization; HIV Diagnostics Modelling Consortium; Danish National Research Foundation [DNRF:126]; MRC [MC_UU_12023/26, MR/K010174/1] Funding Source: UKRI; Medical Research Council [MR/K010174/1, MC_UU_12023/26, MR/K010174/1B, MC_UU_12023/23] Funding Source: researchfish; National Institute of Nursing Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart Lung and Blood Institute; National Institute on Minority Health and Health Disparities; National Institute on Aging; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; National Cancer Institute [P30AI045008] Funding Source: NIH RePORTER
NR 63
TC 139
Z9 155
U1 0
U2 24
PU NATURE PUBLISHING 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 3
PY 2015
VL 528
IS 7580
BP S68
EP S76
DI 10.1038/nature16046
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000013
PM 26633768
DA 2026-03-09
ER

PT J
AU Huang, X
   Chen, H
   Michelsen, K
   Schneider, S
   Shaffer, PL
AF Huang, Xin
   Chen, Hao
   Michelsen, Klaus
   Schneider, Stephen
   Shaffer, Paul L.
TI Crystal structure of human glycine receptor-α3 bound to antagonist strychnine
SO NATURE
LA English
DT Article
ID gated ion-channel; x-ray-structure; functional expression; gating mechanism; binding; receptors; complexes; analogs; reveal
AB Neurotransmitter-gated ion channels of the Cys-loop receptor family are essential mediators of fast neurotransmission throughout the nervous system and are implicated in many neurological disorders. Available X-ray structures of prokaryotic and eukaryotic Cys-loop receptors provide tremendous insights into the binding of agonists, the subsequent opening of the ion channel, and the mechanism of channel activation(1-8). Yet the mechanism of inactivation by antagonists remains unknown. Here we present a 3.0 angstrom X-ray structure of the human glycine receptor-alpha 3 homopentamer in complex with a high affinity, high-specificity antagonist, strychnine. Our structure allows us to explore in detail the molecular recognition of antagonists. Comparisons with previous structures reveal a mechanism for antagonist-induced inactivation of Cys-loop receptors, involving an expansion of the orthosteric binding site in the extracellular domain that is coupled to closure of the ion pore in the transmembrane domain.
C1 [Huang, Xin; Michelsen, Klaus; Shaffer, Paul L.] Amgen Inc, Dept Mol Struct & Characterizat, Cambridge, MA 02142 USA.
   [Chen, Hao] Amgen Inc, Dept Prot Technol, Cambridge, MA 02142 USA.
   [Schneider, Stephen] Amgen Inc, Dept Neurosci, Cambridge, MA 02142 USA.
C3 Amgen; Amgen; Amgen
RP Huang, X (corresponding author), Amgen Inc, Dept Mol Struct & Characterizat, 360 Binney St, Cambridge, MA 02142 USA.
EM hxin@amgen.com; pshaffer@amgen.com
NR 41
TC 202
Z9 226
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 OCT 8
PY 2015
VL 526
IS 7572
BP 277
EP +
DI 10.1038/nature14972
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS9GV
UT WOS:000362399000052
PM 26416729
DA 2026-03-09
ER

PT J
AU Graham, MJ
   Djorgovski, SG
   Stern, D
   Glikman, E
   Drake, AJ
   Mahabal, AA
   Donalek, C
   Larson, S
   Christensen, E
AF Graham, Matthew J.
   Djorgovski, S. G.
   Stern, Daniel
   Glikman, Eilat
   Drake, Andrew J.
   Mahabal, Ashish A.
   Donalek, Ciro
   Larson, Steve
   Christensen, Eric
TI A possible close supermassive black-hole binary in a quasar with optical periodicity
SO NATURE
LA English
DT Article
ID active galactic nuclei; digital sky survey; survey spectroscopic sample; photometric standard stars; time transient survey; accretion disk; jet precession; variability; parsec; mass
AB Quasars have long been known to be variable sources at all wavelengths. Their optical variability is stochastic and can be due to a variety of physical mechanisms; it is also well-described statistically in terms of a damped random walk model(1). The recent availability of large collections of astronomical timeseries of flux measurements (light curves(2-5)) offers new data sets for a systematic exploration of quasar variability. Here we report the detection of a strong, smooth periodic signal in the optical variability of the quasar PG 1302-102 with a mean observed period of 1,884 +/- 88 days. It was identified in a search for periodic variability in a data set of light curves for 247,000 known, spectroscopically confirmed quasars with a temporal baseline of about 9 years. Although the interpretation of this phenomenon is still uncertain, the most plausible mechanisms involve a binary system of two supermassive black holes with a subparsec separation. Such systems are an expected consequence of galaxy mergers and can provide important constraints on models of galaxy formation and evolution.
C1 [Graham, Matthew J.; Djorgovski, S. G.; Drake, Andrew J.; Mahabal, Ashish A.; Donalek, Ciro] CALTECH, Pasadena, CA 91125 USA.
   [Stern, Daniel] CALTECH, Jet Prop Lab, Pasadena, CA 91109 USA.
   [Glikman, Eilat] Middlebury Coll, Dept Phys, Middlebury, VT 05753 USA.
   [Larson, Steve; Christensen, Eric] Univ Arizona, Lunar & Planetary Lab, Dept Planetary Sci, Tucson, AZ 85721 USA.
C3 California Institute of Technology; National Aeronautics & Space Administration (NASA); NASA Jet Propulsion Laboratory (JPL); California Institute of Technology; Middlebury College; University of Arizona
RP Graham, MJ (corresponding author), CALTECH, 1200 East Calif Blvd, Pasadena, CA 91125 USA.
EM mjg@caltech.edu
FU NSF [AST-0909182, IIS-1118031, AST-1313422]; W.M. Keck Foundation; NASA; Direct For Mathematical & Physical Scien; Division Of Astronomical Sciences [1413600] Funding Source: National Science Foundation; Division Of Astronomical Sciences; Direct For Mathematical & Physical Scien [1518308] Funding Source: National Science Foundation
NR 53
TC 309
Z9 344
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 FEB 5
PY 2015
VL 518
IS 7537
BP 74
EP +
DI 10.1038/nature14143
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7LE
UT WOS:000349098000033
PM 25561176
DA 2026-03-09
ER

PT J
AU Rowland, L
   da Costa, ACL
   Galbraith, DR
   Oliveira, RS
   Binks, OJ
   Oliveira, AAR
   Pullen, AM
   Doughty, CE
   Metcalfe, DB
   Vasconcelos, SS
   Ferreira, LV
   Malhi, Y
   Grace, J
   Mencuccini, M
   Meir, P
AF Rowland, L.
   da Costa, A. C. L.
   Galbraith, D. R.
   Oliveira, R. S.
   Binks, O. J.
   Oliveira, A. A. R.
   Pullen, A. M.
   Doughty, C. E.
   Metcalfe, D. B.
   Vasconcelos, S. S.
   Ferreira, L. V.
   Malhi, Y.
   Grace, J.
   Mencuccini, M.
   Meir, P.
TI Death from drought in tropical forests is triggered by hydraulics not carbon starvation
SO NATURE
LA English
DT Article
ID soil-moisture deficit; amazonian rain-forest; foliar uptake; climate; water; trees; vulnerability; mortality; dynamics; xylem
AB Drought threatens tropical rainforests over seasonal to decadal timescales(1-4), but the drivers of tree mortality following drought remain poorly understood(5,6). It has been suggested that reduced availability of non-structural carbohydrates (NSC) critically increases mortality risk through insufficient carbon supply to metabolism ('carbon starvation')(7,8). However, little is known about how NSC stores are affected by drought, especially over the long term, and whether they are more important than hydraulic processes in determining drought-induced mortality. Using data from the world's longest-running experimental drought study in tropical rainforest (in the Brazilian Amazon), we test whether carbon starvation or deterioration of the water-conducting pathways from soil to leaf trigger tree mortality. Biomass loss from mortality in the experimentally droughted forest increased substantially after > 10 years of reduced soil moisture availability. The mortality signal was dominated by the death of large trees, which were at a much greater risk of hydraulic deterioration than smaller trees. However, we find no evidence that the droughted trees suffered carbon starvation, as their NSC concentrations were similar to those of non-droughted trees, and growth rates did not decline in either living or dying trees. Our results indicate that hydraulics, rather than carbon starvation, triggers tree death from drought in tropical rainforest.
C1 [Rowland, L.; Binks, O. J.; Grace, J.; Mencuccini, M.; Meir, P.] Univ Edinburgh, Sch Geosci, Edinburgh EH9 3FF, Midlothian, Scotland.
   [da Costa, A. C. L.; Oliveira, A. A. R.] Fed Univ Para, Ctr Geosciencias, BR-66075110 Belem, Para, Brazil.
   [Galbraith, D. R.] Univ Leeds, Sch Geog, Leeds LS2 9JT, W Yorkshire, England.
   [Oliveira, R. S.] Univ Estadual Campinas, Inst Biol, BR-13083970 Campinas, SP, Brazil.
   [Pullen, A. M.] Univ Cambridge, Cambridge CB2 1TN, England.
   [Doughty, C. E.; Malhi, Y.] Univ Oxford, Environm Change Inst, Oxford OX1 3QY, England.
   [Metcalfe, D. B.] Lund Univ, Dept Phys Geog & Ecosyst Sci, S-22362 Lund, Sweden.
   [Vasconcelos, S. S.] EMBRAPA Amazonia Oriental, BR-66095903 Belem, Para, Brazil.
   [Ferreira, L. V.] Museu Paraense Emilio Goeldi, BR-66077830 Belem, Para, Brazil.
   [Mencuccini, M.] ICREA CREAF, Cerdanyola Del Valles 08193, Spain.
   [Meir, P.] Australian Natl Univ, Res Sch Biol, Canberra, ACT 2601, Australia.
C3 University of Edinburgh; Universidade Federal do Para; University of Leeds; Universidade Estadual de Campinas; Universidade de Sao Paulo; University of Cambridge; University of Oxford; Lund University; Empresa Brasileira de Pesquisa Agropecuaria (EMBRAPA); EMBRAPA Amazonia Oriental; Museu Paraense Emilio Goeldi; ICREA; Centro de Investigacion Ecologica y Aplicaciones Forestales (CREAF-CERCA); Australian National University
RP Rowland, L (corresponding author), Univ Edinburgh, Sch Geosci, Edinburgh EH9 3FF, Midlothian, Scotland.
EM lucy.rowland@ed.ac.uk
FU UK NERC [NE/J011002/1]; CNPQ [457914/2013-0/MCTI/CNPq/FNDCT/LBA/ESECAFLOR]; ARC [FT110100457]; NERC [NER/A/S/2002/00487, GR3/11706, NE/D01025X/1]; EU FP5-Carbonsink; EU FP7-Amazalert; Gordon and Betty Moore Foundation; NERC [NE/D01025X/1, NE/F005040/1, NE/F005776/1, NE/J011002/1] Funding Source: UKRI; Natural Environment Research Council [NE/J011002/1, NE/D01025X/1, NE/F005776/1, NE/F005040/1, NER/A/S/2003/00609] Funding Source: researchfish; ICREA Funding Source: Custom
NR 45
TC 536
Z9 617
U1 17
U2 583
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 3
PY 2015
VL 528
IS 7580
BP 119
EP +
DI 10.1038/nature15539
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000060
PM 26595275
DA 2026-03-09
ER

PT J
AU Wang, XW
   Chen, XJ
AF Wang, Xiaowen
   Chen, Xin Jie
TI A cytosolic network suppressing mitochondria-mediated proteostatic stress and cell death
SO NATURE
LA English
DT Article
ID adenine-nucleotide translocator; cap-independent translation; saccharomyces-cerevisiae; proteomic analysis; isobaric tags; life-span; yeast; diseases; complex; dna
AB Mitochondria are multifunctional organelles whose dysfunction leads to neuromuscular degeneration and ageing. The multifunctionality poses a great challenge for understanding the mechanisms by which mitochondrial dysfunction causes specific pathologies. Among the leading mitochondrial mediators of cell death are energy depletion, free radical production, defects in iron-sulfur cluster biosynthesis, the release of pro-apoptotic and non-cell-autonomous signalling molecules, and altered stress signalling(1-5). Here we identify a new pathway of mitochondria-mediated cell death in yeast. This pathway was named mitochondrial precursor over-accumulation stress (mPOS), and is characterized by aberrant accumulation of mitochondrial precursors in the cytosol. mPOS can be triggered by clinically relevant mitochondrial damage that is not limited to the core machineries of protein import. We also discover a large network of genes that suppress mPOS, by modulating ribosomal biogenesis, messenger RNA decapping, transcript-specific translation, protein chaperoning and turnover. In response to mPOS, several ribosome-associated proteins were upregulated, including Gis2 and Nog2, which promote cap-independent translation and inhibit the nuclear export of the 60S ribosomal subunit, respectively(6,7). Gis2 and Nog2 upregulation promotes cell survival, which may be part of a feedback loop that attenuates mPOS. Our data indicate that mitochondrial dysfunction contributes directly to cytosolic proteostatic stress, and provide an explanation for the association between these two hallmarks of degenerative diseases and ageing. The results are relevant to understanding diseases (for example, spinocerebellar ataxia, amyotrophic lateral sclerosis and myotonic dystrophy) that involve mutations within the anti-degenerative network.
C1 [Wang, Xiaowen; Chen, Xin Jie] SUNY Upstate Med Univ, Dept Biochem & Mol Biol, Syracuse, NY 13210 USA.
C3 State University of New York (SUNY) System; SUNY Upstate Medical University
RP Chen, XJ (corresponding author), SUNY Upstate Med Univ, Dept Biochem & Mol Biol, Syracuse, NY 13210 USA.
EM chenx@upstate.edu
FU National Institutes of Health (NIH) [R01AG023731, R21AG047400]
NR 34
TC 285
Z9 314
U1 1
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 AUG 27
PY 2015
VL 524
IS 7566
BP 481
EP +
DI 10.1038/nature14859
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP7LN
UT WOS:000360069300041
PM 26192197
DA 2026-03-09
ER

PT J
AU Chang, LF
   Zhang, ZG
   Yang, J
   McLaughlin, SH
   Barford, D
AF Chang, Leifu
   Zhang, Ziguo
   Yang, Jing
   McLaughlin, Stephen H.
   Barford, David
TI Atomic structure of the APC/C and its mechanism of protein ubiquitination
SO NATURE
LA English
DT Article
ID anaphase-promoting complex; e3 ligase; crystal-structure; chain elongation; conjugating enzyme; mitotic regulation; activation; reveals; subunit; phosphorylation
AB The anaphase-promoting complex (APC/C) is a multimeric RING E3 ubiquitin ligase that controls chromosome segregation and mitotic exit. Its regulation by coactivator subunits, phosphorylation, the mitotic checkpoint complex and interphase early mitotic inhibitor 1 (Emi1) ensures the correct order and timing of distinct cell-cycle transitions. Here we use cryo-electron microscopy to determine atomic structures of APC/C-coactivator complexes with either Emi1 or a UbcH10-ubiquitin conjugate. These structures define the architecture of all APC/C subunits, the position of the catalytic module and explain how Emi1 mediates inhibition of the two E2s UbcH10 and Ube2S. Definition of Cdh1 interactions with the APC/C indicates how they are antagonized by Cdh1 phosphorylation. The structure of the APC/C with UbcH10-ubiquitin reveals insights into the initiating ubiquitination reaction. Our results provide a quantitative framework for the design of future experiments to investigate APC/C functions in vivo.
C1 [Chang, Leifu; Zhang, Ziguo; Yang, Jing; McLaughlin, Stephen H.; Barford, David] MRC Lab Mol Biol, Cambridge CB2 0QH, England.
C3 MRC Laboratory Molecular Biology
RP Barford, D (corresponding author), MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England.
EM dbarford@mrc-lmb.cam.ac.uk
FU Cancer Research UK; MRC [MC_UP_1201/6] Funding Source: UKRI; Cancer Research UK [14109] Funding Source: researchfish; Medical Research Council [MC_UP_1201/6] Funding Source: researchfish
NR 73
TC 186
Z9 212
U1 3
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 JUN 25
PY 2015
VL 522
IS 7557
BP 450
EP +
DI 10.1038/nature14471
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL2OC
UT WOS:000356782900043
PM 26083744
DA 2026-03-09
ER

PT J
AU Koh, CM
   Bezzi, M
   Low, DHP
   Ang, WX
   Teo, SX
   Gay, FPH
   Al-Haddawi, M
   Tan, SY
   Osato, M
   Sabò, A
   Amati, B
   Wee, KB
   Guccione, E
AF Koh, Cheryl M.
   Bezzi, Marco
   Low, Diana H. P.
   Ang, Wei Xia
   Teo, Shun Xie
   Gay, Florence P. H.
   Al-Haddawi, Muthafar
   Tan, Soo Yong
   Osato, Motomi
   Sabo, Arianna
   Amati, Bruno
   Wee, Keng Boon
   Guccione, Ernesto
TI MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis
SO NATURE
LA English
DT Article
ID factor srsf1; pathway; complex; mouse; prmt5; mutations; proteins; genome; target
AB Deregulated expression of the MYC transcription factor occurs in most human cancers and correlates with high proliferation, reprogrammed cellular metabolism and poor prognosis(1). Overexpressed MYC binds to virtually all active promoters within a cell, although with different binding affinities(2-4), and modulates the expression of distinct subsets of genes(1,2,4,5). However, the critical effectors of MYC in tumorigenesis remain largely unknown. Here we show that during lymphomagenesis in Em-myc transgenic mice, MYC directly upregulates the transcription of the core small nuclear ribonucleoprotein particle assembly genes, including Prmt5, an arginine methyltransferase that methylates Sm proteins(6,7). This coordinated regulatory effect is critical for the core biogenesis of small nuclear ribonucleoprotein particles, effective pre-messenger-RNA splicing, cell survival and proliferation. Our results demonstrate that MYC maintains the splicing fidelity of exons with a weak 5' donor site. Additionally, we identify pre-messenger-RNAs that are particularly sensitive to the perturbation of the MYC-PRMT5 axis, resulting in either intron retention (for example, Dvl1) or exon skipping (for example, Atr, Ep400). Using antisense oligonucleotides, we demonstrate the contribution of these splicing defects to the anti-proliferative/apoptotic phenotype observed in PRMT5-depleted E mu-myc B cells. We conclude that, in addition to its well-documented oncogenic functions in transcription(2-5) and translation(8), MYC also safeguards proper pre-messenger-RNA splicing as an essential step in lymphomagenesis.
C1 [Koh, Cheryl M.; Bezzi, Marco; Low, Diana H. P.; Ang, Wei Xia; Teo, Shun Xie; Gay, Florence P. H.; Al-Haddawi, Muthafar; Tan, Soo Yong; Guccione, Ernesto] ASTAR, IMCB, Singapore 138673, Singapore.
   [Bezzi, Marco; Guccione, Ernesto] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117597, Singapore.
   [Osato, Motomi; Guccione, Ernesto] Natl Univ Singapore, Canc Sci Inst Singapore CSI, Singapore 117599, Singapore.
   [Sabo, Arianna; Amati, Bruno] Fdn Ist Italiano Tecnol IIT, Ctr Genom Sci IIT SEMM, I-20139 Milan, Italy.
   [Amati, Bruno] European Inst Oncol IEO, Dept Expt Oncol, I-20139 Milan, Italy.
   [Wee, Keng Boon] ASTAR, IHPC, Singapore 138632, Singapore.
   [Wee, Keng Boon] ASTAR, Bioinformat Inst BII, Singapore 138671, Singapore.
C3 Agency for Science Technology & Research (A*STAR); A*STAR - Institute of Molecular & Cell Biology (IMCB); National University of Singapore; National University of Singapore; Istituto Italiano di Tecnologia - IIT; Center for Genomic Science IIT; IRCCS European Institute of Oncology (IEO); Agency for Science Technology & Research (A*STAR); A*STAR - Institute of High Performance Computing (IHPC); Agency for Science Technology & Research (A*STAR); A*STAR - Bioinformatics Institute (BII)
RP Guccione, E (corresponding author), ASTAR, IMCB, Singapore 138673, Singapore.
EM eguccione@imcb.a-star.edu.sg
FU AGA-SINGA (SINgapore Graduate Award); IMCB, A-STAR; JCO-ASTAR [1134c001, 11/03/FG/07/04]; European Research Council; Italian health ministry; Italian Association for Cancer Research (AIRC); Grants-in-Aid for Scientific Research [15H04312] Funding Source: KAKEN
NR 33
TC 297
Z9 367
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 JUL 2
PY 2015
VL 523
IS 7558
BP 96
EP +
DI 10.1038/nature14351
PG 26
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL7RN
UT WOS:000357169500039
PM 25970242
DA 2026-03-09
ER

PT J
AU Blake, PR
   McAuliffe, K
   Corbit, J
   Callaghan, TC
   Barry, O
   Bowie, A
   Kleutsch, L
   Kramer, KL
   Ross, E
   Vongsachang, H
   Wrangham, R
   Warneken, F
AF Blake, P. R.
   McAuliffe, K.
   Corbit, J.
   Callaghan, T. C.
   Barry, O.
   Bowie, A.
   Kleutsch, L.
   Kramer, K. L.
   Ross, E.
   Vongsachang, H.
   Wrangham, R.
   Warneken, F.
TI The ontogeny of fairness in seven societies
SO NATURE
LA English
DT Article
ID behavior; egalitarianism; punishment; culture
AB A sense of fairness plays a critical role in supporting human cooperation(1-3). Adult norms of fair resource sharing vary widely across societies, suggesting that culture shapes the acquisition of fairness behaviour during childhood(4,5). Here we examine how fairness behaviour develops in children from seven diverse societies, testing children from 4 to 15 years of age (n = 866 pairs) in a standardized resource decision task(6,7). We measured two key aspects of fairness decisions: disadvantageous inequity aversion (peer receives more than self) and advantageous inequity aversion (self receives more than a peer). We show that disadvantageous inequity aversion emerged across all populations by middle childhood. By contrast, advantageous inequity aversion was more variable, emerging in three populations and only later in development. We discuss these findings in relation to questions about the universality and cultural specificity of human fairness.
C1 [Blake, P. R.] Boston Univ, Dept Psychol & Brain Sci, Boston, MA 02215 USA.
   [McAuliffe, K.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA.
   [McAuliffe, K.] Boston Coll, Dept Psychol, Chestnut Hill, MA 02467 USA.
   [McAuliffe, K.; Bowie, A.; Ross, E.; Vongsachang, H.; Wrangham, R.] Harvard Univ, Dept Human Evolutionary Biol, Cambridge, MA 02138 USA.
   [Corbit, J.] Simon Fraser Univ, Dept Psychol, Burnaby, BC V5A 1S6, Canada.
   [Callaghan, T. C.] St Francis Xavier Univ, Fac Arts & Sci, Dept Psychol, Antigonish, NS B2G 2W5, Canada.
   [Barry, O.] Univ Cheikh Anta Diop, Fac Sci & Technol Educ & Training, Dakar, Senegal.
   [Bowie, A.; Kleutsch, L.; Vongsachang, H.; Warneken, F.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA.
   [Kramer, K. L.] Univ Utah, Dept Anthropol, Salt Lake City, UT 84112 USA.
C3 Boston University; Yale University; Boston College; Harvard University; Simon Fraser University; Saint Francis Xavier University - Canada; University Cheikh Anta Diop Dakar; Harvard University; Utah System of Higher Education; University of Utah
RP Blake, PR (corresponding author), Boston Univ, Dept Psychol & Brain Sci, Boston, MA 02215 USA.
EM pblake@bu.edu; mcaulikg@bc.edu
FU Harvard Academy Junior Faculty Development Grant, Radcliffe Institute for Advanced Study; Herchel Smith Harvard Undergraduate Science Research Program; Harvard College Research Program; John Templeton Foundation; Harvard Department of Human Evolutionary Biology
CR Bahry DL, 2006, J ECON BEHAV ORGAN, V60, P37, DOI 10.1016/j.jebo.2004.07.005
   Blake PR, 2014, TRENDS COGN SCI, V18, P559, DOI 10.1016/j.tics.2014.08.003
   Blake PR, 2011, COGNITION, V120, P215, DOI 10.1016/j.cognition.2011.04.006
   Brosnan SF, 2014, SCIENCE, V346, P314, DOI 10.1126/science.1251776
   Chudek M, 2011, TRENDS COGN SCI, V15, P218, DOI 10.1016/j.tics.2011.03.003
   Dawes CT, 2007, NATURE, V446, P794, DOI 10.1038/nature05651
   Fehr E, 1999, Q J ECON, V114, P817, DOI 10.1162/003355399556151
   Fehr E, 2008, NATURE, V454, P1079, DOI 10.1038/nature07155
   Fehr E, 2013, EUR ECON REV, V64, P369, DOI 10.1016/j.euroecorev.2013.09.006
   Güroglu B, 2014, PLOS ONE, V9, P0, DOI 10.1371/journal.pone.0107996
   Henrich J, 2005, BEHAV BRAIN SCI, V28, P795, DOI 10.1017/S0140525X05000142
   Henrich J, 2006, SCIENCE, V312, P1767, DOI 10.1126/science.1127333
   Henrich J, 2010, BEHAV BRAIN SCI, V33, P61, DOI 10.1017/S0140525X0999152X
   Henrich J, 2010, BEHAV BRAIN SCI, V33, P111, DOI 10.1017/S0140525X10000725
   Henrich J, 2010, SCIENCE, V327, P1480, DOI 10.1126/science.1182238
   Herrmann B, 2008, SCIENCE, V319, P1362, DOI 10.1126/science.1153808
   House BR, 2013, P NATL ACAD SCI USA, V110, P14586, DOI 10.1073/pnas.1221217110
   Keller H, 2006, J CROSS CULT PSYCHOL, V37, P155, DOI 10.1177/0022022105284494
   Leimgruber KL, 2012, PLOS ONE, V7, P0, DOI 10.1371/journal.pone.0048292
   LoBue V, 2011, SOC DEV, V20, P154, DOI 10.1111/j.1467-9507.2009.00560.x
   LOEWENSTEIN GF, 1989, J PERS SOC PSYCHOL, V57, P426, DOI 10.1037/0022-3514.57.3.426
   McAuliffe K, 2014, BIOL LETTERS, V10, P0, DOI 10.1098/rsbl.2014.0743
   McAuliffe K, 2013, PLOS ONE, V8, P0, DOI 10.1371/journal.pone.0080966
   Paulus M, 2015, J EXP CHILD PSYCHOL, V132, P240, DOI 10.1016/j.jecp.2014.12.007
   Robbins E, 2011, FRONT PSYCHOL, V2, P0, DOI 10.3389/fpsyg.2011.00353
   Rochat P, 2009, J CROSS CULT PSYCHOL, V40, P416, DOI 10.1177/0022022109332844
   Schäfer M, 2015, PSYCHOL SCI, V26, P1252, DOI 10.1177/0956797615586188
   Shaw A, 2012, J EXP PSYCHOL GEN, V141, P382, DOI 10.1037/a0025907
   Sheskin M, 2014, COGNITION, V130, P152, DOI 10.1016/j.cognition.2013.10.008
   Smith CE, 2013, PLOS ONE, V8, P0, DOI 10.1371/journal.pone.0059510
   Sutter M, 2007, J ECON PSYCHOL, V28, P69, DOI 10.1016/j.joep.2006.09.001
NR 31
TC 374
Z9 424
U1 8
U2 193
PU NATURE PUBLISHING 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 10
PY 2015
VL 528
IS 7581
BP 258
EP +
DI 10.1038/nature15703
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX9VH
UT WOS:000366053300040
PM 26580018
DA 2026-03-09
ER

PT J
AU Efremov, RG
   Leitner, A
   Aebersold, R
   Raunser, S
AF Efremov, Rouslan G.
   Leitner, Alexander
   Aebersold, Ruedi
   Raunser, Stefan
TI Architecture and conformational switch mechanism of the ryanodine receptor
SO NATURE
LA English
DT Article
ID protein-structure prediction; calcium-release channel; cross-linked peptides; skeletal-muscle; topology; resolution; calmodulin; system; model; forms
AB Muscle contraction is initiated by the release of calcium (Ca2+) from the sarcoplasmic reticulum into the cytoplasm of myocytes through ryanodine receptors (RyRs). RyRs are homotetrameric channels with a molecular mass of more than 2.2 megadaltons that are regulated by several factors, including ions, small molecules and proteins. Numerous mutations in RyRs have been associated with human diseases. The molecular mechanism underlying the complex regulation of RyRs is poorly understood. Using electron cryomicroscopy, here we determine the architecture of rabbit RyR1 at a resolutionof 6.1 angstrom. We show that the cytoplasmic moiety of RyR1 contains two large alpha-solenoid domains and several smaller domains, with folds suggestive of participation in protein-protein interactions. The transmembrane domain represents a chimaera of voltage-gated sodium and pH-activated ion channels. We identify the calcium-binding EF-hand domain and show that it functions as a conformational switch allosterically gating the channel.
C1 [Efremov, Rouslan G.; Raunser, Stefan] Max Planck Inst Mol Physiol, Dept Struct Biochem, D-44227 Dortmund, Germany.
   [Efremov, Rouslan G.] VIB, Struct Biol Res Ctr, B-1050 Brussels, Belgium.
   [Efremov, Rouslan G.] VUB, Struct Biol Brussels, B-1050 Brussels, Belgium.
   [Leitner, Alexander; Aebersold, Ruedi] ETH, Dept Biol, Inst Mol Syst Biol, CH-8093 Zurich, Switzerland.
   [Aebersold, Ruedi] Univ Zurich, Fac Sci, CH-8057 Zurich, Switzerland.
C3 Max Planck Society; Flanders Institute for Biotechnology (VIB); Vrije Universiteit Brussel; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Zurich
RP Efremov, RG (corresponding author), Max Planck Inst Mol Physiol, Dept Struct Biochem, D-44227 Dortmund, Germany.
EM rouslan.efremov@vib-vub.be; stefan.raunser@mpi-dortmund.mpg.de
NR 69
TC 256
Z9 298
U1 0
U2 108
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 1
PY 2015
VL 517
IS 7532
BP 39
EP U72
DI 10.1038/nature13916
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AX8SI
UT WOS:000347178400030
PM 25470059
DA 2026-03-09
ER

PT J
AU Long, JA
   Mark-Kurik, E
   Johanson, Z
   Lee, MSY
   Young, GC
   Min, Z
   Ahlberg, PE
   Newman, M
   Jones, R
   den Blaauwen, J
   Choo, B
   Trinajstic, K
AF Long, John A.
   Mark-Kurik, Elga
   Johanson, Zerina
   Lee, Michael S. Y.
   Young, Gavin C.
   Min, Zhu
   Ahlberg, Per E.
   Newman, Michael
   Jones, Roger
   den Blaauwen, Jan
   Choo, Brian
   Trinajstic, Kate
TI Copulation in antiarch placoderms and the origin of gnathostome internal fertilization
SO NATURE
LA English
DT Article
ID jawed vertebrates; viviparity; evolution
AB Reproduction in jawed vertebrates (gnathostomes) involves either external or internal fertilization(1). It is commonly argued that internal fertilization can evolve from external, but not the reverse. Male copulatory claspers are present in certain placoderms(2-4), fossil jawed vertebrates retrieved as a paraphyletic segment of the gnathostome stem group in recent studies(5-8). This suggests that internal fertilization could be primitive for gnathostomes, but such a conclusion depends on demonstrating that copulation was not just a specialized feature of certain placoderm subgroups. The reproductive biology of antiarchs, consistently identified as the least crownward placoderms(5-8) and thus of great interest in this context, has until now remained unknown. Here we show that certain antiarchs possessed dermal claspers in the males, while females bore paired dermal plates inferred to have facilitated copulation. These structures are not associated with pelvic fins. The clasper morphology resembles that of ptyctodonts, a more crownward placoderm group(7,8), suggesting that all placoderm claspers are homologous and that internal fertilization characterized all placoderms. This implies that external fertilization and spawning, which characterize most extant aquatic gnathostomes, must be derived from internal fertilization, even though this transformation has been thought implausible. Alternatively, the substantial morphological evidence for placoderm paraphyly must be rejected.
C1 [Long, John A.; Choo, Brian] Flinders Univ S Australia, Sch Biol Sci, Adelaide, SA 5001, Australia.
   [Long, John A.; Choo, Brian] Flinders Univ S Australia, Sch Biol Sci, Adelaide, SA 2100, Australia.
   [Long, John A.] Nat Hist Museum Los Angeles Cty, Los Angeles, CA USA.
   [Long, John A.] Museum Victoria, Melbourne, Vic 3001, Australia.
   [Mark-Kurik, Elga] Tallinn Univ Technol, Inst Geol, EE-19086 Tallinn, Estonia.
   [Johanson, Zerina] Nat Hist Museum, Dept Earth Sci, London SW7 5BD, England.
   [Lee, Michael S. Y.] S Australian Museum, Adelaide, SA 5000, Australia.
   [Lee, Michael S. Y.] Univ Adelaide, Sch Earth & Environm Sci, Adelaide, SA 5005, Australia.
   [Young, Gavin C.] Australian Natl Univ, Res Sch Earth Sci, Canberra, ACT 0200, Australia.
   [Min, Zhu] Chinese Acad Sci, Inst Vertebrate Paleontol & Paleoanthropol, Key Lab Evolutionary Systemat Vertebrates, Beijing 100044, Peoples R China.
   [Ahlberg, Per E.] Uppsala Univ, Evolutionary Biol Ctr, Dept Organismal Biol, S-75236 Uppsala, Sweden.
   [Newman, Michael] Vine Lodge, Haverfordwest SA62 3NZ, Pembroke, Wales.
   [den Blaauwen, Jan] Univ Amsterdam, NL-1098 XH Amsterdam, Netherlands.
   [Trinajstic, Kate] Curtin Univ, Dept Chem, Western Australian Organ & Isotope Geochem Ctr, Perth, WA 6102, Australia.
   [Trinajstic, Kate] Western Australian Museum, Earth & Planetary Sci, Perth, WA 6000, Australia.
C3 Flinders University; Flinders University; Museum Victoria; Tallinn University of Technology; Natural History Museum London; Adelaide University; University of Adelaide; Australian National University; Chinese Academy of Sciences; Institute of Vertebrate Paleontology & Paleoanthropology, CAS; Uppsala University; University of Amsterdam; Curtin University; Western Australian Museum
RP Long, JA (corresponding author), Flinders Univ S Australia, Sch Biol Sci, Adelaide, SA 5001, Australia.
EM john.long@flinders.edu.au
FU Australian Research Council
NR 25
TC 92
Z9 112
U1 0
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 JAN 8
PY 2015
VL 517
IS 7533
BP 196
EP U171
DI 10.1038/nature13825
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600035
PM 25327249
DA 2026-03-09
ER

PT J
AU Burke, M
   Hsiang, SM
   Miguel, E
AF Burke, Marshall
   Hsiang, Solomon M.
   Miguel, Edward
TI Global non-linear effect of temperature on economic production
SO NATURE
LA English
DT Article
ID models
AB Growing evidence demonstrates that climatic conditions can have a profound impact on the functioning of modern human societies(1,2), but effects on economic activity appear inconsistent. Fundamental productive elements of modern economies, such as workers and crops, exhibit highly non-linear responses to local temperature even in wealthy countries(3,4). In contrast, aggregate macroeconomic productivity of entire wealthy countries is reported not to respond to temperature(5), while poor countries respond only linearly(5,6). Resolving this conflict between micro and macro observations is critical to understanding the role of wealth in coupled human-natural systems(7,8) and to anticipating the global impact of climate change(9,10). Here we unify these seemingly contradictory results by accounting for non-linearity at the macro scale. We show that overall economic productivity is non-linear in temperature for all countries, with productivity peaking at an annual average temperature of 13 degrees C and declining strongly at higher temperatures. The relationship is globally generalizable, unchanged since 1960, and apparent for agricultural and non-agricultural activity in both rich and poor countries. These results provide the first evidence that economic activity in all regions is coupled to the global climate and establish a new empirical foundation for modelling economic loss in response to climate change(11,12), with important implications. If future adaptation mimics past adaptation, unmitigated warming is expected to reshape the global economy by reducing average global incomes roughly 23% by 2100 and widening global income inequality, relative to scenarios without climate change. In contrast to prior estimates, expected global losses are approximately linear in global mean temperature, with median losses many times larger than leading models indicate.
C1 [Burke, Marshall] Stanford Univ, Dept Earth Syst Sci, Stanford, CA 94305 USA.
   [Burke, Marshall] Stanford Univ, Ctr Food Secur & Environm, Stanford, CA 94305 USA.
   [Hsiang, Solomon M.] Univ Calif Berkeley, Goldman Sch Publ Policy, Berkeley, CA 94720 USA.
   [Hsiang, Solomon M.; Miguel, Edward] Univ Calif Berkeley, Natl Bur Econ Res, Berkeley, CA 94720 USA.
   [Miguel, Edward] Univ Calif Berkeley, Dept Econ, Berkeley, CA 94720 USA.
C3 Stanford University; Stanford University; University of California System; University of California Berkeley; National Bureau of Economic Research; University of California System; University of California Berkeley; University of California System; University of California Berkeley
RP Burke, M (corresponding author), Stanford Univ, Dept Earth Syst Sci, Stanford, CA 94305 USA.
EM mburke@stanford.edu
NR 27
TC 1604
Z9 2105
U1 60
U2 711
PU NATURE PUBLISHING 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 12
PY 2015
VL 527
IS 7577
BP 235
EP +
DI 10.1038/nature15725
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700045
PM 26503051
DA 2026-03-09
ER

PT J
AU Finkelstein, A
   Derdikman, D
   Rubin, A
   Foerster, JN
   Las, L
   Ulanovsky, N
AF Finkelstein, Arseny
   Derdikman, Dori
   Rubin, Alon
   Foerster, Jakob N.
   Las, Liora
   Ulanovsky, Nachum
TI Three-dimensional head-direction coding in the bat brain
SO NATURE
LA English
DT Article
ID medial entorhinal cortex; hippocampal place cells; freely moving rats; grid cells; spatial representation; echolocating bats; path-integration; vertical plane; cognitive map; dynamics
AB Navigation requires a sense of direction ('compass'), which in mammals is thought to be provided by head-direction cells, neurons that discharge when the animal's head points to a specific azimuth. However, it remains unclear whether a three-dimensional (3D) compass exists in the brain. Here we conducted neural recordings in bats, mammals well-adapted to 3D spatial behaviours, and found head-direction cells tuned to azimuth, pitch or roll, or to conjunctive combinations of 3D angles, in both crawling and flying bats. Head-direction cells were organized along a functional-anatomical gradient in the presubiculum, transitioning from 2D to 3D representations. In inverted bats, the azimuth-tuning of neurons shifted by 180 degrees, suggesting that 3D head direction is represented in azimuth x pitch toroidal coordinates. Consistent with our toroidal model, pitch-cell tuning was unimodal, circular, and continuous within the available 360 degrees of pitch. Taken together, these results demonstrate a 3D head-direction mechanism in mammals, which could support navigation in 3D space.
C1 [Finkelstein, Arseny; Derdikman, Dori; Rubin, Alon; Foerster, Jakob N.; Las, Liora; Ulanovsky, Nachum] Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel.
   [Derdikman, Dori] Technion Israel Inst Technol, Rappaport Fac Med, IL-31096 Haifa, Israel.
   [Derdikman, Dori] Technion Israel Inst Technol, Res Inst, IL-31096 Haifa, Israel.
C3 Weizmann Institute of Science; Technion Israel Institute of Technology; Rappaport Faculty of Medicine; Technion Israel Institute of Technology
RP Ulanovsky, N (corresponding author), Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel.
EM nachum.ulanovsky@weizmann.ac.il
FU European Research Council (ERC-NEUROBAT); Human Frontiers Science Program [HFSP RGP0062/2009-C]; Israel Science Foundation [ISF 1017/08, ISF 1319/13]; Minerva Foundation; Clore predoctoral excellence fellowship; MIT-Israel (MISTI) student exchange internship
NR 59
TC 182
Z9 210
U1 1
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 JAN 8
PY 2015
VL 517
IS 7533
BP 159
EP U65
DI 10.1038/nature14031
PG 25
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600027
PM 25470055
DA 2026-03-09
ER

PT J
AU Fan, GZ
   Baker, ML
   Wang, Z
   Baker, MR
   Sinyagovskiy, PA
   Chiu, W
   Ludtke, SJ
   Serysheva, II
AF Fan, Guizhen
   Baker, Matthew L.
   Wang, Zhao
   Baker, Mariah R.
   Sinyagovskiy, Pavel A.
   Chiu, Wah
   Ludtke, Steven J.
   Serysheva, Irina I.
TI Gating machinery of InsP3R channels revealed by electron cryomicroscopy
SO NATURE
LA English
DT Article
ID inositol 1,4,5-trisphosphate receptor; cryo-em structure; ligand-binding; crystal-structure; macromolecular assembly; structure prediction; resolution structure; potassium channel; protein-structure; identification
AB Inositol-1,4,5-trisphosphate receptors (InsP(3)Rs) are ubiquitous ion channels responsible for cytosolic Ca2+ signalling and essential for a broad array of cellular processes ranging from contraction to secretion, and from proliferation to cell death. Despite decades of research on InsP(3)Rs, a mechanistic understanding of their structure-function relationship is lacking. Here we present the first, to our knowledge, near-atomic (4.7 angstrom) resolution electron cryomicroscopy structure of the tetrameric mammalian type 1 InsP(3)R channel in its apo-state. At this resolution, we are able to trace unambiguously similar to 85% of the protein backbone, allowing us to identify the structural elements involved in gating and modulation of this 1.3-megadalton channel. Although the central Ca2+-conduction pathway is similar to other ion channels, including the closely related ryanodine receptor, the cytosolic carboxy termini are uniquely arranged in a left-handed a-helical bundle, directly interacting with the amino-terminal domains of adjacent subunits. This configuration suggests a molecular mechanism for allosteric regulation of channel gating by intracellular signals.
C1 [Fan, Guizhen; Baker, Mariah R.; Sinyagovskiy, Pavel A.; Serysheva, Irina I.] Univ Texas Med Sch Houston, Struct Biol Imaging Ctr, Dept Biochem & Mol Biol, 6431 Fannin St, Houston, TX 77030 USA.
   [Baker, Matthew L.; Wang, Zhao; Chiu, Wah; Ludtke, Steven J.] Baylor Coll Med, Natl Ctr Macromol Imaging, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA.
C3 Baylor College of Medicine; Baylor College Medical Hospital; University of Texas System; University of Texas Health Science Center Houston; Baylor College of Medicine
RP Serysheva, II (corresponding author), Univ Texas Med Sch Houston, Struct Biol Imaging Ctr, Dept Biochem & Mol Biol, 6431 Fannin St, Houston, TX 77030 USA.
EM irina.i.serysheva@uth.tmc.edu
FU National Institutes of Health [R01GM072804, R21AR063255, S10OD016279, P41GM103832, R01GM079429, R01GM080139, R21GM100229]; American Heart Association [14RNT1980029]; Muscular Dystrophy Association [295138]; National Science Foundation [DBI-1356306]; National Institute of General Medical Sciences [R01GM079429, R01GM072804, R01GM080139] Funding Source: NIH RePORTER; Div Of Biological Infrastructure; Direct For Biological Sciences [1356306, 1356388] Funding Source: National Science Foundation
NR 56
TC 177
Z9 206
U1 0
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 19
PY 2015
VL 527
IS 7578
BP 336
EP +
DI 10.1038/nature15249
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9ZN
UT WOS:000365356800047
PM 26458101
DA 2026-03-09
ER

PT J
AU Campi, G
   Bianconi, A
   Poccia, N
   Bianconi, G
   Barba, L
   Arrighetti, G
   Innocenti, D
   Karpinski, J
   Zhigadlo, ND
   Kazakov, SM
   Burghammer, M
   Zimmermann, MV
   Sprung, M
   Ricci, A
AF Campi, G.
   Bianconi, A.
   Poccia, N.
   Bianconi, G.
   Barba, L.
   Arrighetti, G.
   Innocenti, D.
   Karpinski, J.
   Zhigadlo, N. D.
   Kazakov, S. M.
   Burghammer, M.
   Zimmermann, M. V.
   Sprung, M.
   Ricci, A.
TI Inhomogeneity of charge-density-wave order and quenched disorder in a high-Tc superconductor
SO NATURE
LA English
DT Article
ID local lattice-distortions; phase; temperature; instability; complexity; nematicity; evolution; quantum; glass
AB It has recently been established that the high-transition-temperature (high-T-c) superconducting state coexists with short-range charge-density-wave order(1-11) and quenched disorder(12,13) arising from dopants and strain(14-17). This complex, multiscale phase separation(18-21) invites the development of theories of high-temperature superconductivity that include complexity(22-25). The nature of the spatial interplay between charge and dopant order that provides a basis for nanoscale phase separation remains a key open question, because experiments have yet to probe the unknown spatial distribution at both the nanoscale and mesoscale (between atomic and macroscopic scale). Here we report micro X-ray diffraction imaging of the spatial distribution of both short-range charge-density-wave 'puddles' (domains with only a few wavelengths) and quenched disorder in HgBa2CuO4+y, the single-layer cuprate with the highest T-c, 95 kelvin (refs 26-28). We found that the charge-density-wave puddles, like the steam bubbles in boiling water, have a fat-tailed size distribution that is typical of self-organization near a critical point(19). However, the quenched disorder, which arises from oxygen interstitials, has a distribution that is contrary to the usually assumed random, uncorrelated distribution(12,13). The interstitial-oxygen-rich domains are spatially anticorrelated with the charge-density-wave domains, because higher doping does not favour the stripy charge-density-wave puddles, leading to a complex emergent geometry of the spatial landscape for superconductivity.
C1 [Campi, G.; Bianconi, A.] CNR, Inst Crystallog, I-00015 Monterotondo Roma, Italy.
   [Campi, G.; Bianconi, A.; Poccia, N.; Innocenti, D.; Ricci, A.] RICMASS, Superstripes, Rome Int Ctr Mat Sci, I-00185 Rome, Italy.
   [Poccia, N.] Univ Twente, MESA Inst Nanotechnol, NL-7500 AE Enschede, Netherlands.
   [Bianconi, G.] Queen Mary Univ London, Sch Math, London E1 4SN, England.
   [Barba, L.; Arrighetti, G.] Sincrotrone Elettra UOS Trieste, Inst Crystallog, I-34149 Trieste, Italy.
   [Innocenti, D.; Karpinski, J.] Ecole Polytech Fed Lausanne, Inst Condensed Matter Phys, CH-1015 Lausanne, Switzerland.
   [Karpinski, J.; Zhigadlo, N. D.; Kazakov, S. M.] ETH, Swiss Fed Inst Technol Zurich, Solid State Phys Lab, CH-8093 Zurich, Switzerland.
   [Kazakov, S. M.] Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119991, Russia.
   [Burghammer, M.] European Synchrotron Radiat Facil, F-38043 Grenoble, France.
   [Burghammer, M.] Univ Ghent, Dept Analyt Chem, B-9000 Ghent, Belgium.
   [Zimmermann, M. V.; Sprung, M.; Ricci, A.] Deutsch Elektronen Synchrotron DESY, D-22607 Hamburg, Germany.
C3 Consiglio Nazionale delle Ricerche (CNR); Istituto Di Cristallografia (IC-CNR); University of Twente; University of London; Queen Mary University London; Consiglio Nazionale delle Ricerche (CNR); Istituto Di Cristallografia (IC-CNR); Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Swiss Federal Institutes of Technology Domain; ETH Zurich; Lomonosov Moscow State University; European Synchrotron Radiation Facility (ESRF); Ghent University; Helmholtz Association; Deutsches Elektronen-Synchrotron (DESY)
RP Bianconi, A (corresponding author), CNR, Inst Crystallog, Via Salaria Km 29-300, I-00015 Monterotondo Roma, Italy.
EM antonio.bianconi@ricmass.eu
FU Superstripes Institute; Marie Curie Intra-European Fellowship
NR 30
TC 273
Z9 287
U1 3
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 SEP 17
PY 2015
VL 525
IS 7569
BP 359
EP +
DI 10.1038/nature14987
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900039
PM 26381983
DA 2026-03-09
ER

PT J
AU Li, NN
   Zhai, YL
   Zhang, YX
   Li, WQ
   Yang, MJ
   Lei, JL
   Tye, BK
   Gao, N
AF Li, Ningning
   Zhai, Yuanliang
   Zhang, Yixiao
   Li, Wanqiu
   Yang, Maojun
   Lei, Jianlin
   Tye, Bik-Kwoon
   Gao, Ning
TI Structure of the eukaryotic MCM complex at 3.8 Å
SO NATURE
LA English
DT Article
ID replicative helicase mcm2-7; cryo-em structure; archaeal mcm; crystal-structure; mechanistic insights; dna; binding; protein; domain; organization
AB DNA replication in eukaryotes is strictly regulated by several mechanisms. A central step in this replication is the assembly of the heterohexameric minichromosome maintenance (MCM2-7) helicase complex at replication origins during G1 phase as an inactive double hexamer. Here, using cryo-electron microscopy, we report a near-atomic structure of the MCM2-7 double hexamer purified from yeast G1 chromatin. Our structure shows that two single hexamers, arranged in a tilted and twisted fashion through interdigitated amino-terminal domain interactions, form a kinked central channel. Four constricted rings consisting of conserved interior beta-hairpins from the two single hexamers create a narrow passageway that tightly fits duplex DNA. This narrow passageway, reinforced by the offset of the two single hexamers at the double hexamer interface, is flanked by two pairs of gate-forming subunits, MCM2 and MCM5. These unusual features of the twisted and tilted single hexamers suggest a concerted mechanism for the melting of origin DNA that requires structural deformation of the intervening DNA.
C1 [Li, Ningning; Zhang, Yixiao; Li, Wanqiu; Yang, Maojun; Lei, Jianlin; Gao, Ning] Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Minist Educ,Key Lab Prot Sci, Beijing 100084, Peoples R China.
   [Zhai, Yuanliang; Tye, Bik-Kwoon] Hong Kong Univ Sci & Technol, Div Life Sci, Kowloon, Hong Kong, Peoples R China.
   [Zhai, Yuanliang] Hong Kong Univ Sci & Technol, Inst Adv Study, Kowloon, Hong Kong, Peoples R China.
   [Tye, Bik-Kwoon] Cornell Univ, Dept Mol Biol & Genet, Coll Agr & Life Sci, Ithaca, NY 14853 USA.
C3 Tsinghua University; Hong Kong University of Science & Technology; Hong Kong University of Science & Technology; Cornell University
RP Gao, N (corresponding author), Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Minist Educ,Key Lab Prot Sci, Beijing 100084, Peoples R China.
EM zhai@ust.hk; bt16@cornell.edu; ninggao@tsinghua.edu.cn
FU Ministry of Science and Technology of China [2013CB910404]; National Natural Science Foundation of China [31422016]; Research Grants Council of Hong Kong [GRF664013, HKUST12/CRF/13G]; Hong Kong University of Science Technology
NR 74
TC 209
Z9 245
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 AUG 13
PY 2015
VL 524
IS 7564
BP 186
EP +
DI 10.1038/nature14685
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900024
PM 26222030
DA 2026-03-09
ER

PT J
AU Hensen, B
   Bernien, H
   Dréau, AE
   Reiserer, A
   Kalb, N
   Blok, MS
   Ruitenberg, J
   Vermeulen, RFL
   Schouten, RN
   Abellán, C
   Amaya, W
   Pruneri, V
   Mitchell, MW
   Markham, M
   Twitchen, DJ
   Elkouss, D
   Wehner, S
   Taminiau, TH
   Hanson, R
AF Hensen, B.
   Bernien, H.
   Dreau, A. E.
   Reiserer, A.
   Kalb, N.
   Blok, M. S.
   Ruitenberg, J.
   Vermeulen, R. F. L.
   Schouten, R. N.
   Abellan, C.
   Amaya, W.
   Pruneri, V.
   Mitchell, M. W.
   Markham, M.
   Twitchen, D. J.
   Elkouss, D.
   Wehner, S.
   Taminiau, T. H.
   Hanson, R.
TI Loophole-free Bell inequality violation using electron spins separated by 1.3 kilometres
SO NATURE
LA English
DT Article
ID heralded entanglement; photons
AB More than 50 years ago(1), John Bell proved that no theory of nature that obeys locality and realism(2) can reproduce all the predictions of quantum theory: in any local-realist theory, the correlations between outcomes of measurements on distant particles satisfy an inequality that can be violated if the particles are entangled. Numerous Bell inequality tests have been reported(3-13); however, all experiments reported so far required additional assumptions to obtain a contradiction with local realism, resulting in 'loopholes'(13-16). Here we report a Bell experiment that is free of any such additional assumption and thus directly tests the principles underlying Bell's inequality. We use an event-ready scheme(17-19) that enables the generation of robust entanglement between distant electron spins (estimated state fidelity of 0.92 +/- 0.03). Efficient spin read-out avoids the fair-sampling assumption (detection loophole(14,15)), while the use of fast random-basis selection and spin read-out combined with a spatial separation of 1.3 kilometres ensure the required locality conditions(13). We performed 245 trials that tested the CHSH-Bell inequality(20) S <= 2 and found S = 2.42 +/- 0.20 (where S quantifies the correlation between measurement outcomes). A null-hypothesis test yields a probability of at most P = 0.039 that a local-realist model for space-like separated sites could produce data with a violation at least as large as we observe, even when allowing for memory(16,21) in the devices. Our data hence imply statistically significant rejection of the local-realist null hypothesis. This conclusion may be further consolidated in future experiments; for instance, reaching a value of P = 0.001 would require approximately 700 trials for an observed S = 2.4. With improvements, our experiment could be used for testing less-conventional theories, and for implementing device-independent quantum-secure communication(22) and randomness certification(23,24).
C1 [Hensen, B.; Bernien, H.; Dreau, A. E.; Reiserer, A.; Kalb, N.; Blok, M. S.; Ruitenberg, J.; Vermeulen, R. F. L.; Schouten, R. N.; Elkouss, D.; Wehner, S.; Taminiau, T. H.; Hanson, R.] Delft Univ Technol, QuTech, NL-2600 GA Delft, Netherlands.
   [Hensen, B.; Bernien, H.; Dreau, A. E.; Reiserer, A.; Kalb, N.; Blok, M. S.; Ruitenberg, J.; Vermeulen, R. F. L.; Schouten, R. N.; Taminiau, T. H.; Hanson, R.] Delft Univ Technol, Kavli Inst Nanosci, NL-2600 GA Delft, Netherlands.
   [Abellan, C.; Amaya, W.; Pruneri, V.; Mitchell, M. W.] Barcelona Inst Sci & Technol, ICFO Inst Ciencies Fotoniques, Castelldefels 08860, Barcelona, Spain.
   [Pruneri, V.; Mitchell, M. W.] ICREA, Barcelona 08010, Spain.
   [Markham, M.; Twitchen, D. J.] Element Six Innovat, Didcot OX11 0QR, Oxon, England.
C3 Delft University of Technology; Delft University of Technology; Barcelona Institute of Science & Technology; Universitat Politecnica de Catalunya; Institut de Ciencies Fotoniques (ICFO); ICREA; Element Six
RP Hanson, R (corresponding author), Delft Univ Technol, QuTech, POB 5046, NL-2600 GA Delft, Netherlands.
EM r.hanson@tudelft.nl
FU Dutch Organization for Fundamental Research on Matter (FOM); Dutch Technology Foundation (STW); Netherlands Organization for Scientific Research (NWO) through a VENI; Netherlands Organization for Scientific Research (NWO) through VIDI; Defense Advanced Research Projects Agency QuASAR; Spanish MINECO project MAGO [FIS2011-23520]; Explora Ciencia [FIS2014-62181-EXP]; European Regional Development Fund (FEDER) [TEC2013-46168-R]; Fundacio Privada CELLEX; FET Proactive project QUIC; European Research Council through project AQUMET; European Research Council through project HYSCORE; ICREA Funding Source: Custom
NR 32
TC 1914
Z9 2255
U1 11
U2 336
PU NATURE PUBLISHING 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 29
PY 2015
VL 526
IS 7575
BP 682
EP 686
DI 10.1038/nature15759
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CU8ZH
UT WOS:000363832100044
PM 26503041
DA 2026-03-09
ER

PT J
AU Haile-Selassie, Y
   Gibert, L
   Melillo, SM
   Ryan, TM
   Alene, M
   Deino, A
   Levin, NE
   Scott, G
   Saylor, BZ
AF Haile-Selassie, Yohannes
   Gibert, Luis
   Melillo, Stephanie M.
   Ryan, Timothy M.
   Alene, Mulugeta
   Deino, Alan
   Levin, Naomi E.
   Scott, Gary
   Saylor, Beverly Z.
TI New species from Ethiopia further expands Middle Pliocene hominin diversity
SO NATURE
LA English
DT Article
ID australopithecus-anamensis; fossil hominids; hadar formation; eastern africa; allia bay; kanapoi; homo; turkana; maxilla
AB Middle Pliocene hominin species diversity has been a subject of debate over the past two decades, particularly after the naming of Australopithecus bahrelghazali and Kenyanthropus platyops in addition to the well-known species Australopithecus afarensis. Further analyses continue to support the proposal that several hominin species co-existed during this time period. Here we recognize a new hominin species (Australopithecus deyiremeda sp. nov.) from 3.3-3.5-million-year-old deposits in the Woranso-Mille study area, central Afar, Ethiopia. The new species from Woranso-Mille shows that there were at least two contemporaneous hominin species living in the Afar region of Ethiopia between 3.3 and 3.5 million years ago, and further confirms early hominin taxonomic diversity in eastern Africa during the Middle Pliocene epoch. The morphology of Au. deyiremeda also reinforces concerns related to dentognathic (that is, jaws and teeth) homoplasy in Plio-Pleistocene hominins, and shows that some dentognathic features traditionally associated with Paranthropus and Homo appeared in the fossil record earlier than previously thought.
C1 [Haile-Selassie, Yohannes] Cleveland Museum Nat Hist, Cleveland, OH 44106 USA.
   [Haile-Selassie, Yohannes; Saylor, Beverly Z.] Case Western Reserve Univ, Cleveland, OH 44106 USA.
   [Gibert, Luis] Univ Barcelona, E-08028 Barcelona, Spain.
   [Melillo, Stephanie M.] Max Planck Inst Evolutionare Anthropol, D-04103 Leipzig, Germany.
   [Ryan, Timothy M.] Penn State Univ, University Pk, PA 16802 USA.
   [Alene, Mulugeta] Univ Addis Ababa, Addis Ababa, Ethiopia.
   [Deino, Alan; Scott, Gary] Berkeley Geochronol Ctr, Berkeley, CA 94709 USA.
   [Levin, Naomi E.] Johns Hopkins Univ, Baltimore, MD 21218 USA.
C3 Cleveland Museum of Natural History; University System of Ohio; Case Western Reserve University; University of Barcelona; Max Planck Society; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Addis Ababa University; Berkeley Geochronolgy Center; Johns Hopkins University
RP Haile-Selassie, Y (corresponding author), Cleveland Museum Nat Hist, Cleveland, OH 44106 USA.
EM yhailese@cmnh.org
FU LSB Leakey Foundation; National Geographic Society; Cleveland Museum of Natural History; National Science Foundation [BCS-0234320, BCS-0321893, BCS-0542037, BCS-1124705, BCS-1124713, BCS-1124716, BCS-1125157, BCS-1125345]; Direct For Social, Behav & Economic Scie; Division Of Behavioral and Cognitive Sci [1125345, 1124716] Funding Source: National Science Foundation; Division Of Behavioral and Cognitive Sci; Direct For Social, Behav & Economic Scie [1125157, 1322017, 1124705] Funding Source: National Science Foundation
NR 33
TC 98
Z9 126
U1 4
U2 84
PU NATURE PUBLISHING 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 28
PY 2015
VL 521
IS 7553
BP 483
EP U500
DI 10.1038/nature14448
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ2AN
UT WOS:000355286600036
PM 26017448
DA 2026-03-09
ER

PT J
AU Stevens, LA
   Behn, MD
   McGuire, JJ
   Das, SB
   Joughin, I
   Herring, T
   Shean, DE
   King, MA
AF Stevens, Laura A.
   Behn, Mark D.
   McGuire, Jeffrey J.
   Das, Sarah B.
   Joughin, Ian
   Herring, Thomas
   Shean, David E.
   King, Matt A.
TI Greenland supraglacial lake drainages triggered by hydrologically induced basal slip
SO NATURE
LA English
DT Article
ID ice-sheet; surface melt; acceleration; meltwater; flow; deformation; glacier; zone
AB Water-driven fracture propagation beneath supraglacial lakes rapidly transports large volumes of surface meltwater to the base of the Greenland Ice Sheet(1). These drainage events drive transient ice-sheet acceleration(1-3) and establish conduits for additional surface-to-bed meltwater transport for the remainder of the melt season(1,4-6). Although it is well established that cracks must remain water-filled to propagate to the bed(7-9), the precise mechanisms that initiate hydro-fracture events beneath lakes are unknown. Here we show that, for a lake on the western Greenland Ice Sheet, drainage events are preceded by a 6-12 hour period of ice-sheet uplift and/or enhanced basal slip. Our observations from a dense Global Positioning System (GPS) network allow us to determine the distribution of meltwater at the ice-sheet bed before, during, and after three rapid drainages in 2011-2013, each of which generates tensile stresses that promote hydro-fracture beneath the lake. We hypothesize that these precursors are associated with the introduction of meltwater to the bed through neighbouring moulin systems (vertical conduits connecting the surface and base of the ice sheet). Our results imply that as lakes form in less crevassed, interior regions of the ice sheet(10-14), where water at the bed is currently less pervasive(5,14-16), the creation of new surface-to-bed conduits caused by lake-draining hydro-fractures may be limited.
C1 [Stevens, Laura A.] MIT, Woods Hole Oceanog Inst, Joint Program Oceanog Appl Ocean Sci & Engn, Woods Hole, MA 02543 USA.
   [Behn, Mark D.; McGuire, Jeffrey J.; Das, Sarah B.] Woods Hole Oceanog Inst, Dept Geol & Geophys, Woods Hole, MA 02543 USA.
   [Joughin, Ian; Shean, David E.] Univ Washington, Polar Sci Ctr, Appl Phys Lab, Seattle, WA 98105 USA.
   [Herring, Thomas] MIT, Dept Earth Atmospher & Planetary Sci, Cambridge, MA 02139 USA.
   [King, Matt A.] Univ Tasmania, Sch Land & Food, Hobart, Tas 7001, Australia.
   [King, Matt A.] Newcastle Univ, Sch Civil Engn & Geosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England.
C3 Massachusetts Institute of Technology (MIT); Woods Hole Oceanographic Institution; Woods Hole Oceanographic Institution; University of Washington; University of Washington Seattle; Massachusetts Institute of Technology (MIT); University of Tasmania; Newcastle University - UK
RP Stevens, LA (corresponding author), 360 Woods Hole Rd, Woods Hole, MA 02543 USA.
EM stevensl@mit.edu
FU National Science Foundation's Office of Polar Programs (NSF-OPP); National Aeronautics and Space Administration's (NASA's) Cryospheric Sciences Program [ARC-0520077, ARC-1023364, NNX10AI30G, ARC-0520382, ARC-1023382, NNX10AI33G]; Australian Research Council [FT110100207]; NSF [ANT-1043681]; National Science Foundation; Directorate For Geosciences; Office of Polar Programs (OPP) [1023364] Funding Source: National Science Foundation; Directorate For Geosciences; Office of Polar Programs (OPP) [1023382] Funding Source: National Science Foundation; NASA [NNX10AI30G, 132801, 132824, NNX10AI33G] Funding Source: Federal RePORTER
NR 46
TC 91
Z9 112
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 JUN 4
PY 2015
VL 522
IS 7554
BP 73
EP U163
DI 10.1038/nature14480
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ5QP
UT WOS:000355543400031
PM 26040890
DA 2026-03-09
ER

PT J
AU Lawrence, MS
   Sougnez, C
   Lichtenstein, L
   Cibulskisl, K
   Lander, E
   Gabriel, SB
   Getz, G
   Ally, A
   Balasundaram, M
   Birol, I
   Bowlby, R
   Brooks, D
   Butterfield, YSN
   Carlsen, R
   Cheng, D
   Chu, A
   Dhalla, N
   Guin, R
   Holt, RA
   Jones, SJM
   Lee, D
   Li, HYI
   Marra, MA
   Mayo, M
   Moore, RA
   Mungall, AJ
   Robertson, AG
   Schein, JE
   Sipahimalan, P
   Tam, A
   Thiessen, N
   Wong, T
   Protopopov, A
   Santoso, N
   Lee, S
   Parfenov, M
   Zhang, JH
   Mahadeshwar, HS
   Tang, JB
   Ren, XJ
   Seth, S
   Haseley, P
   Zeng, D
   Yang, LX
   Xu, AW
   Song, XZ
   Pantazi, A
   Bristow, CA
   Hadjipanayis, A
   Seidman, J
   Chin, L
   Park, PJ
   Kucherlapati, R
   Akbani, R
   Casasent, T
   Liu, WB
   Le, Y
   Mille, G
   Motter, T
   Weinstein, J
   Diao, LX
   Wang, J
   Fan, YH
   Lie, JZ
   Wang, K
   Auman, JT
   Balu, S
   Bodenheimer, T
   Buda, E
   Hayes, DN
   Hoadley, KA
   Hoyle, AP
   Jefferys, SR
   Jones, CD
   Kimes, PK
   Liu, YF
   Marron, JS
   Meng, SW
   Mieczkowski, PA
   Mose, LE
   Parker, JS
   Perou, CM
   Prins, JF
   Roach, J
   Shi, Y
   Simons, JV
   Singh, D
   Soloway, MG
   Tan, DH
   Veluvolu, U
   Walter, V
   Waring, S
   Wilkerson, MD
   Wu, JY
   Zhao, N
   Cherniack, AD
   Hammerman, PS
   Tward, AD
   Pedamallu, CS
   Saksena, G
   Jung, J
   Ojesina, AI
   Carter, SL
   Zack, TI
   Schumacher, SE
   Beroukhim, R
   Freeman, SS
   Meyerson, M
   Cho, J
   Chin, L
   Getz, G
   Noble, MS
   DiCara, D
   Zhang, H
   Heiman, DI
   Gehlenborg, N
   Voet, D
   Lin, P
   Frazer, S
   Stojanov, P
   Liu, YC
   Zou, LH
   Kim, J
   Sougnez, C
   Gabriel, SB
   Lawrence, MS
   Muzny, D
   Doddapaneni, H
   Kovar, C
   Reid, J
   Morton, D
   Han, Y
   Hale, W
   Chao, H
   Chang, K
   Drummond, JA
   Gibbs, RA
   Kakkar, N
   Wheeler, D
   Xi, L
   Ciriello, G
   Ladanyi, M
   Lee, W
   Ramirez, R
   Sander, C
   Shen, R
   Sinhal, R
   Weinhold, N
   Taylor, BS
   Aksoy, BA
   Dresdner, G
   Gao, JJ
   Gross, B
   Jacobsen, A
   Reva, B
   Schultz, N
   Sumer, SO
   Sun, YC
   Chan, TA
   Morris, LG
   Stuart, J
   Benz, S
   Ng, S
   Benz, C
   Yau, C
   Baylin, SB
   Cope, L
   Danilova, L
   Herman, JG
   Bootwalla, M
   Maglinte, DT
   Larid, PW
   Triche, T
   Weisenberger, DJ
   Van den Berg, DJ
   Agrawal, N
   Bishop, J
   Boutros, PC
   Bruce, JP
   Byers, LA
   Califano, J
   Carey, TE
   Chen, Z
   Cheng, H
   Chiosea, SI
   Cohen, E
   Diergaarde, B
   Egloff, AM
   El-Naggar, AK
   Ferris, RL
   Frederick, MJ
   Grandis, JR
   Guo, Y
   Haddad, RI
   Hammerman, PS
   Harris, T
   Hayes, DN
   Hui, ABY
   Lee, JJ
   Lippman, SM
   Liu, FF
   McHugh, JB
   Myers, J
   Ng, PKS
   Perez-Ordonez, B
   Pickering, CR
   Prystowsky, M
   Romkes, M
   Saleh, AD
   Sartor, MA
   Seethala, R
   Seiwert, TY
   Si, H
   Tward, AD
   Van Waes, C
   Waggott, DM
   Wiznerowicz, M
   Yarbrough, WG
   Zhang, JX
   Zuo, ZX
   Burnett, K
   Crain, D
   Gardner, J
   Lau, K
   Mallery, D
   Morris, S
   Lauskis, JP
   Penny, R
   Shelton, C
   Shelton, T
   Sherman, M
   Yena, P
   Black, AD
   Bowen, J
   Frick, J
   Gastier-Foster, JM
   Harper, HA
   Leraas, K
   Lichtenberg, TM
   Ramirez, NC
   Wise, L
   Zmuda, E
   Baboud, J
   Jensen, MA
   Kahn, AB
   Pihl, TD
   Pot, DA
   Srinivasan, D
   Walton, JS
   Wan, YH
   Burton, RA
   Davidsen, T
   Demchok, JA
   Eley, G
   Ferguson, ML
   Shaw, KRM
   Ozenberger, BA
   Sheth, M
   Sofia, HJ
   Tarnuzzer, R
   Wang, ZN
   Yang, LM
   Zenklusen, JC
   Saller, C
   Tarvi, K
   Chen, C
   Bollag, R
   Weinberger, P
   Golusinski, W
   Golusinski, P
   Ibbs, M
   Korski, K
   Mackiewicz, A
   Suchorska, W
   Szybiak, B
   Wiznerowicz, M
   Burnett, K
   Curley, E
   Gardner, J
   Mallery, D
   Penny, R
   Shelton, T
   Yena, P
   Beard, C
   Mitchell, C
   Sandusky, G
   Agrawal, N
   Ahn, J
   Bishop, J
   Califano, J
   Khan, Z
   Bruce, JP
   Hui, ABY
   Irish, J
   Liu, FF
   Perez-Ordonez, B
   Waldron, J
   Boutros, PC
   Waggott, DM
   Myers, J
   William, WN
   Lippman, SM
   Egea, S
   Gomez-Fernandez, C
   Herbert, L
   Bradford, CR
   Carey, TE
   Chepeha, DB
   Haddad, AS
   Jones, TR
   Komarck, CM
   Malakh, M
   McHugh, JB
   Moyer, JS
   Nguyen, A
   Peterson, LA
   Prince, ME
   Rozek, LS
   Sartor, MA
   Taylor, EG
   Walline, HM
   Wolf, GT
   Boice, L
   Chera, BS
   Funkhouser, WK
   Gulley, ML
   Hackman, TG
   Hayes, DN
   Hayward, MC
   Huang, M
   Rathmell, WK
   Salazar, AH
   Shockley, WW
   Shores, CG
   Thorne, L
   Weissler, MC
   Wrenn, S
   Zanation, AM
   Chiosea, SI
   Diergaarde, B
   Egloff, AM
   Ferris, RL
   Romkes, M
   Seethala, R
   Brown, BT
   Guo, Y
   Pham, M
   Yarbrough, WG
AF Lawrence, Michael S.
   Sougnez, Carrie
   Lichtenstein, Lee
   Cibulskisl, Kristian
   Lander, Eric
   Gabriel, Stacey B.
   Getz, Gad
   Ally, Adrian
   Balasundaram, Miruna
   Birol, Inanc
   Bowlby, Reanne
   Brooks, Denise
   Butterfield, Yaron S. N.
   Carlsen, Rebecca
   Cheng, Dean
   Chu, Andy
   Dhalla, Noreen
   Guin, Ranabir
   Holt, Robert A.
   Jones, Steven J. M.
   Lee, Darlene
   Li, Haiyan I.
   Marra, Marco A.
   Mayo, Michael
   Moore, Richard A.
   Mungall, Andrew J.
   Robertson, A. Gordon
   Schein, Jacqueline E.
   Sipahimalan, Payal
   Tam, Angela
   Thiessen, Nina
   Wong, Tina
   Protopopov, Alexei
   Santoso, Netty
   Lee, Semin
   Parfenov, Michael
   Zhang, Jianhua
   Mahadeshwar, Harshad S.
   Tang, Jiabin
   Ren, Xiaojia
   Seth, Sahil
   Haseley, Psalm
   Zeng, Dong
   Yang, Lixing
   Xu, Andrew W.
   Song, Xingzhi
   Pantazi, Angeliki
   Bristow, Christopher A.
   Hadjipanayis, Angela
   Seidman, Jonathan
   Chin, Lynda
   Park, Peter J.
   Kucherlapati, Raju
   Akbani, Rehan
   Casasent, Tod
   Liu, Wenbin
   Le, Yiling
   Mille, Gordon
   Motter, Thomas
   Weinstein, John
   Diao, Lixia
   Wang, Jing
   Fan, You Hong
   Lie, Jinze
   Wang, Kai
   Auman, J. Todd
   Balu, Saianand
   Bodenheimer, Thomas
   Buda, Elizabeth
   Hayes, D. Neil
   Hoadley, Katherine A.
   Hoyle, Alan P.
   Jefferys, Stuart R.
   Jones, Corbin D.
   Kimes, Patrick K.
   Liu, Yufeng
   Marron, J. S.
   Meng, Shaowu
   Mieczkowski, Piotr A.
   Mose, Lisle E.
   Parker, Joel S.
   Perou, Charles M.
   Prins, Jan F.
   Roach, Jeffrey
   Shi, Yan
   Simons, Janae V.
   Singh, Darshan
   Soloway, Matthew G.
   Tan, Donghui
   Veluvolu, Umadevi
   Walter, Vonn
   Waring, Scot
   Wilkerson, Matthew D.
   Wu, Junyuan
   Zhao, Ni
   Cherniack, Andrew D.
   Hammerman, Peter S.
   Tward, Aaron D.
   Pedamallu, Chandra Sekhar
   Saksena, Gordon
   Jung, Joonil
   Ojesina, Akinyemi I.
   Carter, Scott L.
   Zack, Travis I.
   Schumacher, Steven E.
   Beroukhim, Rameen
   Freeman, Samuel S.
   Meyerson, Matthew
   Cho, Juok
   Chin, Lynda
   Getz, Gad
   Noble, Michael S.
   DiCara, Daniel
   Zhang, Hailei
   Heiman, David I.
   Gehlenborg, Nils
   Voet, Doug
   Lin, Pei
   Frazer, Scott
   Stojanov, Petar
   Liu, Yingchun
   Zou, Lihua
   Kim, Jaegil
   Sougnez, Carrie
   Gabriel, Stacey B.
   Lawrence, Michael S.
   Muzny, Donna
   Doddapaneni, HarshaVardhan
   Kovar, Christie
   Reid, Jeff
   Morton, Donna
   Han, Yi
   Hale, Walker
   Chao, Hsu
   Chang, Kyle
   Drummond, Jennifer A.
   Gibbs, Richard A.
   Kakkar, Nipun
   Wheeler, David
   Xi, Liu
   Ciriello, Giovanni
   Ladanyi, Marc
   Lee, William
   Ramirez, Ricardo
   Sander, Chris
   Shen, Ronglai
   Sinhal, Rileen
   Weinhold, Nils
   Taylor, Barry S.
   Aksoy, B. Arman
   Dresdner, Gideon
   Gao, Jianjiong
   Gross, Benjamin
   Jacobsen, Anders
   Reva, Boris
   Schultz, Nikolaus
   Sumer, S. Onur
   Sun, Yichao
   Chan, Timothy A.
   Morris, Luc G.
   Stuart, Joshua
   Benz, Stephen
   Ng, Sam
   Benz, Christopher
   Yau, Christina
   Baylin, Stephen B.
   Cope, Leslie
   Danilova, Ludmila
   Herman, James G.
   Bootwalla, Moiz
   Maglinte, Dennis T.
   Larid, Peter W.
   Triche, Timothy, Jr.
   Weisenberger, Daniel J.
   Van den Berg, David J.
   Agrawal, Nishant
   Bishop, Justin
   Boutros, Paul C.
   Bruce, Jeff P.
   Byers, Lauren Averett
   Califano, Joseph
   Carey, Thomas E.
   Chen, Zhong
   Cheng, Hui
   Chiosea, Simion I.
   Cohen, Ezra
   Diergaarde, Brenda
   Egloff, Ann Marie
   El-Naggar, Adel K.
   Ferris, Robert L.
   Frederick, Mitchell J.
   Grandis, Jennifer R.
   Guo, Yan
   Haddad, Robert I.
   Hammerman, Peter S.
   Harris, Thomas
   Hayes, D. Neil
   Hui, Angela B. Y.
   Lee, J. Jack
   Lippman, Scott M.
   Liu, Fei-Fei
   McHugh, Jonathan B.
   Myers, Jeff
   Ng, Patrick Kwok Shing
   Perez-Ordonez, Bayardo
   Pickering, Curtis R.
   Prystowsky, Michael
   Romkes, Marjorie
   Saleh, Anthony D.
   Sartor, Maureen A.
   Seethala, Raja
   Seiwert, Tanguy Y.
   Si, Han
   Tward, Aaron D.
   Van Waes, Carter
   Waggott, Daryl M.
   Wiznerowicz, Maciej
   Yarbrough, Wendell G.
   Zhang, Jiexin
   Zuo, Zhixiang
   Burnett, Ken
   Crain, Daniel
   Gardner, Johanna
   Lau, Kevin
   Mallery, David
   Morris, Scott
   Lauskis, Joseph Pau
   Penny, Robert
   Shelton, Candace
   Shelton, Troy
   Sherman, Mark
   Yena, Peggy
   Black, Aaron D.
   Bowen, Jay
   Frick, Jessica
   Gastier-Foster, Julie M.
   Harper, Hollie A.
   Leraas, Kristen
   Lichtenberg, Tara M.
   Ramirez, Nilsa C.
   Wise, Lisa
   Zmuda, Erik
   Baboud, Julien
   Jensen, Mark A.
   Kahn, An B.
   Pihl, Todd D.
   Pot, David A.
   Srinivasan, Deepak
   Walton, Jessica S.
   Wan, Yunhu
   Burton, Robert A.
   Davidsen, Tanja
   Demchok, John A.
   Eley, Greg
   Ferguson, Martin L.
   Shaw, Kenna R. Mills
   Ozenberger, Bradley A.
   Sheth, Margi
   Sofia, Heidi J.
   Tarnuzzer, Roy
   Wang, Zhining
   Yang, Liming
   Zenklusen, Jean Claude
   Saller, Charles
   Tarvi, Katherine
   Chen, Chu
   Bollag, Roni
   Weinberger, Paul
   Golusinski, Wojciech
   Golusinski, Pawel
   Ibbs, Matthew
   Korski, Konstanty
   Mackiewicz, Andrzej
   Suchorska, Wiktoria
   Szybiak, Bartosz
   Wiznerowicz, Maciej
   Burnett, Ken
   Curley, Erin
   Gardner, Johanna
   Mallery, David
   Penny, Robert
   Shelton, Troy
   Yena, Peggy
   Beard, Christina
   Mitchell, Colleen
   Sandusky, George
   Agrawal, Nishant
   Ahn, Julie
   Bishop, Justin
   Califano, Joseph
   Khan, Zubair
   Bruce, Jeff P.
   Hui, Angela B. Y.
   Irish, Jonathan
   Liu, Fei-Fei
   Perez-Ordonez, Bayardo
   Waldron, John
   Boutros, Paul C.
   Waggott, Daryl M.
   Myers, Jeff
   William, William N., Jr.
   Lippman, Scott M.
   Egea, Sophie
   Gomez-Fernandez, Carmen
   Herbert, Lynn
   Bradford, Carol R.
   Carey, Thomas E.
   Chepeha, Douglas B.
   Haddad, Andrea S.
   Jones, Tamara R.
   Komarck, Christine M.
   Malakh, Mayya
   McHugh, Jonathan B.
   Moyer, Jeffrey S.
   Nguyen, Ariane
   Peterson, Lisa A.
   Prince, Mark E.
   Rozek, Laura S.
   Sartor, Maureen A.
   Taylor, Evan G.
   Walline, Heather M.
   Wolf, Gregory T.
   Boice, Lori
   Chera, Bhishamjit S.
   Funkhouser, William K.
   Gulley, Margaret L.
   Hackman, Trevor G.
   Hayes, D. Neil
   Hayward, Michele C.
   Huang, Mei
   Rathmell, W. Kimryn
   Salazar, Ashley H.
   Shockley, William W.
   Shores, Carol G.
   Thorne, Leigh
   Weissler, Mark C.
   Wrenn, Sylvia
   Zanation, Adam M.
   Chiosea, Simion I.
   Diergaarde, Brenda
   Egloff, Ann Marie
   Ferris, Robert L.
   Romkes, Marjorie
   Seethala, Raja
   Brown, Brandee T.
   Guo, Yan
   Pham, Michelle
   Yarbrough, Wendell G.
TI Comprehensive genomic characterization of head and neck squamous cell carcinomas
SO NATURE
LA English
DT Article
ID nf-kappa-b; growth-factor-receptor; lim protein ajuba; cancer growth; activation; egfr; classification; resistance; inhibitors; mutations
AB The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.
C1 [Lichtenstein, Lee; Cibulskisl, Kristian; Lander, Eric; Gabriel, Stacey B.; Cherniack, Andrew D.; Pedamallu, Chandra Sekhar; Saksena, Gordon; Jung, Joonil; Ojesina, Akinyemi I.; Carter, Scott L.; Zack, Travis I.; Schumacher, Steven E.; Beroukhim, Rameen; Freeman, Samuel S.; Meyerson, Matthew; Cho, Juok; Noble, Michael S.; DiCara, Daniel; Zhang, Hailei; Heiman, David I.; Gehlenborg, Nils; Voet, Doug; Lin, Pei; Frazer, Scott; Stojanov, Petar; Liu, Yingchun; Zou, Lihua; Kim, Jaegil] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA.
   Massachusetts Gen Hosp, Boston, MA 02114 USA.
   [Ally, Adrian; Balasundaram, Miruna; Birol, Inanc; Bowlby, Reanne; Brooks, Denise; Butterfield, Yaron S. N.; Carlsen, Rebecca; Cheng, Dean; Chu, Andy; Dhalla, Noreen; Guin, Ranabir; Holt, Robert A.; Jones, Steven J. M.; Lee, Darlene; Li, Haiyan I.; Marra, Marco A.; Mayo, Michael; Moore, Richard A.; Mungall, Andrew J.; Robertson, A. Gordon; Schein, Jacqueline E.; Sipahimalan, Payal; Tam, Angela; Thiessen, Nina; Wong, Tina] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada.
   [Protopopov, Alexei; Zhang, Jianhua; Mahadeshwar, Harshad S.; Tang, Jiabin; Seth, Sahil; Zeng, Dong; Song, Xingzhi; Bristow, Christopher A.; Akbani, Rehan; Casasent, Tod; Liu, Wenbin; Le, Yiling; Mille, Gordon; Motter, Thomas; Weinstein, John; Diao, Lixia; Wang, Jing; Fan, You Hong; Byers, Lauren Averett; El-Naggar, Adel K.; Frederick, Mitchell J.; Lee, J. Jack; Myers, Jeff; Ng, Patrick Kwok Shing; Pickering, Curtis R.; Zhang, Jiexin; William, William N., Jr.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
   [Santoso, Netty; Lee, Semin; Parfenov, Michael; Ren, Xiaojia; Haseley, Psalm; Yang, Lixing; Xu, Andrew W.; Pantazi, Angeliki; Hadjipanayis, Angela; Seidman, Jonathan; Park, Peter J.; Kucherlapati, Raju; Beroukhim, Rameen; Meyerson, Matthew; Tward, Aaron D.] Harvard Univ, Sch Med, Boston, MA 02115 USA.
   [Hadjipanayis, Angela; Park, Peter J.; Kucherlapati, Raju] Brigham & Womens Hosp, Boston, MA 02115 USA.
   [Park, Peter J.] Boston Childrens Hosp, Boston, MA 02115 USA.
   [Lie, Jinze; Wang, Kai] Univ Kentucky, Lexington, KY 40506 USA.
   [Auman, J. Todd; Balu, Saianand; Bodenheimer, Thomas; Buda, Elizabeth; Hoadley, Katherine A.; Hoyle, Alan P.; Jefferys, Stuart R.; Jones, Corbin D.; Kimes, Patrick K.; Liu, Yufeng; Marron, J. S.; Meng, Shaowu; Mieczkowski, Piotr A.; Mose, Lisle E.; Parker, Joel S.; Perou, Charles M.; Prins, Jan F.; Roach, Jeffrey; Shi, Yan; Simons, Janae V.; Singh, Darshan; Soloway, Matthew G.; Tan, Donghui; Veluvolu, Umadevi; Walter, Vonn; Waring, Scot; Wilkerson, Matthew D.; Wu, Junyuan; Zhao, Ni; Boice, Lori; Chera, Bhishamjit S.; Funkhouser, William K.; Gulley, Margaret L.; Hackman, Trevor G.; Hayward, Michele C.; Huang, Mei; Rathmell, W. Kimryn; Salazar, Ashley H.; Shockley, William W.; Shores, Carol G.; Thorne, Leigh; Weissler, Mark C.; Wrenn, Sylvia; Zanation, Adam M.] Univ N Carolina, Chapel Hill, NC 27599 USA.
   [Pedamallu, Chandra Sekhar; Ojesina, Akinyemi I.; Zack, Travis I.; Schumacher, Steven E.; Beroukhim, Rameen; Meyerson, Matthew; Stojanov, Petar; Haddad, Robert I.] Dana Farber Canc Inst, Boston, MA 02115 USA.
   [Zack, Travis I.] Harvard Univ, Boston, MA 02115 USA.
   [Muzny, Donna; Doddapaneni, HarshaVardhan; Kovar, Christie; Reid, Jeff; Morton, Donna; Han, Yi; Hale, Walker; Chao, Hsu; Chang, Kyle; Drummond, Jennifer A.; Gibbs, Richard A.; Kakkar, Nipun; Wheeler, David; Xi, Liu] Baylor Coll Med, Houston, TX 77030 USA.
   [Ciriello, Giovanni; Ladanyi, Marc; Lee, William; Ramirez, Ricardo; Sander, Chris; Shen, Ronglai; Sinhal, Rileen; Weinhold, Nils; Taylor, Barry S.; Aksoy, B. Arman; Dresdner, Gideon; Gao, Jianjiong; Gross, Benjamin; Jacobsen, Anders; Reva, Boris; Schultz, Nikolaus; Sumer, S. Onur; Sun, Yichao; Chan, Timothy A.; Morris, Luc G.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA.
   [Stuart, Joshua; Benz, Stephen; Ng, Sam; Benz, Christopher; Yau, Christina] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA.
   [Baylin, Stephen B.; Cope, Leslie; Danilova, Ludmila; Herman, James G.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA.
   [Bootwalla, Moiz; Maglinte, Dennis T.; Larid, Peter W.; Triche, Timothy, Jr.; Weisenberger, Daniel J.; Van den Berg, David J.] Univ So Calif, Los Angeles, CA 90033 USA.
   [Agrawal, Nishant; Bishop, Justin; Califano, Joseph; Ahn, Julie; Khan, Zubair] Johns Hopkins Med Inst, Baltimore, MD 21205 USA.
   [Boutros, Paul C.; Waggott, Daryl M.] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada.
   [Bruce, Jeff P.; Hui, Angela B. Y.] Ontario Canc Inst, Toronto, ON M5G 2M9, Canada.
   [Carey, Thomas E.; McHugh, Jonathan B.; Sartor, Maureen A.; Bradford, Carol R.; Chepeha, Douglas B.; Haddad, Andrea S.; Jones, Tamara R.; Komarck, Christine M.; Malakh, Mayya; Moyer, Jeffrey S.; Nguyen, Ariane; Peterson, Lisa A.; Prince, Mark E.; Rozek, Laura S.; Taylor, Evan G.; Walline, Heather M.; Wolf, Gregory T.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA.
   [Chen, Zhong; Cheng, Hui; Saleh, Anthony D.; Si, Han; Van Waes, Carter] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA.
   [Chiosea, Simion I.; Diergaarde, Brenda; Egloff, Ann Marie; Ferris, Robert L.; Grandis, Jennifer R.; Romkes, Marjorie; Seethala, Raja] Univ Pittsburgh, Pittsburgh, PA 15213 USA.
   [Cohen, Ezra; Seiwert, Tanguy Y.; Zuo, Zhixiang] Univ Chicago, Chicago, IL 60637 USA.
   [Guo, Yan; Brown, Brandee T.; Pham, Michelle] Vanderbilt Univ, Med Ctr, Med Ctr East 7209, Nashville, TN 37232 USA.
   [Harris, Thomas; Prystowsky, Michael] Albert Einstein Coll Med, Bronx, NY 10461 USA.
   [Lippman, Scott M.] Univ Calif San Diego, La Jolla, CA 92093 USA.
   [Liu, Fei-Fei; Irish, Jonathan; Waldron, John] Univ Toronto, Toronto, ON M5G 2M9, Canada.
   [Perez-Ordonez, Bayardo] Univ Hlth Network, Toronto, ON M5G 2C4, Canada.
   [Wiznerowicz, Maciej; Golusinski, Wojciech; Golusinski, Pawel; Ibbs, Matthew; Korski, Konstanty; Mackiewicz, Andrzej; Suchorska, Wiktoria; Szybiak, Bartosz] Greater Poland Canc Ctr, PL-61866 Poznan, Poland.
   [Yarbrough, Wendell G.] Yale Univ, Sch Med, New Haven, CT 06520 USA.
   [Burnett, Ken; Crain, Daniel; Gardner, Johanna; Lau, Kevin; Mallery, David; Morris, Scott; Lauskis, Joseph Pau; Shelton, Candace; Shelton, Troy; Sherman, Mark; Yena, Peggy; Curley, Erin] Int Genom Consortium, Phoenix, AZ 85004 USA.
   [Black, Aaron D.; Bowen, Jay; Frick, Jessica; Gastier-Foster, Julie M.; Harper, Hollie A.; Leraas, Kristen; Lichtenberg, Tara M.; Ramirez, Nilsa C.; Wise, Lisa; Zmuda, Erik] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA.
   [Baboud, Julien; Jensen, Mark A.; Kahn, An B.; Pihl, Todd D.; Pot, David A.; Srinivasan, Deepak; Walton, Jessica S.; Wan, Yunhu] SRA Int, Fairfax, VA 22033 USA.
   [Burton, Robert A.] Frederick Natl Lab Canc Res, Frederick, MD 21702 USA.
   [Davidsen, Tanja; Demchok, John A.; Ferguson, Martin L.; Shaw, Kenna R. Mills; Sheth, Margi; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean Claude] NCI, Bethesda, MD 20892 USA.
   [Eley, Greg] Scimentis LLC, Atlanta, GA 30666 USA.
   [Ozenberger, Bradley A.; Sofia, Heidi J.] NHGRI, NIH, Bethesda, MD 20892 USA.
   [Saller, Charles; Tarvi, Katherine] Analyt Biol Serv Inc, St Petersburg 198013, Russia.
   [Chen, Chu] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA.
   [Bollag, Roni; Weinberger, Paul] Georgia Regents Univ, Augusta, GA 30912 USA.
   [Beard, Christina; Mitchell, Colleen; Sandusky, George] Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46202 USA.
   [Egea, Sophie; Gomez-Fernandez, Carmen; Herbert, Lynn] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA.
C3 Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; British Columbia Cancer Agency; University of Texas System; UTMD Anderson Cancer Center; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; University of Kentucky; University of North Carolina; University of North Carolina Chapel Hill; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Baylor College of Medicine; Memorial Sloan Kettering Cancer Center; University of California System; University of California Santa Cruz; Johns Hopkins University; Johns Hopkins Medicine; University of Southern California; Johns Hopkins University; Johns Hopkins Medicine; University of Toronto; Ontario Institute for Cancer Research; University of Toronto; University Health Network Toronto; University of Michigan System; University of Michigan; National Institutes of Health (NIH) - USA; NIH National Institute on Deafness & Other Communication Disorders (NIDCD); Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Chicago; Vanderbilt University; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; University of California System; University of California San Diego; University of Toronto; University of Toronto; University Health Network Toronto; Wielkopolskie Centrum Onkologii; Yale University; International Genomics Consortium; University System of Ohio; Ohio State University; Nationwide Childrens Hospital; Research Institute at Nationwide Children's Hospital; SRA International; 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); National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI); Fred Hutchinson Cancer Center; University System of Georgia; Augusta University; Indiana University System; Indiana University Indianapolis; University of Miami
RP Hayes, DN (corresponding author), Univ N Carolina, Chapel Hill, NC 27599 USA.
EM hayes@med.unc.edu; anaggar@mdanderson.org; grandisjr@upmc.edu
FU National Institutes of Health (NIH) [P50CA097190, P50CA16672, U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, RO1 CA 095419]; Bobby F. Garrett Fund for Head and Neck Cancer Research; NIDCD Intramural Projects [ZIA-DC-000016, 73, 74]; National Cancer Institute [P30CA177558, P30CA008748, P30CA047904, P30CA016672] Funding Source: NIH RePORTER; National Institute of Dental and Craniofacial Research [R01DE023685] Funding Source: NIH RePORTER; National Institute of Dental and Craniofacial Research; National Cancer Institute [P50CA097190] Funding Source: NIH RePORTER; National Institute on Deafness and Other Communication Disorders [ZIADC000016, ZIADC000073, ZIADC000074] Funding Source: NIH RePORTER; Direct For Computer & Info Scie & Enginr; Div Of Information & Intelligent Systems [1054631] Funding Source: National Science Foundation
NR 45
TC 3068
Z9 3488
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 JAN 29
PY 2015
VL 517
IS 7536
BP 576
EP 582
DI 10.1038/nature14129
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA2ZL
UT WOS:000348775000035
PM 25631445
DA 2026-03-09
ER

PT J
AU Peng, T
   Frank, DB
   Kadzik, RS
   Morley, MP
   Rathi, KS
   Wang, T
   Zhou, S
   Cheng, L
   Lu, MM
   Morrisey, EE
AF Peng, Tien
   Frank, David B.
   Kadzik, Rachel S.
   Morley, Michael P.
   Rathi, Komal S.
   Wang, Tao
   Zhou, Su
   Cheng, Lan
   Lu, Min Min
   Morrisey, Edward E.
TI Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration
SO NATURE
LA English
DT Article
ID sonic hedgehog; stem-cells; mouse; proliferation; progenitors; activation; plasticity; epithelium; fibrosis; pathway
AB Postnatal tissue quiescence is thought to be a default state in the absence of a proliferative stimulus such as injury. Although previous studies have demonstrated that certain embryonic developmental programs are reactivated aberrantly in adult organs to drive repair and regeneration(1-3), it is not well understood how quiescence is maintained in organs such as the lung, which displays a remarkably low level of cellular turnover(4,5). Here we demonstrate that quiescence in the adult lung is an actively maintained state and is regulated by hedgehog signalling. Epithelial-specific deletion of sonic hedgehog (Shh) during postnatal homeostasis in the murine lung results in a proliferative expansion of the adjacent lung mesenchyme. Hedgehog signalling is initially downregulated during the acute phase of epithelial injury as the mesenchyme proliferates in response, but returns to baseline during injury resolution as quiescence is restored. Activation of hedgehog during acute epithelial injury attenuates the proliferative expansion of the lung mesenchyme, whereas inactivation of hedgehog signalling prevents the restoration of quiescence during injury resolution. Finally, we show that hedgehog also regulates epithelial quiescence and regeneration in response to injury via a mesenchymal feedback mechanism. These results demonstrate that epithelial-mesenchymal interactions coordinated by hedgehog actively maintain postnatal tissue homeostasis, and deregulation of hedgehog during injury leads to aberrant repair and regeneration in the lung.
C1 [Peng, Tien; Morley, Michael P.; Rathi, Komal S.; Morrisey, Edward E.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA.
   [Frank, David B.] Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA.
   [Kadzik, Rachel S.; Morrisey, Edward E.] Univ Penn, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA.
   [Morley, Michael P.; Rathi, Komal S.; Morrisey, Edward E.] Univ Penn, Penn Ctr Pulm Biol, Philadelphia, PA 19104 USA.
   [Morley, Michael P.; Rathi, Komal S.; Wang, Tao; Zhou, Su; Cheng, Lan; Lu, Min Min; Morrisey, Edward E.] Univ Penn, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA.
   [Morrisey, Edward E.] Univ Penn, Penn Inst Regenerat Med, Philadelphia, PA 19104 USA.
C3 University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania
RP Morrisey, EE (corresponding author), Univ Penn, Dept Med, Philadelphia, PA 19104 USA.
EM tien.peng@ucsf.edu; emorrise@mail.med.upenn.edu
FU National Institutes of Health [HL110942, HL100405, HL087825]; American Heart Association Fellow-to-Faculty Transition Award; Actelion ENTELLIGENCE Award;  [K08-HL121146]; National Heart Lung and Blood Institute [T32HL007915, R01HL087825] Funding Source: NIH RePORTER
NR 29
TC 171
Z9 198
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 22
PY 2015
VL 526
IS 7574
BP 578
EP U282
DI 10.1038/nature14984
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV1NX
UT WOS:000364026100051
PM 26436454
DA 2026-03-09
ER

PT J
AU Glancy, B
   Hartnell, LM
   Malide, D
   Yu, ZX
   Combs, CA
   Connelly, PS
   Subramaniam, S
   Balaban, RS
AF Glancy, Brian
   Hartnell, Lisa M.
   Malide, Daniela
   Yu, Zu-Xi
   Combs, Christian A.
   Connelly, Patricia S.
   Subramaniam, Sriram
   Balaban, Robert S.
TI Mitochondrial reticulum for cellular energy distribution in muscle
SO NATURE
LA English
DT Article
ID limb skeletal-muscle; rat diaphragm muscle; in-vivo; 3-dimensional reconstruction; electron-microscopy; creatine-kinase; deficient; myoglobin; mice; fluorescence
AB Intracellular energy distribution has attracted much interest and has been proposed to occur in skeletal muscle via metabolite-facilitated diffusion(1,2;) however, genetic evidence suggests that facilitated diffusion is not critical for normal function(3-7). We hypothesized that mitochondrial structure minimizes metabolite diffusion distances in skeletal muscle. Here we demonstrate a mitochondrial reticulum providing a conductive pathway for energy distribution, in the form of the proton-motive force, throughout the mouse skeletal muscle cell. Within this reticulum, we find proteins associated with mitochondrial proton-motive force production preferentially in the cell periphery and proteins that use the proton-motive force for ATP production in the cell interior near contractile and transport ATPases. Furthermore, we show a rapid, coordinated depolarization of the membrane potential component of the proton-motive force throughout the cell in response to spatially controlled uncoupling of the cell interior. We propose that membrane potential conduction via the mitochondrial reticulum is the dominant pathway for skeletal muscle energy distribution.
C1 [Glancy, Brian; Malide, Daniela; Yu, Zu-Xi; Combs, Christian A.; Connelly, Patricia S.; Balaban, Robert S.] NHLBI, NIH, Bethesda, MD 20892 USA.
   [Hartnell, Lisa M.; Subramaniam, Sriram] NCI, NIH, Bethesda, MD 20892 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
RP Balaban, RS (corresponding author), NHLBI, NIH, Bethesda, MD 20892 USA.
EM Robert.Balaban@nih.gov
FU Division of Intramural Research, National Heart, Lung, and Blood Institute; Center for Cancer Research, National Cancer Institute; National Cancer Institute [ZICBC011574] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [ZICHL005906, ZICHL006019, ZIAHL004610, ZIGHL006020, ZICHL005904] Funding Source: NIH RePORTER
NR 33
TC 366
Z9 423
U1 3
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 JUL 30
PY 2015
VL 523
IS 7562
BP 617
EP +
DI 10.1038/nature14614
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN7ZL
UT WOS:000358655200050
PM 26223627
DA 2026-03-09
ER

PT J
AU Canver, MC
   Smith, EC
   Sher, F
   Pinello, L
   Sanjana, NE
   Shalem, O
   Chen, DD
   Schupp, PG
   Vinjamur, DS
   Garcia, SP
   Luc, S
   Kurita, R
   Nakamura, Y
   Fujiwara, Y
   Maeda, T
   Yuan, GC
   Zhang, F
   Orkin, SH
   Bauer, DE
AF Canver, Matthew C.
   Smith, Elenoe C.
   Sher, Falak
   Pinello, Luca
   Sanjana, Neville E.
   Shalem, Ophir
   Chen, Diane D.
   Schupp, Patrick G.
   Vinjamur, Divya S.
   Garcia, Sara P.
   Luc, Sidinh
   Kurita, Ryo
   Nakamura, Yukio
   Fujiwara, Yuko
   Maeda, Takahiro
   Yuan, Guo-Cheng
   Zhang, Feng
   Orkin, Stuart H.
   Bauer, Daniel E.
TI BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis
SO NATURE
LA English
DT Article
ID beta-globin gene; histone modifications; transcription factors; expression; disease; cas9; vectors; mice
AB Enhancers, critical determinants of cellular identity, are commonly recognized by correlative chromatin marks and gain-of-function potential, although only loss-of-function studies can demonstrate their requirement in the native genomic context. Previously, we identified an erythroid enhancer of human BCL11A, subject to common genetic variation associated with the fetal haemoglobin level, the mouse orthologue of which is necessary for eiythroid BCL11A expression. Here we develop pooled clustered regularly interspaced paiindromic repeat (CRISPR)-Cas9 guide RNA libraries to perform in situ saturating mutagenesis of the human and mouse enhancers. This approach reveals critical minimal features and discrete vulnerabilities of these enhancers. Despite conserved function of the composite enhancers, their architecture diverges. The crucial human sequences appear to be primate-specific. Through editing of primary human progenitors and mouse transgenesis, we validate the BCL11A erythroid enhancer as a target for fetal haemoglobin reinduction. The detailed enhancer map will inform therapeutic genome editing, and the screening approach described here is generally applicable to functional interrogation of non-coding genomic elements
C1 [Canver, Matthew C.; Smith, Elenoe C.; Sher, Falak; Chen, Diane D.; Schupp, Patrick G.; Vinjamur, Divya S.; Luc, Sidinh; Fujiwara, Yuko; Orkin, Stuart H.; Bauer, Daniel E.] Harvard Univ, Boston Childrens Hosp, Dana Farber Canc Inst,Div Hematol Oncol,Med Sch, Harvard Stem Cell Inst,Dept Pediat,Dept Pediat On, Boston, MA 02115 USA.
   [Pinello, Luca; Garcia, Sara P.; Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA.
   [Pinello, Luca; Garcia, Sara P.; Yuan, Guo-Cheng] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA.
   [Sanjana, Neville E.; Shalem, Ophir; Zhang, Feng] MIT, Broad Inst MIT & Harvard, McGovern Inst Brain Res, Dept Brain & Cognit Sci, Cambridge, MA 02142 USA.
   [Sanjana, Neville E.; Shalem, Ophir; Zhang, Feng] MIT, Dept Biol Engn, Cambridge, MA 02142 USA.
   [Kurita, Ryo; Nakamura, Yukio] RIKEN BioResource Ctr, Cell Engn Div, Tsukuba, Ibaraki 3050074, Japan.
   [Nakamura, Yukio] Univ Tsukuba, Comprehens Human Sci, Tsukuba, Ibaraki 3058577, Japan.
   [Fujiwara, Yuko; Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA.
   [Maeda, Takahiro] Harvard Univ, Brigham & Womens Hosp, Dept Med, Div Hematol,Med Sch, Boston, MA 02115 USA.
C3 Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Dana-Farber Cancer Institute; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard T.H. Chan School of Public Health; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Massachusetts Institute of Technology (MIT); RIKEN; University of Tsukuba; Howard Hughes Medical Institute; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard Medical School
RP Bauer, DE (corresponding author), Harvard Univ, Boston Childrens Hosp, Dana Farber Canc Inst,Div Hematol Oncol,Med Sch, Harvard Stem Cell Inst,Dept Pediat,Dept Pediat On, Boston, MA 02115 USA.
EM zhang@broadinstitute.org; stuart_orkin@dfci.harvard.edu; daniel.bauer@childrens.harvard.edu
FU Jane Coffin Childs Memorial Fund for Medical Research Fellowship; NHGRI Career Development Award [K99HG008399]; Simons Center for the Social Brain Postdoctoral Fellowship; NIH NHGRI [K99-HG008171]; Klarman Family Foundation; Leukemia & Lymphoma Society Fellow Award; NIH [R01 A1084905, R01HL119099, R01HG005085]; NIMH [5DP1-MH100706]; NIDDK [5R01-DK097768]; Waterman award from the National Science Foundation; Keck Foundation; McKnight Foundation; Damon Runyon Foundation; Searle Scholars Foundation; Merkin Foundation; Vallee Foundation; Simons Foundation; Bob Metcalfe; Center of Excellence in Molecular Hematology [P01HL032262, P30DK049216]; NIDDK Career Development Award [K08DK093705]; Doris Duke Charitable Foundation Innovations in Clinical Research Award [2013137]; Charles H. Hood Foundation Child Health Research Award;  [F30DK103359-01A1]; National Heart Lung and Blood Institute [P01HL032262, R01HL032259] Funding Source: NIH RePORTER
NR 60
TC 691
Z9 962
U1 9
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 NOV 12
PY 2015
VL 527
IS 7577
BP 192
EP +
DI 10.1038/nature15521
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700036
PM 26375006
DA 2026-03-09
ER

PT J
AU Zhang, X
   Ding, K
   Yu, XK
   Chang, W
   Sun, JC
   Zhou, ZH
AF Zhang, Xing
   Ding, Ke
   Yu, Xuekui
   Chang, Winston
   Sun, Jingchen
   Zhou, Z. Hong
TI In situ structures of the segmented genome and RNA polymerase complex inside a dsRNA virus
SO NATURE
LA English
DT Article
ID cytoplasmic polyhedrosis-virus; cryo-em structure; protein; dna; classification; transcriptase; replication; nucleoside; resolution; mechanism
AB Viruses in the Reoviridae, like the triple-shelled human rotavirus and the single-shelled insect cytoplasmic polyhedrosis virus (CPV), all package a genome of segmented double-stranded RNAs (dsRNAs) inside the viral capsid and carry out endogenous messenger RNA synthesis through a transcriptional enzyme complex (TEC)(1). By direct electron-counting cryoelectron microscopy and asymmetric reconstruction, we have determined the organization of the dsRNA genome inside quiescent CPV (q-CPV) and the in situ atomic structures of TEC within CPV in both quiescent and transcribing (t-CPV) states. We show that the ten segmented dsRNAs in CPV are organized with ten TECs in a specific, non-symmetric manner, with each dsRNA segment attached directly to a TEC. The TEC consists of two extensively interacting subunits: an RNA-dependent RNA polymerase (RdRP) and an NTPase VP4. We find that the bracelet domain of RdRP undergoes marked conformational change when q-CPV is converted to t-CPV, leading to formation of the RNA template entry channel and access to the polymerase active site. An amino-terminal helix from each of two subunits of the capsid shell protein (CSP) interacts with VP4 and RdRP. These findings establish the link between sensing of environmental cues by the external proteins and activation of endogenous RNA transcription by the TEC inside the virus.
C1 [Zhang, Xing; Chang, Winston; Zhou, Z. Hong] Univ Calif Los Angeles, Calif Nanosyst Inst, Los Angeles, CA 90095 USA.
   [Ding, Ke; Yu, Xuekui; Sun, Jingchen; Zhou, Z. Hong] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA.
   [Ding, Ke; Zhou, Z. Hong] Univ Calif Los Angeles, Bioengn, Los Angeles, CA 90095 USA.
   [Sun, Jingchen] South China Agr Univ, Coll Anim Sci, Guangdong Prov Key Lab Agroanim Genom & Mol Breed, Subtrop Sericulture & Mulberry Resources Protect, Guangzhou 510642, Guangdong, Peoples R China.
C3 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 Los Angeles; South China Agricultural University
RP Zhou, ZH (corresponding author), Univ Calif Los Angeles, Calif Nanosyst Inst, Los Angeles, CA 90095 USA.
EM cyfz@scau.edu.cn; Hong.Zhou@ucla.edu
FU National Institutes of Health [AI094386, GM071940]; NSFC [31172263]; NSFGD [S2013010016750]; UCLA; NIH [1S10RR23057, 1S10OD018111]; NSF [DBI-1338135]; National Institute of Allergy and Infectious Diseases [R01AI094386] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM071940] Funding Source: NIH RePORTER; Direct For Biological Sciences [1338135] Funding Source: National Science Foundation; Div Of Biological Infrastructure [1338135] Funding Source: National Science Foundation
NR 45
TC 86
Z9 103
U1 2
U2 81
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 531
EP +
DI 10.1038/nature15767
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500051
PM 26503045
DA 2026-03-09
ER

PT J
AU Rathert, P
   Roth, M
   Neumann, T
   Muerdter, F
   Roe, JS
   Muhar, M
   Deswal, S
   Cerny-Reiterer, S
   Peter, B
   Jude, J
   Hoffmann, T
   Boryn, LM
   Axelsson, E
   Schweifer, N
   Tontsch-Grunt, U
   Dow, LE
   Gianni, D
   Pearson, M
   Valent, P
   Stark, A
   Kraut, N
   Vakoc, CR
   Zuber, J
AF Rathert, Philipp
   Roth, Mareike
   Neumann, Tobias
   Muerdter, Felix
   Roe, Jae-Seok
   Muhar, Matthias
   Deswal, Sumit
   Cerny-Reiterer, Sabine
   Peter, Barbara
   Jude, Julian
   Hoffmann, Thomas
   Boryn, Lukasz M.
   Axelsson, Elin
   Schweifer, Norbert
   Tontsch-Grunt, Ulrike
   Dow, Lukas E.
   Gianni, Davide
   Pearson, Mark
   Valent, Peter
   Stark, Alexander
   Kraut, Norbert
   Vakoc, Christopher R.
   Zuber, Johannes
TI Transcriptional plasticity promotes primary and acquired resistance to BET inhibition
SO NATURE
LA English
DT Article
ID bromodomain inhibition; selective-inhibition; read alignment; self-renewal; c-myc; leukemia; target; rna; classification; activation
AB Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukaemia (AML)(1,2), bromodomain and extra terminal protein (BET) inhibitors are being explored as a promising therapeutic avenue in numerous cancers(3-5). While clinical trials have reported single-agent activity in advanced haematological malignancies(6), mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukaemia, here we perform a chromatin-focused RNAi screen in a sensitive MLL-AF9; Nras(G12D)-driven AML mouse model, and investigate dynamic transcriptional profiles in sensitive and resistantmouse and human leukaemias. Our screen shows that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET inhibitor resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodelling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukaemias regardless of their sensitivity, resistant leukaemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signalling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic chromatin immunoprecipitation sequencing and self-transcribing active regulatory region sequencing of enhancer profiles reveal that BET-resistant states are characterized by remodelled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signalling as a driver and candidate biomarker of primary and acquired BET resistance in leukaemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies.
C1 [Rathert, Philipp; Roth, Mareike; Neumann, Tobias; Muerdter, Felix; Muhar, Matthias; Deswal, Sumit; Jude, Julian; Hoffmann, Thomas; Boryn, Lukasz M.; Axelsson, Elin; Stark, Alexander; Zuber, Johannes] Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria.
   [Roe, Jae-Seok; Vakoc, Christopher R.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA.
   [Cerny-Reiterer, Sabine; Peter, Barbara; Valent, Peter] Med Univ Vienna, Div Hematol & Hemostaseol, Dept Internal Med 1, A-1090 Vienna, Austria.
   [Cerny-Reiterer, Sabine; Peter, Barbara; Valent, Peter] Med Univ Vienna, Ludwig Boltzmann Cluster Oncol, A-1090 Vienna, Austria.
   [Schweifer, Norbert; Tontsch-Grunt, Ulrike; Gianni, Davide; Pearson, Mark; Kraut, Norbert] Boehringer Ingelheim Reg Ctr Vienna GmbH, A-1121 Vienna, Austria.
   [Dow, Lukas E.] Weill Cornell Med Coll, Dept Med Hematol & Med Oncol, New York, NY 10065 USA.
C3 Vienna Biocenter (VBC); Research Institute of Molecular Pathology (IMP); Cold Spring Harbor Laboratory; Medical University of Vienna; Ludwig Boltzmann Institute; Ludwig Boltzmann Cluster Oncology (LBC ONC); Medical University of Vienna; Boehringer Ingelheim; Cornell University; Weill Cornell Medicine
RP Zuber, J (corresponding author), Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria.
EM zuber@imp.ac.at
FU European Research Council (ERC) [336860]; SFB of the Austrian Science Fund (FWF) [F4704, F4710]; European Union; ERC [242922]; Boehringer Ingelheim; National Cancer Institute [P30CA045508, R01CA174793] Funding Source: NIH RePORTER; European Research Council (ERC) [242922, 336860] Funding Source: European Research Council (ERC)
NR 55
TC 438
Z9 508
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 SEP 24
PY 2015
VL 525
IS 7570
BP 543
EP +
DI 10.1038/nature14898
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR8KI
UT WOS:000361599900055
PM 26367798
DA 2026-03-09
ER

PT J
AU Bertotti, A
   Papp, E
   Jones, S
   Adleff, V
   Anagnostou, V
   Lupo, B
   Sausen, M
   Phallen, J
   Hruban, CA
   Tokheim, C
   Niknafs, N
   Nesselbush, M
   Lytle, K
   Sassi, F
   Cottino, F
   Migliardi, G
   Zanella, ER
   Ribero, D
   Russolillo, N
   Mellano, A
   Muratore, A
   Paraluppi, G
   Salizzoni, M
   Marsoni, S
   Kragh, M
   Lantto, J
   Cassingena, A
   Li, QK
   Karchin, R
   Scharpf, R
   Sartore-Bianchi, A
   Siena, S
   Diaz, LA
   Trusolino, L
   Velculescu, VE
AF Bertotti, Andrea
   Papp, Eniko
   Jones, Sian
   Adleff, Vilmos
   Anagnostou, Valsamo
   Lupo, Barbara
   Sausen, Mark
   Phallen, Jillian
   Hruban, Carolyn A.
   Tokheim, Collin
   Niknafs, Noushin
   Nesselbush, Monica
   Lytle, Karli
   Sassi, Francesco
   Cottino, Francesca
   Migliardi, Giorgia
   Zanella, Eugenia R.
   Ribero, Dario
   Russolillo, Nadia
   Mellano, Alfredo
   Muratore, Andrea
   Paraluppi, Gianluca
   Salizzoni, Mauro
   Marsoni, Silvia
   Kragh, Michael
   Lantto, Johan
   Cassingena, Andrea
   Li, Qing Kay
   Karchin, Rachel
   Scharpf, Robert
   Sartore-Bianchi, Andrea
   Siena, Salvatore
   Diaz, Luis A., Jr.
   Trusolino, Livio
   Velculescu, Victor E.
TI The genomic landscape of response to EGFR blockade in colorectal cancer
SO NATURE
LA English
DT Article
ID gene copy number; activating mutations; acquired-resistance; somatic mutation; identification; panitumumab; sequence; insights; therapy; breast
AB Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation(1). Recent studies have identified alterations in KRAS(2-4) and other genes(5-13) as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.
C1 [Bertotti, Andrea; Lupo, Barbara; Migliardi, Giorgia; Zanella, Eugenia R.; Trusolino, Livio] Univ Turin, Sch Med, Dept Oncol, I-10060 Turin, Italy.
   [Bertotti, Andrea; Lupo, Barbara; Sassi, Francesco; Cottino, Francesca; Migliardi, Giorgia; Zanella, Eugenia R.; Mellano, Alfredo; Muratore, Andrea; Marsoni, Silvia; Trusolino, Livio] Fdn Piemonte Oncol IRCCS, Candiolo Canc Inst, Translat Canc Med Surg Oncol & Clin Trials Coord, I-10060 Turin, Italy.
   [Bertotti, Andrea] Natl Inst Biostruct & Biosyst INBB, I-00136 Rome, Italy.
   [Papp, Eniko; Adleff, Vilmos; Anagnostou, Valsamo; Phallen, Jillian; Hruban, Carolyn A.; Li, Qing Kay; Karchin, Rachel; Scharpf, Robert; Diaz, Luis A., Jr.; Velculescu, Victor E.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA.
   [Jones, Sian; Sausen, Mark; Nesselbush, Monica; Lytle, Karli] Personal Genome Diagnost, Baltimore, MD 21224 USA.
   [Tokheim, Collin; Niknafs, Noushin; Karchin, Rachel] Johns Hopkins Univ, Inst Computat Med, Dept Biomed Engn, Baltimore, MD 21204 USA.
   [Ribero, Dario; Russolillo, Nadia] Mauriziano Umberto Hosp, Dept Surg, I-10128 Turin, Italy.
   [Paraluppi, Gianluca; Salizzoni, Mauro] San Giovanni Battista Hosp, Liver Transplantat Ctr, I-10126 Turin, Italy.
   [Salizzoni, Mauro] Univ Turin, Sch Med, Dept Surg Sci, I-10126 Turin, Italy.
   [Kragh, Michael; Lantto, Johan] Symphogen AS, DK-2750 Ballerup, Denmark.
   [Cassingena, Andrea; Sartore-Bianchi, Andrea; Siena, Salvatore] Osped Niguarda Ca Granda, Niguarda Canc Ctr, I-20162 Milan, Italy.
   [Siena, Salvatore] Univ Milan, Sch Med, I-20162 Milan, Italy.
   [Diaz, Luis A., Jr.] Johns Hopkins, Ludwig Ctr Canc Genet & Therapeut, Swim Amer Lab, Baltimore, MD 21287 USA.
C3 University of Turin; IRCCS Fondazione del Piemonte per l'Oncologia; Johns Hopkins University; Johns Hopkins Medicine; Johns Hopkins University; A.O.U. Citta della Salute e della Scienza di Torino; AOU San Giovanni Battista-Molinette; A.O.U. Citta della Salute e della Scienza di Torino; AOU San Giovanni Battista-Molinette; University of Turin; Symphogen; IRCCS Ca Granda Ospedale Maggiore Policlinico; Ospedale Niguarda Ca' Granda; University of Milan; Johns Hopkins University
RP Velculescu, VE (corresponding author), Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA.
EM andrea.bertotti@ircc.it; livio.trusolino@ircc.it; velculescu@jhmi.edu
FU John G. Ballenger Trust; FasterCures Research Acceleration Award; European Community's Seventh Framework Programme; AIRC Italian Association for Cancer Research (Special Program Molecular Clinical Oncology) [531000, 9970]; AIRC Italian Association for Cancer Research [14205, 15571]; American Association for Cancer Research (AACR) - Fight Colorectal Cancer Career Development Award [12-20-16-BERT]; Commonwealth Foundation; Swim Across America; US National Institutes of Health [CA121113]; Fondazione Piemontese per la Ricerca sul Cancro-ONLUS (5x1000 Italian Ministry of Health); Oncologia Ca' Granda ONLUS; SU2C-DCS International Translational Cancer Research Dream Team Grant [SU2C-AACR-DT1415]; National Cancer Institute [P30CA006973, R01CA121113] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007057] Funding Source: NIH RePORTER
NR 39
TC 384
Z9 441
U1 1
U2 96
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 8
PY 2015
VL 526
IS 7572
BP 263
EP +
DI 10.1038/nature14969
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS9GV
UT WOS:000362399000049
PM 26416732
DA 2026-03-09
ER

PT J
AU Inra, CN
   Zhou, BO
   Acar, M
   Murphy, MM
   Richardson, J
   Zhao, ZY
   Morrison, SJ
AF Inra, Christopher N.
   Zhou, Bo O.
   Acar, Melih
   Murphy, Malea M.
   Richardson, James
   Zhao, Zhiyu
   Morrison, Sean J.
TI A perisinusoidal niche for extramedullary haematopoiesis in the spleen
SO NATURE
LA English
DT Article
ID stem-cells; bone-marrow; transgenic mice; progenitor cells; cre recombinase; self-renewal; ng2 cells; expression; receptor; mouse
AB Haematopoietic stresses mobilize haematopoietic stem cells (HSCs) from the bone marrow to the spleen and induce extramedullary haematopoiesis (EMH). However, the cellular nature of the EMH niche is unknown. Here we assessed the sources of the key niche factors, SCF (also known as KITL) and CXCL12, in the mouse spleen after EMH induction by myeloablation, blood loss, or pregnancy. In each case, Scf was expressed by endothelial cells and Tcf21(+) stromal cells, primarily around sinusoids in the red pulp, while Cxcl12 was expressed by a subset of Tcf21(+) stromal cells. EMH induction markedly expanded the Scf-expressing endothelial cells and stromal cells by inducing proliferation. Most splenic HSCs were adjacent to Tcf21(+) stromal cells in red pulp. Conditional deletion of Scf from spleen endothelial cells, or of Scf or Cxcl12 from Tcf21(+) stromal cells, severely reduced spleen EMH and reduced blood cell counts without affecting bone marrow haematopoiesis. Endothelial cells and Tcf21(+) stromal cells thus create a perisinusoidal EMH niche in the spleen, which is necessary for the physiological response to diverse haematopoietic stresses.
C1 [Inra, Christopher N.; Zhou, Bo O.; Acar, Melih; Murphy, Malea M.; Zhao, Zhiyu; Morrison, Sean J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA.
   [Inra, Christopher N.; Zhou, Bo O.; Acar, Melih; Murphy, Malea M.; Zhao, Zhiyu; Morrison, Sean J.] Univ Texas SW Med Ctr Dallas, Childrens Res Inst, Dallas, TX 75390 USA.
   [Richardson, James] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA.
   [Morrison, Sean J.] Univ Texas SW 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; University of Texas System; University of Texas Southwestern Medical Center; Howard Hughes Medical Institute
RP Morrison, SJ (corresponding author), Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA.
EM sean.morrison@utsouthwestern.edu
FU Leukemia and Lymphoma Society; National Institutes of Health National Heart, Lung, and Blood Institute [HL097760]
NR 39
TC 211
Z9 259
U1 0
U2 60
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 466
EP +
DI 10.1038/nature15530
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500037
PM 26570997
DA 2026-03-09
ER

PT J
AU Nelson-Sathi, S
   Sousa, FL
   Roettger, M
   Lozada-Chávez, N
   Thiergart, T
   Janssen, A
   Bryant, D
   Landan, G
   Schönheit, P
   Siebers, B
   McInerney, JO
   Martin, WF
AF Nelson-Sathi, Shijulal
   Sousa, Filipa L.
   Roettger, Mayo
   Lozada-Chavez, Nabor
   Thiergart, Thorsten
   Janssen, Arnold
   Bryant, David
   Landan, Giddy
   Schoenheit, Peter
   Siebers, Bettina
   McInerney, James O.
   Martin, William F.
TI Origins of major archaeal clades correspond to gene acquisitions from bacteria
SO NATURE
LA English
DT Article
ID carbohydrate-metabolism; maximum-likelihood; protein family; life; tree; evolution; genome; phylogeny; diversity; algorithm
AB The mechanisms that underlie the origin of major prokaryotic groups are poorly understood. In principle, the origin of both species and higher taxa among prokaryotes should entail similar mechanisms-ecological interactions with the environment paired with natural genetic variation involving lineage-specific gene innovations and lineage-specific gene acquisitions(1-4). To investigate the origin of higher taxa in archaea, we have determined gene distributions and gene phylogenies for the 267,568 protein-coding genes of 134 sequenced archaeal genomes in the context of their homologues from 1,847 reference bacterial genomes. Archaeal-specific gene families define 13 traditionally recognized archaeal higher taxa in our sample. Here we report that the origins of these 13 groups unexpectedly correspond to 2,264 group-specific gene acquisitions from bacteria. Interdomain gene transfer is highly asymmetric, transfers from bacteria to archaea are more than fivefold more frequent than vice versa. Gene transfers identified at major evolutionary transitions among prokaryotes specifically implicate gene acquisitions for metabolic functions from bacteria as key innovations in the origin of higher archaeal taxa.
C1 [Nelson-Sathi, Shijulal; Sousa, Filipa L.; Roettger, Mayo; Lozada-Chavez, Nabor; Thiergart, Thorsten; Martin, William F.] Univ Dusseldorf, Inst Mol Evolut, D-40225 Dusseldorf, Germany.
   [Janssen, Arnold] Univ Dusseldorf, Math Inst, D-40225 Dusseldorf, Germany.
   [Bryant, David] Univ Otago, Dept Math & Stat, Dunedin 9054, New Zealand.
   [Landan, Giddy] Univ Kiel, Genom Microbiol Grp, Inst Microbiol, D-24118 Kiel, Germany.
   [Schoenheit, Peter] Univ Kiel, Inst Allgemeine Mikrobiol, D-24118 Kiel, Germany.
   [Siebers, Bettina] Univ Duisburg Essen, Fac Chem, Biofilm Ctr, D-45117 Essen, Germany.
   [McInerney, James O.] Natl Univ Ireland, Dept Biol, Maynooth, Kildare, Ireland.
   [Martin, William F.] Univ Nova Lisboa, Inst Tecnol Quim & Biol, P-2780157 Oeiras, Portugal.
C3 Heinrich Heine University Dusseldorf; Heinrich Heine University Dusseldorf; University of Otago; University of Kiel; University of Kiel; University of Duisburg Essen; Maynooth University; Universidade Nova de Lisboa
RP Martin, WF (corresponding author), Univ Dusseldorf, Inst Mol Evolut, D-40225 Dusseldorf, Germany.
EM bill@hhu.de
FU European Research Council (ERC) [232975, 281357]; graduate school E-Norm of the Heinrich-Heine University; DFG [Scho 316/11-1, SI 642/10-1]; BMBF [0316188A]
NR 30
TC 175
Z9 193
U1 0
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 JAN 1
PY 2015
VL 517
IS 7532
BP 77
EP U185
DI 10.1038/nature13805
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AX8SI
UT WOS:000347178400038
PM 25317564
DA 2026-03-09
ER

PT J
AU Turrà, D
   El Ghalid, M
   Rossi, F
   Di Pietro, A
AF Turra, David
   El Ghalid, Mennat
   Rossi, Federico
   Di Pietro, Antonio
TI Fungal pathogen uses sex pheromone receptor for chemotropic sensing of host plant signals
SO NATURE
LA English
DT Article
ID activated protein-kinase; fusarium-oxysporum; horseradish-peroxidase; invasive growth; virulence; pathway; yeast; site; rho1
AB For more than a century, fungal pathogens and symbionts have been known to orient hyphal growth towards chemical stimuli from the host plant(1,2). However, the nature of the plant signals as well as the mechanisms underlying the chemotropic response have remained elusive(3). Here we show that directed growth of the soil-inhabiting plant pathogen Fusarium oxysporum towards the roots of the host tomato (Solanum lycopersicum) is triggered by the catalytic activity of secreted class III peroxidases, a family of haem-containing enzymes present in all land plants(4). The chemotropic response requires conserved elements of the fungal cell integrity mitogen-activated protein kinase (MAPK) cascade(5) and the seven-pass transmembrane protein Ste2, a functional homologue of the Saccharomyces cerevisiae sex pheromone a receptor(6). We further show that directed hyphal growth of F. oxysporum towards nutrient sources such as sugars and amino acids is governed by a functionally distinct MAPK cascade. These results reveal a potentially conserved chemotropic mechanism in root-colonizing fungi, and suggest a new function for the fungal pheromone-sensing machinery in locating plant hosts in a complex environment such as the soil.
C1 [Turra, David; El Ghalid, Mennat; Rossi, Federico; Di Pietro, Antonio] Univ Cordoba, Dept Genet, E-14071 Cordoba, Spain.
C3 Universidad de Cordoba
RP Di Pietro, A (corresponding author), Univ Cordoba, Dept Genet, Campus Excelencia Int Agroalimentario ceiA3, E-14071 Cordoba, Spain.
EM ge2dipia@uco.es
FU Spanish Ministerio de Innovacion y Competitividad (MINECO) [BIO2010-15505, BIO2013-47870-R]; MINECO/ERA-NET PathoGenoMics [BIO2008-04479]; Marie Curie ITN ARIADNE from the European Commission [FP7-PEOPLE-ITN-237936]; ERASMUS student exchange program
CR Arkowitz RA, 2009, CSH PERSPECT BIOL, V1, P0, DOI 10.1101/cshperspect.a001958
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   Bar EE, 2003, J BIOL CHEM, V278, P21798, DOI 10.1074/jbc.M212636200
   Berendsen RL, 2012, TRENDS PLANT SCI, V17, P478, DOI 10.1016/j.tplants.2012.04.001
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   Kretzschmar T, 2012, NATURE, V483, P341, DOI 10.1038/nature10873
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   Passardi F, 2004, TRENDS PLANT SCI, V9, P534, DOI 10.1016/j.tplants.2004.09.002
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NR 29
TC 157
Z9 181
U1 12
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 NOV 26
PY 2015
VL 527
IS 7579
BP 521
EP +
DI 10.1038/nature15516
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500049
PM 26503056
DA 2026-03-09
ER

PT J
AU McNeil, BD
   Pundir, P
   Meeker, S
   Han, L
   Undem, BJ
   Kulka, M
   Dong, XZ
AF McNeil, Benjamin D.
   Pundir, Priyanka
   Meeker, Sonya
   Han, Liang
   Undem, Bradley J.
   Kulka, Marianna
   Dong, Xinzhong
TI Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions
SO NATURE
LA English
DT Article
ID protein-coupled receptor; histamine-release; systemic-anaphylaxis; human skin; gene x2; activation; peptides; agents; mrgx2; mice
AB Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances(1,2). Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions(1,3). The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.
C1 [McNeil, Benjamin D.; Han, Liang; Dong, Xinzhong] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Solomon H Snyder Dept Neurosci,Ctr Sensory Biol, Baltimore, MD 21205 USA.
   [Pundir, Priyanka; Kulka, Marianna] Univ Alberta, Dept Med Microbiol & Immunol, Edmonton, AB T6G 2E1, Canada.
   [Meeker, Sonya; Undem, Bradley J.] Johns Hopkins Univ, Sch Med, Dept Med, Div Allergy & Clin Immunol, Baltimore, MD 21205 USA.
   [Kulka, Marianna] Natl Res Council Canada, Natl Inst Nanotechnol, Edmonton, AB T6G 2M9, Canada.
   [Dong, Xinzhong] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA.
C3 Johns Hopkins University; University of Alberta; Johns Hopkins University; National Research Council Canada; Howard Hughes Medical Institute; Johns Hopkins University
RP Dong, XZ (corresponding author), Johns Hopkins Univ, Sch Med, Dept Neurosurg, Solomon H Snyder Dept Neurosci,Ctr Sensory Biol, Baltimore, MD 21205 USA.
EM xdong2@jhmi.edu
FU National Institutes of Health [R01NS054791, R01GM087369]
NR 34
TC 1011
Z9 1128
U1 12
U2 209
PU NATURE PUBLISHING 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 12
PY 2015
VL 519
IS 7542
BP 237
EP +
DI 10.1038/nature14022
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500040
PM 25517090
DA 2026-03-09
ER

PT J
AU Kang, YY
   Zhou, XE
   Gao, X
   He, YZ
   Liu, W
   Ishchenko, A
   Barty, A
   Sathish, D
   Yefanov, O
   Han, GW
   Xu, QP
   de Waal, PW
   Ke, JY
   Tan, MHE
   Zhang, CH
   Moeller, A
   West, GM
   Pascal, BD
   Van Eps, N
   Caro, LN
   Vishnivetskiy, SA
   Lee, RJ
   Suino-Powell, KM
   Gu, X
   Pal, K
   Ma, JM
   Zhi, XY
   Boutet, S
   Williams, GJ
   Messerschmidt, M
   Gati, C
   Zatsepin, NA
   Wang, DJ
   James, D
   Basu, S
   Roy-Chowdhury, S
   Conrad, CE
   Coe, J
   Liu, HG
   Lisova, S
   Kupitz, C
   Grotjohann, I
   Fromme, R
   Jiang, Y
   Tan, MJ
   Yang, HY
   Li, J
   Wang, MT
   Zheng, Z
   Li, DF
   Howe, N
   Zhao, YM
   Standfuss, J
   Diederichs, K
   Dong, YH
   Potter, CS
   Carragher, B
   Caffrey, M
   Jiang, HL
   Chapman, HN
   Spence, JCH
   Fromme, P
   Weierstall, U
   Ernst, OP
   Katritch, V
   Gurevich, VV
   Griffin, PR
   Hubbell, WL
   Stevens, RC
   Cherezov, V
   Melcher, K
   Xu, HE
AF Kang, Yanyong
   Zhou, X. Edward
   Gao, Xiang
   He, Yuanzheng
   Liu, Wei
   Ishchenko, Andrii
   Barty, Anton
   Sathish, D.
   Yefanov, Oleksandr
   Han, Gye Won
   Xu, Qingping
   de Waal, Parker W.
   Ke, Jiyuan
   Tan, M. H. Eileen
   Zhang, Chenghai
   Moeller, Arne
   West, Graham M.
   Pascal, Bruce D.
   Van Eps, Ned
   Caro, Lydia N.
   Vishnivetskiy, Sergey A.
   Lee, Regina J.
   Suino-Powell, Kelly M.
   Gu, Xin
   Pal, Kuntal
   Ma, Jinming
   Zhi, Xiaoyong
   Boutet, Sebastien
   Williams, Garth J.
   Messerschmidt, Marc
   Gati, Cornelius
   Zatsepin, Nadia A.
   Wang, Dingjie
   James, Daniel
   Basu, Shibom
   Roy-Chowdhury, Shatabdi
   Conrad, Chelsie E.
   Coe, Jesse
   Liu, Haiguang
   Lisova, Stella
   Kupitz, Christopher
   Grotjohann, Ingo
   Fromme, Raimund
   Jiang, Yi
   Tan, Minjia
   Yang, Huaiyu
   Li, Jun
   Wang, Meitian
   Zheng, Zhong
   Li, Dianfan
   Howe, Nicole
   Zhao, Yingming
   Standfuss, Joerg
   Diederichs, Kay
   Dong, Yuhui
   Potter, Clinton S.
   Carragher, Bridget
   Caffrey, Martin
   Jiang, Hualiang
   Chapman, Henry N.
   Spence, John C. H.
   Fromme, Petra
   Weierstall, Uwe
   Ernst, Oliver P.
   Katritch, Vsevolod
   Gurevich, Vsevolod V.
   Griffin, Patrick R.
   Hubbell, Wayne L.
   Stevens, Raymond C.
   Cherezov, Vadim
   Melcher, Karsten
   Xu, H. Eric
TI Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser
SO NATURE
LA English
DT Article
ID lipidic cubic phase; visual arrestin; space-group; protein; activation; binding; expression; microscopy; piggybac; reveal
AB G-protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent pathways. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography. Together with extensive biochemical and mutagenesis data, the structure reveals an overall architecture of the rhodopsin-arrestin assembly in which rhodopsin uses distinct structural elements, including transmembrane helix 7 and helix 8, to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a similar to 20 degrees rotation between the amino and carboxy domains, which opens up a cleft in arrestin to accommodate a short helix formed by the second intracellular loop of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology.
C1 [Kang, Yanyong; Zhou, X. Edward; Gao, Xiang; He, Yuanzheng; de Waal, Parker W.; Ke, Jiyuan; Tan, M. H. Eileen; Zhang, Chenghai; Gu, Xin; Pal, Kuntal; Ma, Jinming; Zhi, Xiaoyong; Melcher, Karsten; Xu, H. Eric] Van Andel Res Inst, Ctr Struct Biol & Drug Discovery, Lab Struct Sci, Grand Rapids, MI 49503 USA.
   [Liu, Wei; Zatsepin, Nadia A.; Wang, Dingjie; James, Daniel; Basu, Shibom; Roy-Chowdhury, Shatabdi; Conrad, Chelsie E.; Coe, Jesse; Liu, Haiguang; Lisova, Stella; Kupitz, Christopher; Grotjohann, Ingo; Fromme, Raimund; Spence, John C. H.; Fromme, Petra; Weierstall, Uwe] Arizona State Univ, Dept Chem & Biochem, Biodesign Inst, Tempe, AZ 85287 USA.
   [Liu, Wei; Zatsepin, Nadia A.; Wang, Dingjie; James, Daniel; Basu, Shibom; Roy-Chowdhury, Shatabdi; Conrad, Chelsie E.; Coe, Jesse; Liu, Haiguang; Lisova, Stella; Kupitz, Christopher; Grotjohann, Ingo; Fromme, Raimund; Spence, John C. H.; Fromme, Petra; Weierstall, Uwe] Arizona State Univ, Ctr Appl Struct Discovery, Biodesign Inst, Tempe, AZ 85287 USA.
   [Ishchenko, Andrii; Han, Gye Won; Stevens, Raymond C.; Cherezov, Vadim] Univ So Calif, Bridge Inst, Dept Chem, Los Angeles, CA 90089 USA.
   [Barty, Anton; Sathish, D.; Yefanov, Oleksandr; Gati, Cornelius; Chapman, Henry N.] Deutsch Elektronen Synchrotron DESY, Ctr Free Elect Laser Sci, D-22607 Hamburg, Germany.
   [Xu, Qingping] SLAC Natl Accelerator Lab, Stanford Synchrotron Radiat Lightsource, Joint Ctr Struct Genom, Menlo Pk, CA 94025 USA.
   [Tan, M. H. Eileen; Li, Jun] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Obstet & Gynecol, Singapore 117595, Singapore.
   [Moeller, Arne; Potter, Clinton S.; Carragher, Bridget] New York Struct Biol Ctr, Natl Resource Automated Mol Microscopy, New York, NY 10027 USA.
   [West, Graham M.; Pascal, Bruce D.; Griffin, Patrick R.] Scripps Florida, Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA.
   [Van Eps, Ned; Hubbell, Wayne L.] Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90095 USA.
   [Van Eps, Ned; Hubbell, Wayne L.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA.
   [Caro, Lydia N.; Ernst, Oliver P.] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada.
   [Vishnivetskiy, Sergey A.; Lee, Regina J.; Suino-Powell, Kelly M.; Gurevich, Vsevolod V.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA.
   [Boutet, Sebastien; Williams, Garth J.; Messerschmidt, Marc] SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA.
   [Messerschmidt, Marc; Zhao, Yingming] NSF Sci & Technol Ctr, BioXFEL, Buffalo, NY 14203 USA.
   [Zatsepin, Nadia A.; Wang, Dingjie; James, Daniel; Basu, Shibom; Roy-Chowdhury, Shatabdi; Spence, John C. H.; Weierstall, Uwe] Arizona State Univ, Dept Phys, Tempe, AZ 85287 USA.
   [Liu, Haiguang] Beijing Computat Sci Res Ctr, Beijing 10084, Peoples R China.
   [Kupitz, Christopher] Univ Wisconsin, Dept Phys, Milwaukee, WI 53211 USA.
   [Jiang, Yi; Tan, Minjia; Yang, Huaiyu; Jiang, Hualiang] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China.
   [Wang, Meitian] Paul Scherrer Inst, Swiss Light Source, CH-5232 Villigen, Switzerland.
   [Zheng, Zhong; Katritch, Vsevolod; Stevens, Raymond C.] Univ So Calif, Bridge Inst, Dept Biol Sci, Los Angeles, CA 90089 USA.
   [Li, Dianfan; Howe, Nicole; Caffrey, Martin] Univ Dublin Trinity Coll, Sch Med & Sch Biochem & Immunol, Dublin 2, Ireland.
   [Zhao, Yingming] Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA.
   [Standfuss, Joerg] Paul Scherrer Inst, Lab Biomol Res, CH-5232 Villigen, Switzerland.
   [Diederichs, Kay] Univ Konstanz, Dept Biol, D-78457 Constance, Germany.
   [Dong, Yuhui] Chinese Acad Sci, Beijing Synchrotron Radiat Facil, Beijing 100049, Peoples R China.
   [Chapman, Henry N.] Ctr Ultrafast Imaging, D-22761 Hamburg, Germany.
   [Ernst, Oliver P.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada.
   [Stevens, Raymond C.] ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China.
   [Xu, H. Eric] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, VARI SIMM Ctr,Ctr Struct & Funct Drug Targets, Shanghai 201203, Peoples R China.
C3 Van Andel Institute; Van Andel Research Institute; Arizona State University; Arizona State University-Tempe; Arizona State University; Arizona State University-Tempe; University of Southern California; Helmholtz Association; Deutsches Elektronen-Synchrotron (DESY); Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; National University of Singapore; State University System of Florida; University of Florida; Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of Toronto; Vanderbilt University; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; National Science Foundation (NSF); NSF - Science and Technology Centers (STCs); Arizona State University; Arizona State University-Tempe; Chinese Academy of Engineering Physics; Beijing Computational Science Research Center (CSRC); University of Wisconsin System; University of Wisconsin Milwaukee; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute; University of Southern California; Trinity College Dublin; University of Chicago; Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute; University of Konstanz; Chinese Academy of Sciences; Institute of High Energy Physics, CAS; University of Toronto; ShanghaiTech University; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS
RP Xu, HE (corresponding author), Van Andel Res Inst, Ctr Struct Biol & Drug Discovery, Lab Struct Sci, Grand Rapids, MI 49503 USA.
EM Eric.Xu@vai.org
FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]; National Institutes of Health [P41GM103393]; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor [085P1000817]; Federal funds from the National Cancer Institute [ACB-12002]; National Institute of General Medical Sciences [AGM-12006]; Office of Science of the US Department of Energy [DE-AC02-06CH11357]; Jay and Betty Van Andel Foundation, Ministry of Science and Technology (China) [2012ZX09301001, 2012CB910403, 2013CB910600, XDB08020303, 2013ZX09507001]; Amway (China); National Institute of Health [DK071662, GM073197, GM103310, GM102545, GM104212, EY011500, GM077561, EY005216, P30EY000331]; National Institutes of Health Common Fund in Structural Biology grants [P50 GM073197, P50 GM073210, GM095583]; NSF Science and Technology Center [1231306]; Swiss National Science Foundation [31003A_141235]; Canada Excellence Research Chair program; Anne & Max Tanenbaum Chair in Neuroscience at the University of Toronto; Science Foundation Ireland [12/IA/1255]; Helmholtz Gemeinschaft; DFG Cluster of Excellence Center for Ultrafast Imaging; BMBF [FKZ 05K12CH1]; Irene and Eric Simon Brain Research Foundation; PIER Helmholtz-Graduate School; Helmholtz Association; National Institute of General Medical Sciences PSI: Biology grants [U54 GM094618, GM108635, U54 GM094599, GM097463, U54 GM094586]; National Eye Institute [R01EY011500, P30EY000331] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM095583, P41GM103310] Funding Source: NIH RePORTER; Swiss National Science Foundation (SNF) [31003A_141235] Funding Source: Swiss National Science Foundation (SNF)
NR 97
TC 653
Z9 754
U1 13
U2 388
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 30
PY 2015
VL 523
IS 7562
BP 561
EP +
DI 10.1038/nature14656
PG 31
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN7ZL
UT WOS:000358655200038
PM 26200343
DA 2026-03-09
ER

PT J
AU Khatter, H
   Myasnikov, AG
   Natchiar, SK
   Klaholz, BP
AF Khatter, Heena
   Myasnikov, Alexander G.
   Natchiar, S. Kundhavai
   Klaholz, Bruno P.
TI Structure of the human 80S ribosome
SO NATURE
LA English
DT Article
ID particle electron cryomicroscopy; transfer-rna binding; o hydrogen-bonds; angstrom resolution; crystal-structure; eukaryotic ribosome; translation initiation; bacterial ribosome; messenger-rna; l1 stalk
AB Ribosomes are translational machineries that catalyse protein synthesis. Ribosome structures from various species are known at the atomic level, but obtaining the structure of the human ribosome has remained a challenge; efforts to address this would be highly relevant with regard to human diseases. Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-eiecfron microscopy and atomic model, building. The structure has an average resolution of 3.6 angstrom, reaching 2.9 angstrom resolution in the most stable regions. It provides unprecedented insights into ribosomal RNA entities and amino acid side chains, notably of the transfer RNA binding sites and specific molecular interactions with the exit site tRINA. It reveals atomic details of the subunit interface, which is seen to remodel strongly upon rotational movements of the ribosomal submits. Furthermore, the structure paves the way for analysing antibiotic side effects and diseases associated with deregulated protein synthesis.
C1 [Khatter, Heena; Myasnikov, Alexander G.; Natchiar, S. Kundhavai; Klaholz, Bruno P.] IGBMC Inst Genet & Mol & Cellular Biol, Dept Integrated Struct Biol, Ctr Integrat Biol CBI, F-67404 Illkirch Graffenstaden, France.
   [Khatter, Heena; Myasnikov, Alexander G.; Natchiar, S. Kundhavai; Klaholz, Bruno P.] CNRS, UMR 7104, F-67404 Illkirch Graffenstaden, France.
   [Khatter, Heena; Myasnikov, Alexander G.; Natchiar, S. Kundhavai; Klaholz, Bruno P.] INSERM, U964, F-67404 Illkirch Graffenstaden, France.
   [Khatter, Heena; Myasnikov, Alexander G.; Natchiar, S. Kundhavai; Klaholz, Bruno P.] Univ Strasbourg, F-67081 Strasbourg, France.
C3 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
RP Klaholz, BP (corresponding author), IGBMC Inst Genet & Mol & Cellular Biol, Dept Integrated Struct Biol, Ctr Integrat Biol CBI, 1 Rue Laurent Fries, F-67404 Illkirch Graffenstaden, France.
EM klaholz@igbmc.fr
FU Equipex Equip@Meso project; CNRS; European Research Council (ERC) [N_243296]; French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INSB-05-01]; Instruct as part of the European Strategy Forum on Research Infrastructures (ESFRI)
NR 59
TC 395
Z9 484
U1 5
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 APR 30
PY 2015
VL 520
IS 7549
BP 640
EP U338
DI 10.1038/nature14427
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700042
PM 25901680
DA 2026-03-09
ER

PT J
AU Chang, AJ
   Ortega, FE
   Riegler, J
   Adison, DVM
   Krasnow, MA
AF Chang, Andy J.
   Ortega, Fabian E.
   Riegler, Johannes
   Adison, Daniel V. M.
   Krasnow, Mark A.
TI Oxygen regulation of breathing through an olfactory receptor activated by lactate
SO NATURE
LA English
DT Article
ID rat carotid-body; mitochondrial respiratory-chain; glomus cells; chemoreceptor discharge; odorant receptors; gene-expression; sensory neurons; cre recombinase; leigh-syndrome; i cells
AB Animals have evolved homeostatic responses to changes in oxygen availability that act on different timescales. Although the hypoxia-inducible factor (HIF) transcriptional pathway that controls long-term responses to low oxygen (hypoxia) has been established(1), the pathway that mediates acute responses to hypoxia in mammals is not well understood. Here we show that the olfactory receptor gene Olfr78 is highly and selectively expressed in oxygen-sensitive glomus cells of the carotid body, a chemosensory organ at the carotid artery bifurcation that monitors blood oxygen and stimulates breathing within seconds when oxygen declines(2). Olfr78 mutants fail to increase ventilation in hypoxia but respond normally to hypercapnia. Glomus cells are present in normal numbers and appear structurally intact, but hypoxia-induced carotid body activity is diminished. Lactate, a metabolite that rapidly accumulates in hypoxia and induces hyperventilation(3-6), activates Olfr78 in heterologous expression experiments, induces calcium transients in glomus cells, and stimulates carotid sinus nerve activity through Olfr78. We propose that, in addition to its role in olfaction, Olfr78 acts as a hypoxia sensor in the breathing circuit by sensing lactate produced when oxygen levels decline.
C1 [Chang, Andy J.; Ortega, Fabian E.; Krasnow, Mark A.] Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA.
   [Chang, Andy J.; Ortega, Fabian E.; Krasnow, Mark A.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Riegler, Johannes] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA.
   [Adison, Daniel V. M.] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; Howard Hughes Medical Institute; Stanford University; Stanford University
RP Krasnow, MA (corresponding author), Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA.
EM krasnow@stanford.edu
FU Stanford University Dean's Postdoctoral Fellowship; National Institutes of Health (NIH) Career Development Program [K12 RFA-HL-07-004]; Helen Hay Whitney Postdoctoral Fellowship; NIH Pediatric Research Loan Repayment Program; Howard Hughes Medical Institute Gilliam Fellowship; NIH [MH065541, NS069375]; Harold and Leila Y. Mathers Charitable Foundation; Howard Hughes Medical Institute
NR 66
TC 225
Z9 246
U1 1
U2 83
PU NATURE PUBLISHING 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 12
PY 2015
VL 527
IS 7577
BP 240
EP +
DI 10.1038/nature15721
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700046
PM 26560302
DA 2026-03-09
ER

PT J
AU Eshel, N
   Bukwich, M
   Rao, V
   Hemmelder, V
   Tian, J
   Uchida, N
AF Eshel, Neir
   Bukwich, Michael
   Rao, Vinod
   Hemmelder, Vivian
   Tian, Ju
   Uchida, Naoshige
TI Arithmetic and local circuitry underlying dopamine prediction errors
SO NATURE
LA English
DT Article
ID ventral tegmental area; negative reward signals; lateral habenula; gaba neurons; in-vivo; responses; inhibition; model; representation; interneurons
AB Dopamine neurons are thought to facilitate learning by comparing actual and expected reward(1,2). Despite two decades of investigation, little is known about how this comparison is made. To determine how dopamine neurons calculate prediction error, we combined optogenetic manipulations with extracellular recordings in the ventral tegmental area while mice engaged in classical conditioning. Here we demonstrate, by manipulating the temporal expectation of reward, that dopamine neurons perform subtraction, a computation that is ideal for reinforcement learning but rarely observed in the brain. Furthermore, selectively exciting and inhibiting neighbouring GABA (c-aminobutyric acid) neurons in the ventral tegmental area reveals that these neurons are a source of subtraction: they inhibit dopamine neurons when reward is expected, causally contributing to prediction-error calculations. Finally, bilaterally stimulating ventral tegmental area GABA neurons dramatically reduces anticipatory licking to conditioned odours, consistent with an important role for these neurons in reinforcement learning. Together, our results uncover the arithmetic and local circuitry underlying dopamine prediction errors.
C1 [Eshel, Neir; Bukwich, Michael; Rao, Vinod; Hemmelder, Vivian; Tian, Ju; Uchida, Naoshige] Harvard Univ, Dept Mol & Cellular Biol, Ctr Brain Sci, Cambridge, MA 02138 USA.
C3 Harvard University
RP Uchida, N (corresponding author), Harvard Univ, Dept Mol & Cellular Biol, Ctr Brain Sci, Cambridge, MA 02138 USA.
EM uchida@mcb.harvard.edu
FU Sackler Fellowship in Psychobiology; National Institutes of Health [T32GM007753, F30MH100729, R01MH095953, R01MH101207]; National Institute of General Medical Sciences [T32GM007753] Funding Source: NIH RePORTER; National Institute of Mental Health [R25MH094612] Funding Source: NIH RePORTER
NR 39
TC 257
Z9 295
U1 0
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 SEP 10
PY 2015
VL 525
IS 7568
BP 243
EP +
DI 10.1038/nature14855
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400037
PM 26322583
DA 2026-03-09
ER

PT J
AU Hay, CC
   Morrow, E
   Kopp, RE
   Mitrovica, JX
AF Hay, Carling C.
   Morrow, Eric
   Kopp, Robert E.
   Mitrovica, Jerry X.
TI Probabilistic reanalysis of twentieth-century sea-level rise
SO NATURE
LA English
DT Article
ID atmospheric-pressure; mass-balance; ice sheets; glaciers; trends
AB Estimating and accounting for twentieth-century global mean sea-level (GMSL) rise is critical to characterizing current and future human-induced sea-level change. Several previous analyses of tide gauge records(1-6)-employing different methods to accommodate the spatial sparsity and temporal incompleteness of the data and to constrain the geometry of long-term sea-level change-have concluded that GMSL rose over the twentieth century at a mean rate of 1.6 to 1.9 millimetres per year. Efforts to account for this rate by summing estimates of individual contributions from glacier and ice-sheet mass loss, ocean thermal expansion, and changes in land water storage fall significantly short in the period before 1990(7). The failure to close the budget of GMSL during this period has led to suggestions that several contributions may have been systematically underestimated(8). However, the extent to which the limitations of tide gauge analyses have affected estimates of the GMSL rate of change is unclear. Here we revisit estimates of twentieth-century GMSL rise using probabilistic techniques(9,10) and find a rate of GMSL rise from 1901 to 1990 of 1.2 +/- 0.2 millimetres per year (90% confidence interval). Based on individual contributions tabulated in the Fifth Assessment Report(7) of the Intergovernmental Panel on Climate Change, this estimate closes the twentieth-century sea-level budget. Our analysis, which combines tide gauge records with physics-based and model-derived geometries of the various contributing signals, also indicates that GMSL rose at a rate of 3.0 +/- 0.7 millimetres per year between 1993 and 2010, consistent with prior estimates from tide gauge records(4). The increase in rate relative to the 1901-90 trend is accordingly larger than previously thought; this revision may affect some projections(11) of future sea-level rise.
C1 [Hay, Carling C.; Morrow, Eric; Mitrovica, Jerry X.] Harvard Univ, Cambridge, MA 02138 USA.
   [Hay, Carling C.; Morrow, Eric; Kopp, Robert E.] Rutgers State Univ, Piscataway, NJ 08854 USA.
   [Kopp, Robert E.] Rutgers State Univ, Rutgers Energy Inst, New Brunswick, NJ 08901 USA.
C3 Harvard University; Rutgers University System; Rutgers University New Brunswick; Rutgers University System; Rutgers University New Brunswick
RP Hay, CC (corresponding author), Harvard Univ, Cambridge, MA 02138 USA.
EM carlinghay@fas.harvard.edu
FU US National Science Foundation [ARC-1203414, ARC-1203415]; New Jersey Sea Grant Consortium; National Oceanic and Atmospheric Administration (NJSGC) [6410-0012]; Rutgers University; Harvard University; Directorate For Geosciences; Office of Polar Programs (OPP) [1203414] Funding Source: National Science Foundation; Office of Polar Programs (OPP); Directorate For Geosciences [1203415] Funding Source: National Science Foundation
NR 46
TC 431
Z9 512
U1 4
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 JAN 22
PY 2015
VL 517
IS 7535
BP 481
EP +
DI 10.1038/nature14093
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AZ4MU
UT WOS:000348196500033
PM 25629092
DA 2026-03-09
ER

PT J
AU Zhao, ML
   Wu, SP
   Zhou, QJ
   Vivona, S
   Cipriano, DJ
   Cheng, YF
   Brunger, AT
AF Zhao, Minglei
   Wu, Shenping
   Zhou, Qiangjun
   Vivona, Sandro
   Cipriano, Daniel J.
   Cheng, Yifan
   Brunger, Axel T.
TI Mechanistic insights into the recycling machine of the SNARE complex
SO NATURE
LA English
DT Article
ID sensitive factor nsf; crystal-structure; electron-microscopy; conformational-changes; terminal domain; alpha-snap; aaa atpase; fusion; proteins; resolution
AB Evolutionarily conserved SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptors) proteins form a complex that drives membrane fusion in eukaryotes. The ATPase NSF (N-ethylmaleimide sensitive factor), together with SNAPs (soluble NSF attachment protein), disassembles the SNARE complex into its protein components, making individual SNAREs available for subsequent rounds of fusion. Here we report structures of ATP- and ADP-bound NSF, and the NSF/SNAP/SNARE (20S) supercomplex determined by single-particle electron cryomicroscopy at nearatomic to sub-nanometre resolution without imposing symmetry. Large, potentially force-generating, conformational differences exist between ATP- and ADP-bound NSF. The 20S supercomplex exhibits broken symmetry, transitioning fromsix-fold symmetry of the NSF ATPase domains to pseudo four-fold symmetry of the SNARE complex. SNAPs interact with the SNARE complex with an opposite structural twist, suggesting an unwinding mechanism. The interfaces between NSF, SNAPs, and SNAREs exhibit characteristic electrostatic patterns, suggesting how one NSF/SNAP species can act on many different SNARE complexes.
C1 [Zhao, Minglei; Zhou, Qiangjun; Vivona, Sandro; Cipriano, Daniel J.; Brunger, Axel T.] Stanford Univ, Howard Hughes Med Inst, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
   [Wu, Shenping; Cheng, Yifan] Univ Calif San Francisco, Dept Biochem & Biophys, Keck Adv Microscopy Lab, San Francisco, CA 94158 USA.
   [Brunger, Axel T.] Stanford Univ, Dept Neurol & Neurol Sci, Dept Biol Struct, Dept Photon Sci, Stanford, CA 94305 USA.
C3 Stanford University; Howard Hughes Medical Institute; University of California System; University of California San Francisco; Stanford University
RP Brunger, AT (corresponding author), Stanford Univ, Howard Hughes Med Inst, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
EM ycheng@ucsf.edu; brunger@stanford.edu
FU National Institutes of Health [R37MH63105, 5-U01AI082051-05, R01GM082893, R01GM098672, P50GM082250]
NR 66
TC 213
Z9 267
U1 0
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 FEB 5
PY 2015
VL 518
IS 7537
BP 61
EP +
DI 10.1038/nature14148
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7LE
UT WOS:000349098000031
PM 25581794
DA 2026-03-09
ER

PT J
AU Locke, AE
   Kahali, B
   Berndt, SI
   Justice, AE
   Pers, TH
   Felix, R
   Powell, C
   Vedantam, S
   Buchkovich, ML
   Yang, J
   Croteau-Chonka, DC
   Esko, T
   Fall, T
   Ferreira, T
   Gustafsson, S
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   Luan, JA
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   Winkler, TW
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   Bragg-Gresham, L
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   Demirkan, A
   Deng, GH
   Ehret, GB
   Feenstra, B
   Feitosa, MF
   Fischer, K
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   Jackson, AU
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   Kinnunen, L
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   Kratzer, W
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   Leander, K
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   Lichtner, P
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   Lindström, J
   Lo, KS
   Lobbens, S
   Lorbeer, R
   Lu, YC
   Mach, F
   Magnusson, PKE
   Mahajan, A
   McArdle, WL
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   Menni, C
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   Stirrups, K
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   Gudnason, V
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   Jöckel, KH
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   Jukema, JW
   Jula, AM
   Kaprio, J
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   Knekt, P
   Kooner, JS
   Kooperberg, C
   Kovacs, P
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   Langenberg, C
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   Lehtimäki, T
   Lyssenko, V
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   Marette, A
   Matise, TC
   McKenzie, CA
   McKnight, B
   Moll, FL
   Morris, AD
   Morris, AP
   Murray, JC
   Nelis, M
   Ohlsson, C
   Oldehinkel, AJ
   Ong, KK
   Madden, PAF
   Pasterkamp, G
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   Peters, A
   Postma, DS
   Pramstaller, PP
   Price, JF
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   Musk, Arthur W.
   Nagaraja, Ramaiah
   Noethen, Markus M.
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   Pilz, Stefan
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   Scholtens, Salome
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   Seufferlein, Thomas
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   Smith, Albert Vernon
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   Stanton, Alice V.
   Steinthorsdottir, Valgerdur
   Stirrups, Kathleen
   Stringham, Heather M.
   Sundstrom, Johan
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   Tan, Sian-Tsung
   Tayo, Bamidele O.
   Thorand, Barbara
   Thorleifsson, Gudmar
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   Vandenput, Liesbeth
   Verhulst, Frank C.
   Vermeulen, Sita H.
   Verweij, Niek
   Vonk, Judith M.
   Waite, Lindsay L.
   Warren, Helen R.
   Waterworth, Dawn
   Weedon, Michael N.
   Wilkens, Lynne R.
   Willenborg, Christina
   Wilsgaard, Tom
   Wojczynski, Mary K.
   Wong, Andrew
   Wrightl, Alan F.
   Zhang, Qunyuan
   Brennan, Eoin P.
   Choi, Murim
   Dastani, Zari
   Drong, Alexander W.
   Eriksson, Per
   Franco-Cereceda, Anders
   Gadin, Jesper R.
   Gharavi, Ali G.
   Goddard, Michael E.
   Handsaker, Robert E.
   Huang, Jinyan
   Karpe, Fredrik
   Kathiresan, Sekar
   Keildson, Sarah
   Kiryluk, Krzysztof
   Kubo, Michiaki
   Lee, Jong-Young
   Liang, Liming
   Lifton, Richard P.
   Ma, Baoshan
   McCarroll, Steven A.
   McKnight, Amy J.
   Min, Josine L.
   Moffatt, Miriam F.
   Montgomery, Grant W.
   Murabito, Joanne M.
   Nicholson, George
   Nyholt, Dale R.
   Okada, Yukinori
   Perry, John R. B.
   Dorajoo, Rajkumar
   Reinmaa, Eva
   Salem, Rany M.
   Sandholm, Niina
   Scott, Robert A.
   Stolk, Lisette
   Takahashi, Atsushi
   Tanaka, Toshihiro
   van 't Hooft, Ferdinand M.
   Vinkhuyzen, Anna A. E.
   Westra, Harm-Jan
   Zheng, Wei
   Zondervan, Krina T.
   Heath, Andrew C.
   Arveiler, Dominique
   Bakker, Stephan J. L.
   Beilby, John
   Bergman, Richard N.
   Blangero, John
   Bovet, Pascal
   Campbell, Harry
   Caulfield, Mark J.
   Cesana, Giancarlo
   Chakravarti, Aravinda
   Chasman, Daniel I.
   Chines, Peter S.
   Collins, Francis S.
   Crawford, Dana C.
   Cupples, L. Adrienne
   Cusi, Daniele
   Danesh, John
   de Faire, Ulf
   den Ruijter, Hester M.
   Dominiczak, Anna F.
   Erbel, Raimund
   Erdmann, Jeanette
   Eriksson, Johan G.
   Farrall, Martin
   Felix, Stephan B.
   Ferrannini, Ele
   Ferrieres, Jean
   Ford, Ian
   Forouhi, Nita G.
   Forrester, Terrence
   Franco, Oscar H.
   Gansevoort, Ron T.
   Gejman, Pablo V.
   Gieger, Christian
   Gottesman, Omri
   Gudnason, Vilmundur
   Gyllensten, Ulf
   Hall, Alistair S.
   Harris, Tamara B.
   Hattersley, Andrew T.
   Hicks, Andrew A.
   Hindorff, Lucia A.
   Hingorani, Aroon D.
   Hofman, Albert
   Homuth, Georg
   Hovingh, G. Kees
   Humphries, Steve E.
   Hunt, Steven C.
   Hypponen, Elina
   Illig, Thomas
   Jacobs, Kevin B.
   Jarvelin, Marjo-Riitta
   Joeckel, Karl-Heinz
   Johansen, Berit
   Jousilahti, Pekka
   Jukema, J. Wouter
   Jula, Antti M.
   Kaprio, Jaakko
   Kastelein, John J. P.
   Keinanen-Kiukaanniemi, Sirkka M.
   Kiemeney, Lambertus A.
   Knekt, Paul
   Kooner, Jaspal S.
   Kooperberg, Charles
   Kovacs, Peter
   Kraja, Aldi T.
   Kumari, Meena
   Kuusisto, Johanna
   Lakka, Timo A.
   Langenberg, Claudia
   Le Marchand, Laic
   Lehtimaki, Terho
   Lyssenko, Valeriya
   Mannisto, Satu
   Marette, Andre
   Matise, Tara C.
   McKenzie, Colin A.
   McKnight, Barbara
   Moll, Frans L.
   Morris, Andrew D.
   Morris, Andrew P.
   Murray, Jeffrey C.
   Nelis, Mari
   Ohlsson, Claes
   Oldehinkel, Albertine J.
   Ong, Ken K.
   Madden, Pamela A. F.
   Pasterkamp, Gerard
   Peden, John F.
   Peters, Annette
   Postma, Dirkje S.
   Pramstaller, Peter P.
   Price, Jackie F.
   Qi, Lu
   Raitakari, Olli T.
   Rankinen, Tuomo
   Rao, D. C.
   Rice, Treva K.
   Ridker, Paul M.
   Rioux, John D.
   Ritchie, Marylyn D.
   Rudan, Igor
   Salomaa, Veikko
   Samani, Nilesh J.
   Saramines, Jouko
   Sarzynski, Mark A.
   Schunkert, Heribert
   Schwarz, Peter E. H.
   Sever, Peter
   Shuldiner, Alan R.
   Sinisalo, Juha
   Stolk, Ronald P.
   Strauch, Konstantin
   Toenjes, Anke
   Tregouet, David-Alexandre
   Tremblay, Angelo
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   Mohlke, Karen L.
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   Beckmann, Jacques S.
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   Speliotes, Elizabeth K.
TI Genetic studies of body mass index yield new insights for obesity biology
SO NATURE
LA English
DT Article
ID genome-wide association; provides insights; glycemic traits; loci; metaanalysis; variants; individuals; hippocampal; architecture; topiramate
AB Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in upto 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for similar to 2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous systemin obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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   [Scherag, Andre] Jena Univ Hosp, Clin Epidemiol Integrated Res & Treatment Ctr, CSCC, D-07743 Jena, Germany.
   [Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.
   [Beckmann, Jacques S.] CHUV Univ Hosp, Serv Med Genet, CH-1011 Lausanne, Switzerland.
   [Barroso, Ines] Univ Cambridge, Metab Res Labs, Inst Metab Sci, Addenbrookes Hosp, Cambridge CB2 0QQ, England.
   [Barroso, Ines] Addenbrookes Hosp, Inst Metab Sci, NIHR Cambridge Biomed Res Ctr, Cambridge CB2 0QQ, England.
   [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA.
   [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA.
C3 University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); NIH National Cancer Institute- Division of Cancer Epidemiology & Genetics; University of North Carolina; University of North Carolina Chapel Hill; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Technical University of Denmark; University of North Carolina; University of North Carolina Chapel Hill; University of Queensland; University of Queensland; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; University of Tartu; Karolinska Institutet; Uppsala University; Uppsala University; University of Oxford; Wellcome Centre for Human Genetics; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); Swiss Institute of Bioinformatics; University of Lausanne; Wellcome Trust Sanger Institute; University of Regensburg; University of Exeter; Harvard University; Harvard T.H. Chan School of Public Health; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Groningen; University of Michigan System; University of Michigan; HudsonAlpha Institute for Biotechnology; Erasmus University Rotterdam; Erasmus MC; The Kids Research Institute Australia; University of Western Australia; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); University of Edinburgh; University of Michigan System; University of Michigan; Rutgers University System; Rutgers University New Brunswick; Rutgers University System; Rutgers University New Brunswick; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Imperial College London; Army Medical University; Johns Hopkins University; University of Geneva; Statens Serum Institut; Washington University (WUSTL); University of Oxford; Fred Hutchinson Cancer Center; University of London; Queen Mary University London; Ruprecht Karls University Heidelberg; Ulm University; Finland National Institute for Health & Welfare; University of Hawaii System; Cancer Research Center of Hawaii; Icahn School of Medicine at Mount Sinai; University of London; King's College London; University of Groningen; Erasmus University Rotterdam; Erasmus MC; Erasmus University Rotterdam; Erasmus MC; QIMR Berghofer Medical Research Institute; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); University of Oxford; Imperial College London; Lund University; Skane University Hospital; Umea University; Umea University; University of Eastern Finland; Karolinska Institutet; Washington University (WUSTL); National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); Universitat Greifswald; Greifswald Medical School; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Utrecht University; Utrecht University Medical Center; Utrecht University; Utrecht University Medical Center; University of Groningen; Science Applications International Corporation (SAIC); SAIC-Frederick; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Pasteur Network; Universite de Lille; Institut Pasteur Lille; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite de Lille; Universite de Lille; Imperial College London; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Dalarna University; University of Cambridge; University of San Carlos; Texas Biomedical Research Institute; Queensland University of Technology (QUT); Ulm University; Leipzig University; Leipzig University; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI); University of Groningen; Norwegian University of Science & Technology (NTNU); University of California System; University of California Los Angeles; University of Oxford; University of Oxford; Harokopio University Athens; University of Dundee; University of Helsinki; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); Uppsala University; Karolinska Institutet; Kaiser Permanente; University Hospitals of Leicester NHS Trust; University of Leicester; Glenfield Hospital; University of Regensburg; Universitat Greifswald; Greifswald Medical School; Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE); Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; German Center for Diabetes Research (DZD); Technische Universitat Dresden; Carl Gustav Carus University Hospital; University of Groningen; University of Edinburgh; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI); Framingham Heart Study; Boston University; Vrije Universiteit Amsterdam; German Centre for Cardiovascular Research; Munich Heart Alliance; German Heart Centre Munich; Technical University of Munich; Norwegian University of Science & Technology (NTNU); Vrije Universiteit Amsterdam; University of Western Australia; SciLifeLab; Uppsala University; University of Helsinki; Ulm University; Finnish Institute of Occupational Health; Medical University of Innsbruck; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Uppsala University; Universite de Montreal; Universitat Greifswald; Greifswald Medical School; Icahn School of Medicine at Mount Sinai; University of Bristol; University of Tartu; University of London; University College London; Consiglio Nazionale delle Ricerche (CNR); Istituto di Ricerca Genetica e Biomedica (IRGB-CNR); Technische Universitat Dresden; Carl Gustav Carus University Hospital; University of Munich; University of Munich; Sir Charles Gairdner Hospital; University of Western Australia; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); University of Bonn; University of Bonn; University of Groningen; Vrije Universiteit Amsterdam; Amsterdam University Medical Center; Medical University of Graz; Universitat Greifswald; Greifswald Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Medical University of Graz; University of Southern California; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Icelandic Heart Association; University of Iceland; University of Groningen; Royal College of Surgeons in Ireland - RCSI; Decode Genetics; Imperial College London; Loyola University Chicago; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; University of Cambridge; University of Gothenburg; Erasmus University Rotterdam; Erasmus MC; Radboud University Nijmegen; Radboud University Nijmegen; University of London; Queen Mary University London; GlaxoSmithKline; Glaxosmithkline USA; German Centre for Cardiovascular Research; University of Lubeck; UiT The Arctic University of Tromso; University of London; University College London; University College Dublin; Seoul National University (SNU); Lady Davis Institute; McGill University; Lady Davis Institute; McGill University; Lady Davis Institute; McGill University; Karolinska Institutet; Columbia University; Department of Primary Industries & Regional Development NSW; University of Melbourne; Harvard University; Harvard T.H. Chan School of Public Health; Chinese Academy of Sciences; Shanghai Jiao Tong University; University of Oxford; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; RIKEN; Korea Disease Control & Prevention Agency (KDCA); Korea National Institute of Health (KNIH); Korea CDC Center for Genome Science; Harvard University; Harvard T.H. Chan School of Public Health; Yale University; Howard Hughes Medical Institute; Dalian Maritime University; Queens University Belfast; Boston University; University of Oxford; MRC Harwell; Queensland University of Technology (QUT); RIKEN; Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU); Agency for Science Technology & Research (A*STAR); A*STAR - Genome Institute of Singapore (GIS); Aalto University; University of Helsinki; Helsinki University Central Hospital; Folkhalsan Research Center; RIKEN; Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU); Vanderbilt University; Vanderbilt University; Vanderbilt University; University of Oxford; Washington University (WUSTL); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; University of Groningen; University of Western Australia; Cedars Sinai Medical Center; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); University of Lausanne; University of Milan; Harvard University; Harvard Medical School; Vanderbilt University; Vanderbilt University; Boston University; University of Milan; University of Cambridge; Utrecht University; Utrecht University Medical Center; University of Glasgow; University of Helsinki; University of Helsinki; Helsinki University Central Hospital; Universitat Greifswald; Greifswald Medical School; German Centre for Cardiovascular Research; University of Pisa; University of Pisa; CHU de Toulouse; Universite Federale Toulouse Midi-Pyrenees (ComUE); University of Glasgow; University West Indies Mona Jamaica; NorthShore University Health System; University of Chicago; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI); University of London; University College London; University of Amsterdam; Academic Medical Center Amsterdam; University of London; University College London; Utah System of Higher Education; University of Utah; Adelaide University; University of South Australia; Adelaide University; University of South Australia; South Australian Health & Medical Research Institute (SAHMRI); University of London; University College London; Hannover Medical School; Finland National Institute for Health & Welfare; Imperial College London; University of Oulu; University of Oulu; University of Oulu; University of Oulu; Radboud University Nijmegen; Imperial College London; University of London; University College London; University of Eastern Finland; University of Eastern Finland Hospital; Kuopio University Hospital; University of Eastern Finland; University of Eastern Finland; University of Eastern Finland; University of Eastern Finland Hospital; Kuopio University Hospital; Tampere University; Tampere University; Steno Diabetes Center; Lund University; Laval University; Laval University Hospital; University of Washington; University of Washington Seattle; Utrecht University; Utrecht University Medical Center; University of Liverpool; University of Iowa; Illumina; University of Groningen; Krankenhaus Bozen; University of Turku; University of Turku; Louisiana State University System; Louisiana State University; Pennington Biomedical Research Center; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; University of Split; German Center for Diabetes Research (DZD); Technische Universitat Dresden; Imperial College London; University System of Maryland; University of Maryland Baltimore; University System of Maryland; University of Maryland Baltimore; US Department of Veterans Affairs; Veterans Health Administration (VHA); Geriatric Research Education & Clinical Center; University of Helsinki; Helsinki University Central Hospital; Sorbonne Universite; Institut National de la Sante et de la Recherche Medicale (Inserm); Sorbonne Universite; Institut National de la Sante et de la Recherche Medicale (Inserm); Institut National de la Sante et de la Recherche Medicale (Inserm); Sorbonne Universite; Laval University; University of Milan; IRCCS Centro Cardiologico Monzino; Laval University; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); University of Lausanne; University of North Carolina; University of North Carolina Chapel Hill; Pasteur Network; Universite de Lille; Institut Pasteur Lille; Universite de Lille; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Lille; Utrecht University; Utrecht University Medical Center; Stanford University; Nanyang Technological University; Ulm University; University of Texas System; University of Texas Health Science Center Houston; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard Medical School; Utrecht University; Utrecht University Medical Center; University of Western Australia; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Wake Forest University; SYNLAB Group; University of Copenhagen; Erasmus University Rotterdam; Erasmus MC; Pirkanmaa Hospital District; University of Pennsylvania; University of Glasgow; Icahn School of Medicine at Mount Sinai; University of Iceland; King Abdulaziz University; Danube University Krems; University of Eastern Finland; University of Eastern Finland; University of Eastern Finland Hospital; Kuopio University Hospital; Newcastle University - UK; Universitat Greifswald; Greifswald Medical School; University of Munich; University of Munich; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Utrecht University; Utrecht University Medical Center; King Abdulaziz University; City St Georges, University of London; Oxford University Hospitals NHS Foundation Trust; University of Michigan System; University of Michigan; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); University of Cambridge; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; University of Cambridge; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; University of North Carolina; University of North Carolina Chapel Hill; Icahn School of Medicine at Mount Sinai
RP Speliotes, EK (corresponding author), Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA.
EM joelh@broadinstitute.org; ruth.loos@mssm.edu; espeliot@med.umich.edu
FU ESRC [ES/J023299/1, ES/F02679X/1] Funding Source: UKRI; MRC [MR/K002414/1, G0600717, MC_UP_A100_1003, MC_UU_12015/2, MC_UU_12019/1, MC_UU_12015/5, MC_PC_U127561128, G0601261, MC_U106179472, MC_UU_12015/1, G0902037, MR/N01104X/1, G1000616, MC_UU_12012/1, MC_UU_12013/1, MR/K013351/1, G1001799, G9521010, MR/L003120/1] Funding Source: UKRI; British Heart Foundation [RG/08/008/25291, RG/07/008/23674, FS/14/55/30806, RG/08/014/24067, RG/10/12/28456] Funding Source: researchfish; Cancer Research UK [14136] Funding Source: researchfish; Chief Scientist Office [CZB/4/710, CZB/4/672] Funding Source: researchfish; Economic and Social Research Council [ES/F02679X/1, ES/J023299/1] Funding Source: researchfish; Lundbeck Foundation [R190-2014-3904] Funding Source: researchfish; Medical Research Council [G19/35, G1000616, MC_UU_12015/2, G8802774, MC_UU_12012/1, MR/K002414/1, MR/N01104X/1, G9521010, G0601261, MC_UP_A100_1003, MC_U106179471, MC_UU_12013/1, MC_UU_12012/5/B, MR/L003120/1, G0401527, G0600717B, MC_UU_12019/1, MC_PC_U127561128, MC_U106179472, MR/K006584/1, G1000143, G1001799, G0902037, MC_UU_12013/4, G0100222, MC_UU_12015/5, MR/K013351/1, MC_UU_12015/1, G0600717] Funding Source: researchfish; National Institute for Health Research [NF-SI-0611-10099, NF-SI-0512-10165, NF-SI-0513-10109, NF-SI-0512-10114, NF-SI-0611-10170, NF-SI-0512-10113, NF-SI-0507-10380, NF-SI-0513-10059, NF-SI-0611-10219, NF-SI-0514-10027] Funding Source: researchfish; NNF Center for Basic Metabolic Research [Pers Group, Kilpeläinen Group] Funding Source: researchfish; Novo Nordisk Fonden [NNF13OC0005785, NNF12OC1016467, NNF14OC0010513, NNF15OC0016416, NNF13OC0004839, NNF14OC0009883] Funding Source: researchfish; British Heart Foundation [BHF_RG/10/12/28456, BHF_FS/14/55/30806, BHF_RG/08/014/24067, BHF_RG/08/008/25291, FS/14/55/30806, RG/08/008/25291, RG/10/12/28456, RG/08/014/24067, RG/07/008/23674] Funding Source: Medline; Cancer Research UK [CRUK_14136, 14136] Funding Source: Medline; Chief Scientist Office [CSO_CZB/4/710, CSO_CZB/4/672, CZB/4/672, CZB/4/710] Funding Source: Medline; Medical Research Council [G0902037, MRC_MC_UU_12015/5, MC_UU_12019/1, MRC_MR/N01104X/1, MRC_MC_U106179472, MRC_G1001799, MRC_MC_UU_12013/1, MRC_G9521010, G0600717, MRC_G0401527, G1000616, MRC_MC_UU_12015/1, MRC_MC_UP_A100_1003, MC_U106179472, MRC_G0601261, MC_UU_12013/1, MRC_MC_PC_U127561128, MR/L003120/1, MC_UU_12015/1, G0401527, MRC_MC_UU_12015/2, MC_UU_12015/2, G8802774, MC_PC_U127561128, MRC_MR/K013351/1, MRC_MC_U106179471, MR/K013351/1, MR/K006584/1, MC_UU_12013/4, MC_U106179471, MRC_MC_UU_12019/1, G0601261, MR/N01104X/1, G1000143, MRC_MC_UU_12012/1, MR/K002414/1, MC_UP_A100_1003, MRC_MR/L003120/1, G19/35, MRC_MR/K006584/1, MRC_G1000143, G0100222, MC_UU_12012/1, G9521010, G1001799, MC_UU_12015/5] Funding Source: Medline; NCATS NIH HHS [TL1 TR001066, UL1 TR001067, UL1 TR000124] Funding Source: Medline; NCI NIH HHS [UM1 CA182910, U01 CA164930, UM1 CA182913, P30 CA071789] Funding Source: Medline; NHGRI NIH HHS [U01 HG007419, U01 HG007416, U01 HG007417, U01 HG007376] Funding Source: Medline; NHLBI NIH HHS [K01 HL116770, R01 HL109946, P30 HL107251, T32 HL007824, T32 HL007055, R01 HL117626, R01 HL117078, R01 HL105756] Funding Source: Medline; NIA NIH HHS [R01 AG033193, R01 AG041517, P30 AG010129, U01 AG009740, U01 AG049505, R01 AG025941] Funding Source: Medline; NICHD NIH HHS [P2C HD050924] Funding Source: Medline; NIDA NIH HHS [R21 DA027040] Funding Source: Medline; NIDDK NIH HHS [R01 DK072193, R01 DK075787, R01 DK062370, P30 DK020541, P60 DK020541, U01 DK062370, P30 DK072488, P30 DK063491, P30 DK020572, K23 DK080145, R01 DK093757, R01 DK089256, R01 DK078150, P30 DK056341] Funding Source: Medline; NIGMS NIH HHS [P30 GM103341, T32 GM007814, T32 GM080178, R25 GM062459] Funding Source: Medline; NIMHD NIH HHS [P20 MD006899] Funding Source: Medline; NINDS NIH HHS [R01 NS017950] Funding Source: Medline; Wellcome Trust [100574, WT100574, WT098017, WT084766, 097117, WT098381, WT085235, 085235, WT097117, 098381, 098017, 084766] Funding Source: Medline; National Cancer Institute [P30CA071789] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [R01HL109946, R01HL105756, T32HL007824, T32HL007055] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK020572, R01DK093757, P30DK020541, U01DK062370, R01DK075787, R01DK062370, R01DK072193, P30DK063491] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007814, T32GM080178] Funding Source: NIH RePORTER; National Institute on Aging [R01NS017950, U01AG009740, ZIAAG000675] Funding Source: NIH RePORTER
NR 73
TC 3430
Z9 3885
U1 15
U2 1083
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 12
PY 2015
VL 518
IS 7538
BP 197
EP +
DI 10.1038/nature14177
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300031
PM 25673413
DA 2026-03-09
ER

PT J
AU Vita, N
   Platsaki, S
   Baslé, A
   Allen, SJ
   Paterson, NG
   Crombie, AT
   Murrell, JC
   Waldron, KJ
   Dennison, C
AF Vita, Nicolas
   Platsaki, Semeli
   Basle, Arnaud
   Allen, Stephen J.
   Paterson, Neil G.
   Crombie, Andrew T.
   Murrell, J. Colin
   Waldron, Kevin J.
   Dennison, Christopher
TI A four-helix bundle stores copper for methane oxidation
SO NATURE
LA English
DT Article
ID ellmans reagent; binding; proteins; affinity; metal; monooxygenase; methanobactin; trafficking; mechanisms; expression
AB Methane-oxidizing bacteria (methanotrophs) require large quantities of copper for the membrane-bound (particulate) methane monooxygenase(1,2). Certain methanotrophs are also able to switch to using the iron-containing soluble methane monooxygenase to catalyse methane oxidation, with this switchover regulated by copper(3,4). Methane monooxygenases are nature's primary biological mechanism for suppressing atmospheric levels of methane, a potent greenhouse gas. Furthermore, methanotrophs and methane monooxygenases have enormous potential in bioremediation and for biotransformations producing bulk and fine chemicals, and in bioenergy, particularly considering increased methane availability from renewable sources and hydraulic fracturing of shale rock(5,6). Here we discover and characterize a novel copper storage protein (Csp1) from the methanotroph Methylosinus trichosporium OB3b that is exported from the cytosol, and stores copper for particulate methane monooxygenase. Csp1 is a tetramer of four-helix bundles with each monomer binding up to 13 Cu(I) ions in a previously unseen manner via mainly Cys residues that point into the core of the bundle. Csp1 is the first example of a protein that stores a metal within an established protein-folding motif. This work provides a detailed insight into how methanotrophs accumulate copper for the oxidation of methane. Understanding this process is essential if the wide-ranging biotechnological applications of methanotrophs are to be realized. Cytosolic homologues of Csp1 are present in diverse bacteria, thus challenging the dogma that such organisms do not use copper in this location.
C1 [Vita, Nicolas; Platsaki, Semeli; Basle, Arnaud; Allen, Stephen J.; Waldron, Kevin J.; Dennison, Christopher] Newcastle Univ, Sch Med, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
   [Paterson, Neil G.] Diamond Light Source, Didcot OX11 0DE, Oxon, England.
   [Crombie, Andrew T.; Murrell, J. Colin] Univ E Anglia, Sch Environm Sci, Norwich NR4 7TJ, Norfolk, England.
C3 Newcastle University - UK; Diamond Light Source; University of East Anglia
RP Dennison, C (corresponding author), Newcastle Univ, Sch Med, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
EM christopher.dennison@ncl.ac.uk
FU Biotechnology and Biological Sciences Research Council [BB/K008439/1]; Newcastle University; Sir Henry Dale Fellowship - Wellcome Trust; Royal Society [098375/Z/12/Z]; Biotechnology and Biological Sciences Research Council [BB/K008439/1, BB/F012713/1] Funding Source: researchfish; Natural Environment Research Council [NER/A/S/2002/00876, NE/E016855/1] Funding Source: researchfish; Wellcome Trust [098375/Z/12/Z] Funding Source: researchfish; BBSRC [BB/K008439/1, BB/F012713/1] Funding Source: UKRI; NERC [NE/E016855/1] Funding Source: UKRI
NR 57
TC 78
Z9 95
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 SEP 3
PY 2015
VL 525
IS 7567
BP 140
EP +
DI 10.1038/nature14854
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100041
PM 26308900
DA 2026-03-09
ER

PT J
AU Waddell, N
   Pajic, M
   Patch, AM
   Chang, DK
   Kassahn, KS
   Bailey, P
   Johns, AL
   Miller, D
   Nones, K
   Quek, K
   Quinn, MCJ
   Robertson, AJ
   Fadlullah, MZH
   Bruxner, TJC
   Christ, AN
   Harliwong, I
   Idrisoglu, S
   Manning, S
   Nourse, C
   Nourbakhsh, E
   Wani, S
   Wilson, PJ
   Markham, E
   Cloonan, N
   Anderson, MJ
   Fink, JL
   Holmes, O
   Kazakoff, SH
   Leonard, C
   Newell, F
   Poudel, B
   Song, S
   Taylor, D
   Waddell, N
   Wood, S
   Xu, QY
   Wu, JM
   Pinese, M
   Cowley, MJ
   Lee, HC
   Jones, MD
   Nagrial, AM
   Humphris, J
   Chantrill, LA
   Chin, V
   Steinmann, AM
   Mawson, A
   Humphrey, ES
   Colvin, EK
   Chou, A
   Scarlett, CJ
   Pinho, AV
   Giry-Laterriere, M
   Rooman, I
   Samra, JS
   Kench, JG
   Pettitt, JA
   Merrett, ND
   Toon, C
   Epari, K
   Nguyen, NQ
   Barbour, A
   Zeps, N
   Jamieson, NB
   Graham, JS
   Niclou, SP
   Bjerkvig, R
   Grützmann, R
   Aust, D
   Hruban, RH
   Maitra, A
   Iacobuzio-Donahue, CA
   Wolfgang, CL
   Morgan, RA
   Lawlor, RT
   Corbo, V
   Bassi, C
   Falconi, M
   Zamboni, G
   Tortora, G
   Tempero, MA
   Gill, AJ
   Eshleman, JR
   Pilarsky, C
   Scarpa, A
   Musgrove, EA
   Pearson, JV
   Biankin, AV
   Grimmond, SM
AF Waddell, Nicola
   Pajic, Marina
   Patch, Ann-Marie
   Chang, David K.
   Kassahn, Karin S.
   Bailey, Peter
   Johns, Amber L.
   Miller, David
   Nones, Katia
   Quek, Kelly
   Quinn, Michael C. J.
   Robertson, Alan J.
   Fadlullah, Muhammad Z. H.
   Bruxner, Tim J. C.
   Christ, Angelika N.
   Harliwong, Ivon
   Idrisoglu, Senel
   Manning, Suzanne
   Nourse, Craig
   Nourbakhsh, Ehsan
   Wani, Shivangi
   Wilson, Peter J.
   Markham, Emma
   Cloonan, Nicole
   Anderson, Matthew J.
   Fink, J. Lynn
   Holmes, Oliver
   Kazakoff, Stephen H.
   Leonard, Conrad
   Newell, Felicity
   Poudel, Barsha
   Song, Sarah
   Taylor, Darrin
   Waddell, Nick
   Wood, Scott
   Xu, Qinying
   Wu, Jianmin
   Pinese, Mark
   Cowley, Mark J.
   Lee, Hong C.
   Jones, Marc D.
   Nagrial, Adnan M.
   Humphris, Jeremy
   Chantrill, Lorraine A.
   Chin, Venessa
   Steinmann, Angela M.
   Mawson, Amanda
   Humphrey, Emily S.
   Colvin, Emily K.
   Chou, Angela
   Scarlett, Christopher J.
   Pinho, Andreia V.
   Giry-Laterriere, Marc
   Rooman, Ilse
   Samra, Jaswinder S.
   Kench, James G.
   Pettitt, Jessica A.
   Merrett, Neil D.
   Toon, Christopher
   Epari, Krishna
   Nguyen, Nam Q.
   Barbour, Andrew
   Zeps, Nikolajs
   Jamieson, Nigel B.
   Graham, Janet S.
   Niclou, Simone P.
   Bjerkvig, Rolf
   Gruetzmann, Robert
   Aust, Daniela
   Hruban, Ralph H.
   Maitra, Anirban
   Iacobuzio-Donahue, Christine A.
   Wolfgang, Christopher L.
   Morgan, Richard A.
   Lawlor, Rita T.
   Corbo, Vincenzo
   Bassi, Claudio
   Falconi, Massimo
   Zamboni, Giuseppe
   Tortora, Giampaolo
   Tempero, Margaret A.
   Gill, Anthony J.
   Eshleman, James R.
   Pilarsky, Christian
   Scarpa, Aldo
   Musgrove, Elizabeth A.
   Pearson, John V.
   Biankin, Andrew V.
   Grimmond, Sean M.
TI Whole genomes redefine the mutational landscape of pancreatic cancer
SO NATURE
LA English
DT Article
ID gemcitabine; instability; patterns; adenocarcinoma; chromothripsis; rearrangement; chemotherapy; metaanalysis; folfirinox; pathways
AB Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.
C1 [Waddell, Nicola; Patch, Ann-Marie; Kassahn, Karin S.; Bailey, Peter; Miller, David; Nones, Katia; Quek, Kelly; Quinn, Michael C. J.; Robertson, Alan J.; Fadlullah, Muhammad Z. H.; Bruxner, Tim J. C.; Christ, Angelika N.; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourse, Craig; Nourbakhsh, Ehsan; Wani, Shivangi; Wilson, Peter J.; Markham, Emma; Cloonan, Nicole; Anderson, Matthew J.; Fink, J. Lynn; Holmes, Oliver; Kazakoff, Stephen H.; Leonard, Conrad; Newell, Felicity; Poudel, Barsha; Song, Sarah; Taylor, Darrin; Waddell, Nick; Wood, Scott; Xu, Qinying; Pearson, John V.; Grimmond, Sean M.] Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, Brisbane, Qld 4072, Australia.
   [Waddell, Nicola; Cloonan, Nicole; Pearson, John V.] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia.
   [Pajic, Marina; Chang, David K.; Johns, Amber L.; Wu, Jianmin; Pinese, Mark; Cowley, Mark J.; Lee, Hong C.; Jones, Marc D.; Nagrial, Adnan M.; Humphris, Jeremy; Chantrill, Lorraine A.; Chin, Venessa; Steinmann, Angela M.; Mawson, Amanda; Humphrey, Emily S.; Colvin, Emily K.; Chou, Angela; Scarlett, Christopher J.; Pinho, Andreia V.; Giry-Laterriere, Marc; Rooman, Ilse; Kench, James G.; Pettitt, Jessica A.; Toon, Christopher; Gill, Anthony J.; Biankin, Andrew V.] Univ New S Wales, Kinghorn Canc Ctr, Canc Div, Garvan Inst Med Res, Sydney, NSW 2010, Australia.
   [Pajic, Marina] Univ New S Wales, Fac Med, St Vincents Clin Sch, Sydney, NSW 2010, Australia.
   [Chang, David K.; Merrett, Neil D.; Biankin, Andrew V.] Bankstown Hosp, Dept Surg, Sydney, NSW 2200, Australia.
   [Chang, David K.; Biankin, Andrew V.] Univ New S Wales, Fac Med, South Western Sydney Clin Sch, Liverpool, NSW 2170, Australia.
   [Chang, David K.; Bailey, Peter; Nourse, Craig; Jones, Marc D.; Jamieson, Nigel B.; Graham, Janet S.; Musgrove, Elizabeth A.; Biankin, Andrew V.; Grimmond, Sean M.] Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Glasgow G61 1BD, Lanark, Scotland.
   [Chou, Angela] St Vincents Hosp, Dept Anat Pathol, Sydney, NSW 2010, Australia.
   [Scarlett, Christopher J.] Univ Newcastle, Sch Environm & Life Sci, Ourimbah, NSW 2258, Australia.
   [Samra, Jaswinder S.] Royal N Shore Hosp, Dept Surg, Sydney, NSW 2065, Australia.
   [Samra, Jaswinder S.; Kench, James G.; Gill, Anthony J.] Univ Sydney, Sydney, NSW 2006, Australia.
   [Kench, James G.] Royal Prince Alfred Hosp, Camperdown, NSW 2050, Australia.
   [Merrett, Neil D.] Univ Western Sydney, Sch Med, Penrith, NSW 2175, Australia.
   [Epari, Krishna] Fremantle Hosp, Dept Surg, Fremantle, WA 6160, Australia.
   [Nguyen, Nam Q.] Royal Adelaide Hosp, Dept Gastroenterol, Adelaide, SA 5000, Australia.
   [Barbour, Andrew] Princess Alexandra Hosp, Dept Surg, Woollongabba, Qld 4102, Australia.
   [Zeps, Nikolajs] Univ Western Australia, Sch Surg M507, Nedlands, WA 6009, Australia.
   [Zeps, Nikolajs] St John God Pathol, Subiaco, WA 6008, Australia.
   [Zeps, Nikolajs] St John God Subiaco Hosp, Bendat Family Comprehens Canc Ctr, Subiaco, WA 6008, Australia.
   [Jamieson, Nigel B.] Univ Glasgow, Glasgow Royal Infirm, Coll Med Vet & Life Sci, Acad Unit Surg,Sch Med, Glasgow G4 0SF, Lanark, Scotland.
   [Jamieson, Nigel B.] Glasgow Royal Infirm, West Scotland Pancreat Unit, Glasgow G31 2ER, Lanark, Scotland.
   [Graham, Janet S.] Beatson West Scotland Canc Ctr, Dept Med Oncol, Glasgow G12 0YN, Lanark, Scotland.
   [Niclou, Simone P.] CRP Sante Luxembourg, Norlux Neurooncol Lab, L-1526 Luxembourg, Luxembourg.
   [Bjerkvig, Rolf] Univ Bergen, Dept Biomed, N-5019 Bergen, Norway.
   [Gruetzmann, Robert; Aust, Daniela; Pilarsky, Christian] Tech Univ Dresden, Dept Surg, D-01307 Dresden, Germany.
   [Gruetzmann, Robert; Aust, Daniela; Pilarsky, Christian] Tech Univ Dresden, Dept Pathol, D-01307 Dresden, Germany.
   [Hruban, Ralph H.; Morgan, Richard A.; Eshleman, James R.] Johns Hopkins Univ, Sch Med, Dept Pathol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21231 USA.
   [Maitra, Anirban] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA.
   [Maitra, Anirban] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA.
   [Iacobuzio-Donahue, Christine A.] Mem Sloan Kettering Canc Ctr, David M Rubenstein Pancreat Canc Res Ctr, New York, NY 10065 USA.
   [Iacobuzio-Donahue, Christine A.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA.
   [Wolfgang, Christopher L.] Johns Hopkins Univ, Sch Med, Sol Goldman Pancreat Canc Res Ctr, Dept Surg, Baltimore, MD 21231 USA.
   [Lawlor, Rita T.; Corbo, Vincenzo; Scarpa, Aldo] Univ Verona, ARC NET Ctr Appl Res Canc, I-37134 Verona, Italy.
   [Lawlor, Rita T.; Corbo, Vincenzo; Bassi, Claudio; Falconi, Massimo; Tortora, Giampaolo; Scarpa, Aldo] Hosp Trust Verona, I-37134 Verona, Italy.
   [Lawlor, Rita T.; Zamboni, Giuseppe; Scarpa, Aldo] Univ Verona, Dept Pathol & Diagnost, I-37134 Verona, Italy.
   [Bassi, Claudio; Falconi, Massimo] Univ Verona, Dept Surg & Oncol, Pancreas Inst, I-37134 Verona, Italy.
   [Falconi, Massimo; Zamboni, Giuseppe] Osped Sacro Cuore Don Calabria Negrar, Dept Surg, I-37024 Verona, Italy.
   [Falconi, Massimo; Zamboni, Giuseppe] Osped Sacro Cuore Don Calabria Negrar, Dept Pathol, I-37024 Verona, Italy.
   [Tortora, Giampaolo] Univ Verona, Dept Oncol, I-37134 Verona, Italy.
   [Tempero, Margaret A.] Univ Calif San Francisco, Div Hematol & Oncol, San Francisco, CA 94122 USA.
C3 University of Queensland; QIMR Berghofer Medical Research Institute; University of New South Wales Sydney; The Kinghorn Cancer Centre; Garvan Institute of Medical Research; University of New South Wales Sydney; NSW Health; Bankstown Lidcombe Hospital; University of New South Wales Sydney; University of Glasgow; NSW Health; St Vincents Hospital Sydney; University of Newcastle; Royal North Shore Hospital; University of Sydney; University of Sydney; University of Sydney; NSW Health; Royal Prince Alfred Hospital; Western Sydney University; University of Western Australia; South Metropolitan Health Service; Fiona Stanley Fremantle Hospitals Group; Fremantle Hospital; Royal Adelaide Hospital; Princess Alexandra Hospital; University of Western Australia; St John of God Health Care; St John of God Health Care; St John of God Subiaco Hospital; University of Glasgow; University of Glasgow; Beatson Oncology Centre; Luxembourg Institute of Health; University of Bergen; Technische Universitat Dresden; Technische Universitat Dresden; Johns Hopkins University; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Johns Hopkins University; University of Verona; University of Verona; Azienda Ospedaliera Universitaria Integrata Verona; University of Verona; University of Verona; IRCCS Sacro Cuore Don Calabria; IRCCS Sacro Cuore Don Calabria; University of Verona; University of California System; University of California San Francisco
RP Grimmond, SM (corresponding author), Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, Brisbane, Qld 4072, Australia.
FU National Health and Medical Research Council of Australia (NHMRC) [631701, 535903, 427601]; Queensland Government (NIRAP); University of Queensland; Institute for Molecular Bioscience; Cancer Research UK [C596/A18076, C29717/A17263]; Australian Government: Department of Innovation, Industry, Science and Research (DIISR); Australian Cancer Research Foundation (ACRF); Cancer Council NSW [SRP06-01, SRP11-01. ICGC]; Cancer Institute NSW [10/ECF/2-26, 06/ECF/1-24, 09/CDF/2-40, 07/CDF/1-03, 10/CRF/1-01, 08/RSA/1-15, 07/CDF/1-28, 10/CDF/2-26, 10/FRL/2-03, 06/RSA/1-05, 09/RIG/1-02, 10/TPG/1-04, 11/REG/1-10, 11/CDF/3-26]; Garvan Institute of Medical Research; Avner Nahmani Pancreatic Cancer Research Foundation; University of Glasgow; Howat Foundation; R.T. Hall Trust; Petre Foundation; Philip Hemstritch Foundation; Gastroenterological Society of Australia (GESA); American Association for Cancer Research (AACR) Landon Foundation - INNOVATOR Award; Royal Australasian College of Surgeons (RACS); Royal Australasian College of Physicians (RACP); Royal College of Pathologists of Australasia (RCPA); Italian Ministry of Research (Cancer Genome) [FIRB RBAP10AHJB]; Associazione Italiana Ricerca Cancro [12182]; Fondazione Italiana Malattie Pancreas - Ministero Salute [CUP_J33G13000210001]; Wilhelm Sander Stiftung [2009.039.2]; National Institutes of Health [P50 CA62924]; National Cancer Institute [P30CA006973, P50CA062924] Funding Source: NIH RePORTER; National Health and Medical Research Council (NHMRC) [427601] Funding Source: National Health and Medical Research Council (NHMRC); Academy of Medical Sciences (AMS) [AMS-SGCL9-Jamieson] Funding Source: researchfish; Cancer Research UK [17263] Funding Source: researchfish; Wellcome Trust [103721/Z/14/Z] Funding Source: researchfish
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NR 41
TC 2098
Z9 2413
U1 4
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 FEB 26
PY 2015
VL 518
IS 7540
BP 495
EP 501
DI 10.1038/nature14169
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC1JP
UT WOS:000350097300038
PM 25719666
DA 2026-03-09
ER

PT J
AU Zabidi, MA
   Arnold, CD
   Schernhuber, K
   Pagani, M
   Rath, M
   Frank, O
   Stark, A
AF Zabidi, Muhammad A.
   Arnold, Cosmas D.
   Schernhuber, Katharina
   Pagani, Michaela
   Rath, Martina
   Frank, Olga
   Stark, Alexander
TI Enhancer-core-promoter specificity separates developmental and housekeeping gene regulation
SO NATURE
LA English
DT Article
ID drosophila embryo; transcription; elements; expression; machinery; motifs; trf2; dpe
AB Gene transcription in animals involves the assembly of RNA polymerase II at core promoters and its cell-type-specific activation by enhancers that can be located more distally(1). However, how ubiquitom expression of housekeeping genes is achieved has been less dear. In particular, it is unknown whether ubiquitously active enhancers exist and how developmental and housekeeping gene regulation is separated. An attractive hypothesis is that different core promoters might exhibit an intrinsic specificity to certain enhancers'. This is conceivable, as various core promoter sequence elements are differentially distributed between genes of different functions', including elements that are predominantly found at either developmentally regulated or at housekeeping genes(2-6). Here we show that thousands of enhancers in Drosophila melanogaster S2 and ovarian somatic cells (OSCs) exhibit a marked specificity to one of two core promoters one derived from a ubiquitously expressed ribosomal protein gene and another from a developmentally regulated transcription factor and confirm the existence of these two classes for five additional core promoters from genes with diverse functions. Housekeeping enhancers are active across the two cell types, while developmental enhancers exhibit strong cell-type specificity. Both enhancer classes differ in their genomic distribution, the functions of neighbouring genes, and the core promoter elements of these neighbouring genes. In addition, we identify two transcription factots Dref and Tr that bind and activate housekeeping versus developmental enhancers, respectively. Our results provide evidence for a sequence-encoded enhancer-core-promoter specificity that separates developmental and housekeeping gene regulatory programs for thousands of enhancers and their target genes across the entire genome.
C1 [Zabidi, Muhammad A.; Arnold, Cosmas D.; Schernhuber, Katharina; Pagani, Michaela; Rath, Martina; Frank, Olga; Stark, Alexander] Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria.
C3 Vienna Biocenter (VBC); Research Institute of Molecular Pathology (IMP)
RP Stark, A (corresponding author), Vienna Bioctr VBC, Res Inst Mol Pathol IMP, Dr Bohr Gasse 7, A-1030 Vienna, Austria.
EM stark@starklab.org
FU Austrian Science Fund (FWF) [F4303-B09]; European Research Council [242922]; Boehringer Ingelheim GmbH; European Research Council (ERC) [242922] Funding Source: European Research Council (ERC); Austrian Science Fund (FWF) [W1207] Funding Source: Austrian Science Fund (FWF)
NR 30
TC 337
Z9 427
U1 2
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 FEB 26
PY 2015
VL 518
IS 7540
BP 556
EP 559
DI 10.1038/nature13994
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC1JP
UT WOS:000350097300051
PM 25517091
DA 2026-03-09
ER

PT J
AU Shi, JJ
   Zhao, Y
   Wang, K
   Shi, XY
   Wang, Y
   Huang, HW
   Zhuang, YH
   Cai, T
   Wang, FC
   Shao, F
AF Shi, Jianjin
   Zhao, Yue
   Wang, Kun
   Shi, Xuyan
   Wang, Yue
   Huang, Huanwei
   Zhuang, Yinghua
   Cai, Tao
   Wang, Fengchao
   Shao, Feng
TI Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death
SO NATURE
LA English
DT Article
ID iii secretion apparatus; bacterial flagellin; nlrc4 inflammasome; intracellular lps; activation; mechanisms; receptors; immunity
AB Inflammatory caspases (caspase-1, -4, -5 and -11) are critical for innate defences. Caspase-1 is activated by ligands of various canonical inflammasomes, and caspase-4, -5 and -11 directly recognize bacterial lipopolysaccharide, both of which trigger pyroptosis. Despite the crucial role in immunity and endotoxic shock, the mechanism for pyroptosis induction by inflammatory caspases is unknown. Here we identify gasdermin D (Gsdmd) by genome-wide clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 nuclease screens of caspase-11- and caspase-1-mediated pyroptosis in mouse bone marrow macrophages. GSDMD-deficient cells resisted the induction of pyroptosis by cytosolic lipopolysaccharide and known canonical inflammasome ligands. Interleukin-1 beta release was also diminished in Gsdmd(-/-) cells, despite intact processing by caspase-1. Caspase-1 and caspase-4/5/11 specifically cleaved the linker between the amino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains in GSDMD, which was required and sufficient for pyroptosis. The cleavage released the intramolecular inhibition on the gasdermin-N domain that showed intrinsic pyroptosis-inducing activity. Other gasdermin family members were not cleaved by inflammatory caspases but shared the autoinhibition; gain-of-function mutations in Gsdma3 that cause alopecia and skin defects disrupted the autoinhibition, allowing its gasdermin-N domain to trigger pyroptosis. These findings offer insight into inflammasome-mediated immunity/diseases and also change our understanding of pyroptosis and programmed necrosis.
C1 [Shi, Jianjin] Tsinghua Univ, Peking Univ Tsinghua Univ Natl Inst Biol Sci Join, Sch Life Sci, Beijing 100084, Peoples R China.
   [Shi, Jianjin; Zhao, Yue; Wang, Kun; Shi, Xuyan; Wang, Yue; Huang, Huanwei; Zhuang, Yinghua; Cai, Tao; Wang, Fengchao; Shao, Feng] Natl Inst Biol Sci, Beijing 102206, Peoples R China.
   [Shao, Feng] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China.
   [Shao, Feng] Collaborat Innovat Ctr Canc Med, Natl Inst Biol Sci, Beijing 102206, Peoples R China.
C3 Tsinghua 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.
EM shaofeng@nibs.ac.cn
FU Chinese Academy of Sciences [XDB08020202]; China National Science Foundation Program for Distinguished Young Scholars [31225002]; Program for International Collaborations [31461143006]; National Basic Research Program of China 973 Program [2012CB518700, 2014CB849602]; Howard Hughes Medical Institute; Beijing Scholar Program
NR 32
TC 5273
Z9 5999
U1 63
U2 1443
PU NATURE PUBLISHING 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 29
PY 2015
VL 526
IS 7575
BP 660
EP 665
DI 10.1038/nature15514
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CU8ZH
UT WOS:000363832100040
PM 26375003
DA 2026-03-09
ER

PT J
AU Sigmundsson, F
   Hooper, A
   Hreinsdóttir, S
   Vogfjörd, KS
   Ofeigsson, BG
   Heimisson, ER
   Dumont, S
   Parks, M
   Spaans, K
   Gudmundsson, GB
   Drouin, V
   Arnadóttir, T
   Jónsdóttir, K
   Gudmundsson, MT
   Högnadóttir, T
   Fridriksdóttir, HM
   Hensch, M
   Einarsson, P
   Magnússon, E
   Samsonov, S
   Brandsdóttir, B
   White, RS
   Agústsdóttir, T
   Greenfield, T
   Green, RG
   Hjartardóttir, AR
   Pedersen, R
   Bennett, RA
   Geirsson, H
   La Femina, PC
   Bjornsson, H
   Pálsson, F
   Sturkell, E
   Bean, CJ
   Möllhoff, M
   Braiden, AK
   Eibl, EPS
AF Sigmundsson, Freysteinn
   Hooper, Andrew
   Hreinsdottir, Sigrun
   Vogfjord, Kristin S.
   Ofeigsson, Benedikt G.
   Heimisson, Elias Rafn
   Dumont, Stephanie
   Parks, Michelle
   Spaans, Karsten
   Gudmundsson, Gunnar B.
   Drouin, Vincent
   Arnadottir, Thora
   Jonsdottir, Kristin
   Gudmundsson, Magnus T.
   Hognadottir, Thordis
   Fridriksdottir, Hildur Maria
   Hensch, Martin
   Einarsson, Pall
   Magnusson, Eyjolfur
   Samsonov, Sergey
   Brandsdottir, Bryndis
   White, Robert S.
   Agustsdottir, Thorbjoerg
   Greenfield, Tim
   Green, Robert G.
   Hjartardottir, Asta Rut
   Pedersen, Rikke
   Bennett, Richard A.
   Geirsson, Halldor
   La Femina, Peter C.
   Bjornsson, Helgi
   Palsson, Finnur
   Sturkell, Erik
   Bean, Christopher J.
   Mollhoff, Martin
   Braiden, Aoife K.
   Eibl, Eva P. S.
TI Segmented lateral dyke growth in a rifting event at Bardarbunga volcanic system, Iceland
SO NATURE
LA English
DT Article
ID crustal structure; dike propagation; deformation; magma; constraints; eruption; deflation; collapse; islands; caldera
AB Crust at many divergent plate boundaries forms primarily by the injection of vertical sheet-like dykes, some tens of kilometres long(1). Previous models of rifting events indicate either lateral dyke growth away from a feeding source, with propagation rates decreasing as the dyke lengthens(2-4), or magma flowing vertically into dykes from an underlying source(5,6), with the role of topography on the evolution of lateral dykes not clear. Here we show how a recent segmented dyke intrusion in the Bardarbunga volcanic system grew laterally for more than 45 kilometres at a variable rate, with topography influencing the direction of propagation. Barriers at the ends of each segment were overcome by the build-up of pressure in the dyke end; then a new segment formed and dyke lengthening temporarily peaked. The dyke evolution, which occurred primarily over 14 days, was revealed by propagating seismicity, ground deformation mapped by Global Positioning System(GPS), interferometric analysis of satellite radar images (InSAR), and graben formation. The strike of the dyke segments varies from an initially radial direction away from the Bardarbunga caldera, towards alignment with that expected from regional stress at the distal end. A model minimizing the combined strain and gravitational potential energy explains the propagation path. Dyke opening and seismicity focused at the most distal segment at any given time, and were simultaneous with magma source deflation and slow collapse at the Bardarbunga caldera, accompanied by a series of magnitude M > 5 earthquakes. Dyke growth was slowed down by an effusive fissure eruption near the end of the dyke. Lateral dyke growth with segment barrier breaking by pressure build-up in the dyke distal end explains how focused upwelling of magma under central volcanoes is effectively redistributed over long distances to create new upper crust at divergent plate boundaries.
C1 [Sigmundsson, Freysteinn; Heimisson, Elias Rafn; Dumont, Stephanie; Parks, Michelle; Drouin, Vincent; Arnadottir, Thora; Gudmundsson, Magnus T.; Hognadottir, Thordis; Fridriksdottir, Hildur Maria; Einarsson, Pall; Magnusson, Eyjolfur; Brandsdottir, Bryndis; Hjartardottir, Asta Rut; Pedersen, Rikke; Bjornsson, Helgi; Palsson, Finnur] Univ Iceland, Inst Earth Sci, Nord Volcanol Ctr, IS-101 Reykjavik, Iceland.
   [Hooper, Andrew; Spaans, Karsten] Univ Leeds, Sch Earth & Environm, Ctr Observat & Modelling Earthquakes & Tecton CCM, Leeds LS2 9JT, W Yorkshire, England.
   [Hreinsdottir, Sigrun] GNS Sci, Lower Hutt 5040, New Zealand.
   [Vogfjord, Kristin S.; Ofeigsson, Benedikt G.; Gudmundsson, Gunnar B.; Jonsdottir, Kristin; Fridriksdottir, Hildur Maria; Hensch, Martin] Iceland Meteorol Off, IS-150 Reykjavik, Iceland.
   [Samsonov, Sergey] Nat Resources Canada, Canada Ctr Mapping & Earth Observat, Ottawa, ON K1A 0EA, Canada.
   [White, Robert S.; Agustsdottir, Thorbjoerg; Greenfield, Tim; Green, Robert G.] Univ Cambridge, Dept Earth Sci, Cambridge CB3 0EZ, England.
   [Bennett, Richard A.] Univ Arizona, Dept Geosci, Tucson, AZ 85721 USA.
   [Geirsson, Halldor; La Femina, Peter C.] Penn State Univ, Dept Geosci, University Pk, PA 16802 USA.
   [Sturkell, Erik] Univ Gothenburg, Dept Earth Sci, SE-40530 Gothenburg, Sweden.
   [Bean, Christopher J.; Mollhoff, Martin; Braiden, Aoife K.; Eibl, Eva P. S.] Univ Coll Dublin, Sch Geol Sci, Seismol Lab, Dublin 4, Ireland.
C3 University of Iceland; University of Leeds; Earth Sciences New Zealand; GNS Science - New Zealand; Natural Resources Canada; Strategic Policy & Results Sector - Natural Resources Canada; Canada Centre for Mapping & Earth Observation (CCMEO); University of Cambridge; University of Arizona; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; University of Gothenburg; University College Dublin
RP Sigmundsson, F (corresponding author), Univ Iceland, Inst Earth Sci, Nord Volcanol Ctr, IS-101 Reykjavik, Iceland.
EM fs@hi.is
FU European Community [308377]; Icelandic Research Fund; Research Fund at the University of Iceland; NERC; Geological Survey of Ireland; US National Science Foundation (NSF); Committee on Earth Observing Satellites (CEOS); DLR [IDEM_GEOL0123]; US NSF and National Aeronautics and Space Administration (NASA) under NSF [EAR-0735156, EAR-0711446]; Natural Environment Research Council [NE/F011407/1, NE/M017427/1, NE/H025006/1, 1210874, come30001] Funding Source: researchfish; Directorate For Geosciences; Division Of Earth Sciences [1261833] Funding Source: National Science Foundation; NERC [NE/M017427/1, NE/F011407/1, come30001, NE/H025006/1] Funding Source: UKRI
NR 47
TC 451
Z9 499
U1 2
U2 219
PU NATURE PUBLISHING 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 8
PY 2015
VL 517
IS 7533
BP 191
EP U158
DI 10.1038/nature14111
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600034
PM 25517098
DA 2026-03-09
ER

PT J
AU Kim, JM
   Wu, SP
   Tomasiak, TM
   Mergel, C
   Winter, MB
   Stiller, SB
   Robles-Colmanares, Y
   Stroud, RM
   Tampé, R
   Craik, CS
   Cheng, YF
AF Kim, JungMin
   Wu, Shenping
   Tomasiak, Thomas M.
   Mergel, Claudia
   Winter, Michael B.
   Stiller, Sebastian B.
   Robles-Colmanares, Yaneth
   Stroud, Robert M.
   Tampe, Robert
   Craik, Charles S.
   Cheng, Yifan
TI Subnanometre-resolution electron cryomicroscopy structure of a heterodimeric ABC exporter
SO NATURE
LA English
DT Article
ID p-glycoprotein; multidrug transporter; crystal-structure; microscopy; visualization; conformation; flexibility; proteins; channel; reveal
AB ATP-binding cassette (ABC) transporters translocate substrates across cell membranes, using energy harnessed from ATP binding and hydrolysis at their nucleotide-binding domains(1,2). ABC exporters are present both in prokaryotes and eukaryotes, with examples implicated in multidrug resistance of pathogens and cancer cells, as well as in many human diseases(3,4). TmrAB is a heterodimeric ABC exporter from the thermophilic Gram-negative eubacterium Therm us thermophilus; it is homologous to various multidrug transporters and contains one degenerate site with a non-catalytic residue next to the Walker B motif. Here we report a subnanometre-resolution structure of detergent-solubilized TmrAB in a nucleotide-free, inward-facing conformation by single-particle electron cryomicroscopy. The reconstructions clearly resolve characteristic features of ABC transporters, including helices in the transmembrane domain and nucleotide-binding domains. A cavity in the transmembrane domain is accessible laterally from the cytoplasmic side of the membrane as well as from the cytoplasm, indicating that the transporter lies in an inward-facing open conformation. The two nucleotide-binding domains remain in contact via their carboxy-terminal helices. Furthermore, comparison between our structure and the crystal structures of other ABC transporters suggests a possible trajectory of conformational changes that involves a sliding and rotating motion between the two nucleotide-binding domains during the transition from the inward-facing to outward-facing conformations.
C1 [Kim, JungMin; Winter, Michael B.; Stroud, Robert M.; Craik, Charles S.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA.
   [Wu, Shenping; Tomasiak, Thomas M.; Robles-Colmanares, Yaneth; Stroud, Robert M.; Cheng, Yifan] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA.
   [Mergel, Claudia; Stiller, Sebastian B.; Tampe, Robert] Goethe Univ Frankfurt, Inst Biochem, Bioctr, D-60438 Frankfurt, Germany.
   [Tampe, Robert] Goethe Univ Frankfurt, Cluster Excellence Macromol Complexes, D-60438 Frankfurt, Germany.
C3 University of California System; University of California San Francisco; University of California System; University of California San Francisco; Goethe University Frankfurt; Goethe University Frankfurt
RP Stroud, RM (corresponding author), Goethe Univ Frankfurt, Inst Biochem, Bioctr, Max von Laue Str 9, D-60438 Frankfurt, Germany.
EM stroud@msg.ucsf.edu; tampe@em.uni-frankfurt.de; Charles.Craik@ucsf.edu; ycheng@ucsf.edu
FU National Institutes of Health [R01GM098672, S10RR026814, P50GM082250, 1 P41CA196276-01, P50GM073210, R37GM024485]; University of California San Francisco Program for Breakthrough Biomedical Research; German Research Foundation [SFB 807, SFB 902, TA157/7]; European Drug Initiative on Channels and Transporters (EDICT) - European Commission Seventh Framework Program; National Institute of General Medical Sciences [R01GM024485] Funding Source: NIH RePORTER
NR 40
TC 96
Z9 114
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 JAN 15
PY 2015
VL 517
IS 7534
BP 396
EP U598
DI 10.1038/nature13872
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300052
PM 25363761
DA 2026-03-09
ER

PT J
AU Prindle, A
   Liu, JT
   Asally, M
   Ly, S
   Garcia-Ojalvo, J
   Süel, GM
AF Prindle, Arthur
   Liu, Jintao
   Asally, Munehiro
   Ly, San
   Garcia-Ojalvo, Jordi
   Sueel, Guerol M.
TI Ion channels enable electrical communication in bacterial communities
SO NATURE
LA English
DT Article
ID bacillus-subtilis; potassium; voltage; protein; mechanism; biofilms; domains; forces; ktrab
AB The study of bacterial ion channels has provided fundamental insights into the structural basis of neuronal signalling; however, the native role of ion channels in bacteria has remained elusive. Here we show that ion channels conduct long-range electrical signals within bacterial biofilm communities through spatially propagating waves of potassium. These waves result from a positive feedback loop, in which a metabolic trigger induces release of intracellular potassium, which in turn depolarizes neighbouring cells. Propagating through the biofilm, this wave of depolarization coordinates metabolic states among cells in the interior and periphery of the biofilm. Deletion of the potassium channel abolishes this response. As predicted by a mathematical model, we further show that spatial propagation can be hindered by specific genetic perturbations to potassium channel gating. Together, these results demonstrate a function for ion channels in bacterial biofilms, and provide a prokaryotic paradigm for active, long-range electrical signalling in cellular communities.
C1 [Prindle, Arthur; Liu, Jintao; Ly, San; Sueel, Guerol M.] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA.
   [Asally, Munehiro] Univ Warwick, Sch Life Sci, Warwick Integrat Synthet Biol Ctr, Coventry CV4 7AL, W Midlands, England.
   [Garcia-Ojalvo, Jordi] Univ Pompeu Fabra, Dept Expt & Hlth Sci, Barcelona 08003, Spain.
C3 University of California System; University of California San Diego; University of Warwick; Pompeu Fabra University
RP Süel, GM (corresponding author), Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA.
EM gsuel@ucsd.edu
FU Ministerio de Economia y Competitividad (Spain); FEDER [FIS2012-37655-C02-01]; ICREA Academia Programme; National Institutes of Health, National Institute of General Medical Sciences [R01 GM088428]; National Science Foundation [MCB-1450867 50867]; San Diego Center for Systems Biology (NIH) [P50 GM085764]; Div Of Molecular and Cellular Bioscience; Direct For Biological Sciences [1450867] Funding Source: National Science Foundation
NR 46
TC 571
Z9 689
U1 10
U2 416
PU NATURE PUBLISHING 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 5
PY 2015
VL 527
IS 7576
BP 59
EP 63
DI 10.1038/nature15709
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV4XV
UT WOS:000364270700042
PM 26503040
DA 2026-03-09
ER

PT J
AU Puente, XS
   Beà, S
   Valdés-Mas, R
   Villamor, N
   Gutiérrez-Abril, J
   Martín-Subero, JI
   Munar, M
   Rubio-Pérez, C
   Jares, P
   Aymerich, M
   Baumann, T
   Beekman, R
   Belver, L
   Carrio, A
   Castellano, G
   Clot, G
   Colado, E
   Colomer, D
   Costa, D
   Delgado, J
   Enjuanes, A
   Estivill, X
   Ferrando, AA
   Gelpí, JL
   González, B
   González, S
   González, M
   Gut, M
   Hernández-Rivas, JM
   López-Guerra, M
   Martín-García, D
   Navarro, A
   Nicolás, P
   Orozco, M
   Payer, AR
   Pinyol, M
   Pisano, DG
   Puente, DA
   Queirós, AC
   Quesada, V
   Romeo-Casabona, CM
   Royo, C
   Royo, R
   Rozman, M
   Russiñol, N
   Salaverría, I
   Stamatopoulos, K
   Stunnenberg, HG
   Tamborero, D
   Terol, MJ
   Valencia, A
   López-Bigas, N
   Torrents, D
   Gut, I
   López-Guillermo, A
   López-Otín, C
   Campo, E
AF Puente, Xose S.
   Bea, Silvia
   Valdes-Mas, Rafael
   Villamor, Neus
   Gutierrez-Abril, Jesus
   Martin-Subero, Jose I.
   Munar, Marta
   Rubio-Perez, Carlota
   Jares, Pedro
   Aymerich, Marta
   Baumann, Tycho
   Beekman, Renee
   Belver, Laura
   Carrio, Anna
   Castellano, Giancarlo
   Clot, Guillem
   Colado, Enrique
   Colomer, Dolors
   Costa, Dolors
   Delgado, Julio
   Enjuanes, Anna
   Estivill, Xavier
   Ferrando, Adolfo A.
   Gelpi, Josep L.
   Gonzalez, Blanca
   Gonzalez, Santiago
   Gonzalez, Marcos
   Gut, Marta
   Hernandez-Rivas, Jesus M.
   Lopez-Guerra, Monica
   Martin-Garcia, David
   Navarro, Alba
   Nicolas, Pilar
   Orozco, Modesto
   Payer, Angel R.
   Pinyol, Magda
   Pisano, David G.
   Puente, Diana A.
   Queiros, Ana C.
   Quesada, Victor
   Romeo-Casabona, Carlos M.
   Royo, Cristina
   Royo, Romina
   Rozman, Maria
   Russinol, Nuria
   Salaverria, Itziar
   Stamatopoulos, Kostas
   Stunnenberg, Hendrik G.
   Tamborero, David
   Terol, Maria J.
   Valencia, Alfonso
   Lopez-Bigas, Nuria
   Torrents, David
   Gut, Ivo
   Lopez-Guillermo, Armando
   Lopez-Otin, Carlos
   Campo, Elias
TI Non-coding recurrent mutations in chronic lymphocytic leukaemia
SO NATURE
LA English
DT Article
ID dna methylation; notch1 mutations; gene-mutations; cancer; aberrations; evolution; hypermutation; expression; signatures; survival
AB Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 39 region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to >= 4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.
C1 [Puente, Xose S.; Valdes-Mas, Rafael; Gutierrez-Abril, Jesus; Puente, Diana A.; Quesada, Victor; Lopez-Otin, Carlos] Univ Oviedo, Inst Univ Oncol IUOPA, Dept Bioquim & Biol Mol, E-33006 Oviedo, Spain.
   [Bea, Silvia; Beekman, Renee; Castellano, Giancarlo; Clot, Guillem; Martin-Garcia, David; Navarro, Alba; Royo, Cristina; Russinol, Nuria; Salaverria, Itziar] IDIBAPS, Barcelona 08036, Spain.
   [Villamor, Neus; Aymerich, Marta; Carrio, Anna; Colomer, Dolors; Costa, Dolors; Gonzalez, Blanca; Lopez-Guerra, Monica; Rozman, Maria; Campo, Elias] Univ Barcelona, IDIBAPS, Hosp Clin, Unitat Hematol, E-08036 Barcelona, Spain.
   [Martin-Subero, Jose I.; Queiros, Ana C.] Univ Barcelona, Dept Anat Patol Microbiol & Farmacol, E-08036 Barcelona, Spain.
   [Munar, Marta; Gelpi, Josep L.; Gonzalez, Santiago; Orozco, Modesto; Royo, Romina; Torrents, David] Univ Barcelona, Spanish Natl Bioinformat Inst, Programa Conjunto Biol Computac, BSC,IRB, E-08028 Barcelona, Spain.
   [Rubio-Perez, Carlota; Tamborero, David; Lopez-Bigas, Nuria] Univ Pompeu Fabra, Dept Expt & Hlth Sci, Res Unit Biomed Informat, Barcelona 08003, Spain.
   [Jares, Pedro; Enjuanes, Anna; Pinyol, Magda] IDIBAPS, Unidad Genom, Barcelona 08036, Spain.
   [Baumann, Tycho; Delgado, Julio; Lopez-Guillermo, Armando] IDIBAPS, Hosp Clin, Serv Hematol, Barcelona 08036, Spain.
   [Belver, Laura; Ferrando, Adolfo A.] Columbia Univ, Inst Canc Genet, New York, NY 10032 USA.
   [Colado, Enrique; Payer, Angel R.] Hosp Univ Cent Asturias, Serv Hematol, Oviedo 33011, Spain.
   [Estivill, Xavier] Pompeu Fabra Univ, Hosp Mar Res Inst IMIM, CRG, Barcelona 08003, Spain.
   [Gonzalez, Marcos; Hernandez-Rivas, Jesus M.] Univ Salamanca, Hosp Univ Salamanca, Ctr Invest Canc, Serv Hematol,IBSAL,CSIC, Salamanca 37007, Spain.
   [Gut, Marta; Gut, Ivo] Ctr Nacl Anal Genom, Barcelona 08028, Spain.
   [Nicolas, Pilar; Romeo-Casabona, Carlos M.] Univ Basque Country, Univ Deusto, Catedra Interuniv Derecho & Genoma Humano, Bilbao 48007, Spain.
   [Pisano, David G.; Valencia, Alfonso] Spanish Natl Bioinformat Inst, Spanish Natl Canc Res Ctr CNIO, Struct Biol & Biocomp Programme, Madrid 28029, Spain.
   [Stamatopoulos, Kostas] Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki 57001, Greece.
   [Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, Nijmegen Ctr Mol Life Sci, Fac Sci, Dept Mol Biol, NL-6500 HB Nijmegen, Netherlands.
   [Terol, Maria J.] Hosp Clin Valencia, Serv Hematol, Valencia 46010, Spain.
C3 University of Oviedo; Instituto Universitario de Oncologia de Asturias; University of Barcelona; Hospital Clinic de Barcelona; IDIBAPS; University of Barcelona; Hospital Clinic de Barcelona; IDIBAPS; University of Barcelona; Barcelona Institute of Science & Technology; Institute for Research in Biomedicine - IRB Barcelona; University of Barcelona; Pompeu Fabra University; University of Barcelona; Hospital Clinic de Barcelona; IDIBAPS; University of Barcelona; Hospital Clinic de Barcelona; IDIBAPS; Columbia University; Central University Hospital Asturias; Hospital del Mar Research Institute; Hospital del Mar; Barcelona Institute of Science & Technology; Pompeu Fabra University; Centre de Regulacio Genomica (CRG); University of Salamanca; Consejo Superior de Investigaciones Cientificas (CSIC); University of Basque Country; University of Deusto; Centro Nacional de Investigaciones Oncologicas (CNIO); Centre for Research & Technology Hellas; Radboud University Nijmegen
RP López-Otín, C (corresponding author), Univ Oviedo, Inst Univ Oncol IUOPA, Dept Bioquim & Biol Mol, E-33006 Oviedo, Spain.
EM ecampo@clinic.ub.es
FU Spanish Ministry of Economy and Competitiveness through the Instituto de Salud Carlos III (ISCIII); Red Tematica de Investigacion del Cancer (RTICC); Banco Santander through its Santander Universities Global Division
NR 55
TC 712
Z9 802
U1 1
U2 101
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 22
PY 2015
VL 526
IS 7574
BP 519
EP U115
DI 10.1038/nature14666
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV1NX
UT WOS:000364026100039
PM 26200345
DA 2026-03-09
ER

PT J
AU Martin, T
   Marugán-Lobón, J
   Vullo, R
   Martín-Abad, H
   Luo, ZX
   Buscalioni, AD
AF Martin, Thomas
   Marugan-Lobon, Jesus
   Vullo, Romain
   Martin-Abad, Hugo
   Luo, Zhe-Xi
   Buscalioni, Angela D.
TI A Cretaceous eutriconodont and integument evolution in early mammals
SO NATURE
LA English
DT Article
ID mammaliaform; follicles; design; skin
AB The Mesozoic era (252-66 million years ago), known as the domain of dinosaurs, witnessed a remarkable ecomorphological diversity of early mammals. The key mammalian characteristics originated during this period and were prerequisite for their evolutionary success after extinction of the non-avian dinosaurs 66 million years ago. Many ecomorphotypes familiar to modern mammal fauna evolved independently early in mammalian evolutionary history. Here we report a 125-million-year-old eutriconodontan mammal from Spain with extraordinary preservation of skin and pelage that extends the record of key mammalian integumentary features into the Mesozoic era. The new mammalian specimen exhibits such typical mammalian features as pelage, mane, pinna, and a variety of skin structures: keratinous dermal scutes, protospines composed of hair-like tubules, and compound follicles with primary and secondary hairs. The skin structures of this new Mesozoic mammal encompass the same combination of integumentary features as those evolved independently in other crown Mammalia, with similarly broad structural variations as in extant mammals. Soft tissues in the thorax and abdomen (alveolar lungs and liver) suggest the presence of a muscular diaphragm. The eutriconodont has molariform tooth replacement, ossified Meckel's cartilage of the middle ear, and specialized xenarthrous articulations of posterior dorsal vertebrae, convergent with extant xenarthran mammals, which strengthened the vertebral column for locomotion.
C1 [Martin, Thomas] Univ Bonn, Steinmann Inst Geol Mineral & Palaontol, D-53115 Bonn, Germany.
   [Marugan-Lobon, Jesus; Martin-Abad, Hugo; Buscalioni, Angela D.] Univ Autonoma Madrid, Fac Ciencias, Dept Biol, Unidad Paleontol, E-28049 Madrid, Spain.
   [Marugan-Lobon, Jesus] Nat Hist Museum Los Angeles Cty, Dinosaur Inst, Los Angeles, CA 90007 USA.
   [Vullo, Romain] Univ Rennes 1, UMR CNRS 6118, Geosci Rennes, F-35042 Rennes, France.
   [Luo, Zhe-Xi] Univ Chicago, Dept Organismal Biol & Anat, Chicago, IL 60637 USA.
C3 University of Bonn; Autonomous University of Madrid; Universite de Rennes; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); University of Chicago
RP Martin, T (corresponding author), Univ Bonn, Steinmann Inst Geol Mineral & Palaontol, Nussallee 8, D-53115 Bonn, Germany.
EM tmartin@uni-bonn.de; zxluo@uchicago.edu; angela.delgado@uam.es
FU Spanish MINECO [CGL-2013-42643 P]; Junta de Comunidades de Castilla-La Mancha
NR 50
TC 77
Z9 92
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 OCT 15
PY 2015
VL 526
IS 7573
BP 380
EP +
DI 10.1038/nature14905
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200041
PM 26469049
DA 2026-03-09
ER

PT J
AU Faller, WJ
   Jackson, TJ
   Knight, JRP
   Ridgway, RA
   Jamieson, T
   Karim, SA
   Jones, C
   Radulescu, S
   Huels, DJ
   Myant, KB
   Dudek, KM
   Casey, HA
   Scopelliti, A
   Cordero, JB
   Vidal, M
   Pende, M
   Ryazanov, AG
   Sonenberg, N
   Meyuhas, O
   Hall, MN
   Bushell, M
   Willis, AE
   Sansom, OJ
AF Faller, William J.
   Jackson, Thomas J.
   Knight, John R. P.
   Ridgway, Rachel A.
   Jamieson, Thomas
   Karim, Saadia A.
   Jones, Carolyn
   Radulescu, Sorina
   Huels, David J.
   Myant, Kevin B.
   Dudek, Kate M.
   Casey, Helen A.
   Scopelliti, Alessandro
   Cordero, Julia B.
   Vidal, Marcos
   Pende, Mario
   Ryazanov, Alexey G.
   Sonenberg, Nahum
   Meyuhas, Oded
   Hall, Michael N.
   Bushell, Martin
   Willis, Anne E.
   Sansom, Owen J.
TI mTORC1-mediated translational elongation limits intestinal tumour initiation and growth
SO NATURE
LA English
DT Article
ID colorectal-cancer; stem-cells; mammalian target; beta-catenin; in-vitro; c-myc; kinase; gene; mtor; inhibition
AB Inactivation of APC is a strongly predisposing event in the development of colorectal cancer(1,2), prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth(3,5), and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP 1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP 1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORCI-56K-eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer.
C1 [Faller, William J.; Ridgway, Rachel A.; Jamieson, Thomas; Karim, Saadia A.; Radulescu, Sorina; Huels, David J.; Myant, Kevin B.; Casey, Helen A.; Scopelliti, Alessandro; Cordero, Julia B.; Vidal, Marcos; Sansom, Owen J.] Canc Res UK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland.
   [Jackson, Thomas J.; Knight, John R. P.; Jones, Carolyn; Dudek, Kate M.; Bushell, Martin; Willis, Anne E.] MRC, Toxicol Unit, Leicester LE1 9HN, Leics, England.
   [Pende, Mario] Inst Necker Enfants Malad, CS 61431, Paris, France.
   [Pende, Mario] INSERM, U1151, F-75014 Paris, France.
   [Pende, Mario] Univ Paris 05, Sorbonne Paris Cite, F-75006 Paris, France.
   [Ryazanov, Alexey G.] Rutgers State Univ, Robert Wood Johnson Med Sch, Dept Pharmacol, Piscataway, NJ 08854 USA.
   [Sonenberg, Nahum] McGill Univ, Dept Biochem, Montreal, PQ H3A 1A3, Canada.
   [Sonenberg, Nahum] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3A 1A3, Canada.
   [Meyuhas, Oded] Hebrew Univ Jerusalem, Hadassah Med Sch, IMRIC, Dept Biochem & Mol Biol, IL-91120 Jerusalem, Israel.
   [Hall, Michael N.] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland.
C3 Beatson Institute; University of Leicester; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Rutgers University System; Rutgers University New Brunswick; Rutgers University Biomedical & Health Sciences; McGill University; McGill University; Hebrew University of Jerusalem; University of Basel
RP Sansom, OJ (corresponding author), Canc Res UK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland.
EM o.sansom@beatson.gla.ac.uk
FU AICR; Cancer Research UK; European Research Council; European Union Seventh Framework Programme [278568]; Biotechnology and Biological Sciences Research Council [BB/H024980/1, BB/F018738/2, BB/F02326X/2] Funding Source: researchfish; Cancer Research UK [11594] Funding Source: researchfish; Cancer Research UK; Versus Arthritis [21139] Funding Source: researchfish; Medical Research Council [MC_EX_G0902052, MC_UP_A600_1023, MC_UP_A600_1024] Funding Source: researchfish; National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [G1000078/1] Funding Source: researchfish; Versus Arthritis; Cancer Research UK [20409] Funding Source: researchfish; BBSRC [BB/F02326X/2, BB/H024980/1, BB/F018738/2] Funding Source: UKRI; MRC [MC_UP_A600_1023, MC_EX_G0902052, MC_UP_A600_1024] Funding Source: UKRI
NR 44
TC 240
Z9 284
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 22
PY 2015
VL 517
IS 7535
BP 497
EP +
DI 10.1038/nature13896
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AZ4MU
UT WOS:000348196500037
PM 25383520
DA 2026-03-09
ER

PT J
AU Fernández-Sánchez, ME
   Barbier, S
   Whitehead, J
   Béalle, G
   Michel, A
   Latorre-Ossa, H
   Rey, C
   Fouassier, L
   Claperon, A
   Brullé, L
   Girard, E
   Servant, N
   Rio-Frio, T
   Marie, H
   Lesieur, S
   Housset, C
   Gennisson, JL
   Tanter, M
   Ménager, C
   Fre, S
   Robine, S
   Farge, E
AF Fernandez-Sanchez, Maria Elena
   Barbier, Sandrine
   Whitehead, Joanne
   Bealle, Gaelle
   Michel, Aude
   Latorre-Ossa, Heldmuth
   Rey, Colette
   Fouassier, Laura
   Claperon, Audrey
   Brulle, Laura
   Girard, Elodie
   Servant, Nicolas
   Rio-Frio, Thomas
   Marie, Helene
   Lesieur, Sylviane
   Housset, Chantal
   Gennisson, Jean-Luc
   Tanter, Mickael
   Menager, Christine
   Fre, Silvia
   Robine, Sylvie
   Farge, Emmanuel
TI Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure
SO NATURE
LA English
DT Article
ID shear-wave elastography; superparamagnetic liposm; potent inhibitor; kinase inhibitor; elasticity; ponatinib; cells; model; apc
AB The tumour microenvironment may contribute to tumorigenesis owing to mechanical forces such as fibrotic stiffness or mechanical pressure caused by the expansion of hyper-proliferative cells(1,2). Here we explore the contribution of the mechanical pressure exerted by tumour growth onto non-tumorous adjacent epithelium. In the early stage of mouse colon tumour development in the Notch(+)Apc(+/1638N) mouse model, we observed mechanistic pressure stress in the non-tumorous epithelial cells caused by hyper-proliferative adjacent crypts overexpressing active Notch, which is associated with increased Ret and beta-catenin signalling. We thus developed a method that allows the delivery of a defined mechanical pressure in vivo, by subcutaneously inserting a magnet close to the mouse colon. The implanted magnet generated a magnetic force on ultra-magnetic liposomes, stabilized in the mesenchymal cells of the connective tissue surrounding colonic crypts after intravenous injection. The magnetically induced pressure quantitatively mimicked the endogenous early tumour growth stress in the order of 1,200 Pa, without affecting tissue stiffness, as monitored by ultrasound strain imaging and shear wave elastography. The exertion of pressure mimicking that of tumour growth led to rapid Ret activation and downstream phosphorylation of beta-catenin on Tyr654, imparing its interaction with the E-cadherin in adherens junctions, and which was followed by beta-catenin nuclear translocation after 15 days. As a consequence, increased expression of beta-catenin-target genes was observed at 1 month, together with crypt enlargement accompanying the formation of early tumorous aberrant crypt foci. Mechanical activation of the tumorigenic beta-catenin pathway suggests unexplored modes of tumour propagation based on mechanical signalling pathways in healthy epithelial cells surrounding the tumour, which may contribute to tumour heterogeneity.
C1 [Fernandez-Sanchez, Maria Elena; Barbier, Sandrine; Whitehead, Joanne; Farge, Emmanuel] PSL Res Univ, Inst Curie,Ctr Rech,CNRS,UMR 168, Physicochim Curie Mech & Genet Embryon & Tumour D, INSERM,Fdn Pierre Gilles de Gennes, F-75005 Paris, France.
   [Bealle, Gaelle; Michel, Aude; Menager, Christine] Sorbonne Univ, UPMC, Lab PHENIX Physicochim Electrolytes & Nanosyst In, CNRS UMR 8234, F-75005 Paris, France.
   [Latorre-Ossa, Heldmuth; Gennisson, Jean-Luc; Tanter, Mickael] PSL Res Univ, Waves & Images ESPCI ParisTech, Langevin Inst, CNRS UMR7587,Inserm U979, F-75005 Paris, France.
   [Rey, Colette; Fouassier, Laura; Claperon, Audrey; Housset, Chantal] Sorbonne Univ, UPMC, F-75012 Paris, France.
   [Rey, Colette; Fouassier, Laura; Claperon, Audrey; Housset, Chantal] INSERM, UMR S 938, CDR St Antoine, F-75012 Paris, France.
   [Brulle, Laura] Inst Curie, Ctr Rech, CNRS UMR3666, INSERM Endocyt Trafficking & Therapeut Delivery U, F-75005 Paris, France.
   [Girard, Elodie; Servant, Nicolas] Inst Curie, MINES ParisTech, Bioinformat Platform, U900, F-75005 Paris, France.
   [Rio-Frio, Thomas] Inst Curie, Next Generat Sequencing Platform, F-75005 Paris, France.
   [Marie, Helene; Lesieur, Sylviane] Univ Paris Sud, Lab Physicochim Syst Polyphases, Fac Pharm, CNRS UMR 8612,Inst Galien Paris Sud,LabEx LERMIT, F-92296 Chatenay Malabry, France.
   [Fre, Silvia] Inst Curie, Unite Genet & Biol Dev, Notch Signaling Stem Cells & Tumors, CNRS UMR 3215,INSERM U934,Ctr Rech, F-75005 Paris, France.
   [Robine, Sylvie] Inst Curie, Ctr Rech, CNRS Compartimentat & Dynam Cellulaires Morphogen, F-75005 Paris, France.
C3 Universite PSL; UNICANCER; Institut Curie; Centre National de la Recherche Scientifique (CNRS); Sorbonne Universite; CNRS - Institute of Chemistry (INC); Institut National de la Sante et de la Recherche Medicale (Inserm); Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Chemistry (INC); Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); CNRS - Institute for Engineering & Systems Sciences (INSIS); Universite Paris Cite; Universite PSL; Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI); Sorbonne Universite; Institut National de la Sante et de la Recherche Medicale (Inserm); Sorbonne Universite; Universite Paris Cite; UNICANCER; Universite PSL; Institut Curie; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Chemistry (INC); Universite PSL; MINES ParisTech; UNICANCER; Institut Curie; Institut National de la Sante et de la Recherche Medicale (Inserm); UNICANCER; Universite PSL; Institut Curie; Universite Paris Saclay; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Chemistry (INC); Universite PSL; UNICANCER; Institut Curie; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); CNRS - National Institute for Biology (INSB); UNICANCER; Universite PSL; Institut Curie
RP Farge, E (corresponding author), PSL Res Univ, Inst Curie,Ctr Rech,CNRS,UMR 168, Physicochim Curie Mech & Genet Embryon & Tumour D, INSERM,Fdn Pierre Gilles de Gennes, F-75005 Paris, France.
EM efarge@curie.fr
FU CNRS; INSERM; ARC [5030, 29324]; ANR [09PIRI0013-01, 11 BSV5014-01]; Labex CelTisPhyBio [11-LBX-0038]; Fonds CSP; Fondation Pierre-Gille de Gennes; Fondation de France; Inca [PLBIO13-172]; Agence Nationale de la Recherche (investissements d'avenir) [ANR-10-EQPX-03, ANR10-INBS-09-08]; Canceropole Ile-de-France
NR 51
TC 291
Z9 339
U1 5
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 JUL 2
PY 2015
VL 523
IS 7558
BP 92
EP +
DI 10.1038/nature14329
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL7RN
UT WOS:000357169500038
PM 25970250
DA 2026-03-09
ER

PT J
AU Taylor-Teeples, M
   Lin, L
   de Lucas, M
   Turco, G
   Toal, TW
   Gaudinier, A
   Young, NF
   Trabucco, GM
   Veling, MT
   Lamothe, R
   Handakumbura, PP
   Xiong, G
   Wang, C
   Corwin, J
   Tsoukalas, A
   Zhang, L
   Ware, D
   Pauly, M
   Kliebenstein, DJ
   Dehesh, K
   Tagkopoulos, I
   Breton, G
   Pruneda-Paz, JL
   Ahnert, SE
   Kay, SA
   Hazen, SP
   Brady, SM
AF Taylor-Teeples, M.
   Lin, L.
   de Lucas, M.
   Turco, G.
   Toal, T. W.
   Gaudinier, A.
   Young, N. F.
   Trabucco, G. M.
   Veling, M. T.
   Lamothe, R.
   Handakumbura, P. P.
   Xiong, G.
   Wang, C.
   Corwin, J.
   Tsoukalas, A.
   Zhang, L.
   Ware, D.
   Pauly, M.
   Kliebenstein, D. J.
   Dehesh, K.
   Tagkopoulos, I.
   Breton, G.
   Pruneda-Paz, J. L.
   Ahnert, S. E.
   Kay, S. A.
   Hazen, S. P.
   Brady, S. M.
TI An Arabidopsis gene regulatory network for secondary cell wall synthesis
SO NATURE
LA English
DT Article
ID vascular-related nac-domain6; transcription factors; functional genomics; expression; identification; pathway; myb46; cellulose; division; family
AB The plant cell wall is an important factor for determining cell shape, function and response to the environment. Secondary cell walls, such as those found in xylem, are composed of cellulose, hemicelluloses and lignin and account for the bulk of plant biomass. The coordination between transcriptional regulation of synthesis for each polymer is complex and vital to cell function. A regulatory hierarchy of developmental switches has been proposed, although the full complement of regulators remains unknown. Here we present a protein-DNA network between Arabidopsis thaliana transcription factors and secondary cell wall metabolic genes with gene expression regulated by a series of feed-forward loops. This model allowed us to develop and validate new hypotheses about secondary wall gene regulation under abiotic stress. Distinct stresses are able to perturb targeted genes to potentially promote functional adaptation. These interactions will serve as a foundation for understanding the regulation of a complex, integral plant component.
C1 [Taylor-Teeples, M.; de Lucas, M.; Turco, G.; Toal, T. W.; Gaudinier, A.; Wang, C.; Dehesh, K.; Brady, S. M.] Univ Calif Davis, Dept Plant Biol, Davis, CA 95616 USA.
   [Taylor-Teeples, M.; de Lucas, M.; Turco, G.; Toal, T. W.; Gaudinier, A.; Tsoukalas, A.; Tagkopoulos, I.; Brady, S. M.] Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA.
   [Lin, L.; Young, N. F.; Trabucco, G. M.; Veling, M. T.; Lamothe, R.; Handakumbura, P. P.; Hazen, S. P.] Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA.
   [Xiong, G.; Pauly, M.] Univ Calif Berkeley, Dept Plant & Microbial Biol, Berkeley, CA 94720 USA.
   [Corwin, J.; Kliebenstein, D. J.] Univ Calif Davis, Dept Plant Sci, Davis, CA 95616 USA.
   [Tsoukalas, A.; Tagkopoulos, I.] Univ Calif Davis, Dept Comp Sci, Davis, CA 95616 USA.
   [Zhang, L.; Ware, D.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA.
   [Ware, D.] ARS, USDA, Ithaca, NY 14853 USA.
   [Breton, G.; Pruneda-Paz, J. L.; Kay, S. A.] Univ Calif San Diego, Div Biol Sci, Sect Cell & Dev Biol, La Jolla, CA 92093 USA.
   [Ahnert, S. E.] Univ Cambridge, Cavendish Lab, Theory Condensed Matter Grp, Cambridge CB3 0HE, England.
C3 University of California System; University of California Davis; University of California System; University of California Davis; University of Massachusetts System; University of Massachusetts Amherst; University of California System; University of California Berkeley; University of California System; University of California Davis; University of California System; University of California Davis; Cold Spring Harbor Laboratory; United States Department of Agriculture (USDA); University of California System; University of California San Diego; University of Cambridge
RP Brady, SM (corresponding author), Univ Calif Davis, Dept Plant Biol, One Shields Ave, Davis, CA 95616 USA.
EM hazen@bio.umass.edu; sbrady@ucdavis.edu
FU Office of Science (BER) Department of Energy [DE-FG02-08ER64700DE]; National Institute of General Medical Sciences of the National Institutes of Health [RO1GM056006, RC2GM092412]; National Institute of Health [RO1GM107311]; National Science Foundation [IOS-1036491, IOS-1352478]; USDA CRIS [1907-21000-030]; Royal Society UK Fellowship; UC Davis Startup Funds; Hellman Fellowship; Division Of Integrative Organismal Systems; Direct For Biological Sciences [1127112] Funding Source: National Science Foundation; Div Of Molecular and Cellular Bioscience; Direct For Biological Sciences [1330337] Funding Source: National Science Foundation; National Institute of General Medical Sciences [R01GM107311] Funding Source: NIH RePORTER
NR 53
TC 619
Z9 705
U1 11
U2 636
PU NATURE PUBLISHING 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 29
PY 2015
VL 517
IS 7536
BP 571
EP U307
DI 10.1038/nature14099
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA2ZL
UT WOS:000348775000034
PM 25533953
DA 2026-03-09
ER

PT J
AU Attardo, A
   Fitzgerald, JE
   Schnitzer, MJ
AF Attardo, Alessio
   Fitzgerald, James E.
   Schnitzer, Mark J.
TI Impermanence of dendritic spines in live adult CA1 hippocampus
SO NATURE
LA English
DT Article
ID long-term potentiation; in-vivo; structural plasticity; pyramidal cells; remote memory; resolution; dynamics; stability; neocortex; synapses
AB The mammalian hippocampus is crucial for episodic memory formation(1) and transiently retains information for about 3-4 weeks in adult mice and longer in humans(2). Although neuroscientists widely believe that neural synapses are elemental sites of information storage(3), there has been no direct evidence that hippocampal synapses persist for time intervals commensurate with the duration of hippocampal-dependent memory. Here we tested the prediction that the lifetimes of hippocampal synapses match the longevity of hippocampal memory. By using time-lapse two-photon microendoscopy(4) in the CA1 hippocampal area of live mice, we monitored the turnover dynamics of the pyramidal neurons' basal dendritic spines, postsynaptic structures whose turnover dynamics are thought to reflect those of excitatory synaptic connections(5,6). Strikingly, CA1 spine turnover dynamics differed sharply from those seen previously in the neocortex(7-9). Mathematical modelling revealed that the data best matched kinetic models with a single population of spines with a mean lifetime of approximately 1-2 weeks. This implies similar to 100% turnover in similar to 2-3 times this interval, a near full erasure of the synaptic connectivity pattern. Although N-methyl-D-aspartate (NMDA) receptor blockade stabilizes spines in the neocortex(10,11), in CA1 it transiently increased the rate of spine loss and thus lowered spine density. These results reveal that adult neocortical and hippocampal pyramidal neurons have divergent patterns of spine regulation and quantitatively support the idea that the transience of hippocampal-dependent memory directly reflects the turnover dynamics of hippocampal synapses.
C1 [Attardo, Alessio; Fitzgerald, James E.; Schnitzer, Mark J.] Stanford Univ, James H Clark Ctr Biomed Engn & Sci, Stanford, CA 94305 USA.
   [Attardo, Alessio; Schnitzer, Mark J.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Schnitzer, Mark J.] Stanford Univ, CNC Program, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; Howard Hughes Medical Institute; Stanford University
RP Schnitzer, MJ (corresponding author), Stanford Univ, James H Clark Ctr Biomed Engn & Sci, Stanford, CA 94305 USA.
EM mschnitz@stanford.edu
FU National Institute of Mental Health; National Institute on Aging; Ellison Foundation; National Science Foundation; Stanford Center for Mind, Brain, and Computation; Direct For Biological Sciences; Div Of Biological Infrastructure [1063292] Funding Source: National Science Foundation
NR 34
TC 273
Z9 347
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 JUL 30
PY 2015
VL 523
IS 7562
BP 592
EP +
DI 10.1038/nature14467
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN7ZL
UT WOS:000358655200045
PM 26098371
DA 2026-03-09
ER

PT J
AU Mischiati, M
   Lin, HT
   Herold, P
   Imler, E
   Olberg, R
   Leonardo, A
AF Mischiati, Matteo
   Lin, Huai-Ti
   Herold, Paul
   Imler, Elliot
   Olberg, Robert
   Leonardo, Anthony
TI Internal models direct dragonfly interception steering
SO NATURE
LA English
DT Article
ID sensorimotor integration; prey; insects; mechanisms; prediction; system; motion; eye
AB Sensorimotor control in vertebrates relies on internal models. When extending an arm to reach for an object, the brain uses predictive models of both limb dynamics and target properties. Whether invertebrates use such models remains unclear. Here we examine to what extent prey interception by dragonflies (Plathemis lydia), a behaviour analogous to targeted reaching, requires internal models. By simultaneously tracking the position and orientation of a dragonfly's head and body during flight, we provide evidence that interception steering is driven by forward and inverse models of dragonfly body dynamics and by models of prey motion. Predictive rotations of the dragonfly's head continuously track the prey's angular position. The head-body angles established by prey tracking appear to guide systematic rotations of the dragonfly's body to align it with the prey's flight path. Model-driven control thus underlies the bulk of interception steering manoeuvres, while vision is used for reactions to unexpected prey movements. These findings illuminate the computational sophistication with which insects construct behaviour.
C1 [Mischiati, Matteo; Lin, Huai-Ti; Herold, Paul; Leonardo, Anthony] Howard Hughes Med Inst, Ashburn, VA 20147 USA.
   [Imler, Elliot] Univ Arizona, Dept Neurosci, Tucson, AZ 85721 USA.
   [Olberg, Robert] Union Coll, Schenectady, NY 12308 USA.
C3 Howard Hughes Medical Institute; University of Arizona; Union College
RP Leonardo, A (corresponding author), Howard Hughes Med Inst, Janelia Res Campus,19700 Helix Dr, Ashburn, VA 20147 USA.
EM leonardoa@janelia.hhmi.org
FU Howard Hughes Medical Institute; AFOSR [FA9550-10-1-0472]
NR 32
TC 214
Z9 262
U1 1
U2 131
PU NATURE PUBLISHING 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 15
PY 2015
VL 517
IS 7534
BP 333
EP U410
DI 10.1038/nature14045
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300038
PM 25487153
DA 2026-03-09
ER

PT J
AU Coric, I
   Mercado, BQ
   Bill, E
   Vinyard, DJ
   Holland, PL
AF Coric, Ilija
   Mercado, Brandon Q.
   Bill, Eckhard
   Vinyard, David J.
   Holland, Patrick L.
TI Binding of dinitrogen to an iron-sulfur-carbon site
SO NATURE
LA English
DT Article
ID femo-cofactor; catalytic-reduction; nitrogenase; complexes; ammonia; ligand; n-2; co
AB Nitrogenases are the enzymes by which certain microorganisms convert atmospheric dinitrogen (N-2) to ammonia, thereby providing essential nitrogen atoms for higher organisms. The most common nitrogenases reduce atmospheric N-2 at the FeMo cofactor, a sulfur-rich iron-molybdenum cluster (FeMoco)(1-5). The central iron sites that are coordinated to sulfur and carbon atoms in FeMoco have been proposed to be the substrate binding sites, on the basis of kinetic and spectroscopic studies(5-7). In the resting state, the central iron sites each have bonds to three sulfur atoms and one carbon atom. Addition of electrons to the resting state causes the FeMoco to react with N-2, but the geometry and bonding environment of N-2-bound species remain unknown(5). Here we describe a synthetic complex with a sulfur-rich coordination sphere that, upon reduction, breaks an Fe-S bond and binds N-2. The product is the first synthetic Fe-N-2 complex in which iron has bonds to sulfur and carbon atoms, providing a model for N-2 coordination in the FeMoco. Our results demonstrate that breaking an Fe-S bond is a chemically reasonable route to N-2 binding in the FeMoco, and show structural and spectroscopic details for weakened N-2 on a sulfur-rich iron site.
C1 [Coric, Ilija; Mercado, Brandon Q.; Vinyard, David J.; Holland, Patrick L.] Yale Univ, Dept Chem, New Haven, CT 06520 USA.
   [Bill, Eckhard] Max Planck Inst Chem Energy Convers, D-45470 Mulheim, Germany.
C3 Yale University; Max Planck Society
RP Holland, PL (corresponding author), Yale Univ, Dept Chem, 225 Prospect St, New Haven, CT 06520 USA.
EM patrick.holland@yale.edu
FU National Institutes of Health [GM065313]; Max Planck Society; NSF [CHE-0650456, CNS 08-21132]; National Institute of General Medical Sciences [R01GM065313] Funding Source: NIH RePORTER
NR 30
TC 217
Z9 240
U1 3
U2 303
PU NATURE PUBLISHING 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 1
PY 2015
VL 526
IS 7571
BP 96
EP 99
DI 10.1038/nature15246
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS5CY
UT WOS:000362095100040
PM 26416755
DA 2026-03-09
ER

PT J
AU Hibar, DP
   Stein, JL
   Renteria, ME
   Arias-Vasquez, A
   Desrivières, S
   Jahanshad, N
   Toro, R
   Wittfeld, K
   Abramovic, L
   Andersson, M
   Aribisala, BS
   Armstrong, NJ
   Bernard, M
   Bohlken, MM
   Boks, MP
   Bralten, J
   Brown, AA
   Chakravarty, MM
   Chen, Q
   Ching, CRK
   Cuellar-Partida, G
   den Braber, A
   Giddaluru, S
   Goldman, AL
   Grimm, O
   Guadalupe, T
   Hass, J
   Woldehawariat, G
   Holmes, AJ
   Hoogman, M
   Janowitz, D
   Jia, TY
   Kim, S
   Klein, M
   Kraemer, B
   Lee, PH
   Loohuis, LMO
   Luciano, M
   Macare, C
   Mather, KA
   Mattheisen, M
   Milaneschi, Y
   Nho, K
   Papmeyer, M
   Ramasamy, A
   Risacher, SL
   Roiz-Santiañez, R
   Rose, EJ
   Salami, A
   Sämann, PG
   Schmaal, L
   Schork, AJ
   Shin, J
   Strike, LT
   Teumer, A
   van Donkelaar, MMJ
   van Eijk, KR
   Walters, RK
   Westlye, LT
   Whelan, CD
   Winkler, AM
   Zwiers, MP
   Alhusaini, S
   Athanasiu, L
   Ehrlich, S
   Hakobjan, MMH
   Hartberg, CB
   Haukvik, UK
   Heister, AJGAM
   Hoehn, D
   Kasperaviciute, D
   Liewald, DCM
   Lopez, LM
   Makkinje, RRR
   Matarin, M
   Naber, MAM
   Mckay, DR
   Needham, M
   Nugent, AC
   Pütz, B
   Royle, NA
   Shen, L
   Sprooten, E
   Trabzuni, D
   van der Marel, SSL
   van Hulzen, KJE
   Walton, E
   Wolf, C
   Almasy, L
   Ames, D
   Arepalli, S
   Assareh, AA
   Bastin, ME
   Brodaty, H
   Bulayeva, KB
   Carless, MA
   Cichon, S
   Corvin, A
   Curran, JE
   Czisch, M
   de Zubicaray, GI
   Dillman, A
   Duggirala, R
   Dyer, TD
   Erk, S
   Fedko, IO
   Ferrucci, L
   Foroud, TM
   Fox, PT
   Fukunaga, M
   Gibbs, JR
   Göring, HHH
   Green, RC
   Guelfi, S
   Hansell, NK
   Hartman, CA
   Hegenscheid, K
   Heinz, A
   Hernandez, DG
   Heslenfeld, DJ
   Hoekstra, PJ
   Holsboer, F
   Homuth, G
   Hottenga, JJ
   Ikeda, M
   Jack, CR
   Jenkinson, M
   Johnson, R
   Kanai, R
   Keil, M
   Kent, JW
   Kochunov, P
   Kwok, JB
   Lawrie, SM
   Liu, XM
   Longo, DL
   McMahon, KL
   Meisenzah, E
   Melle, I
   Mahnke, S
   Montgomery, GW
   Mostert, JC
   Mühleisen, TW
   Nalls, MA
   Nichols, TE
   Nilsson, LG
   Nöthen, MM
   Ohi, K
   Olvera, RL
   Perez-Iglesias, R
   Pike, GB
   Potkin, SG
   Reinvang, I
   Reppermund, S
   Rietschel, M
   Romanczuk-Seiferth, N
   Rosen, GD
   Rujescu, D
   Schnell, K
   Schofield, PR
   Smith, C
   Steen, VM
   Sussmann, JE
   Thalamuthu, A
   Toga, AW
   Traynor, BJ
   Troncoso, J
   Turner, JA
   Hernandez, MCV
   van't Ent, D
   van der Brug, M
   van der Wee, NJA
   van Tol, MJ
   Veltman, DJ
   Wassink, TH
   Westman, E
   Zielke, RH
   Zonderman, AB
   Ashbrook, DG
   Hager, R
   Lu, L
   McMahon, FJ
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   Wardlaw, JM
   Weale, ME
   Weinberger, DR
   Adams, HHH
   Launer, LJ
   Seiler, S
   Schmidt, R
   Chauhan, G
   Satizabal, CL
   Becker, JT
   Yanek, L
   van der Lee, SJ
   Ebling, M
   Fischl, B
   Longstreth, WT
   Greve, D
   Schmidt, H
   Nyquist, P
   Vinke, LN
   van Duijn, CM
   Xue, LT
   Mazoyer, B
   Bis, JC
   Gudnason, V
   Seshadri, S
   Ikram, MA
   Martin, NG
   Wright, MJ
   Schumann, G
   Franke, B
   Thompson, PM
   Medland, SE
AF Hibar, Derrek P.
   Stein, Jason L.
   Renteria, Miguel E.
   Arias-Vasquez, Alejandro
   Desrivieres, Sylvane
   Jahanshad, Neda
   Toro, Roberto
   Wittfeld, Katharina
   Abramovic, Lucija
   Andersson, Micael
   Aribisala, Benjamin S.
   Armstrong, Nicola J.
   Bernard, Manon
   Bohlken, Marc M.
   Boks, Marco P.
   Bralten, Janita
   Brown, Andrew A.
   Chakravarty, M. Mallar
   Chen, Qiang
   Ching, Christopher R. K.
   Cuellar-Partida, Gabriel
   den Braber, Anouk
   Giddaluru, Sudheer
   Goldman, Aaron L.
   Grimm, Oliver
   Guadalupe, Tulio
   Hass, Johanna
   Woldehawariat, Girma
   Holmes, Avram J.
   Hoogman, Martine
   Janowitz, Deborah
   Jia, Tianye
   Kim, Sungeun
   Klein, Marieke
   Kraemer, Bernd
   Lee, Phil H.
   Loohuis, Loes M. Olde
   Luciano, Michelle
   Macare, Christine
   Mather, Karen A.
   Mattheisen, Manuel
   Milaneschi, Yuri
   Nho, Kwangsik
   Papmeyer, Martina
   Ramasamy, Adaikalavan
   Risacher, Shannon L.
   Roiz-Santianez, Roberto
   Rose, Emma J.
   Salami, Alireza
   Saemann, Philipp G.
   Schmaal, Lianne
   Schork, Andrew J.
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   Strike, Lachlan T.
   Teumer, Alexander
   van Donkelaar, Marjolein M. J.
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   Walters, Raymond K.
   Westlye, Lars T.
   Whelan, Christopher D.
   Winkler, Anderson M.
   Zwiers, Marcel P.
   Alhusaini, Saud
   Athanasiu, Lavinia
   Ehrlich, Stefan
   Hakobjan, Marina M. H.
   Hartberg, Cecilie B.
   Haukvik, Unn K.
   Heister, Angelien J. G. A. M.
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   Kasperaviciute, Dalia
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   de Geus, Eco J. C.
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   Wardlaw, Joanna M.
   Weale, Michael E.
   Weinberger, Daniel R.
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   Launer, Lenore J.
   Seiler, Stephan
   Schmidt, Reinhold
   Chauhan, Ganesh
   Satizabal, Claudia L.
   Becker, James T.
   Yanek, Lisa
   van der Lee, Sven J.
   Ebling, Maritza
   Fischl, Bruce
   Longstreth, W. T., Jr.
   Greve, Douglas
   Schmidt, Helena
   Nyquist, Paul
   Vinke, Louis N.
   van Duijn, Cornelia M.
   Xue, Luting
   Mazoyer, Bernard
   Bis, Joshua C.
   Gudnason, Vilmundur
   Seshadri, Sudha
   Ikram, M. Arfan
   Martin, Nicholas G.
   Wright, Margaret J.
   Schumann, Gunter
   Franke, Barbara
   Thompson, Paul M., Jr.
   Medland, Sarah E.
TI Common genetic variants influence human subcortical brain structures
SO NATURE
LA English
DT Article
ID genome-wide association; basal ganglia; expression; chromatin; kinectin; identification; hippocampal; evolution; striatum; dynamics
AB The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume(5) and intracranial volume(6). These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 X 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
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   [Ehrlich, Stefan; Gollub, Randy L.; Ebling, Maritza; Fischl, Bruce; Greve, Douglas; Vinke, Louis N.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.
   [Hartberg, Cecilie B.; Agartz, Ingrid] Diakonhjemmet Hosp, Dept Psychiat Res & Dev, N-0319 Oslo, Norway.
   [Kasperaviciute, Dalia; Sisodiya, Sanjay M.] UCL, Inst Neurol, London, England.
   [Kasperaviciute, Dalia; Sisodiya, Sanjay M.] Epilepsy Soc, London WC1N 3BG, England.
   [Kasperaviciute, Dalia] Univ London Imperial Coll Sci Technol & Med, Dept Med, London W12 0NN, England.
   [Matarin, Mar] UCL, Inst Neurol, Dept Clin & Expt Epilepsy, London WC1N 3BG, England.
   [McKay, D. Reese; Sprooten, Emma; Glahn, David C.] Hartford Hosp, Inst Living, Olin Neuropsychiat Res Ctr, Hartford, CT 06106 USA.
   [Trabzuni, Daniah] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia.
   [Almasy, Laura; Carless, Melanie A.; Curran, Joanne E.; Duggirala, Ravi; Dyer, Thomas D.; Goering, Harald H. H.; Kent, Jack W., Jr.; Blangero, John] Texas Biomed Res Inst, San Antonio, TX 78245 USA.
   [Almasy, Laura; Dyer, Thomas D.; Fox, Peter T.; Blangero, John] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA.
   [Ames, David] Royal Melbourne Hosp, Natl Ageing Res Inst, Melbourne, Vic 3052, Australia.
   [Ames, David; Gibbs, J. Raphael; Hernandez, Dena G.] Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic 3101, Australia.
   [Arepalli, Sampath; Dillman, Allissa; Nalls, Michael A.; Traynor, Bryan J.; Cookson, Mark R.; Singleton, Andrew] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA.
   [Bastin, Mark E.; Valdes Hernandez, Maria C.; Wardlaw, Joanna M.] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH4 2XU, Midlothian, Scotland.
   [Bulayeva, Kazima B.] Russian Acad Sci, IN Vavilov Inst Gen Genet, Moscow 119333, Russia.
   [Cichon, Sven] Univ Basel, Dept Biomed, Div Med Genet, CH-4055 Basel, Switzerland.
   [Cichon, Sven; Muehleisen, Thomas W.; Noethen, Markus M.] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany.
   [Cichon, Sven; Muehleisen, Thomas W.] Forschungszentrum Julich, Inst Neurosci & Med INM 1, D-52425 Julich, Germany.
   [Cichon, Sven; Heinz, Andreas; Muehleisen, Thomas W.; Noethen, Markus M.] Univ Bonn, Dept Genom, D-53127 Bonn, Germany.
   [Cichon, Sven; Heinz, Andreas; Muehleisen, Thomas W.; Noethen, Markus M.] Univ Bonn, Life & Brain Ctr, D-53127 Bonn, Germany.
   [Erk, Susanne; Mahnke, Sebastian; Romanczuk-Seiferth, Nina; Walter, Henrik; Saykin, Andrew J.] Charite, CCM, Dept Psychiat & Psychotherapy, D-10117 Berlin, Germany.
   [Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 20892 USA.
   [Foroud, Tatiana M.; Olvera, Rene L.] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA.
   [Fox, Peter T.] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA.
   [Fukunaga, Masaki] Osaka Univ, Immunol Frontier Res Ctr, Biofunct Imaging, Osaka 5650871, Japan.
   [Green, Robert C.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA.
   [Green, Robert C.; Gollub, Randy L.; Smoller, Jordan W.] Harvard Univ, Sch Med, Boston, MA 02115 USA.
   [Hartman, Catharina A.; Hoekstra, Pieter J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9713 GZ Groningen, Netherlands.
   [Hegenscheid, Katrin; Hosten, Norbert] Univ Med Greifswald, Inst Diagnost Radiolou & Neuroradiol, D-17475 Greifswald, Germany.
   [Heslenfeld, Dirk J.] Vrije Univ Amsterdam, Dept Cognit, NL-1081 BT Amsterdam, Netherlands.
   [Heslenfeld, Dirk J.] Vrije Univ Amsterdam, Dept Clin Neuropsychol, NL-1081 BT Amsterdam, Netherlands.
   [Homuth, Georg] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17489 Greifswald, Germany.
   [Ikeda, Masashi] Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi 4701192, Japan.
   [Jack, Clifford R., Jr.] Mayo Clin, Radiol, Rochester, MN 55905 USA.
   [Jenkinson, Mark; Nichols, Thomas E.] Univ Oxford, FMRIB Ctr, Oxford OX3 9DU, England.
   [Johnson, Robert; Zielke, Ronald H.] Univ Maryland, Sch Med, NICHD Brain & Tissue Bank Dev Disorders, Baltimore, MD 21201 USA.
   [Kanai, Ryota] Univ Sussex, Sch Psychol, Brighton BN1 9QH, E Sussex, England.
   [Kanai, Ryota] UCL, Inst Cognit Neurosci, London WC1N 3AR, England.
   [Kochunov, Peter] Univ Maryland, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA.
   [Kwok, John B.; Schofield, Peter R.] Neurosci Res Australia, Sydney, NSW 2031, Australia.
   [Kwok, John B.; Schofield, Peter R.] UNSW, Sch Med Sci, Sydney, NSW 2052, Australia.
   [Liu, Xinmin] Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY 10032 USA.
   [Longo, Dan L.] NIA, Lymphocyte Cell Biol Unit, Genet Lab, NIH, Baltimore, MD 21224 USA.
   [Meisenzah, Eva; Rujescu, Dan] Univ Munich, Dept Psychiat, D-80336 Munich, Germany.
   [Nichols, Thomas E.] Univ Warwick, Dept Stat, Coventry CV4 7AL, W Midlands, England.
   [Nichols, Thomas E.] Univ Warwick, WMG, Coventry CV4 7AL, W Midlands, England.
   [Ohi, Kazutaka] Osaka Univ, Dept Psychiat, Grad Sch Med, Osaka 5650871, Japan.
   [Perez-Iglesias, Rocio] Kings Coll London, Inst Psychiat, London SE5 8AF, England.
   [Pike, G. Bruce] Univ Calgary, Dept Neurol, Calgary, AB T2N 2T9, Canada.
   [Pike, G. Bruce] Univ Calgary, Dept Clin Neurosci, Calgary, AB T2N 2T9, Canada.
   [Potkin, Steven G.] Univ Calif Irvine, Psychiat & Human Behav, Irvine, CA 92617 USA.
   [Rosen, Glenn D.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA.
   [Rosen, Glenn D.] Harvard Univ, Sch Med, Boston, MA 02115 USA.
   [Schnell, Knut] Heidelberg Univ Hosp, Dept Gen Psychiat, D-69115 Heidelberg, Germany.
   [Smith, Colin] Univ Edinburgh, MRC, Sudden Death Brain Bank Project, Dept Neuropathol, Edinburgh EH8 9AG, Midlothian, Scotland.
   [Toga, Arthur W.] Univ So Calif, Keck Sch Med, Inst Neuroimaging & Informat, Lab Neuro Imaging, Los Angeles, CA 90033 USA.
   [Troncoso, Juan] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21287 USA.
   [Turner, Jessica A.] Georgia State Univ, Dept Psychol, Atlanta, GA 30302 USA.
   [Turner, Jessica A.] Georgia State Univ, Neurosci Inst, Atlanta, GA 30302 USA.
   [van der Brug, Marcel] Genentech Inc, San Francisco, CA 94080 USA.
   [van der Wee, Nic J. A.] Leiden Univ, Med Ctr, Psychiat, NL-2333 ZA Leiden, Netherlands.
   [van der Wee, Nic J. A.] Leiden Univ, Med Ctr, Leiden Inst Brain & Cogniton, NL-2333 ZA Leiden, Netherlands.
   [van Tol, Marie-Jose] Univ Groningen, Univ Med Ctr Groningen, Neuroimaging Ctr, NL-9713 AW Groningen, Netherlands.
   [Wassink, Thomas H.] Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA.
   [Westman, Eric] Karolinska Inst, Dept Neurobiol Care Sci & Soc, SE-14183 Stockholm, Sweden.
   [Zonderman, Alan B.] NIA, Behav Epidemiol Sect, Intramural Res Program, Bethesda, MD 20892 USA.
   [Ashbrook, David G.; Hager, Reinmar] Univ Manchester, Fac Life Sci, Manchester M13 9PT, Lancs, England.
   [Lu, Lu; Williams, Robert W.] Univ Tennessee, Hlth Sci Ctr, Ctr Integrat & Translat Genom, Memphis, TN 38163 USA.
   [Lu, Lu; Williams, Robert W.] Univ Tennessee, Hlth Sci Ctr, Dept Genet Genom & Informat, Memphis, TN 38163 USA.
   [Lu, Lu] Nantong Univ, Coll Med, Jiangsu Prov Key Lab Inflammat & Mol Drug Target, Nantong 226001, Peoples R China.
   [Morris, Derek W.; Donohoe, Gary] Natl Univ Ireland Galway, Sch Psychol, Cognit Genet & Therapy Grp, Galway, Ireland.
   [Morris, Derek W.; Donohoe, Gary] Natl Univ Ireland Galway, Discipline Biochem, Galway, Ireland.
   [Brunner, Han G.] Maastricht Univ, Med Ctr, Dept Clin Genet, NL-6200 MD Maastricht, Netherlands.
   [Buckner, Randy L.] Harvard Univ, Ctr Brain Sci, Dept Psychol, Boston, MA 02138 USA.
   [Buitelaar, Jan K.] Radboud Univ Nijmegen, Med Ctr, Karakter Child & Adolescent Psychiat, NL-6500 HB Nijmegen, Netherlands.
   [Calhoun, Vince D.] Mind Res Network, Albuquerque, NM 87106 USA.
   [Calhoun, Vince D.] LBERI, Albuquerque, NM 87106 USA.
   [Calhoun, Vince D.] Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA.
   [Dale, Anders M.] Univ Calif San Diego, Ctr Translat Imaging & Personalized Med, La Jolla, CA 92093 USA.
   [Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92093 USA.
   [Dale, Anders M.] Univ Calif San Diego, Dept Radiol, San Diego, CA 92093 USA.
   [Dale, Anders M.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.
   [Dale, Anders M.] Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92093 USA.
   [Davies, Gareth E.] Avera Inst Human Genet, Sioux Falls, SD 57108 USA.
   [Delanty, Norman] Beaumont Hosp, Neurol Div, Dublin 9, Ireland.
   [Depondt, Chantal; Pandolfo, Massimo] Univ Libre Bruxelles, Hop Erasme, Dept Neurol, B-1070 Brussels, Belgium.
   [Djurovic, Srdjan] Oslo Univ Hosp, Dept Med Genet, N-0450 Oslo, Norway.
   [Drevets, Wayne C.] Johnson & Johnson, Janssen Res & Dev, Titusville, NJ 08560 USA.
   [Ho, Beng-Choon] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA.
   [Mueller-Myhsok, Bertram] Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany.
   [Mueller-Myhsok, Bertram] Univ Liverpool, Inst Translat Med, Liverpool L69 3BX, Merseyside, England.
   [Nauck, Matthias] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany.
   [Weiner, Michael W.] Univ Calif San Francisco, San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA 94121 USA.
   [White, Tonya] Erasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, NL-3000 CB Rotterdam, Netherlands.
   [White, Tonya; Adams, Hieab H. H.; Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Radiol, NL-3015 CN Rotterdam, Netherlands.
   [Agartz, Ingrid; Joensson, Erik G.] Karolinska Inst, Psychiat Sect, Dept Clin Neurosci, SE-17176 Stockholm, Sweden.
   [Cannon, Dara M.; McDonald, Colm] Natl Univ Ireland Galway, Coll Med Nursing & Hlth Sci, Clin Neuroimaging Lab, Galway, Ireland.
   [Grabe, Hans J.] HELIOS Hosp, Dept Psychiat & Psychotherapy, D-18435 Stralsund, Germany.
   [Hashimoto, Ryota] Osaka Univ, United Grad Sch Child Dev, Mol Res Ctr Childrens Mental Dev, Osaka 5650871, Japan.
   [Kloszewska, Iwona] Med Univ Lodz, PL-90419 Lodz, Poland.
   [Lovestone, Simon] Univ Oxford, Dept Psychiat, Oxford OX3 7JX, England.
   [Lovestone, Simon] Kings Coll London, NIHR Dementia Biomed Res Unit, London SE5 8AF, England.
   [Mattay, Venkata S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA.
   [Mecocci, Patrizia] Univ Perugia, Dept Med, Sect Gerontol & Geriat, I-06156 Perugia, Italy.
   [Paus, Tomas] Univ Toronto, Rotman Res Inst, Toronto, ON M6A 2E1, Canada.
   [Paus, Tomas] Univ Toronto, Dept Psychol, Toronto, ON M5T 1R8, Canada.
   [Paus, Tomas] Univ Toronto, Dept Psychiat, Toronto, ON M5T 1R8, Canada.
   [Pausova, Zdenka] Univ Toronto, Dept Physiol, Toronto, ON M5S 3E2, Canada.
   [Pausova, Zdenka] Univ Toronto, Dept Nutr Sci, Toronto, ON M5S 3E2, Canada.
   [Sachdev, Perminder S.] Prince Wales Hosp, Neuropsychiat Inst, Sydney, NSW 2031, Australia.
   [Simmons, Andy] Kings Coll London, Inst Psychiat, Dept Neuroimaging, London SE5 8AF, England.
   [Simmons, Andy] Kings Coll London, Biomed Res Ctr Mental Hlth, London SE5 8AF, England.
   [Simmons, Andy] Kings Coll London, Biomed Res Unit Dementia, London SE5 8AF, England.
   [Soininen, Hilkka] Univ Eastern Finland, Inst Clin Med, Neurol, FI-70211 Kuopio, Finland.
   [Soininen, Hilkka] Kuopio Univ Hosp, Neuroctr Neurol, FI-70211 Kuopio, Finland.
   [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA.
   [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA.
   [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA.
   [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21205 USA.
   [Adams, Hieab H. H.; van der Lee, Sven J.; van Duijn, Cornelia M.; Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CN Rotterdam, Netherlands.
   [Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA.
   [Seiler, Stephan; Schmidt, Reinhold] Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, A-8010 Graz, Austria.
   [Chauhan, Ganesh] Univ Bordeaux, INSERM, U897, F-33076 Bordeaux, France.
   [Satizabal, Claudia L.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.
   [Satizabal, Claudia L.] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.
   [Becker, James T.; Seshadri, Sudha] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15260 USA.
   [Becker, James T.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA.
   [Becker, James T.] Univ Pittsburgh, Dept Psychol, Dietrich Sch Arts & Sci, Pittsburgh, PA 15260 USA.
   [Yanek, Lisa] Johns Hopkins Sch Med, Gen Internal Med, Baltimore, MD 21205 USA.
   [Ebling, Maritza; Fischl, Bruce; Greve, Douglas; Vinke, Louis N.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA.
   [Fischl, Bruce] MIT, Comp Sci & Al Lab, Boston, MA 02141 USA.
   [Longstreth, W. T., Jr.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA.
   [Schmidt, Helena] Med Univ, Inst Mol Biol & Biochem, A-8010 Graz, Austria.
   [Nyquist, Paul] Johns Hopkins Univ, Dept Neurol, Sch Med, Baltimore, MD 21205 USA.
   [Xue, Luting] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.
   [Mazoyer, Bernard] CEA, Grp Imagerie Neurofonct, UMR5296, CNRS, F-33076 Bordeaux, France.
   [Mazoyer, Bernard] Univ Bordeaux, F-33076 Bordeaux, France.
   [Bis, Joshua C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA.
   [Gudnason, Vilmundur] Univ Iceland, Fac Med, Iceland Heart Assoc, IS-101 Reykjavik, Iceland.
C3 University of Southern California; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; QIMR Berghofer Medical Research Institute; Radboud University Nijmegen; Radboud University Nijmegen; Radboud University Nijmegen; Radboud University Nijmegen; University of London; King's College London; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Centre National de la Recherche Scientifique (CNRS); Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Universite Paris Cite; Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE); Universitat Greifswald; Greifswald Medical School; Utrecht University; Utrecht University Medical Center; Umea University; University of Edinburgh; Lagos State University; University of Edinburgh; University of New South Wales Sydney; University of Sydney; University of Toronto; Hospital for Sick Children (SickKids); University of Oslo; University of Oslo; McGill University; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; Vrije Universiteit Amsterdam; Vrije Universiteit Amsterdam; Vrije Universiteit Amsterdam; Amsterdam University Medical Center; University of Bergen; University of Bergen; Haukeland University Hospital; Central Institute of Mental Health; Ruprecht Karls University Heidelberg; Max Planck Society; Technische Universitat Dresden; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH); National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH); Yale University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Indiana University System; Indiana University Bloomington; Indiana University System; Indiana University Bloomington; Indiana University System; Indiana University Bloomington; University of Gottingen; University of Gottingen Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; University of California System; University of California Los Angeles; University of Edinburgh; Aarhus University; Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH); Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH); Aarhus University; Vrije Universiteit Amsterdam; Royal Infirmary of Edinburgh; University of Edinburgh; University of London; King's College London; University of London; University College London; University of London; University College London; Universidad de Cantabria; Hospital Universitario Marques de Valdecilla (HUMV); CIBER - Centro de Investigacion Biomedica en Red; CIBERSAM; Trinity College Dublin; Trinity College Dublin; Karolinska Institutet; Stockholm University; Max Planck Society; University of California System; University of California San Diego; University of California System; University of California San Diego; University of Queensland; University of Queensland; Universitat Greifswald; Greifswald Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Oslo; University of Oxford; Yale University; McGill University; Royal College of Surgeons in Ireland - RCSI; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Diakonhjemmet Hospital; University of London; University College London; Imperial College London; University of London; University College London; Hartford Hospital; King Faisal Specialist Hospital & Research Center; Texas Biomedical Research Institute; University of Texas System; University of Texas at San Antonio; Melbourne Health; Royal Melbourne Hospital; National Ageing Research Institute; University of Melbourne; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); University of Edinburgh; Russian Academy of Sciences; University of Basel; University of Bonn; Helmholtz Association; Julich Research Centre; University of Bonn; University of Bonn; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); Indiana University System; Indiana University Bloomington; US Department of Veterans Affairs; Veterans Health Administration (VHA); Audie L. Murphy Memorial Veterans Hospital; University of Osaka; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; University of Groningen; Universitat Greifswald; Greifswald Medical School; Vrije Universiteit Amsterdam; Vrije Universiteit Amsterdam; Universitat Greifswald; Greifswald Medical School; Fujita Health University; Mayo Clinic; University of Oxford; University System of Maryland; University of Maryland Baltimore; University of Sussex; University of London; University College London; University System of Maryland; University of Maryland Baltimore; Neuroscience Research Australia; University of New South Wales Sydney; Columbia University; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); University of Munich; University of Warwick; University of Warwick; University of Osaka; University of London; King's College London; University of Calgary; University of Calgary; University of California System; University of California Irvine; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard University; Harvard Medical School; Ruprecht Karls University Heidelberg; University of Edinburgh; University of Southern California; Johns Hopkins University; University System of Georgia; Georgia State University; University System of Georgia; Georgia State University; Roche Holding; Roche Holding USA; Genentech; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; University of Groningen; University of Iowa; Karolinska Institutet; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); University of Manchester; University of Tennessee System; University of Tennessee Health Science Center; University of Tennessee System; University of Tennessee Health Science Center; Nantong University; Ollscoil na Gaillimhe-University of Galway; Ollscoil na Gaillimhe-University of Galway; Maastricht University; Harvard University; Radboud University Nijmegen; Lovelace Respiratory Research Institute; Mind Research Network; Lovelace Respiratory Research Institute; Lovelace Biomedical & Environmental Research Institute; University of New Mexico; 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; University of California System; University of California San Diego; University of California System; University of California San Diego; Beaumont Hospital Dublin; Universite Libre de Bruxelles; University of Oslo; Johnson & Johnson; Johnson & Johnson USA; Janssen Pharmaceuticals; University of Iowa; University of Munich; University of Liverpool; Universitat Greifswald; Greifswald Medical School; University of California System; University of California San Francisco; US Department of Veterans Affairs; Veterans Health Administration (VHA); San Francisco VA Medical Center; Erasmus University Rotterdam; Erasmus MC; Erasmus University Rotterdam; Erasmus MC; Karolinska Institutet; Ollscoil na Gaillimhe-University of Galway; University of Osaka; Medical University Lodz; University of Oxford; University of London; King's College London; Johns Hopkins University; University of Perugia; University of Toronto; Baycrest; University of Toronto; University of Toronto; University of Toronto; University of Toronto; University of New South Wales Sydney; Prince of Wales Hospital (POWH); University of London; King's College London; University of London; King's College London; University of London; King's College London; University of Eastern Finland; Kuopio University Hospital; University of Eastern Finland; University of Eastern Finland Hospital; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Erasmus University Rotterdam; Erasmus MC; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); Medical University of Graz; Universite de Bordeaux; Institut National de la Sante et de la Recherche Medicale (Inserm); Boston University; Framingham Heart Study; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Johns Hopkins University; Johns Hopkins Medicine; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; Massachusetts Institute of Technology (MIT); University of Washington; University of Washington Seattle; Medical University of Graz; Johns Hopkins University; Boston University; CEA; Centre National de la Recherche Scientifique (CNRS); Universite de Bordeaux; Universite de Bordeaux; University of Washington; University of Washington Seattle; University of Iceland; Icelandic Heart Association
RP Thompson, PM (corresponding author), Univ So Calif, Keck Sch Med, Inst Neuroimaging & Informat, Imaging Genet Ctr, Los Angeles, CA 90292 USA.
EM pthomp@usc.edu; Sarah.Medland@qimrberghofer.edu.au
FU Grants-in-Aid for Scientific Research [26293266, 221S0003, 26670541, 25293250] Funding Source: KAKEN; National Center for Advancing Translational Sciences [UL1TR002529] Funding Source: NIH RePORTER; National Institute of Biomedical Imaging and Bioengineering [R01EB015611, P41EB015922] Funding Source: NIH RePORTER; National Institute of Mental Health [ZIAMH002810, T32NS048004] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [T32NS048004] Funding Source: NIH RePORTER; National Institute on Aging [ZIAAG007270, R01NS017950, R01AG019771, U24AG021886, ZIAAG000951, ZIAAG000947] Funding Source: NIH RePORTER; Biotechnology and Biological Sciences Research Council [BB/F019394/1, 1088088] Funding Source: researchfish; Chief Scientist Office [ETM/84] Funding Source: researchfish; Epilepsy Research Institute UK [F1206] Funding Source: researchfish; Lundbeck Foundation [R155-2014-1724] Funding Source: researchfish; Medical Research Council [G9817803B, G0701120, G0802462, G0901858, G0900908, G0700704, G1001245, MR/K026992/1, MR/L016400/1, MR/N000390/1] Funding Source: researchfish; National Institute for Health Research [ACF-2012-17-017, NF-SI-0512-10053] Funding Source: researchfish; Wellcome Trust [100309/A/12/Z] Funding Source: researchfish; BBSRC [BB/F019394/1] Funding Source: UKRI; MRC [G0701120, MR/L016400/1, G0900908, G0901858, G1001245, G0700704, G0802462, MR/N000390/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/F019394/1] Funding Source: Medline; Chief Scientist Office [ETM/84] Funding Source: Medline; Medical Research Council [MR/N000390/1, G0900908, G0701120, MR/L016400/1, MR/K026992/1, G0700704, G1001245, G0901858, G0802462] Funding Source: Medline; NCATS NIH HHS [UL1 TR001108, UL1 TR001120] Funding Source: Medline; NIA NIH HHS [U01 AG049505, R01 AG019771, P30 AG013846, RF1 AG041915, U24 AG021886, R01 AG040060, P50 AG005146, R01 AG033193, P50 AG005134, R01 AG008122, P30 AG010129, P50 AG005133, P30 AG062421] Funding Source: Medline; NIBIB NIH HHS [R01 EB005846, P41 EB015922, U54 EB020403, R01 EB020407, R01 EB015611, R01 EB006841] Funding Source: Medline; NIMH NIH HHS [K01 MH099232, R01 MH090553, K99 MH101367] Funding Source: Medline; NINDS NIH HHS [R01 NS017950, T32 NS048004] Funding Source: Medline; NLM NIH HHS [K99 LM011384, R00 LM011384] Funding Source: Medline; Wellcome Trust [104036, 100309] Funding Source: Medline
NR 57
TC 656
Z9 719
U1 2
U2 462
PU NATURE PUBLISHING 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 9
PY 2015
VL 520
IS 7546
BP 224
EP U216
DI 10.1038/nature14101
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CF3NA
UT WOS:000352454600040
PM 25607358
DA 2026-03-09
ER

PT J
AU Barretto, RPJ
   Gillis-Smith, S
   Chandrashekar, J
   Yarmolinsky, DA
   Schnitzer, MJ
   Ryba, NJP
   Zuker, CS
AF Barretto, Robert P. J.
   Gillis-Smith, Sarah
   Chandrashekar, Jayaram
   Yarmolinsky, David A.
   Schnitzer, Mark J.
   Ryba, Nicholas J. P.
   Zuker, Charles S.
TI The neural representation of taste quality at the periphery
SO NATURE
LA English
DT Article
ID fluorescence microendoscopy; mammalian brain; chorda tympani; umami taste; receptors; stimuli; sweet; cells; mice; buds
AB The mammalian taste system is responsible for sensing and responding to the five basic taste qualities: sweet, sour, bitter, salty and umami. Previously, we showed that each taste is detected by dedicated taste receptor cells (TRCs) on the tongue and palate epithelium(1). To understand how TRCs transmit information to higher neural centres, we examined the tuning properties of large ensembles of neurons in the first neural station of the gustatory system. Here, we generated and characterized a collection of transgenic mice expressing a genetically encoded calcium indicator' in central and peripheral neurons, and used a gradient refractive index microendoscope combined with high-resolution two-photon microscopy to image taste responses from ganglion neurons buried deep at the base of the brain. Our results reveal fine selectivity in the taste preference of ganglion neurons; demonstrate a strong match between TRCs in the tongue and the principal neural afferents relaying taste information to the brain; and expose the highly specific transfer of taste information between taste cells and the central nervous system.
C1 [Barretto, Robert P. J.; Gillis-Smith, Sarah; Yarmolinsky, David A.; Zuker, Charles S.] Columbia Univ, Coll Phys & Surg, Howard Hughes Med Inst, New York, NY 10032 USA.
   [Barretto, Robert P. J.; Gillis-Smith, Sarah; Yarmolinsky, David A.; Zuker, Charles S.] Columbia Univ, Coll Phys & Surg, Dept Biochem & Mol Biophys, New York, NY 10032 USA.
   [Barretto, Robert P. J.; Gillis-Smith, Sarah; Yarmolinsky, David A.; Zuker, Charles S.] Columbia Univ, Coll Phys & Surg, Dept Neurosci, New York, NY 10032 USA.
   [Chandrashekar, Jayaram; Zuker, Charles S.] Howard Hughes Med Inst, Ashburn, VA 20147 USA.
   [Schnitzer, Mark J.] Stanford Univ, James H Clark Ctr, Stanford, CA 94305 USA.
   [Ryba, Nicholas J. P.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA.
C3 Howard Hughes Medical Institute; Columbia University; Columbia University; Columbia University; Howard Hughes Medical Institute; Stanford University; National Institutes of Health (NIH) - USA; NIH National Institute of Dental & Craniofacial Research (NIDCR)
RP Zuker, CS (corresponding author), Columbia Univ, Coll Phys & Surg, Howard Hughes Med Inst, New York, NY 10032 USA.
EM nick.ryba@nih.gov; cz2195@columbia.edu
FU NIDCR; Div Of Biological Infrastructure; Direct For Biological Sciences [1063292] Funding Source: National Science Foundation; National Institute of Dental and Craniofacial Research [ZIADE000561] Funding Source: NIH RePORTER
NR 30
TC 119
Z9 149
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 JAN 15
PY 2015
VL 517
IS 7534
BP 373
EP U511
DI 10.1038/nature13873
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300047
PM 25383521
DA 2026-03-09
ER

PT J
AU Ortega, P
   Lehner, F
   Swingedouw, D
   Masson-Delmotte, V
   Raible, CC
   Casado, M
   Yiou, P
AF Ortega, Pablo
   Lehner, Flavio
   Swingedouw, Didier
   Masson-Delmotte, Valerie
   Raible, Christoph C.
   Casado, Mathieu
   Yiou, Pascal
TI A model-tested North Atlantic Oscillation reconstruction for the past millennium
SO NATURE
LA English
DT Article
ID medieval warm period; tree growth; summer temperatures; arctic oscillation; pinatubo eruption; ellesmere-island; climate-change; system model; nao index; ice-age
AB The North Atlantic Oscillation (NAO) is the major source of variability in winter atmospheric circulation in the Northern Hemisphere, with large impacts on temperature, precipitation and storm tracks(1), and therefore also on strategic sectors such as insurance(2), renewable energy production(3), crop yields(4) and water management(5). Recent developments in dynamical methods offer promise to improve seasonal NAO predictions(6), but assessing potential predictability on multi-annual timescales requires documentation of past low-frequency variability in the NAO. A recent bi-proxy NAO reconstruction(7) spanning the past millennium suggested that long-lasting positive NAO conditions were established during medieval times, explaining the particularly warm conditions in Europe during this period; however, these conclusions are debated. Here, we present a yearly NAO reconstruction for the past millennium, based on an initial selection of 48 annually resolved proxy records distributed around the Atlantic Ocean and built through an ensemble of multivariate regressions. We validate the approach in six past-millenniumclimate simulations, and show that our reconstruction outperforms the bi-proxy index. The final reconstruction shows no persistent positive NAO during the medieval period, but suggests that positive phases were dominant during the thirteenth and fourteenth centuries. The reconstruction also reveals that a positive NAO emerges two years after strong volcanic eruptions, consistent with results obtained from models and satellite observations for the Mt Pinatubo eruption in the Philippines(8,9).
C1 [Ortega, Pablo; Masson-Delmotte, Valerie; Casado, Mathieu; Yiou, Pascal] CEA Saclay, UMR CEA CNRS UVSQ 8212, LSCE IPSL, F-91191 Gif Sur Yvette, France.
   [Lehner, Flavio; Raible, Christoph C.] Univ Bern, Inst Phys, Climate & Environm Phys, CH-3012 Bern, Switzerland.
   [Lehner, Flavio; Raible, Christoph C.] Univ Bern, Oeschger Ctr Climate Change Res, CH-3012 Bern, Switzerland.
   [Swingedouw, Didier] Univ Bordeaux 1, EPOC, F-33615 Pessac, France.
C3 CEA; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Universite Paris Saclay; University of Bern; University of Bern; Universite de Bordeaux
RP Ortega, P (corresponding author), Univ Reading, Dept Meteorol, NCAS Climate, Reading RG6 6BB, Berks, England.
EM pablo.ortega@lsce.ipsl.fr
FU French ANR CEPS project Green Greenland [ANR-10-CEPL-0008]; NCCR-Climate - Swiss National Science Foundation [200020 147174]; Swedish Research Council [C0629701]; Swiss National Science Foundation (SNF) [200020_147174] Funding Source: Swiss National Science Foundation (SNF)
NR 93
TC 243
Z9 274
U1 1
U2 158
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 2
PY 2015
VL 523
IS 7558
BP 71
EP +
DI 10.1038/nature14518
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL7RN
UT WOS:000357169500033
PM 26135450
DA 2026-03-09
ER

PT J
AU Taylor, AI
   Pinheiro, VB
   Smola, MJ
   Morgunov, AS
   Peak-Chew, S
   Cozens, C
   Weeks, KM
   Herdewijn, P
   Holliger, P
AF Taylor, Alexander I.
   Pinheiro, Vitor B.
   Smola, Matthew J.
   Morgunov, Alexey S.
   Peak-Chew, Sew
   Cozens, Christopher
   Weeks, Kevin M.
   Herdewijn, Piet
   Holliger, Philipp
TI Catalysts from synthetic genetic polymers
SO NATURE
LA English
DT Article
ID cleaving dna enzyme; arabinonucleic acids; structural basis; rna secondary; nucleic-acids; evolution; shape; hybridization; sequences; ribozyme
AB The emergence of catalysis in early genetic polymers such as RNA is considered a key transition in the origin of life(1), pre-dating the appearance of protein enzymes. DNA also demonstrates the capacity to fold into three-dimensional structures and form catalysts in vitro(2). However, to what degree these natural biopolymers comprise functionally privileged chemical scaffolds(3) for folding or the evolution of catalysis is not known. The ability of synthetic genetic polymers (XNAs) with alternative backbone chemistries not found in nature to fold into defined structures and bind ligands(4) raises the possibility that these too might be capable of forming catalysts (XNAzymes). Here we report the discovery of such XNAzymes, elaborated in four different chemistries (arabino nucleic acids, ANA(5); 2'-fluoroarabino nucleic acids, FANA(6); hexitol nucleic acids, HNA; and cyclohexene nucleic acids, CeNA(7)) directly from random XNA oligomer pools, exhibiting in trans RNA endonuclease and ligase activities. We also describe an XNA-XNA ligase metalloenzyme in the FANA framework, establishing catalysis in an entirely synthetic system and enabling the synthesis of FANA oligomers and an active RNA endonuclease FANAzyme from its constituent parts. These results extend catalysis beyond biopolymers and establish technologies for the discovery of catalysts in a wide range of polymer scaffolds not found in nature(8). Evolution of catalysis independent of any natural polymer has implications for the definition of chemical boundary conditions for the emergence of life on Earth and elsewhere in the Universe(9).
C1 [Taylor, Alexander I.; Pinheiro, Vitor B.; Morgunov, Alexey S.; Peak-Chew, Sew; Cozens, Christopher; Holliger, Philipp] MRC Lab Mol Biol, Cambridge CB2 0QH, England.
   [Smola, Matthew J.; Weeks, Kevin M.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA.
   [Herdewijn, Piet] Katholieke Univ Leuven, Rea Inst, B-3000 Louvain, Belgium.
   [Herdewijn, Piet] Univ Evry, Inst Syst & Synthet Biol, F-91030 Evry, France.
C3 MRC Laboratory Molecular Biology; University of North Carolina; University of North Carolina Chapel Hill; KU Leuven; Universite Paris Saclay
RP Holliger, P (corresponding author), MRC Lab Mol Biol, Francis Crick Ave,Cambridge Biomed Campus, Cambridge CB2 0QH, England.
EM ph1@mrc-lmb.cam.ac.uk
FU Medical Research Council (MRC) [U105178804]; European Science Foundation (ESF); Biotechnology and Biological Sciences Research Council (BBSRC) UK [09-EuroSYNBIO-OP-013]; European Union; European Research Council [ERC-2012 ADG_20120216/320683]; US National Science Foundation [MCB-1121024]; NSF Graduate Research Fellowship [DGE-1144081]; BBSRC [BB/M005623/1] Funding Source: UKRI; MRC [MC_U105185859, MC_U105178804] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BB/M005623/1] Funding Source: researchfish; Medical Research Council [MC_U105178804, MC_U105185859] Funding Source: researchfish; National Institute of General Medical Sciences [T32GM008570] Funding Source: NIH RePORTER; Div Of Molecular and Cellular Bioscience; Direct For Biological Sciences [1121024] Funding Source: National Science Foundation
NR 41
TC 214
Z9 258
U1 1
U2 174
PU NATURE PUBLISHING 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 19
PY 2015
VL 518
IS 7539
BP 427
EP 430
DI 10.1038/nature13982
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400048
PM 25470036
DA 2026-03-09
ER

PT J
AU Novas, FE
   Salgado, L
   Suárez, M
   Agnolín, FL
   Ezcurra, MD
   Chimento, NR
   de la Cruz, R
   Isasi, MP
   Vargas, AO
   Rubilar-Rogers, D
AF Novas, Fernando E.
   Salgado, Leonardo
   Suarez, Manuel
   Agnolin, Federico L.
   Ezcurra, Martin D.
   Chimento, Nicolas R.
   de la Cruz, Rita
   Isasi, Marcelo P.
   Vargas, Alexander O.
   Rubilar-Rogers, David
TI An enigmatic plant-eating theropod from the Late Jurassic period of Chile
SO NATURE
LA English
DT Article
ID dinosaur; evolution; anatomy; osteology; tetanurae
AB Theropod dinosaurs were the dominant predators inmost Mesozoic era terrestrial ecosystems(1). Early theropod evolution is currently interpreted as the diversification of various carnivorous and cursorial taxa, whereas the acquisition of herbivorism, together with the secondary loss of cursorial adaptations, occurred much later among advanced coelurosaurian theropods(1,2). A new, bizarre herbivorous basal tetanuran from the Upper Jurassic of Chile challenges this conception. The new dinosaur was discovered at Aysen, a fossil locality in the Upper Jurassic Toqui Formation of southern Chile (General Carrera Lake)(3,4). The site yielded abundant and exquisitely preserved three-dimensional skeletons of small archosaurs. Several articulated individuals of Chilesaurus at different ontogenetic stages have been collected, as well as less abundant basal crocodyliforms, and fragmentary remains of sauropod dinosaurs (diplodocids and titanosaurians).
C1 [Novas, Fernando E.; Salgado, Leonardo; Isasi, Marcelo P.] Museo Argentino Ciencias Nat Bernardino Rivadavia, CONICET, Buenos Aires, DF, Argentina.
   [Novas, Fernando E.; Agnolin, Federico L.; Chimento, Nicolas R.; Isasi, Marcelo P.] Museo Argentino Ciencias Nat Bernardino Rivadavia, Buenos Aires, DF, Argentina.
   [Salgado, Leonardo] Univ Nacl Rio Negro, Inst Invest Paleobiol & Geol, CONICET, RA-8332 Gen Roca, Rio Negro, Argentina.
   [Salgado, Leonardo] Univ Nacl Rio Negro, Inst Invest Paleobiol & Geol, RA-8332 Gen Roca, Rio Negro, Argentina.
   [Suarez, Manuel] Univ Andres Bello, Geol, Fac Ingn, Santiago, Chile.
   [Suarez, Manuel] Univ Maimonides, Fdn Hist Nat Felix de Azara, Buenos Aires, DF, Argentina.
   [Ezcurra, Martin D.] Univ Birmingham, Sch Geog Earth & Environm Sci, Birmingham B15 2TT, W Midlands, England.
   [de la Cruz, Rita] Serv Nacl Geol & Mineria, Santiago 8330177, Chile.
   [Vargas, Alexander O.; Rubilar-Rogers, David] Univ Chile, Dept Biol, Lab Ontogenia & Filogenia, Red Paleontol U Chile, Santiago 7800003, Chile.
   [Rubilar-Rogers, David] Museo Nacl Hist Nat Chile, Area Paleontol, Santiago, Chile.
C3 Museo Argentino de Ciencias Naturales Bernardino Rivadavia (MACN); Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); Museo Argentino de Ciencias Naturales Bernardino Rivadavia (MACN); Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); Universidad Andres Bello; University of Birmingham; Universidad de Chile
RP Novas, FE (corresponding author), Museo Argentino Ciencias Nat Bernardino Rivadavia, CONICET, Ave Angel Gallardo 470 C1405DJR, Buenos Aires, DF, Argentina.
EM fernovas@yahoo.com.ar
FU Agencia Nacional de Promocion Cientifica y Tecnologica [PICT 2010-066]; Fondo Nacional de Desarrollo Cientifico y Tecnologico [1121140, 1030162]
NR 27
TC 71
Z9 75
U1 1
U2 35
PU NATURE PUBLISHING 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 18
PY 2015
VL 522
IS 7556
BP 331
EP +
DI 10.1038/nature14307
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK7PU
UT WOS:000356425400051
PM 25915021
DA 2026-03-09
ER

PT J
AU Berta-Thompson, ZK
   Irwin, J
   Charbonneau, D
   Newton, ER
   Dittmann, JA
   Astudillo-Defru, N
   Bonfils, X
   Gillon, M
   Jehin, E
   Stark, AA
   Stalder, B
   Bouchy, F
   Delfosse, X
   Forveille, T
   Lovis, C
   Mayor, M
   Neves, V
   Pepe, F
   Santos, NC
   Udry, S
   Wünsche, A
AF Berta-Thompson, Zachory K.
   Irwin, Jonathan
   Charbonneau, David
   Newton, Elisabeth R.
   Dittmann, Jason A.
   Astudillo-Defru, Nicola
   Bonfils, Xavier
   Gillon, Michael
   Jehin, Emmanuel
   Stark, Antony A.
   Stalder, Brian
   Bouchy, Francois
   Delfosse, Xavier
   Forveille, Thierry
   Lovis, Christophe
   Mayor, Michel
   Neves, Vasco
   Pepe, Francesco
   Santos, Nuno C.
   Udry, Stephane
   Wuensche, Anael
TI A rocky planet transiting a nearby low-mass star
SO NATURE
LA English
DT Article
ID thermal phase curves; m-dwarfs; stellar activity; proper-motion; metallicity; search; calibration; luminosity; systems; kepler
AB M-dwarf stars-hydrogen-burning stars that are smaller than 60 per cent of the size of the Sun-are the most common class of star in our Galaxy and outnumber Sun-like stars by a ratio of 12:1. Recent results have shown that M dwarfs host Earth-sized planets in great numbers(1,2): the average number of M-dwarf planets that are between 0.5 to 1.5 times the size of Earth is at least 1.4 per star(3). The nearest such planets known to transit their star are 39 parsecs away(4), too distant for detailed follow-up observations to measure the planetary masses or to study their atmospheres. Here we report observations of GJ 1132b, a planet with a size of 1.2 Earth radii that is transiting a small star 12 parsecs away. Our Doppler mass measurement of GJ 1132b yields a density consistent with an Earth-like bulk composition, similar to the compositions of the six known exoplanets with masses less than six times that of the Earth and precisely measured densities(5-11). Receiving 19 times more stellar radiation than the Earth, the planet is too hot to be habitable but is cool enough to support a substantial atmosphere, one that has probably been considerably depleted of hydrogen. Because the host star is nearby and only 21 per cent the radius of the Sun, existing and upcoming telescopes will be able to observe the composition and dynamics of the planetary atmosphere.
C1 [Berta-Thompson, Zachory K.] MIT, Kavli Inst Astrophys & Space Res, Cambridge, MA 02139 USA.
   [Berta-Thompson, Zachory K.; Irwin, Jonathan; Charbonneau, David; Newton, Elisabeth R.; Dittmann, Jason A.; Stark, Antony A.] Harvard Smithsonian Ctr Astrophys, Cambridge, MA 02138 USA.
   [Astudillo-Defru, Nicola; Bouchy, Francois; Lovis, Christophe; Mayor, Michel; Pepe, Francesco; Udry, Stephane] Univ Geneva, Observ Geneve, CH-1290 Sauverny, Switzerland.
   [Bonfils, Xavier; Delfosse, Xavier; Forveille, Thierry; Wuensche, Anael] Univ Grenoble Alpes, IPAG, F-33000 Grenoble, France.
   [Bonfils, Xavier; Delfosse, Xavier; Forveille, Thierry; Wuensche, Anael] CNRS, IPAG, F-38000 Grenoble, France.
   [Gillon, Michael; Jehin, Emmanuel] Univ Liege, Inst Astrophys & Geophys, B-4000 Liege, Belgium.
   [Stalder, Brian] Univ Hawaii Manoa, Inst Astron, Honolulu, HI 96822 USA.
   [Bouchy, Francois] Univ Aix Marseille 1, CNRS, Lab Astrophys Marseille, UMR 6110, F-13388 Marseille 13, France.
   [Neves, Vasco] Univ Fed Rio Grande do Norte, Dept Fis, BR-59072970 Natal, RN, Brazil.
   [Santos, Nuno C.] Univ Porto, Inst Astrofis & Ciencias Espaco, CAUP, P-4150762 Oporto, Portugal.
   [Santos, Nuno C.] Univ Porto, Fac Ciencias, Dept Fis & Astron, P-4169007 Oporto, Portugal.
C3 Massachusetts Institute of Technology (MIT); Smithsonian Astrophysical Observatory; Harvard University; Smithsonian Institution; University of Geneva; Institut de Planetologie et d'Astrophysique de Grenoble (IPAG); Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Centre National de la Recherche Scientifique (CNRS); Institut de Planetologie et d'Astrophysique de Grenoble (IPAG); University of Liege; University of Hawaii System; University of Hawaii Manoa; Centre National de la Recherche Scientifique (CNRS); Aix-Marseille Universite; Universidade Federal do Rio Grande do Norte; Universidade do Porto; Universidade do Porto
RP Berta-Thompson, ZK (corresponding author), MIT, Kavli Inst Astrophys & Space Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
EM zkbt@mit.edu
FU David and Lucile Packard Fellowship for Science and Engineering; National Science Foundation; John Templeton Foundation; Belgian Fund for Scientific Research; MIT Torres Fellowship for Exoplanet Research; French Agence Nationale de la Recherche; European Research Council; CNPq/BJT Post Doctorate fellowship; INCT INEspaco; Portuguese National Science Foundation (FCT); COMPETE program; Division Of Astronomical Sciences; Direct For Mathematical & Physical Scien [1009649] Funding Source: National Science Foundation
NR 64
TC 184
Z9 216
U1 0
U2 21
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 12
PY 2015
VL 527
IS 7577
BP 204
EP +
DI 10.1038/nature15762
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700038
PM 26560298
DA 2026-03-09
ER

PT J
AU Bapat, SP
   Suh, JM
   Fang, S
   Liu, SH
   Zhang, Y
   Cheng, A
   Zhou, C
   Liang, YQ
   LeBlanc, M
   Liddle, C
   Atkins, AR
   Yu, RT
   Downes, M
   Evans, RM
   Zheng, Y
AF Bapat, Sagar P.
   Suh, Jae Myoung
   Fang, Sungsoon
   Liu, Sihao
   Zhang, Yang
   Cheng, Albert
   Zhou, Carmen
   Liang, Yuqiong
   LeBlanc, Mathias
   Liddle, Christopher
   Atkins, Annette R.
   Yu, Ruth T.
   Downes, Michael
   Evans, Ronald M.
   Zheng, Ye
TI Depletion of fat-resident Treg cells prevents age-associated insulin resistance
SO NATURE
LA English
DT Article
ID visceral adipose-tissue; rna-seq; orchestrate development; ppar-gamma; beige fat; macrophages; obesity; inflammation; differentiation; accumulation
AB Age-associated insulin resistance (IR) and obesity-associated IR are two physiologically distinct forms of adult-onset diabetes. While macrophage-driven inflammation is a core driver of obesity-associated IR1-6, the underlying mechanisms of the obesity-independent yet highly prevalent age-associated IR7 are largely unexplored. Here we show, using comparative adipo-immune profiling in mice, that fat-resident regulatory T cells, termed fT(reg) cells, accumulate in adipose tissue as a function of age, but not obesity. Supporting the existence of two distinct mechanisms underlying IR, mice deficient in fT(reg) cells are protected against age-associated IR, yet remain susceptible to obesity-associated IR and metabolic disease. By contrast, selective depletion of fT(reg) cells via anti-ST2 antibody treatment increases adipose tissue insulin sensitivity. These findings establish that distinct immune cell populations within adipose tissue underlie ageing- and obesity-associated IR, and implicate fT(reg) cells as adipo-immune drivers and potential therapeutic targets in the treatment of age-associated IR.
C1 [Bapat, Sagar P.; Zhang, Yang; Cheng, Albert; Zhou, Carmen; Liang, Yuqiong; Zheng, Ye] Salk Inst Biol Studies, Immunobiol & Microbial Pathogenesis Lab, La Jolla, CA 92037 USA.
   [Bapat, Sagar P.; Suh, Jae Myoung; Fang, Sungsoon; Liu, Sihao; LeBlanc, Mathias; Atkins, Annette R.; Yu, Ruth T.; Downes, Michael; Evans, Ronald M.] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA.
   [Suh, Jae Myoung] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon 34141, South Korea.
   [Fang, Sungsoon] Sejong Univ, Dept Biotechnol, Coll Life Sci, Seoul 143747, South Korea.
   [Liddle, Christopher] Univ Sydney, Sydney Med Sch, Westmead Millennium Inst, Storr Liver Ctr, Sydney, NSW 2145, Australia.
   [Evans, Ronald M.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA.
C3 Salk Institute; Salk Institute; Korea Advanced Institute of Science & Technology (KAIST); Sejong University; University of Sydney; Westmead Institute for Medical Research; Salk Institute; Howard Hughes Medical Institute
RP Evans, RM (corresponding author), Salk Inst Biol Studies, Gene Express Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA.
EM evans@salk.edu; yzheng@salk.edu
FU National Institutes of Health (NIH) [F30 DK096828, T32 GM007198]; National Health and Medical Research Council of Australia [512354, 632886, 1043199]; NIH [DK057978, DK090962, HL088093, HL105278, ES010337]; Glenn Foundation for Medical Research; Leona M. and Harry B. Helmsley Charitable Trust; Ipsen/Biomeasure; California Institute for Regenerative Medicine; Ellison Medical Foundation; Nomis Foundation; Rita Allen Foundation; Emerald Foundation; Hearst Foundation; National Multiple Sclerosis Society; National Institutes of Health [AI099295, AI107027]; National Cancer Institute [CA014195]; James B. Pendleton Charitable Trust; National Cancer Institute [P30CA014195] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [R01AI107027] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK057978] Funding Source: NIH RePORTER; National Institute of Environmental Health Sciences [P42ES010337] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007198] Funding Source: NIH RePORTER; National Health and Medical Research Council (NHMRC) [1043199] Funding Source: National Health and Medical Research Council (NHMRC)
NR 36
TC 275
Z9 322
U1 1
U2 83
PU NATURE PUBLISHING 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 3
PY 2015
VL 528
IS 7580
BP 137
EP +
DI 10.1038/nature16151
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000064
PM 26580014
DA 2026-03-09
ER

PT J
AU Kakugawa, S
   Langton, PF
   Zebisch, M
   Howell, SA
   Chang, TH
   Liu, Y
   Ten, FZ
   Bineva, G
   O'Reilly, N
   Snijders, AP
   Jones, EY
   Vincent, JP
AF Kakugawa, Satoshi
   Langton, Paul F.
   Zebisch, Matthias
   Howell, Steven A.
   Chang, Tao -Hsin
   Liu, Yon
   Ten Feizi
   Bineva, Ganka
   O'Reilly, Nicola
   Snijders, Ambrosius P.
   Jones, E. Yvonne
   Vincent, Jean-Paul
TI Notum deacylates Wnt proteins to suppress signalling activity
SO NATURE
LA English
DT Article
ID heparan-sulfate proteoglycans; morphogen gradient; cell-surface; drosophila; wingless; hedgehog; activation; dpp; identification; recognition
AB Signalling by Wnt proteins is finely balanced to ensure normal development and tissue homeostasis while avoiding diseases such as cancer. This is achieved in part by Notum, a highly conserved secreted feedback antagonist. Notum has been thought to act as a phospholipase, shedding glypicans and associated Wnt proteins from the cell surface. However, this view fails to explain specificity, as glypicans bind many extracellular ligands. Here we provide genetic evidence in Drosophila that Notum requires glypicans to suppress Wnt signalling, but does not cleave their glycophosphatidylinositol anchor. Structural analyses reveal glycosaminoglycan binding sites on Notum, which probably help Notum to co-localize with Wnt proteins. They also identify, at the active site of human and Drosophila Notum, a large hydrophobic pocket that accommodates palmitoleate. Kinetic and mass spectrometric analyses of human proteins show that Notum is a carboxylesterase that removes an essential palmitoleate moiety from Wnt proteins and thus constitutes the first known extracellular protein deacylase.
C1 [Kakugawa, Satoshi; Langton, Paul F.; Howell, Steven A.; Vincent, Jean-Paul] MRCs Natl Inst Med Res, London NW7 1AA, England.
   [Zebisch, Matthias; Chang, Tao -Hsin; Jones, E. Yvonne] Univ Oxford, Wellcome Trust Ctr Human Genet, Div Struct Biol, Oxford OX3 7BN, England.
   [Liu, Yon; Ten Feizi] Univ London Imperial Coll Sci Technol & Med, Dept Med, Glycosci Lab, London W12 0NN, England.
   [Bineva, Ganka; O'Reilly, Nicola] Canc Res UK, London Res Inst, London WC2A 3LY, England.
   [Snijders, Ambrosius P.] Canc Res UK, Clare Hall Labs, Potters Bar EN6 3LD, Herts, England.
C3 University of Oxford; Wellcome Centre for Human Genetics; Imperial College London; Cancer Research UK; Cancer Research UK
RP Zebisch, M (corresponding author), Univ Oxford, Wellcome Trust Ctr Human Genet, Div Struct Biol, Roosevelt Dr, Oxford OX3 7BN, England.
EM matthias.zebisch@evotec.com; yvonne@strubi.ox.ac.uk; jvincen@nimr.mrc.ac.uk
FU MRC [U117584268, G0900084]; UK Research Council Basic Technology Initiative (Glycoarrays Grant) [GRS/79268]; UK Research Council Basic Technology Initiative (EPSRC Translational Grant) [EP/G037604/1]; Wellcome Trust (Biomedical Resource Grants) [WT093378MA, WT099197MA]; European Union (ERC grant WNTEXPORT) [294523]; European Union (Marie Curie IEF grant); Cancer Research UK [C375/A10976]; Japan Society for the Promotion of Science; Nuffield Department of Medicine Prize Studentship; Clarendon and Somerville College Scholarships; Wellcome Trust Centre grant [090532/Z/09/Z]; EPSRC [EP/G037604/1] Funding Source: UKRI; MRC [MC_U117584268] Funding Source: UKRI; Cancer Research UK [17721] Funding Source: researchfish; Engineering and Physical Sciences Research Council [EP/G037604/1] Funding Source: researchfish; Medical Research Council [MC_U117584268, G0900084] Funding Source: researchfish; The Francis Crick Institute [10013, 10204, 10011] Funding Source: researchfish; European Research Council (ERC) [294523] Funding Source: European Research Council (ERC)
NR 53
TC 362
Z9 432
U1 3
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 MAR 12
PY 2015
VL 519
IS 7542
BP 187
EP +
DI 10.1038/nature14259
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500029
PM 25731175
DA 2026-03-09
ER

PT J
AU Vitorino, P
   Yeung, S
   Crow, A
   Bakke, J
   Smyczek, T
   West, K
   McNamara, E
   Eastham-Anderson, J
   Gould, S
   Harris, SF
   Ndubaku, C
   Ye, WL
AF Vitorino, Philip
   Yeung, Stacey
   Crow, Ailey
   Bakke, Jesse
   Smyczek, Tanya
   West, Kristina
   McNamara, Erin
   Eastham-Anderson, Jeffrey
   Gould, Stephen
   Harris, Seth F.
   Ndubaku, Chudi
   Ye, Weilan
TI MAP4K4 regulates integrin-FERM binding to control endothelial cell motility
SO NATURE
LA English
DT Article
ID signaling pathway; adhesion dynamics; kinase misshapen; matrix adhesions; lumen formation; erm proteins; angiogenesis; migration; polarity; growth
AB Cell migration is a stepwise process that coordinates multiple molecular machineries. Using in vitro angiogenesis screens with short interfering RNA and chemical inhibitors, we define here a MAP4K4-moesin-talin-beta 1-integrin molecular pathway that promotes efficient plasma membrane retraction during endothelial cell migration. Loss of MAP4K4 decreased membrane dynamics, slowed endothelial cell migration, and impaired angiogenesis in vitro and in vivo. In migrating endothelial cells, MAP4K4 phosphorylates moesin in retracting membranes at sites of focal adhesion disassembly. Epistasis analyses indicated that moesin functions downstream of MAP4K4 to inactivate integrin by competing with talin for binding to beta 1-integrin intracellular domain. Consequently, loss of moesin (encoded by the MSN gene) or MAP4K4 reduced adhesion disassembly rate in endothelial cells. Additionally, alpha 5 beta 1-integrin blockade reversed the membrane retraction defects associated with loss of Map4k4 in vitro and in vivo. Our study uncovers a novel aspect of endothelial cell migration. Finally, loss of MAP4K4 function suppressed pathological angiogenesis in disease models, identifying MAP4K4 as a potential therapeutic target.
C1 [Vitorino, Philip; Yeung, Stacey; Crow, Ailey; Smyczek, Tanya; Ye, Weilan] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA.
   [Bakke, Jesse] St Jude Childrens Res Hosp, Chem Biol & Therapeut Dept, Memphis, TN 38105 USA.
   [West, Kristina; McNamara, Erin; Gould, Stephen] Genentech Inc, Translat Oncol Dept, San Francisco, CA 94080 USA.
   [Eastham-Anderson, Jeffrey] Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA.
   [Harris, Seth F.] Genentech Inc, Dept Biol Struct, San Francisco, CA 94080 USA.
   [Ndubaku, Chudi] Genentech Inc, Discovery Chem Dept, San Francisco, CA 94080 USA.
C3 Roche Holding; Roche Holding USA; Genentech; St Jude Children's Research Hospital; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Genentech; Roche Holding USA
RP Ye, WL (corresponding author), Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA.
EM loni@gene.com
NR 42
TC 120
Z9 133
U1 2
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 MAR 26
PY 2015
VL 519
IS 7544
BP 425
EP +
DI 10.1038/nature14323
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE1WF
UT WOS:000351602800046
PM 25799996
DA 2026-03-09
ER

PT J
AU Bever, GS
   Lyson, TR
   Field, DJ
   Bhullar, BAS
AF Bever, G. S.
   Lyson, Tyler R.
   Field, Daniel J.
   Bhullar, Bhart-Anjan S.
TI Evolutionary origin of the turtle skull
SO NATURE
LA English
DT Article
ID permian reptile; phylogeny; paleoecology; insights
AB Transitional fossils informing the origin of turtles are among the most sought-after discoveries in palaeontology(1-5). Despite strong genomic evidence indicating that turtles evolved from within the diapsid radiation (which includes all other living reptiles(6,7)), evidence of the inferred transformation between an ancestral turtle with an open, diapsid skull to the closed, anapsid condition of modern turtles remains elusive. Here we use high-resolution computed tomography and a novel character/taxon matrix to study the skull of Eunotosaurus africanus, a 260-million-year-old fossil reptile from the Karoo Basin of South Africa, whose distinctive post-cranial skeleton shares many unique features with the shelled body plan of turtles(2-4). Scepticism regarding the status of Eunotosaurus as the earliest stem turtle arises from the possibility that these shell-related features are the products of evolutionary convergence. Our phylogenetic analyses indicate strong cranial support for Eunotosaurus as a critical transitional form in turtle evolution, thus fortifying a 40-million-year extension to the turtle stem and moving the ecological context of its origin back onto land(8,9). Furthermore, we find unexpected evidence that Eunotosaurus is a diapsid reptile in the process of becoming secondarily anapsid. This is important because categorizing the skull based on the number of openings in the complex of dermal bone covering the adductor chamber has long held sway in amniote systematics(10), and still represents a common organizational scheme for teaching the evolutionary history of the group. These discoveries allow us to articulate a detailed and testable hypothesis of fenestral closure represents a crucially important link in a chain that will eventually lead to consilience in reptile systematics, paving the way for synthetic studies of amniote evolution and development.
C1 [Bever, G. S.] New York Inst Technol, Coll Osteopath Med, Dept Anat, Old Westbury, NY 11568 USA.
   [Bever, G. S.] Amer Museum Nat Hist, Div Paleontol, New York, NY 10024 USA.
   [Bever, G. S.; Lyson, Tyler R.] Univ Witwatersrand, Evolutionary Studies Inst, ZA-2050 Johannesburg, South Africa.
   [Lyson, Tyler R.] Denver Museum Nat & Sci, Dept Earth Sci, Denver, CO 80205 USA.
   [Field, Daniel J.; Bhullar, Bhart-Anjan S.] Yale Univ, Dept Geol & Geophys, New Haven, CT 06520 USA.
   [Field, Daniel J.; Bhullar, Bhart-Anjan S.] Yale Univ, Peabody Museum Nat Hist, New Haven, CT 06520 USA.
   [Bhullar, Bhart-Anjan S.] Univ Chicago, Dept Organismal Biol & Anat, Chicago, IL 60637 USA.
C3 New York Institute Technology; American Museum of Natural History (AMNH); University of Witwatersrand; Yale University; Yale University; University of Chicago
RP Bever, GS (corresponding author), New York Inst Technol, Coll Osteopath Med, Dept Anat, Old Westbury, NY 11568 USA.
EM gbever@nyit.edu
FU Direct For Biological Sciences; Division Of Environmental Biology [1500798] Funding Source: National Science Foundation; Division Of Earth Sciences; Directorate For Geosciences [1258878] Funding Source: National Science Foundation
NR 37
TC 86
Z9 99
U1 2
U2 188
PU NATURE PUBLISHING 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 10
PY 2015
VL 525
IS 7568
BP 239
EP +
DI 10.1038/nature14900
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400036
PM 26331544
DA 2026-03-09
ER

PT J
AU Daims, H
   Lebedeva, EV
   Pjevac, P
   Han, P
   Herbold, C
   Albertsen, M
   Jehmlich, N
   Palatinszky, M
   Vierheilig, J
   Bulaev, A
   Kirkegaard, RH
   von Bergen, M
   Rattei, T
   Bendinger, B
   Nielsen, PH
   Wagner, M
AF Daims, Holger
   Lebedeva, Elena V.
   Pjevac, Petra
   Han, Ping
   Herbold, Craig
   Albertsen, Mads
   Jehmlich, Nico
   Palatinszky, Marton
   Vierheilig, Julia
   Bulaev, Alexandr
   Kirkegaard, Rasmus H.
   von Bergen, Martin
   Rattei, Thomas
   Bendinger, Bernd
   Nielsen, Per H.
   Wagner, Michael
TI Complete nitrification by Nitrospira bacteria
SO NATURE
LA English
DT Article
ID ammonia-oxidizing bacterium; complete genome sequence; 16s ribosomal-rna; in-situ; oxidation-kinetics; high-accuracy; sp-nov; evolution; soil; archaea
AB Nitrification, the oxidation of ammonia via nitrite to nitrate, has always been considered to be a two-step process catalysed by chemolithoautotrophic microorganisms oxidizing either ammonia or nitrite. No known nitrifier carries out both steps, although complete nitrification should be energetically advantageous. This functional separation has puzzled microbiologists for a century. Here we report on the discovery and cultivation of a completely nitrifying bacterium from the genus Nitrospira, a globally distributed group of nitrite oxidizers. The genome of this chemolithoautotrophic organism encodes the pathways both for ammonia and nitrite oxidation, which are concomitantly expressed during growth by ammonia oxidation to nitrate. Genes affiliated with the phylogenetically distinct ammonia monooxygenase and hydroxylamine dehydrogenase genes of Nitrospira are present in many environments and were retrieved on Nitrospira-contigs in new metagenomes from engineered systems. These findings fundamentally change our picture of nitrification and point to completely nitrifying Nitrospira as key components of nitrogen-cycling microbial communities.
C1 [Daims, Holger; Pjevac, Petra; Han, Ping; Herbold, Craig; Palatinszky, Marton; Vierheilig, Julia; Wagner, Michael] Univ Vienna, Div Microbial Ecol, Dept Microbiol & Ecosyst Sci, A-1090 Vienna, Austria.
   [Lebedeva, Elena V.; Bulaev, Alexandr] Russian Acad Sci, Biotechnol Res Ctr, Winogradsky Inst Microbiol, Moscow 119071, Russia.
   [Albertsen, Mads; Kirkegaard, Rasmus H.; Nielsen, Per H.] Aalborg Univ, Dept Chem & Biosci, Ctr Microbial Communities, DK-9220 Aalborg, Denmark.
   [Jehmlich, Nico; von Bergen, Martin] UFZ Helmholtz Ctr Environm Res, Dept Prote, D-04318 Leipzig, Germany.
   [von Bergen, Martin] UFZ Helmholtz Ctr Environm Res, Dept Metabol, D-04318 Leipzig, Germany.
   [Rattei, Thomas] Univ Vienna, Div Computat Syst Biol, Dept Microbiol & Ecosyst Sci, A-1090 Vienna, Austria.
   [Bendinger, Bernd] Hamburg Univ Technol, DVGW Forsch Stelle TUHH, D-21073 Hamburg, Germany.
C3 University of Vienna; Research Center of Biotechnology RAS; Russian Academy of Sciences; Aalborg University; Helmholtz Association; Helmholtz Center for Environmental Research (UFZ); Helmholtz Association; Helmholtz Center for Environmental Research (UFZ); University of Vienna; Hamburg University of Technology
RP Wagner, M (corresponding author), Univ Vienna, Div Microbial Ecol, Dept Microbiol & Ecosyst Sci, Althanstr 14, A-1090 Vienna, Austria.
EM wagner@microbial-ecology.net
FU European Regional Development Funds (EFRE-Europe funds Saxony); Helmholtz Association; Austrian Science Fund (FWF) [P27319-B21, P25231-B21]; European Research Council Advanced Grant [NITRICARE 294343]; Danish Council for Independent Research [DFF-4005-00369]; Innovation Fund Denmark (EcoDesign); Austrian Science Fund (FWF) [P27319] Funding Source: Austrian Science Fund (FWF); National Human Genome Research Institute [T32HG002536] Funding Source: NIH RePORTER
NR 92
TC 2047
Z9 2517
U1 84
U2 2253
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 24
PY 2015
VL 528
IS 7583
BP 504
EP +
DI 10.1038/nature16461
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900042
PM 26610024
DA 2026-03-09
ER

PT J
AU Zanella, A
   Daddi, E
   Le Floc'h, E
   Bournaud, F
   Gobat, R
   Valentino, F
   Strazzullo, V
   Cibinel, A
   Onodera, M
   Perret, V
   Renaud, F
   Vignali, C
AF Zanella, A.
   Daddi, E.
   Le Floc'h, E.
   Bournaud, F.
   Gobat, R.
   Valentino, F.
   Strazzullo, V.
   Cibinel, A.
   Onodera, M.
   Perret, V.
   Renaud, F.
   Vignali, C.
TI An extremely young massive clump forming by gravitational collapse in a primordial galaxy
SO NATURE
LA English
DT Article
ID star-formation rates; sins/zc-sinf survey; ultra deep field; high-redshift; emission-line; giant clumps; stellar feedback; rapid formation; gas fractions; cold streams
AB When cosmic star formation history reaches a peak (at about redshift z approximate to 2), galaxies vigorously fed by cosmic reservoirs(1,2) are dominated by gas(3,4) and contain massive star-forming clumps(5,6), which are thought to form by violent gravitational instabilities in highly turbulent gas-rich disks(7,8). However, a clump formation event has not yet been observed, and it is debated whether clumps can survive energetic feedback from young stars, and afterwards migrate inwards to form galaxy bulges(9-12). Here we report the spatially resolved spectroscopy of a bright off-nuclear emission line region in a galaxy at z = 1.987. Although this region dominates star formation in the galaxy disk, its stellar continuum remains undetected in deep imaging, revealing an extremely young (less than ten million years old) massive clump, forming through the gravitational collapse of more than one billion solarmasses of gas. Gas consumption in this young clump is more than tenfold faster than in the host galaxy, displaying high star-formation efficiency during this phase, in agreement with our hydrodynamic simulations. The frequency of older clumps with similar masses(13), coupled with our initial estimate of their formation rate (about 2.5 per billion years), supports long lifetimes (about 500 million years), favouring models in which clumps survive feedback and grow the bulges of present-day galaxies.
C1 [Zanella, A.; Daddi, E.; Le Floc'h, E.; Bournaud, F.; Gobat, R.; Valentino, F.; Strazzullo, V.; Cibinel, A.; Renaud, F.] CEA DSM CNRS Univ Paris Diderot, Lab AIM Paris Saclay, Irfu Serv Astrophys, CEA Saclay, F-91191 Gif Sur Yvette, France.
   [Gobat, R.] Korea Inst Adv Study, Sch Phys, Seoul 130722, South Korea.
   [Strazzullo, V.] Univ Munich, Dept Phys, D-81679 Munich, Germany.
   [Cibinel, A.] Univ Sussex, Dept Phys & Astron, Ctr Astron, Brighton BN1 9QH, E Sussex, England.
   [Onodera, M.] Swiss Fed Inst Technol, Inst Astron, CH-8093 Zurich, Switzerland.
   [Perret, V.] Aix Marseille Univ, CNRS, LAM, F-13388 Marseille, France.
   [Renaud, F.] Univ Surrey, Dept Phys, Guildford GU2 7XH, Surrey, England.
   [Vignali, C.] Univ Bologna, Dipartimento Fis & Astron, I-40127 Bologna, Italy.
   [Vignali, C.] INAF Osservatorio Astron Bologna, I-40127 Bologna, Italy.
C3 Universite Paris Saclay; CEA; Centre National de la Recherche Scientifique (CNRS); Universite Paris Cite; Korea Institute for Advanced Study (KIAS); University of Munich; University of Sussex; Swiss Federal Institutes of Technology Domain; ETH Zurich; Centre National de la Recherche Scientifique (CNRS); Aix-Marseille Universite; University of Surrey; University of Bologna; Istituto Nazionale Astrofisica (INAF)
RP Zanella, A (corresponding author), CEA DSM CNRS Univ Paris Diderot, Lab AIM Paris Saclay, Irfu Serv Astrophys, CEA Saclay, F-91191 Gif Sur Yvette, France.
EM anita.zanella@cea.fr
FU Agence Nationale de la Recherche [ANR-12-JS05-0008-01]; European Commission through European Research Council [StG-257720, StG-240039]; Agence Nationale de la Recherche (ANR) [ANR-12-JS05-0008] Funding Source: Agence Nationale de la Recherche (ANR)
NR 71
TC 62
Z9 67
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 MAY 7
PY 2015
VL 521
IS 7550
BP 54
EP U362
DI 10.1038/nature14409
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH4YS
UT WOS:000354040900030
PM 25951282
DA 2026-03-09
ER

PT J
AU Perdiguero, EG
   Klapproth, K
   Schulz, C
   Busch, K
   Azzoni, E
   Crozet, L
   Garner, H
   Trouillet, C
   de Bruijn, MF
   Geissmann, F
   Rodewald, HR
AF Perdiguero, Elisa Gomez
   Klapproth, Kay
   Schulz, Christian
   Busch, Katrin
   Azzoni, Emanuele
   Crozet, Lucile
   Garner, Hannah
   Trouillet, Celine
   de Bruijn, Marella F.
   Geissmann, Frederic
   Rodewald, Hans-Reimer
TI Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors
SO NATURE
LA English
DT Article
ID stem-cell differentiation; microglia derive; monocytes; ontogeny; hematopoiesis; maturation; reveals; embryo; life; myb
AB Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs)(1-3), however, macrophages in adult tissues can self-maintain independently of HSCO4-7. Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCO8-3, and fetal macrophages(13-15) can develop independently of Myb(4), a transcription factor required for HSC16, and can persist in adult tissues(4.17,18). Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear'. Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain '(microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a Tie2(+) (also known as Tek) cellular pathway generating Csf1r(+) erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk sac at embryonic day (E) 8.5, migrate and colonize the nascent fetal liver before E10.5, and give rise to fetal erythrocytes, macrophages, granulocytes and monocytes until at least E16.5. Subsequently, HSC-derived cells replace erythrocytes, granulocytes and monocytes. Kupffer cells, microglia and Langerhans cells are only marginally replaced in oneyear-old mice, whereas alveolar macrophages may be progressively replaced in ageing mice. Our fate-mapping experiments identify, in the fetal liver, a sequence of yolk sac EMP-derived and HSC-derived haematopoiesis, and identify yolk sac EMPs as a common origin for tissue macrophages.
C1 [Perdiguero, Elisa Gomez; Schulz, Christian; Crozet, Lucile; Garner, Hannah; Trouillet, Celine; Geissmann, Frederic] Kings Coll London, CMCBI, London SE1 1UL, England.
   [Klapproth, Kay; Busch, Katrin; Rodewald, Hans-Reimer] German Canc Res Ctr, Div Cellular Immunol, D-69120 Heidelberg, Germany.
   [Azzoni, Emanuele; de Bruijn, Marella F.] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, MRC,Mol Haematol Unit, Oxford OX3 9DS, England.
C3 University of London; King's College London; Helmholtz Association; German Cancer Research Center (DKFZ); University of Oxford
RP Geissmann, F (corresponding author), Kings Coll London, CMCBI, London SE1 1UL, England.
EM frederic.geissmann@kcl.ac.uk
FU Wellcome Trust [WT101853MA]; ERC from European Research Council [2010-StG-261299]; ERC [233074, SFB 938, SFB 873]; MRC [MC_UU_12009/2] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [1168004] Funding Source: researchfish; Medical Research Council [MC_UU_12009/2] Funding Source: researchfish
NR 27
TC 1801
Z9 2190
U1 7
U2 249
PU NATURE PUBLISHING 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 26
PY 2015
VL 518
IS 7540
BP 547
EP 551
DI 10.1038/nature13989
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC1JP
UT WOS:000350097300049
PM 25470051
DA 2026-03-09
ER

PT J
AU Renard, HF
   Simunovic, M
   Lemière, J
   Boucrot, E
   Garcia-Castillo, MD
   Arumugam, S
   Chambon, V
   Lamaze, C
   Wunder, C
   Kenworthy, AK
   Schmidt, AA
   McMahon, HT
   Sykes, C
   Bassereau, P
   Johannes, L
AF Renard, Henri-Francois
   Simunovic, Mijo
   Lemiere, Joel
   Boucrot, Emmanuel
   Garcia-Castillo, Maria Daniela
   Arumugam, Senthil
   Chambon, Valerie
   Lamaze, Christophe
   Wunder, Christian
   Kenworthy, Anne K.
   Schmidt, Anne A.
   McMahon, Harvey T.
   Sykes, Cecile
   Bassereau, Patricia
   Johannes, Ludger
TI Endophilin-A2 functions in membrane scission in clathrin-independent endocytosis
SO NATURE
LA English
DT Article
ID domain-containing proteins; retrograde transport; dynamin; bar; fission; toxin; recruitment; inhibition; curvature; retrieval
AB During endocytosis, energy is invested to narrow the necks of cargo-containing plasma membrane invaginations to radii at which the opposing segments spontaneously coalesce, thereby leading to the detachment by scission of endocytic uptake carriers'. In the clathrin pathway, dynamin uses mechanical energy from GTP hydrolysis to this effect(2-4), assisted by the BIN/amphiphysin/Rvs (BAR) domain-containing protein endophilin(5,6). Clathrin-independent endocytic events are often less reliant on dynamin(7), and whether in these cases BAR domain proteins such as endophilin contribute to scission has remained unexplored. Here we show, in human and other mammalian cell lines, that endophilin-A2 (endoA2) specifically and functionally associates with very early uptake structures that are induced by the bacterial Shiga and cholera toxins, which are both clathrin-independent endocytic cargoes'. In controlled in vitro systems, endoA2 reshapes membranes before scission. Furthermore, we demonstrate that endoA2, dynamin and actin contribute in parallel to the scission of Shiga-toxin-induced tubules. Our results establish a novel function of endoA2 in clathrin-independent endocytosis. They document that distinct scission factors operate in an additive manner, and predict that specificity within a given uptake process arises from defined combinations of universal modules. Our findings highlight a previously unnoticed link between membrane scaffolding by endoA2 and pulling-force-driven dynamic scission.
C1 [Renard, Henri-Francois; Garcia-Castillo, Maria Daniela; Arumugam, Senthil; Chambon, Valerie; Wunder, Christian; Johannes, Ludger] Inst Curie, Ctr Rech, Endocyt Trafficking & Therapeut Delivery Grp, F-75248 Paris 05, France.
   [Renard, Henri-Francois; Garcia-Castillo, Maria Daniela; Arumugam, Senthil; Chambon, Valerie; Lamaze, Christophe; Wunder, Christian; Johannes, Ludger] CNRS, UMR3666, F-75005 Paris, France.
   [Renard, Henri-Francois; Garcia-Castillo, Maria Daniela; Arumugam, Senthil; Chambon, Valerie; Lamaze, Christophe; Wunder, Christian; Johannes, Ludger] INSERM, U1143, F-75005 Paris, France.
   [Simunovic, Mijo; Bassereau, Patricia] Univ Paris 06, CNRS UMR 168, Inst Curie, Ctr Rech,Membrane & Cell Funct Grp, F-75248 Paris 05, France.
   [Simunovic, Mijo] Univ Chicago, Dept Chem, Chicago, IL 60637 USA.
   [Lemiere, Joel; Sykes, Cecile] Univ Paris 06, CNRS UMR 168, Inst Curie, Ctr Rech,Biomimetism Cell Movement Grp, F-75248 Paris 05, France.
   [Lemiere, Joel] Univ Paris Diderot, Sorbonne Paris Cite, F-75205 Paris, France.
   [Boucrot, Emmanuel] UCL, Inst Struct & Mol Biol, London WC1E 6BT, England.
   [Boucrot, Emmanuel] Birkbeck Coll, London WC1E 6BT, England.
   [Lamaze, Christophe] Inst Curie, Ctr Rech, Membrane Dynam & Mech Intracellular Signaling Grp, F-75248 Paris 05, France.
   [Kenworthy, Anne K.] Vanderbilt Univ Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA.
   [Schmidt, Anne A.] Univ Paris Diderot, Sorbonne Paris Cite, CNRS, UMR7592,Inst Jacques Monod, F-75205 Paris 13, France.
   [McMahon, Harvey T.] MRC, Mol Biol Lab, Cambridge CB2 0QH, England.
C3 UNICANCER; Universite PSL; Institut Curie; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Chemistry (INC); Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Sorbonne Universite; UNICANCER; Universite PSL; Institut Curie; University of Chicago; UNICANCER; Universite PSL; Institut Curie; Sorbonne Universite; Universite Paris Cite; University of London; Birkbeck University London; University College London; University of London; Birkbeck University London; UNICANCER; Universite PSL; Institut Curie; Vanderbilt University; Universite Paris Cite; Centre National de la Recherche Scientifique (CNRS); MRC Laboratory Molecular Biology
RP Johannes, L (corresponding author), Inst Curie, Ctr Rech, Endocyt Trafficking & Therapeut Delivery Grp, 26 Rue Ulm, F-75248 Paris 05, France.
EM ludger.johannes@curie.fr
FU Agence Nationale pour la Recherche [ANR-09-BLAN-283, ANR-10-LBX-0038, ANR-11BSV201403, ANR-12-BSV5-0014]; Indo-French Centre for the Promotion of Advanced Science [3803]; Marie Curie Actions - Networks for Initial Training [FP7-PEOPLE-2010-ITN]; European Research Council [340485]; Marie Curie International Reintegration Grant [FP7-RG-277078]; Royal Society [RG120481]; Fondation ARC pour la Recherche sur le Cancer [DEQ20120323737]; National Institutes of Health [R01 GM106720]; La Ligue contre le Cancer, Comite de Paris [RS08/75-89]; Fondation ARC pour la Recherche sur le Cancer; AXA Research Funds; Biological Sciences Research Council; Chateaubriand fellowship; France and Chicago Collaborating in the Sciences grant; Biotechnology and Biological Sciences Research Council [BB/I018921/1] Funding Source: researchfish; Medical Research Council [MC_U105178795] Funding Source: researchfish; Agence Nationale de la Recherche (ANR) [ANR-12-BSV5-0014] Funding Source: Agence Nationale de la Recherche (ANR); BBSRC [BB/I018921/1] Funding Source: UKRI; MRC [MC_U105178795] Funding Source: UKRI
NR 44
TC 248
Z9 279
U1 0
U2 119
PU NATURE PUBLISHING 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 22
PY 2015
VL 517
IS 7535
BP 493
EP +
DI 10.1038/nature14064
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AZ4MU
UT WOS:000348196500036
PM 25517096
DA 2026-03-09
ER

PT J
AU Marini, B
   Kertesz-Farkas, A
   Ali, H
   Lucic, B
   Lisek, K
   Manganaro, L
   Pongor, S
   Luzzati, R
   Recchia, A
   Mavilio, F
   Giacca, M
   Lusic, M
AF Marini, Bruna
   Kertesz-Farkas, Attila
   Ali, Hashim
   Lucic, Bojana
   Lisek, Kamil
   Manganaro, Lara
   Pongor, Sandor
   Luzzati, Roberto
   Recchia, Alessandra
   Mavilio, Fulvio
   Giacca, Mauro
   Lusic, Marina
TI Nuclear architecture dictates HIV-1 integration site selection
SO NATURE
LA English
DT Article
ID immunodeficiency-virus type-1; lentivirus vector; human genome; cells; genes; infection; latency; replication; expression; domain
AB Long-standing evidence indicates that human immunodeficiency virus type 1 (HIV-1) preferentially integrates into a subset of transcriptionally active genes of the host cell genome(1-4). However, the reason why the virus selects only certain genes among all transcriptionally active regions in a target cell remains largely unknown. Here we show that HIV-1 integration occurs in the outer shell of the nucleus in close correspondence with the nuclear pore. This region contains a series of cellular genes, which are preferentially targeted by the virus, and characterized by the presence of active transcription chromatin marks before viral infection. In contrast, the virus strongly disfavours the heterochromatic regions in the nuclear lamin-associated domains(5) and other transcriptionally active regions located centrally in the nucleus. Functional viral integrase and the presence of the cellular Nup153 and LEDGF/p75 integration cofactors are indispensable for the peripheral integration of the virus. Once integrated at the nuclear pore, the HIV-1 DNA makes contact with various nucleoporins; this association takes part in the transcriptional regulation of the viral genome. These results indicate that nuclear topography is an essential determinant of the HIV-1 life cycle.
C1 [Marini, Bruna; Ali, Hashim; Lucic, Bojana; Lisek, Kamil; Manganaro, Lara; Giacca, Mauro; Lusic, Marina] Int Ctr Genet Engn & Biotechnol, Mol Med Lab, I-34149 Trieste, Italy.
   [Kertesz-Farkas, Attila; Pongor, Sandor] Int Ctr Genet Engn & Biotechnol, Prot Struct & Bioinformat Grp, I-34149 Trieste, Italy.
   [Luzzati, Roberto] Azienda Osped Univ, Struttura Complessa Malattie Infett, I-34134 Trieste, Italy.
   [Luzzati, Roberto; Giacca, Mauro] Univ Trieste, Dept Med Surg & Hlth Sci, I-34129 Trieste, Italy.
   [Recchia, Alessandra; Mavilio, Fulvio] Univ Modena & Reggio Emilia, Dept Life Sci, I-41121 Modena, Italy.
   [Mavilio, Fulvio] Genethon, F-91002 Evry, France.
C3 International Center for Genetic Engineering & Biotechnology (ICGEB); International Center for Genetic Engineering & Biotechnology (ICGEB); University of Trieste; University Trieste Hospital; University of Trieste; Universita di Modena e Reggio Emilia
RP Giacca, M (corresponding author), Int Ctr Genet Engn & Biotechnol, Mol Med Lab, I-34149 Trieste, Italy.
EM giacca@icgeb.org; marina.lusic@med.uni-heidelberg.de
FU Italian National Research Programme on AIDS of the Istituto Superiore di Sanita, Italy; Italian Ministry of Health [RF2007-16]
NR 42
TC 256
Z9 304
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 MAY 14
PY 2015
VL 521
IS 7551
BP 227
EP +
DI 10.1038/nature14226
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH9SY
UT WOS:000354377800060
PM 25731161
DA 2026-03-09
ER

PT J
AU Ning, ZJ
   Gong, XW
   Comin, R
   Walters, G
   Fan, FJ
   Voznyy, O
   Yassitepe, E
   Buin, A
   Hoogland, S
   Sargent, EH
AF Ning, Zhijun
   Gong, Xiwen
   Comin, Riccardo
   Walters, Grant
   Fan, Fengjia
   Voznyy, Oleksandr
   Yassitepe, Emre
   Buin, Andrei
   Hoogland, Sjoerd
   Sargent, Edward H.
TI Quantum-dot-in-perovskite solids
SO NATURE
LA English
DT Article
ID pbs nanocrystals; diffusion
AB Heteroepitaxy-atomically aligned growth of a crystalline film atop a different crystalline substrate-is the basis of electrically driven lasers, multijunction solar cells, and blue-light-emitting diodes(1-5). Crystalline coherence is preserved even when atomic identity is modulated, a fact that is the critical enabler of quantum wells, wires, and dots(6-10). The interfacial quality achieved as a result of hetero-epitaxial growth allows new combinations of materials with complementary properties, which enables the design and realization of functionalities that are not available in the single-phase constituents. Here we show that organohalide perovskites and preformed colloidal quantum dots, combined in the solution phase, produce epitaxially aligned 'dots-in-a-matrix' crystals. Using transmission electron microscopy and electron diffraction, we reveal heterocrystals as large as about 60 nanometres and containing at least 20 mutually aligned dots that inherit the crystalline orientation of the perovskite matrix. The heterocrystals exhibit remarkable optoelectronic properties that are traceable to their atom-scale crystalline coherence: photoelectrons and holes generated in the larger-bandgap perovskites are transferred with 80% efficiency to become excitons in the quantum dot nanocrystals, which exploit the excellent photocarrier diffusion of perovskites to produce bright-light emission from infrared-bandgap quantum-tuned materials. By combining the electrical transport properties of the perovskite matrix with the high radiative efficiency of the quantum dots, we engineer a new platform to advance solution-processed infrared optoelectronics.
C1 [Ning, Zhijun; Gong, Xiwen; Comin, Riccardo; Walters, Grant; Fan, Fengjia; Voznyy, Oleksandr; Yassitepe, Emre; Buin, Andrei; Hoogland, Sjoerd; Sargent, Edward H.] Univ Toronto, Dept Elect & Comp Engn, Toronto, ON M5S 1A4, Canada.
C3 University of Toronto
RP Sargent, EH (corresponding author), Univ Toronto, Dept Elect & Comp Engn, 35 St George St, Toronto, ON M5S 1A4, Canada.
EM ted.sargent@utoronto.ca
FU King Abdullah University of Science and Technology (KAUST) [KUS-11-009-21]; Ontario Research Fund Research Excellence Program; Natural Sciences and Engineering Research Council (NSERC) of Canada; FAPESP-BEPE [14/18327-9]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [14/18327-9] Funding Source: FAPESP
NR 42
TC 526
Z9 577
U1 15
U2 1444
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 16
PY 2015
VL 523
IS 7560
BP 324
EP +
DI 10.1038/nature14563
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM8KY
UT WOS:000357950900037
PM 26178963
DA 2026-03-09
ER

PT J
AU Tsubogo, T
   Oyamada, H
   Kobayashi, S
AF Tsubogo, Tetsu
   Oyamada, Hidekazu
   Kobayashi, Shu
TI Multistep continuous-flow synthesis of (R) - and (S) -rolipram using heterogeneous catalysts
SO NATURE
LA English
DT Article
ID carbon bond formation; hydrogenation; chemistry; mechanism; reactors; tools
AB Chemical manufacturing is conducted using either batch systems or continuous-flow systems. Flow systems have several advantages over batch systems, particularly in terms of productivity, heat and mixing efficiency, safety, and reproducibility'. However, for over half a century, pharmaceutical manufacturing has used batch systems because the synthesis of complex molecules such as drugs has been difficult to achieve with continuous-flow systems'''. Here we describe the continuous-flow synthesis of drugs using only columns packed with heterogeneous catalysts. Commercially available starting materials were successively passed through four columns containing achiral and chiral heterogeneous catalysts to produce (R)-rolipram', an anti-inflammatory drug and one of the family of y-aminobutyric acid (GABA) derivatives'. In addition, simply by replacing a column packed with a chiral heterogeneous catalyst with another column packed with the opposing enantiomer, we obtained antipole (S)-rolipram. Similarly, we also synthesized (R)-phenibut, another drug belonging to the GABA family. These flow systems are simple and stable with no leaching of metal catalysts. Our results demonstrate that multistep (eight steps in this case) chemical transformations for drug synthesis can proceed smoothly under flow conditions using only heterogeneous catalysts, without the isolation of any intermediates and without the separation of any catalysts, co-products, by-products, and excess reagents. We anticipate that such syntheses will be useful in pharmaceutical manufacturing.
C1 [Tsubogo, Tetsu; Oyamada, Hidekazu; Kobayashi, Shu] Univ Tokyo, Sch Sci, Dept Chem, Bunkyo Ku, Tokyo 1130033, Japan.
   [Tsubogo, Tetsu; Oyamada, Hidekazu; Kobayashi, Shu] Univ Tokyo, Sch Sci, Green & Sustainable Chem Social Cooperat Lab, Bunkyo Ku, Tokyo 1130033, Japan.
C3 University of Tokyo; University of Tokyo
RP Kobayashi, S (corresponding author), Univ Tokyo, Sch Sci, Dept Chem, Bunkyo Ku, Tokyo 1130033, Japan.
EM shu_kobayashi@chem.s.u-tokyo.ac.jp
FU Global COE Program, The University of Tokyo, MEXT, Japan; ACT-C; Center of Innovation (COI) Program; Japan Science and Technology Agency (JST)
NR 30
TC 341
Z9 361
U1 3
U2 294
PU NATURE PUBLISHING 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 16
PY 2015
VL 520
IS 7547
BP 329
EP 332
DI 10.1038/nature14343
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG0RI
UT WOS:000352974200034
PM 25877201
DA 2026-03-09
ER

PT J
AU Nishi, A
   Shirado, H
   Rand, DG
   Christakis, NA
AF Nishi, Akihiro
   Shirado, Hirokazu
   Rand, David G.
   Christakis, Nicholas A.
TI Inequality and visibility of wealth in experimental social networks
SO NATURE
LA English
DT Article
ID hunter-gatherers; promote cooperation; humans; preferences; aversion
AB Humans prefer relatively equal distributions of resources(1-5), yet societies have varying degrees of economic inequality(6). To investigate some of the possible determinants and consequences of inequality, here we perform experiments involving a networked public goods game in which subjects interact and gain or lose wealth. Subjects (n =1,462) were randomly assigned to have higher or lower initial endowments, and were embedded within social networks with three levels of economic inequality (Gini coefficient=0.0, 0.2, and 0.4). In addition, we manipulated the visibility of the wealth of network neighbours. We show that wealth visibility facilitates the downstream consequences of initial inequality-in initially more unequal situations, wealth visibility leads to greater inequality than when wealth is invisible. This result reflects a heterogeneous response to visibility in richer versus poorer subjects. We also find that making wealth visible has adverse welfare consequences, yielding lower levels of overall cooperation, inter-connectedness, and wealth. High initial levels of economic inequality alone, however, have relatively few deleterious welfare effects.
C1 [Nishi, Akihiro; Shirado, Hirokazu; Rand, David G.; Christakis, Nicholas A.] Yale Univ, Yale Inst Network Sci, New Haven, CT 06520 USA.
   [Nishi, Akihiro; Shirado, Hirokazu; Christakis, Nicholas A.] Yale Univ, Dept Sociol, New Haven, CT 06520 USA.
   [Rand, David G.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA.
   [Rand, David G.] Yale Univ, Dept Econ, New Haven, CT 06520 USA.
   [Christakis, Nicholas A.] Yale Univ, Dept Ecol & Evolutionary Biol, New Haven, CT 06520 USA.
   [Christakis, Nicholas A.] Yale Univ, Dept Med, New Haven, CT 06520 USA.
C3 Yale University; Yale University; Yale University; Yale University; Yale University; Yale University
RP Christakis, NA (corresponding author), Yale Univ, Yale Inst Network Sci, New Haven, CT 06520 USA.
EM nicholas.christakis@yale.edu
FU Japan Society for the Promotion of Science (JSPS); Robert Wood Johnson Foundation
NR 30
TC 291
Z9 328
U1 5
U2 249
PU NATURE PUBLISHING 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 15
PY 2015
VL 526
IS 7573
BP 426
EP +
DI 10.1038/nature15392
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200050
PM 26352469
DA 2026-03-09
ER

PT J
AU Shalapour, S
   Font-Burgada, J
   Di Caro, G
   Zhong, ZY
   Sanchez-Lopez, E
   Dhar, D
   Willimsky, G
   Ammirante, M
   Strasner, A
   Hansel, DE
   Jamieson, C
   Kane, CJ
   Klatte, T
   Birner, P
   Kenner, L
   Karin, M
AF Shalapour, Shabnam
   Font-Burgada, Joan
   Di Caro, Giuseppe
   Zhong, Zhenyu
   Sanchez-Lopez, Elsa
   Dhar, Debanjan
   Willimsky, Gerald
   Ammirante, Massimo
   Strasner, Amy
   Hansel, Donna E.
   Jamieson, Christina
   Kane, Christopher J.
   Klatte, Tobias
   Birner, Peter
   Kenner, Lukas
   Karin, Michael
TI Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy
SO NATURE
LA English
DT Article
ID gene-expression analysis; infiltrating b-cells; prostate-cancer; targeted deletion; mice; autoimmunity; metastasis; mechanisms; immunity; therapy
AB Cancer-associated genetic alterations induce expression of tumour antigens that can activate CD8(+) cytotoxic T cells (CTLs), but the microenvironment of established tumours promotes immune tolerance through poorly understood mechanisms(1,2). Recently developed therapeutics that overcome tolerogenic mechanisms activate tumour-directed CTLs and are effective in some human cancers(1). Immune mechanisms also affect treatment outcome, and certain chemotherapeutic drugs stimulate cancer-specific immune responses by inducing immunogenic cell death and other effector mechanisms(3,4). Our previous studies revealed that B cells recruited by the chemokine CXCL13 into prostate cancer tumours promote the progression of castrate-resistant prostate cancer by producing lymphotoxin, which activates an IkB kinase a (IKK alpha)-BMI1 module in prostate cancer stem cells(5,6). Because castrate-resistant prostate cancer is refractory to most therapies, we examined B cell involvement in the acquisition of chemotherapy resistance. Here we focus on oxaliplatin, an immunogenic chemotherapeutic agent(3,4) that is effective in aggressive prostate cancer(7). We show that mouse B cells modulate the response to low-dose oxaliplatin, which promotes tumour-directed CTL activation by inducing immunogenic cell death. Three different mouse prostate cancer models were refractory to oxaliplatin unless genetically or pharmacologically depleted of B cells. The crucial immunosuppressive B cells are plasmocytes that express IgA, interleukin (IL)-10 and programmed death ligand 1 (PD-L1), the appearance of which depends on TGF beta receptor signalling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumours.
C1 [Shalapour, Shabnam; Font-Burgada, Joan; Di Caro, Giuseppe; Zhong, Zhenyu; Sanchez-Lopez, Elsa; Dhar, Debanjan; Ammirante, Massimo; Strasner, Amy; Karin, Michael] UCSD, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA.
   [Shalapour, Shabnam; Font-Burgada, Joan; Di Caro, Giuseppe; Zhong, Zhenyu; Sanchez-Lopez, Elsa; Dhar, Debanjan; Ammirante, Massimo; Strasner, Amy; Hansel, Donna E.; Karin, Michael] Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA.
   [Willimsky, Gerald] Charite Campus Buch, Inst Immunol, D-13125 Berlin, Germany.
   [Jamieson, Christina; Kane, Christopher J.] Univ Calif San Diego, Div Urol, Dept Surg, San Diego, CA 92093 USA.
   [Klatte, Tobias] Med Univ Vienna, Dept Urol, A-1090 Vienna, Austria.
   [Birner, Peter; Kenner, Lukas] Med Univ Vienna, Dept Pathol, A-1090 Vienna, Austria.
   [Kenner, Lukas] Univ Vet Med Vienna, Med Univ Vienna, Ludwig Boltzmann Inst Canc Res, Clin Inst Pathol,UPLA, A-1210 Vienna, Austria.
C3 University of California System; University of California San Diego; University of California System; University of California San Diego; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; University of California System; University of California San Diego; Medical University of Vienna; Medical University of Vienna; University of Veterinary Medicine Vienna; Medical University of Vienna; Ludwig Boltzmann Institute; Ludwig Boltzmann Institute for Cancer Research
RP Karin, M (corresponding author), UCSD, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, 9500 Gilman Dr, La Jolla, CA 92093 USA.
EM karinoffice@ucsd.edu
FU National Institutes of Health (NIH) [CA127923, AI043477]; DFG; German Cancer Consortium [TR36, DKTK]; Genome Research-Austria project 'Inflammobiota' (FWF) [P26011]; Cure Search Foundation; German Research Foundation (DFG) [SH721/1-1]; Irvington-CRI; CIRM [TG2-01154]; FIRC/AIRC
NR 57
TC 492
Z9 582
U1 4
U2 192
PU NATURE PUBLISHING 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 7
PY 2015
VL 521
IS 7550
BP 94
EP U235
DI 10.1038/nature14395
PG 26
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH4YS
UT WOS:000354040900040
PM 25924065
DA 2026-03-09
ER

PT J
AU Sugimoto, Y
   Vigilante, A
   Darbo, E
   Zirra, A
   Militti, C
   D'Ambrogio, A
   Luscombe, NM
   Ule, J
AF Sugimoto, Yoichiro
   Vigilante, Alessandra
   Darbo, Elodie
   Zirra, Alexandra
   Militti, Cristina
   D'Ambrogio, Andrea
   Luscombe, Nicholas M.
   Ule, Jernej
TI hiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1
SO NATURE
LA English
DT Article
ID genome-wide analysis; binding protein; cross-linking; translation; transcriptome; suppressor; localizes; ligation; package; cells
AB The structure of messenger RNA is important for post-transcriptional regulation, mainly because it affects binding of trans-acting factors(1). However, little is known about the in vivo structure of full-length mRNAs. Here we present hiCLIP, a biochemical technique for transcriptome-wide identification of RNA secondary structures interacting with RNA-binding proteins (RBPs). Using this technique to investigate RNA structures bound by Staufen 1 (STAU1) in human cells, we uncover a dominance of intra-molecular RNA duplexes, a depletion of duplexes from coding regions of highly translated mRNAs, an unexpected prevalence of long-range duplexes in 39 untranslated regions (UTRs), and a decreased incidence of single nucleotide polymorphisms in duplex-forming regions. We also discover a duplex spanning 858 nucleotides in the 39 UTR of the X-box binding protein 1 (XBP1) mRNA that regulates its cytoplasmic splicing and stability. Our study reveals the fundamental role of mRNA secondary structures in gene expression and introduce shiCLIPas a widely applicable method for discovering new, especially long-range, RNA duplexes.
C1 [Sugimoto, Yoichiro; D'Ambrogio, Andrea; Ule, Jernej] MRC, Mol Biol Lab, Cambridge CB2 0QH, England.
   [Zirra, Alexandra; Militti, Cristina; D'Ambrogio, Andrea; Ule, Jernej] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England.
   [Vigilante, Alessandra; Darbo, Elodie; Luscombe, Nicholas M.] Canc Res UK London Res Inst, London WC2A 3LY, England.
   [Vigilante, Alessandra; Luscombe, Nicholas M.] UCL, UCL Genet Inst, Dept Genet Evolut & Environm, London WC1E 6BT, England.
   [Luscombe, Nicholas M.] Okinawa Inst Sci & Technol, Onna Son, Okinawa 9040495, Japan.
C3 MRC Laboratory Molecular Biology; University of London; University College London; Cancer Research UK; University of London; University College London; Okinawa Institute of Science & Technology Graduate University
RP Ule, J (corresponding author), MRC, Mol Biol Lab, Francis Crick Ave,Cambridge Biomed Campus, Cambridge CB2 0QH, England.
EM nicholas.luscombe@ucl.ac.uk; j.ule@ucl.ac.uk
FU Human Frontier Science Program [RGP0024/2008-C]; European Research Council [206726-CLIP, 617837-Translate]; Medical Research Council [U105185858]; Cancer Research UK; UCL; Wellcome Trust [103760/Z/14/Z]; Nakajima Foundation; MRC; Cancer Research UK [16358] Funding Source: researchfish; Medical Research Council [MC_U105185858] Funding Source: researchfish; The Francis Crick Institute [10110] Funding Source: researchfish; Wellcome Trust [103760/Z/14/Z] Funding Source: researchfish; MRC [MC_U105185858] Funding Source: UKRI
NR 59
TC 220
Z9 255
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 MAR 26
PY 2015
VL 519
IS 7544
BP 491
EP +
DI 10.1038/nature14280
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE1WF
UT WOS:000351602800060
PM 25799984
DA 2026-03-09
ER

PT J
AU Palikaras, K
   Lionaki, E
   Tavernarakis, N
AF Palikaras, Konstantinos
   Lionaki, Eirini
   Tavernarakis, Nektarios
TI Coordination of mitophagy and mitochondrial biogenesis during ageing in C-elegans
SO NATURE
LA English
DT Article
ID extends life-span; cell-death; nix; metabolism; clearance; longevity; autophagy; diapause; protein; genes
AB Impaired mitochondrial maintenance in disparate cell types is a shared hallmark of many human pathologies and ageing(1-8). How mitochondrial biogenesis coordinates with the removal of damaged or superfluous mitochondria to maintain cellular homeostasis is not well understood. Here we show that mitophagy, a selective type of autophagy targeting mitochondria for degradation, interfaces with mitochondrial biogenesis to regulate mitochondrial content and longevity in Caenorhabditis elegans. We find that DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans. Impairment of mitophagy compromises stress resistance and triggers mitochondrial retrograde signalling through the SKN-1 transcription factor that regulates both mitochondrial biogenesis genes and mitophagy by enhancing DCT-1 expression. Our findings reveal a homeostatic feedback loop that integrates metabolic signals to coordinate the biogenesis and turnover of mitochondria. Uncoupling of these two processes during ageing contributes to overproliferation of damaged mitochondria and decline of cellular function.
C1 [Palikaras, Konstantinos; Lionaki, Eirini; Tavernarakis, Nektarios] Fdn Res & Technol Hellas, Inst Mol Biol & Biotechnol, Iraklion 70013, Crete, Greece.
   [Palikaras, Konstantinos] Univ Crete, Dept Biol, Iraklion 70013, Crete, Greece.
   [Tavernarakis, Nektarios] Univ Crete, Fac Med, Dept Basic Sci, Iraklion 71110, Crete, Greece.
C3 Foundation for Research & Technology - Hellas (FORTH); University of Crete; University of Crete
RP Tavernarakis, N (corresponding author), Fdn Res & Technol Hellas, Inst Mol Biol & Biotechnol, Nikolaou Plastira 100, Iraklion 70013, Crete, Greece.
EM tavernarakis@imbb.forth.gr
FU National Center for Research Resources of the National Institutes of Health; National Bioresource Project in Japan; European Research Council; European Commission; Greek General Secretariat for Research and Technology
NR 38
TC 592
Z9 667
U1 13
U2 292
PU NATURE PUBLISHING 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 28
PY 2015
VL 521
IS 7553
BP 525
EP U241
DI 10.1038/nature14300
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ2AN
UT WOS:000355286600044
PM 25896323
DA 2026-03-09
ER

PT J
AU Munjal, A
   Philippe, JM
   Munro, E
   Lecuit, T
AF Munjal, Akankshi
   Philippe, Jean-Marc
   Munro, Edwin
   Lecuit, Thomas
TI A self-organized biomechanical network drives shape changes during tissue morphogenesis
SO NATURE
LA English
DT Article
ID light-chain; myosin phosphorylation; apical constriction; nonmuscle myosin; drosophila; dynamics; actin; contractions; cytokinesis; elongation
AB Tissue morphogenesis is orchestrated by cell shape changes. Forces required to power these changes are generated by non-muscle myosin II (MyoII) motor proteins pulling filamentous actin (F-actin). Actomyosin networks undergo cycles of assembly and disassembly (pulses)(1,2) to cause cell deformations alternating with steps of stabilization to result in irreversible shape changes(3-6). Although this ratchet-like behaviour operates in a variety of contexts, the underlying mechanisms remain unclear. Here we investigate the role of MyoII regulation through the conserved Rho1-Rok pathway(7) during Drosophila melanogaster germband extension. This morphogenetic process is powered by cell intercalation, which involves the shrinkage of junctions in the dorsal-ventral axis (vertical junctions) followed by junction extension in the anterior-posterior axis(8). While polarized flows of medial-apical MyoII pulses deform vertical junctions, MyoII enrichment on these junctions (planar polarity) stabilizes them(6). We identify two critical properties of MyoII dynamics that underlie stability and pulsatility: exchange kinetics governed by phosphorylation-dephosphorylation cycles of the MyoII regulatory light chain; and advection due to contraction of the motors on F-actin networks. Spatial control over MyoII exchange kinetics establishes two stable regimes of high and low dissociation rates, resulting in MyoII planar polarity. Pulsatility emerges at intermediate dissociation rates, enabling convergent advection of MyoII and its upstream regulators Rho1 GTP, Rok and MyoII phosphatase. Notably, pulsatility is not an outcome of an upstream Rho1 pacemaker. Rather, it is a self-organized system that involves positive and negative biomechanical feedback between MyoII advection and dissociation rates.
C1 [Munjal, Akankshi; Philippe, Jean-Marc; Lecuit, Thomas] Aix Marseille Univ, CNRS, IBDM UMR7288, F-13009 Marseille, France.
   [Munro, Edwin] Univ Chicago, Dept Mol Genet & Cell Biol, Chicago, IL 60637 USA.
C3 Aix-Marseille Universite; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); University of Chicago
RP Lecuit, T (corresponding author), Aix Marseille Univ, CNRS, IBDM UMR7288, F-13009 Marseille, France.
EM thomas.lecuit@univ-amu.fr
FU Labex INFORM [ANR-11-LABX-0054]; ANR Archiplast; ERC (Biomecamorph) [323027]; HFSP; Ministere de l'Education nationale; Association pour la Recherche contre le Cancer (ARC); France-BioImaging/PICsL infrastructure [ANR-10-INSB-04-01]; European Research Council (ERC) [323027] Funding Source: European Research Council (ERC)
NR 31
TC 269
Z9 337
U1 0
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 20
PY 2015
VL 524
IS 7565
BP 351
EP +
DI 10.1038/nature14603
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP2NN
UT WOS:000359714000036
PM 26214737
DA 2026-03-09
ER

PT J
AU Collins, SH
   Wiggin, MB
   Sawicki, GS
AF Collins, Steven H.
   Wiggin, M. Bruce
   Sawicki, Gregory S.
TI Reducing the energy cost of human walking using an unpowered exoskeleton
SO NATURE
LA English
DT Article
ID work; expenditure; energetics; mechanics; biomechanics; gait; mass
AB With efficiencies derived from evolution, growth and learning, humans are very well-tuned for locomotion(1). Metabolic energy used during walking can be partly replaced by power input from an exoskeleton(2), but is it possible to reduce metabolic rate without providing an additional energy source? This would require an improvement in the efficiency of the human-machine system as a whole, and would be remarkable given the apparent optimality of human gait. Here we show that the metabolic rate of human walking can be reduced by an unpowered ankle exoskeleton. We built a lightweight elastic device that acts in parallel with the user's calf muscles, off-loading muscle force and thereby reducing the metabolic energy consumed in contractions. The device uses a mechanical clutch to hold a spring as it is stretched and relaxed by ankle movements when the foot is on the ground, helping to fulfil one function of the calf muscles and Achilles tendon. Unlike muscles, however, the clutch sustains force passively. The exoskeleton consumes no chemical or electrical energy and delivers no net positive mechanical work, yet reduces the metabolic cost of walking by 7.2 +/- 2.6% for healthy human users under natural conditions, comparable to savings with powered devices. Improving upon walking economy in this way is analogous to altering the structure of the body such that it is more energy-effective at walking. While strong natural pressures have already shaped human locomotion, improvements in efficiency are still possible. Much remains to be learned about this seemingly simple behaviour.
C1 [Collins, Steven H.] Carnegie Mellon Univ, Dept Mech Engn, Pittsburgh, PA 15213 USA.
   [Wiggin, M. Bruce; Sawicki, Gregory S.] N Carolina State Univ, Joint Dept Biomed Engn, Raleigh, NC 27695 USA.
   [Wiggin, M. Bruce; Sawicki, Gregory S.] Univ North Carolina Chapel Hill, Raleigh, NC 27695 USA.
C3 Carnegie Mellon University; North Carolina State University; University of North Carolina; University of North Carolina Chapel Hill
RP Collins, SH (corresponding author), Carnegie Mellon Univ, Dept Mech Engn, 5000 Forbes Ave, Pittsburgh, PA 15213 USA.
EM stevecollins@cmu.edu; greg_sawicki@ncsu.edu
FU North Carolina State Faculty Research and Professional Development Fund; North Carolina State Chancellors Innovation Fund; United States - Israel Binational Science Foundation [2011152]; National Institute of Nursing Research of the National Institutes of Health [R01NR014756]; National Science Foundation [IIS-1355716]; Div Of Civil, Mechanical, & Manufact Inn; Directorate For Engineering [1355716] Funding Source: National Science Foundation
NR 38
TC 779
Z9 975
U1 29
U2 855
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 11
PY 2015
VL 522
IS 7555
BP 212
EP +
DI 10.1038/nature14288
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700038
PM 25830889
DA 2026-03-09
ER

PT J
AU Hohenleutner, M
   Langer, F
   Schubert, O
   Knorr, M
   Huttner, U
   Koch, SW
   Kira, M
   Huber, R
AF Hohenleutner, M.
   Langer, F.
   Schubert, O.
   Knorr, M.
   Huttner, U.
   Koch, S. W.
   Kira, M.
   Huber, R.
TI Real-time observation of interfering crystal electrons in high-harmonic generation
SO NATURE
LA English
DT Article
ID ultrashort laser-pulses; attosecond pulses; terahertz pulses; nonlinear optics; dynamics; molecules
AB Acceleration and collision of particles has been a key strategy for exploring the texture of matter. Strong light waves can control and recollide electronic wavepackets, generating high-harmonic radiation that encodes the structure and dynamics of atoms and molecules and lays the foundations of attosecond science(1-3). The recent discovery of high-harmonic generation in bulk solids(4-6) combines the idea of ultrafast acceleration with complex condensed matter systems, and provides hope for compact solid-state attosecond sources(6-8) and electronics at optical frequencies(3,5,9,10). Yet the underlying quantum motion has not so far been observable in real time. Here we study high-harmonic generation in a bulk solid directly in the time domain, and reveal a new kind of strong-field excitation in the crystal. Unlike established atomic sources(1-3,9,11), our solid emits high-harmonic radiation as a sequence of subcycle bursts that coincide temporally with the field crests of one polarity of the driving terahertz waveform. We show that these features are characteristic of a non-perturbative quantum interference process that involves electrons from multiple valence bands. These results identify key mechanisms for future solid-state attosecond sources and next-generation light-wave electronics. The new quantum interference process justifies the hope for all-optical band-structure reconstruction and lays the foundation for possible quantum logic operations at optical clock rates.
C1 [Hohenleutner, M.; Langer, F.; Schubert, O.; Knorr, M.; Huber, R.] Univ Regensburg, Dept Phys, D-93040 Regensburg, Germany.
   [Huttner, U.; Koch, S. W.; Kira, M.] Univ Marburg, Dept Phys, D-35032 Marburg, Germany.
C3 University of Regensburg; Philipps University Marburg
RP Huber, R (corresponding author), Univ Regensburg, Dept Phys, D-93040 Regensburg, Germany.
EM mackillo.kira@physik.uni-marburg.de; rupert.huber@physik.uni-regensburg.de
FU European Research Council [305003]; Deutsche Forschungsgemeinschaft [HU 1598/2-1, SFB 1083, KI 917/2-2]; European Research Council (ERC) [305003] Funding Source: European Research Council (ERC)
NR 49
TC 534
Z9 587
U1 4
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 JUL 30
PY 2015
VL 523
IS 7562
BP 572
EP +
DI 10.1038/nature14652
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN7ZL
UT WOS:000358655200040
PM 26223624
DA 2026-03-09
ER

PT J
AU Merckx, VSFT
   Hendriks, KP
   Beentjes, KK
   Mennes, CB
   Becking, LE
   Peijnenburg, KTCA
   Afendy, A
   Arumugam, N
   de Boer, H
   Biun, A
   Buang, MM
   Chen, PP
   Chung, AYC
   Dow, R
   Feijen, FAA
   Feijen, H
   Soest, CFV
   Geml, J
   Geurts, R
   Gravendeel, B
   Hovenkamp, P
   Imbun, P
   Ipor, I
   Janssens, SB
   Jocque, M
   Kappes, H
   Khoo, E
   Koomen, P
   Lens, F
   Majapun, RJ
   Morgado, LN
   Neupane, S
   Nieser, N
   Pereira, JT
   Rahman, H
   Sabran, S
   Sawang, A
   Schwallier, RM
   Shim, PS
   Smit, H
   Sol, N
   Spait, M
   Stech, M
   Stokvis, F
   Sugau, JB
   Suleiman, M
   Sumail, S
   Thomas, DC
   van Tol, J
   Tuh, FYY
   Yahya, BE
   Nais, J
   Repin, R
   Lakim, M
   Schilthuizen, M
AF Merckx, Vincent S. F. T.
   Hendriks, Kasper P.
   Beentjes, Kevin K.
   Mennes, Constantijn B.
   Becking, Leontine E.
   Peijnenburg, Katja T. C. A.
   Afendy, Aqilah
   Arumugam, Nivaarani
   de Boer, Hugo
   Biun, Alim
   Buang, Matsain M.
   Chen, Ping-Ping
   Chung, Arthur Y. C.
   Dow, Rory
   Feijen, Frida A. A.
   Feijen, Hans
   Soest, Cobi Feijen-van
   Geml, Jozsef
   Geurts, Rene
   Gravendeel, Barbara
   Hovenkamp, Peter
   Imbun, Paul
   Ipor, Isa
   Janssens, Steven B.
   Jocque, Merlijn
   Kappes, Heike
   Khoo, Eyen
   Koomen, Peter
   Lens, Frederic
   Majapun, Richard J.
   Morgado, Luis N.
   Neupane, Suman
   Nieser, Nico
   Pereira, Joan T.
   Rahman, Homathevi
   Sabran, Suzana
   Sawang, Anati
   Schwallier, Rachel M.
   Shim, Phyau-Soon
   Smit, Harry
   Sol, Nicolien
   Spait, Maipul
   Stech, Michael
   Stokvis, Frank
   Sugau, John B.
   Suleiman, Monica
   Sumail, Sukaibin
   Thomas, Daniel C.
   van Tol, Jan
   Tuh, Fred Y. Y.
   Yahya, Bakhtiar E.
   Nais, Jamili
   Repin, Rimi
   Lakim, Maklarin
   Schilthuizen, Menno
TI Evolution of endemismon a young tropical mountain
SO NATURE
LA English
DT Article
ID diversification; biodiversity; kinabalu; islands; forests; origin; model
AB Tropical mountains are hot spots of biodiversity and endemism(1-3), but the evolutionary origins of their unique biotas are poorly understood(4). In varying degrees, local and regional extinction, long-distance colonization, and local recruitment may all contribute to the exceptional character of these communities(5). Also, it is debated whether mountain endemics mostly originate from local lowland taxa, or from lineages that reach the mountain by long-range dispersal from cool localities elsewhere(6). Here we investigate the evolutionary routes to endemism by sampling an entire tropical mountain biota on the 4,095-metre-high Mount Kinabalu in Sabah, East Malaysia. We discover that most of its unique biodiversity is younger than the mountain itself (6 million years), and comprises a mix of immigrant pre-adapted lineages and descendants from local lowland ancestors, although substantial shifts from lower to higher vegetation zones in this latter group were rare. These insights could improve forecasts of the likelihood of extinction and 'evolutionary rescue'(7) in montane biodiversity hot spots under climate change scenarios.
C1 [Merckx, Vincent S. F. T.; Hendriks, Kasper P.; Beentjes, Kevin K.; Mennes, Constantijn B.; Becking, Leontine E.; Peijnenburg, Katja T. C. A.; de Boer, Hugo; Chen, Ping-Ping; Dow, Rory; Feijen, Frida A. A.; Feijen, Hans; Soest, Cobi Feijen-van; Geml, Jozsef; Gravendeel, Barbara; Hovenkamp, Peter; Kappes, Heike; Lens, Frederic; Morgado, Luis N.; Nieser, Nico; Schwallier, Rachel M.; Smit, Harry; Sol, Nicolien; Stech, Michael; Stokvis, Frank; Thomas, Daniel C.; van Tol, Jan; Schilthuizen, Menno] Nat Biodivers Ctr, NL-2333 CR Leiden, Netherlands.
   [Merckx, Vincent S. F. T.; Geml, Jozsef; Gravendeel, Barbara; Lens, Frederic; Schilthuizen, Menno] Leiden Univ, Inst Biol Leiden, NL-2333 BE Leiden, Netherlands.
   [Hendriks, Kasper P.] Univ Groningen, Groningen Inst Evolutionary Life Sci, NL-9747 AG Groningen, Netherlands.
   [Becking, Leontine E.] Univ Wageningen & Res Ctr, Marine Anim Ecol Grp, NL-6700 AH Wageningen, Netherlands.
   [Becking, Leontine E.] Univ Calif Berkeley, Dept Environm Sci Policy & Management, Berkeley, CA 94720 USA.
   [Peijnenburg, Katja T. C. A.] Univ Amsterdam, Inst Biodivers & Ecosystem Dynam, NL-1098 XH Amsterdam, Netherlands.
   [Afendy, Aqilah; Arumugam, Nivaarani; Rahman, Homathevi; Sawang, Anati; Suleiman, Monica; Yahya, Bakhtiar E.; Schilthuizen, Menno] Univ Malaysia Sabah, Inst Trop Biol & Conservat, Kota Kinabalu 88400, Sabah, Malaysia.
   [Arumugam, Nivaarani] Univ Malaysia Kelantan, Fac Earth Sci, Jeli 17600, Kelantan Darul, Malaysia.
   [de Boer, Hugo] Uppsala Univ, Dept Organismal Biol, S-75236 Uppsala, Sweden.
   [de Boer, Hugo] Univ Oslo, Nat Hist Museum, NO-0318 Oslo, Norway.
   [Biun, Alim; Buang, Matsain M.; Imbun, Paul; Shim, Phyau-Soon; Spait, Maipul; Sumail, Sukaibin; Tuh, Fred Y. Y.; Nais, Jamili; Repin, Rimi; Lakim, Maklarin] Sabah Pk, Kota Kinabalu 88806, Sabah, Malaysia.
   [Chung, Arthur Y. C.; Khoo, Eyen; Majapun, Richard J.; Pereira, Joan T.; Sabran, Suzana; Sugau, John B.] Forest Res Ctr, Sabah Forestry Dept, Sandakan 90175, Sabah, Malaysia.
   [Geurts, Rene] Wageningen Univ, Dept Plant Sci, Mol Biol Lab, NL-6700 AP Wageningen, Netherlands.
   [Gravendeel, Barbara] Univ Appl Sci Leiden, NL-2333 CK Leiden, Netherlands.
   [Ipor, Isa] Univ Malaysia Sarawak, Fac Resource Sci & Technol, Kota Samarahan 94300, Sarawak, Malaysia.
   [Janssens, Steven B.] Bot Garden Meise, B-1860 Meise, Belgium.
   [Jocque, Merlijn] Royal Belgian Inst Nat Sci Aquat & Terr Ecol, B-1000 Brussels, Belgium.
   [Jocque, Merlijn] Rutgers State Univ, Dept Biol Sci, Newark, NJ 07102 USA.
   [Kappes, Heike] Univ Cologne, Inst Zool, D-50674 Cologne, Germany.
   [Koomen, Peter] Nat Museum Fryslan, NL-8911 EM Leeuwarden, Netherlands.
   [Neupane, Suman] Univ Connecticut, EEB Dept, Storrs, CT 06269 USA.
   [Thomas, Daniel C.] Univ Hong Kong, Sch Biol Sci, Hong Kong, Hong Kong, Peoples R China.
   [Thomas, Daniel C.] Singapore Bot Gardens, Singapore 259569, Singapore.
C3 Naturalis Biodiversity Center; Leiden University; Leiden University - Excl LUMC; University of Groningen; Wageningen University & Research; University of California System; University of California Berkeley; University of Amsterdam; Universiti Malaysia Sabah; Universiti Malaysia Kelantan; Uppsala University; University of Oslo; Pusat Penyelidikan Hutan; Wageningen University & Research; University of Malaysia Sarawak; Royal Belgian Institute of Natural Sciences; Rutgers University System; Rutgers University Newark; Rutgers University New Brunswick; University of Cologne; University of Connecticut; University of Hong Kong
RP Schilthuizen, M (corresponding author), Nat Biodivers Ctr, Darwinweg 2, NL-2333 CR Leiden, Netherlands.
EM Menno.Schilthuizen@naturalis.nl
FU Netherlands FES; Netherlands Organization for Scientific Research [821.01.002, 825.12.007]; Alberta Mennega Foundation; Ecology Fund of the Royal Netherlands Academy of Sciences; Uyttenboogaart-Eliasen Foundation; Pro Acarologia Basiliensis; ESEB Outreach Fund; Treub Foundation
NR 34
TC 243
Z9 274
U1 2
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 AUG 20
PY 2015
VL 524
IS 7565
BP 347
EP +
DI 10.1038/nature14949
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP2NN
UT WOS:000359714000035
PM 26266979
DA 2026-03-09
ER

PT J
AU Zhou, Y
   Liu, X
   Engstrom, EM
   Nimchuk, ZL
   Pruneda-Paz, JL
   Tarr, PT
   Yan, A
   Kay, SA
   Meyerowitz, EM
AF Zhou, Yun
   Liu, Xing
   Engstrom, Eric M.
   Nimchuk, Zachary L.
   Pruneda-Paz, Jose L.
   Tarr, Paul T.
   Yan, An
   Kay, Steve A.
   Meyerowitz, Elliot M.
TI Control of plant stem cell function by conserved interacting transcriptional regulators
SO NATURE
LA English
DT Article
ID arabidopsis shoot meristems; gene-expression; protein; wuschel; patterns; maintenance; homeostasis; niches; fate; apex
AB Plant stem cells in the shoot apical meristem (SAM) and root apical meristem are necessary for postembryonic development of above-ground tissues and roots, respectively, while secondary vascular stem cells sustain vascular development(1-4). WUSCHEL (WUS), a homeodomain transcription factor expressed in the rib meristem of the Arabidopsis SAM, is a key regulatory factor controlling SAM stem cell populations(5,6), and is thought to establish the shoot stem cell niche through a feedback circuit involving the CLAVATA3 (CLV3) peptide signalling pathway(7). WUSCHEL-RELATED HOMEOBOX 5 (WOX5), which is specifically expressed in the root quiescent centre, defines quiescent centre identity and functions interchangeably with WUS in the control of shoot and root stem cell niches(8). WOX4, expressed in Arabidopsisprocambial cells, defines the vascular stem cell niche(9-11). WUS/WOX family proteins are evolutionarily and functionally conserved throughout the plant kingdom(1,2) and emerge as key actors in the specification and maintenance of stem cells within all meristems13. However, the nature of the genetic regime in stem cell niches that centre on WOX gene function has been elusive, and molecular links underlying conserved WUS/WOX function in stem cell niches remain unknown. Here we demonstrate that the Arabidopsis HAIRY MERISTEM (HAM) family of transcription regulators act as conserved interacting cofactors with WUS/WOX proteins. HAM and WUS share common targets in vivo and their physical interaction is important in driving downstream transcriptional programs and in promoting shoot stem cell proliferation. Differences in the overlapping expression patterns of WOX and HAM family members underlie the formation of diverse stem cell niche locations, and the HAM family is essential for all of these stem cell niches. These findings establish a new framework for the control of stem cell production during plant development.
C1 [Zhou, Yun; Liu, Xing; Nimchuk, Zachary L.; Tarr, Paul T.; Yan, An; Meyerowitz, Elliot M.] CALTECH, Div Biol, Pasadena, CA 91125 USA.
   [Engstrom, Eric M.] Coll William & Mary, Dept Biol, Williamsburg, VA 23187 USA.
   [Nimchuk, Zachary L.; Meyerowitz, Elliot M.] CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA.
   [Pruneda-Paz, Jose L.] Univ Calif San Diego, Sect Cell & Dev Biol, Div Biol Sci, La Jolla, CA 92093 USA.
   [Kay, Steve A.] Univ So Calif, Dept Biol Sci, Dana & David Dornsife Coll Letters Arts & Sci, Los Angeles, CA 90089 USA.
C3 California Institute of Technology; William & Mary; California Institute of Technology; Howard Hughes Medical Institute; University of California System; University of California San Diego; University of Southern California
RP Meyerowitz, EM (corresponding author), CALTECH, Div Biol, 1200 East Calif Blvd, Pasadena, CA 91125 USA.
EM meyerow@caltech.edu
FU National Institutes of Health (NIH) [R01 GM104244]; Howard Hughes Medical Institute; Gordon and Betty Moore Foundation [GBMF3406]; NIH [GM094212, GM056006, GM067837]; Jane Coffin Childs (JCC) Memorial Fund for Medical Research; National Institute of General Medical Sciences [R37GM067837] Funding Source: NIH RePORTER
NR 41
TC 208
Z9 238
U1 7
U2 246
PU NATURE PUBLISHING 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 15
PY 2015
VL 517
IS 7534
BP 377
EP U528
DI 10.1038/nature13853
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300048
PM 25363783
DA 2026-03-09
ER

PT J
AU McHugh, CA
   Chen, CK
   Chow, A
   Surka, CF
   Tran, C
   McDonel, P
   Pandya-Jones, A
   Blanco, M
   Burghard, C
   Moradian, A
   Sweredoski, MJ
   Shishkin, AA
   Su, JL
   Lander, ES
   Hess, S
   Plath, K
   Guttman, M
AF McHugh, Colleen A.
   Chen, Chun-Kan
   Chow, Amy
   Surka, Christine F.
   Tran, Christina
   McDonel, Patrick
   Pandya-Jones, Amy
   Blanco, Mario
   Burghard, Christina
   Moradian, Annie
   Sweredoski, Michael J.
   Shishkin, Alexander A.
   Su, Julia
   Lander, Eric S.
   Hess, Sonja
   Plath, Kathrin
   Guttman, Mitchell
TI The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3
SO NATURE
LA English
DT Article
ID identification rates; matrix protein; x-inactivation; rna; binding; repression; prc2; dna; localization; recruitment
AB Many long non-coding RNAs (lncRNAs) affect gene expression(1), but the mechanisms by which they act are still largely unknown(2). One of the best-studied lncRNAs is Xist, which is required for transcriptional silencing of one X chromosome during development in female mammals(3,4). Despite extensive efforts to define the mechanism of Xist-mediated transcriptional silencing, we still do not know any proteins required for this role(3). The main challenge is that there are currently no methods to comprehensively define the proteins that directly interact with a lncRNA in the cell(5). Here we develop a method to purify a lncRNA from cells and identify proteins interacting with it directly using quantitative mass spectrometry. We identify ten proteins that specifically associate with Xist, three of these proteins-SHARP, SAF-A and LBR-are required for Xist-mediated transcriptional silencing. We show that SHARP, which interacts with the SMRT co-repressor(6) that activates HDAC3(7), is not only essential for silencing, but is also required for the exclusion of RNA polymerase II (Pol II) from the inactive X. Both SMRT and HDAC3 are also required for silencing and Pol II exclusion. In addition to silencing transcription, SHARP and HDAC3 are required for Xist-mediated recruitment of the polycomb repressive complex 2 (PRC2) across the X chromosome. Our results suggest that Xist silences transcription by directly interacting with SHARP, recruiting SMRT, activating HDAC3, and deacetylating histones to exclude Pol II across the X chromosome.
C1 [McHugh, Colleen A.; Chen, Chun-Kan; Chow, Amy; Surka, Christine F.; Tran, Christina; Blanco, Mario; Burghard, Christina; Shishkin, Alexander A.; Su, Julia; Guttman, Mitchell] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
   [McDonel, Patrick; Lander, Eric S.] Broad Inst MIT & Harvard, Cambridge, MA 02139 USA.
   [Pandya-Jones, Amy; Plath, Kathrin] Univ Calif Los Angeles, Inst Mol Biol, Dept Biol Chem, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA.
   [Pandya-Jones, Amy; Plath, Kathrin] Univ Calif Los Angeles, David Geffen Sch Med, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA.
   [Moradian, Annie; Sweredoski, Michael J.; Hess, Sonja] CALTECH, Beckman Inst, Proteome Explorat Lab, Pasadena, CA 91125 USA.
C3 California Institute of Technology; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; UCLA Jonsson Comprehensive Cancer Center; 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; California Institute of Technology
RP Guttman, M (corresponding author), CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
EM mguttman@caltech.edu
FU Caltech; NIH NRSA [T32GM07616]; Caltech Beckman Institute; Arnold and Mabel Beckman Foundation; Gordon and Betty Moore Foundation [GBMF775]; Beckman Institute; NIH [1S10RR029591-01A1, DP5OD012190]; Rose Hills Foundation; Edward Mallinckrodt Foundation; Sontag Foundation; Searle Scholars Program; California Institute of Technology
NR 45
TC 885
Z9 1062
U1 2
U2 248
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAY 14
PY 2015
VL 521
IS 7551
BP 232
EP +
DI 10.1038/nature14443
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH9SY
UT WOS:000354377800061
PM 25915022
DA 2026-03-09
ER

PT J
AU Marino, G
   Rohling, EJ
   Rodríguez-Sanz, L
   Grant, KM
   Heslop, D
   Roberts, AP
   Stanford, JD
   Yu, J
AF Marino, G.
   Rohling, E. J.
   Rodriguez-Sanz, L.
   Grant, K. M.
   Heslop, D.
   Roberts, A. P.
   Stanford, J. D.
   Yu, J.
TI Bipolar seesaw control on last interglacial sea level
SO NATURE
LA English
DT Article
ID long-term variations; penultimate glacial maximum; oxygen isotopic composition; epica dome c; antarctic temperature; chronology aicc2012; climate variability; mediterranean sea; atmospheric co2; global climate
AB Our current understanding of ocean-atmosphere-cryosphere interactions at ice-age terminations relies largely on assessments of the most recent (last) glacial-interglacial transition(1-3), Termination I (T-I). But the extent to which T-I is representative of previous terminations remains unclear. Testing the consistency of termination processes requires comparison of time series of critical climate parameters with detailed absolute and relative age control. However, such age control has been lacking for even the penultimate glacial termination (T-II), which culminated in a sea-level highstand during the last interglacial period that was several metres above present(4). Here we show that Heinrich Stadial 11 (HS11), a prominent North Atlantic cold episode(5,6), occurred between 135 +/- 1 and 130 +/- 2 thousand years ago and was linked with rapid sea-level rise during T-II. Our conclusions are based on new and existing(6-9) data for T-II and the last interglacial that we collate onto a single, radiometrically constrained chronology. The HS11 cold episode(5,6) punctuated T-II and coincided directly with a major deglacial meltwater pulse, which predominantly entered the North Atlantic Ocean and accounted for about 70 per cent of the glacial-interglacial sea-level rise(8,9). We conclude that, possibly in response to stronger insolation and CO2 forcing earlier in T-II, the relationship between climate and ice-volume changes differed fundamentally from that of T-I. In T-I, the major sea-level rise clearly post-dates(3,10,11) Heinrich Stadial 1. We also find that HS11 coincided with sustained Antarctic warming, probably through a bipolar seesaw temperature response(12), and propose that this heat gain at high southern latitudes promoted Antarctic ice-sheet melting that fuelled the last interglacial sea-level peak.
C1 [Marino, G.; Rohling, E. J.; Rodriguez-Sanz, L.; Grant, K. M.; Heslop, D.; Roberts, A. P.; Yu, J.] Australian Natl Univ, Res Sch Earth Sci, Canberra, ACT 2601, Australia.
   [Rohling, E. J.] Univ Southampton, Ocean & Earth Sci, Natl Oceanog Ctr, Southampton SO14 3ZH, Hants, England.
   [Stanford, J. D.] Swansea Univ, Dept Geog, Swansea SA2 8PP, W Glam, Wales.
C3 Australian National University; NERC National Oceanography Centre; University of Southampton; Swansea University
RP Marino, G (corresponding author), Australian Natl Univ, Res Sch Earth Sci, GPO Box 4, Canberra, ACT 2601, Australia.
EM Gianluca.Marino@anu.edu.au
FU Australian Research Council Australian Laureate Fellowship [FL120100050]; UK-NERC [NE/I009906/1]; Natural Environment Research Council [bosc01001, NE/I009906/1, NE/I02044X/1] Funding Source: researchfish; NERC [NE/I009906/1, bosc01001, NE/I02044X/1] Funding Source: UKRI
NR 79
TC 138
Z9 151
U1 2
U2 125
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 11
PY 2015
VL 522
IS 7555
BP 197
EP +
DI 10.1038/nature14499
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700035
PM 26062511
DA 2026-03-09
ER

PT J
AU Peifer, M
   Hertwig, F
   Roels, F
   Dreidax, D
   Gartlgruber, M
   Menon, R
   Krämer, A
   Roncaioli, JL
   Sand, F
   Heuckmann, JM
   Ikram, F
   Schmidt, R
   Ackermann, S
   Engesser, A
   Kahlert, Y
   Vogel, W
   Altmüller, J
   Nürnberg, P
   Thierry-Mieg, J
   Thierry-Mieg, D
   Mariappan, A
   Heynck, S
   Mariotti, E
   Henrich, KO
   Gloeckner, C
   Bosco, G
   Leuschner, I
   Schweiger, MR
   Savelyeva, L
   Watkins, SC
   Shao, CX
   Bell, E
   Höfer, T
   Achter, V
   Lang, U
   Theissen, J
   Volland, R
   Saadati, M
   Eggert, A
   de Wilde, B
   Berthold, F
   Peng, ZY
   Zhao, C
   Shi, LM
   Ortmann, M
   Büttner, R
   Perner, S
   Hero, B
   Schramm, A
   Schulte, JH
   Herrmann, C
   O'Sullivan, RJ
   Westermann, F
   Thomas, RK
   Fischer, M
AF Peifer, Martin
   Hertwig, Falk
   Roels, Frederik
   Dreidax, Daniel
   Gartlgruber, Moritz
   Menon, Roopika
   Kraemer, Andrea
   Roncaioli, Justin L.
   Sand, Frederik
   Heuckmann, Johannes M.
   Ikram, Fakhera
   Schmidt, Rene
   Ackermann, Sandra
   Engesser, Anne
   Kahlert, Yvonne
   Vogel, Wenzel
   Altmueller, Janine
   Nuernberg, Peter
   Thierry-Mieg, Jean
   Thierry-Mieg, Danielle
   Mariappan, Aruljothi
   Heynck, Stefanie
   Mariotti, Erika
   Henrich, Kai-Oliver
   Gloeckner, Christian
   Bosco, Graziella
   Leuschner, Ivo
   Schweiger, Michal R.
   Savelyeva, Larissa
   Watkins, Simon C.
   Shao, Chunxuan
   Bell, Emma
   Hoefer, Thomas
   Achter, Viktor
   Lang, Ulrich
   Theissen, Jessica
   Volland, Ruth
   Saadati, Maral
   Eggert, Angelika
   de Wilde, Bram
   Berthold, Frank
   Peng, Zhiyu
   Zhao, Chen
   Shi, Leming
   Ortmann, Monika
   Buettner, Reinhard
   Perner, Sven
   Hero, Barbara
   Schramm, Alexander
   Schulte, Johannes H.
   Herrmann, Carl
   O'Sullivan, Roderick J.
   Westermann, Frank
   Thomas, Roman K.
   Fischer, Matthias
TI Telomerase activation by genomic rearrangements in high-risk neuroblastoma
SO NATURE
LA English
DT Article
ID tert promoter mutations; gene; landscape; enhancers; melanoma
AB Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system(1). Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive(2-4). Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type(1,2,5). In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.
C1 [Peifer, Martin; Bosco, Graziella; Thomas, Roman K.] Univ Cologne, Ctr Integrated Oncol Cologne Bonn, Fac Med, Dept Translat Genom, D-50931 Cologne, Germany.
   [Peifer, Martin; Hertwig, Falk; Roels, Frederik; Kraemer, Andrea; Sand, Frederik; Ikram, Fakhera; Ackermann, Sandra; Nuernberg, Peter; Mariappan, Aruljothi; Fischer, Matthias] Univ Cologne, Ctr Mol Med Cologne CMMC, D-50931 Cologne, Germany.
   [Hertwig, Falk; Roels, Frederik; Kraemer, Andrea; Ikram, Fakhera; Ackermann, Sandra; Engesser, Anne; Kahlert, Yvonne; Theissen, Jessica; Volland, Ruth; Berthold, Frank; Hero, Barbara; Fischer, Matthias] Univ Cologne, Univ Childrens Hosp Cologne, Fac Med, Dept Pediat Oncol & Hematol, D-50937 Cologne, Germany.
   [Dreidax, Daniel; Gartlgruber, Moritz; Henrich, Kai-Oliver; Savelyeva, Larissa; Bell, Emma; Westermann, Frank] German Canc Res Ctr, Div Neuroblastoma Genom B087, D-69120 Heidelberg, Germany.
   [Menon, Roopika; Vogel, Wenzel; Perner, Sven] Univ Hosp Bonn, Ctr Integrated Oncol Cologne Bonn, Inst Pathol, Dept Prostate Canc Res, D-53127 Bonn, Germany.
   [Menon, Roopika; Heuckmann, Johannes M.; Heynck, Stefanie; Mariotti, Erika; Gloeckner, Christian] NEO New Oncol AG, D-51105 Cologne, Germany.
   [Roncaioli, Justin L.; O'Sullivan, Roderick J.] Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA.
   [Ikram, Fakhera; Altmueller, Janine; Nuernberg, Peter] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany.
   [Schmidt, Rene] Univ Munster, Inst Biostat & Clin Res, D-48149 Munster, Germany.
   [Nuernberg, Peter] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany.
   [Thierry-Mieg, Jean; Thierry-Mieg, Danielle] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA.
   [Leuschner, Ivo] Univ Kiel, Dept Pathol, D-24118 Kiel, Germany.
   [Schweiger, Michal R.] Univ Cologne, Funct Epigen, D-50931 Cologne, Germany.
   [Watkins, Simon C.] Univ Pittsburgh, Ctr Biol Imaging, Dept Cell Biol, Pittsburgh, PA 15261 USA.
   [Shao, Chunxuan; Hoefer, Thomas] German Canc Res Ctr, Div Theoret Syst Biol, D-69120 Heidelberg, Germany.
   [Achter, Viktor; Lang, Ulrich] Univ Cologne, Comp Ctr, D-50931 Cologne, Germany.
   [Lang, Ulrich] Univ Cologne, Dept Informat, D-50931 Cologne, Germany.
   [Saadati, Maral] German Canc Res Ctr, Div Biostat, D-69120 Heidelberg, Germany.
   [Eggert, Angelika; Schulte, Johannes H.] Charite Univ Med Ctr Berlin, Dept Pediat Oncol & Hematol, D-10117 Berlin, Germany.
   [de Wilde, Bram] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium.
   [Peng, Zhiyu] BGI Shenzhen, Shenzhen 518083, Guangdong, Peoples R China.
   [Zhao, Chen; Shi, Leming] Fudan Univ, Ctr Pharmacogen, State Key Lab Genet Engn, Shanghai 201203, Peoples R China.
   [Zhao, Chen; Shi, Leming] Fudan Univ, Fudan Zhangjiang Ctr Clin Genom, State Key Lab Genet Engn, Shanghai 201203, Peoples R China.
   [Zhao, Chen; Shi, Leming] Fudan Univ, Sch Pharm, MOE Key Lab Contemporary Anthropol, Shanghai 201203, Peoples R China.
   [Zhao, Chen; Shi, Leming] Fudan Univ, Sch Life Sci, Shanghai 201203, Peoples R China.
   [Ortmann, Monika; Buettner, Reinhard; Thomas, Roman K.] Univ Cologne, Dept Pathol, D-50937 Cologne, Germany.
   [Schramm, Alexander] Univ Childrens Hosp, Dept Pediat Oncol & Hematol, D-45147 Essen, Germany.
   [Schulte, Johannes H.] German Canc Consortium DKTK, D-10117 Berlin, Germany.
   [Schulte, Johannes H.] German Canc Res Ctr, D-69120 Heidelberg, Germany.
   [Herrmann, Carl] Heidelberg Univ, Inst Pharm & Mol Biotechnol, D-69120 Heidelberg, Germany.
   [Herrmann, Carl] Heidelberg Univ, Bioquant Ctr, D-69120 Heidelberg, Germany.
   [Herrmann, Carl] German Canc Res Ctr, Div Theoret Bioinformat, D-69120 Heidelberg, Germany.
   [Fischer, Matthias] Max Planck Inst Metab Res, D-50931 Cologne, Germany.
C3 University of Cologne; University of Cologne; University of Cologne; Helmholtz Association; German Cancer Research Center (DKFZ); University of Bonn; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Cologne; University of Munster; University of Cologne; National Institutes of Health (NIH) - USA; NIH National Library of Medicine (NLM); University of Kiel; University of Cologne; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Helmholtz Association; German Cancer Research Center (DKFZ); University of Cologne; University of Cologne; Helmholtz Association; German Cancer Research Center (DKFZ); Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Ghent University; Beijing Genomics Institute (BGI); Fudan University; Fudan University; Fudan University; Fudan University; University of Cologne; University of Duisburg Essen; Helmholtz Association; German Cancer Research Center (DKFZ); Helmholtz Association; German Cancer Research Center (DKFZ); Ruprecht Karls University Heidelberg; Ruprecht Karls University Heidelberg; Helmholtz Association; German Cancer Research Center (DKFZ)
RP Fischer, M (corresponding author), Univ Cologne, Ctr Mol Med Cologne CMMC, D-50931 Cologne, Germany.
EM mpeifer@uni-koeln.de; frank.westermann@dkfz-heidelberg.de; roman.thomas@uni-koeln.de; matthias.fischer@uk-koeln.de
FU German Cancer Aid [110122]; German Ministry of Science and Education (BMBF) as part of the e:Med initiative [01ZX1303A, 01ZX1406, 01ZX1307D]; BMBF [0316076A]; European Union [259348]; Fordergesellschaft Kinderkrebs-Neuroblastom-Forschung e.V.; German-Israeli Helmholtz Research School in Cancer Biology; Volkswagenstiftung (Lichtenberg Program); Center for Molecular Medicine Cologne; National Cancer Institute [P30CA047904] Funding Source: NIH RePORTER
NR 24
TC 441
Z9 516
U1 2
U2 101
PU NATURE PUBLISHING 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 29
PY 2015
VL 526
IS 7575
BP 700
EP 704
DI 10.1038/nature14980
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CU8ZH
UT WOS:000363832100048
PM 26466568
DA 2026-03-09
ER

PT J
AU Nuñez, JK
   Harrington, LB
   Kranzusch, PJ
   Engelman, AN
   Doudna, JA
AF Nunez, James K.
   Harrington, Lucas B.
   Kranzusch, Philip J.
   Engelman, Alan N.
   Doudna, Jennifer A.
TI Foreign DNA capture during CRISPR-Cas adaptive immunity
SO NATURE
LA English
DT Article
ID spacer acquisition; repeats; system; rna; bacteriophage; sequence; elements; defense; memory; tools
AB Bacteria and archaea generate adaptive immunity against phages and plasmids by integrating foreign DNA of specific 30-40-base-pair lengths into clustered regularly interspaced short palindromic repeat (CRISPR) loci as spacer segments(1-6). The universally conserved Cas1-Cas2 integrase complex catalyses spacer acquisition using a direct nucleophilic integration mechanism similar to retroviral integrases and transposases(7-13). How the Cas1-Cas2 complex selects foreign DNA substrates for integration remains unknown. Here we present X-ray crystal structures of the Escherichia coli Cas1-Cas2 complex bound to cognate 33-nucleotide protospacer DNA substrates. The protein complex creates a curved binding surface spanning the length of the DNA and splays the ends of the protospacer to allow each terminal nucleophilic 3'-OH to enter a channel leading into the Cas1 active sites. Phosphodiester backbone interactions between the protospacer and the proteins explain the sequence-nonspecific substrate selection observed in vivo(2-4). Our results uncover the structural basis for foreign DNA capture and the mechanism by which Cas1-Cas2 functions as a molecular ruler to dictate the sequence architecture of CRISPR loci.
C1 [Nunez, James K.; Harrington, Lucas B.; Kranzusch, Philip J.; Doudna, Jennifer A.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
   [Kranzusch, Philip J.; Doudna, Jennifer A.] Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA.
   [Engelman, Alan N.] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA.
   [Engelman, Alan N.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.
   [Doudna, Jennifer A.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
   [Doudna, Jennifer A.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA.
   [Doudna, Jennifer A.] Univ Calif Berkeley, Innovat Genom Initiat, Berkeley, CA 94720 USA.
   [Doudna, Jennifer A.] Univ Calif Berkeley, Ctr RNA Syst Biol, Berkeley, CA 94720 USA.
C3 University of California System; University of California Berkeley; Howard Hughes Medical Institute; University of California System; University of California Berkeley; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; 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; University of California System; University of California Berkeley
RP Doudna, JA (corresponding author), Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
EM doudna@berkeley.edu
FU UC Office of the President; Multicampus Research Programs; Program for Breakthrough Biomedical Research - Sandler Foundation; US National Science Foundation [1244557]; NIH [AI070042]; US National Science Foundation Graduate Research Fellowships; UC Berkeley Chancellor's Graduate Fellowship;  [MR-15-328599]
NR 29
TC 153
Z9 191
U1 4
U2 88
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 535
EP +
DI 10.1038/nature15760
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500052
PM 26503043
DA 2026-03-09
ER

PT J
AU Usami, Y
   Wu, YF
   Göttlinger, HG
AF Usami, Yoshiko
   Wu, Yuanfei
   Goettlinger, Heinrich G.
TI SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef
SO NATURE
LA English
DT Article
ID immunodeficiency-virus type-1; murine leukemia-virus; cd4 down-regulation; optimal viral infectivity; primary t-lymphocytes; cell-surface cd4; glycosylated-gag; cytoplasmic domain; virion fusion; replication
AB HIV-1 Nef and the unrelated mouse leukaemia virus glycosylated Gag (glycoGag) strongly enhance the infectivity of HIV-1 virions produced in certain cell types in a clathrin-dependent manner. Here we show that Nef and glycoGag prevent the incorporation of the multipass transmembrane proteins serine incorporator 3 (SERINC3) and SERINC5 into HIV-1 virions to an extent that correlates with infectivity enhancement. Silencing of both SERINC3 and SERINC5 precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. The infectivity of nef-deficient virions increased more than 100-fold when produced in double-knockout human CD4(+) T cells that lack both SERINC3 and SERINC5, and re-expression experiments confirmed that the absence of SERINC3 and SERINC5 accounted for the infectivity enhancement. Furthermore, SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. SERINC3 and SERINC5 are highly expressed in primary human HIV-1 target cells, and inhibiting their downregulation by Nef is a potential strategy to combat HIV/AIDS.
C1 [Usami, Yoshiko; Wu, Yuanfei; Goettlinger, Heinrich G.] Univ Massachusetts, Sch Med, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA.
C3 University of Massachusetts System; University of Massachusetts Worcester
RP Göttlinger, HG (corresponding author), Univ Massachusetts, Sch Med, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA.
EM heinrich.gottlinger@umassmed.edu
FU NIAID/NIH [R01AI029873]; NIDA/NIH [DP1DA038034]
NR 59
TC 369
Z9 469
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 OCT 8
PY 2015
VL 526
IS 7572
BP 218
EP +
DI 10.1038/nature15400
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS9GV
UT WOS:000362399000039
PM 26416733
DA 2026-03-09
ER

PT J
AU Kondo, A
   Shahpasand, K
   Mannix, R
   Qiu, JH
   Moncaster, J
   Chen, CH
   Yao, YD
   Lin, YM
   Driver, JA
   Sun, Y
   Wei, S
   Luo, ML
   Albayram, O
   Huang, PY
   Rotenberg, A
   Ryo, A
   Goldstein, LE
   Pascual-Leone, A
   McKee, AC
   Meehan, W
   Zhou, XZ
   Lu, KP
AF Kondo, Asami
   Shahpasand, Koorosh
   Mannix, Rebekah
   Qiu, Jianhua
   Moncaster, Juliet
   Chen, Chun-Hau
   Yao, Yandan
   Lin, Yu-Min
   Driver, Jane A.
   Sun, Yan
   Wei, Shuo
   Luo, Man-Li
   Albayram, Onder
   Huang, Pengyu
   Rotenberg, Alexander
   Ryo, Akihide
   Goldstein, Lee E.
   Pascual-Leone, Alvaro
   McKee, Ann C.
   Meehan, William
   Zhou, Xiao Zhen
   Lu, Kun Ping
TI Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy
SO NATURE
LA English
DT Article
ID prolyl isomerase pin1; chronic traumatic encephalopathy; alzheimers-disease; head-injury; pathology; protein; immunotherapy; model; onset; transmission
AB Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer's disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term 'cistauosis', appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer's disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.
C1 [Kondo, Asami; Shahpasand, Koorosh; Chen, Chun-Hau; Yao, Yandan; Lin, Yu-Min; Driver, Jane A.; Wei, Shuo; Luo, Man-Li; Albayram, Onder; Huang, Pengyu; Zhou, Xiao Zhen; Lu, Kun Ping] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Translat Therapeut, Dept Med,Med Sch, Boston, MA 02215 USA.
   [Kondo, Asami; Shahpasand, Koorosh; Chen, Chun-Hau; Yao, Yandan; Lin, Yu-Min; Wei, Shuo; Luo, Man-Li; Albayram, Onder; Huang, Pengyu; Zhou, Xiao Zhen; Lu, Kun Ping] Harvard Univ, Beth Israel Deaconess Med Ctr, Canc Res Inst, Sch Med, Boston, MA 02215 USA.
   [Mannix, Rebekah; Qiu, Jianhua] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Emergency Med, Boston, MA 02115 USA.
   [Moncaster, Juliet; Goldstein, Lee E.; McKee, Ann C.] Boston Univ, Sch Med, Alzheimers Dis Ctr, CTE Program, Boston, MA 02118 USA.
   [Driver, Jane A.] Harvard Univ, Sch Med, Geriatr Res Educ & Clin Ctr, VA Boston Healthcare Syst, Boston, MA 02130 USA.
   [Sun, Yan; Rotenberg, Alexander] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Neurol, Boston, MA 02115 USA.
   [Ryo, Akihide] Yokohama City Univ, Dept Microbiol, Sch Med, Yokohama, Kanagawa 2360004, Japan.
   [Pascual-Leone, Alvaro] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Neurol, Boston, MA 02215 USA.
   [Meehan, William] Harvard Univ, Sch Med, Childrens Hosp Boston, Micheli Ctr Sports Injury Prevent, Boston, MA 02115 USA.
C3 Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; Boston University; Harvard University; Harvard Medical School; Geriatric Research Education & Clinical Center; Harvard University Medical Affiliates; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Boston Healthcare System; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; Yokohama City University; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard Medical School
RP Lu, KP (corresponding author), Harvard Univ, Beth Israel Deaconess Med Ctr, Div Translat Therapeut, Dept Med,Med Sch, Boston, MA 02215 USA.
EM xzhou@bidmc.harvard.edu; klu@bidmc.harvard.edu
FU NIH [S10RR017927, T32HD040128, UO1NS086659-01, P30AG13846, R01AG029385, R01CA167677, R01HL111430, R01AG046319]; NIA; VA Career Development Award; Susan G. Komen postdoctoral fellowship; Boston Children's Hospital Pilot Grant Award; NFLPA; VA; Sports Legacy Institute; Andlinger Foundation; NFL; WWE; Alzheimer's Association [DVT-14-322623]; BIDMC; Eunice Kennedy Shriver National Institute of Child Health and Human Development [T32HD040128] Funding Source: NIH RePORTER
NR 50
TC 376
Z9 425
U1 3
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 JUL 23
PY 2015
VL 523
IS 7561
BP 431
EP U118
DI 10.1038/nature14658
PG 26
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN4DD
UT WOS:000358378900030
PM 26176913
DA 2026-03-09
ER

PT J
AU Barzel, A
   Paulk, NK
   Shi, Y
   Huang, Y
   Chu, K
   Zhang, F
   Valdmanis, PN
   Spector, LP
   Porteus, MH
   Gaensler, KM
   Kay, MA
AF Barzel, A.
   Paulk, N. K.
   Shi, Y.
   Huang, Y.
   Chu, K.
   Zhang, F.
   Valdmanis, P. N.
   Spector, L. P.
   Porteus, M. H.
   Gaensler, K. M.
   Kay, M. A.
TI Promoter less gene targeting without nucleases ameliorates haemophilia B in mice
SO NATURE
LA English
DT Article
ID recombinant adenoassociated virus; in-vivo; liver transduction; mouse model; therapy; integration; vectors
AB Site-specific gene addition can allow stable transgene expression for gene therapy. When possible, this is preferred over the use of promiscuously integrating vectors, which are sometimes associated with clonal expansion(1) and oncogenesis(2). Site-specific endonudeases that can induce high rates of targeted genome editing are finding increasing applications in biological discovery and gene therapy(3). However, two safety concerns persist: endonudease-associated adverse effects, both on-target(4) and off-target(5,6); and oncogene activation caused by promoter integration, even without nucleases(7). Here we perform recombinant adeno-associated virus (rAAV)-mediated promoterless gene targeting without nucleases and demonstrate amelioration of the bleeding diathesis in haemophilia B mice. In particular, we target a promoterless human coagulation factor IX (F9) gene to the liver-expressed mouse albumin (Alb) locus. F9 is targeted, along with a preceding 2A-peptide coding sequence, to be integrated just upstream to the Alb stop codon. While F9 is fused to Alb at the DNA and RNA levels, two separate proteins are synthesized by way of ribosomal skipping. Thus, F9 expression is linked to robust hepatic albumin expression without disrupting it. We injected an AAV8-F9 vector into neonatal and adult mice and achieved on-target integration into similar to 0.5% of the albumin alleles in hepatocytes. We established that F9 was produced only from on-target integration, and ribosomal skipping was highly efficient. Stable F9 plasma levels at 7-20% of normal were obtained, and treated F9-deficient mice had normal coagulation times. In conclusion, transgene integration as a 2A-fusion to a highly expressed endogenous gene may obviate the requirement for nucleases and/or vector-borne promoters. This method may allow for safe and efficacious gene targeting in both infants and adults by greatly diminishing off-target effects while still providing therapeutic levels of expression from integration.
C1 [Barzel, A.; Paulk, N. K.; Huang, Y.; Chu, K.; Zhang, F.; Valdmanis, P. N.; Spector, L. P.; Porteus, M. H.; Kay, M. A.] Dept Pediat, Stanford, CA 94305 USA.
   [Barzel, A.; Paulk, N. K.; Huang, Y.; Chu, K.; Zhang, F.; Valdmanis, P. N.; Spector, L. P.; Kay, M. A.] Dept Genet, Stanford, CA 94305 USA.
   [Shi, Y.; Gaensler, K. M.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.
C3 University of California System; University of California San Francisco
RP Kay, MA (corresponding author), Dept Pediat, 269 Campus Dr,CCSR Bldg,Room 2105, Stanford, CA 94305 USA.
EM markay@stanford.edu
FU National Heart Lung & Blood Institute [R01-HL064274, F32-HL119059]; Lucile Packard Foundation for Children's Health, Stanford NIH-NCATS-CTSA [UL1 TR001085]; Child Health Research Institute of Stanford University; American Liver Foundation; Stanford Dean's Fellowship; Laurie Krauss Lacob Faculty Scholar Fund in Pediatric Translational Medicine; National Heart Lung and Blood Institute [R01HL064274] Funding Source: NIH RePORTER; National Human Genome Research Institute [T32HG000044] Funding Source: NIH RePORTER
NR 35
TC 213
Z9 275
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 JAN 15
PY 2015
VL 517
IS 7534
BP 360
EP U476
DI 10.1038/nature13864
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300044
PM 25363772
DA 2026-03-09
ER

PT J
AU Van Keymeulen, A
   Lee, MY
   Ousset, M
   Brohée, S
   Rorive, S
   Giraddi, RR
   Wuidart, A
   Bouvencourt, G
   Dubois, C
   Salmon, I
   Sotiriou, C
   Phillips, WA
   Blanpain, C
AF Van Keymeulen, Alexandra
   Lee, May Yin
   Ousset, Marielle
   Brohee, Sylvain
   Rorive, Sandrine
   Giraddi, Rajshekhar R.
   Wuidart, Aline
   Bouvencourt, Gaelle
   Dubois, Christine
   Salmon, Isabelle
   Sotiriou, Christos
   Phillips, Wayne A.
   Blanpain, Cedric
TI Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity
SO NATURE
LA English
DT Article
ID mammary-gland development; mouse model; stem-cells; cancer; activation; identification; etv6-ntrk3; mutations; package; fate
AB Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes(1,2). PIK3CA and P53 (also known as TP53) are the two most frequently mutated genes and are associated with different types of human breast cancers(3). The cellular origin and the mechanisms leading to PIK3CA-induced tumour heterogeneity remain unknown. Here we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and the impact of mutations in this gene on tumour heterogeneity. Surprisingly, oncogenic Pik3ca(H1047R) mutant expression at physiological levels(4) in basal cells using keratin (K)5-CreER(T2) mice induced the formation of luminal oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive tumours, while its expression in luminal cells using K8-CReERT2 mice gave rise to luminal ER+PR+ tumours or basal-like ER-PR- tumours. Concomitant deletion of p53 and expression of Pik3ca(H1047R) accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation.
C1 [Van Keymeulen, Alexandra; Lee, May Yin; Ousset, Marielle; Giraddi, Rajshekhar R.; Wuidart, Aline; Bouvencourt, Gaelle; Dubois, Christine; Blanpain, Cedric] Univ Libre Bruxelles, IRIBHM, B-1070 Brussels, Belgium.
   [Brohee, Sylvain; Sotiriou, Christos] Univ Libre Bruxelles, Inst Jules Bordet, B-1000 Brussels, Belgium.
   [Rorive, Sandrine; Salmon, Isabelle] Univ Libre Bruxelles, Erasme Hosp, Dept Pathol, B-1070 Brussels, Belgium.
   [Rorive, Sandrine; Salmon, Isabelle] CMMI, DIAPATH, B-6041 Gosselies, Belgium.
   [Phillips, Wayne A.] Peter MacCallum Canc Ctr, Surg Oncol Res Lab, Melbourne, Vic 3002, Australia.
   [Phillips, Wayne A.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3002, Australia.
   [Blanpain, Cedric] Univ Libre Bruxelles, WELBIO, B-1070 Brussels, Belgium.
C3 Universite Libre de Bruxelles; Universite Libre de Bruxelles; Institut Jules Bordet; Universite Libre de Bruxelles; Universite Catholique Louvain; Cliniques Universitaires Saint-Luc; Peter Maccallum Cancer Center; University of Melbourne; Peter Maccallum Cancer Center; Universite Libre de Bruxelles; WELBIO
RP Blanpain, C (corresponding author), Univ Libre Bruxelles, IRIBHM, B-1070 Brussels, Belgium.
EM avkeymeu@ulb.ac.be; Cedric.Blanpain@ulb.ac.be
FU Agency for Science, Technology and Research (A*STAR, Singapore); FNRS; TELEVIE; foundation "Amis de l'institut Jules Bordet"; European Regional Development Fund; Wallonia; National Health and Medical Research Council of Australia; Fondation Contre le Cancer; ULB fondation; Fond Yvonne Boel; Fond Gaston Ithier; foundation Bettencourt Schueller; foundation Baillet Latour; European Research Council
NR 43
TC 279
Z9 319
U1 0
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 SEP 3
PY 2015
VL 525
IS 7567
BP 119
EP 123
DI 10.1038/nature14665
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100037
PM 26266985
DA 2026-03-09
ER

PT J
AU Touboul, M
   Puchtel, IS
   Walker, RJ
AF Touboul, Mathieu
   Puchtel, Igor S.
   Walker, Richard J.
TI Tungsten isotopic evidence for disproportional late accretion to the Earth and Moon
SO NATURE
LA English
DT Article
ID siderophile element constraints; core formation; giant impact; differentiation; osmium; age; systematics; hf; meteorites; evolution
AB Characterization of the hafnium-tungsten systematics (Hf-182 decaying to W-182 and emitting two electrons with a half-life of 8.9 million years) of the lunar mantle will enable better constraints on the timescale and processes involved in the currently accepted giant-impact theory for the formation and evolution of the Moon, and for testing the late-accretion hypothesis. Uniform, terrestrial-mantle-like W isotopic compositions have been reported(1,2) among crystallization products of the lunar magma ocean. These observations were interpreted to reflect formation of the Moon and crystallization of the lunar magma ocean after Hf-182 was no longer extant-that is, more than about 60 million years after the Solar System formed. Here we present W isotope data for three lunar samples that are more precise by a factor of >= 4 than those previously reported(1,2). The new data reveal that the lunar mantle has a well-resolved W-182 excess of 20.6 +/- 5.1 parts per million (+/- 2 standard deviations), relative to the modern terrestrial mantle. The offset between the mantles of the Moon and the modern Earth is best explained by assuming that the W isotopic compositions of the two bodies were identical immediately following formation of the Moon, and that they then diverged as a result of disproportional late accretion to the Earth and Moon(3,4). One implication of this model is that metal from the core of the Moon-forming impactor must have efficiently stripped the Earth's mantle of highly siderophile elements on its way to merge with the terrestrial core, requiring a substantial, but still poorly defined, level of metal-silicate equilibration.
C1 [Touboul, Mathieu; Puchtel, Igor S.; Walker, Richard J.] Univ Maryland, Dept Geol, Isotope Geochem Lab, College Pk, MD 20742 USA.
C3 University System of Maryland; University of Maryland College Park
RP Touboul, M (corresponding author), Univ Lyon 1, Ecole Normale Super Lyon, Lab Geol Lyon, Labex LIO, F-69364 Lyon 7, France.
EM mathieu.touboul@ens-lyon.fr; ipuchtel@umd.edu; rjwalker@umd.edu
FU NASA [NNX13AF83G]; NASA [474442, NNX13AF83G] Funding Source: Federal RePORTER
NR 38
TC 124
Z9 140
U1 0
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 23
PY 2015
VL 520
IS 7548
BP 530
EP +
DI 10.1038/nature14355
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500040
PM 25855299
DA 2026-03-09
ER

PT J
AU Riedel, C
   Gabizon, R
   Wilson, CAM
   Hamadani, K
   Tsekouras, K
   Marqusee, S
   Pressé, S
   Bustamante, C
AF Riedel, Clement
   Gabizon, Ronen
   Wilson, Christian A. M.
   Hamadani, Kambiz
   Tsekouras, Konstantinos
   Marqusee, Susan
   Presse, Steve
   Bustamante, Carlos
TI The heat released during catalytic turnover enhances the diffusion of an enzyme
SO NATURE
LA English
DT Article
ID fluorescence correlation spectroscopy; calorimetry; catalase; propulsion; driven
AB Recent studies have shown that the diffusivity of enzymes increases in a substrate-dependent manner during catalysis(1,2). Although this observation has been reported and characterized for several different systems(3-10), the precise origin of this phenomenon is unknown. Calorimetric methods are often used to determine enthalpies from enzyme-catalysed reactions and can therefore provide important insight into their reaction mechanisms(11,12). The ensemble averages involved in traditional bulk calorimetry cannot probe the transient effects that the energy exchanged in a reaction may have on the catalyst. Here we obtain single-molecule fluorescence correlation spectroscopy data and analyse them within the framework of a stochastic theory to demonstrate a mechanistic link between the enhanced diffusion of a single enzyme molecule and the heat released in the reaction. We propose that the heat released during catalysis generates an asymmetric pressure wave that results in a differential stress at the protein-solvent interface that transiently displaces the centre-of-mass of the enzyme (chemoacoustic effect). This novel perspective on how enzymes respond to the energy released during catalysis suggests a possible effect of the heat of reaction on the structural integrity and internal degrees of freedom of the enzyme.
C1 [Riedel, Clement; Gabizon, Ronen; Wilson, Christian A. M.; Hamadani, Kambiz; Marqusee, Susan; Bustamante, Carlos] Univ Calif Berkeley, Calif Inst Quantitat Biosci, QB3, Berkeley, CA 94720 USA.
   [Wilson, Christian A. M.] Univ Chile, Fac Ciencias Quim & Farmaceut, Dept Bioquim & Biol Mol, Santiago 1058, Chile.
   [Tsekouras, Konstantinos; Presse, Steve] Indiana Univ Purdue Univ, Dept Phys, Indianapolis, IN 46202 USA.
   [Marqusee, Susan; Bustamante, Carlos] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
   [Presse, Steve] Indiana Univ Sch Med, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA.
   [Bustamante, Carlos] Univ Calif Berkeley, Jason L Choy Lab Single Mol Biophys, Berkeley, CA 94720 USA.
   [Bustamante, Carlos] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Bustamante, Carlos] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
   [Bustamante, Carlos] Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA.
   [Bustamante, Carlos] Univ Calif Berkeley, Kavli Energy Nano Sci Inst, Berkeley, CA 94720 USA.
   [Bustamante, Carlos] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA.
C3 University of California System; University of California Berkeley; Universidad de Chile; Purdue University System; Purdue University; Purdue University in Indianapolis; University of California System; University of California Berkeley; Indiana University System; Indiana University Bloomington; 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; University of California System; University of California Berkeley; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory
RP Pressé, S (corresponding author), Indiana Univ Purdue Univ, Dept Phys, Indianapolis, IN 46202 USA.
EM stevenpresse@gmail.com; carlosjbustamante@gmail.com
FU NIH [R01-GM0325543, R01-GM05945]; US Department of Energy, Office of Basic Energy Sciences, Division of Materials Sciences and Engineering [DE-AC02-05CH11231]; NSF [MCB-1412259, MCB-1122225]; grant NIGMS [R01-GM65050]; Human Frontier Science Program; Burroughs-Wellcome Fund; Div Of Molecular and Cellular Bioscience; Direct For Biological Sciences [1412259, 1122225] Funding Source: National Science Foundation; National Institute of General Medical Sciences [R01GM065050, R01GM050945] Funding Source: NIH RePORTER
NR 34
TC 193
Z9 231
U1 2
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 JAN 8
PY 2015
VL 517
IS 7533
BP 227
EP U288
DI 10.1038/nature14043
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600042
PM 25487146
DA 2026-03-09
ER

PT J
AU Nguyen, LV
   Pellacani, D
   Lefort, S
   Kannan, N
   Osako, T
   Makarem, M
   Cox, CL
   Kennedy, W
   Beer, P
   Carles, A
   Moksa, M
   Bilenky, M
   Balani, S
   Babovic, S
   Sun, I
   Rosin, M
   Aparicio, S
   Hirst, M
   Eaves, CJ
AF Nguyen, Long V.
   Pellacani, Davide
   Lefort, Sylvain
   Kannan, Nagarajan
   Osako, Tomo
   Makarem, Maisam
   Cox, Claire L.
   Kennedy, William
   Beer, Philip
   Carles, Annaick
   Moksa, Michelle
   Bilenky, Misha
   Balani, Sneha
   Babovic, Sonja
   Sun, Ivan
   Rosin, Miriam
   Aparicio, Samuel
   Hirst, Martin
   Eaves, Connie J.
TI Barcoding reveals complex clonal dynamics of de novo transformed human mammary cells
SO NATURE
LA English
DT Article
ID epithelial stem-cells; breast-cancer; diverse growth; expression; therapy
AB Most human breast cancers have diversified genomically and biologically by the time they become clinically evident(1-3). Early events involved in their genesis and the cellular context in which these events occur have thus been difficult to characterize. Here we present the first formal evidence of the shared and independent ability of basal cells and luminal progenitors, isolated from normal human mammary tissue and transduced with a single oncogene (KRASG12D), to produce serially transplantable, polyclonal, invasive ductal carcinomas within 8 weeks of being introduced either subrenally or subcutaneously into immunodeficient mice(4). DNA barcoding(5,6) of the initial cells revealed a dramatic change in the numbers and sizes of clones generated from them within 2 weeks, and the first appearance of many 'new' clones in tumours passaged into secondary recipients. Both primary and secondary tumours were phenotypically heterogeneous and primary tumours were categorized transcriptionally as 'normal-like'. This system challenges previous concepts that carcinogenesis in normal human epithelia is necessarily a slow process requiring the acquisition of multiple driver mutations. It also presents the first description of initial events that accompany the genesis and evolution of malignant human mammary cell populations, thereby contributing new understanding of the rapidity with which heterogeneity in their properties can develop.
C1 [Nguyen, Long V.; Pellacani, Davide; Lefort, Sylvain; Kannan, Nagarajan; Makarem, Maisam; Cox, Claire L.; Kennedy, William; Beer, Philip; Balani, Sneha; Babovic, Sonja; Eaves, Connie J.] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada.
   [Pellacani, Davide; Eaves, Connie J.] Univ British Columbia, Dept Med Genet, Vancouver, BC V6T 2B5, Canada.
   [Kannan, Nagarajan; Osako, Tomo; Aparicio, Samuel] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V6T 2B5, Canada.
   [Osako, Tomo; Aparicio, Samuel] British Columbia Canc Agcy, Dept Mol Oncol, Vancouver, BC V5Z 1L3, Canada.
   [Carles, Annaick; Moksa, Michelle; Bilenky, Misha; Hirst, Martin] Univ British Columbia, Dept Microbiol & Immunol, Ctr High Throughput Biol, Vancouver, BC V6T 1Z4, Canada.
   [Bilenky, Misha; Hirst, Martin] British Columbia Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada.
   [Sun, Ivan; Rosin, Miriam] Simon Fraser Univ, Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada.
   [Sun, Ivan; Rosin, Miriam] British Columbia Canc Agcy, Canc Control Unit, Vancouver, BC V5Z 1L3, Canada.
C3 British Columbia Cancer Agency; University of British Columbia; University of British Columbia; British Columbia Cancer Agency; University of British Columbia; British Columbia Cancer Agency; Simon Fraser University; British Columbia Cancer Agency
RP Eaves, CJ (corresponding author), British Columbia Canc Agcy, Terry Fox Lab, 675 West 10th Ave, Vancouver, BC V5Z 1L3, Canada.
EM ceaves@bccrc.ca
FU Canadian Cancer Society Research Institute; Canadian Breast Cancer Foundation; Canadian Breast Cancer Research Alliance; Canadian Institutes of Health Research (CIHR); MITACS Elevate Fellowship; Molecular Oncologic Pathology Fellowship from CIHR; Terry Fox Foundation; Sumitomo Life Welfare and Culture Foundation; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Takashi Tsuruo Memorial Fund; Canada Research Chair
NR 24
TC 96
Z9 110
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 DEC 10
PY 2015
VL 528
IS 7581
BP 267
EP +
DI 10.1038/nature15742
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX9VH
UT WOS:000366053300042
PM 26633636
DA 2026-03-09
ER

PT J
AU Hershkovitz, I
   Marder, O
   Ayalon, A
   Bar-Matthews, M
   Yasur, G
   Boaretto, E
   Caracuta, V
   Alex, B
   Frumkin, A
   Goder-Goldberger, M
   Gunz, P
   Holloway, RL
   Latimer, B
   Lavi, R
   Matthews, A
   Slon, V
   Mayer, DBY
   Berna, F
   Bar-Oz, G
   Yeshurun, R
   May, H
   Hans, MG
   Weber, GW
   Barzilai, O
AF Hershkovitz, Israel
   Marder, Ofer
   Ayalon, Avner
   Bar-Matthews, Miryam
   Yasur, Gal
   Boaretto, Elisabetta
   Caracuta, Valentina
   Alex, Bridget
   Frumkin, Amos
   Goder-Goldberger, Mae
   Gunz, Philipp
   Holloway, Ralph L.
   Latimer, Bruce
   Lavi, Ron
   Matthews, Alan
   Slon, Viviane
   Mayer, Daniella Bar-Yosef
   Berna, Francesco
   Bar-Oz, Guy
   Yeshurun, Reuven
   May, Hila
   Hans, Mark G.
   Weber, Gerhard W.
   Barzilai, Omry
TI Levantine cranium from Manot Cave (Israel) foreshadows the first European modern humans
SO NATURE
LA English
DT Article
ID modern human colonization; burial site; africa; pleistocene; diversity; sequence; skeleton; remains; sea
AB A key event in human evolution is the expansion of modern humans of African origin across Eurasia between 60 and 40 thousand years (kyr) before present (BP), replacing all other forms of hominins(1). Owing to the scarcity of human fossils from this period, these ancestors of all present-day non-African modern populations remain largely enigmatic. Here we describe a partial calvaria, recently discovered at Manot Cave (Western Galilee, Israel) and dated to 54.7 +/- 5.5 kyr BP (arithmetic mean 2 standard deviations) by uranium-thorium dating, that sheds light on this crucial event. The overall shape and discrete morphological features of the Manot I calvaria demonstrate that this partial skull is unequivocally modern. It is similar in shape to recent African skulls as well as to European skulls from the Upper Palaeolithic period, but different from most other early anatomically modern humans in the Levant. This suggests that the Manot people could be closely related to the first modern humans who later successfully colonized Europe. Thus, the anatomical features used to support the 'assimilation model' in Europe might not have been inherited from European Neanderthals, but rather from earlier Levantine populations. Moreover, at present, Manot I is the only modern human specimen to provide evidence that during the Middle to Upper Palaeolithic interface, both modern humans and Neanderthals contemporaneously inhabited the southern Levant, close in time to the likely interbreeding event with Neanderthals(2,3).
C1 [Hershkovitz, Israel; Slon, Viviane] Tel Aviv Univ, Sackler Fac Med, Dan David Lab Search & Study Modern Humans, IL-6997801 Tel Aviv, Israel.
   [Hershkovitz, Israel; Mayer, Daniella Bar-Yosef; May, Hila] Tel Aviv Univ, Steinhardt Museum Nat Hist & Natl Res Ctr, IL-6997801 Tel Aviv, Israel.
   [Marder, Ofer] Ben Gurion Univ Negev, Archaeol Div, IL-8410501 Beer Sheva, Israel.
   [Ayalon, Avner; Bar-Matthews, Miryam; Yasur, Gal] Geol Survey Israel, IL-95501 Jerusalem, Israel.
   [Boaretto, Elisabetta; Caracuta, Valentina; Alex, Bridget] Weizmann Inst Sci, D REAMS Radiocarbon Lab, Max Planck Soc Weizmann Inst Ctr Integrat Archaeo, IL-76100 Rehovot, Israel.
   [Alex, Bridget] Harvard Univ, Dept Anthropol & Human Evolutionary Biol, Cambridge, MA 02138 USA.
   [Frumkin, Amos] Hebrew Univ Jerusalem, Dept Geog, IL-91905 Jerusalem, Israel.
   [Goder-Goldberger, Mae] Hebrew Univ Jerusalem, Inst Archaeol, IL-91905 Jerusalem, Israel.
   [Gunz, Philipp] Max Planck Inst Evolutionare Anthropol, Dept Human Evolut, D-04103 Leipzig, Germany.
   [Holloway, Ralph L.] Columbia Univ, Dept Anthropol, New York, NY 10027 USA.
   [Latimer, Bruce] Case Western Reserve Univ, Dept Anat, Cleveland, OH 44106 USA.
   [Latimer, Bruce; Hans, Mark G.] Case Western Reserve Univ, Sch Dent Med, Dept Orthodont, Cleveland, OH 44106 USA.
   [Matthews, Alan; Bar-Oz, Guy; Yeshurun, Reuven] Hebrew Univ Jerusalem, Inst Earth Sci, IL-91904 Jerusalem, Israel.
   [Berna, Francesco] Simon Fraser Univ, Dept Archaeol, Burnaby, BC V5A 1S6, Canada.
   [Bar-Oz, Guy; Yeshurun, Reuven] Univ Haifa, Zinman Inst Archaeol, IL-3498838 Haifa, Israel.
   [May, Hila] Tel Aviv Univ, Sackler Fac Med, Dept Anat & Anthropol, IL-6997801 Tel Aviv, Israel.
   [Weber, Gerhard W.] Univ Vienna, Dept Anthropol, A-1090 Vienna, Austria.
   [Weber, Gerhard W.] Univ Vienna, Core Facil Microcomp Tomog, A-1090 Vienna, Austria.
   [Barzilai, Omry] Israel Antiqu Author, IL-91004 Jerusalem, Israel.
C3 Tel Aviv University; Sackler Faculty of Medicine; Tel Aviv University; Ben-Gurion University of the Negev; Geological Survey Israel; Weizmann Institute of Science; Harvard University; Hebrew University of Jerusalem; Hebrew University of Jerusalem; Max Planck Society; Columbia University; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; Hebrew University of Jerusalem; Simon Fraser University; University of Haifa; Tel Aviv University; Sackler Faculty of Medicine; University of Vienna; University of Vienna
RP Hershkovitz, I (corresponding author), Tel Aviv Univ, Sackler Fac Med, Dan David Lab Search & Study Modern Humans, POB 39040, IL-6997801 Tel Aviv, Israel.
EM anatom2@post.tau.ac.il
FU Dan David Foundation; Israel Antiquities Authority; Case Western Reserve University; Leakey Foundation; Irene Levi Sala CARE Archaeological Foundation; Keren Kayemet L'Israel; Israel Science Foundation; National Science Foundation; Exilarch's Foundation; Max Planck Society-Weizman Institute Joint Center for Integrative Archaeology and Anthropology; Bertha and Louis Weinstein Research Fund
NR 35
TC 163
Z9 187
U1 0
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 9
PY 2015
VL 520
IS 7546
BP 216
EP U178
DI 10.1038/nature14134
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CF3NA
UT WOS:000352454600038
PM 25629628
DA 2026-03-09
ER

PT J
AU Chassaing, B
   Koren, O
   Goodrich, JK
   Poole, AC
   Srinivasan, S
   Ley, RE
   Gewirtz, AT
AF Chassaing, Benoit
   Koren, Omry
   Goodrich, Julia K.
   Poole, Angela C.
   Srinivasan, Shanthi
   Ley, Ruth E.
   Gewirtz, Andrew T.
TI Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome
SO NATURE
LA English
DT Article
ID intestinal microbiota; crohns-disease; escherichia-coli; mice; inflammation; bacteria; immunoglobulins; flagellin; deletion; unifrac
AB The intestinal tract is inhabited by a large and diverse community of microbes collectively referred to as the gut microbiota. While the gut microbiota provides important benefits to its host, especially in metabolism and immune development, disturbance of the microbiota-host relationship is associated with numerous chronic inflammatory diseases, including inflammatory bowel disease and the group of obesity-associated diseases collectively referred to as metabolic syndrome. A primary means by which the intestine is protected from its microbiota is via multi-layered mucus structures that cover the intestinal surface, thereby allowing the vast majority of gut bacteria to be kept at a safe distance from epithelial cells that line the intestine(1). Thus, agents that disrupt mucus-bacterial interactions might have the potential to promote diseases associated with gut inflammation. Consequently, it has been hypothesized that emulsifiers, detergent-like molecules that are a ubiquitous component of processed foods and that can increase bacterial translocation across epithelia in vitro(2), might be promoting the increase in inflammatory bowel disease observed since the mid-twentieth century(3). Here we report that, in mice, relatively low concentrations of two commonly used emulsifiers, namely carboxymethylcellulose and polysorbate-80, induced low-grade inflammation and obesity/metabolic syndrome in wild-type hosts and promoted robust colitis in mice predisposed to this disorder. Emulsifier-induced metabolic syndrome was associated with microbiota encroachment, altered species composition and increased pro-inflammatory potential. Use of germ-free mice and faecal transplants indicated that such changes in microbiota were necessary and sufficient for both low-grade inflammation and metabolic syndrome. These results support the emerging concept that perturbed host-microbiota interactions resulting in low-grade inflammation can promote adiposity and its associated metabolic effects. Moreover, they suggest that the broad use of emulsifying agents might be contributing to an increased societal incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.
C1 [Chassaing, Benoit; Gewirtz, Andrew T.] Georgia State Univ, Inst Biomed Sci, Ctr Inflammat Immun & Infect, Atlanta, GA 30303 USA.
   [Koren, Omry] Bar Ilan Univ, Fac Med, IL-13115 Safed, Israel.
   [Goodrich, Julia K.; Poole, Angela C.; Ley, Ruth E.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA.
   [Srinivasan, Shanthi] Emory Univ, Sch Med, Dept Med, Digest Dis Div, Atlanta, GA 30322 USA.
C3 University System of Georgia; Georgia State University; Bar Ilan University; Cornell University; Emory University
RP Gewirtz, AT (corresponding author), Georgia State Univ, Inst Biomed Sci, Ctr Inflammat Immun & Infect, Atlanta, GA 30303 USA.
EM agewirtz@gsu.edu
FU NIH [DK099071, DK083890]; Crohn's and Colitis Foundation of America (CCFA); National Institute of Diabetes and Digestive and Kidney Diseases [R01DK099071, R01DK083890] Funding Source: NIH RePORTER; Crohn&apos;s & Colitis Foundation [276509] Funding Source: researchfish
NR 45
TC 1556
Z9 1797
U1 25
U2 723
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 5
PY 2015
VL 519
IS 7541
BP 92
EP U192
DI 10.1038/nature14232
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC4EQ
UT WOS:000350304000042
PM 25731162
DA 2026-03-09
ER

PT J
AU Wang, KH
   Penmatsa, A
   Gouaux, E
AF Wang, Kevin H.
   Penmatsa, Aravind
   Gouaux, Eric
TI Neurotransmitter and psychostimulant recognition by the dopamine transporter
SO NATURE
LA English
DT Article
ID biogenic-amine transporters; rat-brain synaptosm; cocaine binding; conformational dynamics; serotonin transporter; substrate transport; alternating-access; transmitter uptake; bacterial homolog; mammalian-cells
AB Na+/Cl--coupled biogenic amine transporters are the primary targets of therapeutic and abused drugs, ranging from antidepressants to the psychostimulants cocaine and amphetamines, and to their cognate substrates. Here we determine X-ray crystal structures of the Drosophila melanogaster dopamine transporter (dDAT) bound to its substrate dopamine, a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants D-amphetamine and methamphetamine, or to cocaine and cocaine analogues. All ligands bind to the central binding site, located approximately halfway across the membrane bilayer, in close proximity to bound sodium and chloride ions. The central binding site recognizes three chemically distinct classes of ligands via conformational changes that accommodate varying sizes and shapes, thus illustrating molecular principles that distinguish substrates from inhibitors in biogenic amine transporters.
C1 [Wang, Kevin H.; Penmatsa, Aravind; Gouaux, Eric] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA.
   [Gouaux, Eric] Oregon Hlth & Sci Univ, Howard Hughes Med Inst, Portland, OR 97239 USA.
C3 Oregon Health & Science University; Oregon Health & Science University; Howard Hughes Medical Institute
RP Gouaux, E (corresponding author), Oregon Hlth & Sci Univ, Vollum Inst, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA.
EM gouauxe@ohsu.edu
FU NIMH Ruth Kirschstein postdoctoral fellowship; Brain and Behavior Research Foundation Young Investigator research award; American Heart Association; NIH; Methamphetamine Abuse Research Center of OHSU [P50DA018165]
NR 60
TC 362
Z9 405
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 MAY 21
PY 2015
VL 521
IS 7552
BP 322
EP +
DI 10.1038/nature14431
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CI5RM
UT WOS:000354816500049
PM 25970245
DA 2026-03-09
ER

PT J
AU Cheloufi, S
   Elling, U
   Hopfgartner, B
   Jung, YL
   Murn, J
   Ninova, M
   Hubmann, M
   Badeaux, AI
   Ang, CE
   Tenen, D
   Wesche, DJ
   Abazova, N
   Hogue, M
   Tasdemir, N
   Brumbaugh, J
   Rathert, P
   Jude, J
   Ferrari, F
   Blanco, A
   Fellner, M
   Wenzel, D
   Zinner, M
   Vidal, SE
   Bell, O
   Stadtfeld, M
   Chang, HY
   Almouzni, G
   Lowe, SW
   Rinn, J
   Wernig, M
   Aravin, A
   Shi, Y
   Park, PJ
   Penninger, JM
   Zuber, J
   Hochedlinger, K
AF Cheloufi, Sihem
   Elling, Ulrich
   Hopfgartner, Barbara
   Jung, Youngsook L.
   Murn, Jernej
   Ninova, Maria
   Hubmann, Maria
   Badeaux, Aimee I.
   Ang, Cheen Euong
   Tenen, Danielle
   Wesche, Daniel J.
   Abazova, Nadezhda
   Hogue, Max
   Tasdemir, Nilgun
   Brumbaugh, Justin
   Rathert, Philipp
   Jude, Julian
   Ferrari, Francesco
   Blanco, Andres
   Fellner, Michaela
   Wenzel, Daniel
   Zinner, Marietta
   Vidal, Simon E.
   Bell, Oliver
   Stadtfeld, Matthias
   Chang, Howard Y.
   Almouzni, Genevieve
   Lowe, Scott W.
   Rinn, John
   Wernig, Marius
   Aravin, Alexei
   Shi, Yang
   Park, Peter J.
   Penninger, Josef M.
   Zuber, Johannes
   Hochedlinger, Konrad
TI The histone chaperone CAF-1 safeguards somatic cell identity
SO NATURE
LA English
DT Article
ID differential expression analysis; nuclear transfer; chromatin; heterochromatin; replication; binding; deposition; sequences; establish; alignment
AB Cellular differentiation involves profound remodelling of chromatic landscapes, yet the mechanisms by which somatic cell identity is subsequently maintained remain incompletely understood. To further elucidate regulatory pathways that safeguard the somatic state, we performed two comprehensive RNA interference (RNAi) screens targeting chromatin factors during transcription-factor-mediated reprogramming of mouse fibroblasts to induced pluripotent stem cells (iPS cells). Subunits of the chromatin assembly factor-1 (CAF-1) complex, including Chaf1a and Chaf1b, emerged as the most prominent hits from both screens, followed by modulators of lysine sumoylation and heterochromatin maintenance. Optimal modulation of both CAF-1 and transcription factor levels increased reprogramming efficiency by several orders of magnitude and facilitated iPS cell formation in as little as 4 days. Mechanistically, CAF-1 suppression led to a more accessible chromatin structure at enhancer elements early during reprogramming. These changes were accompanied by a decrease in somatic heterochromatin domains, increased binding of Sox2 to pluripotency-specific targets and activation of associated genes. Notably, suppression of CAF-1 also enhanced the direct conversion of B cells into macrophages and fibroblasts into neurons. Together, our findings reveal the histone chaperone CAF-1 to be a novel regulator of somatic cell identity during transcription-factor-induced cell-fate transitions and provide a potential strategy to modulate cellular plasticity in a regenerative setting.
C1 [Cheloufi, Sihem; Wesche, Daniel J.; Abazova, Nadezhda; Hogue, Max; Brumbaugh, Justin; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Dept Mol Biol, Boston, MA 02114 USA.
   [Cheloufi, Sihem; Wesche, Daniel J.; Abazova, Nadezhda; Hogue, Max; Brumbaugh, Justin; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.
   [Cheloufi, Sihem; Tenen, Danielle; Wesche, Daniel J.; Abazova, Nadezhda; Hogue, Max; Brumbaugh, Justin; Rinn, John; Hochedlinger, Konrad] Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.
   [Cheloufi, Sihem; Tenen, Danielle; Wesche, Daniel J.; Abazova, Nadezhda; Hogue, Max; Brumbaugh, Justin; Rinn, John; Hochedlinger, Konrad] Harvard Stem Cell Inst, Cambridge, MA 02138 USA.
   [Cheloufi, Sihem; Wesche, Daniel J.; Abazova, Nadezhda; Hogue, Max; Brumbaugh, Justin; Chang, Howard Y.; Lowe, Scott W.; Hochedlinger, Konrad] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
   [Elling, Ulrich; Hubmann, Maria; Wenzel, Daniel; Zinner, Marietta; Bell, Oliver; Penninger, Josef M.] Austrian Acad Sci IMBA, Inst Mol Biotechnol, Vienna Bioctr VBC, A-1030 Vienna, Austria.
   [Hopfgartner, Barbara; Rathert, Philipp; Jude, Julian; Fellner, Michaela; Zuber, Johannes] Res Inst Mol Pathol IMP, Vienna Bioctr VBC, A-1030 Vienna, Austria.
   [Jung, Youngsook L.; Ferrari, Francesco; Park, Peter J.] Harvard Univ, Sch Med, Dept Biomed Informat, Boston, MA 02115 USA.
   [Jung, Youngsook L.; Ferrari, Francesco; Park, Peter J.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA.
   [Murn, Jernej; Badeaux, Aimee I.; Blanco, Andres; Shi, Yang] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA.
   [Murn, Jernej; Badeaux, Aimee I.; Blanco, Andres; Shi, Yang] Boston Childrens Hosp, Div Newborn Med, Boston, MA 02115 USA.
   [Ninova, Maria; Aravin, Alexei] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
   [Ang, Cheen Euong; Wernig, Marius] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Dept Pathol, Stanford, CA 94305 USA.
   [Ang, Cheen Euong; Wernig, Marius] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.
   [Tenen, Danielle; Rinn, John] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA 02142 USA.
   [Tasdemir, Nilgun; Lowe, Scott W.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA.
   [Vidal, Simon E.; Stadtfeld, Matthias] NYU, Sch Med, Skirball Inst Biomol Med, Helen L & Martin S Kimmel Ctr Biol & Med,Dept Cel, New York, NY 10016 USA.
   [Chang, Howard Y.] Stanford Univ, Sch Med, Ctr Personal Dynam Regulomes, Stanford, CA 94305 USA.
   [Chang, Howard Y.] Stanford Univ, Sch Med, Program Epithelial Biol, Stanford, CA 94305 USA.
   [Almouzni, Genevieve] Inst Curie, Ctr Rech, F-75248 Paris, France.
C3 Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Howard Hughes Medical Institute; Austrian Academy of Sciences; Vienna Biocenter (VBC); Institute of Molecular Biotechnology (IMBA); Vienna Biocenter (VBC); Research Institute of Molecular Pathology (IMP); Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; California Institute of Technology; Stanford University; Stanford University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Memorial Sloan Kettering Cancer Center; New York University; Stanford University; Stanford University; UNICANCER; Universite PSL; Institut Curie
RP Hochedlinger, K (corresponding author), Massachusetts Gen Hosp, Ctr Canc, Dept Mol Biol, Boston, MA 02114 USA.
EM johannes.zuber@imp.ac.at; khochedlinger@mgh.harvard.edu
FU PRCRP at the Department of Defense [CA 120212]; NIH [P50-HG007735, R01 HD058013-06]; IMBA; Austrian National Foundation; cancer center support grant; NCI; ERC GA [341036]; Innovator Award/Era of Hope Award [W81XWH-12-1-0093]; ERC [336860]; Boehringer Ingelheim; MGH; HHMI; Gerald and Darlene Jordan Chair in Regenerative Medicine; European Research Council (ERC) [336860, 341036] Funding Source: European Research Council (ERC); National Cancer Institute [P30CA008748, P01CA013106] Funding Source: NIH RePORTER
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NR 54
TC 210
Z9 282
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 10
PY 2015
VL 528
IS 7581
BP 218
EP +
DI 10.1038/nature15749
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX9VH
UT WOS:000366053300032
PM 26659182
DA 2026-03-09
ER

PT J
AU Zalk, R
   Clarke, OB
   des Georges, A
   Grassucci, RA
   Reiken, S
   Mancia, F
   Hendrickson, WA
   Frank, J
   Marks, AR
AF Zalk, Ran
   Clarke, Oliver B.
   des Georges, Amedee
   Grassucci, Robert A.
   Reiken, Steven
   Mancia, Filippo
   Hendrickson, Wayne A.
   Frank, Joachim
   Marks, Andrew R.
TI Structure of a mammalian ryanodine receptor
SO NATURE
LA English
DT Article
ID calcium-release channel; particle electron cryomicroscopy; em structure determination; skeletal-muscle; cryo-em; intracellular calcium; defective regulation; heart-failure; microscopy; domain
AB Ryanodine receptors (RyRs) mediate the rapid release of calcium (Ca2+) from intracellular stores into the cytosol, which is essential for numerous cellular functions including excitation-contraction coupling in muscle. Lack of sufficient structural detail has impeded understanding of RyR gating and regulation. Here we report the closed-state structure of the 2.3-megadalton complex of the rabbit skeletal muscle type 1 RyR (RyR1), solved by single-particle electron cryomicroscopy at an overall resolution of 4.8 angstrom. We fitted a polyalanine-level model to all 3,757 ordered residues in each protomer, defining the transmembrane pore in unprecedented detail and placing all cytosolic domains as tertiary folds. The cytosolic assembly is built on an extended alpha-solenoid scaffold connecting key regulatory domains to the pore. The RyR1 pore architecture places it in the six-transmembrane ion channel superfamily. A unique domain inserted between the second and third transmembrane helices interacts intimately with paired EF-hands originating from the alpha-solenoid scaffold, suggesting a mechanism for channel gating by Ca2+.
C1 [Zalk, Ran; Reiken, Steven; Mancia, Filippo; Hendrickson, Wayne A.; Marks, Andrew R.] Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY 10032 USA.
   [Clarke, Oliver B.; des Georges, Amedee; Grassucci, Robert A.; Hendrickson, Wayne A.; Frank, Joachim] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA.
   [Grassucci, Robert A.; Frank, Joachim] Columbia Univ, Howard Hughes Med Inst, New York, NY 10032 USA.
   [Frank, Joachim] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA.
   [Marks, Andrew R.] Columbia Univ, Dept Med, New York, NY 10032 USA.
   [Marks, Andrew R.] Columbia Univ, Wu Ctr Mol Cardiol, Coll Phys & Surg, New York, NY 10032 USA.
C3 Columbia University; Columbia University; Howard Hughes Medical Institute; Columbia University; Columbia University; Columbia University; Columbia University
RP Marks, AR (corresponding author), Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY 10032 USA.
EM wayne@xtl.cumc.columbia.edu; jf2192@columbia.edu; arm42@columbia.edu
FU Howard Hughes Medical Institute Funding Source: Medline; NHLBI NIH HHS [R01 HL083418, R01HL061503, R01 HL061503, P01 HL081172] Funding Source: Medline; NIAMS NIH HHS [R01 AR060037, R01AR060037] Funding Source: Medline; NIGMS NIH HHS [U54GM095315, R01GM29169, R01 GM029169, U54 GM095315] Funding Source: Medline
NR 54
TC 337
Z9 393
U1 6
U2 132
PU NATURE PUBLISHING 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 1
PY 2015
VL 517
IS 7532
BP 44
EP U90
DI 10.1038/nature13950
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AX8SI
UT WOS:000347178400031
PM 25470061
DA 2026-03-09
ER

PT J
AU Haedler, AT
   Kreger, K
   Issac, A
   Wittmann, B
   Kivala, M
   Hammer, N
   Köhler, J
   Schmidt, HW
   Hildner, R
AF Haedler, Andreas T.
   Kreger, Klaus
   Issac, Abey
   Wittmann, Bernd
   Kivala, Milan
   Hammer, Natalie
   Koehler, Juergen
   Schmidt, Hans-Werner
   Hildner, Richard
TI Long-range energy transport in single supramolecular nanofibres at room temperature
SO NATURE
LA English
DT Article
ID exciton diffusion; nanotubes; migration; polymers; heterotriangulenes; fluorescence; coherence; crystals; blinking; length
AB Efficient transport of excitation energy over long distances is a key process in light-harvesting systems, as well as in molecular electronics(1-3). However, in synthetic disordered organic materials, the exciton diffusion length is typically only around 10 nanometres (refs 4, 5), or about 50 nanometres in exceptional cases(6,7), a distance that is largely determined by the probability laws of incoherent exciton hopping. Only for highly ordered organic systems has the transport of excitation energy over macroscopic distances been reported-for example, for triplet excitons in anthracene single crystals at room temperature(8), as well as along single polydiacetylene chains embedded in their monomer crystalline matrix at cryogenic temperatures (at 10 kelvin, or -263 degrees Celsius)(9). For supramolecular nanostructures, uniaxial long-range transport has not been demonstrated at room temperature. Here we show that individual self-assembled nanofibres with molecular-scale diameter efficiently transport singlet excitons at ambient conditions over more than four micrometres, a distance that is limited only by the fibre length. Our data suggest that this remarkable long-range transport is predominantly coherent. Such coherent long-range transport is achieved by one-dimensional self-assembly of supramolecular building blocks, based on carbonyl-bridged triarylamines10, into well defined H-type aggregates (in which individual monomers are aligned cofacially) with substantial electronic interactions. These findings may facilitate the development of organic nanophotonic devices and quantum information technology.
C1 [Haedler, Andreas T.; Kreger, Klaus; Schmidt, Hans-Werner] Univ Bayreuth, Macromol Chem 1, Bayreuth Inst Macromol Res, D-95440 Bayreuth, Germany.
   [Haedler, Andreas T.; Kreger, Klaus; Schmidt, Hans-Werner] Univ Bayreuth, Bayreuth Ctr Colloids & Interfaces, D-95440 Bayreuth, Germany.
   [Issac, Abey; Wittmann, Bernd; Koehler, Juergen; Hildner, Richard] Univ Bayreuth, Expt Phys 4, D-95440 Bayreuth, Germany.
   [Issac, Abey; Wittmann, Bernd; Koehler, Juergen; Hildner, Richard] Univ Bayreuth, Bayreuth Inst Macromol Res, D-95440 Bayreuth, Germany.
   [Kivala, Milan; Hammer, Natalie] Univ Erlangen Nurnberg, Dept Chem & Pharm, Chair Organ Chem 1, D-91054 Erlangen, Germany.
C3 University of Bayreuth; University of Bayreuth; University of Bayreuth; University of Bayreuth; University of Erlangen Nuremberg
RP Hildner, R (corresponding author), Univ Bayreuth, Expt Phys 4, D-95440 Bayreuth, Germany.
EM hans-werner.schmidt@uni-bayreuth.de; richard.hildner@uni-bayreuth.de
FU Bavarian State Ministry of Science, Research, and the Arts for the Collaborative Research Network 'Solar Technologies go Hybrid'; Deutsche Forschungsgemeinschaft (DFG) [GRK1640, SFB953]; Cluster of Excellence 'Engineering of Advanced Materials' (EAM) at the University of Erlangen-Nurnberg; 'Macromolecular Science' elite study program at the University of Bayreuth; 'Elite Netzwerk Bayern' fellowship
NR 32
TC 298
Z9 347
U1 8
U2 488
PU NATURE PUBLISHING 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 9
PY 2015
VL 523
IS 7559
BP 196
EP U127
DI 10.1038/nature14570
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM4ZO
UT WOS:000357695900031
PM 26156373
DA 2026-03-09
ER

PT J
AU Liu, W
   Martinon-Torres, M
   Cai, YJ
   Xing, S
   Tong, HW
   Pei, SW
   Sier, MJ
   Wu, XH
   Edwards, RL
   Cheng, H
   Li, YY
   Yang, XX
   de Castro, JMB
   Wu, XJ
AF Liu, Wu
   Martinon-Torres, Maria
   Cai, Yan-jun
   Xing, Song
   Tong, Hao-wen
   Pei, Shu-wen
   Sier, Mark Jan
   Wu, Xiao-hong
   Edwards, R. Lawrence
   Cheng, Hai
   Li, Yi-yuan
   Yang, Xiong-xin
   Bermudez de Castro, Jose Maria
   Wu, Xiu-jie
TI The earliest unequivocally modern humans in southern China
SO NATURE
LA English
DT Article
ID morphometric-analysis; hominin teeth; africa; remains; dispersals; history; route; cave; java; site
AB The hominin record from southern Asia for the early Late Pleistocene epoch is scarce. Well-dated and well-preserved fossils older than similar to 45,000 years that can be unequivocally attributed to Homo sapiens are lacking(1-4). Here we present evidence from the newly excavated Fuyan Cave in Damian (southern China). This site has provided 47 human teeth dated to more than 80,000 years old, and with an inferred maximum age of 120,000 years. The morphological and metric assessment of this sample supports its unequivocal assignment to H. sapiens. The Daoxian sample is more derived than any other anatomically modern humans, resembling middle-to-late Late Pleistocene specimens and even contemporary humans. Our study shows that fully modern morphologies were present in southern China 30,000-70,000 years earlier than in the Levant and Europe(5-7). Our data fill a chronological and geographical gap that is relevant for understanding when H. sapiens first appeared in southern Asia. The Damian teeth also support the hypothesis that during the same period, southern China was inhabited by more derived populations than central and northern China. This evidence is important for the study of dispersal routes of modern humans.. Finally, our results are relevant to exploring the reasons for the relatively late entry of H. sapiens into Europe. Some studies have investigated how the competition with H. sapiens may have caused Neanderthals' extinction. (see ref. 8 and references therein). Notably, although fully modern humans were already present in southern China at least as early as 80,000 years ago, there is no evidence that they entered Europe before similar to 45,000 years ago. This could indicate that H. neanderthalensis was indeed an additional ecological barrier for modern humans, who could only enter Europe when the demise of Neanderthals had already started.
C1 [Liu, Wu; Xing, Song; Tong, Hao-wen; Pei, Shu-wen; Wu, Xiu-jie] Chinese Acad Sci, Inst Vertebrate Paleontol & Paleoanthropol, Key Lab Vertebrate Evolut & Human Origins, Beijing 100044, Peoples R China.
   [Martinon-Torres, Maria; Bermudez de Castro, Jose Maria] UCL Anthropol, London WC1H 0BW, England.
   [Martinon-Torres, Maria] Univ Burgos, Dept Ciencias Hist & Geog, Burgos 09001, Spain.
   [Martinon-Torres, Maria; Sier, Mark Jan; Bermudez de Castro, Jose Maria] Ctr Nacl Invest Evoluc Humana CENIEH, Burgos 09002, Spain.
   [Cai, Yan-jun] Chinese Acad Sci, Inst Earth Environm, State Key Lab Loess & Quaternary Geol, Xian 710075, Peoples R China.
   [Sier, Mark Jan] Univ Utrecht, Fac Geosci, Dept Earth Sci, Paleomagnet Lab Ft Hoofddijk, NL-3584 CD Utrecht, Netherlands.
   [Sier, Mark Jan] Leiden Univ, Fac Archaeol, NL-2300 RA Leiden, Netherlands.
   [Wu, Xiao-hong] Peking Univ, Sch Archaeol & Museol, Beijing 100871, Peoples R China.
   [Edwards, R. Lawrence] Univ Minnesota, Dept Geol & Geophys, Minneapolis, MN 55455 USA.
   [Cheng, Hai] Xi An Jiao Tong Univ, Inst Global Environm Change, Xian 710049, Peoples R China.
   [Li, Yi-yuan] Inst Cultural Rel & Archaeol, Changsha 410008, Hunan, Peoples R China.
   [Yang, Xiong-xin] Cultural Rel Adm Daoxian Cty, Daoxian 425300, Peoples R China.
C3 Chinese Academy of Sciences; Institute of Vertebrate Paleontology & Paleoanthropology, CAS; University of London; University College London; Universidad de Burgos; Centro Nacional de Investigacion de La Evolucion Humana (CENIEH); Chinese Academy of Sciences; Institute of Earth Environment, CAS; Utrecht University; Leiden University; Leiden University - Excl LUMC; Peking University; University of Minnesota System; University of Minnesota Twin Cities; Xi'an Jiaotong University
RP Martinon-Torres, M (corresponding author), UCL Anthropol, 14 Taviton St, London WC1H 0BW, England.
EM liuwu@ivpp.ac.cn; maria.martinon-torres@ucl.ac.uk; wuxiujie@ivpp.ac.cn
FU Chinese Academy of Sciences [KZZD-EW-03, XDA05130101, GJHZ201314]; National Natural Science Foundation of China [41272034, 41302016, 41271229]; Netherlands Organisation for Scientific Research [NWO-ALW 823.01.003]; Direccion General de Investigacion of the Spanish Ministerio de Educacion y Ciencia [CGL2012-38434-C03-02]; Direccion General de Investigacion of the Spanish Ministerio de Educacion y Ciencia (Accion Integrada Espana Francia) [HF2007-0115]; Consejeria de Educacion de Junta de Castilla y Leon [CEN074A12-2]; Leakey Foundation
NR 28
TC 310
Z9 386
U1 7
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 29
PY 2015
VL 526
IS 7575
BP 696
EP 699
DI 10.1038/nature15696
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CU8ZH
UT WOS:000363832100047
PM 26466566
DA 2026-03-09
ER

PT J
AU Mou, Y
   Yu, JY
   Wannier, TM
   Guo, CL
   Mayo, SL
AF Mou, Yun
   Yu, Jiun-Yann
   Wannier, Timothy M.
   Guo, Chin-Lin
   Mayo, Stephen L.
TI Computational design of co-assembling protein-DNA nanowires
SO NATURE
LA English
DT Article
ID binding-specificity; stability
AB Biomolecular self-assemblies are of great interest to nanotechnologists because of their functional versatility and their biocompatibility(1). Over the past decade, sophisticated single-component nanostructures composed exclusively of nucleic acids(2-5), peptides(6-8) and proteins(9-15) have been reported, and these nanostructures have been used in a wide range of applications, from drug delivery(16) to molecular computing(17). Despite these successes, the development of hybrid co-assemblies of nucleic acids and proteins has remained elusive. Here we use computational protein design to create a protein-DNA co-assembling nanomaterial whose assembly is driven via non-covalent interactions. To achieve this, a homodimerization interface is engineered onto the Drosophila Engrailed homeodomain (ENH), allowing the dimerized protein complex to bind to two double-stranded DNA (dsDNA) molecules. By varying the arrangement of protein-binding sites on the dsDNA, an irregular bulk nanoparticle or a nanowire with single-molecule width can be spontaneously formed by mixing the protein and dsDNA building blocks. We characterize the protein-DNA nanowire using fluorescence microscopy, atomic force microscopy and X-ray crystallography, confirming that the nanowire is formed via the proposed mechanism. This work lays the foundation for the development of new classes of protein-DNA hybrid materials. Further applications can be explored by incorporating DNA origami, DNA aptamers and/or peptide epitopes into the protein-DNA framework presented here.
C1 [Mou, Yun; Mayo, Stephen L.] CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA.
   [Yu, Jiun-Yann; Wannier, Timothy M.; Mayo, Stephen L.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
   [Guo, Chin-Lin] CALTECH, Div Engn & Appl Sci, Pasadena, CA 91125 USA.
C3 California Institute of Technology; California Institute of Technology; California Institute of Technology
RP Mou, Y (corresponding author), CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA.
EM mouung@caltech.edu; steve@mayo.caltech.edu
FU Defense Advanced Research Projects Agency Protein Design Processes Program, a National Security Science and Engineering Faculty Fellowship (NSSEFF) [N00244-09-1-0011, N00244-09-1-0082]; Gordon and Betty Moore Foundation [GBMF2809]; Gordon and Betty Moore Foundation; Department of Energy; National Institutes of Health
NR 40
TC 74
Z9 95
U1 3
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 SEP 10
PY 2015
VL 525
IS 7568
BP 230
EP +
DI 10.1038/nature14874
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400034
PM 26331548
DA 2026-03-09
ER

PT J
AU Suga, M
   Akita, F
   Hirata, K
   Ueno, G
   Murakami, H
   Nakajima, Y
   Shimizu, T
   Yamashita, K
   Yamamoto, M
   Ago, H
   Shen, JR
AF Suga, Michihiro
   Akita, Fusamichi
   Hirata, Kunio
   Ueno, Go
   Murakami, Hironori
   Nakajima, Yoshiki
   Shimizu, Tetsuya
   Yamashita, Keitaro
   Yamamoto, Masaki
   Ago, Hideo
   Shen, Jian-Ren
TI Native structure of photosystem II at 1.95 Å resolution viewed by femtosecond X-ray pulses
SO NATURE
LA English
DT Article
ID oxygen-evolving complex; crystal-structure; manganese complex; water; diffraction; models; damage; cluster; states; exafs
AB Photosynthesis converts light energy into biologically useful chemical energy vital to life on Earth. The initial reaction of photosynthesis takes place in photosystem II (PSII), a 700-kilodalton homodimeric membrane protein complex that catalyses photo-oxidation of water into dioxygen through an S-state cycle of the oxygen evolving complex (OEC). The structure of PSII has been solved by X-ray diffraction (XRD) at 1.9 angstrom resolution, which revealed that the OEC is a Mn4CaO5-cluster coordinated by a well defined protein environment(1). However, extended X-ray absorption fine structure (EXAFS) studies showed that the manganese cations in the OEC are easily reduced by X-ray irradiation(2), and slight differences were found in the Mn-Mn distances determined by XRD1, EXAFS(3-7) and theoretical studies(8-14). Here we report a 'radiation-damage-free' structure of PSII from Thermosynechococcus vulcanus in the S-1 state at a resolution of 1.95 angstroms using femtosecond X-ray pulses of the SPring-8 angstrom compact free-electron laser (SACLA) and hundreds of large, highly isomorphous PSII crystals. Compared with the structure from XRD, the OEC in the X-ray free electron laser structure has Mn-Mn distances that are shorter by 0.1-0.2 angstroms. The valences of each manganese atom were tentatively assigned as Mn1D(III), Mn2C(IV), Mn3B(IV) and Mn4A(III), based on the average Mn-ligand distances and analysis of the Jahn-Teller axis on Mn(III). One of the oxo-bridged oxygens, O5, has significantly longer distances to Mn than do the other oxo-oxygen atoms, suggesting that O5 is a hydroxide ion instead of a normal oxygen dianion and therefore may serve as one of the substrate oxygen atoms. These findings provide a structural basis for the mechanism of oxygen evolution, and we expect that this structure will provide a blueprint for the design of artificial catalysts for water oxidation.
C1 [Suga, Michihiro; Akita, Fusamichi; Nakajima, Yoshiki; Shimizu, Tetsuya; Shen, Jian-Ren] Okayama Univ, Grad Sch Nat Sci & Technol, Photosynth Res Ctr, Okayama 7008530, Japan.
   [Hirata, Kunio; Ueno, Go; Murakami, Hironori; Yamashita, Keitaro; Yamamoto, Masaki; Ago, Hideo] RIKEN, SPring Ctr 8, Mikazuki, Hyogo 6795148, Japan.
   [Hirata, Kunio] Japan Sci & Technol Agcy JST, Core Res Evolut Sci & Technol CREST, Kawaguchi, Saitama 3320012, Japan.
C3 Okayama University; RIKEN; Japan Science & Technology Agency (JST)
RP Ago, H (corresponding author), RIKEN, SPring Ctr 8, 1-1-1 Kouto Sayo, Mikazuki, Hyogo 6795148, Japan.
EM yamamoto@riken.jp; ago@spring8.or.jp; shen@cc.okayama-u.ac.jp
FU The Ministry of Education, Culture, Sports, Science and Technology of Japan, MEXT; JST/CREST; Japan Synchrotron Radiation Research Institute (JASRI) [2012A8011, 2012B8040, 2013A8047, 2013B8052, 2014A8036]; Grants-in-Aid for Scientific Research [26840023, 24000018] Funding Source: KAKEN
NR 35
TC 991
Z9 1124
U1 16
U2 886
PU NATURE PUBLISHING 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 1
PY 2015
VL 517
IS 7532
BP 99
EP U265
DI 10.1038/nature13991
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AX8SI
UT WOS:000347178400043
PM 25470056
DA 2026-03-09
ER

PT J
AU Janoschka, T
   Martin, N
   Martin, U
   Friebe, C
   Morgenstern, S
   Hiller, H
   Hager, MD
   Schubert, US
AF Janoschka, Tobias
   Martin, Norbert
   Martin, Udo
   Friebe, Christian
   Morgenstern, Sabine
   Hiller, Hannes
   Hager, Martin D.
   Schubert, Ulrich S.
TI An aqueous, polymer-based redox-flow battery using non-corrosive, safe, and low-cost materials
SO NATURE
LA English
DT Article
ID electrical energy-storage; electrochemical property; radical polymers; membranes; reduction; progress
AB For renewable energy sources such as solar, wind, and hydroelectric to be effectively used in the grid of the future, flexible and scalable energy-storage solutions are necessary to mitigate output fluctuations(1). Redox-flow batteries (RFBs) were first built in the 1940s(2) and are considered a promising large-scale energy-storage technology(1,3,4). A limited number of redox-active materials(4,5-10)-mainly metal salts, corrosive halogens, and low-molar-mass organic compounds have been investigated as active materials, and only a few membrane materials(3,5,11-14), such as Nafion, have been considered for RFBs. However, for systems that are intended for both domestic and large-scale use, safety and cost must be taken into account as well as energy density and capacity, particularly regarding long-term access to metal resources, which places limits on the lithium-ion-based and vanadium-based RFB development(15,16). Here we describe an affordable, safe, and scalable battery system, which uses organic polymers as the charge-storage material in combination with inexpensive dialysis membranes, which separate the anode and the cathode by the retention of the non-metallic, active (macro-molecular) species, and an aqueous sodium chloride solution as the electrolyte. This water- and polymer-based RFB has an energy density of 10 watt hours per litre, current densities of up to 100 milliamperes per square centimetre, and stable long-term cycling capability. The polymer-based RFB we present uses an environmentally benign sodium chloride solution and cheap, commercially available filter membranes instead of highly corrosive acid electrolytes and expensive membrane materials.
C1 [Janoschka, Tobias; Friebe, Christian; Morgenstern, Sabine; Hiller, Hannes; Hager, Martin D.; Schubert, Ulrich S.] Univ Jena, Lab Organ & Macromol Chem IOMC, D-07743 Jena, Germany.
   [Janoschka, Tobias; Friebe, Christian; Morgenstern, Sabine; Hiller, Hannes; Hager, Martin D.; Schubert, Ulrich S.] Univ Jena, CEEC Jena, D-07743 Jena, Germany.
   [Martin, Norbert; Martin, Udo] JenaBattenes GmbH, D-07743 Jena, Germany.
C3 Friedrich Schiller University of Jena; Friedrich Schiller University of Jena
RP Schubert, US (corresponding author), Univ Jena, Lab Organ & Macromol Chem IOMC, D-07743 Jena, Germany.
EM ulrich.schubert@uni-jena.de
FU European Regional Development Fund for Thuringia (EFRE); Thuringer Aufbaubank (TAB); Thuringian Ministry for Economic Affairs, Science and Digital Society (TMWWdG); Fonds der Chemischen Industrie
NR 29
TC 799
Z9 932
U1 36
U2 1390
PU NATURE PUBLISHING 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 5
PY 2015
VL 527
IS 7576
BP 78
EP 81
DI 10.1038/nature15746
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV4XV
UT WOS:000364270700046
PM 26503039
DA 2026-03-09
ER

PT J
AU Blees, MK
   Barnard, AW
   Rose, PA
   Roberts, SP
   McGill, KL
   Huang, PY
   Ruyack, AR
   Kevek, JW
   Kobrin, B
   Muller, DA
   McEuen, PL
AF Blees, Melina K.
   Barnard, Arthur W.
   Rose, Peter A.
   Roberts, Samantha P.
   McGill, Kathryn L.
   Huang, Pinshane Y.
   Ruyack, Alexander R.
   Kevek, Joshua W.
   Kobrin, Bryce
   Muller, David A.
   McEuen, Paul L.
TI Graphene kirigami
SO NATURE
LA English
DT Article
ID membranes; fluctuations; ripples; sheets
AB For centuries, practitioners of origami ('ori', fold; 'kami', paper) and kirigami ('kiru', cut) have fashioned sheets of paper into beautiful and complex three-dimensional structures. Both techniques are scalable, and scientists and engineers are adapting them to different two-dimensional starting materials to create structures from the macro-to the microscale(1,2). Here we show that graphene(3-6) is well suited for kirigami, allowing us to build robust microscale structures with tunable mechanical properties. The material parameter crucial for kirigami is the Foppl-von Karman number(7,8) gamma: an indication of the ratio between in-plane stiffness and out-of-plane bending stiffness, with high numbers corresponding to membranes that more easily bend and crumple than they stretch and shear. To determine gamma, we measure the bending stiffness of graphene monolayers that are 10-100 micrometres in size and obtain a value that is thousands of times higher than the predicted atomic-scale bending stiffness. Interferometric imaging attributes this finding to ripples in the membrane(9-13) that stiffen the graphene sheets considerably, to the extent that gamma is comparable to that of a standard piece of paper. We may therefore apply ideas from kirigami to graphene sheets to build mechanical metamaterials such as stretchable electrodes, springs, and hinges. These results establish graphene kirigami as a simple yet powerful and customizable approach for fashioning one-atom-thick graphene sheets into resilient and movable parts with microscale dimensions.
C1 [Blees, Melina K.; Rose, Peter A.; Roberts, Samantha P.; McGill, Kathryn L.; Kevek, Joshua W.; Kobrin, Bryce; McEuen, Paul L.] Cornell Univ, Lab Atom & Solid State Phys, Ithaca, NY 14853 USA.
   [Barnard, Arthur W.; Huang, Pinshane Y.; Muller, David A.] Cornell Univ, Sch Appl & Engn Phys, Ithaca, NY 14853 USA.
   [Ruyack, Alexander R.] Cornell Univ, Sch Elect & Comp Engn, Ithaca, NY 14853 USA.
   [Muller, David A.; McEuen, Paul L.] Cornell Univ, Kavli Inst, Cornell Nanoscale Sci, Ithaca, NY 14853 USA.
C3 Cornell University; Cornell University; Cornell University; Cornell University
RP McEuen, PL (corresponding author), Cornell Univ, Lab Atom & Solid State Phys, Ithaca, NY 14853 USA.
EM plm23@cornell.edu
FU Cornell Center for Materials Research (National Science Foundation, NSF) [DMR-1120296]; Office of Naval Research [N00014-13-1-0749]; Kavli Institute at Cornell for Nanoscale Science; NSF [ECCS-0335765]; NSF Graduate Research Fellowship Program [DGE-1144153, DGE-0707428]; SBIR [DE-SC0011385]; U.S. Department of Energy (DOE) [DE-SC0011385] Funding Source: U.S. Department of Energy (DOE)
NR 27
TC 779
Z9 917
U1 27
U2 998
PU NATURE PUBLISHING 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 13
PY 2015
VL 524
IS 7564
BP 204
EP +
DI 10.1038/nature14588
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900028
PM 26222025
DA 2026-03-09
ER

PT J
AU Kundaje, A
   Meuleman, W
   Ernst, J
   Bilenky, M
   Yen, A
   Heravi-Moussavi, A
   Kheradpour, P
   Zhang, Z
   Wang, J
   Ziller, MJ
   Amin, V
   Whitaker, JW
   Schultz, MD
   Ward, LD
   Sarkar, A
   Quon, G
   Sandstrom, RS
   Eaton, ML
   Wu, YC
   Pfenning, AR
   Wang, X
   Claussnitzer, M
   Liu, Y
   Coarfa, C
   Harris, RA
   Shoresh, N
   Epstein, CB
   Gjoneska, E
   Leung, D
   Xie, W
   Hawkins, RD
   Lister, R
   Hong, C
   Gascard, P
   Mungall, AJ
   Moore, R
   Chuah, E
   Tam, A
   Canfield, TK
   Hansen, RS
   Kaul, R
   Sabo, PJ
   Bansal, MS
   Carles, A
   Dixon, JR
   Farh, KH
   Feizi, S
   Karlic, R
   Kim, AR
   Kulkarni, A
   Li, D
   Lowdon, R
   Elliott, G
   Mercer, TR
   Neph, SJ
   Onuchic, V
   Polak, P
   Rajagopal, N
   Ray, P
   Sallari, RC
   Siebenthall, KT
   Sinnott-Armstrong, NA
   Stevens, M
   Thurman, RE
   Wu, J
   Zhang, B
   Zhou, X
   Beaudet, AE
   Boyer, LA
   De Jager, PL
   Farnham, PJ
   Fisher, SJ
   Haussler, D
   Jones, SJM
   Li, W
   Marra, MA
   McManus, MT
   Sunyaev, S
   Thomson, JA
   Tlsty, TD
   Tsai, LH
   Wang, W
   Waterland, RA
   Zhang, MQ
   Chadwick, LH
   Bernstein, BE
   Costello, JF
   Ecker, JR
   Hirst, M
   Meissner, A
   Milosavljevic, A
   Ren, B
   Stamatoyannopoulos, JA
   Wang, T
   Kellis, M
AF Kundaje, Anshul
   Meuleman, Wouter
   Ernst, Jason
   Bilenky, Misha
   Yen, Angela
   Heravi-Moussavi, Alireza
   Kheradpour, Pouya
   Zhang, Zhizhuo
   Wang, Jianrong
   Ziller, Michael J.
   Amin, Viren
   Whitaker, John W.
   Schultz, Matthew D.
   Ward, Lucas D.
   Sarkar, Abhishek
   Quon, Gerald
   Sandstrom, Richard S.
   Eaton, Matthew L.
   Wu, Yi-Chieh
   Pfenning, Andreas R.
   Wang, Xinchen
   Claussnitzer, Melina
   Liu, Yaping
   Coarfa, Cristian
   Harris, R. Alan
   Shoresh, Noam
   Epstein, Charles B.
   Gjoneska, Elizabeta
   Leung, Danny
   Xie, Wei
   Hawkins, R. David
   Lister, Ryan
   Hong, Chibo
   Gascard, Philippe
   Mungall, Andrew J.
   Moore, Richard
   Chuah, Eric
   Tam, Angela
   Canfield, Theresa K.
   Hansen, R. Scott
   Kaul, Rajinder
   Sabo, Peter J.
   Bansal, Mukul S.
   Carles, Annaick
   Dixon, Jesse R.
   Farh, Kai-How
   Feizi, Soheil
   Karlic, Rosa
   Kim, Ah-Ram
   Kulkarni, Ashwinikumar
   Li, Daofeng
   Lowdon, Rebecca
   Elliott, GiNell
   Mercer, Tim R.
   Neph, Shane J.
   Onuchic, Vitor
   Polak, Paz
   Rajagopal, Nisha
   Ray, Pradipta
   Sallari, Richard C.
   Siebenthall, Kyle T.
   Sinnott-Armstrong, Nicholas A.
   Stevens, Michael
   Thurman, Robert E.
   Wu, Jie
   Zhang, Bo
   Zhou, Xin
   Beaudet, Arthur E.
   Boyer, Laurie A.
   De Jager, Philip L.
   Farnham, Peggy J.
   Fisher, Susan J.
   Haussler, David
   Jones, Steven J. M.
   Li, Wei
   Marra, Marco A.
   McManus, Michael T.
   Sunyaev, Shamil
   Thomson, James A.
   Tlsty, Thea D.
   Tsai, Li-Huei
   Wang, Wei
   Waterland, Robert A.
   Zhang, Michael Q.
   Chadwick, Lisa H.
   Bernstein, Bradley E.
   Costello, Joseph F.
   Ecker, Joseph R.
   Hirst, Martin
   Meissner, Alexander
   Milosavljevic, Aleksandar
   Ren, Bing
   Stamatoyannopoulos, John A.
   Wang, Ting
   Kellis, Manolis
TI Integrative analysis of 111 reference human epigenomes
SO NATURE
LA English
DT Article
ID genome-wide association; dynamic dna methylation; chromatin-state; histone modifications; regulatory motifs; binding; risk; resolution; metaanalysis; enhancers
AB The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.
C1 [Kundaje, Anshul; Meuleman, Wouter; Ernst, Jason; Yen, Angela; Kheradpour, Pouya; Zhang, Zhizhuo; Wang, Jianrong; Ward, Lucas D.; Sarkar, Abhishek; Quon, Gerald; Eaton, Matthew L.; Wu, Yi-Chieh; Pfenning, Andreas R.; Wang, Xinchen; Claussnitzer, Melina; Liu, Yaping; Bansal, Mukul S.; Feizi, Soheil; Kim, Ah-Ram; Sallari, Richard C.; Sinnott-Armstrong, Nicholas A.; Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA.
   [Kundaje, Anshul; Meuleman, Wouter; Ernst, Jason; Yen, Angela; Kheradpour, Pouya; Zhang, Zhizhuo; Wang, Jianrong; Ziller, Michael J.; Ward, Lucas D.; Sarkar, Abhishek; Quon, Gerald; Eaton, Matthew L.; Wu, Yi-Chieh; Pfenning, Andreas R.; Wang, Xinchen; Claussnitzer, Melina; Liu, Yaping; Shoresh, Noam; Epstein, Charles B.; Gjoneska, Elizabeta; Bansal, Mukul S.; Farh, Kai-How; Feizi, Soheil; Kim, Ah-Ram; Polak, Paz; Sallari, Richard C.; Sinnott-Armstrong, Nicholas A.; De Jager, Philip L.; Sunyaev, Shamil; Tsai, Li-Huei; Bernstein, Bradley E.; Meissner, Alexander; Kellis, Manolis] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.
   [Kundaje, Anshul] Stanford Univ, Dept Genet, Dept Comp Sci, Stanford, CA 94305 USA.
   [Ernst, Jason] Univ Calif Davis, Dept Biol Chem, Los Angeles, CA 90095 USA.
   [Bilenky, Misha; Heravi-Moussavi, Alireza; Mungall, Andrew J.; Moore, Richard; Chuah, Eric; Tam, Angela; Jones, Steven J. M.; Marra, Marco A.; Hirst, Martin] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada.
   [Ziller, Michael J.; Meissner, Alexander] Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.
   [Amin, Viren; Coarfa, Cristian; Harris, R. Alan; Onuchic, Vitor; Milosavljevic, Aleksandar] Baylor Coll Med, Epigenome Ctr, Houston, TX 77030 USA.
   [Whitaker, John W.; Leung, Danny; Xie, Wei; Hawkins, R. David; Dixon, Jesse R.; Rajagopal, Nisha; Wang, Wei; Ren, Bing] Univ Calif San Diego, Inst Genom Med, Dept Cellular & Mol Med, Dept Chem & Biochem, La Jolla, CA 92093 USA.
   [Schultz, Matthew D.; Lister, Ryan; Ecker, Joseph R.] Howard Hughes Med Inst, Genom Anal Lab, La Jolla, CA 92037 USA.
   [Schultz, Matthew D.; Lister, Ryan; Ecker, Joseph R.] Salk Inst Biol Studies, La Jolla, CA 92037 USA.
   [Sandstrom, Richard S.; Canfield, Theresa K.; Sabo, Peter J.; Neph, Shane J.; Siebenthall, Kyle T.; Thurman, Robert E.; Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.
   [Wang, Xinchen; Boyer, Laurie A.] MIT, Dept Biol, Cambridge, MA 02142 USA.
   [Gjoneska, Elizabeta; Tsai, Li-Huei] MIT, Picower Inst Learning & Memory, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA.
   [Leung, Danny; Xie, Wei; Hawkins, R. David; Dixon, Jesse R.; Rajagopal, Nisha; Ren, Bing] Ludwig Inst Canc Res, La Jolla, CA 92093 USA.
   [Hong, Chibo; Costello, Joseph F.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Dept Neurosurg, San Francisco, CA 94158 USA.
   [Gascard, Philippe; Tlsty, Thea D.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA.
   [Hansen, R. Scott; Kaul, Rajinder] Univ Washington, Div Med Genet, Dept Med, Seattle, WA 98121 USA.
   [Bansal, Mukul S.] Univ Connecticut, Dept Comp Sci & Engn, Storrs, CT 06269 USA.
   [Carles, Annaick; Hirst, Martin] Univ British Columbia, Dept Microbiol & Immunol, Vancouver, BC V6T 1Z4, Canada.
   [Carles, Annaick; Hirst, Martin] Univ British Columbia, Ctr High Throughput Biol, Vancouver, BC V6T 1Z4, Canada.
   [Karlic, Rosa] Univ Zagreb, Div Biol, Dept Mol Biol, Bioinformat Grp, Zagreb 10000, Croatia.
   [Kulkarni, Ashwinikumar; Ray, Pradipta; Zhang, Michael Q.] Univ Texas Dallas, Dept Mol & Cell Biol, Ctr Syst Biol, NSERL, Dallas, TX 75080 USA.
   [Li, Daofeng; Lowdon, Rebecca; Elliott, GiNell; Stevens, Michael; Zhang, Bo; Zhou, Xin; Wang, Ting] Washington Univ, Dept Genet, Ctr Genome Sci & Syst Biol, St Louis, MO 63108 USA.
   [Mercer, Tim R.] Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia.
   [Polak, Paz; De Jager, Philip L.; Sunyaev, Shamil] Brigham & Womens Hosp, Boston, MA 02115 USA.
   [Wu, Jie] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA.
   [Wu, Jie] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA.
   [Beaudet, Arthur E.] Baylor Coll Med, Mol & Human Genet Dept, Houston, TX 77030 USA.
   [De Jager, Philip L.; Sunyaev, Shamil] Harvard Univ, Sch Med, Boston, MA 02115 USA.
   [Farnham, Peggy J.] Univ So Calif, Keck Sch Med, Dept Biochem, Los Angeles, CA 90089 USA.
   [Fisher, Susan J.] Univ Calif San Francisco, San Francisco, CA 94143 USA.
   [Haussler, David] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA.
   [Jones, Steven J. M.] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada.
   [Jones, Steven J. M.; Marra, Marco A.] Univ British Columbia, Dept Med Genet, Vancouver, BC V6T 1Z4, Canada.
   [Li, Wei] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA.
   [McManus, Michael T.] Univ Calif San Francisco, Ctr Diabet, Dept Microbiol & Immunol, San Francisco, CA 94143 USA.
   [Thomson, James A.] Univ Wisconsin, Madison, WI 53715 USA.
   [Waterland, Robert A.] Baylor Coll Med, USDA ARS, Childrens Nutr Res Ctr, Houston, TX 77030 USA.
   [Zhang, Michael Q.] Tsinghua Univ, Bioinformat Div, Ctr Synthet & Syst Biol, TNLIST, Beijing 100084, Peoples R China.
   [Chadwick, Lisa H.] NIEHS, Res Triangle Pk, NC 27709 USA.
   [Bernstein, Bradley E.] Massachusetts Gen Hosp, Boston, MA 02114 USA.
   [Bernstein, Bradley E.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
   [Thomson, James A.] Morgridge Inst Res, Madison, WI 53707 USA.
   [Stevens, Michael] Washington Univ, Dept Comp Sci & Engn, St Louis, MO 63130 USA.
C3 Massachusetts Institute of Technology (MIT); Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Stanford University; University of California System; University of California Davis; British Columbia Cancer Agency; Baylor College of Medicine; University of California System; University of California San Diego; Howard Hughes Medical Institute; Salk Institute; University of Washington; University of Washington Seattle; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Ludwig Institute for Cancer Research; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of California System; University of California San Francisco; University of Washington; University of Washington Seattle; University of Connecticut; University of British Columbia; University of British Columbia; University of Zagreb; University of Texas System; University of Texas Dallas; Washington University (WUSTL); University of Queensland; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; State University of New York (SUNY) System; Stony Brook University; Cold Spring Harbor Laboratory; Baylor College of Medicine; Harvard University; Harvard Medical School; University of Southern California; University of California System; University of California San Francisco; University of California System; University of California Santa Cruz; Simon Fraser University; University of British Columbia; Baylor College of Medicine; University of California System; University of California San Francisco; University of Wisconsin System; University of Wisconsin Madison; Baylor College of Medicine; United States Department of Agriculture (USDA); Tsinghua University; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS); Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Howard Hughes Medical Institute; University of Wisconsin System; University of Wisconsin Madison; The Morgridge Institute for Research, Inc.; Washington University (WUSTL)
RP Kundaje, A (corresponding author), MIT, Comp Sci & Artificial Intelligence Lab, 32 Vassar St, Cambridge, MA 02139 USA.
EM manoli@mit.edu
FU NIH Common Fund as part of the NIH Roadmap Epigenomics Program [U01ES017155, U01ES017154, U01ES017166, U01ES017156, U01DA025956]; NHGRI [RC1HG005334, R01HG004037, R01HG004037-S1, RO1NS078839]; NIH [ES017166, F32HL110473, K99HL119617]; NSFC [91019016]; NBRPC [2012CB316503]; NSF CAREER [1254200];  [5R24HD000836];  [P30AG10161];  [R01AG15819];  [R01AG17917];  [U01AG46152]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Aging; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Allergy and Infectious Diseases; National Institute of Mental Health [R24HD000836] Funding Source: NIH RePORTER; National Human Genome Research Institute [R01HG007175] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [U54DK106829] Funding Source: NIH RePORTER; National Institute of Environmental Health Sciences [T32ES007032] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007266, T32GM007198] Funding Source: NIH RePORTER; National Institute of Mental Health [P50MH096890] Funding Source: NIH RePORTER; National Institute on Aging [R01AG015819, R01AG017917] Funding Source: NIH RePORTER; Direct For Biological Sciences [1254200] Funding Source: National Science Foundation; Div Of Biological Infrastructure [1254200] Funding Source: National Science Foundation; Div Of Biological Infrastructure; Direct For Biological Sciences [0644282] Funding Source: National Science Foundation
NR 112
TC 4583
Z9 5402
U1 8
U2 565
PU NATURE PUBLISHING 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 19
PY 2015
VL 518
IS 7539
BP 317
EP 330
DI 10.1038/nature14248
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400028
PM 25693563
DA 2026-03-09
ER

PT J
AU Joordens, JCA
   d'Errico, F
   Wesselingh, FP
   Munro, S
   de Vos, J
   Wallinga, J
   Ankjærgaard, C
   Reimann, T
   Wijbrans, JR
   Kuiper, KF
   Mücher, HJ
   Coqueugniot, H
   Prie, V
   Joosten, I
   van Os, B
   Schulp, AS
   Panuel, M
   van der Haas, V
   Lustenhouwer, W
   Reijmer, JJG
   Roebroeks, W
AF Joordens, Josephine C. A.
   d'Errico, Francesco
   Wesselingh, Frank P.
   Munro, Stephen
   de Vos, John
   Wallinga, Jakob
   Ankjaergaard, Christina
   Reimann, Tony
   Wijbrans, Jan R.
   Kuiper, Klaudia F.
   Muecher, Herman J.
   Coqueugniot, Helene
   Prie, Vincent
   Joosten, Ineke
   van Os, Bertil
   Schulp, Anne S.
   Panuel, Michel
   van der Haas, Victoria
   Lustenhouwer, Wim
   Reijmer, John J. G.
   Roebroeks, Wil
TI Homo erectus at Trinil on Java used shells for tool production and engraving
SO NATURE
LA English
DT Article
ID luminescence signals; quartz; age; sediments; sangiran; record; rates
AB The manufacture of geometric engravings is generally interpreted as indicative of modern cognition and behaviour(1). Key questions in the debate on the origin of such behaviour are whether this innovation is restricted to Homo sapiens, and whether it has a uniquely African origin(1). Here we report on a fossil freshwater shell assemblage from the Hauptknochenschicht ('main bone layer') of Trinil (Java, Indonesia), the type locality of Homo erectus discovered by Eugene Dubois in 1891 (refs 2 and 3). In the Dubois collection(in the Naturalis museum, Leiden, The Netherlands) we found evidence for freshwater shellfish consumption by hominins, one unambiguous shell tool, and a shell with a geometric engraving. We dated sediment contained in the shells with 40Ar/39Ar and luminescence dating methods, obtaining a maximum age of 0.54 +/- 0.10 million years and a minimum age of 0.43 +/- 0.05 million years. This implies that the Trinil Hauptkno-chenschicht is younger than previously estimated. Together, our data indicate that the engraving was made by Homo erectus, and that it is considerably older than the oldest geometric engravings described so far(4,5). Although it is at present not possible to assess the function or meaning of the engraved shell, this discovery suggests that engraving abstract patterns was in the realm of Asian Homo erectus cognition and neuromotor control.
C1 [Joordens, Josephine C. A.; Muecher, Herman J.; van der Haas, Victoria; Roebroeks, Wil] Leiden Univ, Fac Archaeol, NL-2300 RA Leiden, Netherlands.
   [Joordens, Josephine C. A.; Wijbrans, Jan R.; Kuiper, Klaudia F.; Schulp, Anne S.; Lustenhouwer, Wim; Reijmer, John J. G.] Vrije Univ Amsterdam, Fac Earth & Life Sci, NL-1081 HV Amsterdam, Netherlands.
   [d'Errico, Francesco; Coqueugniot, Helene] Univ Bordeaux, CNRS, UMR 5199, F-33615 Pessac, France.
   [d'Errico, Francesco] Univ Bergen, Inst Archaeol Hist Cultural Studies & Relig, Bergen, Norway.
   [Wesselingh, Frank P.; de Vos, John; Schulp, Anne S.] Naturalis Biodivers Ctr, NL-2300 RA Leiden, Netherlands.
   [Munro, Stephen] Australian Natl Univ, Sch Archaeol & Anthropol, Canberra, ACT 0200, Australia.
   [Munro, Stephen] Natl Museum Australia, Canberra, ACT 2601, Australia.
   [Wallinga, Jakob; Ankjaergaard, Christina; Reimann, Tony] Wageningen Univ, Soil Geog & Landscape Grp, NL-6700 AA Wageningen, Netherlands.
   [Wallinga, Jakob; Ankjaergaard, Christina; Reimann, Tony] Wageningen Univ, Netherlands Ctr Luminescence Dating, NL-6700 AA Wageningen, Netherlands.
   [Wallinga, Jakob; Ankjaergaard, Christina; Reimann, Tony] Delft Univ Technol, Fac Sci Appl, NL-2629 JB Delft, Netherlands.
   [Prie, Vincent] Museum Natl Hist Nat, Inst Systemat, UMR 7205, CP51, F-75005 Paris, France.
   [Prie, Vincent] Biotope Rech & Dev, F-34140 Meze, France.
   [Joosten, Ineke; van Os, Bertil] Cultural Heritage Agcy Netherlands, NL-3800 BP Amersfoort, Netherlands.
   [Schulp, Anne S.] Nat Hist Museum Maastricht, NL-6211 KJ Maastricht, Netherlands.
   [Panuel, Michel] Univ Aix Marseille, CNRS, Fac Med, EFS,UMR 7268, F-13344 Marseille, France.
   [Panuel, Michel] Hop Nord Marseille, Assistance Publ Hop Marseille, Dept Med Imaging, F-13915 Marseille, France.
C3 Leiden University; Leiden University - Excl LUMC; Vrije Universiteit Amsterdam; Universite de Bordeaux; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Ecology & Environment (INEE); University of Bergen; Naturalis Biodiversity Center; Australian National University; Wageningen University & Research; Wageningen University & Research; Delft University of Technology; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Ecology & Environment (INEE); Sorbonne Universite; Museum National d'Histoire Naturelle (MNHN); Aix-Marseille Universite; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Ecology & Environment (INEE); Aix-Marseille Universite; Assistance Publique-Hopitaux de Marseille
RP Joordens, JCA (corresponding author), Leiden Univ, Fac Archaeol, POB 9515, NL-2300 RA Leiden, Netherlands.
EM j.c.a.joordens@arch.leidenuniv.nl
FU Netherlands Organization for Scientific Research NWO [28-548, 825.11.03]; European Research Council [TRACSYMBOLS 249587]; STW Technology Foundation [STW.10502]
NR 62
TC 255
Z9 296
U1 2
U2 169
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 12
PY 2015
VL 518
IS 7538
BP 228
EP U182
DI 10.1038/nature13962
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300037
PM 25470048
DA 2026-03-09
ER

PT J
AU Yu, M
   Selvaraj, SK
   Liang-Chu, MMY
   Aghajani, S
   Busse, M
   Yuan, J
   Lee, G
   Peale, F
   Klijn, C
   Bourgon, R
   Kaminker, JS
   Neve, RM
AF Yu, Mamie
   Selvaraj, Suresh K.
   Liang-Chu, May M. Y.
   Aghajani, Sahar
   Busse, Matthew
   Yuan, Jean
   Lee, Genee
   Peale, Franklin
   Klijn, Christiaan
   Bourgon, Richard
   Kaminker, Joshua S.
   Neve, Richard M.
TI A resource for cell line authentication, annotation and quality control
SO NATURE
LA English
DT Article
ID species identification; cross-contamination; cancer
AB Cell line misidentification, contamination and poor annotation affect scientific reproducibility. Here we outline simple measures to detect or avoid cross-contamination, present a framework for cell line annotation linked to short tandem repeat and single nucleotide polymorphism profiles, and provide a catalogue of synonymous cell lines. This resource will enable our community to eradicate the use of misidentified lines and generate credible cell-based data.
C1 [Yu, Mamie; Selvaraj, Suresh K.; Liang-Chu, May M. Y.; Lee, Genee; Neve, Richard M.] Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA.
   [Aghajani, Sahar; Busse, Matthew; Yuan, Jean; Klijn, Christiaan; Bourgon, Richard; Kaminker, Joshua S.] Genentech Inc, Dept Bioinformat & Computat Biol, San Francisco, CA 94080 USA.
   [Peale, Franklin] Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA.
C3 Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech
RP Neve, RM (corresponding author), Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA.
EM neve.richard@gene.com
NR 35
TC 170
Z9 191
U1 1
U2 48
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 16
PY 2015
VL 520
IS 7547
BP 307
EP +
DI 10.1038/nature14397
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG0RI
UT WOS:000352974200029
PM 25877200
DA 2026-03-09
ER

PT J
AU Errico, C
   Pierre, J
   Pezet, S
   Desailly, Y
   Lenkei, Z
   Couture, O
   Tanter, M
AF Errico, Claudia
   Pierre, Juliette
   Pezet, Sophie
   Desailly, Yann
   Lenkei, Zsolt
   Couture, Olivier
   Tanter, Mickael
TI Ultrafast ultrasound localization microscopy for deep super-resolution vascular imaging
SO NATURE
LA English
DT Article
ID acoustic superresolution; mouse-brain; breaking; velocity; limit
AB Non-invasive imaging deep into organs at microscopic scales remains an open quest in biomedical imaging. Although optical microscopy is still limited to surface imaging owing to optical wave diffusion and fast decorrelation in tissue, revolutionary approaches such as fluorescence photo-activated localization microscopy led to a striking increase in resolution by more than an order of magnitude in the last decade(1). In contrast with optics, ultrasonic waves propagate deep into organs without losing their coherence and are much less affected by in vivo decorrelation processes. However, their resolution is impeded by the fundamental limits of diffraction, which impose a long-standing trade-off between resolution and penetration. This limits clinical and preclinical ultrasound imaging to a sub-millimetre scale. Here we demonstrate in vivo that ultrasound imaging at ultrafast frame rates (more than 500 frames per second) provides an analogue to optical localization microscopy by capturing the transient signal decorrelation of contrast agents-inert gas microbubbles. Ultrafast ultrasound localization microscopy allowed both non-invasive sub-wavelength structural imaging and haemodynamic quantification of rodent cerebral microvessels (less than ten micrometres in diameter) more than ten millimetres below the tissue surface, leading to transcranial whole-brain imaging within short acquisition times (tens of seconds). After intravenous injection, single echoes from individual microbubbles were detected through ultrafast imaging. Their localization, not limited by diffraction, was accumulated over 75,000 images, yielding 1,000,000 events per coronal plane and statistically independent pixels of ten micrometres in size. Precise temporal tracking of microbubble positions allowed us to extract accurately in-plane velocities of the blood flow with a large dynamic range (from one millimetre per second to several centimetres per second). These results pave the way for deep non-invasive microscopy in animals and humans using ultrasound. We anticipate that ultrafast ultrasound localization microscopy may become an invaluable tool for the fundamental understanding and diagnostics of various disease processes that modify the microvascular blood flow, such as cancer, stroke and arteriosclerosis.
C1 [Errico, Claudia; Pierre, Juliette; Desailly, Yann; Couture, Olivier; Tanter, Mickael] INSERM, Inst Langevin, 1 Rue Jussieu, F-75005 Paris, France.
   [Errico, Claudia; Pierre, Juliette; Desailly, Yann; Couture, Olivier; Tanter, Mickael] PSL Res Univ, ESPCI ParisTech, Inst Langevin, F-75005 Paris, France.
   [Errico, Claudia; Pierre, Juliette; Desailly, Yann; Couture, Olivier; Tanter, Mickael] CNRS, UMR 7587, F-75005 Paris, France.
   [Pezet, Sophie; Lenkei, Zsolt] CNRS, UMR 8249, F-75005 Paris, France.
   [Pezet, Sophie; Lenkei, Zsolt] PSL Res Univ, ESPCI ParisTech, Brain Plast Unit, F-75005 Paris, France.
C3 Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Universite Paris Cite; Universite PSL; Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI); Sorbonne Universite; Universite Paris Cite; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute for Engineering & Systems Sciences (INSIS); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite PSL; Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI)
RP Tanter, M (corresponding author), INSERM, Inst Langevin, 1 Rue Jussieu, F-75005 Paris, France.
EM mickael.tanter@espci.fr
FU Agence Nationale de la Recherche (ANR), within the project ANR MUSLI; Fondation Pierre-Gilles de Gennes; LABEX WIFI (Laboratory of Excellence) within the French Program "Investments for the Future" [ANR-10-LABX-24, ANR-10-IDEX-0001-02 PSL*]
NR 32
TC 1058
Z9 1215
U1 32
U2 767
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 499
EP +
DI 10.1038/nature16066
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500044
PM 26607546
DA 2026-03-09
ER

PT J
AU Levy, SF
   Blundell, JR
   Venkataram, S
   Petrov, DA
   Fisher, DS
   Sherlock, G
AF Levy, Sasha F.
   Blundell, Jamie R.
   Venkataram, Sandeep
   Petrov, Dmitri A.
   Fisher, Daniel S.
   Sherlock, Gavin
TI Quantitative evolutionary dynamics using high-resolution lineage tracking
SO NATURE
LA English
DT Article
ID site-specific recombination; beneficial mutations; staphylococcus-aureus; clonal interference; genealogy; maintenance; populations; adaptation; selection; spectrum
AB Evolution of large asexual cell populations underlies similar to 30% of deaths worldwide, including those caused by bacteria, fungi, parasites, and cancer. However, the dynamics underlying these evolutionary processes remain poorly understood because they involve many competing beneficial lineages, most of which never rise above extremely low frequencies in the population. To observe these normally hidden evolutionary dynamics, we constructed a sequencing-based ultra high-resolution lineage tracking system in Saccharomyces cerevisiae that allowed us to monitor the relative frequencies of similar to 500,000 lineages simultaneously. In contrast to some expectations, we found that the spectrum of fitness effects of beneficial mutations is neither exponential nor monotonic. Early adaptation is a predictable consequence of this spectrum and is strikingly reproducible, but the initial small-effect mutations are soon outcompeted by rarer large-effect mutations that result in variability between replicates. These results suggest that early evolutionary dynamics may be deterministic for a period of time before stochastic effects become important.
C1 [Levy, Sasha F.; Sherlock, Gavin] Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
   [Levy, Sasha F.] SUNY Stony Brook, Laufer Ctr Phys & Quantitat Biol, Stony Brook, NY 11794 USA.
   [Levy, Sasha F.] SUNY Stony Brook, Dept Biochem & Cellular Biol, Stony Brook, NY 11794 USA.
   [Blundell, Jamie R.; Fisher, Daniel S.] Stanford Univ, Dept Appl Phys, Stanford, CA 94305 USA.
   [Blundell, Jamie R.; Venkataram, Sandeep; Petrov, Dmitri A.; Fisher, Daniel S.] Stanford Univ, Dept Biol, Stanford, CA 94305 USA.
C3 Stanford University; State University of New York (SUNY) System; Stony Brook University; State University of New York (SUNY) System; Stony Brook University; Stanford University; Stanford University
RP Fisher, DS (corresponding author), Stanford Univ, Dept Appl Phys, Stanford, CA 94305 USA.
EM dsfisher@stanford.edu; gsherloc@stanford.edu
FU NIH [R01 HG003328, 5-T32-HG-44-17, R25 GM067110]; NSF [DMS-1120699, PHY-1305433]; Stanford University [Bio-X IIP6-63]; Betty Moore Foundation [2919]; Louis and Beatrice Laufer Center; National Human Genome Research Institute [T32HG000044] Funding Source: NIH RePORTER; Division Of Mathematical Sciences; Direct For Mathematical & Physical Scien [1120699] Funding Source: National Science Foundation; Division Of Physics; Direct For Mathematical & Physical Scien [1305433] Funding Source: National Science Foundation
NR 50
TC 296
Z9 375
U1 1
U2 101
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 12
PY 2015
VL 519
IS 7542
BP 181
EP +
DI 10.1038/nature14279
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500028
PM 25731169
DA 2026-03-09
ER

PT J
AU Adhikari, A
   Lerner, TN
   Finkelstein, J
   Pak, S
   Jennings, JH
   Davidson, TJ
   Ferenczi, E
   Gunaydin, LA
   Irzabekov, JJM
   Ye, L
   Kim, SY
   Lei, A
   Deisseroth, K
AF Adhikari, Avishek
   Lerner, Talia N.
   Finkelstein, Joel
   Pak, Sally
   Jennings, Joshua H.
   Davidson, Thomas J.
   Ferenczi, Emily
   Gunaydin, Lisa A.
   Irzabekov, Julie J. M.
   Ye, Li
   Kim, Sung-Yon
   Lei, Anna
   Deisseroth, Karl
TI Basomedial amygdala mediates top-down control of anxiety and fear
SO NATURE
LA English
DT Article
ID ventromedial prefrontal cortex; c-fos expression; infralimbic cortex; conditioned fear; basolateral amygdala; intercalated neurons; corticosterone injections; prelimbic cortex; in-vivo; rat
AB nxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC-BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway.
C1 [Adhikari, Avishek; Lerner, Talia N.; Finkelstein, Joel; Pak, Sally; Jennings, Joshua H.; Davidson, Thomas J.; Ferenczi, Emily; Gunaydin, Lisa A.; Irzabekov, Julie J. M.; Ye, Li; Kim, Sung-Yon; Lei, Anna; Deisseroth, Karl] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.
   [Adhikari, Avishek; Lerner, Talia N.; Jennings, Joshua H.; Davidson, Thomas J.; Ye, Li; Deisseroth, Karl] Stanford Univ, CNC Program, Stanford, CA 94304 USA.
   [Ferenczi, Emily; Gunaydin, Lisa A.; Kim, Sung-Yon; Deisseroth, Karl] Stanford Univ, Neurosci Program, Stanford, CA 94305 USA.
   [Deisseroth, Karl] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA.
   [Deisseroth, Karl] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Howard Hughes Medical Institute
RP Deisseroth, K (corresponding author), Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.
EM deissero@stanford.edu
FU Walter V. and Idun Berry award; K99 award [NIMH K99MH106649]; NARSAD Young Investigator fellowship; NIMH; DARPA Neuro-FAST program; NIDA; NSF; Simons Foundation; Gatsby Foundation; Wiegers Family Fund; Nancy and James Grosfeld Foundation; H. L. Snyder Medical Foundation; Samuel and Betsy Reeves Fund; Vincent V. C. Woo Fund; Albert Yu Foundation; Mary Bechman Foundation; National Institute on Drug Abuse [R37DA035377] Funding Source: NIH RePORTER
NR 50
TC 384
Z9 473
U1 2
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 NOV 12
PY 2015
VL 527
IS 7577
BP 179
EP +
DI 10.1038/nature15698
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700034
PM 26536109
DA 2026-03-09
ER

PT J
AU Juric, D
   Castel, P
   Griffith, M
   Griffith, OL
   Won, HH
   Ellis, H
   Ebbesen, SH
   Ainscough, BJ
   Ramu, A
   Iyer, G
   Shah, RH
   Huynh, T
   Mino-Kenudson, M
   Sgroi, D
   Isakoff, S
   Thabet, A
   Elamine, L
   Solit, DB
   Lowe, S
   Quadt, C
   Peters, M
   Derti, A
   Schegel, R
   Huang, A
   Mardis, ER
   Berger, MF
   Baselga, J
   Scaltriti, M
AF Juric, Dejan
   Castel, Pau
   Griffith, Malachi
   Griffith, Obi L.
   Won, Helen H.
   Ellis, Haley
   Ebbesen, Saya H.
   Ainscough, Benjamin J.
   Ramu, Avinash
   Iyer, Gopa
   Shah, Ronak H.
   Huynh, Tiffany
   Mino-Kenudson, Mari
   Sgroi, Dennis
   Isakoff, Steven
   Thabet, Ashraf
   Elamine, Leila
   Solit, David B.
   Lowe, ScottW.
   Quadt, Cornelia
   Peters, Malte
   Derti, Adnan
   Schegel, Robert
   Huang, Alan
   Mardis, Elaine R.
   Berger, Michael F.
   Baselga, Jose
   Scaltriti, Maurizio
TI Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor
SO NATURE
LA English
DT Article
ID intratumor heterogeneity; domain mutations; evolution; cancers; growth
AB Broad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones(1,2). There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion to that occurring in infectious diseases. Here we studied tumour genomic evolution in a patient (index patient) with metastatic breast cancer bearing an activating PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PI(3)K alpha) mutation. The patient was treated with the PI(3)K alpha inhibitor BYL719, which achieved a lasting clinical response, but the patient eventually became resistant to this drug (emergence of lung metastases) and died shortly thereafter. A rapid autopsy was performed and material from a total of 14 metastatic sites was collected and sequenced. All metastatic lesions, when compared to the pre-treatment tumour, had a copy loss of PTEN (phosphatase and tensin homolog) and those lesions that became refractory to BYL719 had additional and different PTEN genetic alterations, resulting in the loss of PTEN expression. To put these results in context, we examined six other patients also treated with BYL719. Acquired bi-allelic loss of PTEN was found in one of these patients, whereas in two others PIK3CA mutations present in the primary tumour were no longer detected at the time of progression. To characterize our findings functionally, we examined the effects of PTEN knockdown in several preclinical models (both in cell lines intrinsically sensitive to BYL719 and in PTEN-null xenografts derived from our index patient), which we found resulted in resistance to BYL719, whereas simultaneous PI(3) K p110 beta blockade reverted this resistance phenotype. We conclude that parallel genetic evolution of separate metastatic sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)K alpha inhibition.
C1 [Juric, Dejan; Huynh, Tiffany; Mino-Kenudson, Mari; Sgroi, Dennis; Isakoff, Steven; Thabet, Ashraf; Elamine, Leila] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA.
   [Castel, Pau; Won, Helen H.; Ellis, Haley; Iyer, Gopa; Shah, Ronak H.; Solit, David B.; Berger, Michael F.; Baselga, Jose; Scaltriti, Maurizio] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program HOPP, New York, NY 10065 USA.
   [Griffith, Malachi; Mardis, Elaine R.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA.
   [Griffith, Malachi; Griffith, Obi L.; Mardis, Elaine R.] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO 63110 USA.
   [Griffith, Malachi; Griffith, Obi L.; Ainscough, Benjamin J.; Ramu, Avinash; Mardis, Elaine R.] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63108 USA.
   [Griffith, Obi L.; Mardis, Elaine R.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA.
   [Won, Helen H.; Berger, Michael F.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA.
   [Ebbesen, Saya H.; Lowe, ScottW.] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA.
   [Iyer, Gopa; Solit, David B.] Mem Sloan Kettering Canc Ctr, Dept Med, Div Genitourinary Oncol, New York, NY 10065 USA.
   [Lowe, ScottW.] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, Canc Biol & Genet Program, New York, NY 10065 USA.
   [Quadt, Cornelia; Peters, Malte] Novartis Pharma AG, CH-4056 Basel, Switzerland.
   [Derti, Adnan; Schegel, Robert; Huang, Alan] Novartis Inst BioMed Res, Cambridge, MA 02139 USA.
   [Baselga, Jose] Mem Sloan Kettering Canc Ctr, Dept Med, Breast Med Serv, New York, NY 10065 USA.
C3 Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Memorial Sloan Kettering Cancer Center; Washington University (WUSTL); Washington University (WUSTL); Siteman Cancer Center; Washington University (WUSTL); Washington University (WUSTL); Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Novartis; Novartis; Novartis USA; Memorial Sloan Kettering Cancer Center
RP Scaltriti, M (corresponding author), Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program HOPP, 1275 York Ave,Box 20, New York, NY 10065 USA.
EM bergerm1@mskcc.org; baselgaj@mskcc.org; scaltrim@mskcc.org
FU "Stand Up to Cancer" Dream Team Translational Research Grant; Entertainment Industry Foundation [SU2C-AACR-DT0209]; Breast Cancer Research Foundation; Geoffrey Beene Cancer Research Center; Starr Cancer Consortium; MMHCC [CA105388]; National Institutes of Health [T32 CA-71345-15]; National Cancer Institute [T32CA071345, P30CA008748, T32CA113275] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM065094] Funding Source: NIH RePORTER
NR 27
TC 479
Z9 539
U1 0
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 FEB 12
PY 2015
VL 518
IS 7538
BP 240
EP U230
DI 10.1038/nature13948
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300040
PM 25409150
DA 2026-03-09
ER

PT J
AU Boersma, V
   Moatti, N
   Segura-Bayona, S
   Peuscher, MH
   van der Torre, J
   Wevers, BA
   Orthwein, A
   Durocher, D
   Jacobs, JJL
AF Boersma, Vera
   Moatti, Nathalie
   Segura-Bayona, Sandra
   Peuscher, Marieke H.
   van der Torre, Jaco
   Wevers, Brigitte A.
   Orthwein, Alexandre
   Durocher, Daniel
   Jacobs, Jacqueline J. L.
TI MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5′ end resection
SO NATURE
LA English
DT Article
ID damage response; polymerase-zeta; protection; hallmarks; mutation; roles; rif1; rev7; trf2; nhej
AB Appropriate repair of DNA lesions and the inhibition of DNA repair activities at telomeres are crucial to prevent genomic instability. By fuelling the generation of genetic alterations and by compromising cell viability, genomic instability is a driving force in cancer and ageing(1,2). Here we identify MAD2L2 (also known as MAD2B or REV7) through functional genetic screening as a novel factor controlling DNA repair activities at mammalian telomeres. We show that MAD2L2 accumulates at uncapped telomeres and promotes non-homologous end-joining (NHEJ)-mediated fusion of deprotected chromosome ends and genomic instability. MAD2L2 depletion causes elongated 39 telomeric overhangs, indicating that MAD2L2 inhibits 59 end resection. End resection blocks NHEJ while committing to homology-directed repair, and is under the control of 53BP1, RIF1 and PTIP3. Consistent with MAD2L2 promoting NHEJ-mediated telomere fusion by inhibiting 5' end resection, knockdown of the nucleases CTIP or EXO1 partially restores telomere-driven genomic instability in MAD2L2-depleted cells. Control of DNA repair by MAD2L2 is not limited to telomeres. MAD2L2 also accumulates and inhibits end resection at irradiation-induced DNA double-strand breaks and promotes end-joining of DNA double-strand breaks in several settings, including during immunoglobulin class switch recombination. These activities of MAD2L2 depend on ATM kinase activity, RNF8, RNF168, 53BP1 and RIF1, but not on PTIP, REV1 and REV3, the latter two acting with MAD2L2 in translesion synthesis(4). Together, our data establish MAD2L2 as a crucial contributor to the control of DNA repair activity by 53BP1 that promotes NHEJ by inhibiting 5' end resection downstream of RIF1.
C1 [Boersma, Vera; Moatti, Nathalie; Segura-Bayona, Sandra; Peuscher, Marieke H.; van der Torre, Jaco; Wevers, Brigitte A.; Jacobs, Jacqueline J. L.] Netherlands Canc Inst, Div Mol Oncol, NL-1066 CX Amsterdam, Netherlands.
   [Orthwein, Alexandre; Durocher, Daniel] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada.
   [Durocher, Daniel] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada.
C3 Netherlands Cancer Institute; University of Toronto; Sinai Health System Toronto; Lunenfeld Tanenbaum Research Institute; University of Toronto
RP Jacobs, JJL (corresponding author), Netherlands Canc Inst, Div Mol Oncol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands.
EM j.jacobs@nki.nl
FU European Research Council [ERCStG 311565]; Dutch Cancer Society [KWF-NKI2007-3907]; Canadian Institutes for Health Research [CIHR MOP89754]; La Caixa fellowship; CIHR
NR 32
TC 247
Z9 285
U1 5
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 MAY 28
PY 2015
VL 521
IS 7553
BP 537
EP U291
DI 10.1038/nature14216
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ2AN
UT WOS:000355286600047
PM 25799990
DA 2026-03-09
ER

PT J
AU Lai, F
   Gardini, A
   Zhang, AD
   Shiekhattar, R
AF Lai, Fan
   Gardini, Alessandro
   Zhang, Anda
   Shiekhattar, Ramin
TI Integrator mediates the biogenesis of enhancer RNAs
SO NATURE
LA English
DT Article
ID gene-expression; super-enhancers; polymerase-ii; cell identity; transcription; activation; chromatin; architecture; initiation; promoters
AB Integrator is a multi-subunit complex stably associated with the carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII)(1). Integrator is endowed with a core catalytic RNA endonuclease activity, which is required for the 3'-end processing of non-polyadenylated, RNAPII-dependent, uridylate-rich, small nuclearRNAgenes(1). Here we examine the requirement of Integrator in the biogenesis of transcripts derived from distal regulatory elements (enhancers) involved in tissue-and temporal-specific regulation of gene expression in metazoans(2-5). Integrator is recruited to enhancers and super-enhancers in a stimulus-dependent manner. Functional depletion of Integrator subunits diminishes the signal-dependent induction of enhancer RNAs (eRNAs) and abrogates stimulus-induced enhancer-promoter chromatin looping. Global nuclear run-on and RNAPII profiling reveals a role for Integrator in 3'-end cleavage of eRNA primary transcripts leading to transcriptional termination. In the absence of Integrator, eRNAs remain bound to RNAPII and their primary transcripts accumulate. Notably, the induction of eRNAs and gene expression responsiveness requires the catalytic activity of Integrator complex. We propose a role for Integrator in biogenesis of eRNAs and enhancer function in metazoans.
C1 [Lai, Fan; Gardini, Alessandro; Zhang, Anda; Shiekhattar, Ramin] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Dept Human Genet, Miami, FL 33136 USA.
C3 University of Miami
RP Shiekhattar, R (corresponding author), Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Dept Human Genet, Biomed Res Bldg,Room 719,1501 NW 10th Ave, Miami, FL 33136 USA.
EM rshiekhattar@med.miami.edu
FU University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center; National Institute of Health [R01GM078455, R01 GM105754]; National Institute of General Medical Sciences [R01GM078455] Funding Source: NIH RePORTER
CR Albrecht TR, 2012, MOL CELL BIOL, V32, P1112, DOI 10.1128/MCB.06511-11
   Baillat D, 2005, CELL, V123, P265, DOI 10.1016/j.cell.2005.08.019
   Bhatt DM, 2012, CELL, V150, P279, DOI 10.1016/j.cell.2012.05.043
   De Santa F, 2010, PLOS BIOL, V8, P0, DOI 10.1371/journal.pbio.1000384
   Gardini A, 2014, MOL CELL, V56, P128, DOI 10.1016/j.molcel.2014.08.004
   Gerstein MB, 2012, NATURE, V489, P91, DOI 10.1038/nature11245
   Hah N, 2011, CELL, V145, P622, DOI 10.1016/j.cell.2011.03.042
   Hnisz D, 2013, CELL, V155, P934, DOI 10.1016/j.cell.2013.09.053
   Kim TK, 2010, NATURE, V465, P182, DOI 10.1038/nature09033
   Koch F, 2011, NAT STRUCT MOL BIOL, V18, P956, DOI 10.1038/nsmb.2085
   Lai F, 2013, NATURE, V494, P497, DOI 10.1038/nature11884
   Lam MTY, 2013, NATURE, V498, P511, DOI 10.1038/nature12209
   Langmead B, 2009, GENOME BIOL, V10, P0, DOI 10.1186/gb-2009-10-3-r25
   Li WB, 2013, NATURE, V498, P516, DOI 10.1038/nature12210
   Lovén J, 2013, CELL, V153, P320, DOI 10.1016/j.cell.2013.03.036
   Melo CA, 2013, MOL CELL, V49, P524, DOI 10.1016/j.molcel.2012.11.021
   Mousavi K, 2013, MOL CELL, V51, P606, DOI 10.1016/j.molcel.2013.07.022
   Orom UA, 2010, CELL, V143, P46, DOI 10.1016/j.cell.2010.09.001
   Sanyal A, 2012, NATURE, V489, P109, DOI 10.1038/nature11279
   Schaukowitch K, 2014, MOL CELL, V56, P29, DOI 10.1016/j.molcel.2014.08.023
   Shen L, 2014, BMC GENOMICS, V15, P0, DOI 10.1186/1471-2164-15-284
   Sigova AA, 2013, P NATL ACAD SCI USA, V110, P2876, DOI 10.1073/pnas.1221904110
   Skaar JR, 2015, CELL RES, V25, P288, DOI 10.1038/cr.2015.19
   Stadelmayer B, 2014, NAT COMMUN, V5, P0, DOI 10.1038/ncomms6531
   Wang D, 2011, NATURE, V474, P390, DOI 10.1038/nature10006
   Wang KC, 2011, NATURE, V472, P120, DOI 10.1038/nature09819
   Wang LG, 2012, BIOINFORMATICS, V28, P2184, DOI 10.1093/bioinformatics/bts356
   Whyte WA, 2013, CELL, V153, P307, DOI 10.1016/j.cell.2013.03.035
   Yamamoto J, 2014, NAT COMMUN, V5, P0, DOI 10.1038/ncomms5263
   Yang LQ, 2013, NATURE, V500, P598, DOI 10.1038/nature12451
   Ye T, 2011, NUCLEIC ACIDS RES, V39, P0, DOI 10.1093/nar/gkq1287
NR 31
TC 249
Z9 303
U1 2
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 SEP 17
PY 2015
VL 525
IS 7569
BP 399
EP +
DI 10.1038/nature14906
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900048
PM 26308897
DA 2026-03-09
ER

PT J
AU Peng, YQ
   Gillis-Smith, S
   Jin, H
   Tränkner, D
   Ryba, NJP
   Zuker, CS
AF Peng, Yueqing
   Gillis-Smith, Sarah
   Jin, Hao
   Traenkner, Dimitri
   Ryba, Nicholas J. P.
   Zuker, Charles S.
TI Sweet and bitter taste in the brain of awake behaving animals
SO NATURE
LA English
DT Article
ID gustatory stimuli; mimetic responses; mammalian sweet; reactivity test; umami taste; receptors; rats; representation; circuit; neurons
AB Taste is responsible for evaluating the nutritious content of food, guiding essential appetitive behaviours, preventing the ingestion of toxic substances, and helping to ensure the maintenance of a healthy diet. Sweet and bitter are two of the most salient sensory percepts for humans and other animals; sweet taste allows the identification of energy-rich nutrients whereas bitter warns against the intake of potentially noxious chemicals(1). In mammals, information from taste receptor cells in the tongue is transmitted through multiple neural stations to the primary gustatory cortex in the brain(2). Recent imaging studies have shown that sweet and bitter are represented in the primary gustatory cortex by neurons organized in a spatial map(3,4), with each taste quality encoded by distinct cortical fields(4). Here we demonstrate that by manipulating the brain fields representing sweet and bitter taste we directly control an animal's internal representation, sensory perception, and behavioural actions. These results substantiate the segregation of taste qualities in the cortex, expose the innate nature of appetitive and aversive taste responses, and illustrate the ability of gustatory cortex to recapitulate complex behaviours in the absence of sensory input.
C1 [Peng, Yueqing; Gillis-Smith, Sarah; Jin, Hao; Traenkner, Dimitri; Zuker, Charles S.] Columbia Univ Coll Phys & Surg, Howard Hughes Med Inst, New York, NY 10032 USA.
   [Peng, Yueqing; Gillis-Smith, Sarah; Jin, Hao; Traenkner, Dimitri; Zuker, Charles S.] Columbia Univ Coll Phys & Surg, Dept Biochem, New York, NY 10032 USA.
   [Peng, Yueqing; Gillis-Smith, Sarah; Jin, Hao; Traenkner, Dimitri; Zuker, Charles S.] Columbia Univ Coll Phys & Surg, Dept Mol Biophys, New York, NY 10032 USA.
   [Peng, Yueqing; Gillis-Smith, Sarah; Jin, Hao; Traenkner, Dimitri; Zuker, Charles S.] Columbia Univ Coll Phys & Surg, Dept Neurosci, New York, NY 10032 USA.
   [Traenkner, Dimitri; Zuker, Charles S.] HHMI Janelia Farm Res Campus, Ashburn, VA 20147 USA.
   [Ryba, Nicholas J. P.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA.
C3 Howard Hughes Medical Institute; Columbia University; Columbia University; Columbia University; Columbia University; Howard Hughes Medical Institute; National Institutes of Health (NIH) - USA; NIH National Institute of Dental & Craniofacial Research (NIDCR)
RP Zuker, CS (corresponding author), Columbia Univ Coll Phys & Surg, Howard Hughes Med Inst, New York, NY 10032 USA.
EM nick.ryba@nih.gov; cz2195@cumc.columbia.edu
FU National Institute of Drug Abuse [DA035025]; Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research; National Institute of Dental and Craniofacial Research [ZIADE000561] Funding Source: NIH RePORTER
NR 27
TC 165
Z9 207
U1 4
U2 136
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 512
EP +
DI 10.1038/nature15763
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500047
PM 26580015
DA 2026-03-09
ER

PT J
AU Hie, L
   Nathel, NFF
   Shah, TK
   Baker, EL
   Hong, X
   Yang, YF
   Liu, P
   Houk, KN
   Garg, NK
AF Hie, Liana
   Nathel, Noah F. Fine
   Shah, Tejas K.
   Baker, Emma L.
   Hong, Xin
   Yang, Yun-Fang
   Liu, Peng
   Houk, K. N.
   Garg, Neil K.
TI Conversion of amides to esters by the nickel-catalysed activation of amide C-N bonds
SO NATURE
LA English
DT Article
ID cross-coupling reactions; aryl carboxylates; methyl-esters; azoles; chemoselectivity; transamidation; cleavage; amines; scope; mild
AB Amides are common functional groups that have been studied for more than a century(1). They are the key building blocks of proteins and are present in a broad range of other natural and synthetic compounds. Amides are known to be poor electrophiles, which is typically attributed to the resonance stability of the amide bond(1,2). Although amides can readily be cleaved by enzymes such as proteases(3), it is difficult to selectively break the carbon-nitrogen bond of an amide using synthetic chemistry. Here we demonstrate that amide carbon-nitrogen bonds can be activated and cleaved using nickel catalysts. We use this methodology to convert amides to esters, which is a challenging and underdeveloped transformation. The reaction methodology proceeds under exceptionally mild reaction conditions, and avoids the use of a large excess of an alcohol nucleophile. Density functional theory calculations provide insight into the thermodynamics and catalytic cycle of the amide-to-ester transformation. Our results provide a way to harness amide functional groups as synthetic building blocks and are expected to lead to the further use of amides in the construction of carbon-heteroatom or carbon-carbon bonds using non-precious-metal catalysis.
C1 [Hie, Liana; Nathel, Noah F. Fine; Shah, Tejas K.; Baker, Emma L.; Hong, Xin; Yang, Yun-Fang; Liu, Peng; Houk, K. N.; Garg, Neil K.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA.
C3 University of California System; University of California Los Angeles
RP Houk, KN (corresponding author), Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA.
EM houk@chem.ucla.edu; neilgarg@chem.ucla.edu
FU Boehringer Ingelheim; DuPont; Bristol-Myers Squibb; Camille and Henry Dreyfus Foundation; A. P. Sloan Foundation; S. T. Li Foundation; University of California, Los Angeles (UCLA); NIH-NIGMS [GM036700]; NIH [F31 GM101951-02]; NSF [DGE-1144087, OCI-1053575, CHE-1048804]; Foote Family; ACS Division of Organic Chemistry; National Center for Research Resources [S10RR025631]
NR 30
TC 496
Z9 546
U1 10
U2 419
PU NATURE PUBLISHING 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 6
PY 2015
VL 524
IS 7563
BP 79
EP 83
DI 10.1038/nature14615
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO2QS
UT WOS:000359002300035
PM 26200342
DA 2026-03-09
ER

PT J
AU Yin, J
   Mobarec, JC
   Kolb, P
   Rosenbaum, DM
AF Yin, Jie
   Mobarec, Juan Carlos
   Kolb, Peter
   Rosenbaum, Daniel M.
TI Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant
SO NATURE
LA English
DT Article
ID protein-coupled receptors; beta(2)-adrenergic receptor; membrane-proteins; antagonist; discovery; binding; sleep; activation; narcolepsy; insights
AB The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) respond to orexin neuropeptides in the central nervous system to regulate sleep and other behavioural functions in humans(1). Defects in orexin signalling are responsible for the human diseases of narcolepsy and cataplexy; inhibition of orexin receptors is an effective therapy for insomnia(2). The human OX2 receptor (OX2R) belongs to the beta branch of the rhodopsin family of GPCRs(3), and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-Band the potent therapeutic inhibitor suvorexant(4). Here, using lipid-mediated crystallization and protein engineering with a novel fusion chimaera, we solved the structure of the human OX2R bound to suvorexant at 2.5 angstrom resolution. The structure reveals how suvorexant adopts pi-stacked horseshoe-like conformation and binds to the receptor deep in the orthosteric pocket, stabilizing a network of extracellular salt bridges and blocking transmembrane helix motions necessary for activation. Computational docking suggests how other classes of synthetic antagonists may interact with the receptor at a similar position in an analogous pi-stacked fashion. Elucidation of the molecular architecture of the human OX2R expands our understanding of peptidergic GPCR ligand recognition and will aid further efforts to modulate orexin signalling for therapeutic ends.
C1 [Yin, Jie; Rosenbaum, Daniel M.] Univ Texas SW Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA.
   [Mobarec, Juan Carlos; Kolb, Peter] Univ Marburg, Dept Pharmaceut Chem, D-35032 Marburg, Germany.
C3 University of Texas System; University of Texas Southwestern Medical Center; Philipps University Marburg
RP Rosenbaum, DM (corresponding author), Univ Texas SW Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA.
EM dan.rosenbaum@utsouthwestern.edu
FU Welch Foundation [I-1770]; Searle Scholars Program; Packard Foundation Fellowship; Emmy Noether Fellowship of the German Research Foundation [KO-4095/1-1]; COST Action GLISTEN [CM1207]; National Cancer Institute [ACB-12002]; National Institute of General Medical Sciences [AGM-12006]
NR 47
TC 185
Z9 201
U1 0
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 MAR 12
PY 2015
VL 519
IS 7542
BP 247
EP +
DI 10.1038/nature14035
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500042
PM 25533960
DA 2026-03-09
ER

PT J
AU Mesa, KR
   Rompolas, P
   Zito, G
   Myung, P
   Sun, TY
   Brown, S
   Gonzalez, DG
   Blagoev, KB
   Haberman, AM
   Greco, V
AF Mesa, Kailin R.
   Rompolas, Panteleimon
   Zito, Giovanni
   Myung, Peggy
   Sun, Thomas Y.
   Brown, Samara
   Gonzalez, David G.
   Blagoev, Krastan B.
   Haberman, Ann M.
   Greco, Valentina
TI Niche-induced cell death and epithelial phagocytosis regulate hair follicle stem cell pool
SO NATURE
LA English
DT Article
ID dermal papilla; regression; catenin; activation; apoptosis; dynamics; progeny; growth
AB Tissue homeostasis is achieved through a balance of cell production (growth) and elimination (regression)(1,2). In contrast to tissue growth, the cells and molecular signals required for tissue regression remain unknown. To investigate physiological tissue regression, we use the mouse hair follicle, which cycles stereotypically between phases of growth and regression while maintaining a pool of stem cells to perpetuate tissue regeneration(3). Here we show by intravital microscopy in live mice(4-6) that the regression phase eliminates the majority of the epithelial cells by two distinct mechanisms: terminal differentiation of suprabasal cells and a spatial gradient of apoptosis of basal cells. Furthermore, we demonstrate that basal epithelial cells collectively act as phagocytes to clear dying epithelial neighbours. Through cellular and genetic ablation we show that epithelial cell death is extrinsically induced through transforming growth factor (TGF)-beta activation and mesenchymal crosstalk. Strikingly, our data show that regression acts to reduce the stem cell pool, as inhibition of regression results in excess basal epithelial cells with regenerative abilities. This study identifies the cellular behaviours and molecular mechanisms of regression that counterbalance growth to maintain tissue homeostasis.
C1 [Mesa, Kailin R.; Rompolas, Panteleimon; Myung, Peggy; Sun, Thomas Y.; Brown, Samara; Greco, Valentina] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA.
   [Zito, Giovanni] Univ Palermo, Dept Biopathol & Med Biotechnol, I-90100 Palermo, Italy.
   [Myung, Peggy; Greco, Valentina] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06510 USA.
   [Gonzalez, David G.; Haberman, Ann M.] Yale Univ, Sch Med, Dept Immunobiol, Dept Lab Med, New Haven, CT 06510 USA.
   [Blagoev, Krastan B.] Natl Sci Fdn, Arlington, VA 22230 USA.
   [Blagoev, Krastan B.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging,Dept Radiol, Boston, MA 02114 USA.
   [Greco, Valentina] Yale Univ, Sch Med, Yale Stem Cell Ctr, New Haven, CT 06510 USA.
   [Greco, Valentina] Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT 06510 USA.
C3 Yale University; University of Palermo; Yale University; Yale University; National Science Foundation (NSF); Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; Yale University; Yale University; Yale New Haven Hospital
RP Greco, V (corresponding author), Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA.
EM valentina.greco@yale.edu
FU National Institutes of Health (NIH) [5T32 GM007223]; American Cancer Society [RSG-12-059-02]; National Cancer Institute, NIH [2P50CA121974]; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH [1R01AR063663-01]; New York Stem Cell Foundation; NIAMS Rheumatic Diseases Research Core Centers [5 P30 AR053495-07]; NSF; National Cancer Institute [P50CA121974] Funding Source: NIH RePORTER; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR063663] Funding Source: NIH RePORTER
NR 28
TC 126
Z9 163
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 JUN 4
PY 2015
VL 522
IS 7554
BP 94
EP U236
DI 10.1038/nature14306
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ5QP
UT WOS:000355543400036
PM 25849774
DA 2026-03-09
ER

PT J
AU Rovner, AJ
   Haimovich, AD
   Katz, SR
   Li, Z
   Grome, MW
   Gassaway, BM
   Amiram, M
   Patel, JR
   Gallagher, RR
   Rinehart, J
   Isaacs, FJ
AF Rovner, Alexis J.
   Haimovich, Adrian D.
   Katz, Spencer R.
   Li, Zhe
   Grome, Michael W.
   Gassaway, Brandon M.
   Amiram, Miriam
   Patel, Jaymin R.
   Gallagher, Ryan R.
   Rinehart, Jesse
   Isaacs, Farren J.
TI Recoded organisms engineered to depend on synthetic amino acids
SO NATURE
LA English
DT Article
ID biological containment; protein-synthesis; rna; expression; construction; salmonella; bacteria; system
AB Genetically modified organisms (GMOs) are increasingly used in research and industrial systemsto produce high-value pharmaceuticals, fuels and chemicals(1). Genetic isolation and intrinsic biocontainment would provide essential biosafety measures to secure these closed systems and enable safe applications of GMOs in open systems(2,3), which include bioremediation(4) and probiotics(5). Although safeguards have been designed to control cell growth by essential gene regulation(6), inducible toxin switches(7) and engineered auxotrophies8, these approaches are compromised by cross-feeding of essential metabolites, leaked expression of essential genes, or genetic mutations(9,10). Here we describe the construction of a series of genomically recoded organisms (GROs)(11) whose growth is restricted by the expression of multiple essential genes that depend on exogenously supplied synthetic aminoacids (sAAs). We introduced a Methanocaldococcus jannaschii tRNA: aminoacyl-tRNA synthetase pair into the chromosome of a GRO derived from Escherichia coli that lacks all TAG codons and release factor 1, endowing this organism with the orthogonal translational components to convert TAG into a dedicated sense codon for sAAs. Using multiplex automated genome engineering(12), we introduced in-frame TAG codons into 22 essential genes, linking their expression to the incorporation of synthetic phenylalanine-derived amino acids. Of the 60 sAA-dependent variants isolated, a notable strain harbouring three TAG codons inconserved functional residues(13) of MurG, DnaA and SerS and containing targeted tRNA deletions maintained robust growth and exhibited undetectable escape frequencies upon culturing similar to 10(11) cells on solid media for 7 days or in liquid media for 20 days. This is a significant improvement over existing biocontainment approaches(2,3,6-10). We constructed synthetic auxotrophs dependent on sAAs that were not rescued by cross-feeding in environmental growth assays. These auxotrophic GROs possess alternative genetic codes that impart genetic isolation by impeding horizontal gene transfer(11) and now depend on the use of synthetic biochemical building blocks, advancing orthogonal barriers between engineered organisms and the environment.
C1 [Rovner, Alexis J.; Haimovich, Adrian D.; Katz, Spencer R.; Li, Zhe; Grome, Michael W.; Amiram, Miriam; Patel, Jaymin R.; Gallagher, Ryan R.; Isaacs, Farren J.] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA.
   [Rovner, Alexis J.; Haimovich, Adrian D.; Katz, Spencer R.; Li, Zhe; Grome, Michael W.; Gassaway, Brandon M.; Amiram, Miriam; Patel, Jaymin R.; Gallagher, Ryan R.; Rinehart, Jesse; Isaacs, Farren J.] Yale Univ, Syst Biol Inst, West Haven, CT 06516 USA.
   [Rinehart, Jesse] Yale Univ, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA.
C3 Yale University; Yale University; Yale University
RP Isaacs, FJ (corresponding author), Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA.
EM farren.isaacs@yale.edu
FU Defense Advanced Research Projects Agency [N66001-12-C-4020, N66001-12-C-4211]; DuPont Inc.; Arnold and Mabel Beckman Foundation;  [NIH-MSTP-TG-T32GM07205]
NR 43
TC 285
Z9 370
U1 2
U2 422
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 5
PY 2015
VL 518
IS 7537
BP 89
EP +
DI 10.1038/nature14095
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7LE
UT WOS:000349098000037
PM 25607356
DA 2026-03-09
ER

PT J
AU Thorslund, T
   Ripplinger, A
   Hoffmann, S
   Wild, T
   Uckelmann, M
   Villumsen, B
   Narita, T
   Sixma, TK
   Choudhary, C
   Bekker-Jensen, S
   Mailand, N
AF Thorslund, Tina
   Ripplinger, Anita
   Hoffmann, Saskia
   Wild, Thomas
   Uckelmann, Michael
   Villumsen, Bine
   Narita, Takeo
   Sixma, Titia K.
   Choudhary, Chunaram
   Bekker-Jensen, Simon
   Mailand, Niels
TI Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage
SO NATURE
LA English
DT Article
ID polyubiquitin chains; dependent response; ubiquitylation; localization; proteins; binding; sites; 53bp1
AB DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions that trigger non-proteolytic ubiquitylation of adjacent chromatin areas to generate binding sites for DNA repair factors. This depends on the sequential actions of the E3 ubiquitin ligases RNF8 and RNF168 (refs 1-6), and UBC13 (also known as UBE2N), an E2 ubiquitin-conjugating enzyme that specifically generates K63-linked ubiquitin chains(7). Whereas RNF168 is known to catalyse ubiquitylation of H2A-type histones, leading to the recruitment of repair factors such as 53BP1 (refs 8-10), the critical substrates of RNF8 and K63-linked ubiquitylation remain elusive. Here we elucidate how RNF8 and UBC13 promote recruitment of RNF168 and downstream factors to DSB sites in human cells. We establish that UBC13-dependent K63-linked ubiquitylation at DSB sites is predominantly mediated by RNF8 but not RNF168, and that H1-type linker histones, but not core histones, represent major chromatin-associated targets of this modification. The RNF168 module (UDM1) recognizing RNF8-generated ubiquitylations(11) is a high-affinity reader of K63-ubiquitylated H1, mechanistically explaining the essential roles of RNF8 and UBC13 in recruiting RNF168 to DSBs. Consistently, reduced expression or chromatin association of linker histones impair accumulation of K63-linked ubiquitin conjugates and repair factors at DSB-flanking chromatin. These results identify histone H1 as a key target of RNF8-UBC13 in DSB signalling and expand the concept of the histone code(12,13) by showing that posttranslational modifications of linker histones can serve as important marks for recognition by factors involved in genome stability maintenance, and possibly beyond.
C1 [Thorslund, Tina; Ripplinger, Anita; Hoffmann, Saskia; Villumsen, Bine; Bekker-Jensen, Simon; Mailand, Niels] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, Ubiquitin Signaling Grp,Prot Signaling Program, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
   [Wild, Thomas; Narita, Takeo; Choudhary, Chunaram] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, Prote Program, DK-2200 Copenhagen, Denmark.
   [Uckelmann, Michael; Sixma, Titia K.] Netherlands Canc Inst, Canc Genom Ctr, Div Biochem, NL-1066 CX Amsterdam, Netherlands.
C3 University of Copenhagen; University of Copenhagen; Netherlands Cancer Institute
RP Mailand, N (corresponding author), Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, Ubiquitin Signaling Grp,Prot Signaling Program, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
EM niels.mailand@cpr.ku.dk
FU Novo Nordisk Foundation [NNF14CC0001, NNF12OC0002114]; European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek-Chemische Wetenschappen (NWO-CW); Danish Cancer Society; Danish Council for Independent Research; Novo Nordisk Fonden [NNF12OC0002114] Funding Source: researchfish; Novo Nordisk Foundation Center for Protein Research [PI Niels Mailand, PI Chunaram Choudhary] Funding Source: researchfish
NR 41
TC 322
Z9 408
U1 0
U2 63
PU NATURE PUBLISHING 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 19
PY 2015
VL 527
IS 7578
BP 389
EP +
DI 10.1038/nature15401
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9ZN
UT WOS:000365356800059
PM 26503038
DA 2026-03-09
ER

PT J
AU Toutov, AA
   Liu, WB
   Betz, KN
   Fedorov, A
   Stoltz, BM
   Grubbs, RH
AF Toutov, Anton A.
   Liu, Wen-Bo
   Betz, Kerry N.
   Fedorov, Alexey
   Stoltz, Brian M.
   Grubbs, Robert H.
TI Silylation of C-H bonds in aromatic heterocycles by an Earth-abundant metal catalyst
SO NATURE
LA English
DT Article
ID functionalization; activation; chemistry; arenes
AB Heteroaromatic compounds containing carbon-silicon(C-Si) bonds are of great interest in the fields of organic electronics and photonics(1), drug discovery(2), nuclear medicine(3) and complex molecule synthesis(4-6), because these compounds have very useful physicochemical properties. Many of the methods now used to construct heteroaromatic C-Si bonds involve stoichiometric reactions between heteroaryl organometallic species and silicon electrophiles(6,7) or direct, transition metal-catalysed intermolecular carbon-hydrogen (C-H) silylation using rhodium or iridium complexes in the presence of excess hydrogen acceptors(8,9). Both approaches are useful, but their limitations include functional group in compatibility, narrow scope of application, high cost and low availability of the catalysts, and unproven scalability. For this reason, a new and general catalytic approach to heteroaromatic C-Si bond construction that avoids such limitations is highly desirable. Here we report an example of cross-dehydrogenative heteroaromatic C-H functionalization catalysed by an Earth-abundant alkali metal species. We found that readily available and inexpensive potassium tert-butoxide catalyses the direct silylation of aromatic heterocycles with hydrosilanes, furnishing heteroarylsilanes in a single step. The silylation proceeds under mild conditions, in the absence of hydrogen acceptors, ligands or additives, and is scalable to greater than 100 grams under optionally solvent-free conditions. Substrate classes that are difficult to activate with precious metal catalysts are silylated in good yield and with excellent regioselectivity. The derived heteroarylsilane products readily engage in versatile transformations enabling new synthetic strategies for heteroaromatic elaboration, and are useful in their own right in pharmaceutical and materials science applications.
C1 [Toutov, Anton A.; Liu, Wen-Bo; Betz, Kerry N.; Fedorov, Alexey; Stoltz, Brian M.; Grubbs, Robert H.] CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA.
C3 California Institute of Technology
RP Grubbs, RH (corresponding author), CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA.
EM stoltz@caltech.edu; rhg@caltech.edu
FU NSF under the CCI Center for Selective C-H Functionalization [CHE-1205646, CHE-1212767]; BP under the XC2 initiative; Resnick Sustainability Institute at Caltech; Dow Chemical; NSERC; Shanghai Institute of Organic Chemistry (SIOC); Direct For Mathematical & Physical Scien; Division Of Chemistry [1205646] Funding Source: National Science Foundation
NR 30
TC 367
Z9 420
U1 7
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 FEB 5
PY 2015
VL 518
IS 7537
BP 80
EP 84
DI 10.1038/nature14126
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7LE
UT WOS:000349098000035
PM 25652999
DA 2026-03-09
ER

PT J
AU McCarthy, GD
   Haigh, ID
   Hirschi, JJM
   Grist, JP
   Smeed, DA
AF McCarthy, Gerard D.
   Haigh, Ivan D.
   Hirschi, Joel J. -M.
   Grist, Jeremy P.
   Smeed, David A.
TI Ocean impact on decadal Atlantic climate variability revealed by sea-level observations
SO NATURE
LA English
DT Article
ID surface heat-flux; transport variability; coast; volume; rise; circulation
AB Decadal variability is a notable feature of the Atlantic Ocean and the climate of the regions it influences. Prominently, this is manifested in the Atlantic Multidecadal Oscillation (AMO) in sea surface temperatures. Positive (negative) phases of the AMO coincide with warmer (colder) North Atlantic sea surface temperatures. The AMO is linked with decadal climate fluctuations, such as Indian and Sahel rainfall(1), European summer precipitation(2), Atlantic hurricanes(3) and variations in global temperatures(4). It is widely believed that ocean circulation drives the phase changes of the AMO by controlling ocean heat content(5). However, there are no direct observations of ocean circulation of sufficient length to support this, leading to questions about whether the AMO is controlled from another source(6). Here we provide observational evidence of the widely hypothesized link between ocean circulation and the AMO. We take a new approach, using sea level along the east coast of the United States to estimate ocean circulation on decadal timescales. We show that ocean circulation responds to the first mode of Atlantic atmospheric forcing, the North Atlantic Oscillation, through circulation changes between the subtropical and subpolar gyres-the intergyre region(7). These circulation changes affect the decadal evolution of North Atlantic heat content and, consequently, the phases of the AMO. The Atlantic overturning circulation is declining(8) and the AMO is moving to a negative phase. This may offer a brief respite from the persistent rise of global temperatures(4), but in the coupled system we describe, there are compensating effects. In this case, the negative AMO is associated with a continued acceleration of sea-level rise along the northeast coast of the United States(9,10).
C1 [McCarthy, Gerard D.; Hirschi, Joel J. -M.; Grist, Jeremy P.; Smeed, David A.] Univ Southampton, Natl Oceanog Ctr, Southampton SO14 3ZH, Hants, England.
   [Haigh, Ivan D.] Univ Southampton, Natl Oceanog Ctr, Ocean & Earth Sci, Southampton SO14 3ZH, Hants, England.
C3 NERC National Oceanography Centre; University of Southampton; University of Southampton; NERC National Oceanography Centre
RP McCarthy, GD (corresponding author), Univ Southampton, Natl Oceanog Ctr, Waterfront Campus,European Way, Southampton SO14 3ZH, Hants, England.
EM gerard.mccarthy@noc.ac.uk
FU UK Natural Environment Research Council (NERC) RAPID-WATCH programme; UK NERC consortium project iGlass [NE/I009906/1]; NERC; Natural Environment Research Council [NE/M006107/1, noc010010, noc010012, NE/I009906/1] Funding Source: researchfish; NERC [NE/I009906/1, NE/M006107/1, noc010010] Funding Source: UKRI
NR 31
TC 287
Z9 327
U1 2
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 MAY 28
PY 2015
VL 521
IS 7553
BP 508
EP U172
DI 10.1038/nature14491
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ2AN
UT WOS:000355286600040
PM 26017453
DA 2026-03-09
ER

PT J
AU Minocherhomji, S
   Ying, SM
   Bjerregaard, VA
   Bursomanno, S
   Aleliunaite, A
   Wu, W
   Mankouri, HW
   Shen, HH
   Liu, Y
   Hickson, ID
AF Minocherhomji, Sheroy
   Ying, Songmin
   Bjerregaard, Victoria A.
   Bursomanno, Sara
   Aleliunaite, Aiste
   Wu, Wei
   Mankouri, Hocine W.
   Shen, Huahao
   Liu, Ying
   Hickson, Ian D.
TI Replication stress activates DNA repair synthesis in mitosis
SO NATURE
LA English
DT Article
ID break-induced replication; common fragile sites; holliday junction resolution; human-cells; chromosm; mus81-eme1; reveals; endonuclease; transmission; bubble
AB Oncogene-induced DNA replication stress has been implicated as a driver of tumorigenesis(1). Many chromosomal rearrangements characteristic of human cancers originate from specific regions of the genome called common fragile sites (CFSs)(2-5). CFSs are difficult-to-replicate loci that manifest as gaps or breaks on metaphase chromosomes (termed CFS 'expression'), particularly when cells have been exposed to replicative stress(6). The MUS81-EME1 structure-specific endonuclease promotes the appearance of chromosome gaps or breaks at CFSs following replicative stress(7-9). Here we show that entry of cells into mitotic prophase triggers the recruitment of MUS81 to CFSs. The nuclease activity of MUS81 then promotes POLD3-dependent DNA synthesis at CFSs, which serves to minimize chromosome mis-segregation and non-disjunction. We propose that the attempted condensation of incompletely duplicated loci in early mitosis serves as the trigger for completion of DNA replication at CFS loci in human cells. Given that this POLD3-dependent mitotic DNA synthesis is enhanced in aneuploid cancer cells that exhibit intrinsically high levels of chromosomal instability (CIN+) and replicative stress, we suggest that targeting this pathway could represent a new therapeutic approach.
C1 [Minocherhomji, Sheroy; Bjerregaard, Victoria A.; Bursomanno, Sara; Aleliunaite, Aiste; Wu, Wei; Mankouri, Hocine W.; Liu, Ying; Hickson, Ian D.] Univ Copenhagen, Panum Inst, Dept Cellular & Mol Med, Ctr Chromosome Stabil & Ctr Hlth Aging, DK-2200 Copenhagen N, Denmark.
   [Ying, Songmin; Shen, Huahao] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Resp & Crit Care Med, Hangzhou 310009, Zhejiang, Peoples R China.
   [Ying, Songmin] Zhejiang Univ, Sch Med, Dept Pharmacol, Hangzhou 310058, Zhejiang, Peoples R China.
   [Shen, Huahao] SKLRD, Guangzhou 510120, Peoples R China.
C3 University of Copenhagen; Zhejiang University; Zhejiang University
RP Shen, HH (corresponding author), Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Resp & Crit Care Med, Hangzhou 310009, Zhejiang, Peoples R China.
EM huahaoshen@163.com; ying@sund.ku.dk; iandh@sund.ku.dk
FU European Research Council; Danish National Research Foundation; Nordea Foundation; National 1000 Talents Program; National Natural Science Foundation of China [31370901, 81422031]; Zhejiang Provincial Natural Science Foundation of China [LR14H160001]; National Key Scientific and Technology Support Program: Collaborative innovation of Clinical Research for chronic obstructive pulmonary disease and lung cancer [2013BAI09B09]; Danish Medical Research Council
NR 30
TC 430
Z9 478
U1 3
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 10
PY 2015
VL 528
IS 7581
BP 286
EP +
DI 10.1038/nature16139
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX9VH
UT WOS:000366053300046
PM 26633632
DA 2026-03-09
ER

PT J
AU Horányi, M
   Szalay, JR
   Kempf, S
   Schmidt, J
   Grün, E
   Srama, R
   Sternovsky, Z
AF Horanyi, M.
   Szalay, J. R.
   Kempf, S.
   Schmidt, J.
   Gruen, E.
   Srama, R.
   Sternovsky, Z.
TI A permanent, asymmetric dust cloud around the Moon
SO NATURE
LA English
DT Article
ID planetary satellites; lunar atmosphere; ejecta; exosphere; impacts
AB Interplanetary dust particles hit the surfaces of airless bodies in the Solar System, generating charged(1) and neutral(2) gas clouds, as well as secondary ejecta dust particles(3). Gravitationally bound ejecta clouds that form dust exospheres were recognized by in situ dust instruments around the icy moons of Jupiter(4) and Saturn(5), but have hitherto not been observed near bodies with refractory regolith surfaces. High-altitude Apollo 15 and 17 observations of a 'horizon glow' indicated a putative population of high-density small dust particles near the lunar terminators(6,7), although later orbital observations(8,9) yielded upper limits on the abundance of such particles that were a factor of about 10(4) lower than that necessary to produce the Apollo results. Here we report observations of a permanent, asymmetric dust cloud around the Moon, caused by impacts of high-speed cometary dust particles on eccentric orbits, as opposed to particles of asteroidal origin following near-circular paths striking the Moon at lower speeds. The density of the lunar ejecta cloud increases during the annual meteor showers, especially the Geminids, because the lunar surface is exposed to the same stream of interplanetary dust particles. We expect all airless planetary objects to be immersed in similar tenuous clouds of dust.
C1 [Horanyi, M.; Szalay, J. R.; Kempf, S.; Gruen, E.; Sternovsky, Z.] Univ Colorado, Lab Atmospher & Space Phys, Boulder, CO 80303 USA.
   [Horanyi, M.; Szalay, J. R.; Kempf, S.] Univ Colorado, Dept Phys, Boulder, CO 80309 USA.
   [Horanyi, M.; Szalay, J. R.; Kempf, S.; Gruen, E.; Sternovsky, Z.] Univ Colorado, Inst Modeling Plasma Atmospheres & Cosm Dust IMPA, Boulder, CO 80303 USA.
   [Schmidt, J.] Univ Oulu, Astron & Space Phys, FI-90014 Oulu, Finland.
   [Gruen, E.] Max Planck Inst Kernphys, D-69117 Heidelberg, Germany.
   [Srama, R.] Univ Stuttgart, Inst Raumfahrtsyst, Raumfahrtzentrum Baden Wurttemberg, D-70569 Stuttgart, Germany.
   [Sternovsky, Z.] Univ Colorado, Aerosp Engn Sci, Boulder, CO 80309 USA.
C3 University of Colorado System; University of Colorado Boulder; University of Colorado System; University of Colorado Boulder; University of Colorado System; University of Colorado Boulder; University of Oulu; Max Planck Society; University of Stuttgart; University of Colorado System; University of Colorado Boulder
RP Horányi, M (corresponding author), Univ Colorado, Lab Atmospher & Space Phys, Boulder, CO 80303 USA.
EM horanyi@colorado.edu
FU NASA; NASA's Solar System Exploration Research Virtual Institute (SSERVI)
NR 33
TC 194
Z9 218
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 18
PY 2015
VL 522
IS 7556
BP 324
EP +
DI 10.1038/nature14479
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK7PU
UT WOS:000356425400049
PM 26085272
DA 2026-03-09
ER

PT J
AU Tong, YG
   Shi, WF
   Liu, D
   Qian, J
   Liang, L
   Bo, XC
   Liu, J
   Ren, HG
   Fan, H
   Ni, M
   Sun, Y
   Jin, Y
   Teng, Y
   Li, Z
   Kargbo, D
   Dafae, F
   Kanu, A
   Chen, CC
   Lan, ZH
   Jiang, H
   Luo, Y
   Lu, HJ
   Zhang, XG
   Yang, F
   Hu, Y
   Cao, YX
   Deng, YQ
   Su, HX
   Sun, Y
   Liu, WS
   Wang, Z
   Wang, CY
   Bu, ZY
   Guo, ZD
   Zhang, LB
   Nie, WM
   Bai, CQ
   Sun, CH
   An, XP
   Xu, PS
   Zhang, XLL
   Huang, Y
   Mi, ZQ
   Yu, D
   Yao, HW
   Feng, Y
   Xia, ZP
   Zheng, XX
   Yang, ST
   Lu, B
   Jiang, JF
   Kargbo, B
   He, FC
   Gao, GF
   Cao, WC
AF Tong, Yi-Gang
   Shi, Wei-Feng
   Liu, Di
   Qian, Jun
   Liang, Long
   Bo, Xiao-Chen
   Liu, Jun
   Ren, Hong-Guang
   Fan, Hang
   Ni, Ming
   Sun, Yang
   Jin, Yuan
   Teng, Yue
   Li, Zhen
   Kargbo, David
   Dafae, Foday
   Kanu, Alex
   Chen, Cheng-Chao
   Lan, Zhi-Heng
   Jiang, Hui
   Luo, Yang
   Lu, Hui-Jun
   Zhang, Xiao-Guang
   Yang, Fan
   Hu, Yi
   Cao, Yu-Xi
   Deng, Yong-Qiang
   Su, Hao-Xiang
   Sun, Yu
   Liu, Wen-Sen
   Wang, Zhuang
   Wang, Cheng-Yu
   Bu, Zhao-Yang
   Guo, Zhen-Dong
   Zhang, Liu-Bo
   Nie, Wei-Min
   Bai, Chang-Qing
   Sun, Chun-Hua
   An, Xiao-Ping
   Xu, Pei-Song
   Zhang, Xiang-Li-Lan
   Huang, Yong
   Mi, Zhi-Qiang
   Yu, Dong
   Yao, Hong-Wu
   Feng, Yong
   Xia, Zhi-Ping
   Zheng, Xue-Xing
   Yang, Song-Tao
   Lu, Bing
   Jiang, Jia-Fu
   Kargbo, Brima
   He, Fu-Chu
   Gao, George F.
   Cao, Wu-Chun
TI Genetic diversity and evolutionary dynamics of Ebola virus in Sierra Leone
SO NATURE
LA English
DT Article
ID molecular evolution; inference
AB A novel Ebola virus (EBOV) first identified in March 2014 has infected more than 25,000 people in West Africa, resulting in more than 10,000 deaths(1,2). Preliminary analyses of genome sequences of 81 EBOV collected from March to June 2014 from Guinea and Sierra Leone suggest that the 2014 EBOV originated from an independent transmission event from its natural reservoir(3) followed by sustained human-to-human infections(4). It has been reported that the EBOV genome variation might have an effect on the efficacy of sequence-based virus detection and candidate therapeutics(5,6). However, only limited viral information has been available since July 2014, when the outbreak entered a rapid growth phase(7). Here we describe 175 full-length EBOV genome sequences from five severely stricken districts in Sierra Leone from 28 September to 11 November 2014. We found that the 2014 EBOV has become more phylogenetically and genetically diverse from July to November 2014, characterized by the emergence of multiple novel lineages. The substitution rate for the 2014 EBOV was estimated to be 1.23x10(-3) substitutions per site per year (95% highest posterior density interval, 1.04x10(-3) to 1.41x10(-3) substitutions per site per year), approximating to that observed between previous EBOV outbreaks. The sharp increase in genetic diversity of the 2014 EBOV warrants extensive EBOV surveillance in Sierra Leone, Guinea and Liberia to better understand the viral evolution and transmission dynamics of the ongoing outbreak. These data will facilitate the international efforts to develop vaccines and therapeutics.
C1 [Tong, Yi-Gang; Liang, Long; Ren, Hong-Guang; Fan, Hang; Jin, Yuan; Teng, Yue; Hu, Yi; Deng, Yong-Qiang; Sun, Yu; Wang, Zhuang; Sun, Chun-Hua; An, Xiao-Ping; Zhang, Xiang-Li-Lan; Huang, Yong; Mi, Zhi-Qiang; Yu, Dong; Yao, Hong-Wu; Lu, Bing; Jiang, Jia-Fu; Cao, Wu-Chun] State Key Lab Pathogen & Biosecur, Beijing 100071, Peoples R China.
   [Shi, Wei-Feng] Taishan Med Coll, Inst Pathogen Biol, Tai An 271000, Shandong, Peoples R China.
   [Liu, Di; Gao, George F.] Chinese Acad Sci, Inst Microbiol, Beijing 100101, Peoples R China.
   [Bo, Xiao-Chen; Ni, Ming; Li, Zhen; Xu, Pei-Song] Beijing Key Lab New Mol Diagnost Technol, Beijing 100850, Peoples R China.
   [Qian, Jun; Sun, Yang; Lu, Hui-Jun; Liu, Wen-Sen; Wang, Cheng-Yu; Bu, Zhao-Yang; Guo, Zhen-Dong; Xia, Zhi-Ping; Zheng, Xue-Xing; Yang, Song-Tao] Key Lab Jilin Prov Zoonosis Prevent & Control, Changchun 130122, Peoples R China.
   [Liu, Jun; Zhang, Xiao-Guang; Cao, Yu-Xi; Gao, George F.] Chinese Ctr Dis Control & Prevent, Inst Viral Dis Control & Prevent, Beijing 102206, Peoples R China.
   [Kargbo, David; Dafae, Foday; Kargbo, Brima] Sierra Leone Minist Hlth & Sanitat, Freetown, Sierra Leone.
   [Kanu, Alex] Sierra Leone China Friendship Hosp, Freetown, Sierra Leone.
   [Chen, Cheng-Chao; Lan, Zhi-Heng; Jiang, Hui] BGI Shenzhen, Shenzhen 518083, Peoples R China.
   [Luo, Yang] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.
   [Yang, Fan; Su, Hao-Xiang] Chinese Acad Med Sci, Beijing 100730, Peoples R China.
   [Yang, Fan; Su, Hao-Xiang] Peking Union Med Coll, Beijing 100730, Peoples R China.
   [Zhang, Liu-Bo] Chinese Ctr Dis Control & Prevent, Inst Environm Hlth & Related Prod Safet, Beijing 100021, Peoples R China.
   [Nie, Wei-Min] 302 Hosp, Beijing 100039, Peoples R China.
   [Bai, Chang-Qing] 307 Hosp, Beijing 100071, Peoples R China.
   [Feng, Yong] Natl Hlth & Family Planning Commiss, Dept Int Cooperat, Beijing 100044, Peoples R China.
   [He, Fu-Chu] State Key Lab Prote, Beijing 102206, Peoples R China.
   [Gao, George F.] Chinese Ctr Dis Control & Prevent, Beijing 102206, Peoples R China.
C3 Shandong First Medical University & Shandong Academy of Medical Sciences; Chinese Academy of Sciences; Institute of Microbiology, CAS; Chinese Center for Disease Control & Prevention; Ministry of Health & Sanitation Sierra Leone; Beijing Genomics Institute (BGI); Wellcome Trust Sanger Institute; Chinese Academy of Medical Sciences - Peking Union Medical College; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Chinese Center for Disease Control & Prevention; National Institute of Environmental Health, Chinese Center for Disease Control & Prevention; Fifth Medical Center of Chinese PLA General Hospital; Fifth Medical Center of Chinese PLA General Hospital; Chinese Center for Disease Control & Prevention
RP Cao, WC (corresponding author), State Key Lab Pathogen & Biosecur, Beijing 100071, Peoples R China.
EM hefc@nic.bmi.ac.cn; gaof@im.ac.cn; caowc@bmi.ac.cn
FU special project of Ebola virus research from the President Foundation of Chinese Academy of Sciences; China Mega-Project on Infectious Disease Prevention [2013ZX10004202-002, 2013ZX10004605]; China Mega-Project on Major Drug Development [2013ZX09304101]; National Hi-Tech Research and Development (863) Program of China [2014AA021402, 2014AA021501]; Innovative Research Group of the National Natural Science Foundation of China, NSFC [81321063]
NR 17
TC 128
Z9 167
U1 6
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 AUG 6
PY 2015
VL 524
IS 7563
BP 93
EP U191
DI 10.1038/nature14490
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO2QS
UT WOS:000359002300038
PM 25970247
DA 2026-03-09
ER

PT J
AU Xu, GT
   Chapman, JR
   Brandsma, I
   Yuan, JS
   Mistrik, M
   Bouwman, P
   Bartkova, J
   Gogola, E
   Warmerdam, D
   Barazas, M
   Jaspers, JE
   Watanabe, K
   Pieterse, M
   Kersbergen, A
   Sol, W
   Celie, PHN
   Schouten, PC
   van den Broek, B
   Salman, A
   Nieuwland, M
   de Rink, I
   de Ronde, J
   Jalink, K
   Boulton, SJ
   Chen, JJ
   van Gent, DC
   Bartek, J
   Jonkers, J
   Borst, P
   Rottenberg, S
AF Xu, Guotai
   Chapman, J. Ross
   Brandsma, Inger
   Yuan, Jingsong
   Mistrik, Martin
   Bouwman, Peter
   Bartkova, Jirina
   Gogola, Ewa
   Warmerdam, Daniel
   Barazas, Marco
   Jaspers, Janneke E.
   Watanabe, Kenji
   Pieterse, Mark
   Kersbergen, Ariena
   Sol, Wendy
   Celie, Patrick H. N.
   Schouten, Philip C.
   van den Broek, Bram
   Salman, Ahmed
   Nieuwland, Marja
   de Rink, Iris
   de Ronde, Jorma
   Jalink, Kees
   Boulton, Simon J.
   Chen, Junjie
   van Gent, Dik C.
   Bartek, Jiri
   Jonkers, Jos
   Borst, Piet
   Rottenberg, Sven
TI REV7 counteracts DNA double-strand break resection and affects PARP inhibition
SO NATURE
LA English
DT Article
ID class switch recombination; polymerase-zeta; pol-zeta; repair; 53bp1; damage; cells; resistance; complex
AB Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway(1). In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers(2,3). Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration(4). Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases(5). In particular, little is known about BRCA1-independent restoration of HR. Here we show that loss of REV7 (also known as MAD2L2) in mouse and human cell lines re-establishes CTIP-dependent endresection of DSBs in BRCA1 deficient cells, leading to HR restoration and PARP inhibitor resistance, which is reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway, and seems to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance(6). Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining during immunoglobulin class switch recombination. Our results reveal an unexpected crucial function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells.
C1 [Xu, Guotai; Gogola, Ewa; Barazas, Marco; Jaspers, Janneke E.; Kersbergen, Ariena; Sol, Wendy; Borst, Piet; Rottenberg, Sven] Netherlands Canc Inst, Div Mol Oncol, NL-1066 CX Amsterdam, Netherlands.
   [Chapman, J. Ross; Salman, Ahmed] Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.
   [Brandsma, Inger; van Gent, Dik C.] Erasmus, Univ Med Ctr, Dept Genet, NL-3000 CA Rotterdam, Netherlands.
   [Yuan, Jingsong; Chen, Junjie] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA.
   [Mistrik, Martin; Bartek, Jiri] Palacky Univ, Fac Med & Dent, Inst Mol & Translat Med, Olomouc 77900, Czech Republic.
   [Bouwman, Peter; Pieterse, Mark; Schouten, Philip C.; Jonkers, Jos] Netherlands Canc Inst, Div Mol Pathol, NL-1066 CX Amsterdam, Netherlands.
   [Bartkova, Jirina; Watanabe, Kenji; Bartek, Jiri] Danish Canc Soc, Res Ctr, DK-2100 Copenhagen, Denmark.
   [Warmerdam, Daniel; van den Broek, Bram; Jalink, Kees] Netherlands Canc Inst, Div Cell Biol, NL-1066 CX Amsterdam, Netherlands.
   [Celie, Patrick H. N.] Netherlands Canc Inst, Prot Facil, NL-1066 CX Amsterdam, Netherlands.
   [Nieuwland, Marja; de Rink, Iris] Netherlands Canc Inst, Deep Sequencing Core Facil, NL-1066 CX Amsterdam, Netherlands.
   [de Ronde, Jorma] Netherlands Canc Inst, Div Mol Carcinogenesis, NL-1066 CX Amsterdam, Netherlands.
   [Boulton, Simon J.] Canc Res UK, London Res Inst, DNA Damage Response Lab, South Mimms EN6 3LD, Herts, England.
   [Rottenberg, Sven] Univ Bern, Vetsuisse Fac, Inst Anim Pathol, CH-3012 Bern, Switzerland.
C3 Netherlands Cancer Institute; University of Oxford; Wellcome Centre for Human Genetics; Erasmus University Rotterdam - Excl Erasmus MC; Erasmus University Rotterdam; University of Texas System; UTMD Anderson Cancer Center; Palacky University Olomouc; Netherlands Cancer Institute; Danish Cancer Society; Netherlands Cancer Institute; Netherlands Cancer Institute; Netherlands Cancer Institute; Netherlands Cancer Institute; Cancer Research UK; University of Bern
RP Rottenberg, S (corresponding author), Netherlands Canc Inst, Div Mol Oncol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands.
EM sven.rottenberg@vetsuisse.unibe.ch
FU Netherlands Organization for Scientific Research (NWO-Toptalent); Netherlands Organization for Scientific Research (NWO-VIDI); Dutch Cancer Society; CTMM Breast Care; Swiss National Science Foundation; European Union (EU); Wellcome Trust; Danish Cancer Society; Danish Council for Independent Research; Lundbeck Foundation; Czech National Program of Sustainability; Cancer Research UK; ERC; Royal Society; Wellcome Trust [104558/Z/14/Z] Funding Source: Wellcome Trust; MRC [MR/M009971/1] Funding Source: UKRI; Cancer Research UK [11581] Funding Source: researchfish; Cancer Research UK; The Francis Crick Institute [10048] Funding Source: researchfish; Medical Research Council [MR/M009971/1] Funding Source: researchfish; Novo Nordisk Fonden [NNF12OC0002290] Funding Source: researchfish; Wellcome Trust [104558/Z/14/Z] Funding Source: researchfish; National Cancer Institute [P30CA016672] Funding Source: NIH RePORTER
NR 30
TC 501
Z9 577
U1 4
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 MAY 28
PY 2015
VL 521
IS 7553
BP 541
EP U308
DI 10.1038/nature14328
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ2AN
UT WOS:000355286600048
PM 25799992
DA 2026-03-09
ER

PT J
AU Basan, M
   Hui, S
   Okano, H
   Zhang, ZG
   Shen, Y
   Williamson, JR
   Hwa, T
AF Basan, Markus
   Hui, Sheng
   Okano, Hiroyuki
   Zhang, Zhongge
   Shen, Yang
   Williamson, James R.
   Hwa, Terence
TI Overflow metabolism in Escherichia coli results from efficient proteome allocation
SO NATURE
LA English
DT Article
ID gene-expression; acetate formation; growth-rate; flux; coordination; tradeoffs; mechanism; transport; reveals; culture
AB Overflow metabolism refers to the seemingly wasteful strategy in which cells use fermentation instead of the more efficient respiration to generate energy, despite the availability of oxygen. Known as the Warburg effect in the context of cancer growth, this phenomenon occurs ubiquitously for fast-growing cells, including bacteria, fungi and mammalian cells, but its origin has remained unclear despite decades of research. Here we study metabolic overflow in Escherichia coli, and show that it is a global physiological response used to cope with changing proteomic demands of energy biogenesis and biomass synthesis under different growth conditions. A simple model of proteomic resource allocation can quantitatively account for all of the observed behaviours, and accurately predict responses to new perturbations. The key hypothesis of the model, that the proteome cost of energy biogenesis by respiration exceeds that by fermentation, is quantitatively confirmed by direct measurement of protein abundances via quantitative mass spectrometry.
C1 [Basan, Markus; Hui, Sheng; Okano, Hiroyuki; Hwa, Terence] Univ Calif San Diego, Dept Phys, La Jolla, CA 92093 USA.
   [Basan, Markus] ETH, Inst Mol Syst Biol, CH-8093 Zurich, Switzerland.
   [Okano, Hiroyuki; Zhang, Zhongge; Shen, Yang; Hwa, Terence] Univ Calif San Diego, Mol Biol Sect, Div Biol Sci, La Jolla, CA 92093 USA.
   [Williamson, James R.] Scripps Res Inst, Dept Chem, Skaggs Inst Chem Biol, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA.
   [Hwa, Terence] ETH, Inst Theoret Studies, CH-8092 Zurich, Switzerland.
C3 University of California System; University of California San Diego; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of California System; University of California San Diego; Scripps Research Institute; Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Hwa, T (corresponding author), Univ Calif San Diego, Dept Phys, La Jolla, CA 92093 USA.
EM hwa@ucsd.edu
FU NIH [R01-GM109069]; Simons Foundation [330378]; M. Rossler, the Walter Haefner Foundation; ETH Foundation; SystemsX TPdF; Hong Kong Baptist University [FRG2/11-12/159, SKLP-14-15-P012]; National Institute of General Medical Sciences [R01GM109069, R01GM095903] Funding Source: NIH RePORTER
NR 63
TC 530
Z9 624
U1 9
U2 267
PU NATURE PUBLISHING 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 3
PY 2015
VL 528
IS 7580
BP 99
EP +
DI 10.1038/nature15765
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000055
PM 26632588
DA 2026-03-09
ER

PT J
AU Miller, JM
   Kaastra, JS
   Miller, MC
   Reynolds, MT
   Brown, G
   Cenko, SB
   Drake, JJ
   Gezari, S
   Guillochon, J
   Gultekin, K
   Irwin, J
   Levan, A
   Maitra, D
   Maksym, WP
   Mushotzky, R
   O'Brien, P
   Paerels, F
   de Plaa, J
   Ramirez-Ruiz, E
   Strohmayer, T
   Tanvir, N
AF Miller, Jon M.
   Kaastra, Jelle S.
   Miller, M. Coleman
   Reynolds, Mark T.
   Brown, Gregory
   Cenko, S. Bradley
   Drake, Jeremy J.
   Gezari, Suvi
   Guillochon, James
   Gultekin, Kayhan
   Irwin, Jimmy
   Levan, Andrew
   Maitra, Dipankar
   Maksym, W. Peter
   Mushotzky, Richard
   O'Brien, Paul
   Paerels, Frits
   de Plaa, Jelle
   Ramirez-Ruiz, Enrico
   Strohmayer, Tod
   Tanvir, Nial
TI Flows of X-ray gas reveal the disruption of a star by a massive black hole
SO NATURE
LA English
DT Article
ID tidal disruption; events; galaxy; calibration; telescope; outburst; mission; winds
AB Tidal forces close to massive black holes can violently disrupt stars that make a close approach. These extreme events are discovered via bright X-ray(1-4) and optical/ultraviolet(5,6) flares in galactic centres. Prior studies based on modelling decaying flux trends have been able to estimate broad properties, such as the mass accretion rate(6,7). Here we report the detection of flows of hot, ionized gas in high-resolution X-ray spectra of a nearby tidal disruption event, ASASSN-14li in the galaxy PGC043234. Variability within the absorption-dominated spectra indicates that the gas is relatively close to the black hole. Narrow linewidths indicate that the gas does not stretch over a large range of radii, giving a low volume filling factor. Modest outflow speeds of a few hundred kilometres per second are observed; these are below the escape speed from the radius set by variability. The gas flow is consistent with a rotating wind from the inner, super-Eddington region of a nascent accretion disk, or with a filament of disrupted stellar gas near to the apocentre of an elliptical orbit. Flows of this sort are predicted by fundamental analytical theory(8) and more recent numerical simulations(7,9-14).
C1 [Miller, Jon M.; Reynolds, Mark T.; Gultekin, Kayhan] Univ Michigan, Dept Astron, Ann Arbor, MI 48103 USA.
   [Kaastra, Jelle S.; de Plaa, Jelle] SRON Netherlands Inst Space Res, NL-3584 CA Utrecht, Netherlands.
   [Kaastra, Jelle S.] Univ Utrecht, Dept Phys & Astron, NL-3508 TA Utrecht, Netherlands.
   [Kaastra, Jelle S.] Leiden Univ, Leiden Observ, NL-2300 RA Leiden, Netherlands.
   [Miller, M. Coleman; Gezari, Suvi; Mushotzky, Richard] Univ Maryland, Dept Astron, College Pk, MD 20742 USA.
   [Brown, Gregory; Levan, Andrew] Univ Warwick, Dept Phys, Coventry CV4 7AL, W Midlands, England.
   [Cenko, S. Bradley; Strohmayer, Tod] Univ Maryland, Joint Space Sci Inst, College Pk, MD 20742 USA.
   [Cenko, S. Bradley] NASA, Goddard Space Flight Ctr, Astrophys Sci Div, Greenbelt, MD 20771 USA.
   [Drake, Jeremy J.] Smithsonian Astrophys Observ, Cambridge, MA 02138 USA.
   [Guillochon, James] Harvard Smithsonian Ctr Astrophys, Inst Theory & Computat, Cambridge, MA 02138 USA.
   [Irwin, Jimmy; Maksym, W. Peter] Univ Alabama, Dept Phys & Astron, Tuscaloosa, AL 35487 USA.
   [Maitra, Dipankar] Wheaton Coll, Dept Phys & Astron, Norton, MA 02766 USA.
   [O'Brien, Paul; Tanvir, Nial] Univ Leicester, Dept Phys & Astron, Leicester LE1 7RH, Leics, England.
   [Paerels, Frits] Columbia Univ, Columbia Astrophys Lab, New York, NY 10027 USA.
   [Paerels, Frits] Columbia Univ, Dept Astron, New York, NY 10027 USA.
   [Ramirez-Ruiz, Enrico] Univ Calif Santa Cruz, Dept Astron & Astrophys, Santa Cruz, CA 95064 USA.
C3 University of Michigan System; University of Michigan; Utrecht University; Leiden University; Leiden University - Excl LUMC; University System of Maryland; University of Maryland College Park; University of Warwick; University System of Maryland; University of Maryland College Park; National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center; Harvard University; Smithsonian Astrophysical Observatory; Smithsonian Institution; Harvard University; Smithsonian Astrophysical Observatory; Smithsonian Institution; University of Alabama System; University of Alabama Tuscaloosa; University of Leicester; Columbia University; Columbia University; University of California System; University of California Santa Cruz
RP Miller, JM (corresponding author), Univ Michigan, Dept Astron, 1085 South Univ Ave, Ann Arbor, MI 48103 USA.
EM jonmm@umich.edu
FU NASA [NAS8-03060]; Netherlands Organization for Scientific Research (NWO); University of Alabama Research Stimulation Program; STFC [ST/H001972/1, ST/L000733/1, ST/K001000/1] Funding Source: UKRI; Science and Technology Facilities Council [ST/L000733/1, ST/K001000/1, ST/H001972/1] Funding Source: researchfish
NR 37
TC 186
Z9 200
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 22
PY 2015
VL 526
IS 7574
BP 542
EP U173
DI 10.1038/nature15708
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV1NX
UT WOS:000364026100043
PM 26490619
DA 2026-03-09
ER

PT J
AU Domcke, S
   Bardet, AF
   Ginno, PA
   Hartl, D
   Burger, L
   Schübeler, D
AF Domcke, Silvia
   Bardet, Anais Flore
   Ginno, Paul Adrian
   Hartl, Dominik
   Burger, Lukas
   Schuebeler, Dirk
TI Competition between DNA methylation and transcription factors determines binding of NRF1
SO NATURE
LA English
DT Article
ID ground-state; elements; gene; sequence; absence; identification; encyclopedia; expression; promoter; database
AB Eukaryotic transcription factors (TFs) are key determinants of gene activity, yet they bind only a fraction of their corresponding DNA sequence motifs in any given cell type(1). Chromatin has the potential to restrict accessibility of binding sites; however, in which context chromatin states are instructive for TF binding remains mainly unknown(1,2). To explore the contribution of DNA methylation to constrained TF binding, we mapped DNase-I-hypersensitive sites in murine stem cells in the presence and absence of DNA methylation. Methylation-restricted sites are enriched for TF motifs containing CpGs, especially for those of NRF1. In fact, the TF NRF1 occupies several thousand additional sites in the unmethylated genome, resulting in increased transcription. Restoring de novo methyltransferase activity initiates remethylation at these sites and outcompetes NRF1 binding. This suggests that binding of DNA-methylation-sensitive TFs relies on additional determinants to induce local hypomethylation. In support of this model, removal of neighbouring motifs in cis or of a TF in trans causes local hypermethylation and subsequent loss of NRF1 binding. This competition between DNA methylation and TFs in vivo reveals a case of cooperativity between TFs that acts indirectly via DNA methylation. Methylation removal by methylation-insensitive factors enables occupancy of methylation-sensitive factors, a principle that rationalizes hypomethylation of regulatory regions.
C1 [Domcke, Silvia; Bardet, Anais Flore; Ginno, Paul Adrian; Hartl, Dominik; Burger, Lukas; Schuebeler, Dirk] Friedrich Miescher Inst Biomed Res, CH-4058 Basel, Switzerland.
   [Domcke, Silvia; Hartl, Dominik; Schuebeler, Dirk] Univ Basel, Fac Sci, CH-4003 Basel, Switzerland.
   [Burger, Lukas] Swiss Inst Bioinformat, CH-4058 Basel, Switzerland.
C3 Friedrich Miescher Institute for Biomedical Research; University of Basel; Swiss Institute of Bioinformatics
RP Schübeler, D (corresponding author), Friedrich Miescher Inst Biomed Res, Maulbeerstr 66, CH-4058 Basel, Switzerland.
EM dirk@fmi.ch
FU Novartis Research Foundation; European Union (NoE 'EpiGeneSys') [FP7-HEALTH-2010-257082]; European Union ('Blueprint' consortium) [FP7-282510]; European Research Council (EpiGePlas); Swiss initiative in Systems Biology (RTD Cell Plasticity); EMBO postdoctoral long-term fellowships; Boehringer Ingelheim Fonds
NR 54
TC 374
Z9 442
U1 3
U2 109
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 24
PY 2015
VL 528
IS 7583
BP 575
EP +
DI 10.1038/nature16462
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900057
PM 26675734
DA 2026-03-09
ER

PT J
AU Betley, JN
   Xu, SJ
   Cao, ZFH
   Gong, R
   Magnus, CJ
   Yu, Y
   Sternson, SM
AF Betley, J. Nicholas
   Xu, Shengjin
   Cao, Zhen Fang Huang
   Gong, Rong
   Magnus, Christopher J.
   Yu, Yang
   Sternson, Scott M.
TI Neurons for hunger and thirst transmit a negative-valence teaching signal
SO NATURE
LA English
DT Article
ID lateral hypothalamus; circuit; food; agrp; activation; depression; nucleus; switch; water
AB Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics of two separate neuron populations that regulate energy and fluid homeostasis by using cell-type-specific activity manipulations in mice. We found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal. Mice avoided activation of AGRP neurons, indicating that AGRP neuron activity has negative valence. AGRP neuron inhibition conditioned preference for flavours and places. Correspondingly, deep-brain calcium imaging revealed that AGRP neuron activity rapidly reduced in response to food-related cues. Complementary experiments activating thirst-promoting neurons also conditioned avoidance. Therefore, these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-valence signals during restoration of homeostasis.
C1 [Betley, J. Nicholas; Xu, Shengjin; Cao, Zhen Fang Huang; Gong, Rong; Magnus, Christopher J.; Yu, Yang; Sternson, Scott M.] Janelia Res Campus, Howard Hughes Med Inst, Ashburn, VA 20147 USA.
C3 Howard Hughes Medical Institute
RP Sternson, SM (corresponding author), Janelia Res Campus, Howard Hughes Med Inst, 19700 Helix Dr, Ashburn, VA 20147 USA.
EM sternsons@janelia.hhmi.org
FU Howard Hughes Medical Institute; HHMI Janelia Farm Graduate Scholar program
NR 47
TC 511
Z9 606
U1 2
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 MAY 14
PY 2015
VL 521
IS 7551
BP 180
EP +
DI 10.1038/nature14416
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH9SY
UT WOS:000354377800050
PM 25915020
DA 2026-03-09
ER

PT J
AU Marlin, BJ
   Mitre, M
   D'amour, JA
   Chao, MV
   Froemke, RC
AF Marlin, Bianca J.
   Mitre, Mariela
   D'amour, James A.
   Chao, Moses V.
   Froemke, Robert C.
TI Oxytocin enables maternal behaviour by balancing cortical inhibition
SO NATURE
LA English
DT Article
ID mouse auditory-cortex; ultrasonic communication; central amygdala; social-behavior; mice; vasopressin; recognition; parturition; neurons; hypothalamus
AB Oxytocin is important for social interactions and maternal behaviour. However, little is known about when, where and how oxytocin modulates neural circuits to improve social cognition. Here we show how oxytocin enables pup retrieval behaviour in female mice by enhancing auditory cortical pup call responses. Retrieval behaviour required the left but not right auditory cortex, was accelerated by oxytocin in the left auditory cortex, and oxytocin receptors were preferentially expressed in the left auditory cortex. Neural responses to pup calls were lateralized, with co-tuned and temporally precise excitatory and inhibitory responses in the left cortex of maternal but not pup-naive adults. Finally, pairing calls with oxytocin enhanced responses by balancing the magnitude and timing of inhibition with excitation. Our results describe fundamental synaptic mechanisms by which oxytocin increases the salience of acoustic social stimuli. Furthermore, oxytocin-induced plasticity provides a biological basis for lateralization of auditory cortical processing.
C1 [Marlin, Bianca J.; Mitre, Mariela; D'amour, James A.; Chao, Moses V.; Froemke, Robert C.] NYU, Sch Med, Skirball Inst Biomol Med, New York, NY 10016 USA.
   [Marlin, Bianca J.; Mitre, Mariela; D'amour, James A.; Chao, Moses V.; Froemke, Robert C.] NYU, Sch Med, Neurosci Inst, New York, NY 10016 USA.
   [Marlin, Bianca J.; Mitre, Mariela; D'amour, James A.; Froemke, Robert C.] NYU, Sch Med, Dept Otolaryngol, New York, NY 10016 USA.
   [Marlin, Bianca J.; Mitre, Mariela; D'amour, James A.; Chao, Moses V.; Froemke, Robert C.] NYU, Sch Med, Dept Neurosci & Physiol, New York, NY 10016 USA.
   [Mitre, Mariela; Chao, Moses V.] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA.
   [Mitre, Mariela; Chao, Moses V.] NYU, Sch Med, Dept Psychiat, New York, NY 10016 USA.
   [Chao, Moses V.; Froemke, Robert C.] NYU, Ctr Neural Sci, New York, NY 10003 USA.
C3 New York University; New York University; New York University; New York University; New York University; New York University; New York University
RP Froemke, RC (corresponding author), NYU, Sch Med, Skirball Inst Biomol Med, New York, NY 10016 USA.
EM robert.froemke@med.nyu.edu
FU NIDCD [DC009635, DC12557]; Klingenstein Fellowship; McKnight Scholarship; Pew Scholarship; Sloan Research Fellowship; Whitehead Foundation; Skirball Institute Collaborative Research Award; NIMH [T32]; National Cancer Institute [P30CA016087] Funding Source: NIH RePORTER; National Institute of Mental Health [T32MH019524] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [T32NS086750] Funding Source: NIH RePORTER; National Institute on Deafness and Other Communication Disorders [R01DC012557] Funding Source: NIH RePORTER
NR 56
TC 546
Z9 677
U1 5
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 APR 23
PY 2015
VL 520
IS 7548
BP 499
EP +
DI 10.1038/nature14402
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500034
PM 25874674
DA 2026-03-09
ER

PT J
AU Wang, B
   Zhao, LD
   Fish, M
   Logan, CY
   Nusse, R
AF Wang, Bruce
   Zhao, Ludan
   Fish, Matt
   Logan, Catriona Y.
   Nusse, Roel
TI Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver
SO NATURE
LA English
DT Article
ID stem-cells; mature hepatocytes; gene-expression; wnt proteins; mouse; proliferation; expansion; activation; zonation; fate
AB The source of new hepatocytes in the uninjured liver has remained an open question. By lineage tracing using the Wnt-responsive gene Axin2 in mice, we identify a population of proliferating and self-renewing cells adjacent to the central vein in the liver lobule. These pericentral cells express the early liver progenitor marker Tbx3, are diploid, and thereby differ from mature hepatocytes, which are mostly polyploid. The descendants of pericentral cells differentiate into Tbx3-negative, polyploid hepatocytes, and can replace all hepatocytes along the liver lobule during homeostatic renewal. Adjacent central vein endothelial cells provide Wnt signals that maintain the pericentral cells, thereby constituting the niche. Thus, we identify a cell population in the liver that subserves homeostatic hepatocyte renewal, characterize its anatomical niche, and identify molecular signals that regulate its activity.
C1 [Wang, Bruce; Zhao, Ludan; Fish, Matt; Logan, Catriona Y.; Nusse, Roel] Stanford Univ, Howard Hughes Med Inst, Stanford Inst Stem Cell Biol & Regenerat Med, Dept Dev Biol,Sch Med, Stanford, CA 94305 USA.
   [Wang, Bruce] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.
   [Wang, Bruce] Univ Calif San Francisco, Ctr Liver, San Francisco, CA 94143 USA.
C3 Howard Hughes Medical Institute; Stanford University; University of California System; University of California San Francisco; University of California System; University of California San Francisco
RP Nusse, R (corresponding author), Stanford Univ, Howard Hughes Med Inst, Stanford Inst Stem Cell Biol & Regenerat Med, Dept Dev Biol,Sch Med, Stanford, CA 94305 USA.
EM bruce.wang@ucsf.edu; rnusse@stanford.edu
FU Howard Hughes Medical Institute; Reed-Stinehart foundation;  [F32DK091005]; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK026743] Funding Source: NIH RePORTER
NR 48
TC 552
Z9 655
U1 2
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 AUG 13
PY 2015
VL 524
IS 7564
BP 180
EP +
DI 10.1038/nature14863
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900023
PM 26245375
DA 2026-03-09
ER

PT J
AU Joshi, PK
   Esko, T
   Mattsson, H
   Eklund, N
   Gandin, I
   Nutile, T
   Jackson, AU
   Schurmann, C
   Smith, AV
   Zhang, WH
   Okada, Y
   Stancáková, A
   Faul, JD
   Zhao, W
   Bartz, TM
   Concas, MP
   Franceschini, N
   Enroth, S
   Vitart, V
   Trompet, S
   Guo, XQ
   Chasman, DI
   O'Connel, JR
   Corre, T
   Nongmaithem, SS
   Chen, Y
   Mangino, M
   Ruggiero, D
   Michela, T
   Farmaki, AE
   Kacprowski, T
   Bjonnes, A
   van der Spek, A
   Wu, Y
   Giri, AK
   Yanek, LR
   Wang, LH
   Hofer, E
   Rietveld, CA
   McLeod, O
   Cornelis, MC
   Pattaro, C
   Verweij, N
   Baumbach, C
   Abdellaoui, A
   Warren, HR
   Vuckovic, D
   Mei, H
   Bouchard, C
   Perry, JRB
   Cappellani, S
   Mirza, SS
   Benton, MC
   Broeckel, U
   Medland, SE
   Lind, P
   Malerba, G
   Drong, A
   Yengo, L
   Bielak, LF
   Zhi, DG
   van der Most, PJ
   Shriner, D
   Mägi, R
   Hemani, G
   Karaderi, T
   Wang, ZM
   Liu, T
   Demuth, I
   Zhao, JH
   Meng, WH
   Lataniotis, L
   van der Laan, SW
   Bradfield, JP
   Wood, AR
   Bonnefond, A
   Ahluwalia, TS
   Hall, L
   Salvi, E
   Yazar, S
   Carstensen, L
   de Haan, HG
   Abney, M
   Afzal, U
   Allison, MA
   Amin, N
   Asselbergs, FW
   Bakker, SJL
   Barr, RG
   Baumeister, SE
   Benjamin, DJ
   Bergmann, S
   Boerwinkle, E
   Bottinger, EP
   Campbell, A
   Chakravarti, A
   Chan, YL
   Chanock, SJ
   Chen, C
   Chen, YDI
   Collins, FS
   Connell, J
   Correa, A
   Cupples, LA
   Smith, GD
   Davies, G
   Dörr, M
   Ehret, G
   Ellis, SB
   Feenstra, B
   Feitosa, MF
   Ford, I
   Fox, CS
   Frayling, TM
   Friedrich, N
   Geller, F
   Scotland, G
   Gillham-Nasenya, I
   Gottesman, O
   Graff, M
   Grodstein, F
   Gu, C
   Haley, C
   Hammond, CJ
   Harris, SE
   Harris, TB
   Hastie, ND
   Heard-Costa, NL
   Heikkilä, K
   Hocking, LJ
   Homuth, G
   Hottenga, JJ
   Huang, JY
   Huffman, JE
   Hysi, PG
   Ikram, MA
   Ingelsson, E
   Joensuu, A
   Johansson, A
   Jousilahti, P
   Jukema, JW
   Kähönen, M
   Kamatani, Y
   Kanoni, S
   Kerr, SM
   Khan, NM
   Koellinger, P
   Koistinen, HA
   Kooner, MK
   Kubo, M
   Kuusisto, J
   Lahti, J
   Launer, LJ
   Lea, RA
   Lehne, B
   Lehtimäki, T
   Liewald, DCM
   Lind, L
   Loh, M
   Lokki, ML
   London, SJ
   Loomis, SJ
   Loukola, A
   Lu, YC
   Lumley, T
   Lundqvist, A
   Männistö, S
   Marques-Vidal, P
   Masciullo, C
   Matchan, A
   Mathias, RA
   Matsuda, K
   Meigs, JB
   Meisinger, C
   Meitinger, T
   Menni, C
   Mentch, FD
   Mihailov, E
   Milani, L
   Montasser, ME
   Montgomery, G
   Morrison, A
   Myers, RH
   Nadukuru, R
   Navarro, P
   Nelis, M
   Nieminen, MS
   Nolte, IM
   O'Connor, GT
   Ogunniyi, A
   Padmanabhan, S
   Palmas, WR
   Pankow, JS
   Patarcic, I
   Pavani, F
   Peyser, PA
   Pietilainen, K
   Poulter, N
   Prokopenko, I
   Ralhan, S
   Redmond, P
   Rich, SS
   Rissanen, H
   Robino, A
   Rose, LM
   Rose, R
   Sala, C
   Salako, B
   Salomaa, V
   Sarin, AP
   Saxena, R
   Schmidt, H
   Scott, LJ
   Scott, WR
   Sennblad, B
   Seshadri, S
   Sever, P
   Shrestha, S
   Smith, BH
   Smith, JA
   Soranzo, N
   Sotoodehnia, N
   Southam, L
   Stanton, AV
   Stathopoulou, MG
   Strauch, K
   Strawbridge, RJ
   Suderman, MJ
   Tandon, N
   Tang, ST
   Taylor, KD
   Tayo, BO
   Töglhofer, AM
   Tomaszewski, M
   Tsernikova, N
   Tuomilehto, J
   Uitterlinden, AG
   Vaidya, D
   Vlieg, AV
   van Setten, J
   Vasankari, T
   Vedantam, S
   Vlachopoulou, E
   Vozzi, D
   Vuoksimaa, E
   Waldenberger, M
   Ware, EB
   Wentworth-Shields, W
   Whitfield, JB
   Wild, S
   Willemsen, G
   Yajnik, CS
   Yao, J
   Zaza, G
   Zhu, XF
   Salem, RM
   Melbye, M
   Bisgaard, H
   Samani, NJ
   Cusi, D
   Mackey, DA
   Cooper, RS
   Froguel, P
   Pasterkamp, G
   Grant, SFA
   Hakonarson, H
   Ferrucci, L
   Scott, RA
   Morris, AD
   Palmer, CNA
   Dedoussis, G
   Deloukas, P
   Bertram, L
   Lindenberger, U
   Berndt, SI
   Lindgren, CM
   Timpson, NJ
   Tönjes, A
   Munroe, PB
   Sorensen, TIA
   Rotimi, CN
   Arnett, DK
   Oldehinkel, AJ
   Kardia, SLR
   Balkau, B
   Gambaro, G
   Morris, AP
   Eriksson, JG
   Wright, MJ
   Martin, NG
   Hunt, SC
   Starr, JM
   Deary, IJ
   Griffiths, LR
   Tiemeier, H
   Pirastu, N
   Kaprio, J
   Wareham, NJ
   Péerusse, L
   Wilson, JG
   Girotto, G
   Caulfield, MJ
   Raitakari, O
   Boomsma, DI
   Gieger, C
   van der Harst, P
   Hicks, AA
   Kraft, P
   Sinisalo, J
   Knekt, P
   Johannesson, M
   Magnusson, PKE
   Hamsten, A
   Schmidt, R
   Borecki, IB
   Vartiainen, E
   Becker, DM
   Bharadwaj, D
   Mohlke, KL
   Boehnke, M
   van Duijn, CM
   Sanghera, DK
   Teumer, A
   Zeggini, E
   Metspalu, A
   Gasparini, P
   Ulivi, S
   Ober, C
   Toniolo, D
   Rudan, I
   Porteous, DJ
   Ciullo, M
   Spector, TD
   Hayward, C
   Dupuis, J
   Loos, RJF
   Wright, AF
   Chandak, GR
   Vollenweider, P
   Shuldiner, AR
   Ridker, PM
   Rotter, JI
   Sattar, N
   Gyllensten, U
   North, KE
   Pirastu, M
   Psaty, BM
   Weir, DR
   Laakso, M
   Gudnason, V
   Takahashi, A
   Chambers, JC
   Kooner, JS
   Strachan, DP
   Campbell, H
   Hirschhorn, JN
   Perola, M
   Polasek, O
   Wilson, JF
AF Joshi, Peter K.
   Esko, Tonu
   Mattsson, Hannele
   Eklund, Niina
   Gandin, Ilaria
   Nutile, Teresa
   Jackson, Anne U.
   Schurmann, Claudia
   Smith, Albert V.
   Zhang, Weihua
   Okada, Yukinori
   Stancakova, Alena
   Faul, Jessica D.
   Zhao, Wei
   Bartz, Traci M.
   Concas, Maria Pina
   Franceschini, Nora
   Enroth, Stefan
   Vitart, Veronique
   Trompet, Stella
   Guo, Xiuqing
   Chasman, Daniel I.
   O'Connel, Jeffrey R.
   Corre, Tanguy
   Nongmaithem, Suraj S.
   Chen, Yuning
   Mangino, Massimo
   Ruggiero, Daniela
   Traglia, Michela
   Farmaki, Aliki-Eleni
   Kacprowski, Tim
   Bjonnes, Andrew
   van der Spek, Ashley
   Wu, Ying
   Giri, Anil K.
   Yanek, Lisa R.
   Wang, Lihua
   Hofer, Edith
   Rietveld, Cornelius A.
   McLeod, Olga
   Cornelis, Marilyn C.
   Pattaro, Cristian
   Verweij, Niek
   Baumbach, Clemens
   Abdellaoui, Abdel
   Warren, Helen R.
   Vuckovic, Dragana
   Mei, Hao
   Bouchard, Claude
   Perry, John R. B.
   Cappellani, Stefania
   Mirza, Saira S.
   Benton, Miles C.
   Broeckel, Ulrich
   Medland, Sarah E.
   Lind, PenelopeA.
   Malerba, Giovanni
   Drong, Alexander
   Yengo, Loic
   Bielak, Lawrence F.
   Zhi, Degui
   van der Most, Peter J.
   Shriner, Daniel
   Maegi, Reedik
   Hemani, Gibran
   Karaderi, Tugce
   Wang, Zhaoming
   Liu, Tian
   Demuth, Ilja
   Zhao, Jing Hua
   Meng, Weihua
   Lataniotis, Lazaros
   van der Laan, Sander W.
   Bradfield, Jonathan P.
   Wood, Andrew R.
   Bonnefond, Amelie
   Ahluwalia, Tarunveer S.
   Hall, LeanneM.
   Salvi, Erika
   Yazar, Seyhan
   Carstensen, Lisbeth
   de Haan, Hugoline G.
   Abney, Mark
   Afzal, Uzma
   Allison, Matthew A.
   Amin, Najaf
   Asselbergs, Folkert W.
   Bakker, Stephan J. L.
   Barr, R. Graham
   Baumeister, Sebastian E.
   Benjamin, Daniel J.
   Bergmann, Sven
   Boerwinkle, Eric
   Bottinger, Erwin P.
   Campbell, Archie
   Chakravarti, Aravinda
   Chan, Yingleong
   Chanock, Stephen J.
   Chen, Constance
   Chen, Y. -D. Ida
   Collins, Francis S.
   Connell, John
   Correa, Adolfo
   Cupples, L. Adrienne
   Smith, George Davey
   Davies, Gail
   Doerr, Marcus
   Ehret, Georg
   Ellis, Stephen B.
   Feenstra, Bjarke
   Feitosa, Mary F.
   Ford, Ian
   Fox, Caroline S.
   Frayling, Timothy M.
   Friedrich, Nele
   Geller, Frank
   Scotland, Generation
   Gillham-Nasenya, Irina
   Gottesman, Omri
   Graff, Misa
   Grodstein, Francine
   Gu, Charles
   Haley, Chris
   Hammond, Christopher J.
   Harris, Sarah E.
   Harris, Tamara B.
   Hastie, Nicholas D.
   Heard-Costa, Nancy L.
   Heikkila, Kauko
   Hocking, Lynne J.
   Homuth, Georg
   Hottenga, Jouke-Jan
   Huang, Jinyan
   Huffman, Jennifer E.
   Hysi, Pirro G.
   Ikram, M. Arfan
   Ingelsson, Erik
   Joensuu, Anni
   Johansson, Asa
   Jousilahti, Pekka
   Jukema, J. Wouter
   Kahonen, Mika
   Kamatani, Yoichiro
   Kanoni, Stavroula
   Kerr, Shona M.
   Khan, Nazir M.
   Koellinger, Philipp
   Koistinen, Heikki A.
   Kooner, Manraj K.
   Kubo, Michiaki
   Kuusisto, Johanna
   Lahti, Jari
   Launer, Lenore J.
   Lea, Rodney A.
   Lehne, Benjamin
   Lehtimaki, Terho
   Liewald, David C. M.
   Lind, Lars
   Loh, Marie
   Lokki, Marja-Liisa
   London, Stephanie J.
   Loomis, Stephanie J.
   Loukola, Anu
   Lu, Yingchang
   Lumley, Thomas
   Lundqvist, Annamari
   Mannisto, Satu
   Marques-Vidal, Pedro
   Masciullo, Corrado
   Matchan, Angela
   Mathias, Rasika A.
   Matsuda, Koichi
   Meigs, James B.
   Meisinger, Christa
   Meitinger, Thomas
   Menni, Cristina
   Mentch, Frank D.
   Mihailov, Evelin
   Milani, Lili
   Montasser, May E.
   Montgomery, GrantW.
   Morrison, Alanna
   Myers, Richard H.
   Nadukuru, Rajiv
   Navarro, Pau
   Nelis, Mari
   Nieminen, Markku S.
   Nolte, Ilja M.
   O'Connor, George T.
   Ogunniyi, Adesola
   Padmanabhan, Sandosh
   Palmas, Walter R.
   Pankow, James S.
   Patarcic, Inga
   Pavani, Francesca
   Peyser, Patricia A.
   Pietilainen, Kirsi
   Poulter, Neil
   Prokopenko, Inga
   Ralhan, Sarju
   Redmond, Paul
   Rich, Stephen S.
   Rissanen, Harri
   Robino, Antonietta
   Rose, Lynda M.
   Rose, Richard
   Sala, Cinzia
   Salako, Babatunde
   Salomaa, Veikko
   Sarin, Antti-Pekka
   Saxena, Richa
   Schmidt, Helena
   Scott, Laura J.
   Scott, William R.
   Sennblad, Bengt
   Seshadri, Sudha
   Sever, Peter
   Shrestha, Smeeta
   Smith, Blair H.
   Smith, Jennifer A.
   Soranzo, Nicole
   Sotoodehnia, Nona
   Southam, Lorraine
   Stanton, Alice V.
   Stathopoulou, Maria G.
   Strauch, Konstantin
   Strawbridge, Rona J.
   Suderman, Matthew J.
   Tandon, Nikhil
   Tang, Sian-Tsun
   Taylor, Kent D.
   Tayo, Bamidele O.
   Toeglhofer, Anna Maria
   Tomaszewski, Maciej
   Tsernikova, Natalia
   Tuomilehto, Jaakko
   Uitterlinden, Andre G.
   Vaidya, Dhananjay
   Vlieg, Astrid van Hylckama
   van Setten, Jessica
   Vasankari, Tuula
   Vedantam, Sailaja
   Vlachopoulou, Efthymia
   Vozzi, Diego
   Vuoksimaa, Eero
   Waldenberger, Melanie
   Ware, Erin B.
   Wentworth-Shields, William
   Whitfield, John B.
   Wild, Sarah
   Willemsen, Gonneke
   Yajnik, Chittaranjan S.
   Yao, Jie
   Zaza, Gianluigi
   Zhu, Xiaofeng
   Salem, Rany M.
   Melbye, Mads
   Bisgaard, Hans
   Samani, Nilesh J.
   Cusi, Daniele
   Mackey, David A.
   Cooper, Richard S.
   Froguel, Philippe
   Pasterkamp, Gerard
   Grant, Struan F. A.
   Hakonarson, Hakon
   Ferrucci, Luigi
   Scott, Robert A.
   Morris, Andrew D.
   Palmer, Colin N. A.
   Dedoussis, George
   Deloukas, Panos
   Bertram, Lars
   Lindenberger, Ulman
   Berndt, Sonja I.
   Lindgren, Cecilia M.
   Timpson, Nicholas J.
   Toenjes, Anke
   Munroe, Patricia B.
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   Takahashi, Atsushi
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   Wilson, James F.
TI Directional dominance on stature and cognition in diverse human populations
SO NATURE
LA English
DT Article
ID genetic-variants; blood-pressure; association; intelligence; homozygosity; architecture; traits
AB Homozygosity has long been associated with rare, often devastating, Mendelian disorders(1), and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness(2). However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power(3,4). Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 x 10(-300), 2.1 x 10(-6), 2.5 x 10(-10) and 1.8 x 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples(5,6), no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection(7), this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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   [Poulter, Neil; Sever, Peter] Univ London Imperial Coll Sci Technol & Med, Int Ctr Circulatory Hlth, London W2 1LA, England.
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   [Ralhan, Sarju] Hero DMC Heart Inst, Dept Cardiol & Cardio Thorac Surg, Civil Lines, Ludhiana 141001, Punjab, India.
   [Rich, Stephen S.] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA.
   [Rose, Richard] Indiana Univ Bloomington, Dept Psychol & Brain Sci, Bloomington, IN 47405 USA.
   [Schmidt, Helena; Toeglhofer, Anna Maria] Med Univ Graz, Inst Mol Biol & Biochem, A-8010 Graz, Austria.
   [Sennblad, Bengt] Karolinska Inst, Sci Life Lab, SE-17121 Stockholm, Sweden.
   [Smith, Blair H.] Univ Dundee, Dundee DD2 4DB, Scotland.
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   [Stanton, Alice V.] Royal Coll Surgeons Ireland, Mol & Cellular Therapeut, Dublin 2, Ireland.
   [Stathopoulou, Maria G.] UMR INSERM U1122, F-54000 Nancy, France.
   [Stathopoulou, Maria G.] Univ Lorraine, INSERM, IGE PCV Interact Geneenvironm Physiopathol Cardio, F-54000 Nancy, France.
   [Strauch, Konstantin] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany.
   [Tandon, Nikhil] All India Inst Med Sci, Dept Endocrinol, New Delhi 110029, India.
   ImpColl London, Natl Heart & Lung Inst, London W12 0NN, England.
   [Tang, Sian-Tsun; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London W12 0NN, England.
   [Tayo, Bamidele O.; Cooper, Richard S.] Loyola Univ Chicago, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 60153 USA.
   [Tomaszewski, Maciej; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England.
   [Tsernikova, Natalia; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia.
   [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, A-3500 Krems, Austria.
   [Tuomilehto, Jaakko] King Abdulaziz Univ, Res Grp, Jeddah 21589, Saudi Arabia.
   [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands.
   [Vaidya, Dhananjay] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA.
   [Vasankari, Tuula] Finnish Lung Hlth Assoc, FI-00250 Helsinki, Finland.
   [Whitfield, John B.; Martin, Nicholas G.] QIMR Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld 4006, Australia.
   [Yajnik, Chittaranjan S.] KEM Hosp & Res Ctr, Diabet Unit, Pune 411011, Maharashtra, India.
   [Zaza, Gianluigi] Univ Verona, Dept Med, Renal Unit, I-37124 Verona, Italy.
   [Zhu, Xiaofeng] CaseWestern Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA.
   [Melbye, Mads] Stanford Univ, Dept Med, Stanford, CA 94305 USA.
   [Grant, Struan F. A.; Hakonarson, Hakon] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA.
   [Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21225 USA.
   [Morris, Andrew D.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH16 4UX, Midlothian, Scotland.
   [Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Sch Med, Med Res Inst, Ctr Pharmacogenet & Pharmacogen, Dundee DD1 9SY, Scotland.
   [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia.
   [Bertram, Lars] Univ London Imperial Coll Sci Technol & Med, Fac Med, London W6 8RP, England.
   [Toenjes, Anke] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany.
   [Sorensen, Thorkild I. A.] Bispebjerg & Frederiksberg Hosp, Inst Prevent Med, DK-2000 Copenhagen, Denmark.
   [Arnett, Donna K.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA.
   [Oldehinkel, Albertine J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9700 RB Groningen, Netherlands.
   [Balkau, Beverley] INSERM, Epidemiol Diabet Obes & Chron Kidney Dis Lifecour, CESP Ctr Res Epidemiol & Populat Hlth, U1018, F-94807 Villejuif, France.
   [Gambaro, Giovanni] Univ Cattolica Sacro Cuore, Dipartimento Sci Med, I-00168 Rome, Italy.
   [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3GA, Merseyside, England.
   [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, FI-00014 Helsinki, Finland.
   [Eriksson, Johan G.] Vasa Cent Hosp, FI-65130 Vaasa, Finland.
   [Eriksson, Johan G.] Univ Helsinki, Folkhalsan Reasearch Ctr, FI-00014 Helsinki, Finland.
   [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, FI-00290 Helsinki, Finland.
   [Wright, Margie J.] QIMR Berghofer Med Res Inst, Neuroimaging Genet, Brisbane, Qld 4006, Australia.
   [Hunt, Steven C.] Univ Utah, Cardiovasc Genet Div, Salt Lake City, UT 84117 USA.
   [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland.
   [Tiemeier, Henning] Erasmus MC, Dept Psychiat, NL-3000 CA Rotterdam, Netherlands.
   [Kaprio, Jaakko] Natl Inst Hlth & Welf THL, FI-00271 Helsinki, Finland.
   [Perusse, Louis] Univ Laval, Dept Kinesiol, Quebec City, PQ 2300, Canada.
   [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA.
   [Raitakari, Olli] Univ Turku, Dept Clin Physiol & Nucl Med, FI-20521 Turku, Finland.
   [Raitakari, Olli] Turku Univ Hosp, FI-20521 Turku, Finland.
   [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FI-20521 Turku, Finland.
   [van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.
   [Johannesson, Magnus] Stockholm Sch Econ, Dept Econ, S-11383 Stockholm, Sweden.
   [Magnusson, Patrik K. E.] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden.
   [Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet & Biostat, St Louis, MO 63108 USA.
   [Becker, Diane M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21205 USA.
   [Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Dept Pediat, Oklahoma City, OK 73104 USA.
   [Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Dept Pharmaceut Sci, Oklahoma City, OK 73104 USA.
   [Gasparini, Paolo] Sidra Med & Res Ctr, Doha, Qatar.
   [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA.
   [Chandak, Giriraj R.] Genome Inst Singapore, Singapore 138672, Singapore.
   [Shuldiner, Alan R.] Univ Maryland, Sch Med, Dept Med, Program Personalised & Genom Med, Baltimore, MD 21201 USA.
   [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21201 USA.
   [Sattar, Naveed] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland.
   [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA.
   [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA.
   [Psaty, Bruce M.] Univ Washington, Dept Epidemiol & Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA.
   [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA.
   [Chambers, John C.; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Imperial Coll Healthcare NHS Trust, London W2 1NY, England.
   [Strachan, David P.] Univ London, Populat Hlth Res Inst, London SW17 0RE, England.
   [Ahluwalia, Tarunveer S.] Steno Diabet Ctr, DK-2820 Gentofte, Denmark.
   [Loh, Marie] ASTAR, Translat Lab Genet Med TLGM, Singapore 138648, Singapore.
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   [Bertram, Lars] Med Univ Lubeck, Inst Neurogenet, D-23562 Lubeck, Germany.
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RP Joshi, PK (corresponding author), Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland.
FU UK Medical Research Council (MRC); MRC Human Genetics Unit "QTL in Health and Disease" programme; Biotechnology and Biological Sciences Research Council [BB/F019394/1] Funding Source: researchfish; Chief Scientist Office [CZD/16/6/4, CZD/16/6/2, CZB/4/710, CZB/4/505, ETM/55] Funding Source: researchfish; Medical Research Council [MC_U106179472, MC_PC_13048, 1201677, MC_UU_12013/1, MC_UU_12013/3, MC_PC_15018, MC_PC_U127592696, MC_PC_13046, G0700931, G0700704, MR/K026992/1, G9521010, G0601966, G0701863, MC_U127561128, G1001799, MR/N01104X/1, MC_UU_12015/1, MR/K006584/1, G9815508, MC_UU_12015/2, MC_U106179471, MR/K002414/1, MC_PC_U127561128] Funding Source: researchfish; National Institute for Health Research [NF-SI-0512-10135, NF-SI-0513-10059, NIHR-RP-R3-12-013, SRF/01/010, NF-SI-0512-10113, NF-SI-0514-10027] Funding Source: researchfish; NNF Center for Basic Metabolic Research [Hansen Group] Funding Source: researchfish; Novo Nordisk Fonden [NNF10OC1013354] Funding Source: researchfish; Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD056465] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [R01HL077612] Funding Source: NIH RePORTER; National Human Genome Research Institute [ZIAHG200362] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [U01DK062370, P30DK020572, R01DK075787, R01DK093757, R01DK072193, P30DK063491] Funding Source: NIH RePORTER; National Institute of Environmental Health Sciences [ZIAES043012] Funding Source: NIH RePORTER; National Institute on Aging [R01NS017950, ZIAAG007270, P30AG017265, U01AG009740] Funding Source: NIH RePORTER; BBSRC [BB/F019394/1] Funding Source: UKRI; MRC [MC_PC_U127561128, G0700931, MC_U106179472, G0601966, MC_UU_12015/2, MC_UU_12013/3, MC_UU_12015/1, G0700704, G1001799, MR/N01104X/1, MC_UU_12013/1, G9521010, MR/K002414/1, MC_PC_13048, MC_PC_13046, MC_U127561128, MC_PC_U127592696, G0701863] Funding Source: UKRI; Grants-in-Aid for Scientific Research [25293168, 15H05911, 15H05670] Funding Source: KAKEN
NR 44
TC 131
Z9 146
U1 1
U2 174
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 23
PY 2015
VL 523
IS 7561
BP 459
EP U176
DI 10.1038/nature14618
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN4DD
UT WOS:000358378900036
PM 26131930
DA 2026-03-09
ER

PT J
AU Oldridge, DA
   Wood, AC
   Weichert-Leahey, N
   Crimmins, I
   Sussman, R
   Winter, C
   McDaniel, LD
   Diamond, M
   Hart, LS
   Zhu, SZ
   Durbin, AD
   Abraham, BJ
   Anders, L
   Tian, LF
   Zhang, SL
   Wei, JS
   Khan, J
   Bramlett, K
   Rahman, N
   Capasso, M
   Iolascon, A
   Gerhard, DS
   Auvil, JMG
   Young, RA
   Hakonarson, H
   Diskin, SJ
   Look, AT
   Maris, JM
AF Oldridge, Derek A.
   Wood, Andrew C.
   Weichert-Leahey, Nina
   Crimmins, Ian
   Sussman, Robyn
   Winter, Cynthia
   McDaniel, Lee D.
   Diamond, Maura
   Hart, Lori S.
   Zhu, Shizhen
   Durbin, Adam D.
   Abraham, Brian J.
   Anders, Lars
   Tian, Lifeng
   Zhang, Shile
   Wei, Jun S.
   Khan, Javed
   Bramlett, Kelli
   Rahman, Nazneen
   Capasso, Mario
   Iolascon, Achille
   Gerhard, Daniela S.
   Auvil, Jaime M. Guidry
   Young, Richard A.
   Hakonarson, Hakon
   Diskin, Sharon J.
   Look, A. Thomas
   Maris, John M.
TI Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism
SO NATURE
LA English
DT Article
ID cell identity; human genome; transcription; inhibition; locus; susceptibility; association; disease; cancer; mycn
AB Neuroblastoma is a paediatric malignancy that typically arises in early childhood, and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumours with excellent outcomes to widely metastatic disease in which long-term survival is approximately 40% despite intensive therapy. A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumour cells(1). Here we investigate the causal DNA variant at this locus and the mechanism by which it leads to neuroblastoma tumorigenesis. We first imputed all possible genotypes across the LMO1 locus and then mapped highly associated single nucleotide polymorphism (SNPs) to areas of chromatin accessibility, evolutionary conservation and transcription factor binding sites. We show that SNP rs2168101 G>T is the most highly associated variant (combined P = 7.47 x 10(-29), odds ratio 0.65, 95% confidence interval 0.60-0.70), and resides in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 within the first intron of LMO1. The ancestral G allele that is associated with tumour formation resides in a conserved GATA transcription factor binding motif. We show that the newly evolved protective TATA allele is associated with decreased total LMO1 expression (P = 0.028) in neuroblastoma primary tumours, and ablates GATA3 binding (P < 0.0001). We demonstrate allelic imbalance favouring the G-containing strand in tumours heterozygous for this SNP, as demonstrated both by RNA sequencing (P < 0.0001) and reporter assays (P = 0.002). These findings indicate that a recently evolved polymorphism within a super-enhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis, and this leads to an oncogenic dependency in tumour cells.
C1 [Oldridge, Derek A.; Crimmins, Ian; Sussman, Robyn; Winter, Cynthia; McDaniel, Lee D.; Diamond, Maura; Hart, Lori S.; Diskin, Sharon J.; Maris, John M.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA.
   [Oldridge, Derek A.; Crimmins, Ian; Sussman, Robyn; Winter, Cynthia; McDaniel, Lee D.; Diamond, Maura; Hart, Lori S.; Diskin, Sharon J.; Maris, John M.] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA.
   [Oldridge, Derek A.] Univ Penn, Perelman Sch Med, Med Scientist Training Program, Philadelphia, PA 19104 USA.
   [Wood, Andrew C.] Univ Auckland, Dept Mol Med & Pathol, Auckland 1, Auckland Region, New Zealand.
   [Weichert-Leahey, Nina; Durbin, Adam D.; Look, A. Thomas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.
   [Weichert-Leahey, Nina; Durbin, Adam D.; Look, A. Thomas] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA.
   [Zhu, Shizhen] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN 55905 USA.
   [Abraham, Brian J.; Anders, Lars; Young, Richard A.] Whitehead Inst Biomed Res, Boston, MA 02142 USA.
   [Abraham, Brian J.; Anders, Lars; Young, Richard A.] MIT, Boston, MA 02142 USA.
   [Tian, Lifeng; Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA.
   [Zhang, Shile; Wei, Jun S.; Khan, Javed] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA.
   [Bramlett, Kelli] Thermo Fisher Sci, Austin, TX 78744 USA.
   [Rahman, Nazneen] Inst Canc Res, Sutton SM2 5NG, Surrey, England.
   [Capasso, Mario; Iolascon, Achille] Univ Naples 2, I-80131 Naples, Italy.
   [Capasso, Mario; Iolascon, Achille] CEINGE Biotecnol Avanzate, I-80131 Naples, Italy.
   [Gerhard, Daniela S.; Auvil, Jaime M. Guidry] NCI, Off Canc Genom, Bethesda, MD 20892 USA.
   [Hakonarson, Hakon; Diskin, Sharon J.; Maris, John M.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA.
   [Diskin, Sharon J.; Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA.
C3 University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; University of Auckland; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Mayo Clinic; Massachusetts Institute of Technology (MIT); Whitehead Institute; Massachusetts Institute of Technology (MIT); University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Thermo Fisher Scientific; University of London; Institute of Cancer Research - UK; Universita della Campania Vanvitelli; CEINGE Biotecnologie Avanzate; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Center for Cancer Genomics (CCG); University of Pennsylvania; University of Pennsylvania
RP Maris, JM (corresponding author), Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA.
EM maris@chop.edu
FU NIH [R01-CA124709, R01-CA180692, R00-CA151869, RC1MD004418, 1K99CA178189, T32-HG000046, R01-CA109901]; Giulio D'Angio Endowed Chair; PressOn Foundation; Andrew's Army Foundation; Abramson Family Cancer Research Institute; Brooke Mulford Foundation; University of Pennsylvania Genome Frontiers Institute; Alex's Lemonade Stand Foundation Innovation Award; Alex's Lemonade Stand Foundation; CureSearch for Children's Cancer Foundation; German Cancer Aid 110801; St Baldrick's Foundation Fellow award; George L. Ohrstrom Jr foundation; Wellcome Trust [100210/Z/12/Z]; NHS; Fondazione Italiana per la Lotta al Neuroblastoma; Associazione Oncologia Pediatrica e Neuroblastoma; Associazione Italiana per la Ricerca sul Cancro; National Cancer Institute [ZIABC011002] Funding Source: NIH RePORTER; National Human Genome Research Institute [T32HG000046] Funding Source: NIH RePORTER; Rosetrees [M28-F1-CD2] Funding Source: researchfish; Wellcome Trust [100210/Z/12/Z] Funding Source: Wellcome Trust
NR 30
TC 251
Z9 284
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 DEC 17
PY 2015
VL 528
IS 7582
BP 418
EP +
DI 10.1038/nature15540
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CY8SM
UT WOS:000366678600057
PM 26560027
DA 2026-03-09
ER

PT J
AU Kimmey, JM
   Huynh, JP
   Weiss, LA
   Park, S
   Kambal, A
   Debnath, J
   Virgin, HW
   Stallings, CL
AF Kimmey, Jacqueline M.
   Huynh, Jeremy P.
   Weiss, Leslie A.
   Park, Sunmin
   Kambal, Amal
   Debnath, Jayanta
   Virgin, Herbert W.
   Stallings, Christina L.
TI Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection
SO NATURE
LA English
DT Article
ID mycobacterium-tuberculosis; interferon-gamma; alveolar macrophages; lung inflammation; autophagy; cells; mice; mouse; responses; atg16l1
AB Mycobacterium tuberculosis, a major global health threat, replicates in macrophages in part by inhibiting phagosome-lysosome fusion, until interferon-gamma (IFN gamma) activates the macrophage to traffic M. tuberculosis to the lysosome. How IFN gamma elicits this effect is unknown, but many studies suggest a role for macroautophagy (herein termed autophagy), a process by which cytoplasmic contents are targeted for lysosomal degradation(1). The involvement of autophagy has been defined based on studies in cultured cells where M. tuberculosis co-localizes with autophagy factors ATG5, ATG12, ATG16L1, p62, NDP52, BECN1 and LC3 (refs 2-6), stimulation of autophagy increases bacterial killing(6-8), and inhibition of autophagy increases bacterial survival(1,2,4,6,7). Notably, these studies reveal modest (similar to 1.5-3-fold change) effects on M. tuberculosis replication. By contrast, mice lacking ATG5 in monocyte-derived cells and neutrophils (polymorponuclear cells, PMNs) succumb to M. tuberculosis within 30 days(4,9), an extremely severe phenotype similar to mice lacking IFN gamma signalling(10,11). Importantly, ATG5 is the only autophagy factor that has been studied during M. tuberculosis infection in vivo and autophagy-independent functions of ATG5 have been described(12-18). For this reason, we used a genetic approach to elucidate the role for multiple autophagy-related genes and the requirement for autophagy in resistance to M. tuberculosis infection in vivo. Here we show that, contrary to expectation, autophagic capacity does not correlate with the outcome of M. tuberculosis infection. Instead, ATG5 plays a unique role in protection against M. tuberculosis by preventing PMN-mediated immunopathology. Furthermore, while Atg5 is dispensable in alveolar macrophages during M. tuberculosis infection, loss of Atg5 in PMNs can sensitize mice to M. tuberculosis. These findings shift our understanding of the role of ATG5 during M. tuberculosis infection, reveal new outcomes of ATG5 activity, and shed light on early events in innate immunity that are required to regulate disease pathology and bacterial replication.
C1 [Kimmey, Jacqueline M.; Huynh, Jeremy P.; Weiss, Leslie A.; Stallings, Christina L.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA.
   [Park, Sunmin; Kambal, Amal; Virgin, Herbert W.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA.
   [Debnath, Jayanta] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA.
   [Debnath, Jayanta] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA.
C3 Washington University (WUSTL); Washington University (WUSTL); 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 Stallings, CL (corresponding author), Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA.
EM stallings@wusm.wustl.edu
FU Beckman Young Investigator Award from the Arnold and Mabel Beckman Foundation; National Science Foundation Graduate Research Fellowship [DGE-1143954]; NIGMS Cell and Molecular Biology Training Grant [GM007067];  [U19 AI109725]
NR 36
TC 305
Z9 356
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 DEC 24
PY 2015
VL 528
IS 7583
BP 565
EP +
DI 10.1038/nature16451
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900055
PM 26649827
DA 2026-03-09
ER

PT J
AU Breneman, AW
   Halford, A
   Millan, R
   McCarthy, M
   Fennell, J
   Sample, J
   Woodger, L
   Hospodarsky, G
   Wygant, JR
   Cattell, CA
   Goldstein, J
   Malaspina, D
   Kletzing, CA
AF Breneman, A. W.
   Halford, A.
   Millan, R.
   McCarthy, M.
   Fennell, J.
   Sample, J.
   Woodger, L.
   Hospodarsky, G.
   Wygant, J. R.
   Cattell, C. A.
   Goldstein, J.
   Malaspina, D.
   Kletzing, C. A.
TI Global-scale coherence modulation of radiation-belt electron loss from plasmaspheric hiss
SO NATURE
LA English
DT Article
AB Over 40 years ago it was suggested that electron loss in the region of the radiation belts that overlaps with the region of high plasma density called the plasmasphere, within four to five Earth radii(1,2), arises largely from interaction with an electromagnetic plasma wave called plasmaspheric hiss(3-5) . This interaction strongly influences the evolution of the radiation belts during a geomagnetic storm, and over the course of many hours to days helps to return the radiation-belt structure to its 'quiet' pre-storm configuration. Observations have shown that the long-term electron-loss rate is consistent with this theory but the temporal and spatial dynamics of the loss process remain to be directly verified. Here we report simultaneous measurements of structured radiation-belt electron losses and the hiss phenomenon that causes the losses. Losses were observed in the form of bremsstrahlung X-rays generated by hiss-scattered electrons colliding with the Earth's atmosphere after removal from the radiation belts. Our results show that changes of up to an order of magnitude in the dynamics of electron loss arising from hiss occur on timescales as short as one to twenty minutes, in association with modulations in plasma density and magnetic field. Furthermore, these loss dynamics are coherent with hiss dynamics on spatial scales comparable to the size of the plasmasphere. This nearly global-scale coherence was not predicted and may affect the short-term evolution of the radiation belts during active times.
C1 [Breneman, A. W.; Wygant, J. R.; Cattell, C. A.] Univ Minnesota, Sch Phys & Astron, Minneapolis, MN 55455 USA.
   [Halford, A.; Millan, R.; Woodger, L.] Dartmouth Coll, Dept Phys & Astron, Hanover, NH 03755 USA.
   [McCarthy, M.] Univ Washington, Earth & Space Sci, Seattle, WA 98195 USA.
   [Fennell, J.] Aerosp Corp, Los Angeles, CA 90009 USA.
   [Sample, J.] Univ Calif Berkeley, Space Sci Lab, Berkeley, CA 94720 USA.
   [Hospodarsky, G.; Kletzing, C. A.] Univ Iowa, Dept Phys & Astron, Iowa City, IA 52242 USA.
   [Goldstein, J.] SW Res Inst, San Antonio, TX 78238 USA.
   [Malaspina, D.] Univ Colorado, Lab Atmospher & Space Phys LASP, Boulder, CO 80303 USA.
C3 University of Minnesota System; University of Minnesota Twin Cities; Dartmouth College; University of Washington; University of Washington Seattle; Aerospace Corporation - USA; University of California System; University of California Berkeley; University of Iowa; Southwest Research Institute; University of Colorado System; University of Colorado Boulder
RP Breneman, AW (corresponding author), Univ Minnesota, Sch Phys & Astron, Minneapolis, MN 55455 USA.
EM awbrenem@gmail.com
NR 25
TC 96
Z9 102
U1 0
U2 20
PU NATURE PUBLISHING 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 9
PY 2015
VL 523
IS 7559
BP 193
EP U321
DI 10.1038/nature14515
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM4ZO
UT WOS:000357695900030
PM 26123022
DA 2026-03-09
ER

PT J
AU Ju, L
   Shi, ZW
   Nair, N
   Lv, YC
   Jin, CH
   Velasco, J
   Ojeda-Aristizabal, C
   Bechtel, HA
   Martin, MC
   Zettl, A
   Analytis, J
   Wang, F
AF Ju, Long
   Shi, Zhiwen
   Nair, Nityan
   Lv, Yinchuan
   Jin, Chenhao
   Velasco, Jairo, Jr.
   Ojeda-Aristizabal, Claudia
   Bechtel, Hans A.
   Martin, Michael C.
   Zettl, Alex
   Analytis, James
   Wang, Feng
TI Topological valley transport at bilayer graphene domain walls
SO NATURE
LA English
DT Article
ID electronic-structure; spectroscopy; plasmons; states; phase
AB Electron valley, a degree of freedom that is analogous to spin, can lead to novel topological phases in bilayer graphene. A tunable bandgap can be induced in bilayer graphene by an external electric field', and such gapped bilayer graphene is predicted to be a topological insulating phase protected by no-valley mixing symmetry, featuring quantum valley Hall effects and chiral edge states'. Observation of such chiral edge states, however, is challenging because inter-valley scattering is induced by atomic-scale defects at real bilayer graphene edges". Recent theoretical work"' has shown that domain walls between AB- and BA-stacked bilayer graphene can support protected chiral edge states of quantum valley Hall insulators. Here we report an experimental observation of ballistic (that is, with no scattering of electrons) conducting channels at bilayer graphene domain walls. We employ near-field infrared nanometre-scale microscopy (nanoscopy)'" to image in situ bilayer graphene layer-stacking domain walls on device substrates, and we fabricate dual-gated field effect transistors based on the domain walls. Unlike single-domain bilayer graphene, which shows gapped insulating behaviour under a vertical electrical field, bilayer graphene domain walls feature one-dimensional valley-polarized conducting channels with a ballistic length of about 400 nanometres at 4 kelvin. Such topologically protected one-dimensional chiral states at bilayer graphene domain walls open up opportunities for exploring unique topological phases and valley physics in graphene.
C1 [Ju, Long; Shi, Zhiwen; Nair, Nityan; Lv, Yinchuan; Jin, Chenhao; Velasco, Jairo, Jr.; Ojeda-Aristizabal, Claudia; Zettl, Alex; Analytis, James; Wang, Feng] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Bechtel, Hans A.; Martin, Michael C.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Adv Light Source Div, Berkeley, CA 94720 USA.
   [Zettl, Alex; Analytis, James; Wang, Feng] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Mat Sci Div, Berkeley, CA 94720 USA.
   [Zettl, Alex; Analytis, James; Wang, Feng] Univ Calif Berkeley, Kavli Energy NanoSci Inst, Berkeley, CA 94720 USA.
   [Zettl, Alex; Analytis, James; Wang, Feng] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA.
C3 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; 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 California System; University of California Berkeley; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory
RP Wang, F (corresponding author), Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
EM fengwang76@berkeley.edu
FU Office of Basic Energy Science, Department of Energy [DE-SC0003949, DE-AC02-05CH11231]; Office of Naval Research [N00014-13-1-0464]; David and Lucile Packard fellowship; Office of Science, Office of Basic Energy Sciences, of the US Department of Energy [DE-AC02-05CH11231]; U.S. Department of Energy (DOE) [DE-SC0003949] Funding Source: U.S. Department of Energy (DOE)
NR 32
TC 601
Z9 686
U1 20
U2 624
PU NATURE PUBLISHING 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 30
PY 2015
VL 520
IS 7549
BP 650
EP U356
DI 10.1038/nature14364
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700044
PM 25901686
DA 2026-03-09
ER

PT J
AU Rodrigues, NTL
   Lekomtsev, S
   Jananji, S
   Kriston-Vizi, J
   Hickson, GRX
   Baum, B
AF Rodrigues, Nelio T. L.
   Lekomtsev, Sergey
   Jananji, Silvana
   Kriston-Vizi, Janos
   Hickson, Gilles R. X.
   Baum, Buzz
TI Kinetochore-localized PP1-Sds22 couples chromosome segregation to polar relaxation
SO NATURE
LA English
DT Article
ID cell-shape changes; aurora b; cytokinesis; spindle; drosophila; polarization; anaphase; contractility; membrane; position
AB Cell division requires the precise coordination of chromosome segregation and cytokinesis. This coordination is achieved by the recruitment of an actomyosin regulator, Ect2, to overlapping microtubules at the centre of the elongating anaphase spindle(1). Ect2 then signals to the overlying cortex to promote the assembly and constriction of an actomyosin ring between segregating chromosomes(1). Here, by studying division in proliferating Drosophila and human cells, we demonstrate the existence of a second, parallel signalling pathway, which triggers the relaxation of the polar cell cortex at mid anaphase. This is independent of furrow formation, centrosomes and microtubules and, instead, depends on PP1 phosphatase and its regulatory subunit Sds22 (refs 2, 3). As separating chromosomes move towards the polar cortex at mid anaphase, kinetochore-localized PP1-Sds22 helps to break cortical symmetry by inducing the dephosphorylation and inactivation of ezrin/radixin/moesin proteins at cell poles. This promotes local softening of the cortex(2,3), facilitating anaphase elongation and orderly cell division. In summary, this identifies a conserved kinetochore-based phosphatase signal and substrate, which function together to link anaphase chromosome movements to cortical polarization, thereby coupling chromosome segregation to cell division.
C1 [Rodrigues, Nelio T. L.; Lekomtsev, Sergey; Kriston-Vizi, Janos; Baum, Buzz] UCL, MRC Lab Mol Cell Biol, London WC1E 6BT, England.
   [Jananji, Silvana; Hickson, Gilles R. X.] St Justine Hosp Res Ctr, Montreal, PQ H3T 1C5, Canada.
   [Hickson, Gilles R. X.] Univ Montreal, Dept Pathol & Cell Biol, Montreal, PQ H3T 1J4, Canada.
   [Baum, Buzz] UCL, Inst Phys Living Syst, London WC1E 6BT, England.
   [Baum, Buzz] Inst Curie, CelTisPhyBio Labex, F-75248 Paris 05, France.
C3 MRC Laboratory Molecular Biology; University of London; University College London; Universite de Montreal; Centre Hospitalier Universitaire Sainte-Justine; Universite de Montreal; University of London; University College London; UNICANCER; Universite PSL; Institut Curie
RP Baum, B (corresponding author), UCL, MRC Lab Mol Cell Biol, Gower St, London WC1E 6BT, England.
EM b.baum@ucl.ac.uk
FU Cancer Research UK; Medical Research Council; Canadian Institutes of Health Research; Canada Foundation for Innovation; Fonds de Recherche du Quebec-Sante; Cole Foundation; INCa; BBSRC [BB/K009001/1]; Biotechnology and Biological Sciences Research Council [BB/K009001/1] Funding Source: researchfish; Cancer Research UK [9786, 17343] Funding Source: researchfish; Medical Research Council [MC_CF12266] Funding Source: researchfish; BBSRC [BB/K009001/1] Funding Source: UKRI
NR 35
TC 86
Z9 105
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 AUG 27
PY 2015
VL 524
IS 7566
BP 489
EP +
DI 10.1038/nature14496
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP7LN
UT WOS:000360069300043
PM 26168397
DA 2026-03-09
ER

PT J
AU Koren, S
   Reavie, L
   Couto, JP
   De Silva, D
   Stadler, MB
   Roloff, T
   Britschgi, A
   Eichlisberger, T
   Kohler, H
   Aina, O
   Cardiff, RD
   Bentires-Alj, M
AF Koren, Shany
   Reavie, Linsey
   Couto, Joana Pinto
   De Silva, Duvini
   Stadler, Michael B.
   Roloff, Tim
   Britschgi, Adrian
   Eichlisberger, Tobias
   Kohler, Hubertus
   Aina, Olulanu
   Cardiff, Robert D.
   Bentires-Alj, Mohamed
TI PIK3CAH1047R induces multipotency and multi-lineage mammary tumours
SO NATURE
LA English
DT Article
ID stem-cells; gland; mouse; basal; expression; progenitors; population; mutations
AB The adult mouse mammary epithelium contains self-sustained cell lineages that form the inner luminal and outer basal cell layers, with stem and progenitor cells contributing to its proliferative and regenerative potential(1-4). A key issue in breast cancer biology is the effect of genomic lesions in specific mammary cell lineages on tumour heterogeneity and progression. The impact of transforming events on fate conversion in cancer cells of origin and thus their contribution to tumour heterogeneity remains largely elusive. Using in situ genetic lineage tracing and limiting dilution transplantation, we have unravelled the potential of PIK3CA(H1047R), one of the most frequent mutations occurring in human breast cancer(5), to induce multipotency during tumorigenesis in the mammary gland. Here we show that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5-positive and luminal keratin-8-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multi-lineage mammary tumours. Moreover, we show that the tumour cell of origin influences the frequency of malignant mammary tumours. Our results define a key effect of PIK3CA(H1047R) on mammary cell fate in the pre-neoplastic mammary gland and show that the cell of origin of PIK3CA(H1047R) tumours dictates their malignancy, thus revealing a mechanism underlying tumour heterogeneity and aggressiveness.
C1 [Koren, Shany; Reavie, Linsey; Couto, Joana Pinto; De Silva, Duvini; Stadler, Michael B.; Roloff, Tim; Britschgi, Adrian; Eichlisberger, Tobias; Kohler, Hubertus; Bentires-Alj, Mohamed] Friedrich Miescher Inst Biomed Res FMI, CH-4058 Basel, Switzerland.
   [Stadler, Michael B.] Swiss Inst Bioinformat, CH-4058 Basel, Switzerland.
   [Aina, Olulanu; Cardiff, Robert D.] Univ Calif Davis, Dept Pathol, Ctr Comparat Med, Davis, CA 95616 USA.
C3 Friedrich Miescher Institute for Biomedical Research; Swiss Institute of Bioinformatics; University of California System; University of California Davis
RP Bentires-Alj, M (corresponding author), Friedrich Miescher Inst Biomed Res FMI, CH-4058 Basel, Switzerland.
EM Bentires@fmi.ch
FU National Cancer Institute [U01 CA141582]; Novartis Research Foundation; European Research Council (ERC) [243211-PTPsBDC]; Swiss Cancer League; Swiss National Foundation; Krebsliga Beider Basel
NR 32
TC 249
Z9 294
U1 0
U2 35
PU NATURE PUBLISHING 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 3
PY 2015
VL 525
IS 7567
BP 114
EP +
DI 10.1038/nature14669
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100036
PM 26266975
DA 2026-03-09
ER

PT J
AU Sigl, M
   Winstrup, M
   McConnell, JR
   Welten, KC
   Plunkett, G
   Ludlow, F
   Büntgen, U
   Caffee, M
   Chellman, N
   Dahl-Jensen, D
   Fischer, H
   Kipfstuhl, S
   Kostick, C
   Maselli, OJ
   Mekhaldi, F
   Mulvaney, R
   Muscheler, R
   Pasteris, DR
   Pilcher, JR
   Salzer, M
   Schüpbach, S
   Steffensen, JP
   Vinther, BM
   Woodruff, TE
AF Sigl, M.
   Winstrup, M.
   McConnell, J. R.
   Welten, K. C.
   Plunkett, G.
   Ludlow, F.
   Buentgen, U.
   Caffee, M.
   Chellman, N.
   Dahl-Jensen, D.
   Fischer, H.
   Kipfstuhl, S.
   Kostick, C.
   Maselli, O. J.
   Mekhaldi, F.
   Mulvaney, R.
   Muscheler, R.
   Pasteris, D. R.
   Pilcher, J. R.
   Salzer, M.
   Schuepbach, S.
   Steffensen, J. P.
   Vinther, B. M.
   Woodruff, T. E.
TI Timing and climate forcing of volcanic eruptions for the past 2,500 years
SO NATURE
LA English
DT Article
ID continuous-flow analysis; tree-ring width; ice cores; millennium eruption; bristlecone-pine; common era; ad 774-775; greenland; temperature; variability
AB Volcanic eruptions contribute to climate variability, but quantifying these contributions has been limited by inconsistencies in the timing of atmospheric volcanic aerosol loading determined from ice cores and subsequent cooling from climate proxies such as tree rings. Here we resolve these inconsistencies and show that large eruptions in the tropics and high latitudes were primary drivers of interannual-to-decadal temperature variability in the Northern Hemisphere during the past 2,500 years. Our results are based on new records of atmospheric aerosol loading developed from high-resolution, multi-parameter measurements from an array of Greenland and Antarctic ice cores as well as distinctive age markers to constrain chronologies. Overall, cooling was proportional to the magnitude of volcanic forcing and persisted for up to ten years after some of the largest eruptive episodes. Our revised timescale more firmly implicates volcanic eruptions as catalysts in the major sixth-century pandemics, famines, and socioeconomic disruptions in Eurasia and Mesoamerica while allowing multi-millennium quantification of climate response to volcanic forcing.
C1 [Sigl, M.; McConnell, J. R.; Chellman, N.; Maselli, O. J.; Pasteris, D. R.] Nevada Syst Higher Educ, Desert Res Inst, Reno, NV 89512 USA.
   [Winstrup, M.] Univ Washington, Dept Earth & Space Sci, Seattle, WA 98195 USA.
   [Welten, K. C.] Univ Calif Berkeley, Space Sci Lab, Berkeley, CA 94720 USA.
   [Plunkett, G.; Pilcher, J. R.] Queens Univ Belfast, Sch Geog Archaeol & Palaeoecol, Belfast BT7 1NN, Antrim, North Ireland.
   [Ludlow, F.] Yale Univ, Yale Climate & Energy Inst, New Haven, CT 06511 USA.
   [Ludlow, F.] Yale Univ, Dept Hist, New Haven, CT 06511 USA.
   [Buentgen, U.] Swiss Fed Res Inst WSL, CH-8903 Birmensdorf, Switzerland.
   [Buentgen, U.; Fischer, H.] Univ Bern, Oeschger Ctr Climate Change Res, CH-3012 Bern, Switzerland.
   [Buentgen, U.] Global Change Res Ctr AS CR, Brno 60300, Czech Republic.
   [Caffee, M.; Woodruff, T. E.] Purdue Univ, Dept Phys, W Lafayette, IN 47907 USA.
   [Caffee, M.] Purdue Univ, Dept Earth Atmospher & Planetary Sci, W Lafayette, IN 47907 USA.
   [Dahl-Jensen, D.; Steffensen, J. P.; Vinther, B. M.] Univ Copenhagen, Niels Bohr Inst, Ctr Ice & Climate, DK-2100 Copenhagen, Denmark.
   [Fischer, H.; Schuepbach, S.] Univ Bern, Climate & Environm Phys, CH-3012 Bern, Switzerland.
   [Kipfstuhl, S.] Helmholtz Zentrum Polar & Meeresforsch, Alfred Wegener Inst, D-27570 Bremerhaven, Germany.
   [Kostick, C.] Univ Nottingham, Dept Hist, Nottingham NG7 2RD, England.
   [Mekhaldi, F.; Muscheler, R.] Lund Univ, Quaternary Sci, Dept Geol, S-22362 Lund, Sweden.
   [Mulvaney, R.] British Antarctic Survey, NERC, Cambridge CB3 0ET, England.
   [Salzer, M.] Univ Arizona, Tree Ring Res Lab, Tucson, AZ 85721 USA.
C3 Nevada System of Higher Education (NSHE); Desert Research Institute NSHE; University of Washington; University of Washington Seattle; University of California System; University of California Berkeley; Queens University Belfast; Yale University; Yale University; Swiss Federal Institutes of Technology Domain; Swiss Federal Institute for Forest, Snow & Landscape Research; University of Bern; Czech Academy of Sciences; Global Change Research Centre of the Czech Academy of Sciences; Purdue University System; Purdue University; Purdue University System; Purdue University; University of Copenhagen; Niels Bohr Institute; University of Bern; Helmholtz Association; Alfred Wegener Institute, Helmholtz Centre for Polar & Marine Research; University of Nottingham; Lund University; UK Research & Innovation (UKRI); Natural Environment Research Council (NERC); NERC British Antarctic Survey; University of Arizona
RP McConnell, JR (corresponding author), Nevada Syst Higher Educ, Desert Res Inst, Reno, NV 89512 USA.
EM joe.mcconnell@dri.edu
FU US National Science Foundation (NSF); FNRS-CFB in Belgium; FWO in Belgium; NRCan/GSC in Canada; CAS in China; FIST in Denmark; IPEV in France; CNRS/INSU in France; CEA in France; ANR in France; AWI in Germany; RannIs in Iceland; NIPR in Japan; KOPRI in Korea; NWO/ALW in The Netherlands; VR in Sweden; SNF in Switzerland; NERC in UK; US NSF, Office of Polar Programs in USA; NSF/OPP [0839093, 0968391, 1142166, 0909541, 1023672, 1204176, 0636964, 0839137, 0839042, 0636815]; Villum Foundation; Yale Climate and Energy Institute; Initiative for the Science of the Human Past at Harvard; Rachel Carson Center for Environment and Society of the Ludwig-Maximilians-Universitat (LMU Munich); Marie Curie FP7 Integration Grant within the 7th European Union Framework Programme; NSF [ATM1203749]; Swedish Research Council [DNR2013-8421]; SNF; Oeschger Centre; NERC [bas0100034] Funding Source: UKRI; Directorate For Geosciences [0636964] Funding Source: National Science Foundation; Directorate For Geosciences; Div Atmospheric & Geospace Sciences [1203749] Funding Source: National Science Foundation; Directorate For Geosciences; Div Atmospheric & Geospace Sciences [1203301] Funding Source: National Science Foundation; Directorate For Geosciences; Division Of Earth Sciences [1153689] Funding Source: National Science Foundation; Directorate For Geosciences; Office of Polar Programs (OPP) [0636815, 1023672, 0839137, 1204176] Funding Source: National Science Foundation; Office of Polar Programs (OPP) [0636964] Funding Source: National Science Foundation; Office of Polar Programs (OPP); Directorate For Geosciences [1142166, 0944348, 0839042] Funding Source: National Science Foundation; Office Of The Director; Office Of Internatl Science &Engineering [0968391] Funding Source: National Science Foundation; Natural Environment Research Council [bas0100034] Funding Source: researchfish
NR 93
TC 881
Z9 989
U1 14
U2 486
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 30
PY 2015
VL 523
IS 7562
BP 543
EP +
DI 10.1038/nature14565
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN7ZL
UT WOS:000358655200035
PM 26153860
DA 2026-03-09
ER

PT J
AU Braunschweig, H
   Dewhurst, RD
   Hupp, F
   Nutz, M
   Radacki, K
   Tate, CW
   Vargas, A
   Ye, Q
AF Braunschweig, Holger
   Dewhurst, Rian D.
   Hupp, Florian
   Nutz, Marco
   Radacki, Krzysztof
   Tate, Christopher W.
   Vargas, Alfredo
   Ye, Qing
TI Multiple complexation of CO and related ligands to a main-group element
SO NATURE
LA English
DT Article
ID boron triple bond; dative bonds; solid-state; activation; reactivity; compound; carbenes; carbonyl; arrows; adduct
AB The ability of an atom or molecular fragment to bind multiple carbon monoxide (CO) molecules to form multicarbonyl adducts is a fundamental trait of transition metals. Transition-metal carbonyl complexes are vital to industry, appear naturally in the active sites of a number of enzymes (such as hydrogenases), are promising therapeutic agents(1), and have even been observed in interstellar dust clouds(2). Despite the wealth of established transition-metal multicarbonyl complexes(3), no elements outside groups 4 to 12 of the periodic table have yet been shown to react directly with two or more CO units to form stable multicarbonyl adducts. Here we present the synthesis of a borylene dicarbonyl complex, the first multicarbonyl complex of a main-group element prepared using CO. The compound is additionally stable towards ambient air and moisture. The synthetic strategy used-liberation of a borylene ligand from a transition metal using donor ligands-is broadly applicable, leading to a number of unprecedented monovalent boron species with different Lewis basic groups. The similarity of these compounds to conventional transition-metal carbonyl complexes is demonstrated by photolytic liberation of CO and subsequent intramolecular carbon-carbon bond activation.
C1 [Braunschweig, Holger; Dewhurst, Rian D.; Hupp, Florian; Nutz, Marco; Radacki, Krzysztof; Tate, Christopher W.; Ye, Qing] Univ Wurzburg, Inst Anorgan Chem, D-97074 Wurzburg, Germany.
   [Vargas, Alfredo] Univ Sussex, Sch Life Sci, Dept Chem, Brighton BN1 9QJ, E Sussex, England.
C3 University of Wurzburg; University of Sussex
RP Braunschweig, H (corresponding author), Univ Wurzburg, Inst Anorgan Chem, D-97074 Wurzburg, Germany.
EM h.braunschweig@uni-wuerzburg.de
FU European Research Council
NR 30
TC 268
Z9 304
U1 4
U2 196
PU NATURE PUBLISHING 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 18
PY 2015
VL 522
IS 7556
BP 327
EP 330
DI 10.1038/nature14489
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK7PU
UT WOS:000356425400050
PM 26085273
DA 2026-03-09
ER

PT J
AU McDonald, TM
   Mason, JA
   Kong, XQ
   Bloch, ED
   Gygi, D
   Dani, A
   Crocellà, V
   Giordanino, F
   Odoh, SO
   Drisdell, WS
   Vlaisavljevich, B
   Dzubak, AL
   Poloni, R
   Schnell, SK
   Planas, N
   Lee, K
   Pascal, T
   Wan, LWF
   Prendergast, D
   Neaton, JB
   Smit, B
   Kortright, JB
   Gagliardi, L
   Bordiga, S
   Reimer, JA
   Long, JR
AF McDonald, Thomas M.
   Mason, Jarad A.
   Kong, Xueqian
   Bloch, Eric D.
   Gygi, David
   Dani, Alessandro
   Crocella, Valentina
   Giordanino, Filippo
   Odoh, Samuel O.
   Drisdell, Walter S.
   Vlaisavljevich, Bess
   Dzubak, Allison L.
   Poloni, Roberta
   Schnell, Sondre K.
   Planas, Nora
   Lee, Kyuho
   Pascal, Tod
   Wan, Liwen F.
   Prendergast, David
   Neaton, Jeffrey B.
   Smit, Berend
   Kortright, Jeffrey B.
   Gagliardi, Laura
   Bordiga, Silvia
   Reimer, Jeffrey A.
   Long, Jeffrey R.
TI Cooperative insertion of CO2 in diamine-appended metal-organic frameworks
SO NATURE
LA English
DT Article
ID carbon-dioxide capture; total-energy calculations; coordination polymer; crystal-structure; adsorption; pseudopotentials; transitions; isotherms; solvents; binding
AB The process of carbon capture and sequestration has been proposed as a method of mitigating the build-up of greenhouse gases in the atmosphere. If implemented, the cost of electricity generated by a fossil fuel-burning power plant would rise substantially, owing to the expense of removing CO2 from the effluent stream. There is therefore an urgent need for more efficient gas separation technologies, such as those potentially offered by advanced solid adsorbents. Here we show that diamine-appended metal-organic frameworks can behave as 'phase-change' adsorbents, with unusual step-shaped CO2 adsorption isotherms that shift markedly with temperature. Results from spectroscopic, diffraction and computational studies show that the origin of the sharp adsorption step is an unprecedented cooperative process in which, above a metal-dependent threshold pressure, CO2 molecules insert into metal-amine bonds, inducing a reorganization of the amines into well-ordered chains of ammonium carbamate. As a consequence, large CO2 separation capacities can be achieved with small temperature swings, and regeneration energies appreciably lower than achievable withstate-of-the-art aqueous amine solutions become feasible. The results provide a mechanistic framework for designing highly efficient adsorbents for removing CO2 from various gas mixtures, and yield insights into the conservation of Mg2+ within the ribulose-1,5-bisphosphate carboxylase/oxygenase family of enzymes.
C1 [McDonald, Thomas M.; Mason, Jarad A.; Bloch, Eric D.; Gygi, David; Long, Jeffrey R.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
   [Kong, Xueqian; Vlaisavljevich, Bess; Schnell, Sondre K.; Lee, Kyuho; Smit, Berend; Reimer, Jeffrey A.] Univ Calif Berkeley, Dept Chem & Biol Engn, Berkeley, CA 94720 USA.
   [Kong, Xueqian] Zhejiang Univ, Dept Chem, Hangzhou 310027, Zhejiang, Peoples R China.
   [Dani, Alessandro; Crocella, Valentina; Giordanino, Filippo; Bordiga, Silvia] Univ Turin, NIS & INSTM Ctr Reference, Dept Chem, I-10135 Turin, Italy.
   [Odoh, Samuel O.; Dzubak, Allison L.; Planas, Nora; Gagliardi, Laura] Univ Minnesota, Dept Chem, Chem Theory Ctr, Minneapolis, MN 55455 USA.
   [Odoh, Samuel O.; Dzubak, Allison L.; Planas, Nora; Gagliardi, Laura] Univ Minnesota, Supercomp Inst, Minneapolis, MN 55455 USA.
   [Drisdell, Walter S.; Smit, Berend; Kortright, Jeffrey B.; Reimer, Jeffrey A.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Mat Sci Div, Berkeley, CA 94720 USA.
   [Poloni, Roberta] Univ Grenoble Alpes, F-38000 Grenoble, France.
   [Poloni, Roberta] Sci & Ingn Mat & Proc SIMAP, F-38000 Grenoble, France.
   [Poloni, Roberta] CNRS, SIMAP, F-38000 Grenoble, France.
   [Schnell, Sondre K.] Norwegian Univ Sci & Technol, Dept Chem, N-7491 Trondheim, Norway.
   [Pascal, Tod; Wan, Liwen F.; Prendergast, David; Neaton, Jeffrey B.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Mol Foundry, Berkeley, CA 94720 USA.
   [Neaton, Jeffrey B.] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Neaton, Jeffrey B.] Univ Calif Berkeley, Kavli Energy Nanosci Inst, Berkeley, CA 94720 USA.
   [Smit, Berend] EPFL, Inst Sci & Ingn Chim, Valais, CH-1950 Sion, Switzerland.
C3 University of California System; University of California Berkeley; University of California System; University of California Berkeley; Zhejiang University; University of Turin; University of Minnesota System; University of Minnesota Twin Cities; University of Minnesota System; University of Minnesota Twin Cities; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; University of California System; University of California Berkeley; Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Communaute Universite Grenoble Alpes; Institut National Polytechnique de Grenoble; Universite Grenoble Alpes (UGA); Centre National de la Recherche Scientifique (CNRS); Norwegian University of Science & Technology (NTNU); 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
RP Long, JR (corresponding author), Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
EM jrlong@berkeley.edu
FU Advanced Research Projects Agency-Energy (ARPA-E), US Department of Energy (DOE) [DE-AR0000103, DE-AR0000402]; DOE, Office of Science, Office of Basic Energy Sciences [DE-SC0001015]; GENCI (CINES) [2014-c2015097211]; Nanoporous Materials Genome Center of the DOE, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences, and Biosciences [DE-FG02-12ER16362]; DOE Office of Science [DE-AC02-06CH11357]; Office of Science, Office of Basic Energy Sciences of the DOE [DE-AC02-05CH11231]; National Science Foundation; Research Council of Norway [230534];  [MIUR-PRIN 2010-2011]
NR 62
TC 1135
Z9 1298
U1 29
U2 1391
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 19
PY 2015
VL 519
IS 7543
BP 303
EP +
DI 10.1038/nature14327
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD6AY
UT WOS:000351171900031
PM 25762144
DA 2026-03-09
ER

PT J
AU Wauer, T
   Simicek, M
   Schubert, A
   Komander, D
AF Wauer, Tobias
   Simicek, Michal
   Schubert, Alexander
   Komander, David
TI Mechanism of phospho-ubiquitin-induced PARKIN activation
SO NATURE
LA English
DT Article
ID mitochondrial translocation; phosphorylation; disease; pink1; reveals; domain; ring; chain; e3; mitophagy
AB The E3 ubiquitin ligase PARKIN (encoded by PARK2) and the protein kinase PINK1 (encoded by PARK6) are mutated in autosomal-recessive juvenile Parkinsonism (AR-JP) and work together in the disposal of damaged mitochondria by mitophagy(1-3). PINK1 is stabilized on the outside of depolarized mitochondria and phosphorylates polyubiquitin(4-8) as well as the PARKIN ubiquitin-like (Ubl) domain(9,10). These phosphorylation events lead to PARKIN recruitment to mitochondria, and activation by an unknown allosteric mechanism(4-12). Here we present the crystal structure of Pediculus humanus PARKIN in complex with Ser65-phosphorylated ubiquitin (phosphoUb), revealing the molecular basis for PARKIN recruitment and activation. The phosphoUb binding site on PARKIN comprises a conserved phosphate pocket and harbours residues mutated in patients with AR-JP. PhosphoUb binding leads to straightening of a helix in the RING1 domain, and the resulting conformational changes release the Ubl domain from the PARKIN core; this activates PARKIN. Moreover, phosphoUb-mediated Ubl release enhances Ubl phosphorylation by PINK1, leading to conformational changes within the Ubl domain and stabilization of an open, active conformation of PARKIN. We redefine the role of the Ubl domain not only as an inhibitory(13) but also as an activating element that is restrained in inactive PARKIN and released by phosphoUb. Our work opens up new avenues to identify small-molecule PARKIN activators.
C1 [Wauer, Tobias; Simicek, Michal; Schubert, Alexander; Komander, David] MRC, Mol Biol Lab, Cambridge CB2 0QH, England.
C3 MRC Laboratory Molecular Biology
RP Komander, D (corresponding author), MRC, Mol Biol Lab, Francis Crick Ave, Cambridge CB2 0QH, England.
EM dk@mrc-lmb.cam.ac.uk
FU Medical Research Council [U105192732]; European Research Council [309756]; Lister Institute for Preventive Medicine; EMBO; MRC [MC_U105192732] Funding Source: UKRI; Medical Research Council [MC_U105192732, 1571029] Funding Source: researchfish; European Research Council (ERC) [309756] Funding Source: European Research Council (ERC)
NR 37
TC 394
Z9 454
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 AUG 20
PY 2015
VL 524
IS 7565
BP 370
EP +
DI 10.1038/nature14879
PG 27
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP2NN
UT WOS:000359714000040
PM 26161729
DA 2026-03-09
ER

PT J
AU Helled, R
   Galanti, E
   Kaspi, Y
AF Helled, Ravit
   Galanti, Eli
   Kaspi, Yohai
TI Saturn's fast spin determined from its gravitational field and oblateness
SO NATURE
LA English
DT Article
ID rotation period; giant planets; interior; radio; satellites; atmosphere; jupiter; models; system
AB The alignment of Saturn's magnetic pole with its rotation axis precludes the use of magnetic field measurements to determine its rotation period(1). The period was previously determined from radio measurements by the Voyager spacecraft to be 10 h 39 min 22.4s (ref. 2). When the Cassini spacecraft measured a period of 10 h 47 min 6s, which was additionally found to change between sequential measurements(3,4,5), it became clear that the radio period could not be used to determine the bulk planetary rotation period. Estimates based upon Saturn's measured wind fields have increased the uncertainty even more, giving numbers smaller than the Voyager rotation period, and at present Saturn's rotation period is thought to be between 10 h 32 mm and 10 h 47 min, which is unsatisfactory for such a fundamental property. Here we report a period of 10 h 32 mm 45 s 46 s, based upon an optimization approach using Saturn's measured gravitational field and limits on the observed shape and possible internal density profiles. Moreover, even when solely using the constraints from its gravitational field, the rotation period can be inferred with a precision of several minutes. To validate our method, we applied the same procedure to Jupiter and correctly recovered its well-known rotation period.
C1 [Helled, Ravit] Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Dept Geosci, IL-69978 Tel Aviv, Israel.
   [Galanti, Eli; Kaspi, Yohai] Weizmann Inst Sci, Dept Earth & Planetary Sci, IL-76100 Rehovot, Israel.
C3 Tel Aviv University; Weizmann Institute of Science
RP Helled, R (corresponding author), Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Dept Geosci, IL-69978 Tel Aviv, Israel.
EM rhelled@post.tau.ac.il
FU Israel Space Agency [3-11485, 3-11481]
NR 31
TC 54
Z9 57
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 APR 9
PY 2015
VL 520
IS 7546
BP 202
EP U140
DI 10.1038/nature14278
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CF3NA
UT WOS:000352454600034
PM 25807487
DA 2026-03-09
ER

PT J
AU Hallinan, G
   Littlefair, SP
   Cotter, G
   Bourke, S
   Harding, LK
   Pineda, JS
   Butler, RP
   Golden, A
   Basri, G
   Doyle, JG
   Kao, MM
   Berdyugina, SV
   Kuznetsov, A
   Rupen, MP
   Antonova, A
AF Hallinan, G.
   Littlefair, S. P.
   Cotter, G.
   Bourke, S.
   Harding, L. K.
   Pineda, J. S.
   Butler, R. P.
   Golden, A.
   Basri, G.
   Doyle, J. G.
   Kao, M. M.
   Berdyugina, S. V.
   Kuznetsov, A.
   Rupen, M. P.
   Antonova, A.
TI Magnetospherically driven optical and radio aurorae at the end of the stellar main sequence
SO NATURE
LA English
DT Article
ID simultaneous multiwavelength observations; brown dwarf; ultracool dwarfs; magnetic activity; m8.5 dwarf; variability; emissions; rotation; temperature; transition
AB Aurorae are detected from all the magnetized planets in our Solar System, including Earth(1). They are powered by magnetospheric current systems that lead to the precipitation of energetic electrons into the high-latitude regions of the upper atmosphere. In the case of the gas-giant planets, these aurorae include highly polarized radio emission at kilohertz and megahertz frequencies produced by the precipitating electrons(2), as well as continuum and line emission in the infrared, optical, ultraviolet and X-ray parts of the spectrum, associated with the collisional excitation and heating of the hydrogen-dominated atmosphere(3). Here we report simultaneous radio and optical spectroscopic observations of an object at the end of the stellar main sequence, located right at the boundary between stars and brown dwarfs, from which we have detected radio and optical auroral emissions both powered by magnetospheric currents. Whereas the magnetic activity of stars like our Sun is powered by processes that occur in their lower atmospheres, these aurorae are powered by processes originating much further out in the magnetosphere of the dwarf star that couple energy into the lower atmosphere. The dissipated power is at least four orders of magnitude larger than what is produced in the Jovian magnetosphere, revealing aurorae to be a potentially ubiquitous signature of large-scale magnetospheres that can scale to luminosities far greater than those observed in our Solar System. These magnetospheric current systems may also play a part in powering some of the weather phenomena reported on brown dwarfs.
C1 [Hallinan, G.; Bourke, S.; Pineda, J. S.; Kao, M. M.] CALTECH, Pasadena, CA 91125 USA.
   [Littlefair, S. P.] Univ Sheffield, Dept Phys & Astron, Sheffield S3 7RH, S Yorkshire, England.
   [Cotter, G.] Univ Oxford, Dept Astrophys, Oxford OX1 3RH, England.
   [Harding, L. K.] CALTECH, Jet Prop Lab, Pasadena, CA 91109 USA.
   [Butler, R. P.] Natl Univ Ireland, Ctr Astron, Galway, Ireland.
   [Golden, A.] Yeshiva Univ, Dept Math Sci, New York, NY 10033 USA.
   [Basri, G.] Univ Calif Berkeley, Dept Astron, Berkeley, CA 94720 USA.
   [Doyle, J. G.] Armagh Observ, Armagh BT61 9DG, North Ireland.
   [Berdyugina, S. V.] Kiepenheuer Inst Sonnenphys, D-79104 Freiburg, Germany.
   [Kuznetsov, A.] Inst Solar Terr Phys, Irkutsk 664033, Russia.
   [Rupen, M. P.] Natl Radio Astron Observ, Socorro, NM 87801 USA.
   [Antonova, A.] Sofia Univ St Kliment Ohridski, Dept Astron, Fac Phys, Sofia 1164, Bulgaria.
C3 California Institute of Technology; University of Sheffield; University of Oxford; California Institute of Technology; National Aeronautics & Space Administration (NASA); NASA Jet Propulsion Laboratory (JPL); Ollscoil na Gaillimhe-University of Galway; Yeshiva University; University of California System; University of California Berkeley; Kiepenheuer Institut fur Sonnenphysik; Irkutsk Science Centre of the Russian Academy of Sciences; Russian Academy of Sciences; Institute of Solar-Terrestrial Physics of the Siberian Branch of the Russian Academy of Sciences; National Radio Astronomy Observatory (NRAO); University of Sofia
RP Hallinan, G (corresponding author), CALTECH, 1200 East Calif Blvd, Pasadena, CA 91125 USA.
EM gh@astro.caltech.edu
FU W.M. Keck Foundation; Northern Ireland Department of Culture, Arts and Leisure; National Science Foundation [AST-1212226/DGE-1144469]; University of Oxford; STFC [ST/M006190/1]; STFC [ST/H001921/1, ST/M001350/1, ST/M002012/1, ST/K005596/1, ST/M006190/1, ST/H002456/1, ST/I003673/1] Funding Source: UKRI; Science and Technology Facilities Council [ST/M001350/1, ST/M006190/1, ST/I003673/1, ST/M002012/1, ST/K005596/1, ST/H002456/1, ST/H001921/1] Funding Source: researchfish
NR 34
TC 133
Z9 147
U1 1
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 30
PY 2015
VL 523
IS 7562
BP 568
EP +
DI 10.1038/nature14619
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN7ZL
UT WOS:000358655200039
PM 26223623
DA 2026-03-09
ER

PT J
AU Liu, JT
   Prindle, A
   Humphries, J
   Gabalda-Sagarra, M
   Asally, M
   Lee, DYD
   Ly, S
   Garcia-Ojalvo, J
   Süel, GM
AF Liu, Jintao
   Prindle, Arthur
   Humphries, Jacqueline
   Gabalda-Sagarra, Marcal
   Asally, Munehiro
   Lee, Dong-Yeon D.
   Ly, San
   Garcia-Ojalvo, Jordi
   Sueel, Guerol M.
TI Metabolic co-dependence gives rise to collective oscillations within biofilms
SO NATURE
LA English
DT Article
ID bacillus-subtilis; bacterial biofilms; transport; assimilation; cooperation; operon
AB Cells that reside within a community can cooperate and also compete with each other for resources. It remains unclear how these opposing interactions are resolved at the population level. Here we investigate such an internal conflict within a microbial (Bacillus subtilis) biofilm community: cells in the biofilm periphery not only protect interior cells from external attack but also starve them through nutrient consumption. We discover that this conflict between protection and starvation is resolved through emergence of long-range metabolic co-dependence between peripheral and interior cells. As a result, biofilm growth halts periodically, increasing nutrient availability for the sheltered interior cells. We show that this collective oscillation in biofilm growth benefits the community in the event of a chemical attack. These findings indicate that oscillations support population-level conflict resolution by coordinating competing metabolic demands in space and time, suggesting new strategies to control biofilm growth.
C1 [Liu, Jintao; Prindle, Arthur; Humphries, Jacqueline; Lee, Dong-Yeon D.; Ly, San; Sueel, Guerol M.] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA.
   [Gabalda-Sagarra, Marcal; Garcia-Ojalvo, Jordi] Univ Pompeu Fabra, Dept Expt & Hlth Sci, Barcelona 08003, Spain.
   [Asally, Munehiro] Univ Warwick, Sch Life Sci, Warwick Integrat Synthet Biol Ctr, Coventry CV4 7AL, W Midlands, England.
   [Asally, Munehiro] Univ Warwick, Sch Life Sci, Warwick Integrat Synthet Biol Ctr, Coventry CV4 7AL, W Midlands, England.
C3 University of California System; University of California San Diego; Pompeu Fabra University; University of Warwick; University of Warwick
RP Süel, GM (corresponding author), Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA.
EM gsuel@ucsd.edu
FU UCSD Cell and Molecular Genetics Training Grant; Ministerio de Economia y Competitividad (Spain) [FIS2012-37655-C02-01]; FEDER [FIS2012-37655-C02-01]; ICREA Academia Programme; National Institutes of Health, National Institute of General Medical Sciences [R01 GM088428]; National Science Foundation [MCB-1450867]; Div Of Molecular and Cellular Bioscience; Direct For Biological Sciences [1450867] Funding Source: National Science Foundation
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   Kim M, 2012, MOL SYST BIOL, V8, P0, DOI 10.1038/msb.2012.46
   KLEINER D, 1985, FEMS MICROBIOL LETT, V32, P87, DOI 10.1111/j.1574-6968.1985.tb01185.x
   NAKANO MM, 1995, J BACTERIOL, V177, P573, DOI 10.1128/jb.177.3.573-579.1995
   Oliveira NM, 2014, P NATL ACAD SCI USA, V111, P17941, DOI 10.1073/pnas.1412673111
   Stannek L, 2015, ENV MICROBIOL, V0, P0
   Vlamakis H, 2008, GENE DEV, V22, P945, DOI 10.1101/gad.1645008
   Wilking JN, 2013, P NATL ACAD SCI USA, V110, P848, DOI 10.1073/pnas.1216376110
   Wingreen NS, 2006, PLOS BIOL, V4, P1486, DOI 10.1371/journal.pbio.0040299
   Yildiz FH, 2009, TRENDS MICROBIOL, V17, P109, DOI 10.1016/j.tim.2008.12.004
   Zeigler DR, 2008, J BACTERIOL, V190, P6983, DOI 10.1128/JB.00722-08
NR 29
TC 351
Z9 439
U1 8
U2 376
PU NATURE PUBLISHING 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 30
PY 2015
VL 523
IS 7562
BP 550
EP +
DI 10.1038/nature14660
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN7ZL
UT WOS:000358655200036
PM 26200335
DA 2026-03-09
ER

PT J
AU Showalter, MR
   Hamilton, DP
AF Showalter, M. R.
   Hamilton, D. P.
TI Resonant interactions and chaotic rotation of Pluto's small moons
SO NATURE
LA English
DT Article
ID orbital resonances; satellites; masses; charon; system; larissa; proteus; albedos; period; nix
AB Four small moons-Styx, Nix, Kerberos and Hydra-follow near-circular, near-equatorial orbits around the central 'binary planet' comprising Pluto and its large moon, Charon. New observational details of the system have emerged following the discoveries of Kerberos and Styx. Here we report that Styx, Nix and Hydra are tied together by a three-body resonance, which is reminiscent of the Laplace resonance linking Jupiter's moons Io, Europa and Ganymede. Perturbations by the other bodies, however, inject chaos into this otherwise stable configuration. Nix and Hydra have bright surfaces similar to that of Charon. Kerberos may be much darker, raising questions about how a heterogeneous satellite system might have formed. Nix and Hydra rotate chaotically, driven by the large torques of the Pluto-Charon binary.
C1 [Showalter, M. R.] SETI Inst, Mountain View, CA 94043 USA.
   [Hamilton, D. P.] Univ Maryland, Dept Astron, College Pk, MD 20742 USA.
C3 SETI Institute; University System of Maryland; University of Maryland College Park
RP Showalter, MR (corresponding author), SETI Inst, 189 Bernardo Ave, Mountain View, CA 94043 USA.
EM mshowalter@seti.org
FU NASA [NNX12AQ11G, NNX14AO40G, NAS5-26555, NNX12AI80G]; NASA through Space Telescope Science Institute [GO-12436]; NASA [NNX12AI80G, 21529, NNX14AO40G, 677730] Funding Source: Federal RePORTER
NR 40
TC 75
Z9 82
U1 1
U2 20
PU NATURE PUBLISHING 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 4
PY 2015
VL 522
IS 7554
BP 45
EP U57
DI 10.1038/nature14469
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ5QP
UT WOS:000355543400026
PM 26040889
DA 2026-03-09
ER

PT J
AU Hu, LL
   Lu, JY
   Cheng, JD
   Rao, QH
   Li, Z
   Hou, HF
   Lou, ZY
   Zhang, L
   Li, W
   Gong, W
   Liu, MJ
   Sun, C
   Yin, XT
   Li, J
   Tan, XS
   Wang, PC
   Wang, YS
   Fang, D
   Cui, Q
   Yang, PY
   He, C
   Jiang, HL
   Luo, C
   Xu, YH
AF Hu, Lulu
   Lu, Junyan
   Cheng, Jingdong
   Rao, Qinhui
   Li, Ze
   Hou, Haifeng
   Lou, Zhiyong
   Zhang, Lei
   Li, Wei
   Gong, Wei
   Liu, Mengjie
   Sun, Chang
   Yin, Xiaotong
   Li, Jie
   Tan, Xiangshi
   Wang, Pengcheng
   Wang, Yinsheng
   Fang, Dong
   Cui, Qiang
   Yang, Pengyuan
   He, Chuan
   Jiang, Hualiang
   Luo, Cheng
   Xu, Yanhui
TI Structural insight into substrate preference for TET- mediated oxidation
SO NATURE
LA English
DT Article
ID dna; 5-formylcytosine; 5-hydroxymethylcytosine; 5-methylcytosine; demethylation; reveals; roles; tdg
AB DNA methylation is an important epigenetic modification(1-3). Ten-eleven translocation (TET) proteins are involved in DNA demethylation through iteratively oxidizing 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC)(4-8). Here we show that human TET1 and TET2 are more active on 5mC-DNA than 5hmC/5fC-DNA substrates. We determine the crystal structures of TET2-5hmC-DNA and TET2-5fC-DNA complexes at 1.80 angstrom and 1.97 angstrom resolution, respectively. The cytosine portion of 5hmC/5fC is specifically recognized by TET2 in a manner similar to that of 5mC in the TET2-5mC-DNA structure(9), and the pyrimidine base of 5mC/5hmC/5fC adopts an almost identical conformation within the catalytic cavity. However, the hydroxyl group of 5hmC and carbonyl group of 5fC face towards the opposite direction because the hydroxymethyl group of 5hmC and formyl group of 5fC adopt restrained conformations through forming hydrogen bonds with the 1-carboxylate of NOG and N4 exocyclic nitrogen of cytosine, respectively. Biochemical analyses indicate that the substrate preference of TET2 results from the different efficiencies of hydrogen abstraction in TET2-mediated oxidation. The restrained conformation of 5hmC and 5fC within the catalytic cavity may prevent their abstractable hydrogen(s) adopting a favourable orientation for hydrogen abstraction and thus result in low catalytic efficiency. Our studies demonstrate that the substrate preference of TET2 results from the intrinsic value of its substrates at their 5mC derivative groups and suggest that 5hmC is relatively stable and less prone to further oxidation by TET proteins. Therefore, TET proteins are evolutionarily tuned to be less reactive towards 5hmC and facilitate the generation of 5hmC as a potentially stable mark for regulatory functions.
C1 [Hu, Lulu; Cheng, Jingdong; Rao, Qinhui; Li, Ze; Zhang, Lei; Li, Wei; Gong, Wei; Liu, Mengjie; Sun, Chang; Yin, Xiaotong; Li, Jie; Tan, Xiangshi; Yang, Pengyuan; Xu, Yanhui] Fudan Univ, Shanghai Med Coll, Inst Biomed Sci, Shanghai Canc Ctr, Shanghai 200032, Peoples R China.
   [Hu, Lulu; Cheng, Jingdong; Rao, Qinhui; Li, Ze; Zhang, Lei; Gong, Wei; Liu, Mengjie; Sun, Chang; Yin, Xiaotong; Li, Jie; Yang, Pengyuan; Xu, Yanhui] Fudan Univ, Shanghai Med Coll, Sch Basic Med Sci, Key Lab Mol Med,Minist Educ,Dept Syst Biol Med, Shanghai 200032, Peoples R China.
   [Hu, Lulu; Xu, Yanhui] Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, State Key Lab Genet Engn, Shanghai 200433, Peoples R China.
   [Lu, Junyan; Jiang, Hualiang; Luo, Cheng] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China.
   [Hou, Haifeng] Chinese Acad Sci, Inst High Energy Phys, Beijing Synchrotron Radiat Facil, Beijing 100049, Peoples R China.
   [Lou, Zhiyong] Tsinghua Univ, Lab Struct Biol, Beijing 100084, Peoples R China.
   [Lou, Zhiyong] Tsinghua Univ, Sch Med, MOE Lab Prot Sci, Beijing 100084, Peoples R China.
   [Wang, Pengcheng; Wang, Yinsheng] Univ Calif Riverside, Dept Chem, Riverside, CA 92521 USA.
   [Fang, Dong; Cui, Qiang] Univ Wisconsin, Dept Chem, Theoret Chem Inst, Madison, WI 53706 USA.
   [He, Chuan] Univ Chicago, Dept Chem, Chicago, IL 60637 USA.
   [He, Chuan] Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA.
   [He, Chuan] Univ Chicago, Howard Hughes Med Inst, Chicago, IL 60637 USA.
C3 Fudan University; Fudan University; Fudan University; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Chinese Academy of Sciences; Institute of High Energy Physics, CAS; Tsinghua University; Tsinghua University; University of California System; University of California Riverside; University of Wisconsin System; University of Wisconsin Madison; University of Chicago; University of Chicago; University of Chicago; Howard Hughes Medical Institute
RP Xu, YH (corresponding author), Fudan Univ, Shanghai Med Coll, Inst Biomed Sci, Shanghai Canc Ctr, Shanghai 200032, Peoples R China.
EM cluo@simm.ac.cn; xuyh@fudan.edu.cn
FU National Basic Research Program of China [2011CB965300]; National Science & Technology Major Project 'Key New Drug Creation and Manufacturing Program' of China [2014ZX09507-002]; National Natural Science Foundation of China [U1432242, 31425008, 91419301, 91313000, 31270779, 21210003]; Basic Research Project of Shanghai Science and Technology Commission [12JC1402700]; Program of Shanghai Subject Chief Scientist [14XD1400500]; Hi-Tech Research and Development Program of China [2012AA020302, 2012AA01A305]; Chinese Academy of Sciences [XDA01040305]
NR 28
TC 225
Z9 286
U1 0
U2 211
PU NATURE PUBLISHING 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 5
PY 2015
VL 527
IS 7576
BP 118
EP 122
DI 10.1038/nature15713
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV4XV
UT WOS:000364270700055
PM 26524525
DA 2026-03-09
ER

PT J
AU Howes, LM
   Casey, AR
   Asplund, M
   Keller, SC
   Yong, D
   Nataf, DM
   Poleski, R
   Lind, K
   Kobayashi, C
   Owen, CI
   Ness, M
   Bessell, MS
   Da Costa, GS
   Schmidt, BP
   Tisserand, P
   Udalski, A
   Szymanski, MK
   Soszynski, I
   Pietrzynski, G
   Ulaczyk, K
   Wyrzykowski, L
   Pietrukowicz, P
   Skowron, J
   Kozlowski, S
   Mróz, P
AF Howes, L. M.
   Casey, A. R.
   Asplund, M.
   Keller, S. C.
   Yong, D.
   Nataf, D. M.
   Poleski, R.
   Lind, K.
   Kobayashi, C.
   Owen, C. I.
   Ness, M.
   Bessell, M. S.
   Da Costa, G. S.
   Schmidt, B. P.
   Tisserand, P.
   Udalski, A.
   Szymanski, M. K.
   Soszynski, I.
   Pietrzynski, G.
   Ulaczyk, K.
   Wyrzykowski, L.
   Pietrukowicz, P.
   Skowron, J.
   Kozlowski, S.
   Mroz, P.
TI Extremely metal-poor stars from the cosmic dawn in the bulge of the Milky Way
SO NATURE
LA English
DT Article
ID galactic bulge; high-resolution; chemical abundances; line formation; 1st stars; evolution; parameters; spectra; halo; ii.
AB The first stars are predicted to have formed within 200 million years after the Big Bang(1), initiating the cosmic dawn. A true first star has not yet been discovered, although stars(2-4) with tiny amounts of elements heavier than helium ('metals') have been found in the outer regions ('halo') of the Milky Way. The first stars and their immediate successors should, however, preferentially be found today in the central regions ('bulges') of galaxies, because they formed in the largest over-densities that grew gravitationally with time(5,6). The Milky Way bulge underwent a rapid chemical enrichment during the first 1-2 billion years(7), leading to a dearth of early, metal-poor stars(8,9). Here we report observations of extremely metal-poor stars in the Milky Way bulge, including one star with an iron abundance about 10,000 times lower than the solar value without noticeable carbon enhancement. We confirm that most of the metal-poor bulge stars are on tight orbits around the Galactic Centre, rather than being halo stars passing through the bulge, as expected for stars formed at redshifts greater than 15. Their chemical compositions are in general similar to typical halo stars of the same metallicity although intriguing differences exist, including lower abundances of carbon.
C1 [Howes, L. M.; Asplund, M.; Keller, S. C.; Yong, D.; Nataf, D. M.; Kobayashi, C.; Owen, C. I.; Bessell, M. S.; Da Costa, G. S.; Schmidt, B. P.; Tisserand, P.] Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT 2601, Australia.
   [Casey, A. R.] Univ Cambridge, Inst Astron, Cambridge CB3 0HA, England.
   [Poleski, R.; Udalski, A.; Szymanski, M. K.; Soszynski, I.; Pietrzynski, G.; Ulaczyk, K.; Wyrzykowski, L.; Pietrukowicz, P.; Skowron, J.; Kozlowski, S.; Mroz, P.] Univ Warsaw Observ, PL-00473 Warsaw, Poland.
   [Poleski, R.] Ohio State Univ, Dept Astron, Columbus, OH 43210 USA.
   [Lind, K.] Uppsala Univ, Div Astron & Space Phys, Dept Phys & Astron, SE-75120 Uppsala, Sweden.
   [Kobayashi, C.] Univ Hertfordshire, Sch Phys Astron & Math, Ctr Astrophys Res, Hatfield AL10 9AB, Herts, England.
   [Ness, M.] Max Planck Inst Astron, D-69117 Heidelberg, Germany.
   [Tisserand, P.] Univ Paris 06, Sorbonne Univ, F-75014 Paris, France.
   [Tisserand, P.] CNRS, Inst Astrophys Paris, UMR 7095, F-75014 Paris, France.
   [Pietrzynski, G.] Univ Concepcion, Dept Astron, Concepcion, Chile.
   [Ulaczyk, K.] Univ Warwick, Dept Phys, Coventry CV4 7AL, W Midlands, England.
C3 Australian National University; University of Cambridge; University of Warsaw; Warsaw University Observatory; University System of Ohio; Ohio State University; Uppsala University; University of Hertfordshire; Max Planck Society; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Sorbonne Universite; Universidad de Concepcion; University of Warwick
RP Howes, LM (corresponding author), Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT 2601, Australia.
EM louise.howes@anu.edu.au
FU Collaborative Research Infrastructure Strategy of the Australian Federal Government; Australian Research Council [FL110100012, DP120101237, DP150103294]; European Union FP7 programme through ERC [320360]; NSC, Poland [2014/14/A/ST9/00121]; STFC [ST/M001008/1, ST/M000958/1] Funding Source: UKRI; Science and Technology Facilities Council [ST/M001008/1, ST/M000958/1] Funding Source: researchfish
NR 46
TC 99
Z9 104
U1 0
U2 8
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 484
EP +
DI 10.1038/nature15747
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500040
PM 26560034
DA 2026-03-09
ER

PT J
AU Watson, D
   Christensen, L
   Knudsen, KK
   Richard, J
   Gallazzi, A
   Michalowski, MJ
AF Watson, Darach
   Christensen, Lise
   Knudsen, Kirsten Kraiberg
   Richard, Johan
   Gallazzi, Anna
   Michalowski, Michal Jerzy
TI A dusty, normal galaxy in the epoch of reionization
SO NATURE
LA English
DT Article
ID star-forming galaxy; similar-to 7; lyman break galaxy; submillimeter galaxy; physical-property; starburst galaxy; molecular gas; simple-model; redshift; ultraviolet
AB Candidates for the modest galaxies that formed most of the stars in the early Universe, at redshifts z> 7, have been found in large numbers with extremely deep restframe-ultraviolet imagingl. But it has proved difficult for existing spectrographs to characterize them using their ultraviolet light(2-4). The detailed properties of these galaxies could be measured from dust and cool gas emission at far-infrared wavelengths if the galaxies have become sufficiently enriched in dust and metals. So far, however, the most distant galaxy discovered via its ultraviolet emission and subsequently detected in dust emission is only at z = 3.2 (ref. 5), and recent results have cast doubt on whether dust and molecules can be found in typical galaxies at z >= 7(6-8). Here we report thermal dust emission from an archetypal early Universe star-forming galaxy, A1689-zDI. We detect its stellar continuum in spectroscopy and determine its redshift to be z = 7.5 +/- 0.2 from a spectroscopic detection of the Lyman-a break. A1689-zD1 is representative of the star-forming population during the epoch of reionization(9), with a total star-formation rate of about 12 solar masses per year. The galaxy is highly evolved: it has a large stellar mass and is heavily enriched in dust, with a dust-to-gas ratio close to that of the Milky Way. Dusty, evolved galaxies are thus present among the fainter star-forming population at z> 7.
C1 [Watson, Darach; Christensen, Lise; Gallazzi, Anna] Univ Copenhagen, Niels Bohr Inst, Dark Cosmol Ctr, DK-2100 Copenhagen O, Denmark.
   [Knudsen, Kirsten Kraiberg] Chalmers Univ Technol, Onsala Space Observ, Dept Earth & Space Sci, SE-43992 Onsala, Sweden.
   [Richard, Johan] Univ Lyon 1, Ctr Rech Astrophys Lyon, F-69561 St Genis Laval, France.
   [Gallazzi, Anna] Osserv Astrofis Arcetri, Ist Nazl Astrofis, I-50125 Florence, Italy.
   [Michalowski, Michal Jerzy] Univ Edinburgh, Royal Observ, Inst Astron, Scottish Univ Phys Alliance, Edinburgh EH9 3HJ, Midlothian, Scotland.
C3 University of Copenhagen; Niels Bohr Institute; Chalmers University of Technology; Universite Lyon 1; Ecole Normale Superieure de Lyon (ENS de LYON); Istituto Nazionale Astrofisica (INAF); University of Edinburgh
RP Watson, D (corresponding author), Univ Copenhagen, Niels Bohr Inst, Dark Cosmol Ctr, Juliane Maries Vej 32, DK-2100 Copenhagen O, Denmark.
EM darach@dark-cosmology.dk
FU Danish National Research Foundation; EU under a Marie Curie Intra-European Fellowship [PIEF-GA-2010-274117]; Swedish Research Council; Knut and Alice Wallenberg Foundation; European Research Council starting grant; CALENDS; Career Integration Grant [294074]; European Union Seventh Framework Programme (FP7) [267251]; Science and Technology Facilities Council
NR 50
TC 313
Z9 339
U1 0
U2 12
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 19
PY 2015
VL 519
IS 7543
BP 327
EP +
DI 10.1038/nature14164
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD6AY
UT WOS:000351171900035
PM 25731171
DA 2026-03-09
ER

PT J
AU Makino, DL
   Schuch, B
   Stegmann, E
   Baumgärtner, M
   Basquin, C
   Conti, E
AF Makino, Debora Lika
   Schuch, Benjamin
   Stegmann, Elisabeth
   Baumgaertner, Marc
   Basquin, Claire
   Conti, Elena
TI RNA degradation paths in a 12-subunit nuclear exosome complex
SO NATURE
LA English
DT Article
ID crystal-structure; quality-control; ribosomal-rna; core; subunit; reveals; phenix; rrp6p; dis3
AB The eukaryotic exosome is a conserved RNA-degrading complex that functions in RNA surveillance, turnover and processing. How the same machinery can either completely degrade or precisely trim RNA substrates has long remained unexplained. Here we report the crystal structures of a yeast nuclear exosome containing the 9-subunit core, the 3'-5' RNases Rrp44 and Rrp6, and the obligate Rrp6-binding partner Rrp47 in complex with different RNAs. The combined structural and biochemical data of this 12-subunit complex reveal how a single-stranded RNA can reach the Rrp44 or Rrp6 active sites directly or can bind Rrp6 and be threaded via the central channel towards the distal RNase Rrp44. When a bulky RNA is stalled at the entrance of the channel, Rrp6-Rrp47 swings open. The results suggest how the same molecular machine can coordinate processive degradation and partial trimming in an RNA-dependent manner by a concerted swinging mechanism of the two RNase subunits.
C1 [Makino, Debora Lika; Schuch, Benjamin; Stegmann, Elisabeth; Baumgaertner, Marc; Basquin, Claire; Conti, Elena] Max Planck Inst Biochem, Dept Struct Cell Biol, D-82152 Martinsried, Germany.
C3 Max Planck Society
RP Conti, E (corresponding author), Max Planck Inst Biochem, Dept Struct Cell Biol, Klopferspitz 18A, D-82152 Martinsried, Germany.
EM conti@biochem.mpg.de
FU Max Planck Gesellschaft; European Commission (ERC Advanced Investigator Grant) [294371]; European Commission (Marie Curie ITN RNPnet); Deutsche Forschungsgemeinschaft [DFG SFB646, SFB1035, GRK1721, FOR1680]; Deutsche Forschungsgemeinschaft (CIPSM); Louis Jeantet Foundation; European Research Council (ERC) [294371] Funding Source: European Research Council (ERC)
NR 43
TC 116
Z9 137
U1 2
U2 63
PU NATURE PUBLISHING 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 6
PY 2015
VL 524
IS 7563
BP 54
EP U89
DI 10.1038/nature14865
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO2QS
UT WOS:000359002300030
PM 26222026
DA 2026-03-09
ER

PT J
AU Gould, J
AF Gould, J.
TI Cannabis: 4 big questions
SO NATURE
LA English
DT Article
NR 0
TC 3
Z9 5
U1 1
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 24
PY 2015
VL 525
IS 7570
BP S18
EP S18
DI 10.1038/525S18a
PG 1
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR8KI
UT WOS:000361599900062
PM 26398735
DA 2026-03-09
ER

PT J
AU Rouvinski, A
   Guardado-Calvo, P
   Barba-Spaeth, G
   Duquerroy, S
   Vaney, MC
   Kikuti, CM
   Sanchez, MEN
   Dejnirattisai, W
   Wongwiwat, W
   Haouz, A
   Girard-Blanc, C
   Petres, S
   Shepard, WE
   Desprès, P
   Arenzana-Seisdedos, F
   Dussart, P
   Mongkolsapaya, J
   Screaton, GR
   Rey, FA
AF Rouvinski, Alexander
   Guardado-Calvo, Pablo
   Barba-Spaeth, Giovanna
   Duquerroy, Stephane
   Vaney, Marie-Christine
   Kikuti, Carlos M.
   Sanchez, M. Erika Navarro
   Dejnirattisai, Wanwisa
   Wongwiwat, Wiyada
   Haouz, Ahmed
   Girard-Blanc, Christine
   Petres, Stephane
   Shepard, William E.
   Despres, Philippe
   Arenzana-Seisdedos, Fernando
   Dussart, Philippe
   Mongkolsapaya, Juthathip
   Screaton, Gavin R.
   Rey, Felix A.
TI Recognition determinants of broadly neutralizing human antibodies against dengue viruses
SO NATURE
LA English
DT Article
ID borne encephalitis-virus; fab fragments; maturation; immature; refinement; electrostatics; glycoprotein; mechanism; proteins; complex
AB Dengue disease is caused by four different flavivirus(1) serotypes, which infect 390 million people yearly with 25% symptomatic cases(2) and for which no licensed vaccine is available. Recent phase III vaccine trials showed partial protection, and in particular no protection for dengue virus serotype 2 (refs 3, 4). Structural studies so far have characterized only epitopes recognized by serotype-specific human antibodies(5,6). We recently isolated human antibodies potently neutralizing all four dengue virus serotypes(7). Here we describe the X-ray structures of four of these broadly neutralizing antibodies in complex with the envelope glycoprotein E from dengue virus serotype 2, revealing that the recognition determinants are at a serotype-invariant site at the E-dimer interface, including the exposed main chain of the E fusion loop(8) and the two conserved glycan chains. This 'E-dimer-dependent epitope' is also the binding site for the viral glycoprotein prM during virus maturation in the secretory pathway of the infected cell(9), explaining its conservation across serotypes and highlighting an Achilles' heel of the virus with respect to antibody neutralization. These findings will be instrumental for devising novel immunogens to protect simultaneously against all four serotypes of dengue virus.
C1 [Rouvinski, Alexander; Guardado-Calvo, Pablo; Barba-Spaeth, Giovanna; Duquerroy, Stephane; Vaney, Marie-Christine; Kikuti, Carlos M.; Sanchez, M. Erika Navarro; Rey, Felix A.] Inst Pasteur, Dept Virol, Unite Virol Struct, F-75724 Paris 15, France.
   [Rouvinski, Alexander; Guardado-Calvo, Pablo; Barba-Spaeth, Giovanna; Duquerroy, Stephane; Vaney, Marie-Christine; Kikuti, Carlos M.; Sanchez, M. Erika Navarro; Rey, Felix A.] CNRS, UMR Virol 3569, F-75724 Paris 15, France.
   [Duquerroy, Stephane] Univ Paris Sud, Fac Sci, F-91405 Orsay, France.
   [Dejnirattisai, Wanwisa; Wongwiwat, Wiyada; Mongkolsapaya, Juthathip; Screaton, Gavin R.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Div Immunol & Inflammat, London W12 0NN, England.
   [Haouz, Ahmed; Girard-Blanc, Christine; Petres, Stephane; Rey, Felix A.] Inst Pasteur, Proteopole, CNRS, UMR 3528, F-75724 Paris 15, France.
   [Shepard, William E.] Orme Merisiers, Synchrotron SOLEIL, F-91192 Gif Sur Yvette, France.
   [Despres, Philippe] Inst Pasteur, Dept Virol, Unite Interact Mol Flavivirus Hotes, F-75724 Paris 15, France.
   [Arenzana-Seisdedos, Fernando] Inst Pasteur, Dept Virol, Unite Pathogenie Virale, INSERM,U1108, F-75724 Paris 15, France.
   [Dussart, Philippe] Inst Pasteur, Cayenne 97306, French Guiana.
   [Mongkolsapaya, Juthathip] Mahidol Univ, Siriraj Hosp, Fac Med, Dengue Hemorrhag Fever Res Unit,Off Res & Dev, Bangkok 10700, Thailand.
C3 Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Centre National de la Recherche Scientifique (CNRS); Universite Paris Saclay; Imperial College London; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Centre National de la Recherche Scientifique (CNRS); SOLEIL Synchrotron; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Mahidol University
RP Rey, FA (corresponding author), Inst Pasteur, Dept Virol, Unite Virol Struct, F-75724 Paris 15, France.
EM j.mongkolsapaya@imperial.ac.uk; g.screaton@imperial.ac.uk; rey@pasteur.fr
FU European Union; Insitut Pasteur, from the French Government's 'Investissements d'Avenir' program: Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' [ANR-10-LABX-62-IBEID]; CNRS; Medical Research Council, UK; Wellcome Trust, UK; National Institute for Health Research Biomedical Research Centre; Pediatrics Dengue Vaccine Initiative; Medical Research Council [G0400720, G0600000, G0801508] Funding Source: researchfish; National Institute for Health Research [NF-SI-0507-10303] Funding Source: researchfish; MRC [G0400720, G0801508] Funding Source: UKRI
NR 49
TC 293
Z9 352
U1 0
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 APR 2
PY 2015
VL 520
IS 7545
BP 109
EP +
DI 10.1038/nature14130
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE7NE
UT WOS:000352027700047
PM 25581790
DA 2026-03-09
ER

PT J
AU Huang, W
   Thomas, B
   Flynn, RA
   Gavzy, SJ
   Wu, L
   Kim, SV
   Hall, JA
   Miraldi, ER
   Ng, CP
   Rigo, FW
   Meadows, S
   Montoya, NR
   Herrera, NG
   Domingos, AI
   Rastinejad, F
   Myers, RM
   Fuller-Pace, FV
   Bonneau, R
   Chang, HY
   Acuto, O
   Littman, DR
AF Huang, Wendy
   Thomas, Benjamin
   Flynn, Ryan A.
   Gavzy, Samuel J.
   Wu, Lin
   Kim, Sangwon V.
   Hall, Jason A.
   Miraldi, Emily R.
   Ng, Charles P.
   Rigo, Frank W.
   Meadows, Sarah
   Montoya, Nina R.
   Herrera, Natalia G.
   Domingos, Ana I.
   Rastinejad, Fraydoon
   Myers, Richard M.
   Fuller-Pace, Frances V.
   Bonneau, Richard
   Chang, Howard Y.
   Acuto, Oreste
   Littman, Dan R.
TI RETRACTED: DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions (Retracted article. See vol. 562, pg. 150, 2018)
SO NATURE
LA English
DT Article; Retracted Publication
ID ror-gamma-t; long noncoding rna; p68 ddx5; helicase p68; th17 cells; phase-i; differentiation; transcription; proteins; susceptibility
AB T helper 17 (T(H)17) lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by ROR gamma t, a ligand-regulated nuclear receptor. Here we identify the RNA helicase DEAD-box protein 5 (DDX5) as a ROR gamma t partner that coordinates transcription of selective T(H)17 genes, and is required for T(H)17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with ROR gamma t and coactivate its targets depends on intrinsic RNA helicase activity and binding of a conserved nuclear long noncoding RNA (lncRNA), Rmrp, which is mutated in patients with cartilage-hair hypoplasia. A targeted Rmrp gene mutation in mice, corresponding to a gene mutation in cartilage-hair hypoplasia patients, altered lncRNA chromatin occupancy, and reduced the DDX5-ROR gamma t interaction and ROR gamma t target gene transcription. Elucidation of the link between Rmrp and the DDX5-ROR gamma t complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation, and provides new opportunities for therapeutic intervention in T(H)17-dependent diseases.
C1 [Huang, Wendy; Gavzy, Samuel J.; Wu, Lin; Kim, Sangwon V.; Hall, Jason A.; Miraldi, Emily R.; Ng, Charles P.; Montoya, Nina R.; Herrera, Natalia G.; Littman, Dan R.] NYU, Sch Med, Kimmel Ctr Biol & Med, Skirball Inst, New York, NY 10016 USA.
   [Thomas, Benjamin; Acuto, Oreste] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England.
   [Flynn, Ryan A.; Chang, Howard Y.] Stanford Univ, Ctr Personal Dynam Regulomes, Stanford, CA 94305 USA.
   [Miraldi, Emily R.; Bonneau, Richard] NYU, Dept Biol, Ctr Genom & Syst Biol, New York, NY 10003 USA.
   [Miraldi, Emily R.; Bonneau, Richard] NYU, Courant Inst Math Sci, Dept Comp Sci, New York, NY 10012 USA.
   [Miraldi, Emily R.; Bonneau, Richard] Simons Fdn, Simons Ctr Data Anal, New York, NY 10010 USA.
   [Rigo, Frank W.] ISIS Pharmaceut, Carlsbad, CA 92010 USA.
   [Meadows, Sarah; Myers, Richard M.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA.
   [Domingos, Ana I.] Inst Gulbenkian Ciencias, P-2780156 Oeiras, Portugal.
   [Rastinejad, Fraydoon] Sanford Burnham Prebys Med Discovery Inst, Integrat Metab Program, Orlando, FL 32827 USA.
   [Fuller-Pace, Frances V.] Univ Dundee, Div Canc Res, Dundee DD1 9SY, Scotland.
   [Littman, Dan R.] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA.
C3 New York University; University of Oxford; Stanford University; New York University; New York University; Simons Foundation; Ionis Pharmaceuticals, Inc.; HudsonAlpha Institute for Biotechnology; Instituto Gulbenkian de Ciencia; Sanford Burnham Prebys Medical Discovery Institute; University of Dundee; New York University; Howard Hughes Medical Institute
RP Littman, DR (corresponding author), NYU, Sch Med, Kimmel Ctr Biol & Med, Skirball Inst, New York, NY 10016 USA.
EM dan.littman@med.nyu.edu
FU Cancer Research Institute Irvington Postdoctoral Fellowship; Institutional NRSA [T32 CA009161_Levy]; National Multiple Sclerosis Society postdoctoral fellowship [FG 2089-A-1]; Crohn's and Colitis Foundation of America [329388]; Dale and Betty Frey Fellowship of the Damon Runyon Cancer Research Foundation [2105-12]; HHMI Exceptional Research Opportunities Program; NIH [F30 1F30CA189514-01, P50-HG007735, R01HG004361, R01AI080885, R01DK103358]; Howard Hughes Medical Institute; National Cancer Institute [P30CA016087] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [T32AI100853] Funding Source: NIH RePORTER
NR 60
TC 146
Z9 167
U1 4
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 DEC 24
PY 2015
VL 528
IS 7583
BP 517
EP +
DI 10.1038/nature16193
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900044
PM 26675721
DA 2026-03-09
ER

PT J
AU Stransky, N
   Ghandi, M
   Kryukov, GV
   Garraway, LA
   Lehár, J
   Liu, M
   Sonkin, D
   Kauffmann, A
   Venkatesan, K
   Edelman, EJ
   Riester, M
   Barretina, J
   Caponigro, G
   Schlegel, R
   Sellers, WR
   Stegmeier, F
   Morrissey, M
   Amzallag, A
   Pruteanu-Malinici, I
   Haber, DA
   Ramaswamy, S
   Benes, CH
   Menden, MP
   Iorio, F
   Stratton, MR
   McDermott, U
   Garnett, MJ
   Saez-Rodriguez, J
AF Stransky, Nicolas
   Ghandi, Mahmoud
   Kryukov, Gregory V.
   Garraway, Levi A.
   Lehar, Joseph
   Liu, Manway
   Sonkin, Dmitriy
   Kauffmann, Audrey
   Venkatesan, Kavitha
   Edelman, Elena J.
   Riester, Markus
   Barretina, Jordi
   Caponigro, Giordano
   Schlegel, Robert
   Sellers, William R.
   Stegmeier, Frank
   Morrissey, Michael
   Amzallag, Arnaud
   Pruteanu-Malinici, Iulian
   Haber, Daniel A.
   Ramaswamy, Sridhar
   Benes, Cyril H.
   Menden, Michael P.
   Iorio, Francesco
   Stratton, Michael R.
   McDermott, Ultan
   Garnett, Mathew J.
   Saez-Rodriguez, Julio
TI Pharmacogenomic agreement between two cancer cell line data sets
SO NATURE
LA English
DT Article
ID drug-sensitivity
AB Large cancer cell line collections broadly capture the genomic diversity of human cancers and provide valuable insight into anti-cancer drug response. Here we show substantial agreement and biological consilience between drug sensitivity measurements and their associated genomic predictors from two publicly available large-scale pharmacogenomics resources: The Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer databases.
C1 [Stransky, Nicolas; Ghandi, Mahmoud; Kryukov, Gregory V.; Garraway, Levi A.; Broad Inst] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Garraway, Levi A.] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol,Dept Med,Med Sch, Boston, MA 02115 USA.
   [Amzallag, Arnaud; Pruteanu-Malinici, Iulian; Haber, Daniel A.; Ramaswamy, Sridhar; Benes, Cyril H.; Massachusetts Gen Hosp] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA.
   [Lehar, Joseph; Liu, Manway; Sonkin, Dmitriy; Kauffmann, Audrey; Venkatesan, Kavitha; Edelman, Elena J.; Riester, Markus; Barretina, Jordi; Caponigro, Giordano; Schlegel, Robert; Sellers, William R.; Stegmeier, Frank; Morrissey, Michael; Novartis Inst Biomed Res] Novartis Inst Biorvlecl Res, Cambridge, MA 02139 USA.
   [Menden, Michael P.; Iorio, Francesco; Saez-Rodriguez, Julio] European Mol Biol Lab, European Bioinformat Inst, Hinxton CB10 1SD, England.
   [Iorio, Francesco; Stratton, Michael R.; McDermott, Ultan; Garnett, Mathew J.] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England.
C3 Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard Medical School; Brigham & Women's Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute; Wellcome Trust Sanger Institute
RP Garraway, LA (corresponding author), Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA.
EM Levi_Garraway@dfci.harvard.edu; CBENES@mgh.harvard.edu
FU Novartis Institutes for BioMedical Research; Wellcome Trust [086357, 102696]; National Institutes of Health [1U54HG006097-01]; Novartis; Dr. Miriam and Sheldon Adelson Medical Research Foundation; Slim Foundation; EMBL-EBI; Wellcome Trust Sanger Institute Post-Doctoral (ESPOD) programme; Cancer Research UK Clinician Scientist Fellowship [A16629]
NR 9
TC 319
Z9 369
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 DEC 3
PY 2015
VL 528
IS 7580
BP 84
EP +
DI 10.1038/nature15736
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000052
PM 26570998
DA 2026-03-09
ER

PT J
AU Qu, QM
   Haitina, T
   Zhu, M
   Ahlberg, PE
AF Qu, Qingming
   Haitina, Tatjana
   Zhu, Min
   Ahlberg, Per Erik
TI New genomic and fossil data illuminate the origin of enamel
SO NATURE
LA English
DT Article
ID bony vertebrates; teeth; scales; evolution; fish; lepisosteus; ganoine; models; tissue
AB Enamel, the hardest vertebrate tissue, covers the teeth of almost all sarcopterygians (lobe-finned bony fishes and tetrapods) as well as the scales and dermal bones of many fossil lobe-fins(1-5). Enamel deposition requires an organic matrix containing the unique enamel matrix proteins (EMPs) amelogenin (AMEL), enamelin (ENAM) and ameloblastin (AMBN)(6). Chondrichthyans (cartilaginous fishes) lack both enamel and EMP genes(7,8). Many fossil and a few living non-teleost actinopterygians (ray-finned bony fishes) such as the gar, Lepisosteus, have scales and dermal bones covered with a proposed enamel homologue called ganoine(1,9). However, no gene or transcript data for EMPs have been described from actinopterygians(10,11). Here we show that Psarolepis romeri, a bony fish from the the Early Devonian period, combines enamel-covered dermal odontodes on scales and skull bones with teeth of naked dentine, and that Lepisosteus oculatus (the spotted gar) has enam andambn genes that are expressed in the skin, probably associated with ganoine formation. The genetic evidence strengthens the hypothesis that ganoine is homologous with enamel. The fossil evidence, further supported by the Silurian bony fish Andreolepis, which has enamel-covered scales but teeth and odontodes on its dermal bones made of naked dentine(12-16), indicates that this tissue originated on the dermal skeleton, probably on the scales. It subsequently underwent heterotopic expansion across two highly conserved patterning boundaries (scales/head-shoulder and dermal/oral) within the odontode skeleton.
C1 [Qu, Qingming; Haitina, Tatjana; Ahlberg, Per Erik] Uppsala Univ, Dept Organismal Biol, Subdept Evolut & Dev, SE-75236 Uppsala, Sweden.
   [Zhu, Min] Chinese Acad Sci, Inst Vertebrate Paleontol & Paleoanthropol, Key Lab Vertebrate Evolut & Human Origins, Beijing 100044, Peoples R China.
C3 Uppsala University; Chinese Academy of Sciences; Institute of Vertebrate Paleontology & Paleoanthropology, CAS
RP Ahlberg, PE (corresponding author), Uppsala Univ, Dept Organismal Biol, Subdept Evolut & Dev, Norbyvagen 18A, SE-75236 Uppsala, Sweden.
EM per.ahlberg@ebc.uu.se
FU Knut and Alice Wallenberg Foundation; Vetenskapsradet (Swedish Research Council); National Basic Research Programme of China [2012CB821902]
NR 35
TC 65
Z9 78
U1 2
U2 100
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 1
PY 2015
VL 526
IS 7571
BP 108
EP +
DI 10.1038/nature15259
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS5CY
UT WOS:000362095100043
PM 26416752
DA 2026-03-09
ER

PT J
AU Kawaharada, Y
   Kelly, S
   Nielsen, MW
   Hjuler, CT
   Gysel, K
   Muszynski, A
   Carlson, RW
   Thygesen, MB
   Sandal, N
   Asmussen, MH
   Vinther, M
   Andersen, SU
   Krusell, L
   Thirup, S
   Jensen, KJ
   Ronson, CW
   Blaise, M
   Radutoiu, S
   Stougaard, J
AF Kawaharada, Y.
   Kelly, S.
   Nielsen, M. Wibroe
   Hjuler, C. T.
   Gysel, K.
   Muszynski, A.
   Carlson, R. W.
   Thygesen, M. B.
   Sandal, N.
   Asmussen, M. H.
   Vinther, M.
   Andersen, S. U.
   Krusell, L.
   Thirup, S.
   Jensen, K. J.
   Ronson, C. W.
   Blaise, M.
   Radutoiu, S.
   Stougaard, J.
TI Receptor-mediated exopolysaccharide perception controls bacterial infection
SO NATURE
LA English
DT Article
ID legume lotus-japonicus; host-symbiont interactions; genetic-linkage map; rhizobium-meliloti; sinorhizobium-meliloti; structural-characterization; nodule organogenesis; medicago-truncatula; organ development; innate immunity
AB Surface polysaccharides are important for bacterial interactions with multicellular organisms, and some are virulence factors in pathogens. In the legume-rhizobium symbiosis, bacterial exopolysaccharides (EPS) are essential for the development of infected root nodules. We have identified a gene in Lotus japonicus, Epr3, encoding a receptor-like kinase that controls this infection. We show that epr3 mutants are defective in perception of purified EPS, and that EPR3 binds EPS directly and distinguishes compatible and incompatible EPS in bacterial competition studies. Expression of Epr3 in epidermal cells within the susceptible root zone shows that the protein is involved in bacterial entry, while rhizobial and plant mutant studies suggest that Epr3 regulates bacterial passage through the plant's epidermal cell layer. Finally, we show that Epr3 expression is inducible and dependent on host perception of bacterial nodulation ( Nod) factors. Plant-bacterial compatibility and bacterial access to legume roots is thus regulated by a two-stage mechanism involving sequential receptor-mediated recognition of Nod factor and EPS signals.
C1 [Kawaharada, Y.; Kelly, S.; Nielsen, M. Wibroe; Hjuler, C. T.; Gysel, K.; Thygesen, M. B.; Sandal, N.; Asmussen, M. H.; Vinther, M.; Andersen, S. U.; Krusell, L.; Thirup, S.; Jensen, K. J.; Ronson, C. W.; Blaise, M.; Radutoiu, S.; Stougaard, J.] Aarhus Univ, Ctr Carbohydrate Recognit & Signalling, DK-8000 Aarhus C, Denmark.
   [Kawaharada, Y.; Kelly, S.; Nielsen, M. Wibroe; Gysel, K.; Sandal, N.; Asmussen, M. H.; Vinther, M.; Andersen, S. U.; Krusell, L.; Thirup, S.; Blaise, M.; Radutoiu, S.; Stougaard, J.] Aarhus Univ, Dept Mol Biol & Genet, DK-8000 Aarhus C, Denmark.
   [Kelly, S.; Ronson, C. W.] Univ Otago, Dept Microbiol & Immunol, Dunedin 9054, New Zealand.
   [Hjuler, C. T.; Thygesen, M. B.; Jensen, K. J.] Univ Copenhagen, Dept Chem, DK-1871 Frederiksberg C, Denmark.
   [Muszynski, A.; Carlson, R. W.] Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA.
C3 Aarhus University; Aarhus University; University of Otago; University of Copenhagen; University System of Georgia; University of Georgia
RP Stougaard, J (corresponding author), Aarhus Univ, Ctr Carbohydrate Recognit & Signalling, DK-8000 Aarhus C, Denmark.
EM stougaard@mbg.au.dk
FU Danish National Research Foundation [DNRF79]; ERC Advanced Grant [268523]; Chemical Sciences, Geosciences and Biosciences Division, Office of Basic Energy Sciences, US Department of Energy [DE-FG02-93ER20097]
NR 62
TC 315
Z9 348
U1 12
U2 315
PU NATURE PUBLISHING 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 16
PY 2015
VL 523
IS 7560
BP 308
EP +
DI 10.1038/nature14611
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM8KY
UT WOS:000357950900033
PM 26153863
DA 2026-03-09
ER

PT J
AU Rutz, S
   Kayagaki, N
   Phung, QT
   Eidenschenk, C
   Noubade, R
   Wang, XT
   Lesch, J
   Lu, RZ
   Newton, K
   Huang, OW
   Cochran, AG
   Vasser, M
   Fauber, BP
   DeVoss, J
   Webster, J
   Diehl, L
   Modrusan, Z
   Kirkpatrick, DS
   Lill, JR
   Ouyang, WJ
   Dixit, VM
AF Rutz, Sascha
   Kayagaki, Nobuhiko
   Phung, Qui T.
   Eidenschenk, Celine
   Noubade, Rajkumar
   Wang, Xiaoting
   Lesch, Justin
   Lu, Rongze
   Newton, Kim
   Huang, Oscar W.
   Cochran, Andrea G.
   Vasser, Mark
   Fauber, Benjamin P.
   DeVoss, Jason
   Webster, Joshua
   Diehl, Lauri
   Modrusan, Zora
   Kirkpatrick, Donald S.
   Lill, Jennie R.
   Ouyang, Wenjun
   Dixit, Vishva M.
TI Deubiquitinase DUBA is a post-translational brake on interleukin-17 production in T cells
SO NATURE
LA English
DT Article
ID t(h)17 cells; multiple-sclerosis; regulatory network; expression; identification; inflammation; cytokine; protein; il-17; mice
AB helper type 17 (T(H)17) cells that produce the cytokines interleukin-17A (IL-17A) and IL-17F are implicated in the pathogenesis of several autoimmune diseases(1,2). The differentiation of T(H)17 cells is regulated by transcription factors such as ROR gamma t(3,4), but post-translational mechanisms preventing the rampant production of pro-inflammatory IL-17A have received less attention. Here we show that the deubiquitylating enzyme DUBA is a negative regulator of IL-17A production in T cells. Mice with DUBA-deficient T cells developed exacerbated inflammation in the small intestine after challenge with anti-CD3 antibodies. DUBA interacted with the ubiquitin ligase UBR5, which suppressed DUBA abundance in naive T cells. DUBA accumulated in activated T cells and stabilized UBR5, which then ubiquitylated ROR gamma t inresponse toTGF-beta signalling. Our data identify DUBA as a cell-intrinsic suppressor of IL-17 production.
C1 [Rutz, Sascha; Eidenschenk, Celine; Noubade, Rajkumar; Wang, Xiaoting; Lesch, Justin; Lu, Rongze; DeVoss, Jason; Ouyang, Wenjun] Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA.
   [Kayagaki, Nobuhiko; Newton, Kim; Dixit, Vishva M.] Genentech Inc, Dept Physiol Chem, San Francisco, CA 94080 USA.
   [Phung, Qui T.; Vasser, Mark; Kirkpatrick, Donald S.; Lill, Jennie R.] Genentech Inc, Dept Prot Chem, San Francisco, CA 94080 USA.
   [Huang, Oscar W.; Cochran, Andrea G.] Genentech Inc, Dept Early Discovery Biochem, San Francisco, CA 94080 USA.
   [Fauber, Benjamin P.] Genentech Inc, Discovery Chem, San Francisco, CA 94080 USA.
   [Webster, Joshua; Diehl, Lauri] Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA.
   [Modrusan, Zora] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA.
C3 Roche Holding; Genentech; Roche Holding USA; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Genentech; Roche Holding USA; 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 Ouyang, WJ (corresponding author), Genentech Inc, Dept Immunol, 1 DNA Way, San Francisco, CA 94080 USA.
EM ouyang@gene.com; dixit@gene.com
NR 37
TC 110
Z9 120
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 FEB 19
PY 2015
VL 518
IS 7539
BP 417
EP 421
DI 10.1038/nature13979
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400046
PM 25470037
DA 2026-03-09
ER

PT J
AU French, SW
   Romanowicz, B
AF French, Scott W.
   Romanowicz, Barbara
TI Broad plumes rooted at the base of the Earth's mantle beneath major hotspots
SO NATURE
LA English
DT Article
ID shear velocity structure; spectral element method; wave-form tomography; excess temperature; model; evolution; reveals; surface; flow
AB Plumes of hot upwelling rock rooted in the deep mantle have been proposed as a possible origin of hotspot volcanoes, but this idea is the subject of vigorous debate(1,2). On the basis of geodynamic computations, plumes of purely thermal origin should comprise thin tails, only several hundred kilometres wide(3), and be difficult to detect using standard seismic tomography techniques. Here we describe the use of a whole-mantle seismic imaging technique-combining accurate wavefield computations with information contained in whole seismic waveforms(4)-that reveals the presence of broad (not thin), quasi-vertical conduits beneath many prominent hotspots. These conduits extend from the core-mantle boundary to about 1,000 kilometres below Earth's surface, where some are deflected horizontally, as though entrained into more vigorous upper-mantle circulation. At the base of the mantle, these conduits are rooted in patches of greatly reduced shear velocity that, in the case of Hawaii, Iceland and Samoa, correspond to the locations of known large ultralow-velocity zones(5-7). This correspondence clearly establishes a continuous connection between such zones and mantle plumes. We also show that the imaged conduits are robustly broader than classical thermal plume tails, suggesting that they are long-lived(8), and may have a thermochemical origin(9-11). Their vertical orientation suggests very sluggish background circulation below depths of 1,000 kilometres. Our results should provide constraints on studies of viscosity layering of Earth's mantle and guide further research into thermochemical convection.
C1 [French, Scott W.; Romanowicz, Barbara] Univ Calif Berkeley, Berkeley Seismol Lab, Dept Earth & Planetary Sci, Berkeley, CA 94720 USA.
   [Romanowicz, Barbara] Univ Paris Diderot, Inst Phys Globe, F-75238 Paris, France.
   [Romanowicz, Barbara] Coll France, F-75005 Paris, France.
C3 University of California System; University of California Berkeley; Universite Paris Cite; Universite PSL; College de France
RP Romanowicz, B (corresponding author), Univ Calif Berkeley, Berkeley Seismol Lab, Dept Earth & Planetary Sci, Berkeley, CA 94720 USA.
EM barbara@seismo.berkeley.edu
FU NSF Graduate Research Fellowship; NSF [EAR-1417229]; ERC Advanced Grant WAVETOMO; US Department of Energy Office of Science [DE-AC02-05CH11231]; Directorate For Geosciences [1417229] Funding Source: National Science Foundation; Division Of Earth Sciences [1417229] Funding Source: National Science Foundation
NR 51
TC 715
Z9 832
U1 11
U2 327
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 3
PY 2015
VL 525
IS 7567
BP 95
EP +
DI 10.1038/nature14876
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100032
PM 26333468
DA 2026-03-09
ER

PT J
AU Ritz, C
   Edwards, TL
   Durand, G
   Payne, AJ
   Peyaud, V
   Hindmarsh, RCA
AF Ritz, Catherine
   Edwards, Tamsin L.
   Durand, Gael
   Payne, Antony J.
   Peyaud, Vincent
   Hindmarsh, Richard C. A.
TI Potential sea-level rise from Antarctic ice-sheet instability constrained by observations
SO NATURE
LA English
DT Article
ID pine island; west antarctica; grounding line; thwaites; retreat; discharge; glaciers
AB Large parts of the Antarctic ice sheet lying on bedrock below sea level may be vulnerable to marine-ice-sheet instability (MISI)(1), a self-sustaining retreat of the grounding line triggered by oceanic or atmospheric changes. There is growing evidence(2-4) that MISI may be underway throughout the Amundsen Sea embayment (ASE), which contains ice equivalent to more than a metre of global sea-level rise. If triggered in other regions(5-8), the centennial to millennial contribution could be several metres. Physically plausible projections are challenging(9): numerical models with sufficient spatial resolution to simulate grounding-line processes have been too computationally expensive(2,3,10) to generate large ensembles for uncertainty assessment, and lower-resolution model projections(11) rely on parameterizations that are only loosely constrained by present day changes. Here we project that the Antarctic ice sheet will contribute up to 30 cm sea-level equivalent by 2100 and 72 cm by 2200 (95% quantiles) where the ASE dominates. Our process-based, statistical approach gives skewed and complex probability distributions (single mode, 10 cm, at 2100; two modes, 49 cm and 6 cm, at 2200). The dependence of sliding on basal friction is a key unknown: nonlinear relationships favour higher contributions. Results are conditional on assessments of MISI risk on the basis of projected triggers under the climate scenario A1B (ref. 9), although sensitivity to these is limited by theoretical and topographical constraints on the rate and extent of ice loss. We find that contributions are restricted by a combination of these constraints, calibration with success in simulating observed ASE losses, and low assessed risk in some basins. Our assessment suggests that upper-bound estimates from low-resolution models and physical arguments9 (up to a metre by 2100 and around one and a half by 2200) are implausible under current understanding of physical mechanisms and potential triggers.
C1 [Ritz, Catherine; Durand, Gael; Peyaud, Vincent] CNRS, LGGE, F-38041 Grenoble, France.
   [Ritz, Catherine; Durand, Gael; Peyaud, Vincent] Univ Grenoble Alpes, LGGE, F-38041 Grenoble, France.
   [Edwards, Tamsin L.] Open Univ, Fac Sci, Dept Environm Earth & Ecosyst, Milton Keynes MK7 6AA, Bucks, England.
   [Edwards, Tamsin L.; Payne, Antony J.] Univ Bristol, Dept Geog Sci, Bristol BS8 1SS, Avon, England.
   [Hindmarsh, Richard C. A.] British Antarctic Survey, Nat Environm Res Council, Cambridge CB3 0ET, England.
C3 Centre National de la Recherche Scientifique (CNRS); Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Open University - UK; University of Bristol; UK Research & Innovation (UKRI); Natural Environment Research Council (NERC); NERC British Antarctic Survey
RP Edwards, TL (corresponding author), Open Univ, Fac Sci, Dept Environm Earth & Ecosyst, Walton Hall, Milton Keynes MK7 6AA, Bucks, England.
EM tamsin.edwards@open.ac.uk
FU ice2sea project - European Commission's 7th Framework Programme [226375, ice2sea119]; UK National Centre for Earth Observation; NERC iGlass project; NERC; UK Met Office Joint Weather and Climate Research Programme; French National Research Agency (ANR) under the SUMER [Blanc SIMI 6, ANR-12-BS06-0018]; Rhone-Alpes region [CPER07 13 CIRA]; NERC [NE/F015526/1, NE/I010874/1, bas0100034, NE/F01550X/1, NE/J008087/1] Funding Source: UKRI; Natural Environment Research Council [NE/I010874/1, NE/F01550X/1, bas0100034, NE/F015526/1, NE/J008087/1] Funding Source: researchfish; Agence Nationale de la Recherche (ANR) [ANR-12-BS06-0018] Funding Source: Agence Nationale de la Recherche (ANR)
NR 24
TC 293
Z9 319
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 DEC 3
PY 2015
VL 528
IS 7580
BP 115
EP +
DI 10.1038/nature16147
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000059
PM 26580020
DA 2026-03-09
ER

PT J
AU Jaunmuktane, Z
   Mead, S
   Ellis, M
   Wadsworth, JDF
   Nicoll, AJ
   Kenny, J
   Launchbury, F
   Linehan, J
   Richard-Loendt, A
   Walker, AS
   Rudge, P
   Collinge, J
   Brandner, S
AF Jaunmuktane, Zane
   Mead, Simon
   Ellis, Matthew
   Wadsworth, Jonathan D. F.
   Nicoll, Andrew J.
   Kenny, Joanna
   Launchbury, Francesca
   Linehan, Jacqueline
   Richard-Loendt, Angela
   Walker, A. Sarah
   Rudge, Peter
   Collinge, John
   Brandner, Sebastian
TI Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
SO NATURE
LA English
DT Article
ID creutzfeldt-jakob-disease; human prion disease; alzheimer-type neuropathology; pituitary growth-hormone; transgenic mice; induction; brain; risk; deposition; recipients
AB More than two hundred individuals developed Creutzfeldt-Jakob disease (CJD) worldwide as a result of treatment, typically in childhood, with human cadaveric pituitary-derived growth hormone contaminated with prions(1,2). Although such treatment ceased in 1985, iatrogenic CJD (iCJD) continues to emerge because of the prolonged incubation periods seen in human prion infections. Unexpectedly, in an autopsy study of eight individuals with iCJD, aged 36-51 years, in four we found moderate to severe grey matter and vascular amyloid-beta (A beta) pathology. The A beta deposition in the grey matter was typical of that seen in Alzheimer's disease and A beta in the blood vessel walls was characteristic of cerebral amyloid angiopathy(3) and did not co-localize with prion protein deposition. None of these patients had pathogenic mutations, APOE epsilon 4 or other high-risk alleles(4) associated with early-onset Alzheimer's disease. Examination of a series of 116 patients with other prion diseases from a prospective observational cohort study(5) showed minimal or no A beta pathology in cases of similar age range, or a decade older, without APOE epsilon 4 risk alleles. We also analysed pituitary glands from individuals with A beta pathology and found marked A beta deposition in multiple cases. Experimental seeding of A beta pathology has been previously demonstrated in primates and transgenic mice by central nervous system or peripheral inoculation with Alzheimer's disease brain homogenate(6-11). The marked deposition of parenchymal and vascular A beta in these relatively young patients with iCJD, in contrast with other prion disease patients and population controls, is consistent with iatrogenic transmission of A beta pathology in addition to CJD and suggests that healthy exposed individuals may also be at risk of iatrogenic Alzheimer's disease and cerebral amyloid angiopathy. These findings should also prompt investigation of whether other known iatrogenic routes of prion transmission may also be relevant to A beta and other proteopathic seeds associated with neurodegenerative and other human diseases.
C1 [Jaunmuktane, Zane; Brandner, Sebastian] Natl Hosp Neurol & Neurosurg, Div Neuropathol, London WC1N 3BG, England.
   [Mead, Simon; Wadsworth, Jonathan D. F.; Nicoll, Andrew J.; Kenny, Joanna; Linehan, Jacqueline; Rudge, Peter; Collinge, John; Brandner, Sebastian] MRC, Prion Unit, London WC1 3BG, England.
   [Mead, Simon; Ellis, Matthew; Wadsworth, Jonathan D. F.; Nicoll, Andrew J.; Launchbury, Francesca; Richard-Loendt, Angela; Collinge, John; Brandner, Sebastian] UCL Inst Neurol, Dept Neurodegenerat Dis, London WC1N 3BG, England.
   [Mead, Simon; Kenny, Joanna; Rudge, Peter; Collinge, John] Natl Hosp Neurol & Neurosurg, Natl Prion Clin, London WC1N 3BG, England.
   [Walker, A. Sarah] UCL, MRC Clin Trials Unit, London WC2B 6NH, England.
C3 University of London; University College London; UCL Medical School; University College London Hospitals NHS Foundation Trust; National Hospital for Neurology & Neurosurgery; University of London; University College London; University of London; University College London; UCL Medical School; University College London Hospitals NHS Foundation Trust; National Hospital for Neurology & Neurosurgery; University of London; University College London; Medical Research Council Clinical Trials Unit
RP Brandner, S (corresponding author), Natl Hosp Neurol & Neurosurg, Div Neuropathol, Queen Sq, London WC1N 3BG, England.
EM j.collinge@prion.ucl.ac.uk; s.brandner@ucl.ac.uk
FU UK Medical Research Council; National Institute of Health Research (NIHR) UCLH/UCL Biomedical Research Centre; Dementia Biomedical Research Unit; Medical Research Council [MC_U123160657, MC_U123160655, MC_UU_12023/22, MC_U123192748] Funding Source: researchfish; MRC [MC_U123160655, MC_U123160657, MC_U123192748, MC_UU_12023/22] Funding Source: UKRI
NR 39
TC 395
Z9 450
U1 3
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 SEP 10
PY 2015
VL 525
IS 7568
BP 247
EP +
DI 10.1038/nature15369
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400038
PM 26354483
DA 2026-03-09
ER

PT J
AU Rassam, P
   Copeland, NA
   Birkholz, O
   Toth, C
   Chavent, M
   Duncan, AL
   Cross, SJ
   Housden, NG
   Kaminska, R
   Seger, U
   Quinn, DM
   Garrod, TJ
   Sansom, MSP
   Piehler, J
   Baumann, CG
   Kleanthous, C
AF Rassam, Patrice
   Copeland, Nikki A.
   Birkholz, Oliver
   Toth, Csaba
   Chavent, Matthieu
   Duncan, Anna L.
   Cross, Stephen J.
   Housden, Nicholas G.
   Kaminska, Renata
   Seger, Urban
   Quinn, Diana M.
   Garrod, Tamsin J.
   Sansom, Mark S. P.
   Piehler, Jacob
   Baumann, Christoph G.
   Kleanthous, Colin
TI Supramolecular assemblies underpin turnover of outer membrane proteins in bacteria
SO NATURE
LA English
DT Article
ID single-molecule; escherichia-coli; r-domain; diffusion; insertion; receptor; porin; dynamics; surface; stoichiometry
AB Gram-negative bacteria inhabit a broad range of ecological niches. For Escherichia coli, this includes river water as well as humans and animals, where it can be both a commensal and a pathogen(1-3). Intricate regulatory mechanisms ensure that bacteria have the right complement of beta-barrel outer membrane proteins (OMPs) to enable adaptation to a particular habitat(4,5). Yet no mechanism is known for replacing OMPs in the outer membrane, an issue that is further confounded by the lack of an energy source and the high stability(6) and abundance of OMPs(5). Here we uncover the process underpinning OMP turnover in Escherichia coli and show it to be passive and binary in nature, in which old OMPs are displaced to the poles of growing cells as new OMPs take their place. Using fluorescent colicins as OMP-specific probes, in combination with ensemble and single-molecule fluorescence microscopy in vivo and in vitro, as well as molecular dynamics simulations, we established the mechanism for binary OMP partitioning. OMPs clustered to form 0.5-mu m diameter islands, where their diffusion is restricted by promiscuous interactions with other OMPs. OMP islands were distributed throughout the cell and contained the Bam complex, which catalyses the insertion of OMPs in the outer membrane(7,8). However, OMP biogenesis occurred as a gradient that was highest at mid-cell but largely absent at cell poles. The cumulative effect is to push old OMP islands towards the poles of growing cells, leading to a binary distribution when cells divide. Hence, the outer membrane of a Gram-negative bacterium is a spatially and temporally organized structure, and this organization lies at the heart of how OMPs are turned over in the membrane.
C1 [Rassam, Patrice; Chavent, Matthieu; Duncan, Anna L.; Housden, Nicholas G.; Kaminska, Renata; Sansom, Mark S. P.; Kleanthous, Colin] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England.
   [Rassam, Patrice; Copeland, Nikki A.; Toth, Csaba; Cross, Stephen J.; Seger, Urban; Quinn, Diana M.; Garrod, Tamsin J.; Baumann, Christoph G.] Univ York, Dept Biol, York YO10 5DD, N Yorkshire, England.
   [Birkholz, Oliver; Piehler, Jacob] Univ Osnabruck, Dept Biol, D-49076 Osnabruck, Germany.
C3 University of Oxford; University of York - UK; University Osnabruck
RP Kleanthous, C (corresponding author), Univ Oxford, Dept Biochem, S Parks Rd, Oxford OX1 3QU, England.
EM christoph.baumann@york.ac.uk; colin.kleanthous@bioch.ox.ac.uk
FU Royal Society [2004/R1]; University of York (Research Priming Fund); BBSRC LoLa grant [BB/G020671/1]; Deutsche Forschungsgemeinschaft [SFB 944]; BBSRC [BB/L002558/1]; Wellcome Trust [WT092970MA]; BBSRC [BB/H000267/1, BB/G020671/1, BB/I019855/1, BB/G020671/2, BB/L002558/1] Funding Source: UKRI; EPSRC [EP/J010421/1, EP/L000253/1] Funding Source: UKRI; Biotechnology and Biological Sciences Research Council [BEP17032, BB/G020671/2, BB/H000267/1, BBS/B/16011, BB/L002558/1, BB/I019855/1, B19456, BB/G020671/1] Funding Source: researchfish; Engineering and Physical Sciences Research Council [EP/J010421/1, EP/L000253/1] Funding Source: researchfish
NR 58
TC 174
Z9 200
U1 2
U2 165
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 16
PY 2015
VL 523
IS 7560
BP 333
EP +
DI 10.1038/nature14461
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM8KY
UT WOS:000357950900039
PM 26061769
DA 2026-03-09
ER

PT J
AU Grow, EJ
   Flynn, RA
   Chavez, SL
   Bayless, NL
   Wossidlo, M
   Wesche, DJ
   Martin, L
   Ware, CB
   Blish, CA
   Chang, HY
   Pera, RAR
   Wysocka, J
AF Grow, Edward J.
   Flynn, Ryan A.
   Chavez, Shawn L.
   Bayless, Nicholas L.
   Wossidlo, Mark
   Wesche, Daniel J.
   Martin, Lance
   Ware, Carol B.
   Blish, Catherine A.
   Chang, Howard Y.
   Pera, Renee A. Reijo
   Wysocka, Joanna
TI Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells
SO NATURE
LA English
DT Article
ID herv-k; regulatory circuitry; identification; elements; protein; family; herv-k(hml-2); expression; induction; dynamics
AB Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections, and comprise nearly 8% of the human genome(1). The most recently acquired human ERV is HERVK(HML-2), which repeatedly infected the primate lineage both before and after the divergence of the human and chimpanzee common ancestor(2,3). Unlike most other human ERVs, HERVK retained multiple copies of intact open reading frames encoding retroviral proteins(4). However, HERVK is transcriptionally silenced by the host, with the exception of in certain pathological contexts such as germ-cell tumours, melanoma or human immunodeficiency virus (HIV) infection(5-7). Here we demonstrate that DNA hypomethylation at long terminal repeat elements representing the most recent genomic integrations, together with transactivation by OCT4 (also known as POU5F1), synergistically facilitate HERVK expression. Consequently, HERVK is transcribed during normal human embryogenesis, beginning with embryonic genome activation at the eight-cell stage, continuing through the emergence of epiblast cells in preimplantation blastocysts, and ceasing during human embryonic stem cell derivation from blastocyst outgrowths. Remarkably, we detected HERVK viral-like particles and Gag proteins in human blastocysts, indicating that early human development proceeds in the presence of retroviral products. We further show that overexpression of one such product, the HERVK accessory protein Rec, in a pluripotent cell line is sufficient to increase IFITM1 levels on the cell surface and inhibit viral infection, suggesting at least one mechanism through which HERVK can induce viral restriction pathways in early embryonic cells. Moreover, Rec directly binds a subset of cellular RNAs and modulates their ribosome occupancy, indicating that complex interactions between retroviral proteins and host factors can fine-tune pathways of early human development.
C1 [Grow, Edward J.; Wossidlo, Mark; Pera, Renee A. Reijo] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA.
   [Flynn, Ryan A.; Martin, Lance; Chang, Howard Y.] Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Flynn, Ryan A.; Martin, Lance; Chang, Howard Y.] Stanford Univ, Sch Med, Program Epithelial Biol, Stanford, CA 94305 USA.
   [Chavez, Shawn L.; Wossidlo, Mark; Wesche, Daniel J.; Pera, Renee A. Reijo; Wysocka, Joanna] Stanford Univ, Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA.
   [Chavez, Shawn L.; Wossidlo, Mark; Pera, Renee A. Reijo] Stanford Univ, Sch Med, Dept Obstet & Gynecol, Stanford, CA 94305 USA.
   [Chavez, Shawn L.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Reprod & Dev Sci, Beaverton, OR 97006 USA.
   [Bayless, Nicholas L.] Stanford Univ, Sch Med, Stanford Immunol, Stanford, CA 94305 USA.
   [Ware, Carol B.] Univ Washington, Dept Comparat Med, Seattle, WA 98195 USA.
   [Blish, Catherine A.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA.
   [Pera, Renee A. Reijo] Montana State Univ, Dept Cell Biol & Neurosci, Bozeman, MT 59717 USA.
   [Wysocka, Joanna] Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 USA.
   [Wysocka, Joanna] Stanford Univ, Sch Med, Dept Dev Biol, Stanford, CA 94305 USA.
C3 Stanford University; Howard Hughes Medical Institute; Stanford University; Stanford University; Stanford University; Stanford University; Oregon Health & Science University; Oregon National Primate Research Center; Stanford University; University of Washington; University of Washington Seattle; Stanford University; Montana State University System; Montana State University Bozeman; Stanford University; Stanford University
RP Wysocka, J (corresponding author), Stanford Univ, Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA.
EM wysocka@stanford.edu
FU National Institutes of Health (NIH) [P01GM099130, R01 GM112720]; Stanford Genome Sciences Training Program; National Science Foundation Graduate Research Fellowship Program; NIH [1F30CA189514-01, DP2AI11219301, P50-HG007735, 1S10RR02933801, 1S10RR02678001]; Smith Family Stanford Graduate Fellowship; CIRM [RB4-05763, RB3-02209]; March of Dimes [6-FY10-351, U01 HL100397]; National Cancer Institute [T32CA009302] Funding Source: NIH RePORTER; National Human Genome Research Institute [T32HG000044] Funding Source: NIH RePORTER
NR 41
TC 467
Z9 539
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 JUN 11
PY 2015
VL 522
IS 7555
BP 221
EP +
DI 10.1038/nature14308
PG 26
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700040
PM 25896322
DA 2026-03-09
ER

PT J
AU Zauri, M
   Berridge, G
   Thézénas, ML
   Pugh, KM
   Goldin, R
   Kessler, BM
   Kriaucionis, S
AF Zauri, Melania
   Berridge, Georgina
   Thezenas, Marie-Laetitia
   Pugh, Kathryn M.
   Goldin, Robert
   Kessler, Benedikt M.
   Kriaucionis, Skirmantas
TI CDA directs metabolism of epigenetic nucleosides revealing a therapeutic window in cancer
SO NATURE
LA English
DT Article
ID human-leukemic cells; monophosphate kinase; dna; expression; 5-methyl-2'-deoxycytidine; 5-hydroxymethylcytosine; 5-formylcytosine; 5-methylcytosine; replication; glycosylase
AB Cells require nucleotides to support DNA replication and repair damaged DNA. In addition to de novo synthesis, cells recycle nucleotides from the DNA of dying cells or from cellular material ingested through the diet. Salvaged nucleosides come with the complication that they can contain epigenetic modifications. Because epigenetic inheritance of DNA methylation mainly relies on copying of the modification pattern from parental strands(1-3), random incorporation of pre-modified bases during replication could have profound implications for epigenome fidelity and yield adverse cellular phenotypes. Although the salvage mechanism of 5-methyl-2'deoxycytidine (5mdC) has been investigated before(4-6), it remains unknown how cells deal with the recently identified oxidized forms of 5mdC: 5-hydroxymethyl-2'deoxycytidine (5hmdC), 5-formy-2'deoxycytidine (5fdC) and 5-carboxyl-2'deoxycytidine (5cadC)(7-10). Here we show that enzymes of the nucleotide salvage pathway display substrate selectivity, effectively protecting newly synthesized DNA from the incorporation of epigenetically modified forms of cytosine. Thus, cell lines and animals can tolerate high doses of these modified cytidines without any deleterious effects on physiology. Notably, by screening cancer cell lines for growth defects after exposure to 5hmdC, we unexpectedly identify a subset of cell lines in which 5hmdC or 5fdC administration leads to cell lethality. Using genomic approaches, we show that the susceptible cell lines overexpress cytidine deaminase (CDA). CDA converts 5hmdC and 5fdC into variants of uridine that are incorporated into DNA, resulting in accumulation of DNA damage, and ultimately, cell death. Our observations extend current knowledge of the nucleotide salvage pathway by revealing the metabolism of oxidized epigenetic bases, and suggest a new therapeutic option for cancers, such as pancreatic cancer, that have CDA overexpression and are resistant to treatment with other cytidine analogues(11).
C1 [Zauri, Melania; Kriaucionis, Skirmantas] Univ Oxford, Nuffield Dept Med, Ludwig Canc Res, Oxford OX3 7DQ, England.
   [Berridge, Georgina; Thezenas, Marie-Laetitia; Pugh, Kathryn M.; Kessler, Benedikt M.] Univ Oxford, Nuffield Dept Med, Target Discovery Inst, Oxford OX3 7FZ, England.
   [Pugh, Kathryn M.] Univ Oxford, Nuffield Dept Med, Struct Genom Consortium, Oxford OX3 7DQ, England.
   [Goldin, Robert] Univ London Imperial Coll Sci Technol & Med, Ctr Pathol, London W2 1NY, England.
C3 University of Oxford; University of Oxford; University of Oxford; Imperial College London
RP Kriaucionis, S (corresponding author), Univ Oxford, Nuffield Dept Med, Ludwig Canc Res, Oxford OX3 7DQ, England.
EM skirmantas.kriaucionis@ludwig.ox.ac.uk
FU Ludwig Cancer Research; BBSRC; John Fell Fund [133/075]; Wellcome Trust [097813/Z/11/Z]; Wellcome Trust [097813/Z/11/Z] Funding Source: Wellcome Trust; Biotechnology and Biological Sciences Research Council [BB/M001873/1] Funding Source: researchfish; BBSRC [BB/M001873/1] Funding Source: UKRI
NR 40
TC 89
Z9 111
U1 2
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 AUG 6
PY 2015
VL 524
IS 7563
BP 114
EP U269
DI 10.1038/nature14948
PG 26
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO2QS
UT WOS:000359002300043
PM 26200337
DA 2026-03-09
ER

PT J
AU Peng, DJ
   Kryczek, I
   Nagarsheth, N
   Zhao, LL
   Wei, S
   Wang, WM
   Sun, YQ
   Zhao, ED
   Vatan, L
   Szeliga, W
   Kotarski, J
   Tarkowski, R
   Dou, YL
   Cho, K
   Hensley-Alford, S
   Munkarah, A
   Liu, R
   Zou, WP
AF Peng, Dongjun
   Kryczek, Ilona
   Nagarsheth, Nisha
   Zhao, Lili
   Wei, Shuang
   Wang, Weimin
   Sun, Yuqing
   Zhao, Ende
   Vatan, Linda
   Szeliga, Wojciech
   Kotarski, Jan
   Tarkowski, Rafal
   Dou, Yali
   Cho, Kathleen
   Hensley-Alford, Sharon
   Munkarah, Adnan
   Liu, Rebecca
   Zou, Weiping
TI Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy
SO NATURE
LA English
DT Article
ID t-cells; cancer; blockade; inhibition; survival; death; model; ezh2; utx
AB Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism(1). However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (T(H)1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade(2-4) and adoptive T-cell transfusion(5) in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of T(H)1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape(6) in cancer and may enhance the clinical efficacy of cancer therapy.
C1 [Peng, Dongjun; Kryczek, Ilona; Nagarsheth, Nisha; Wei, Shuang; Wang, Weimin; Zhao, Ende; Vatan, Linda; Szeliga, Wojciech; Zou, Weiping] Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI 48109 USA.
   [Kryczek, Ilona; Nagarsheth, Nisha; Zou, Weiping] Univ Michigan, Grad Program Immunol, Ann Arbor, MI 48109 USA.
   [Zhao, Lili] Univ Michigan, Sch Med, Dept Biostat, Ann Arbor, MI 48109 USA.
   [Sun, Yuqing; Dou, Yali; Cho, Kathleen] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA.
   [Kotarski, Jan; Tarkowski, Rafal] Med Univ Lublin, Dept Gynecol Oncol & Gynecol 1, PL-20081 Lublin, Poland.
   [Cho, Kathleen; Liu, Rebecca; Zou, Weiping] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA.
   [Hensley-Alford, Sharon; Munkarah, Adnan] Henry Ford Hlth Syst, Dept Womens Hlth Serv, Detroit, MI 48202 USA.
   [Liu, Rebecca] Univ Michigan, Sch Med, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA.
   [Zou, Weiping] Univ Michigan, Grad Program Tumor Biol, Ann Arbor, MI 48109 USA.
C3 University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Medical University of Lublin; University of Michigan System; University of Michigan; Henry Ford Health System; Henry Ford Hospital; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan
RP Zou, WP (corresponding author), Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI 48109 USA.
EM wzou@med.umich.edu
FU NIH [CA190176, CA123088, CA099985, CA156685, CA193136, CA152470, CA171306, 5P30CA46592]; Rivkin Ovarian Cancer Center; Ovarian Cancer Research Fund; National Cancer Institute [P30CA046592] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM082856] Funding Source: NIH RePORTER
NR 35
TC 968
Z9 1100
U1 8
U2 197
PU NATURE PUBLISHING 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 12
PY 2015
VL 527
IS 7577
BP 249
EP +
DI 10.1038/nature15520
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700048
PM 26503055
DA 2026-03-09
ER

PT J
AU Howell, K
   White, JG
   Hobert, O
AF Howell, Kelly
   White, John G.
   Hobert, Oliver
TI Spatiotemporal control of a novel synaptic organizer molecule
SO NATURE
LA English
DT Article
ID heterochronic gene lin-14; motor-neurons; receptor; protein; gaba; identification; transmission; motoneuron; encodes; pattern
AB Synapse formation is a process tightly controlled in space and time. How gene regulatory mechanisms specify spatial and temporal aspects of synapse formation is not well understood. In the nematode Caenorhabditis elegans, two subtypes of the D-type inhibitory motor neuron (MN) classes, the dorsal D (DD) and ventral D (VD) neurons, extend axons along both the dorsal and ventral nerve cords(1). The embryonically generated DD motor neurons initially innervate ventral muscles in the first (L1) larval stage and receive their synaptic input from cholinergic motor neurons in the dorsal cord. They rewire by the end of the L1 moult to innervate dorsal muscles and to be innervated by newly formed ventral cholinergic motor neurons(1). VD motor neurons develop after the L1 moult; they take over the innervation of ventral muscles and receive their synaptic input from dorsal cholinergic motor neurons. We show here that the spatiotemporal control of synaptic wiring of the D-type neurons is controlled by an intersectional transcriptional strategy in which the UNC-30 Pitx-type homeodomain transcription factor acts together, in embryonic and early larval stages, with the temporally controlled LIN-14 transcription factor to prevent premature synapse rewiring of the DD motor neurons and, together with the UNC-55 nuclear hormone receptor, to prevent aberrant VD synaptic wiring in later larval and adult stages. A key effector of this intersectional transcription factor combination is a novel synaptic organizer molecule, the single immunoglobulin domain protein OIG-1. OIG-1 is perisynaptically localized along the synaptic outputs of the D-type motor neurons in a temporally controlled manner and is required for appropriate selection of both pre-and post-synaptic partners.
C1 [Howell, Kelly; Hobert, Oliver] Columbia Univ, Dept Biochem & Mol Biophys, Howard Hughes Med Inst, Med Ctr, New York, NY 10032 USA.
   [White, John G.] MRC, Mol Biol Lab, Cambridge CB2 2QH, England.
C3 Columbia University; Howard Hughes Medical Institute; MRC Laboratory Molecular Biology
RP Howell, K (corresponding author), Columbia Univ, Dept Biochem & Mol Biophys, Howard Hughes Med Inst, Med Ctr, 630 W 168th St, New York, NY 10032 USA.
EM kh2512@columbia.edu; or38@columbia.edu
FU National Institutes of Health [R01NS039996-05, R01NS050266-03]; Howard Hughes Medical Institute; UK Medical Research Council; MRC [MC_U105178783] Funding Source: UKRI; National Institute of Neurological Disorders and Stroke [R01NS039996] Funding Source: NIH RePORTER; Medical Research Council [MC_U105178783] Funding Source: researchfish
NR 34
TC 53
Z9 72
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 JUL 2
PY 2015
VL 523
IS 7558
BP 83
EP +
DI 10.1038/nature14545
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL7RN
UT WOS:000357169500036
PM 26083757
DA 2026-03-09
ER

PT J
AU Krupic, J
   Bauza, M
   Burton, S
   Barry, C
   O'Keefe, J
AF Krupic, Julija
   Bauza, Marius
   Burton, Stephen
   Barry, Caswell
   O'Keefe, John
TI Grid cell symmetry is shaped by environmental geometry
SO NATURE
LA English
DT Article
ID entorhinal cortex; spatial map; rats; navigation; representation; location; memory; theta; model
AB Grid cells represent an animal's location by firing in multiple fields arranged in a striking hexagonal array(1). Such an impressive and constant regularity prompted suggestions that grid cells represent a universal and environmental-invariant metric for navigation(1,2). Originally the properties of grid patterns were believed to be independent of the shape of the environment and this notion has dominated almost all theoretical grid cell models(3-6). However, several studies indicate that environmental boundaries influence grid firing(7-10), though the strength, nature and longevity of this effect is unclear. Here we show that grid orientation, scale, symmetry and homogeneity are strongly and permanently affected by environmental geometry. We found that grid patterns orient to the walls of polarized enclosures such as squares, but not circles. Furthermore, the hexagonal grid symmetry is permanently broken in highly polarized environments such as trapezoids, the pattern being more elliptical and less homogeneous. Our results provide compelling evidence for the idea that environmental boundaries compete with the internal organization of the grid cell system to drive grid firing. Notably, grid cell activity is more local than previously thought and as a consequence cannot provide a universal spatial metric in all environments.
C1 [Krupic, Julija; Bauza, Marius; Burton, Stephen; Barry, Caswell; O'Keefe, John] UCL, Dept Cell & Dev Biol, London WC1E 6BT, England.
   [O'Keefe, John] UCL, Sainsbury Wellcome Ctr, London WC1E 6BT, England.
C3 University of London; University College London; University of London; University College London
RP Krupic, J (corresponding author), UCL, Dept Cell & Dev Biol, Mortimer St, London WC1E 6BT, England.
EM j.krupic@ucl.ac.uk
FU Wellcome Trust; Gatsby Charitable Foundation; Biotechnology and Biological Sciences Research Council [BB/J009792/1] Funding Source: researchfish; Medical Research Council [G1100669] Funding Source: researchfish; Wellcome Trust [101208/Z/13/Z, 103896/Z/14/Z] Funding Source: researchfish; Wellcome Trust [101208/Z/13/Z] Funding Source: Wellcome Trust; BBSRC [BB/J009792/1] Funding Source: UKRI
NR 23
TC 232
Z9 281
U1 1
U2 107
PU NATURE PUBLISHING 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 12
PY 2015
VL 518
IS 7538
BP 232
EP U199
DI 10.1038/nature14153
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300038
PM 25673417
DA 2026-03-09
ER

PT J
AU Elshenawy, MM
   Jergic, S
   Xu, ZQ
   Sobhy, MA
   Takahashi, M
   Oakley, AJ
   Dixon, NE
   Hamdan, SM
AF Elshenawy, Mohamed M.
   Jergic, Slobodan
   Xu, Zhi-Qiang
   Sobhy, Mohamed A.
   Takahashi, Masateru
   Oakley, Aaron J.
   Dixon, Nicholas E.
   Hamdan, Samir M.
TI Replisome speed determines the efficiency of the Tus-Ter replication termination barrier
SO NATURE
LA English
DT Article
ID escherichia-coli; dna-replication; single-molecule; chromosome-replication; polar arrest; fork trap; helicase; complex; protein; refinement
AB In all domains of life, DNA synthesis occurs bidirectionally from replication origins. Despite variable rates of replication fork progression, fork convergence often occurs at specific sites(1). Escherichia coli sets a 'replication fork trap' that allows the first arriving fork to enter but not to leave the terminus region(2-5). The trap is set by oppositely oriented Tus-bound Ter sites that block forks on approach fromonly one direction(3-7). However, the efficiency of fork blockage by Tus-Ter does not exceed 50% in vivo despite its apparent ability to almost permanently arrest replication forks in vitro(8,9). Here we use data from single-molecule DNA replication assays and structural studies to show that both polarity and fork-arrest efficiency are determined by a competition between rates of Tus displacement and rearrangement of Tus-Ter interactions that leads to blockage of slower moving replisomes by two distinct mechanisms. To our knowledge this is the first example where intrinsic differences in rates of individual replisomes have different biological outcomes.
C1 [Elshenawy, Mohamed M.; Sobhy, Mohamed A.; Takahashi, Masateru; Hamdan, Samir M.] King Abdullah Univ Sci & Technol, Div Biol & Environm Sci Engn, Thuwal 23955, Saudi Arabia.
   [Jergic, Slobodan; Xu, Zhi-Qiang; Oakley, Aaron J.; Dixon, Nicholas E.] Illawarra Hlth & Med Res, Ctr Med & Mol Biosci, Wollongong, NSW 2522, Australia.
   [Jergic, Slobodan; Xu, Zhi-Qiang; Oakley, Aaron J.; Dixon, Nicholas E.] Univ Wollongong, Wollongong, NSW 2522, Australia.
C3 King Abdullah University of Science & Technology; University of Wollongong
RP Dixon, NE (corresponding author), Illawarra Hlth & Med Res, Ctr Med & Mol Biosci, Wollongong, NSW 2522, Australia.
EM nickd@uow.edu.au; samir.hamdan@kaust.edu.sa
FU King Abdullah University of Science and Technology; Faculty Initiated Collaborative Award; Australian Research Council [DP0877658, DP0984797, FT0990287]; Australian Research Council [DP0877658, FT0990287, DP0984797] Funding Source: Australian Research Council
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   Emsley P, 2010, ACTA CRYSTALLOGR D, V66, P486, DOI 10.1107/S0907444910007493
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   Oakley AJ, 2003, ACTA CRYSTALLOGR D, V59, P1192, DOI 10.1107/S0907444903009958
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   Pandey M, 2015, NUCLEIC ACIDS RES, V43, P5924, DOI 10.1093/nar/gkv527
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   van Oijen AM, 2003, SCIENCE, V301, P1235, DOI 10.1126/science.1084387
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   Yao NY, 2009, P NATL ACAD SCI USA, V106, P13236, DOI 10.1073/pnas.0906157106
NR 36
TC 38
Z9 45
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 SEP 17
PY 2015
VL 525
IS 7569
BP 394
EP +
DI 10.1038/nature14866
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900047
PM 26322585
DA 2026-03-09
ER

PT J
AU Mateos-Gomez, PA
   Gong, FD
   Nair, N
   Miller, KM
   Lazzerini-Denchi, E
   Sfeir, A
AF Mateos-Gomez, Pedro A.
   Gong, Fade
   Nair, Nidhi
   Miller, Kyle M.
   Lazzerini-Denchi, Eros
   Sfeir, Agnel
TI Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination
SO NATURE
LA English
DT Article
ID double-strand breaks; homologous recombination; dna-replication; end-protection; repair; telomeres; instability; pathways; cells; mechanism
AB The alternative non-homologous end-joining (NHEJ) machinery facilitates several genomic rearrangements, some of which can lead to cellular transformation. This error-prone repair pathway is triggered upon telomere de-protection to promote the formation of deleterious chromosome end-to-end fusions(1-3). Using next-generation sequencing technology, here we show that repair by alternative NHEJ yields non-TTAGGG nucleotide insertions at fusion breakpoints of dysfunctional telomeres. Investigating the enzymatic activity responsible for the random insertions enabled us to identify polymerase theta (Pol theta; encoded by Polq in mice) as a crucial alternative NHEJ factor in mammalian cells. Polq inhibition suppresses alternative NHEJ at dysfunctional telomeres, and hinders chromosomal translocations at non-telomeric loci. In addition, we found that loss of Polq in mice results in increased rates of homology-directed repair, evident by recombination of dysfunctional telomeres and accumulation of RAD51 at double-stranded breaks. Lastly, we show that depletion of Pol theta has a synergistic effect on cell survival in the absence of BRCA genes, suggesting that the inhibition of this mutagenic polymerase represents a valid therapeutic avenue for tumours carrying mutations in homology-directed repair genes.
C1 [Mateos-Gomez, Pedro A.; Sfeir, Agnel] NYU, Sch Med, Dept Cell Biol, Skirball Inst Biomol Med, New York, NY 10016 USA.
   [Gong, Fade; Miller, Kyle M.] Univ Texas Austin, Inst Cellular & Mol Biol, Dept Mol Biosci, Austin, TX 78712 USA.
   [Nair, Nidhi; Lazzerini-Denchi, Eros] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA.
C3 New York University; University of Texas System; University of Texas Austin; Scripps Research Institute
RP Sfeir, A (corresponding author), NYU, Sch Med, Dept Cell Biol, Skirball Inst Biomol Med, New York, NY 10016 USA.
EM agnel.sfeir@med.nyu.edu
FU Breast Cancer Alliance; V-foundation; Department of Defense Breast Cancer Research Program [BC134020]; Pew-Stewart Scholars Award; Pew Scholars Award; Novartis Advanced Discovery Institute; National Institutes of Health (NIH) [AG038677]; Helen L. and Martin S. Kimmel Center for Stem Cell Biology; University of Texas at Austin; Cancer Prevention Research Institute of Texas (CPRIT) [R116]; National Cancer Institute [P30CA016087] Funding Source: NIH RePORTER
NR 34
TC 592
Z9 773
U1 2
U2 119
PU NATURE PUBLISHING 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 12
PY 2015
VL 518
IS 7538
BP 254
EP U285
DI 10.1038/nature14157
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300043
PM 25642960
DA 2026-03-09
ER

PT J
AU Hu, CMJ
   Fang, RH
   Wang, KC
   Luk, BT
   Thamphiwatana, S
   Dehaini, D
   Nguyen, P
   Angsantikul, P
   Wen, CH
   Kroll, AV
   Carpenter, C
   Ramesh, M
   Qu, V
   Patel, SH
   Zhu, J
   Shi, W
   Hofman, FM
   Chen, TC
   Gao, WW
   Zhang, K
   Chien, S
   Zhang, LF
AF Hu, Che-Ming J.
   Fang, Ronnie H.
   Wang, Kuei-Chun
   Luk, Brian T.
   Thamphiwatana, Soracha
   Dehaini, Diana
   Phu Nguyen
   Angsantikul, Pavimol
   Wen, Cindy H.
   Kroll, Ashley V.
   Carpenter, Cody
   Ramesh, Manikantan
   Qu, Vivian
   Patel, Sherrina H.
   Zhu, Jie
   Shi, William
   Hofman, Florence M.
   Chen, Thomas C.
   Gao, Weiwei
   Zhang, Kang
   Chien, Shu
   Zhang, Liangfang
TI Nanoparticle biointerfacing by platelet membrane cloaking
SO NATURE
LA English
DT Article
ID polymeric nanoparticles; bacterial pathogens; blood-platelets; surface; complement; delivery; expression; binding; protein; toxins
AB Development of functional nanoparticles can be encumbered by unanticipated material properties and biological events, which can affect nanoparticle effectiveness in complex, physiologically relevant systems(1-3). Despite the advances in bottom-up nanoengineering and surface chemistry, reductionist functionalization approaches remain inadequate in replicating the complex interfaces present in nature and cannot avoid exposure of foreign materials. Here we report on the preparation of polymeric nanoparticles enclosed in the plasma membrane of human platelets, which are a unique population of cellular fragments that adhere to a variety of disease-relevant substrates(4-7). The resulting nanoparticles possess a right-side-out unilamellar membrane coating functionalized with immunomodulatory and adhesion antigens associated with platelets. Compared to uncoated particles, the platelet membrane-cloaked nanoparticles have reduced cellular uptake by macrophage-like cells and lack particle-induced complement activation in autologous human plasma. The cloaked nanoparticles also display platelet-mimicking properties such as selective adhesion to damaged human and rodent vasculatures as well as enhanced binding to platelet-adhering pathogens. In an experimental rat model of coronary restenosis and a mouse model of systemic bacterial infection, docetaxel and vancomycin, respectively, show enhanced therapeutic efficacy when delivered by the platelet-mimetic nanoparticles. The multifaceted biointerfacing enabled by the platelet membrane cloaking method provides a new approach in developing functional nanoparticles for disease-targeted delivery.
C1 [Hu, Che-Ming J.; Fang, Ronnie H.; Thamphiwatana, Soracha; Dehaini, Diana; Angsantikul, Pavimol; Kroll, Ashley V.; Carpenter, Cody; Ramesh, Manikantan; Qu, Vivian; Gao, Weiwei; Zhang, Kang; Zhang, Liangfang] Univ Calif San Diego, Dept NanoEngn, La Jolla, CA 92093 USA.
   [Hu, Che-Ming J.; Fang, Ronnie H.; Luk, Brian T.; Thamphiwatana, Soracha; Dehaini, Diana; Angsantikul, Pavimol; Kroll, Ashley V.; Gao, Weiwei; Zhang, Liangfang] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA.
   [Wang, Kuei-Chun; Luk, Brian T.; Phu Nguyen; Chien, Shu] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA.
   [Wang, Kuei-Chun; Phu Nguyen; Zhang, Kang; Chien, Shu; Zhang, Liangfang] Univ Calif San Diego, Inst Engn Med, La Jolla, CA 92093 USA.
   [Wen, Cindy H.; Patel, Sherrina H.; Zhu, Jie; Zhang, Kang] Univ Calif San Diego, Shiley Eye Inst, La Jolla, CA 92093 USA.
   [Hofman, Florence M.; Chen, Thomas C.] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA.
   [Zhang, Kang] Vet Adm Healthcare Syst, San Diego, CA 92093 USA.
C3 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; University of California System; University of California San Diego; University of California System; University of California San Diego; University of Southern California
RP Zhang, LF (corresponding author), Univ Calif San Diego, Dept NanoEngn, La Jolla, CA 92093 USA.
EM kang.zhang@gmail.com; shuchien@ucsd.edu; zhang@ucsd.edu
FU National Institutes of Health [R01DK095168, R01HL108735, R01EY25090]; Defense Threat Reduction Agency Joint Science and Technology Office for Chemical and Biological Defense [HDTRA1-14-1-0064]; National Institutes of Health from the National Cancer Institute [R25CA153915]; National Heart Lung and Blood Institute [R01HL108735] Funding Source: NIH RePORTER
NR 30
TC 1542
Z9 1718
U1 23
U2 1468
PU NATURE PUBLISHING 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 1
PY 2015
VL 526
IS 7571
BP 118
EP +
DI 10.1038/nature15373
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS5CY
UT WOS:000362095100045
PM 26374997
DA 2026-03-09
ER

PT J
AU Lakdawala, SS
   Jayaraman, A
   Halpin, RA
   Lamirande, EW
   Shih, AR
   Stockwell, TB
   Lin, XD
   Simenauer, A
   Hanson, CT
   Vogel, L
   Paskel, M
   Minai, M
   Moore, I
   Orandle, M
   Das, SR
   Wentworth, DE
   Sasisekharan, R
   Subbarao, K
AF Lakdawala, Seema S.
   Jayaraman, Akila
   Halpin, Rebecca A.
   Lamirande, Elaine W.
   Shih, Angela R.
   Stockwell, Timothy B.
   Lin, Xudong
   Simenauer, Ari
   Hanson, Christopher T.
   Vogel, Leatrice
   Paskel, Myeisha
   Minai, Mahnaz
   Moore, Ian
   Orandle, Marlene
   Das, Suman R.
   Wentworth, David E.
   Sasisekharan, Ram
   Subbarao, Kanta
TI The soft palate is an important site of adaptation for transmissible influenza viruses
SO NATURE
LA English
DT Article
ID human respiratory-tract; airborne transmission; receptor specificity; a/h5n1 virus; in-vitro; a virus; ferrets; h1n1; hemagglutinin; pathogenesis
AB Influenza A viruses pose a major public health threat by causing seasonal epidemics and sporadic pandemics. Their epidemiological success relies on airborne transmission from person to person; however, the viral properties governing airborne transmission of influenza A viruses are complex. Influenza A virus infection is mediated via binding of the viral haemagglutinin (HA) to terminally attached alpha 2,3 or alpha 2,6 sialic acids on cell surface glycoproteins. Human influenza A viruses preferentially bind alpha 2,6-linked sialic acids whereas avian influenza A viruses bind alpha 2,3-linked sialic acids on complex glycans on airway epithelial cells(1,2). Historically, influenza A viruses with preferential association with alpha 2,3-linked sialic acids have not been transmitted efficiently by the airborne route in ferrets(3,4). Here we observe efficient airborne transmission of a 2009 pandemic H1N1 (H1N1pdm) virus (A/California/07/2009) engineered to preferentially bind alpha 2,3-linked sialic acids. Airborne transmission was associated with rapid selection of virus with a change at a single HA site that conferred binding to long-chain alpha 2,6-linked sialic acids, without loss of alpha 2,3-linked sialic acid binding. The transmissible virus emerged in experimentally infected ferrets within 24 hours after infection and was remarkably enriched in the soft palate, where long-chain alpha 2,6-linked sialic acids predominate on the nasopharyngeal surface. Notably, presence of long-chain alpha 2,6-linked sialic acids is conserved in ferret, pig and human soft palate. Using a loss-of-function approach with this one virus, we demonstrate that the ferret soft palate, a tissue not normally sampled in animal models of influenza, rapidly selects for transmissible influenza A viruses with human receptor (alpha 2,6-linked sialic acids) preference.
C1 [Lakdawala, Seema S.; Lamirande, Elaine W.; Shih, Angela R.; Hanson, Christopher T.; Vogel, Leatrice; Paskel, Myeisha; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA.
   [Jayaraman, Akila; Sasisekharan, Ram] MIT, Dept Biol Engn, Koch Inst Integrat Canc Res, Singapore MIT Alliance Res & Technol, Cambridge, MA 02139 USA.
   [Halpin, Rebecca A.; Stockwell, Timothy B.; Lin, Xudong; Simenauer, Ari; Das, Suman R.; Wentworth, David E.] J Craig Venter Inst, Rockville, MD 20850 USA.
   [Minai, Mahnaz; Moore, Ian; Orandle, Marlene] NIAID, Comparat Med Branch, NIH, Bethesda, MD 20892 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Massachusetts Institute of Technology (MIT); Singapore-MIT Alliance for Research & Technology Centre (SMART); J. Craig Venter Institute; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
RP Sasisekharan, R (corresponding author), MIT, Dept Biol Engn, Koch Inst Integrat Canc Res, Singapore MIT Alliance Res & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
EM rams@mit.edu; ksubbarao@niaid.nih.gov
FU Intramural Research Program of NIAID, NIH; NIAID, NIH, DHHS [HHSN272200900007C]; NIAID/NIH Genomic Centers for Infectious Diseases (GCID) program [U19-AI-110819]; NIH Merit Award [R37 GM057073-13]; National Research Foundation supported Interdisciplinary Research group in Infectious Diseases of SMART (Singapore MIT alliance for Research and Technology); Skolkovo Foundation; National Institute of Allergy and Infectious Diseases [ZIGAI001047] Funding Source: NIH RePORTER
NR 30
TC 133
Z9 160
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 1
PY 2015
VL 526
IS 7571
BP 122
EP +
DI 10.1038/nature15379
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS5CY
UT WOS:000362095100046
PM 26416728
DA 2026-03-09
ER

PT J
AU George, J
   Lim, JS
   Jang, SJ
   Cun, YP
   Ozretic, L
   Kong, G
   Leenders, F
   Lu, X
   Fernández-Cuesta, L
   Bosco, G
   Müller, C
   Dahmen, I
   Jahchan, NS
   Park, KS
   Yang, D
   Karnezis, AN
   Vaka, D
   Torres, A
   Wang, MS
   Korbel, JO
   Menon, R
   Chun, SM
   Kim, D
   Wilkerson, M
   Hayes, N
   Engelmann, D
   Pützer, B
   Bos, M
   Michels, S
   Vlasic, I
   Seidel, D
   Pinther, B
   Schaub, P
   Becker, C
   Altmüller, J
   Yokota, J
   Kohno, T
   Iwakawa, R
   Tsuta, K
   Noguchi, M
   Muley, T
   Hoffmann, H
   Schnabel, PA
   Petersen, I
   Chen, Y
   Soltermann, A
   Tischler, V
   Choi, CM
   Kim, YH
   Massion, PP
   Zou, Y
   Jovanovic, D
   Kontic, M
   Wright, GM
   Russell, PA
   Solomon, B
   Koch, I
   Lindner, M
   Muscarella, LA
   la Torre, A
   Field, JK
   Jakopovic, M
   Knezevic, J
   Castaños-Vélez, E
   Roz, L
   Pastorino, U
   Brustugun, OT
   Lund-Iversen, M
   Thunnissen, E
   Köhler, J
   Schuler, M
   Botling, J
   Sandelin, M
   Sanchez-Cespedes, M
   Salvesen, HB
   Achter, V
   Lang, U
   Bogus, M
   Schneider, PM
   Zander, T
   Ansén, S
   Hallek, M
   Wolf, J
   Vingron, M
   Yatabe, Y
   Travis, WD
   Nürnberg, P
   Reinhardt, C
   Perner, S
   Heukamp, L
   Büttner, R
   Haas, SA
   Brambilla, E
   Peifer, M
   Sage, J
   Thomas, RK
AF George, Julie
   Lim, Jing Shan
   Jang, Se Jin
   Cun, Yupeng
   Ozretic, Luka
   Kong, Gu
   Leenders, Frauke
   Lu, Xin
   Fernandez-Cuesta, Lynnette
   Bosco, Graziella
   Mueller, Christian
   Dahmen, Ilona
   Jahchan, Nadine S.
   Park, Kwon-Sik
   Yang, Dian
   Karnezis, Anthony N.
   Vaka, Dedeepya
   Torres, Angela
   Wang, Maia Segura
   Korbel, Jan O.
   Menon, Roopika
   Chun, Sung-Min
   Kim, Deokhoon
   Wilkerson, Matt
   Hayes, Neil
   Engelmann, David
   Puetzer, Brigitte
   Bos, Marc
   Michels, Sebastian
   Vlasic, Ignacija
   Seidel, Danila
   Pinther, Berit
   Schaub, Philipp
   Becker, Christian
   Altmueller, Janine
   Yokota, Jun
   Kohno, Takashi
   Iwakawa, Reika
   Tsuta, Koji
   Noguchi, Masayuki
   Muley, Thomas
   Hoffmann, Hans
   Schnabel, Philipp A.
   Petersen, Iver
   Chen, Yuan
   Soltermann, Alex
   Tischler, Verena
   Choi, Chang-min
   Kim, Yong-Hee
   Massion, Pierre P.
   Zou, Yong
   Jovanovic, Dragana
   Kontic, Milica
   Wright, Gavin M.
   Russell, Prudence A.
   Solomon, Benjamin
   Koch, Ina
   Lindner, Michael
   Muscarella, Lucia A.
   la Torre, Annamaria
   Field, John K.
   Jakopovic, Marko
   Knezevic, Jelena
   Castanos-Velez, Esmeralda
   Roz, Luca
   Pastorino, Ugo
   Brustugun, Odd-Terje
   Lund-Iversen, Marius
   Thunnissen, Erik
   Koehler, Jens
   Schuler, Martin
   Botling, Johan
   Sandelin, Martin
   Sanchez-Cespedes, Montserrat
   Salvesen, Helga B.
   Achter, Viktor
   Lang, Ulrich
   Bogus, Magdalena
   Schneider, Peter M.
   Zander, Thomas
   Ansen, Sascha
   Hallek, Michael
   Wolf, Juergen
   Vingron, Martin
   Yatabe, Yasushi
   Travis, William D.
   Nuernberg, Peter
   Reinhardt, Christian
   Perner, Sven
   Heukamp, Lukas
   Buettner, Reinhard
   Haas, Stefan A.
   Brambilla, Elisabeth
   Peifer, Martin
   Sage, Julien
   Thomas, Roman K.
TI Comprehensive genomic profiles of small cell lung cancer
SO NATURE
LA English
DT Article
ID cycle arrest; c-kit; neuroendocrine; mutations; notch; carcinoma; pathway; growth; genes; heterogeneity
AB We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
C1 [George, Julie; Cun, Yupeng; Leenders, Frauke; Lu, Xin; Fernandez-Cuesta, Lynnette; Bosco, Graziella; Mueller, Christian; Dahmen, Ilona; Bos, Marc; Seidel, Danila; Pinther, Berit; Schaub, Philipp; Peifer, Martin; Thomas, Roman K.] Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany.
   [Lim, Jing Shan; Jahchan, Nadine S.; Park, Kwon-Sik; Yang, Dian; Vaka, Dedeepya; Torres, Angela; Sage, Julien] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA.
   [Lim, Jing Shan; Jahchan, Nadine S.; Park, Kwon-Sik; Yang, Dian; Vaka, Dedeepya; Torres, Angela; Sage, Julien] Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
   [Jang, Se Jin; Chun, Sung-Min] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul 138736, South Korea.
   [Jang, Se Jin; Chun, Sung-Min] Univ Ulsan, Coll Med, Asan Med Ctr, Ctr Canc Genome Discovery, Seoul 138736, South Korea.
   [Ozretic, Luka; Heukamp, Lukas; Buettner, Reinhard; Thomas, Roman K.] Univ Hosp Cologne, Dept Pathol, D-50937 Cologne, Germany.
   [Kong, Gu] Hanyang Univ, Dept Pathol, Coll Med, Seoul 133791, South Korea.
   [Karnezis, Anthony N.] Vancouver Gen Hosp, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada.
   [Wang, Maia Segura; Korbel, Jan O.] European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany.
   [Menon, Roopika] Univ Hosp Bonn, Inst Pathol, Ctr Integrated Oncol Cologne Bonn, D-53127 Bonn, Germany.
   [Kim, Deokhoon; Perner, Sven] Univ Ulsan, Coll Med, Asan Med Ctr, Ctr Canc Genome Discovery, Seoul 138736, South Korea.
   [Wilkerson, Matt] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC 27599 USA.
   [Hayes, Neil] Univ N Carolina, UNC Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA.
   [Engelmann, David; Puetzer, Brigitte] Univ Rostock, Med Ctr, Inst Expt Gene Therapy & Canc Res, D-18057 Rostock, Germany.
   [Michels, Sebastian; Ansen, Sascha; Hallek, Michael; Wolf, Juergen] Univ Hosp Cologne, Ctr Integrated Oncol Cologne Bonn, Dept Internal Med 1, D-50937 Cologne, Germany.
   [Vlasic, Ignacija; Reinhardt, Christian] Univ Hosp Cologne, Dept Internal Med, D-50931 Cologne, Germany.
   [Becker, Christian; Altmueller, Janine; Nuernberg, Peter] Univ Cologne, CCG, D-50931 Cologne, Germany.
   [Altmueller, Janine] Univ Hosp Cologne, Inst Human Genet, D-50931 Cologne, Germany.
   [Yokota, Jun; Kohno, Takashi; Iwakawa, Reika] Natl Canc Ctr, Res Inst, Div Genome Biol, Chuo Ku, Tokyo 1040045, Japan.
   [Yokota, Jun] Inst Predict & Personalized Med Canc IMPPC, Genom & Epigen Canc Predict Program, Barcelona 08916, Spain.
   [Tsuta, Koji] Natl Canc Ctr, Dept Pathol & Clin Labs, Chuo Ku, Tokyo 1040045, Japan.
   [Noguchi, Masayuki] Univ Tsukuba, Fac Med, Dept Pathol, Tsukuba, Ibaraki 3058575, Japan.
   [Muley, Thomas; Hoffmann, Hans] Univ Heidelberg Hosp, Thoraxklin, D-69126 Heidelberg, Germany.
   [Muley, Thomas; Schnabel, Philipp A.] TLRC H, D-69126 Heidelberg, Germany.
   [Schnabel, Philipp A.] Heidelberg Univ, Inst Pathol, D-69120 Heidelberg, Germany.
   [Petersen, Iver; Chen, Yuan] Univ Jena, Jena Univ Hosp, Inst Pathol, D-07743 Jena, Germany.
   [Soltermann, Alex; Tischler, Verena] Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland.
   [Choi, Chang-min] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Oncol, Seoul 138736, South Korea.
   [Kim, Yong-Hee] Univ Ulsan, Coll Med, Dept Thorac & Cardiovasc Surg, Asan Med Ctr, Seoul 138736, South Korea.
   [Massion, Pierre P.; Zou, Yong] Vanderbilt Ingram Canc Ctr, Thorac Program, Nashville, TN 37232 USA.
   [Jovanovic, Dragana; Kontic, Milica] Univ Belgrade, Sch Med, Univ Hosp Pulmonol, Clin Ctr Serbia, Belgrade 11000, Serbia.
   [Wright, Gavin M.] St Vincents Hosp, Peter MacCallum Canc Ctr, Dept Surg, Melbourne, Vic 3065, Australia.
   [Russell, Prudence A.] St Vincents Hosp, Peter MacCallum Canc Ctr, Dept Pathol, Melbourne, Vic 3065, Australia.
   Peter MacCallum Canc Ctr, Dept Haematol & Med Oncol, Melbourne, Vic 3065, Australia.
   [Koch, Ina; Lindner, Michael] Asklepios Fachkliniken, Comprehens Pneumol Ctr Munich, Asklepios Biobank Lungenerkrankungen, D-82131 Munich, Germany.
   [Muscarella, Lucia A.; la Torre, Annamaria] IRCCS Casa Sollievo Sofferenza, Lab Oncol, I-71013 San Giovanni, Rotondo, Italy.
   [Field, John K.] Univ Liverpool, Canc Res Ctr, Roy Castle Lung Canc Res Programme, Dept Mol & Clin Canc Med,Inst Translat Med, Liverpool L69 3GA, Merseyside, England.
   [Jakopovic, Marko] Univ Zagreb, Sch Med, Dept Resp Dis Jordanovac, Univ Hosp Ctr Zagreb, Zagreb 10000, Croatia.
   [Knezevic, Jelena] Rudjer Boskovic Inst, Lab Translat Med, Zagreb 10000, Croatia.
   [Castanos-Velez, Esmeralda] Charite Campus Mitte, Charite Comprehens Canc Ctr, D-10115 Berlin, Germany.
   [Roz, Luca] Fdn IRCCS Ist Nazl Tumori, Dept Expt Oncol & Mol Med, Tumor Genom Unit, I-20133 Milan, Italy.
   [Pastorino, Ugo] Fdn IRCCS Ist Nazl Tumori, Dept Surg, Thorac Surg Unit, I-20133 Milan, Italy.
   [Brustugun, Odd-Terje] Univ Oslo, Fac Med, Inst Clin Med, N-0424 Oslo, Norway.
   [Brustugun, Odd-Terje] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Oncol, N-0310 Oslo, Norway.
   [Lund-Iversen, Marius] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Pathol, N-0310 Oslo, Norway.
   [Thunnissen, Erik] Vrije Univ Amsterdam Med Ctr, Dept Pathol, NL-1007 MB Amsterdam, Netherlands.
   [Koehler, Jens; Schuler, Martin] Univ Hosp Essen, Dept Med Oncol, West German Canc Ctr, D-45147 Essen, Germany.
   [Koehler, Jens; Schuler, Martin] German Canc Consortium DKTK, D-69120 Heidelberg, Germany.
   [Botling, Johan; Sandelin, Martin] Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden.
   [Botling, Johan; Sandelin, Martin] Uppsala Univ, Dept Med Sci Resp Allergy & Sleep Res, S-75185 Uppsala, Sweden.
   [Sanchez-Cespedes, Montserrat] Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Genes & Canc Grp, Barcelona 08908, Spain.
   [Salvesen, Helga B.] Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, N-5058 Bergen, Norway.
   [Salvesen, Helga B.] Haukeland Hosp, Dept Gynecol & Obstet, N-5058 Bergen, Norway.
   [Achter, Viktor; Lang, Ulrich] Univ Cologne, Ctr Comp, D-50931 Cologne, Germany.
   [Lang, Ulrich; Bogus, Magdalena] Univ Cologne, Dept Informat, D-50931 Cologne, Germany.
   [Schneider, Peter M.] Univ Cologne, Inst Legal Med, D-50823 Cologne, Germany.
   [Zander, Thomas] Univ Hosp Cologne, Dept Internal Med 1, Ctr Integrated Oncol Cologne Bonn, Gastrointestinal Canc Grp Cologne, D-50937 Cologne, Germany.
   [Hallek, Michael; Nuernberg, Peter] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany.
   [Vingron, Martin; Haas, Stefan A.] Max Planck Inst Mol Genet, Computat Mol Biol Grp, D-14195 Berlin, Germany.
   [Yatabe, Yasushi] Aichi Canc Ctr, Dept Pathol & Mol Diagnost, Nagoya, Aichi 4648681, Japan.
   [Travis, William D.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA.
   [Nuernberg, Peter; Peifer, Martin] Univ Cologne, CMMC, D-50931 Cologne, Germany.
   [Brambilla, Elisabeth] Univ Grenoble 1, Inst Albert Bonniot 38043, Dept Pathol, CHU Grenoble,INSERM,U823, F-38043 Grenoble, France.
C3 University of Cologne; Stanford University; Stanford University; University of Ulsan; Asan Medical Center; University of Ulsan; Asan Medical Center; University of Cologne; Hanyang University; University of British Columbia; European Molecular Biology Laboratory (EMBL); University of Bonn; University of Ulsan; Asan Medical Center; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of Rostock; University of Cologne; University of Cologne; University of Cologne; University of Cologne; National Cancer Center - Japan; National Cancer Center - Japan; University of Tsukuba; Ruprecht Karls University Heidelberg; Ruprecht Karls University Heidelberg; Friedrich Schiller University of Jena; University of Zurich; University Zurich Hospital; University of Ulsan; Asan Medical Center; University of Ulsan; Asan Medical Center; Vanderbilt University; University of Belgrade; Peter Maccallum Cancer Center; NSW Health; St Vincents Hospital Sydney; St Vincent's Health; St Vincent's Hospital Melbourne; Peter Maccallum Cancer Center; St Vincent's Health; St Vincent's Hospital Melbourne; NSW Health; St Vincents Hospital Sydney; Peter Maccallum Cancer Center; IRCCS Casa Sollievo Della Sofferenza; University of Liverpool; University of Zagreb; University of Zagreb Hospital; Rudjer Boskovic Institute; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Fondazione IRCCS Istituto Nazionale Tumori Milan; Fondazione IRCCS Istituto Nazionale Tumori Milan; University of Oslo; University of Oslo; University of Oslo; Vrije Universiteit Amsterdam; Amsterdam University Medical Center; University of Duisburg Essen; Helmholtz Association; German Cancer Research Center (DKFZ); Uppsala University; Uppsala University; Institut d'Investigacio Biomedica de Bellvitge (IDIBELL); University of Bergen; University of Bergen; Haukeland University Hospital; University of Cologne; University of Cologne; University of Cologne; University of Cologne; University of Cologne; Max Planck Society; Aichi Cancer Center; Memorial Sloan Kettering Cancer Center; University of Cologne; Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); CHU Grenoble Alpes; Institut National de la Sante et de la Recherche Medicale (Inserm)
RP Thomas, RK (corresponding author), Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany.
EM mpeifer@uni-koeln.de; julsage@stanford.edu; roman.thomas@uni-koeln.de
FU DFG; German Cancer Aid (Deutsche Krebshilfe) as part of the small cell lung cancer genome sequencing consortium [109679]; Korea Research Foundation [KRF 2011-0030105]; NIH [5R01CA114102-08]; German Ministry of Science and Education (BMBF) [01GS08101, 01ZX1303A, 01ZX1406]; Deutsche Forschungsgemeinschaft (DFG) [TH1386/3-1, KFO-286]; German federal state North Rhine Westphalia (NRW); European Union as part of the PerMed NRW initiative [005-1111-0025]; Deutsche Krebshilfe as part of the Oncology Centers of Excellence; EU [HEALTH-F2-2010-258677]; Stand Up To Cancer-American Association of Cancer Research Innovative Research Grant [SU2C-AACR-IR60109]; German Consortium for Translational Cancer Research (DKTK); National Cancer Center Research and Development Fund [NCC Biobank: 23A-1]; Italian Ministry of Health [RC1303LO57, 2010-2316264]; Roy Castle Lung Cancer Foundation UK; AIRC/MGAF [12983]; A*STAR in Singapore;  [SFB832];  [TP6];  [TP5]; Grants-in-Aid for Scientific Research [25293090] Funding Source: KAKEN
NR 50
TC 1819
Z9 2044
U1 11
U2 256
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 6
PY 2015
VL 524
IS 7563
BP 47
EP 53
DI 10.1038/nature14664
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO2QS
UT WOS:000359002300029
PM 26168399
DA 2026-03-09
ER

PT J
AU Zhang, L
   Zhan, SY
   Yao, J
   Lowery, FJ
   Zhang, QL
   Huang, WC
   Li, P
   Li, M
   Wang, X
   Zhang, CY
   Wang, H
   Ellis, K
   Cheerathodi, M
   McCarty, JH
   Palmieri, D
   Saunus, J
   Lakhani, S
   Huang, SY
   Sahin, AA
   Aldape, KD
   Steeg, PS
   Yu, DH
AF Zhang, Lin
   Zhan, Siyuan
   Yao, Jun
   Lowery, Frank J.
   Zhang, Qingling
   Huang, Wen-Chien
   Li, Ping
   Li, Min
   Wang, Xiao
   Zhang, Chenyu
   Wang, Hai
   Ellis, Kenneth
   Cheerathodi, Mujeeburahiman
   McCarty, Joseph H.
   Palmieri, Diane
   Saunus, Jodi
   Lakhani, Sunil
   Huang, Suyun
   Sahin, Aysegul A.
   Aldape, Kenneth D.
   Steeg, Patricia S.
   Yu, Dihua
TI Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth
SO NATURE
LA English
DT Article
ID breast-cancer; cells; mir-17-92; phosphatase; family
AB The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells' adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites(1). Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs(2). Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth(3,4). Yet, it is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumour cells leads to an increased secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumour cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth. Our findings signify the dynamic and reciprocal cross-talk between tumour cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for brain metastasis patients.
C1 [Zhang, Lin; Zhan, Siyuan; Yao, Jun; Lowery, Frank J.; Zhang, Qingling; Huang, Wen-Chien; Li, Ping; Li, Min; Wang, Xiao; Zhang, Chenyu; Wang, Hai; Ellis, Kenneth; Yu, Dihua] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA.
   [Zhang, Lin; Lowery, Frank J.; Yu, Dihua] Univ Texas Houston, Hlth Sci Ctr, Grad Sch Biomed Sci, Canc Biol Program, Houston, TX 77030 USA.
   [Zhan, Siyuan] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA.
   [Cheerathodi, Mujeeburahiman; McCarty, Joseph H.; Huang, Suyun] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA.
   [Palmieri, Diane; Steeg, Patricia S.] NCI, Womans Malignancies Branch, Bethesda, MD 20892 USA.
   [Saunus, Jodi; Lakhani, Sunil] Univ Queensland, Clin Res Ctr, Brisbane, Qld 4029, Australia.
   [Lakhani, Sunil] Sch Med & Pathol Queensland, Brisbane, Qld 4029, Australia.
   [Lakhani, Sunil] Royal Brisbane & Womens Hosp, Brisbane, Qld 4029, Australia.
   [Sahin, Aysegul A.; Aldape, Kenneth D.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA.
   [Yu, Dihua] China Med Univ, Ctr Mol Med, Taichung 40402, Taiwan.
C3 University of Texas System; UTMD Anderson Cancer Center; University of Texas System; University of Texas Health Science Center Houston; University of Notre Dame; University of Texas System; UTMD Anderson Cancer Center; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); University of Queensland; Royal Brisbane & Women's Hospital; University of Texas System; UTMD Anderson Cancer Center; China Medical University Taiwan
RP Yu, DH (corresponding author), Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA.
EM dyu@mdanderson.org
FU DOD Center of Excellence [W81XWH-06-2-0033]; NIH [5R00CA158066-05]; DOD [W81XWH-11-1-0003]; Isaiah Fidler Fellowship in Cancer [PO1-CA099031]; Susan G. Komen Breast Cancer Foundation [KG091020]; METAvivor Research Grant; Breast and Ovarian Cancers Moon Shot program; China Medical University Research Fund; Sowell-Huggins Pre-doctoral Fellowship and Professorship in Cancer Research;  [RO1-CA112567-06];  [R01CA184836]; National Cancer Institute [P30CA016672, ZIABC010538] Funding Source: NIH RePORTER; National Institute of Neurological Disorders and Stroke [R01NS087635] Funding Source: NIH RePORTER
NR 26
TC 980
Z9 1125
U1 8
U2 392
PU NATURE PUBLISHING 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 5
PY 2015
VL 527
IS 7576
BP 100
EP 104
DI 10.1038/nature15376
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV4XV
UT WOS:000364270700051
PM 26479035
DA 2026-03-09
ER

PT J
AU Alexander, JM
   Diez, JM
   Levine, JM
AF Alexander, Jake M.
   Diez, Jeffrey M.
   Levine, Jonathan M.
TI Novel competitors shape species' responses to climate change
SO NATURE
LA English
DT Article
ID biotic interactions; plant-response; global change; dispersal; range; community; future; shifts
AB Understanding how species respond to climate change is critical for forecasting the future dynamics and distribution of pests, diseases and biological diversity(1-3). Although ecologists have long acknowledged species' direct physiological and demographic responses to climate, more recent work suggests that these direct responses can be overwhelmed by indirect effects mediated via other interacting community members(2-7). Theory suggests that some of the most dramatic impacts of community change will probably arise through the assembly of novel species combinations after asynchronous migrations with climate(8-10). Empirical tests of this prediction are rare, as existing work focuses on the effects of changing interactions between competitors that co-occur today(7,11-15). To explore how species' responses to climate warming depend on how their competitors migrate to track climate, we transplanted alpine plant species and intact plant communities along a climate gradient in the Swiss Alps. Here we show that when alpine plants were transplanted to warmer climates to simulate a migration failure, their performance was strongly reduced by novel competitors that could migrate upwards from lower elevation; these effects generally exceeded the impact of warming on competition with current competitors. In contrast, when we grew the focal plants under their current climate to simulate climate tracking, a shift in the competitive environment to novel high-elevation competitors had little to no effect. This asymmetry in the importance of changing competitor identity at the leading versus trailing range edges is best explained by the degree of functional similarity between current and novel competitors. We conclude that accounting for novel competitive interactions may be essential to predict species' responses to climate change accurately.
C1 [Alexander, Jake M.; Levine, Jonathan M.] ETH, Inst Integrat Biol, CH-8092 Zurich, Switzerland.
   [Diez, Jeffrey M.] Univ Calif Riverside, Dept Bot & Plant Sci, Riverside, CA 92521 USA.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich; University of California System; University of California Riverside
RP Alexander, JM (corresponding author), ETH, Inst Integrat Biol, Univ Str 16, CH-8092 Zurich, Switzerland.
EM jake.alexander@usys.ethz.ch
FU ETH Zurich
NR 30
TC 545
Z9 642
U1 14
U2 626
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD SEP 24
PY 2015
VL 525
IS 7570
BP 515
EP +
DI 10.1038/nature14952
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR8KI
UT WOS:000361599900050
PM 26374998
DA 2026-03-09
ER

PT J
AU Hofmann, J
   Hahm, HS
   Seeberger, PH
   Pagel, K
AF Hofmann, J.
   Hahm, H. S.
   Seeberger, P. H.
   Pagel, K.
TI Identification of carbohydrate anomers using ion mobility-mass spectrometry
SO NATURE
LA English
DT Article
ID collision cross-sections; solid-phase synthesis; isomeric oligosaccharides; automated synthesis; n-glycans; separation; ms
AB Carbohydrates are ubiquitous biological polymers that are important in a broad range of biological processes(1-3). However, owing to their branched structures and the presence of stereogenic centres at each glycosidic linkage between monomers, carbohydrates are harder to characterize than are peptides and oligonucleotides(4). Methods such as nuclear magnetic resonance spectroscopy can be used to characterize glycosidic linkages, but this technique requires milligram amounts of material and cannot detect small amounts of coexisting isomers(5). Mass spectrometry, on the other hand, can provide information on carbohydrate composition and connectivity for even small amounts of sample, but it cannot be used to distinguish between stereoisomers(6). Here, we demonstrate that ion mobility-mass spectrometry-a method that separates molecules according to their mass, charge, size, and shape-can unambiguously identify carbohydrate linkage-isomers and stereoisomers. We analysed six synthetic carbohydrate isomers that differ in composition, connectivity, or configuration. Our data show that coexisting carbohydrate isomers can be identified, and relative concentrations of the minor isomer as low as 0.1 per cent can be detected. In addition, the analysis is rapid, and requires no derivatization and only small amounts of sample. These results indicate that ion-mobility-mass spectrometry is an effective tool for the analysis of complex carbohydrates. This method could have an impact on the field of carbohydrate synthesis similar to that of the advent of high-performance liquid chromatography on the field of peptide assembly in the late 1970s.
C1 [Hofmann, J.; Pagel, K.] Max Planck Gesell, Fritz Haber Inst, D-14195 Berlin, Germany.
   [Hofmann, J.; Hahm, H. S.; Seeberger, P. H.; Pagel, K.] Free Univ Berlin, Inst Chem & Biochem, D-14195 Berlin, Germany.
   [Hahm, H. S.; Seeberger, P. H.] Max Planck Inst Colloids & Interfaces, Dept Biomol Syst, D-14476 Potsdam, Germany.
C3 Max Planck Society; Fritz Haber Institute of the Max Planck Society; Free University of Berlin; Max Planck Society
RP Seeberger, PH (corresponding author), Max Planck Inst Colloids & Interfaces, Dept Biomol Syst, Muhlenberg 1, D-14476 Potsdam, Germany.
EM peter.seeberger@mpikg.mpg.de; kevin.pagel@fu-berlin.de
FU Free University Berlin; Max Planck Society
NR 33
TC 308
Z9 375
U1 8
U2 381
PU NATURE PUBLISHING 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 8
PY 2015
VL 526
IS 7572
BP 241
EP +
DI 10.1038/nature15388
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS9GV
UT WOS:000362399000044
PM 26416727
DA 2026-03-09
ER

PT J
AU Band, G
   Rockett, KA
   Spencer, CCA
   Kwiatkowski, DP
   Band, G
   Le, QS
   Clarke, GM
   Kivinen, K
   Leffler, EM
   Rockett, KA
   Kwiatkowski, DP
   Spencer, CCA
   Rockett, KA
   Spencer, CCA
   Cornelius, V
   Conway, DJ
   Williams, TN
   Taylor, T
   Kwiatkowski, DP
   Conway, DJ
   Bojang, KA
   Doumbo, O
   Thera, MA
   Modiano, D
   Sirima, SB
   Wilson, MD
   Koram, KA
   Agbenyega, T
   Achidi, E
   Williams, TN
   Marsh, K
   Reyburn, H
   Drakeley, C
   Riley, E
   Taylor, T
   Molyneux, M
   Jallow, M
   Bojang, KA
   Conway, DJ
   Pinder, M
   Doumbo, O
   Thera, MA
   Toure, OB
   Konate, S
   Sissoko, S
   Bougouma, EC
   Mangano, VD
   Modiano, D
   Sirima, SB
   Amenga-Etego, LN
   Ghansah, AK
   Hodgson, AVO
   Koram, KA
   Wilson, MD
   Agbenyega, T
   Ansong, D
   Enimil, A
   Evans, J
   Achidi, E
   Apinjoh, TO
   Macharia, A
   Marsh, K
   Ndila, CM
   Newton, C
   Peshu, N
   Uyoga, S
   Williams, TN
   Drakeley, C
   Manjurano, A
   Reyburn, H
   Riley, E
   Kachala, D
   Molyneux, M
   Nyirongo, V
   Taylor, T
   Rockett, KA
   Kivinen, K
   Mead, D
   Drury, E
   Auburn, S
   Campino, SG
   MacInnis, B
   Stalker, J
   Gray, E
   Hubbart, C
   Jeffreys, AE
   Rowlands, K
   Mendy, A
   Craik, R
   Fitzpatrick, K
   Molloy, S
   Hart, L
   Hutton, R
   Kerasidou, A
   Johnson, KJ
   Cornelius, V
AF Band, Gavin
   Rockett, Kirk A.
   Spencer, Chris C. A.
   Kwiatkowski, Dominic P.
   Band, Gavin
   Le, Quang Si
   Clarke, Geraldine M.
   Kivinen, Katja
   Leffler, Ellen M.
   Rockett, Kirk A.
   Kwiatkowski, Dominic P.
   Spencer, Chris C. A.
   Rockett, Kirk A.
   Spencer, Chris C. A.
   Cornelius, Victoria
   Conway, David J.
   Williams, Thomas N.
   Taylor, Terrie
   Kwiatkowski, Dominic P.
   Conway, David J.
   Bojang, Kalifa A.
   Doumbo, Ogobara
   Thera, Mahamadou A.
   Modiano, David
   Sirima, Sodiomon B.
   Wilson, Michael D.
   Koram, Kwadwo A.
   Agbenyega, Tsiri
   Achidi, Eric
   Williams, Thomas N.
   Marsh, Kevin
   Reyburn, Hugh
   Drakeley, Chris
   Riley, Eleanor
   Taylor, Terrie
   Molyneux, Malcolm
   Jallow, Muminatou
   Bojang, Kalifa A.
   Conway, David J.
   Pinder, Margaret
   Doumbo, Ogobara
   Thera, Mahamadou A.
   Toure, Ousmane B.
   Konate, Salimata
   Sissoko, Sibiri
   Bougouma, Edith C.
   Mangano, Valentina D.
   Modiano, David
   Sirima, Sodiomon B.
   Amenga-Etego, Lucas N.
   Ghansah, Anita K.
   Hodgson, Abraham V. O.
   Koram, Kwadwo A.
   Wilson, Michael D.
   Agbenyega, Tsiri
   Ansong, Daniel
   Enimil, Anthony
   Evans, Jennifer
   Achidi, Eric
   Apinjoh, Tobias O.
   Macharia, Alexander
   Marsh, Kevin
   Ndila, Carolyne M.
   Newton, Charles
   Peshu, Norbert
   Uyoga, Sophie
   Williams, Thomas N.
   Drakeley, Chris
   Manjurano, Alphaxard
   Reyburn, Hugh
   Riley, Eleanor
   Kachala, David
   Molyneux, Malcolm
   Nyirongo, Vysaul
   Taylor, Terrie
   Rockett, Kirk A.
   Kivinen, Katja
   Mead, Daniel
   Drury, Eleanor
   Auburn, Sarah
   Campino, Susana G.
   MacInnis, Bronwyn
   Stalker, Jim
   Gray, Emma
   Hubbart, Christina
   Jeffreys, Anna E.
   Rowlands, Kate
   Mendy, Alieu
   Craik, Rachel
   Fitzpatrick, Kathryn
   Molloy, Sile
   Hart, Lee
   Hutton, Robert
   Kerasidou, Angeliki
   Johnson, Kimberly J.
   Cornelius, Victoria
TI A novel locus of resistance to severe malaria in a region of ancient balancing selection
SO NATURE
LA English
DT Article
ID genome-wide association; plasmodium-falciparum; natural-selection; population-structure; origin; susceptibility; polymorphisms; glycophorins; algorithm; receptor
AB The high prevalence of sickle haemoglobin in Africa shows that malaria has been a major force for human evolutionary selection, but surprisingly few other polymorphisms have been proven to confer resistance to malaria in large epidemiological studies(1-3). To address this problem, we conducted a multi-centre genome-wide association study (GWAS) of life-threatening Plasmodium falciparum infection (severe malaria) in over 11,000 African children, with replication data in a further 14,000 individuals. Here we report a novel malaria resistance locus close to a cluster of genes encoding glycophorins that are receptors for erythrocyte invasion by P. falciparum. We identify a haplotype at this locus that provides 33% protection against severe malaria (odds ratio = 0.67, 95% confidence interval = 0.60-0.76, P value = 9.5 x 10(-11)) and is linked to polymorphisms that have previously been shown to have features of ancient balancing selection, on the basis of haplotype sharing between humans and chimpanzees(4). Taken together with previous observations on the malaria-protective role of blood group O-1-3,O-5, these data reveal that two of the strongest GWAS signals for severe malaria lie in or close to genes encoding the glycosylated surface coat of the erythrocyte cell membrane, both within regions of the genome where it appears that evolution has maintained diversity for millions of years. These findings provide new insights into the host-parasite interactions that are critical in determining the outcome of malaria infection.
C1 [Band, Gavin; Rockett, Kirk A.; Spencer, Chris C. A.; Kwiatkowski, Dominic P.; Band, Gavin; Le, Quang Si; Clarke, Geraldine M.; Leffler, Ellen M.; Rockett, Kirk A.; Kwiatkowski, Dominic P.; Spencer, Chris C. A.; Rockett, Kirk A.; Spencer, Chris C. A.; Cornelius, Victoria; Kwiatkowski, Dominic P.; Rockett, Kirk A.; Auburn, Sarah; Hubbart, Christina; Jeffreys, Anna E.; Rowlands, Kate; Mendy, Alieu; Craik, Rachel; Fitzpatrick, Kathryn; Molloy, Sile; Hart, Lee; Hutton, Robert; Kerasidou, Angeliki; Johnson, Kimberly J.; Cornelius, Victoria] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.
   [Rockett, Kirk A.; Kivinen, Katja; Kwiatkowski, Dominic P.; Rockett, Kirk A.; Kwiatkowski, Dominic P.; Rockett, Kirk A.; Kivinen, Katja; Mead, Daniel; Drury, Eleanor; Campino, Susana G.; MacInnis, Bronwyn; Stalker, Jim; Gray, Emma] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.
   [Conway, David J.; Conway, David J.; Bojang, Kalifa A.; Jallow, Muminatou; Bojang, Kalifa A.; Conway, David J.; Pinder, Margaret] MRC Unit, Fajara, Gambia.
   [Conway, David J.; Conway, David J.] Univ London London Sch Hyg & Trop Med, Dept Pathogen Mol Biol, London WC1E 7HT, England.
   [Williams, Thomas N.; Williams, Thomas N.; Marsh, Kevin; Macharia, Alexander; Marsh, Kevin; Ndila, Carolyne M.; Newton, Charles; Peshu, Norbert; Uyoga, Sophie; Williams, Thomas N.] KEMRI Wellcome Trust Res Programme CGMRC, Kilifi, Kenya.
   [Williams, Thomas N.; Williams, Thomas N.; Williams, Thomas N.] Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Med, London SW7 2AZ, England.
   [Taylor, Terrie; Taylor, Terrie; Taylor, Terrie] Queen Elizabeth Cent Hosp, Coll Med, Blantyre Malaria Project, Chichiri, Malawi.
   [Taylor, Terrie; Taylor, Terrie; Taylor, Terrie] Michigan State Univ, Coll Osteopath Med, E Lansing, MI 48824 USA.
   [Doumbo, Ogobara; Thera, Mahamadou A.; Doumbo, Ogobara; Thera, Mahamadou A.; Toure, Ousmane B.; Konate, Salimata; Sissoko, Sibiri] Univ Bamako, Fac Med, Malaria Res & Training Ctr, Bamako, Mali.
   [Modiano, David; Mangano, Valentina D.; Modiano, David] Univ Roma La Sapienza, I-00185 Rome, Italy.
   [Sirima, Sodiomon B.; Bougouma, Edith C.; Sirima, Sodiomon B.] CNRFP, Ouagadougou, Burkina Faso.
   [Wilson, Michael D.; Koram, Kwadwo A.; Ghansah, Anita K.; Koram, Kwadwo A.; Wilson, Michael D.] Univ Ghana, Noguchi Mem Inst Med Res, Legon, Accra, Ghana.
   [Agbenyega, Tsiri; Agbenyega, Tsiri; Ansong, Daniel; Enimil, Anthony; Mendy, Alieu] Komfo Anokye Teaching Hosp, Kumasi, Ghana.
   [Agbenyega, Tsiri; Ansong, Daniel] Kwame Nkrumah Univ Sci & Technol, Kumasi, Ghana.
   [Achidi, Eric; Achidi, Eric] Univ Buea, Dept Med Lab Sci, Buea, South West Regi, Cameroon.
   [Reyburn, Hugh; Drakeley, Chris; Drakeley, Chris; Manjurano, Alphaxard; Reyburn, Hugh] Kilimanjaro Christian Med Ctr, Joint Malaria Programme, Moshi, Tanzania.
   [Reyburn, Hugh; Drakeley, Chris; Riley, Eleanor; Drakeley, Chris; Manjurano, Alphaxard; Reyburn, Hugh; Riley, Eleanor] Univ London London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London WC1E 7HT, England.
   [Molyneux, Malcolm; Kachala, David; Molyneux, Malcolm; Nyirongo, Vysaul] Queen Elizabeth Cent Hosp, Coll Med, Malawi Liverpool Wellcome Trust Clin Res Programm, Blantyre, Malawi.
   [Jallow, Muminatou] Royal Victoria Teaching Hosp, Banjul, Gambia.
   [Amenga-Etego, Lucas N.; Hodgson, Abraham V. O.] Navrongo Hlth Res Ctr, Navrongo, Ghana.
   [Evans, Jennifer] Bernhard Nocht Inst Trop Med, Dept Mol Med, D-20324 Hamburg, Germany.
   [Evans, Jennifer] KNUST, Sch Med Sci, Kumasi Ctr Collaborat Res, Kumasi, Ghana.
   [Apinjoh, Tobias O.] Univ Buea, Dept Biochem & Mol Biol, Buea, South West Regi, Cameroon.
   [Kerasidou, Angeliki] Univ Oxford, Nuffield Dept Populat Hlth, Ethox Ctr, Oxford OX3 7LF, England.
C3 University of Oxford; Wellcome Centre for Human Genetics; Wellcome Trust Sanger Institute; University of London; London School of Hygiene & Tropical Medicine; University of London; London School of Hygiene & Tropical Medicine; Imperial College London; University of Malawi; Michigan State University; Michigan State University College of Osteopathic Medicine; University of Bamako; Sapienza University Rome; University of Ghana; Kwame Nkrumah University Science & Technology; Kwame Nkrumah University Science & Technology; Kilimanjaro Christian Medical Centre; University of London; London School of Hygiene & Tropical Medicine; University of Malawi; Malawi-Liverpool Wellcome Trust Clinical Research Programme; QUEEN ELIZABETH CENTRAL HOSPITAL; Navrongo Health Research Center; Leibniz Association; Bernhard Nocht Institut fur Tropenmedizin; Kumasi Center for Collaborative Research; Kwame Nkrumah University Science & Technology; University of Oxford
RP Band, G (corresponding author), Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England.
FU Wellcome Trust [WT077383/Z/05/Z, 090770/Z/09/Z, 075491/Z/04, 090532/Z/09/Z, 077012/Z/05/Z, 098051, 076934/Z/05/Z, 091758/Z/10/Z, 084538]; Bill & Melinda Gates Foundation through the Foundations of the National Institutes of Health (NIH) as part of the Grand Challenges in Global Health Initiative [566]; Medical Research Council (MRC) [G0600718, G0600230]; Wellcome Trust Biomedical ethics Enhancement Award [087285]; Strategic Award [096527]; MRC [G19/9, G9901439]; Wellcome Trust Career Development Fellowship [097364/Z/11/Z]; National Institute of Allergy and Infectious Diseases (NIAID) [N01AI85346, U19AI065683]; Fogarty International Centre, NIH [D43TW001589]; Mali-NIAID/NIH International Center for Excellence in Research at the University of Sciences, Techniques, and Technology of Bamako; European Community's Seventh Framework Programme (FP7) [242095-EVIMalaR]; Central African Network for Tuberculosis, HIV/AIDS and Malaria (CANTAM) - European and Developing Countries Clinical Trials Partnership (EDCTP); Medical Research Council [G0600718, MC_UP_A900_1118, MR/M006212/1, G19/9, G0600230] Funding Source: researchfish; MRC [G0600230, MC_UP_A900_1118, MR/M006212/1, G0600718, G19/9] Funding Source: UKRI; Wellcome Trust [091758/Z/10/Z] Funding Source: Wellcome Trust
NR 52
TC 145
Z9 160
U1 3
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 OCT 8
PY 2015
VL 526
IS 7572
BP 253
EP +
DI 10.1038/nature15390
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS9GV
UT WOS:000362399000047
PM 26416757
DA 2026-03-09
ER

PT J
AU Han, JB
   Li, EW
   Chen, LQ
   Zhang, YY
   Wei, FC
   Liu, JY
   Deng, HT
   Wang, YG
AF Han, Jinbo
   Li, Erwei
   Chen, Liqun
   Zhang, Yuanyuan
   Wei, Fangchao
   Liu, Jieyuan
   Deng, Haiteng
   Wang, Yiguo
TI The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1
SO NATURE
LA English
DT Article
ID diet-induced obesity; insulin-resistance; copii vesicles; energy-balance; er-stress; sensitivity; lipogenesis; gluconeogenesis; pathway; liver
AB Abnormal accumulation of triglycerides in the liver, caused in part by increasedde novo lipogenesis, results in non-alcoholic fatty liver disease and insulin resistance(1,2). Sterol regulatory element-binding protein 1 (SREBP1), an important transcriptional regulator of lipogenesis, is synthesized as an inactive precursor that binds to the endoplasmic reticulum (ER). In response to insulin signalling, SREBP1 is transported from the ER to the Golgi in a COPII-dependent manner, processed by proteases in the Golgi, and then shuttled to the nucleus to induce lipogenic gene expression(3-5); however, the mechanisms underlying enhanced SREBP1 activity in insulin-resistant obesity and diabetes remain unclear. Here we show in mice that CREB regulated transcription coactivator 2 (CRTC2)(6) functions as a mediator of mTOR(7) signalling to modulate COPII-dependent SREBP1 processing. CRTC2 competes with Sec23A, a subunit of the COPII complex(8), to interact with Sec31A, another COPII subunit, thus disrupting SREBP1 transport. During feeding, mTOR phosphorylates CRTC2 and attenuates its inhibitory effect on COPII-dependent SREBP1 maturation. As hepatic overexpression of an mTOR-defective CRTC2 mutant in obese mice improved the lipogenic program and insulin sensitivity, these results demonstrate how the transcriptional coactivator CRTC2 regulates mTOR-mediated lipid homeostasis in the fed state and in obesity.
C1 [Han, Jinbo; Li, Erwei; Chen, Liqun; Zhang, Yuanyuan; Wei, Fangchao; Wang, Yiguo] Tsinghua Univ, Sch Life Sci, Tsinghua Peking Ctr Life Sci, MOE Key Lab Bioinformat, Beijing 100084, Peoples R China.
   [Liu, Jieyuan; Deng, Haiteng] Tsinghua Univ, Sch Life Sci, Prote Facil, Beijing 100084, Peoples R China.
C3 Tsinghua University; Tsinghua University
RP Wang, YG (corresponding author), Tsinghua Univ, Sch Life Sci, Tsinghua Peking Ctr Life Sci, MOE Key Lab Bioinformat, Beijing 100084, Peoples R China.
EM wangyiguo@biomed.tsinghua.edu.cn
FU 1000 Talents Program for Young Scholars; National Science Foundation of China [31322027, 31321003, 31471127]
NR 29
TC 271
Z9 313
U1 3
U2 172
PU NATURE PUBLISHING 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 13
PY 2015
VL 524
IS 7564
BP 243
EP +
DI 10.1038/nature14557
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900037
PM 26147081
DA 2026-03-09
ER

PT J
AU Jandzik, D
   Garnett, AT
   Square, TA
   Cattell, MV
   Yu, JK
   Medeiros, DM
AF Jandzik, David
   Garnett, Aaron T.
   Square, Tyler A.
   Cattell, Maria V.
   Yu, Jr-Kai
   Medeiros, Daniel M.
TI Evolution of the new vertebrate head by co-option of an ancient chordate skeletal tissue
SO NATURE
LA English
DT Article
ID fibroblast-growth-factor; neural crest; cartilaginous tissue; gene; amphioxus; lamprey; soxe; expression; origin; fgf
AB A defining feature of vertebrates (craniates) is a pronounced head that is supported and protected by a robust cellular endoskeleton. In the first vertebrates, this skeleton probably consisted of collagenous cellular cartilage, which forms the embryonic skeleton of all vertebrates and the adult skeleton of modern jawless and cartilaginous fish. In the head, most cellular cartilage is derived from a migratory cell population called the neural crest, which arises from the edges of the central nervous system. Because collagenous cellular cartilage and neural crest cells have not been described in invertebrates', the appearance of cellular cartilage derived from neural crest cells is considered a turning point in vertebrate evolution'. Here we show that a tissue with many of the defining features of vertebrate cellular cartilage transiently forms in the larvae of the invertebrate chordate Branchiostoma floridae (Florida amphioxus). We also present evidence that during evolution, a key regulator of vertebrate cartilage development, SoxE, gained new cis-regulatory sequences that subsequently directed its novel expression in neural crest cells. Together, these results suggest that the origin of the vertebrate head skeleton did not depend on the evolution of a new skeletal tissue, as is commonly thought, but on the spread of this tissue throughout the head. We further propose that the evolution of cis-regulatory elements near an ancient regulator of cartilage differentiation was a major factor in the evolution of the vertebrate head skeleton.
C1 [Jandzik, David; Garnett, Aaron T.; Square, Tyler A.; Cattell, Maria V.; Medeiros, Daniel M.] Univ Colorado, Dept Ecol & Evolutionary Biol, Boulder, CO 80309 USA.
   [Jandzik, David] Comenius Univ, Dept Zool, Bratislava 84215, Slovakia.
   [Yu, Jr-Kai] Acad Sinica, Inst Cellular & Organism Biol, Taipei 11529, Taiwan.
C3 University of Colorado System; University of Colorado Boulder; Comenius University Bratislava; Academia Sinica - Taiwan
RP Medeiros, DM (corresponding author), Univ Colorado, Dept Ecol & Evolutionary Biol, Boulder, CO 80309 USA.
EM Daniel.Medeiros@Colorado.edu
FU National Science Foundation [IOS 1257040, IOS 1160733, DBI 0905991]; University of Colorado, Boulder start-up funds; National Science Council Taiwan [NSC101-2923-B-001-004-MY2, NSC102-2311-B-001-011-MY3]; Academia Sinica Taiwan [AS-98-CDA-L06]
NR 29
TC 75
Z9 83
U1 2
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 FEB 26
PY 2015
VL 518
IS 7540
BP 534
EP 537
DI 10.1038/nature14000
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC1JP
UT WOS:000350097300046
PM 25487155
DA 2026-03-09
ER

PT J
AU Stockbridge, RB
   Kolmakova-Partensky, L
   Shane, T
   Koide, A
   Koide, S
   Miller, C
   Newstead, S
AF Stockbridge, Randy B.
   Kolmakova-Partensky, Ludmila
   Shane, Tania
   Koide, Akiko
   Koide, Shohei
   Miller, Christopher
   Newstead, Simon
TI Crystal structures of a double-barrelled fluoride ion channel
SO NATURE
LA English
DT Article
ID resistance; selectivity; proteins; emre; evolution
AB To contend with hazards posed by environmental fluoride, microorganisms export this anion through F--specific ion channels of the Fluc family(1-4). Since the recent discovery of Fluc channels, numerous idiosyncratic features of these proteins have been unearthed, including strong selectivity for F- over Cl- and dual-topology dimeric assembly(5,6). To understand the chemical basis for F- permeation and how the antiparallel subunits convene to form a F--selective pore, here we solve the crystal structures of two bacterial Fluc homologues in complex with three different monobody inhibitors, with and without F- present, to a maximum resolution of 2.1 angstrom. The structures reveal a surprising 'double-barrelled' channel architecture in which two F- ion pathways span the membrane, and the dual-topology arrangement includes a centrally coordinated cation, most likely Na+center dot F- selectivity is proposed to arise from the very narrow pores and an unusual anion coordination that exploits the quadrupolar edges of conserved phenylalanine rings.
C1 [Stockbridge, Randy B.; Kolmakova-Partensky, Ludmila; Shane, Tania; Miller, Christopher] Brandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02454 USA.
   [Koide, Akiko; Koide, Shohei] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA.
   [Miller, Christopher] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QU, England.
   [Newstead, Simon] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England.
C3 Howard Hughes Medical Institute; Brandeis University; University of Chicago; University of Oxford; University of Oxford
RP Newstead, S (corresponding author), Univ Oxford, Dept Biochem, Oxford OX1 3QU, England.
EM simon.newstead@bioch.ox.ac.uk
FU Wellcome Trust [102890/Z/13/Z]; National Institutes of Health (NIH) [RO1-GM107023, U54-GM087519]; NIH [K99-GM-111767]; Wellcome Trust [102890/Z/13/Z] Funding Source: researchfish
NR 41
TC 106
Z9 132
U1 3
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 SEP 24
PY 2015
VL 525
IS 7570
BP 548
EP +
DI 10.1038/nature14981
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR8KI
UT WOS:000361599900056
PM 26344196
DA 2026-03-09
ER

PT J
AU Fischer, N
   Neumann, P
   Konevega, AL
   Bock, LV
   Ficner, R
   Rodnina, MV
   Stark, H
AF Fischer, Niels
   Neumann, Piotr
   Konevega, Andrey L.
   Bock, Lars V.
   Ficner, Ralf
   Rodnina, Marina V.
   Stark, Holger
TI Structure of the E. coli ribosome-EF-Tu complex at &lt;3 Å resolution by Cs-corrected cryo-EM
SO NATURE
LA English
DT Article
ID peptidyl transferase center; aminoacyl-transfer-rna; elongation-factor tu; crystal-structure; translation; methylations; refinement; resistance; initiation; mechanism
AB Single particle electron cryomicroscopy (cryo-EM) has recently made significant progress in high-resolution structure determination of macromolecular complexes due to improvements in electron microscopic instrumentation and computational image analysis. However, cryo-EM structures can be highly non-uniform in local resolution" and all structures available to date have been limited to resolutions above 3 angstrom(3,4). Here we present the cryo-EM structure of the 70S ribosome from Escherichia coli in complex with elongation factor Tu, aminoacyl-tRNA and the antibiotic kirromycin at 2.65-2.9 angstrom resolution using spherical aberration (c)-corrected cryo-EM. Overall, the cryo-EM reconstruction at 2.9 angstrom resolution is comparable to the best-resolved X-ray structure of the E. coil 70S ribosome(5) (2.8 angstrom), but provides more detailed information (2.65 angstrom) at the functionally important ribosomal core. The cryo-EM map elucidates for the first time the structure of all 35 rRNA modifications in the bacterial ribosome, explaining their roles in fine-tuning ribosome structure and function and modulating the action of antibiotics. We also obtained atomic models for flexible parts of the ribosome such as ribosomal proteins L9 and L31. The refined cryo-EM -based model presents the currently most complete high-resolution structure of the E. coil ribosome, which demonstrates the power of cryo-EM in structure determination of large and dynamic macromolecular complexes.
C1 [Fischer, Niels; Stark, Holger] Max Planck Inst Biophys Chem, Electron Cryomicroscopy Grp 3D, D-37077 Gottingen, Germany.
   [Neumann, Piotr; Ficner, Ralf] Univ Gottingen, Abt Mol Strukturbiol, Inst Mikrobiol & Genet, GZMB, D-37077 Gottingen, Germany.
   [Konevega, Andrey L.] Kurchatov Inst, BP Konstantinov Petersburg Nucl Phys Inst, Natl Res Ctr, Mol & Radiat Biophys Dept, Gatchina 188300, Russia.
   [Konevega, Andrey L.] St Petersburg Polytech Univ, St Petersburg 195251, Russia.
   [Konevega, Andrey L.; Rodnina, Marina V.] Max Planck Inst Biophys Chem, Dept Phys Biochem, D-37077 Gottingen, Germany.
   [Bock, Lars V.] Max Planck Inst Biophys Chem, Dept Theoret & Computat Biophys, D-37077 Gottingen, Germany.
   [Stark, Holger] Univ Gottingen, Inst Microbiol & Genet, Dept Electron Cryomicroscopy 3D, D-37077 Gottingen, Germany.
C3 Max Planck Society; University of Gottingen; National Research Centre - Kurchatov Institute; Petersburg Nuclear Physics Institute; Peter the Great St. Petersburg Polytechnic University; Max Planck Society; Max Planck Society; University of Gottingen
RP Fischer, N (corresponding author), Max Planck Inst Biophys Chem, Electron Cryomicroscopy Grp 3D, Fassberg 11, D-37077 Gottingen, Germany.
EM niels.fischer@mpibpc.mpg.de; hstark1@gwdg.de
FU Deutsche Forschungsgemeinschaft [FOR 1805];  [Sonderforschungsbereich 860]
NR 42
TC 300
Z9 360
U1 0
U2 207
PU NATURE PUBLISHING 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 23
PY 2015
VL 520
IS 7548
BP 567
EP +
DI 10.1038/nature14275
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500049
PM 25707802
DA 2026-03-09
ER

PT J
AU Leslie, S
   Winney, B
   Hellenthal, G
   Davison, D
   Boumertit, A
   Day, T
   Hutnik, K
   Royrvik, EC
   Cunliffe, B
   Lawson, DJ
   Falush, D
   Freeman, C
   Pirinen, M
   Myers, S
   Robinson, M
   Donnelly, P
   Bodmer, W
AF Leslie, Stephen
   Winney, Bruce
   Hellenthal, Garrett
   Davison, Dan
   Boumertit, Abdelhamid
   Day, Tammy
   Hutnik, Katarzyna
   Royrvik, Ellen C.
   Cunliffe, Barry
   Lawson, Daniel J.
   Falush, Daniel
   Freeman, Colin
   Pirinen, Matti
   Myers, Simon
   Robinson, Mark
   Donnelly, Peter
   Bodmer, Walter
TI The fine-scale genetic structure of the British population
SO NATURE
LA English
DT Article
ID linkage disequilibrium; inference; admixture; ancestry; africa; model
AB Fine-scale genetic variation between human Populations is interesting as a signature of historical demographic events and because of its potential for confounding disease studies. We use haplotype-based statistical methods to analyse genome-wide single nucleotide polymorphism (SNP) data from a carefully chosen geographically diverse sample of 2,039 individuals from the United Kingdom. This reveals a rich and detailed pattern of genetic differentiation with remarkable concordance between genetic clusters and geography. The regional genetic differentiation and differing patterns of shared ancestry with 6,209 individuals from across Europe carry clear signals of historical demographic events. We estimate the genetic contribution to southeastern England from Anglo-Saxon migrations to be under half, and identify the regions not carrying genetic material from these migrations. We suggest significant pre-Roman but post-Mesolithic movement into southeastern England from continental Europe, and show that in non-Saxon parts of the United Kingdom, there exist genetically differentiated subgroups rather than a general 'Celtic' population.
C1 [Leslie, Stephen] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia.
   [Leslie, Stephen] Univ Melbourne, Dept Math & Stat, Parkville, Vic 3010, Australia.
   [Leslie, Stephen; Winney, Bruce; Boumertit, Abdelhamid; Day, Tammy; Hutnik, Katarzyna; Royrvik, Ellen C.; Bodmer, Walter] Univ Oxford, Dept Oncol, Oxford OX3 7DQ, England.
   [Hellenthal, Garrett] Univ Coll London Genet Inst, London WC1E 6BT, England.
   [Davison, Dan] Counsyl, San Francisco, CA 94080 USA.
   [Cunliffe, Barry] Univ Oxford, Inst Archaeol, Oxford OX1 2PG, England.
   [Lawson, Daniel J.] Univ Bristol, Dept Math, Bristol BS8 1TW, Avon, England.
   [Falush, Daniel] Swansea Univ, Coll Med, Swansea SA2 8PP, W Glam, Wales.
   [Freeman, Colin; Donnelly, Peter] Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.
   [Pirinen, Matti] Univ Helsinki, FI-00014 Helsinki, Finland.
   [Myers, Simon; Donnelly, Peter] Univ Oxford, Dept Stat, Oxford OX1 3TG, England.
   [Robinson, Mark] Univ Oxford, Univ Museum Nat Hist, Oxford OX1 3PW, England.
C3 Murdoch Children's Research Institute; Royal Children's Hospital Melbourne; University of Melbourne; University of Oxford; University of London; University College London; University of Oxford; University of Bristol; Swansea University; University of Oxford; Wellcome Centre for Human Genetics; University of Helsinki; University of Oxford; University of Oxford
RP Donnelly, P (corresponding author), Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England.
EM donnelly@well.ox.ac.uk
FU Wellcome Trust [072974/Z/03/Z, 088262/Z/09/Z, 075491/Z/04/Z, 075491/Z/04/A, 075491/Z/04/B, 090532/Z/09/Z, 084818/Z/08/Z, 095552/Z/11/Z, 085475/Z/08/Z, 098387/Z/12/Z, 098386/Z/12/Z]; Academy of Finland [257654]; Australian National Health and Medical Research Council [APP1053756]; Wolfson-Royal Society Merit Award; Arts and Humanities Research Council [AH/K002600/1] Funding Source: researchfish; Medical Research Council [MR/M501608/1, MC_UU_12013/1] Funding Source: researchfish; Wellcome Trust [098386/Z/12/Z, 095552/Z/11/Z] Funding Source: researchfish; AHRC [AH/K002600/1] Funding Source: UKRI; MRC [MR/M501608/1, MC_UU_12013/1] Funding Source: UKRI; Wellcome Trust [075491/Z/04/A, 098387/Z/12/Z, 088262/Z/09/Z, 084818/Z/08/Z] Funding Source: Wellcome Trust
NR 38
TC 312
Z9 356
U1 1
U2 191
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 19
PY 2015
VL 519
IS 7543
BP 309
EP +
DI 10.1038/nature14230
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD6AY
UT WOS:000351171900032
PM 25788095
DA 2026-03-09
ER

PT J
AU De Sanctis, MC
   Capaccioni, F
   Ciarniello, M
   Filacchione, G
   Formisano, M
   Mottola, S
   Raponi, A
   Tosi, F
   Bockelée-Morvan, D
   Erard, S
   Leyrat, C
   Schmitt, B
   Ammannito, E
   Arnold, G
   Barucci, MA
   Combi, M
   Capria, MT
   Cerroni, P
   Ip, WH
   Kuehrt, E
   McCord, TB
   Palomba, E
   Beck, P
   Quirico, E
AF De Sanctis, M. C.
   Capaccioni, F.
   Ciarniello, M.
   Filacchione, G.
   Formisano, M.
   Mottola, S.
   Raponi, A.
   Tosi, F.
   Bockelee-Morvan, D.
   Erard, S.
   Leyrat, C.
   Schmitt, B.
   Ammannito, E.
   Arnold, G.
   Barucci, M. A.
   Combi, M.
   Capria, M. T.
   Cerroni, P.
   Ip, W-H
   Kuehrt, E.
   McCord, T. B.
   Palomba, E.
   Beck, P.
   Quirico, E.
TI The diurnal cycle of water ice on comet 67P/Churyumov-Gerasimenko
SO NATURE
LA English
DT Article
ID optical-constants; crystalline h2o-ice; thermal evolution; surface; spectrometer; nuclei; impact
AB Observations of cometary nuclei have revealed a very limited amount of surface water ice(1-7), which is insufficient to explain the observed water outgassing. This was clearly demonstrated on comet 9P/Tempel 1, where the dust jets (driven by volatiles) were only partially correlated with the exposed ice regions(8). The observations(6,7) of 67P/Churyumov-Gerasimenko have revealed that activity has a diurnal variation in intensity arising from changing insolation conditions. It was previously concluded that water vapour was generated in ice-rich subsurface layers with a transport mechanism linked to solar illumination(1-3,5), but that has not hitherto been observed. Periodic condensations of water vapour very close to, or on, the surface were suggested(3,9) to explain short-lived outbursts seen near sunrise on comet 9P/Tempel 1. Here we report observations of water ice on the surface of comet 67P/ChuryumovGerasimenko, appearing and disappearing in a cyclic pattern that follows local illumination conditions, providing a source of localized activity. This water cycle appears to be an important process in the evolution of the comet, leading to cyclical modification of the relative abundance of water ice on its surface.
C1 [De Sanctis, M. C.; Capaccioni, F.; Ciarniello, M.; Filacchione, G.; Formisano, M.; Raponi, A.; Tosi, F.; Ammannito, E.; Capria, M. T.; Cerroni, P.; Palomba, E.] Ist Astrofis & Planetol Spaziali INAF, Via Fosso Cavaliere 100, I-00133 Rome, Italy.
   [Mottola, S.; Arnold, G.; Kuehrt, E.] DLR, Inst Planetary Res, D-12489 Berlin, Germany.
   [Bockelee-Morvan, D.; Erard, S.; Leyrat, C.; Barucci, M. A.] Univ Paris 06, Univ Paris Diderot, LESIA Observ Paris, CNRS, F-92195 Meudon, France.
   [Schmitt, B.; Beck, P.; Quirico, E.] Univ Grenoble Alpes, CNRS, Inst Planetol & Astrophys Grenoble, F-38041 Grenoble 9, France.
   [Ammannito, E.] Univ Calif Los Angeles, Los Angeles, CA 90095 USA.
   [Combi, M.] Univ Michigan, Dept Atmospher Ocean & Space Sci, Ann Arbor, MI 48109 USA.
   [Ip, W-H] Natl Cent Univ, Taoyuan 32001, Taiwan.
   [McCord, T. B.] Bear Fight Inst, Winthrop, WA 98862 USA.
C3 Istituto Nazionale Astrofisica (INAF); Helmholtz Association; German Aerospace Centre (DLR); Universite Paris Cite; Universite PSL; Observatoire de Paris; Centre National de la Recherche Scientifique (CNRS); Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Institut de Planetologie et d'Astrophysique de Grenoble (IPAG); University of California System; University of California Los Angeles; University of Michigan System; University of Michigan; National Central University
RP De Sanctis, MC (corresponding author), Ist Astrofis & Planetol Spaziali INAF, Via Fosso Cavaliere 100, I-00133 Rome, Italy.
EM mariacristina.desanctis@iaps.inaf.it
FU Italian Space Agency (ASI, Italy); Centre National d'Etudes Spatiales (CNES, France); Deutsches Zentrum fur Luft- und Raumfahrt (DLR, Germany); National Aeronautic and Space Administration (NASA, USA); ASI; CNES (France); DLR (Germany); Science and Technology Facilities Council [ST/K00106X/1] Funding Source: researchfish; STFC [ST/K00106X/1] Funding Source: UKRI
NR 30
TC 152
Z9 154
U1 1
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 SEP 24
PY 2015
VL 525
IS 7570
BP 500
EP +
DI 10.1038/nature14869
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR8KI
UT WOS:000361599900046
PM 26399830
DA 2026-03-09
ER

PT J
AU Banerjee, R
   Proshlyakov, Y
   Lipscomb, JD
   Proshlyakov, DA
AF Banerjee, Rahul
   Proshlyakov, Yegor
   Lipscomb, John D.
   Proshlyakov, Denis A.
TI Structure of the key species in the enzymatic oxidation of methane to methanol
SO NATURE
LA English
DT Article
ID monooxygenase catalytic cycle; o-o bond; methylosinus-trichosporium ob3b; density-functional calculations; diamond core; intermediate-q; spectroscopic characterization; peroxodiferric intermediate; ribonucleotide reductase; delta(9) desaturase
AB Methane monooxygenase (MMO) catalyses the O-2-dependent conversion of methane to methanol in methanotrophic bacteria, thereby preventing the atmospheric egress of approximately one billion tons of this potent greenhouse gas annually. The key reaction cycle intermediate of the soluble form of MMO(sMMO) is termed compoundQ (Q). Q contains a unique dinuclear Fe-IV cluster that reacts with methane to break an exceptionally strong 105 kcal mol(-1) C-H bond and insert one oxygen atom(1,2). No other biological oxidant, except that found in the particulate form of MMO, is capable of such catalysis. The structure of Q remains controversial despite numerous spectroscopic, computational and synthetic model studies(2-7). A definitive structural assignment can be made from resonance Raman vibrational spectroscopy but, despite efforts over the past two decades, no vibrational spectrum of Q has yet been obtained. Here we report the core structures of Q and the following product complex, compound T, using time-resolved resonance Raman spectroscopy (TR3). TR3 permits fingerprinting of intermediates by their unique vibrational signatures through extended signal averaging for short-lived species. We report unambiguous evidence that Q possesses a bis-mu-oxo diamond core structure and show that both bridging oxygens originate from O-2. This observation strongly supports a homolytic mechanism for O-Obond cleavage. We also show that T retains a single oxygen atom from O-2 as a bridging ligand, while the other oxygen atom is incorporated into the product(8). Capture of the extreme oxidizing potential of Q is of great contemporary interest for bioremediation and the development of synthetic approaches to methane-based alternative fuels and chemical industry feedstocks. Insight into the formation and reactivity of Q from the structure reported here is an important step towards harnessing this potential.
C1 [Banerjee, Rahul; Lipscomb, John D.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA.
   [Banerjee, Rahul; Lipscomb, John D.] Univ Minnesota, Ctr Met Biocatalysis, Minneapolis, MN 55455 USA.
   [Proshlyakov, Yegor; Proshlyakov, Denis A.] Michigan State Univ, Dept Chem, E Lansing, MI 48824 USA.
C3 University of Minnesota System; University of Minnesota Twin Cities; University of Minnesota System; University of Minnesota Twin Cities; Michigan State University
RP Proshlyakov, DA (corresponding author), Michigan State Univ, Dept Chem, E Lansing, MI 48824 USA.
EM lipsc001@umn.edu; dapro@chemistry.msu.edu
FU NIH [GM40466, GM100943, GM096132]; STFC [ST/K00106X/1, ST/I005765/1, ST/L001314/1] Funding Source: UKRI; Science and Technology Facilities Council [ST/K00106X/1, ST/I005765/1, ST/L001314/1] Funding Source: researchfish; UK Space Agency [ST/J004812/1, ST/G003874/1, ST/F012373/1] Funding Source: researchfish
NR 41
TC 236
Z9 291
U1 6
U2 537
PU NATURE PUBLISHING 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 19
PY 2015
VL 518
IS 7539
BP 431
EP 434
DI 10.1038/nature14160
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400049
PM 25607364
DA 2026-03-09
ER

PT J
AU Reubold, TF
   Faelber, K
   Plattner, N
   Posor, Y
   Ketel, K
   Curth, U
   Schlegel, J
   Anand, R
   Manstein, DJ
   Noé, F
   Haucke, V
   Daumke, O
   Eschenburg, S
AF Reubold, Thomas F.
   Faelber, Katja
   Plattner, Nuria
   Posor, York
   Ketel, Katharina
   Curth, Ute
   Schlegel, Jeanette
   Anand, Roopsee
   Manstein, Dietmar J.
   Noe, Frank
   Haucke, Volker
   Daumke, Oliver
   Eschenburg, Susanne
TI Crystal structure of the dynamin tetramer
SO NATURE
LA English
DT Article
ID clathrin-mediated endocytosis; molecular-dynamics; membrane fission; stalk region; domain; protein; software; insights; gtpase; ultracentrifugation
AB The mechanochemical protein dynamin is the prototype of the dynamin superfamily of large GTPases, which shape and remodel membranes in diverse cellular processes(1). Dynamin forms predominantly tetramers in the cytosol, which oligomerize at the neck of clathrin-coated vesicles to mediate constriction and subsequent scission of the membrane(1). Previous studies have described the architecture of dynamin dimers(2,3), but the molecular determinants for dynamin assembly and its regulation have remained unclear. Here we present the crystal structure of the human dynamin tetramer in the nucleotide-free state. Combining structural data with mutational studies, oligomerization measurements and Markov state models of molecular dynamics simulations, we suggest a mechanism by which oligomerization of dynamin is linked to the release of intramolecular autoinhibitory interactions. We elucidate how mutations that interfere with tetramer formation and autoinhibition can lead to the congenital muscle disorders Charcot-Marie-Tooth neuropathy(4) and centronuclear myopathy(5), respectively. Notably, the bent shape of the tetramer explains how dynamin assembles into a right-handed helical oligomer of defined diameter, which has direct implications for its function in membrane constriction.
C1 [Reubold, Thomas F.; Curth, Ute; Anand, Roopsee; Manstein, Dietmar J.; Eschenburg, Susanne] Hannover Med Sch, Inst Biophys Chem, D-30625 Hannover, Germany.
   [Faelber, Katja; Schlegel, Jeanette; Daumke, Oliver] Max Delbruck Ctr Mol Med, Kristallog, D-13125 Berlin, Germany.
   [Plattner, Nuria] Free Univ Berlin, Inst Math, D-14195 Berlin, Germany.
   [Posor, York; Ketel, Katharina; Haucke, Volker] Leibniz Inst Mol Pharmacol, D-13125 Berlin, Germany.
   [Curth, Ute; Manstein, Dietmar J.] Hannover Med Sch, Forsch Einrichtung Strukt Analyse, D-30625 Hannover, Germany.
   [Haucke, Volker; Daumke, Oliver] Free Univ Berlin, Inst Chem & Biochem, D-14195 Berlin, Germany.
C3 Hannover Medical School; Helmholtz Association; Max Delbruck Center for Molecular Medicine; Free University of Berlin; Leibniz Association; Leibniz Forschungsinstitut furr Molekulare Pharmakologie (FMP); Hannover Medical School; Free University of Berlin
RP Faelber, K (corresponding author), Max Delbruck Ctr Mol Med, Kristallog, Robert Rossle Str 10, D-13125 Berlin, Germany.
EM katja.faelber@mdc-berlin.de; oliver.daumke@mdc-berlin.de; Eschenburg.Susanne@mh-hannover.de
FU Deutsche Forschungsgemeinschaft [MA1081/8-2, SFB740/D7, SFB958/A04, SFB740/C8, SFB 958/A7, SFB 740/C7, SFB958/A12, ES410/2-1]; ERC consolidator grant [ERC-2013-CoG-616024]; ERC starting grant; Einstein Foundation Berlin (SOoPiC); Cluster of Excellence REBIRTH [DFG EXC 62/1]
NR 53
TC 106
Z9 121
U1 1
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 SEP 17
PY 2015
VL 525
IS 7569
BP 404
EP +
DI 10.1038/nature14880
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900049
PM 26302298
DA 2026-03-09
ER

PT J
AU Davies, DR
   Rawlinson, N
   Iaffaldano, G
   Campbell, IH
AF Davies, D. R.
   Rawlinson, N.
   Iaffaldano, G.
   Campbell, I. H.
TI Lithospheric controls on magma composition along Earth's longest continental hotspot track
SO NATURE
LA English
DT Article
ID seismological reference model; mantle plumes; australian lithosphere; flood basalts; volcanism; tomography; convection; component; origin; margin
AB Hotspots are anomalous regions of volcanism at Earth's surface that show no obvious association with tectonic plate boundaries. Classic examples include the Hawaiian-Emperor chain and the Yellowstone-Snake River Plain province. The majority are believed to form as Earth's tectonic plates move over long-lived mantle plumes: buoyant upwellings that bring hot material from Earth's deep mantle to its surface(1). It has long been recognized that lithospheric thickness limits the rise height of plumes(2-4) and, thereby, their minimum melting pressure. It should, therefore, have a controlling influence on the geochemistry of plume-related magmas, although unambiguous evidence of this has, so far, been lacking. Here we integrate observational constraints from surface geology, geochronology, plate-motion reconstructions, geochemistry and seismology to ascertain plume melting depths beneath Earth's longest continental hotspot track, a 2,000-kilometre-long track in eastern Australia that displays a record of volcanic activity between 33 and 9 million years ago(5,6), which we call the Cosgrove track. Our analyses highlight a strong correlation between lithospheric thickness and magma composition along this track, with: (1) standard basaltic compositions in regions where lithospheric thickness is less than 110 kilometres; (2) volcanic gaps in regions where lithospheric thickness exceeds 150 kilometres; and (3) lowvolume, leucitite-bearing volcanism in regions of intermediate lithospheric thickness. Trace-element concentrations from samples along this track support the notion that these compositional variations result from different degrees of partial melting, which is controlled by the thickness of overlying lithosphere. Our results place the first observational constraints on the sub-continental melting depth of mantle plumes and provide direct evidence that lithospheric thickness has a dominant influence on the volume and chemical composition of plume-derived magmas.
C1 [Davies, D. R.; Iaffaldano, G.; Campbell, I. H.] Australian Natl Univ, Res Sch Earth Sci, Canberra, ACT 2601, Australia.
   [Rawlinson, N.] Univ Aberdeen, Sch Geosci, Aberdeen AB24 3UE, Scotland.
C3 Australian National University; University of Aberdeen
RP Davies, DR (corresponding author), Australian Natl Univ, Res Sch Earth Sci, Canberra, ACT 2601, Australia.
EM rhodri.davies@anu.edu.au
FU Australian Research Council Future Fellowship [FT140101262]; Ringwood Fellowship at the Australian National University; NERC [NE/H015329/1] Funding Source: UKRI; Natural Environment Research Council [NE/H015329/1] Funding Source: researchfish
NR 42
TC 142
Z9 149
U1 1
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 SEP 24
PY 2015
VL 525
IS 7570
BP 511
EP +
DI 10.1038/nature14903
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR8KI
UT WOS:000361599900049
PM 26367795
DA 2026-03-09
ER

PT J
AU Seweryn, P
   Van, LB
   Kjeldgaard, M
   Russo, CJ
   Passmore, LA
   Hove-Jensen, B
   Jochimsen, B
   Brodersen, DE
AF Seweryn, Paulina
   Van, Lan Bich
   Kjeldgaard, Morten
   Russo, Christopher J.
   Passmore, Lori A.
   Hove-Jensen, Bjarne
   Jochimsen, Bjarne
   Brodersen, Ditlev E.
TI Structural insights into the bacterial carbon-phosphorus lyase machinery
SO NATURE
LA English
DT Article
ID radical sam; mechanism; phosphate; validation; metabolism; products; reveals; complex; system; tilt
AB Phosphorus is required for all life and microorganisms can extract it from their environment through several metabolic pathways. When phosphate is in limited supply, some bacteria are able to use phosphonate compounds, which require specialized enzymatic machinery to break the stable carbon-phosphorus (C-P) bond. Despite its importance, the details of how this machinery catabolizes phosphonates remain unknown. Here we determine the crystal structure of the 240-kilodalton Escherichia coli C-P lyase core complex (PhnG-PhnH-PhnI-PhnJ; PhnGHIJ), and show that it is a two-fold symmetric hetero-octamer comprising an intertwined network of subunits with unexpected self-homologies. It contains two potential active sites that probably couple phosphonate compounds to ATP and subsequently hydrolyse the C-P bond. We map the binding site of PhnK on the complex using electron microscopy, and show that it binds to a conserved insertion domain of PhnJ. Our results provide a structural basis for understanding microbial phosphonate breakdown.
C1 [Seweryn, Paulina; Van, Lan Bich; Kjeldgaard, Morten; Hove-Jensen, Bjarne; Jochimsen, Bjarne; Brodersen, Ditlev E.] Aarhus Univ, Dept Mol Biol & Genet, DK-8000 Aarhus C, Denmark.
   [Russo, Christopher J.; Passmore, Lori A.] Med Res Council Lab Mol Biol, Cambridge CB2 0QH, England.
C3 Aarhus University; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); MRC Laboratory Molecular Biology
RP Brodersen, DE (corresponding author), Aarhus Univ, Dept Mol Biol & Genet, Gustav Wieds Vej 10c, DK-8000 Aarhus C, Denmark.
EM deb@mbg.au.dk
FU European Research Council [261151]; MRC [MC_U105192715]; Danish National Research Foundation 'Centre for mRNP biogenesis and metabolism'; MRC [MC_U105192715] Funding Source: UKRI; European Research Council (ERC) [261151] Funding Source: European Research Council (ERC); Medical Research Council [MC_U105192715] Funding Source: researchfish; Novo Nordisk Fonden [NNF12OC0002082] Funding Source: researchfish
NR 48
TC 69
Z9 83
U1 8
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 SEP 3
PY 2015
VL 525
IS 7567
BP 68
EP +
DI 10.1038/nature14683
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ4SE
UT WOS:000360594100026
PM 26280334
DA 2026-03-09
ER

PT J
AU Zarzar, LD
   Sresht, V
   Sletten, EM
   Kalow, JA
   Blankschtein, D
   Swager, TM
AF Zarzar, Lauren D.
   Sresht, Vishnu
   Sletten, Ellen M.
   Kalow, Julia A.
   Blankschtein, Daniel
   Swager, Timothy M.
TI Dynamically reconfigurable complex emulsions via tunable interfacial tensions
SO NATURE
LA English
DT Article
ID multiple emulsions; phase-separation; air-water; surfactants; microfluidics; fabrication; adsorption; particles; release; hexane
AB Emulsification is a powerful, well-known technique for mixing and dispersing immiscible components within a continuous liquid phase. Consequently, emulsions are central components of medicine, food and performance materials. Complex emulsions, including Janus droplets (that is, droplets with faces of differing chemistries) and multiple emulsions, are of increasing importance' in pharmaceuticals and medical diagnostics', in the fabrication of microparticles and capsules' for food', in chemical separations', in cosmetics', and in dynamic optics'. Because complex emulsion properties and functions are related to the droplet geometry and composition, the development of rapid, simple fabrication approaches allowing precise control over the droplets' physical and chemical characteristics is critical. Significant advances in the fabrication of complex emulsions have been made using a number of procedures, ranging from largescale, less precise techniques that give compositional heterogeneity using high-shear mixers and membranes'', to small-volume but more precise microfluidic methodsn'''. However, such approaches have yet to create droplet morphologies that can be controllably altered after emulsification. Reconfigurable complex liquids potentially have great utility as dynamically tunable materials. Here we describe an approach to the one-step fabrication of three- and four-phase complex emulsions with highly controllable and reconfigurable morphologies. The fabrication makes use of the temperature-sensitive miscibility of hydrocarbon, silicone and fluorocarbon liquids, and is applied to both the microfluidic and the scalable batch production of complex droplets. We demonstrate that droplet geometries can be alternated between encapsulated and Janus configurations by varying the interfacial tensions using hydrocarbon and fluorinated surfactants including stimuli-responsive and cleavable surfactants. This yields a generalizable strategy for the fabrication of multiphase emulsions with controllably reconfigurable morphologies and the potential to create a wide range of responsive materials.
C1 [Zarzar, Lauren D.; Sletten, Ellen M.; Kalow, Julia A.; Swager, Timothy M.] MIT, Dept Chem, Cambridge, MA 02139 USA.
   [Zarzar, Lauren D.; Sletten, Ellen M.; Kalow, Julia A.; Swager, Timothy M.] MIT, Inst Soldier Nanotechnol, Cambridge, MA 02139 USA.
   [Sresht, Vishnu; Blankschtein, Daniel] MIT, Dept Chem Engn, Cambridge, MA 02139 USA.
C3 Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT)
RP Blankschtein, D (corresponding author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA.
EM dblank@mit.edu; tswager@mit.edu
FU Eni S.p.A. under Eni-MIT Alliance Solar Frontiers Program; US Army Research Laboratory; US Army Research Office through Institute for Soldier Nanotechnologies [W911NF-13-D-0001]; F32 Ruth L. Kirschtein NRSA Fellowships [EB014682, GM106550]
NR 31
TC 363
Z9 412
U1 25
U2 1050
PU NATURE PUBLISHING 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 26
PY 2015
VL 518
IS 7540
BP 520
EP 524
DI 10.1038/nature14168
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC1JP
UT WOS:000350097300043
PM 25719669
DA 2026-03-09
ER

PT J
AU Hengrung, N
   El Omari, K
   Martin, IS
   Vreede, FT
   Cusack, S
   Rambo, RP
   Vonrhein, C
   Bricogne, G
   Stuart, DI
   Grimes, JM
   Fodor, E
AF Hengrung, Narin
   El Omari, Kamel
   Martin, Itziar Serna
   Vreede, Frank T.
   Cusack, Stephen
   Rambo, Robert P.
   Vonrhein, Clemens
   Bricogne, Gerard
   Stuart, David I.
   Grimes, Jonathan M.
   Fodor, Ervin
TI Crystal structure of the RNA-dependent RNA polymerase from influenza C virus
SO NATURE
LA English
DT Article
ID replication; complex
AB Negative-sense RNA viruses, such as influenza, encode large, multidomain RNA-dependent RNA polymerases that can both transcribe and replicate the viral RNA genome(1). In influenza virus, the polymerase (FluPol) is composed of three polypeptides: PB1, PB2 and PA/P3. PB1 houses the polymerase active site, whereas PB2 and PA/P3 contain, respectively, cap-binding and endonuclease domains required for transcription initiation by cap-snatching(2). Replication occurs through de novo initiation and involves a complementary RNA intermediate. Currently available structures of the influenza A and B virus polymerases include promoter RNA (the 5' and 3' termini of viral genome segments), showing FluPol in transcription pre-initiation states(3,4). Here we report the structure of apo-FluPol from an influenza C virus, solved by X-ray crystallography to 3.9 angstrom, revealing a new 'closed' conformation. The apo-FluPol forms a compact particle with PB1 at its centre, capped on one face by PB2 and clamped between the two globular domains of P3. Notably, this structure is radically different from those of promoter-bound FluPols(3,4). The endonudease domain of P3 and the domains within the carboxy-terminal two-thirds of PB2 are completely rearranged. The cap-binding site is occluded by PB2, resulting in a conformation that is incompatible with transcription initiation. Thus, our structure captures FluPol in a closed, transcription pre-activation state. This reveals the conformation of newly made apo-FluPol in an infected cell, but may also apply to FluPol in the context of a non-transcribing ribonucleoprotein complex. Comparison of the apo-FluPol structure with those of promoter-bound FluPols allows us to propose a mechanism for FluPol activation. Our study demonstrates the remarkable flexibility of influenza virus RNA polymerase, and aids our understanding of the mechanisms controlling transcription and genome replication.
C1 [Hengrung, Narin; Martin, Itziar Serna; Vreede, Frank T.; Fodor, Ervin] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England.
   [Hengrung, Narin; El Omari, Kamel; Stuart, David I.; Grimes, Jonathan M.] Univ Oxford, Div Struct Biol, Oxford OX3 7BN, England.
   [Cusack, Stephen] European Mol Biol Lab, Grenoble Outstn, F-38042 Grenoble 9, France.
   [Cusack, Stephen] Univ Grenoble Alpes, CNRS, EMBL Unit Virus Host Cell Interact, F-38042 Grenoble 9, France.
   [Rambo, Robert P.; Stuart, David I.; Grimes, Jonathan M.] Diamond Light Source Ltd, Didcot OX11 0DE, Oxon, England.
   [Vonrhein, Clemens; Bricogne, Gerard] Global Phasing Ltd, Cambridge CB3 0AX, England.
C3 University of Oxford; University of Oxford; European Molecular Biology Laboratory (EMBL); Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Centre National de la Recherche Scientifique (CNRS); Diamond Light Source; Global Phasing Limited
RP Grimes, JM (corresponding author), Univ Oxford, Div Struct Biol, Henry Wellcome Bldg Genom Med, Oxford OX3 7BN, England.
EM jonathan@strubi.ox.ac.uk; ervin.fodor@path.ox.ac.uk
FU Medical Research Council (MRC) [MR/K000241/1, G1100138, G1000099]; Wellcome Trust [092931/Z/10/Z, 075491/Z/04]; MRC; MRC [G1100138, G1000099, MR/N00065X/1, MR/K000241/1] Funding Source: UKRI; Medical Research Council [G1100138, MR/K000241/1, 1374922, MR/N00065X/1, G1100525, G1000099] Funding Source: researchfish; Wellcome Trust [092931/Z/10/Z] Funding Source: Wellcome Trust
NR 18
TC 138
Z9 161
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 NOV 5
PY 2015
VL 527
IS 7576
BP 114
EP 117
DI 10.1038/nature15525
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV4XV
UT WOS:000364270700054
PM 26503046
DA 2026-03-09
ER

PT J
AU Reniere, ML
   Whiteley, AT
   Hamilton, KL
   John, SM
   Lauer, P
   Brennan, RG
   Portnoy, DA
AF Reniere, Michelle L.
   Whiteley, Aaron T.
   Hamilton, Keri L.
   John, Sonya M.
   Lauer, Peter
   Brennan, Richard G.
   Portnoy, Daniel A.
TI Glutathione activates virulence gene expression of an intracellular pathogen
SO NATURE
LA English
DT Article
ID listeria-monocytogenes; prfa; regulator; protein; acta; survival; requires; binding; thiol
AB Intracellular pathogens are responsible for much of the world-wide morbidity and mortality due to infectious diseases. To colonize their hosts successfully, pathogens must sense their environment and regulate virulence gene expression appropriately. Accordingly, on entry into mammalian cells, the facultative intracellular bacterial pathogen Listeria monocytogenes remodels its transcriptional program by activating the master virulence regulator PrfA. Here we show that bacterial and host-derived glutathione are required to activate PrfA. In this study a genetic selection led to the identification of a bacterial mutant in glutathione synthase that exhibited reduced virulence gene expression and was attenuated 150-fold in mice. Genome sequencing of suppressor mutants that arose spontaneously in vivo revealed a single nucleotide change in prfA that locks the protein in the active conformation (PrfA*) and completely bypassed the requirement for glutathione during infection. Biochemical and genetic studies support a model in which glutathione-dependent PrfA activation is mediated by allosteric binding of glutathione to PrfA. Whereas glutathione and other low-molecular-weight thiols have important roles in redox homeostasis in all forms of life, here we demonstrate that glutathione represents a critical signalling molecule that activates the virulence of an intracellular pathogen.
C1 [Reniere, Michelle L.; John, Sonya M.; Portnoy, Daniel A.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
   [Whiteley, Aaron T.] Univ Calif Berkeley, Sch Publ Hlth, Grad Grp Infect Dis & Immun, Berkeley, CA 94720 USA.
   [Hamilton, Keri L.; Brennan, Richard G.] Duke Univ, Sch Med, Dept Biochem, Durham, NC 27710 USA.
   [Lauer, Peter] Aduro BioTech Inc, Berkeley, CA 94710 USA.
   [Portnoy, Daniel A.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA.
C3 University of California System; University of California Berkeley; University of California System; University of California Berkeley; Duke University; University of California System; University of California Berkeley
RP Portnoy, DA (corresponding author), Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
EM portnoy@berkeley.edu
FU NIH [S10RR029668, S10RR027303]; UCSF; National Institutes of Health [1PO1 AI63302, 1R01 AI27655]; NSF GRFP [DGE 1106400];  [F32AI104247];  [F32GM008487]; National Institute of Allergy and Infectious Diseases [R01AI027655, P01AI063302] Funding Source: NIH RePORTER
NR 37
TC 218
Z9 271
U1 1
U2 82
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 8
PY 2015
VL 517
IS 7533
BP 170
EP U100
DI 10.1038/nature14029
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600029
PM 25567281
DA 2026-03-09
ER

PT J
AU Cichon, J
   Gan, WB
AF Cichon, Joseph
   Gan, Wen-Biao
TI Branch-specific dendritic Ca2+ spikes cause persistent synaptic plasticity
SO NATURE
LA English
DT Article
ID neocortical pyramidal neurons; long-term potentiation; barrel cortex; in-vivo; calcium signals; transgenic mice; integration; cells; memory; spines
AB The brain has an extraordinary capacity for memory storage, but how it or new information without disrupting previously acquired memories remains unknown. Here we show that different motor learning tasks induce dendritic Ca2+ spikes on different apical tuft branches of individual layer V pyramidal neurons in the mouse motor cortex . These ask-related, branch-specific Ca2+ spikes cause long-lasting potentiation of postsynaptic dendritic spines active at the time of spike generation. When somatostatin-expressing interneurons are inactivated, different motor tasks frequently induce Ca2+ spikes on the same branches. On those branches, spines potentiated during one task are depotentiated when they are active seconds before Ca2+ spikes induced by another task. Concomitantly, increased neuronal activity and performance improvement after learning one task are disrupted when another task is learned. These findings indicate that dendritic-branch-specific generation of Ca2+ spikes is crucial for establishing long-lasting synaptic plasticity, thereby facilitating information storage associated with different learning experiences
C1 [Cichon, Joseph; Gan, Wen-Biao] NYU, Sch Med, Skirball Inst, Dept Neurosci & Physiol, New York, NY 10016 USA.
C3 New York University
RP Gan, WB (corresponding author), NYU, Sch Med, Skirball Inst, Dept Neurosci & Physiol, New York, NY 10016 USA.
EM gan@saturn.med.nyu.edu
FU National Institutes of Health [R01 NS047325, P01 NS074972]; National Institute of Neurological Disorders and Stroke [P01NS074972] Funding Source: NIH RePORTER
NR 47
TC 369
Z9 441
U1 2
U2 107
PU NATURE PUBLISHING 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 9
PY 2015
VL 520
IS 7546
BP 180
EP U80
DI 10.1038/nature14251
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CF3NA
UT WOS:000352454600030
PM 25822789
DA 2026-03-09
ER

PT J
AU Khachatryan, V
   Sirunyan, AM
   Tumasyan, A
   Adam, W
   Bergauer, T
   Dragicevic, M
   Erö, J
   Friedl, M
   Frühwirth, R
   Ghete, VM
   Hartl, C
   Hörmann, N
   Hrubec, J
   Jeitler, M
   Kiesenhofer, W
   Knünz, V
   Krammer, M
   Krätschmer, I
   Liko, D
   Mikulec, I
   Rabady, D
   Rahbaran, B
   Rohringer, H
   Schöfbeck, R
   Strauss, J
   Treberer-Treberspurg, W
   Waltenberger, W
   Wulz, CE
   Mossolov, V
   Shumeiko, N
   Gonzalez, JS
   Alderweireldt, S
   Bansal, S
   Cornelis, T
   De Wolf, EA
   Janssen, X
   Knutsson, A
   Lauwers, J
   Luyckx, S
   Ochesanu, S
   Rougny, R
   Van De Klundert, M
   Van Haevermaet, H
   Van Mechelen, P
   Van Remortel, N
   Van Spilbeeck, A
   Blekman, F
   Blyweert, S
   D'Hondt, J
   Daci, N
   Heracleous, N
   Keaveney, J
   Lowette, S
   Maes, M
   Olbrechts, A
   Python, Q
   Strom, D
   Tavernier, S
   Van Doninck, W
   Van Mulders, P
   Van Onsem, GP
   Villella, I
   Caillol, C
   Clerbaux, B
   De Lentdecker, G
   Dobur, D
   Favart, L
   Gay, APR
   Grebenyuk, A
   Léonard, A
   Mohammadi, A
   Perniè, L
   Randle-conde, A
   Reis, T
   Seva, T
   Thomas, L
   Vander Velde, C
   Vanlaer, P
   Wang, J
   Zenoni, F
   Adler, V
   Beernaert, K
   Benucci, L
   Cimmino, A
   Costantini, S
   Crucy, S
   Dildick, S
   Fagot, A
   Garcia, G
   Mccartin, J
   Rios, AAO
   Ryckbosch, D
   Diblen, SS
   Sigamani, M
   Strobbe, N
   Thyssen, F
   Tytgat, M
   Yazgan, E
   Zaganidis, N
   Basegmez, S
   Beluffi, C
   Bruno, G
   Castello, R
   Caudron, A
   Ceard, L
   Da Silveira, GG
   Delaere, C
   du Pree, T
   Favart, D
   Forthomme, L
   Giammanco, A
   Hollar, J
   Jafari, A
   Jez, P
   Komm, M
   Lemaitre, V
   Nuttens, C
   Pagano, D
   Perrini, L
   Pin, A
   Piotrzkowski, K
   Popov, A
   Quertenmont, L
   Selvaggi, M
   Marono, MV
   Garcia, JMV
   Beliy, N
   Caebergs, T
   Daubie, E
   Hammad, GH
   Aldá, WL Jr
   Alves, GA
   Brito, L
   Martins, MC Jr
   Martins, TD
   Herrera, CM
   Pol, ME
   Teles, PR
   Carvalho, W
   Chinellato, J
   Custodio, A
   Da Costa, EM
   Damiao, DD
   Martins, CD
   De Souza, SF
   Malbouisson, H
   Figueiredo, DM
   Mundim, L
   Nogima, H
   Da Silva, WLP
   Santaolalla, J
   Santoro, A
   Sznajder, A
   Manganote, EJT
   Pereira, AV
   Bernardes, CA
   Dogra, S
   Tomei, TRFP
   Gregores, EM
   Mercadante, PG
   Novaes, SF
   Padula, SS
   Aleksandrov, A
   Genchev, V
   Hadjiiska, R
   Iaydjiev, P
   Marinov, A
   Piperov, S
   Rodozov, M
   Sultanov, G
   Vutova, M
   Dimitrov, A
   Glushkov, I
   Litov, L
   Pavlov, B
   Petkov, P
   Bian, JG
   Chen, GM
   Chen, HS
   Chen, M
   Cheng, T
   Du, R
   Jiang, CH
   Plestina, R
   Romeo, F
   Tao, J
   Wang, Z
   Asawatangtrakuldee, C
   Ban, Y
   Li, Q
   Liu, S
   Mao, Y
   Qian, SJ
   Wang, D
   Xu, Z
   Zou, W
   Avila, C
   Cabrera, A
   Sierra, LFC
   Florez, C
   Gomez, JP
   Moreno, BG
   Sanabria, JC
   Godinovic, N
   Lelas, D
   Polic, D
   Puljak, I
   Antunovic, Z
   Kovac, M
   Brigljevic, V
   Kadija, K
   Luetic, J
   Mekterovic, D
   Sudic, L
   Attikis, A
   Mavromanolakis, G
   Mousa, J
   Nicolaou, C
   Ptochos, F
   Razis, PA
   Bodlak, M
   Finger, M
   Finger, M
   Assran, Y
   Kamel, AE
   Mahmoud, MA
   Radi, A
   Kadastik, M
   Murumaa, M
   Raidal, M
   Tiko, A
   Eerola, P
   Fedi, G
   Voutilainen, M
   Härkönen, J
   Karimäki, V
   Kinnunen, R
   Kortelainen, MJ
   Lampén, T
   Lassila-Perini, K
   Lehti, S
   Lindén, T
   Luukka, P
   Mäenpää, T
   Peltola, T
   Tuominen, E
   Tuominiemi, J
   Tuovinen, E
   Wendland, L
   Talvitie, J
   Tuuva, T
   Besancon, M
   Couderc, F
   Dejardin, M
   Denegri, D
   Fabbro, B
   Faure, JL
   Favaro, C
   Ferri, F
   Ganjour, S
   Givernaud, A
   Gras, P
   de Monchenault, GH
   Jarry, P
   Locci, E
   Malcles, J
   Rander, J
   Rosowsky, A
   Titov, M
   Baffioni, S
   Beaudette, F
   Busson, P
   Charlot, C
   Dahms, T
   Dalchenko, M
   Dobrzynski, L
   Filipovic, N
   Florent, A
   de Cassagnac, RG
   Mastrolorenzo, L
   Miné, P
   Mironov, C
   Naranjo, IN
   Nguyen, M
   Ochando, C
   Ortona, G
   Paganini, P
   Regnard, S
   Salerno, R
   Sauvan, JB
   Sirois, Y
   Veelken, C
   Yilmaz, Y
   Zabi, A
   Agram, JL
   Andrea, J
   Aubin, A
   Bloch, D
   Brom, JM
   Chabert, EC
   Collard, C
   Conte, E
   Fontaine, JC
   Gelé, D
   Goerlach, U
   Goetzmann, C
   Le Bihan, AC
   Skovpen, K
   Van Hove, P
   Gadrat, S
   Beauceron, S
   Beaupere, N
   Boudoul, G
   Bouvier, E
   Brochet, S
   Montoya, CAC
   Chasserat, J
   Chierici, R
   Contardo, D
   Depasse, P
   El Mamouni, H
   Fan, J
   Fay, J
   Gascon, S
   Gouzevitch, M
   Ille, B
   Kurca, T
   Lethuillier, M
   Mirabito, L
   Perries, S
   Alvarez, JDR
   Sabes, D
   Sgandurra, L
   Sordini, V
   Vander Donckt, M
   Verdier, P
   Viret, S
   Xiao, H
   Tsamalaidze, Z
   Autermann, C
   Beranek, S
   Bontenackels, M
   Edelhoff, M
   Feld, L
   Heister, A
   Hindrichs, O
   Klein, K
   Ostapchuk, A
   Raupach, F
   Sammet, J
   Schael, S
   Schulte, JF
   Weber, H
   Wittmer, B
   Zhukov, V
   Ata, M
   Brodski, M
   Dietz-Laursonn, E
   Duchardt, D
   Erdmann, M
   Fischer, R
   Güth, A
   Hebbeker, T
   Heidemann, C
   Hoepfner, K
   Klingebiel, D
   Knutzen, S
   Kreuzer, P
   Merschmeyer, M
   Meyer, A
   Millet, P
   Olschewski, M
   Padeken, K
   Papacz, P
   Reithler, H
   Schmitz, SA
   Sonnenschein, L
   Teyssier, D
   Thüer, S
   Weber, M
   Cherepanov, V
   Erdogan, Y
   Flügge, G
   Geenen, H
   Geisler, M
   Ahmad, WH
   Hoehle, F
   Kargoll, B
   Kress, T
   Kuessel, Y
   Künsken, A
   Lingemann, J
   Nowack, A
   Nugent, IM
   Pooth, O
   Stahl, A
   Martin, MA
   Asin, I
   Bartosik, N
   Behr, J
   Behrens, U
   Bell, AJ
   Bethani, A
   Borras, K
   Burgmeier, A
   Cakir, A
   Calligaris, L
   Campbell, A
   Choudhury, S
   Costanza, F
   Pardos, CD
   Dolinska, G
   Dooling, S
   Dorland, T
   Eckerlin, G
   Eckstein, D
   Eichhorn, T
   Flucke, G
   Garcia, JG
   Geiser, A
   Gunnellini, P
   Hauk, J
   Hempel, M
   Jung, H
   Kalogeropoulos, A
   Kasemann, M
   Katsas, P
   Kieseler, J
   Kleinwort, C
   Korol, I
   Krücker, D
   Lange, W
   Leonard, J
   Lipka, K
   Lobanov, A
   Lohmann, W
   Lutz, B
   Mankel, R
   Marfin, I
   Melzer-Pellmann, IA
   Meyer, AB
   Mittag, G
   Mnich, J
   Mussgiller, A
   Naumann-Emme, S
   Nayak, A
   Ntomari, E
   Perrey, H
   Pitzl, D
   Placakyte, R
   Raspereza, A
   Cipriano, PMR
   Roland, B
   Ron, E
   Sahin, MÖ
   Salfeld-Nebgen, J
   Saxena, P
   Schoerner-Sadenius, T
   Schröder, M
   Seitz, C
   Spannagel, S
   Trevino, ADRV
   Walsh, R
   Wissing, C
   Blobel, V
   Vignali, MC
   Draeger, AR
   Erfle, J
   Garutti, E
   Goebel, K
   Görner, M
   Haller, J
   Hoffmann, M
   Höing, RS
   Junkes, A
   Kirschenmann, H
   Klanner, R
   Kogler, R
   Lange, J
   Lapsien, T
   Lenz, T
   Marchesini, I
   Ott, J
   Peiffer, T
   Perieanu, A
   Pietsch, N
   Poehlsen, J
   Poehlsen, T
   Rathjens, D
   Sander, C
   Schettler, H
   Schleper, P
   Schlieckau, E
   Schmidt, A
   Seidel, M
   Sola, V
   Stadie, H
   Steinbrück, G
   Troendle, D
   Usai, E
   Vanelderen, L
   Vanhoefer, A
   Barth, C
   Baus, C
   Berger, J
   Böser, C
   Butz, E
   Chwalek, T
   De Boer, W
   Descroix, A
   Dierlamm, A
   Feindt, M
   Frensch, F
   Giffels, M
   Gilbert, A
   Hartmann, F
   Hauth, T
   Husemann, U
   Katkov, I
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TI Observation of the rare Bs0→μ+μ- decay from the combined analysis of CMS and LHCb data
SO NATURE
LA English
DT Article
ID b-meson decays; search; mu(+)mu(-); b-s(0); b-0; violation; models; ratio
AB The standard model of particle physics describes the fundamental particles and their interactions via the strong, electromagnetic and weak forces. It provides precise predictions for measurable quantities that can be tested experimentally. The probabilities, or branching fractions, of the strange B meson (B-s(0)) and the B-0 meson decaying into two oppositely charged muons (mu(+) and mu(-)) are especially interesting because of their sensitivity to theories that extend the standard model. The standard model predicts that the B-s(0)->mu(+)mu(-) and B-0 ->mu(+)mu(-) decays are very rare, with about four of the former occurring for every billion B-s(0) mesons produced, and one of the latter occurring for every ten billion B-0 mesons(1). A difference in the observed branching fractions with respect to the predictions of the standard model would provide a direction in which the standard model should be extended. Before the Large Hadron Collider (LHC) at CERN2 started operating, no evidence for either decay mode had been found. Upper limits on the branching fractions were an order of magnitude above the standard model predictions. The CMS (Compact Muon Solenoid) and LHCb(Large Hadron Collider beauty) collaborations have performed a joint analysis of the data from proton-proton collisions that they collected in 2011 at a centre-of-mass energy of seven teraelectronvolts and in 2012 at eight teraelectronvolts. Here we report the first observation of the B-s(0)->mu(+)mu(-) decay, with a statistical significance exceeding six standard deviations, and the best measurement so far of its branching fraction. Furthermore, we obtained evidence for the B-0 ->mu(+)mu(-) decay with a statistical significance of three standard deviations. Both measurements are statistically compatible with standard model predictions and allow stringent constraints to be placed on theories beyond the standard model. The LHC experiments will resume taking data in 2015, recording proton-proton collisions at a centre-of-mass energy of 13 teraelectronvolts, which will approximately double the production rates of B-s(0) and B-0 mesons and lead to further improvements in the precision of these crucial tests of the standard model.
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   [Makovec, A.; Raics, P.; Trocsanyi, Z. L.; Ujvari, B.] Debrecen Univ Med, H-4012 Debrecen, Hungary.
   [Sahoo, N.; Swain, S. K.] Natl Inst Sci Educ & Res, Bhubaneswar, Orissa, India.
   [Beri, S. B.; Bhatnagar, V.; Gupta, R.; Bhawandeep, U.; Kalsi, A. K.; Kaur, M.; Kumar, R.; Mittal, M.; Nishu, N.; Singh, J. B.] Panjab Univ, Chandigarh 160014, India.
   [Kumar, Ashok; Kumar, Arun; Ahuja, S.; Bhardwaj, A.; Choudhary, B. C.; Kumar, A.; Malhotra, S.; Naimuddin, M.; Ranjan, K.; Sharma, V.] Univ Delhi, Delhi 110007, India.
   [Banerjee, S.; Bhattacharya, S.; Chatterjee, K.; Dutta, S.; Gomber, B.; Jain, Sa.; Jain, Sh.; Khurana, R.; Modak, A.; Mukherjee, S.; Roy, D.; Sarkar, S.; Sharan, M.] Saha Inst Nucl Phys, Kolkata, India.
   [Abdulsalam, A.; Dutta, D.; Kailas, S.; Kumar, V.; Mohanty, A. K.; Pant, L. M.; Shukla, P.; Topkar, A.] Bhabha Atom Res Ctr, Bombay 400085, Maharashtra, India.
   [Aziz, T.; Banerjee, S.; Bhowmik, S.; Chatterjee, R. M.; Dewanjee, R. K.; Dugad, S.; Ganguly, S.; Ghosh, S.; Guchait, M.; Gurtu, A.; Kole, G.; Kumar, S.; Maity, M.; Majumder, G.; Mazumdar, K.; Mohanty, G. B.; Parida, B.; Sudhakar, K.; Wickramage, N.] Tata Inst Fundamental Res, Bombay 400005, Maharashtra, India.
   [Bakhshiansohi, H.; Behnamian, H.; Etesami, S. M.; Fahim, A.; Goldouzian, R.; Khakzad, M.; Najafabadi, M. Mohammadi; Naseri, M.; Mehdiabadi, S. Paktinat; Hosseinabadi, F. Rezaei; Safarzadeh, B.; Zeinali, M.] Inst Res Fundamental Sci IPM, Tehran, Iran.
   [Felcini, M.; Grunewald, M.] Univ Coll Dublin, Dublin 2, Ireland.
   Univ Bari, Ist Nazl Fis Nucl, Sez Bari, Politecn Bari, Bari, Italy.
   [Abbrescia, M.; Calabria, C.; Chhibra, S. S.; Colaleo, A.; Creanza, D.; De Filippis, N.; De Palma, M.; Fiore, L.; Iaselli, G.; Maggi, G.; Maggi, M.; My, S.; Nuzzo, S.; Pompili, A.; Pugliese, G.; Radogna, R.; Selvaggi, G.; Sharma, A.; Silvestris, L.; Venditti, R.; Verwilligen, P.] Ist Nazl Fis Nucl, Sez Bari, I-40126 Bologna, Italy.
   [Abbrescia, M.; Calabria, C.; Chhibra, S. S.; De Palma, M.; Nuzzo, S.; Pompili, A.; Radogna, R.; Selvaggi, G.; Venditti, R.] Univ Bari, Bologna, Italy.
   [Creanza, D.; De Filippis, N.; Iaselli, G.; Maggi, G.; My, S.; Pugliese, G.] Politecn Bari, Bologna, Italy.
   Univ Bologna, Ist Nazl Fis Nucl, Sez Bologna, Bologna, Italy.
   [Abbiendi, G.; Benvenuti, A. C.; Bonacorsi, D.; Braibant-Giacomelli, S.; Brigliadori, L.; Campanini, R.; Capiluppi, P.; Castro, A.; Cavallo, F. R.; Codispoti, G.; Cuffiani, M.; Dallavalle, G. M.; Fabbri, F.; Fanfani, A.; Fasanella, D.; Giacomelli, P.; Grandi, C.; Guiducci, L.; Marcellini, S.; Masetti, G.; Montanari, A.; Navarria, F. L.; Perrotta, A.; Primavera, F.; Rossi, A. M.; Rovelli, T.; Siroli, G. P.; Tosi, N.; Travaglini, R.] Ist Nazl Fis Nucl, Sez Bologna, I-95129 Catania, Italy.
   [Bonacorsi, D.; Braibant-Giacomelli, S.; Brigliadori, L.; Campanini, R.; Capiluppi, P.; Castro, A.; Codispoti, G.; Cuffiani, M.; Fanfani, A.; Fasanella, D.; Guiducci, L.; Navarria, F. L.; Primavera, F.; Rossi, A. M.; Rovelli, T.; Siroli, G. P.; Tosi, N.; Travaglini, R.] Univ Bologna, Catania, Italy.
   Univ Catania, Ist Nazl Fis Nucl, Sez Catania, CSFNSM, Catania, Italy.
   [Albergo, S.; Cappello, G.; Chiorboli, M.; Costa, S.; Giordano, F.; Potenza, R.; Tricomi, A.; Tuve, C.] Ist Nazl Fis Nucl, Sez Catania, I-50125 Florence, Italy.
   [Albergo, S.; Chiorboli, M.; Costa, S.; Potenza, R.; Tricomi, A.; Tuve, C.] Univ Catania, Florence, Italy.
   CSFNSM, Florence, Italy.
   Univ Florence, Ist Nazl Fis Nucl, Sez Firenze, Florence, Italy.
   [Barbagli, G.; Ciulli, V.; Civinini, C.; D'Alessandro, R.; Focardi, E.; Gallo, E.; Gonzi, S.; Gori, V.; Lenzi, P.; Meschini, M.; Paoletti, S.; Sguazzoni, G.; Tropiano, A.] Ist Nazl Fis Nucl, Sez Firenze, Frascati, Italy.
   [Ciulli, V.; D'Alessandro, R.; Focardi, E.; Gonzi, S.; Gori, V.; Lenzi, P.; Tropiano, A.] Univ Florence, Frascati, Italy.
   [Benussi, L.; Bianco, S.; Fabbri, F.; Piccolo, D.] Ist Nazl Fis Nucl, Lab Nazl Frascati, I-00044 Frascati, Italy.
   Univ Genoa, Ist Nazl Fis Nucl, Sez Genova, Genoa, Italy.
   [Ferretti, R.; Ferro, F.; Lo Vetere, M.; Robutti, E.; Tosi, S.] Ist Nazl Fis Nucl, Sez Genova, I-20133 Milan, Italy.
   [Ferretti, R.; Lo Vetere, M.; Tosi, S.] Univ Genoa, Milan, Italy.
   Univ Milano Bicocca, Ist Nazl Fis Nucl, Sez Milano Bicocca, Milan, Italy.
   [Dinardo, M. E.; Fiorendi, S.; Gennai, S.; Gerosa, R.; Ghezzi, A.; Govoni, P.; Lucchini, M. T.; Malvezzi, S.; Manzoni, R. A.; Martelli, A.; Marzocchi, B.; Menasce, D.; Moroni, L.; Paganoni, M.; Pedrini, D.; Ragazzi, S.; Redaelli, N.; Tabarelli de Fatis, T.] Ist Nazl Fis Nucl, Sez Milano Bicocca, I-80125 Naples, Italy.
   [Dinardo, M. E.; Fiorendi, S.; Gerosa, R.; Ghezzi, A.; Govoni, P.; Lucchini, M. T.; Manzoni, R. A.; Martelli, A.; Marzocchi, B.; Paganoni, M.; Ragazzi, S.; Tabarelli de Fatis, T.] Univ Milano Bicocca, Naples, Italy.
   Univ Naples Federico II, Ist Nazl Fis Nucl, Sez Napoli, Naples, Italy.
   Univ Basilicata Potenza, Naples, Italy.
   Univ G Marconi Roma, Naples, Italy.
   [Buontempo, S.; Cavallo, N.; Di Guida, S.; Fabozzi, F.; Iorio, A. O. M.; Lista, L.; Meola, S.; Merola, M.; Paolucci, P.] Ist Nazl Fis Nucl, Sez Napoli, Naples, Italy.
   [Iorio, A. O. M.] Univ Naples Federico II, Naples, Italy.
   [Cavallo, N.; Fabozzi, F.] Univ Basilicata, Potenza, Italy.
   [Meola, S.] Univ G Marconi, Rome, Italy.
   Univ Padua, Ist Nazl Fis Nucl, Sez Padova, Padua, Italy.
   [Kanishchev, K.] Univ Trento, Trento, Italy.
   [Azzi, P.; Bacchetta, N.; Bisello, D.; Branca, A.; Carlin, R.; Checchia, P.; Dall'Osso, M.; Dorigo, T.; Dosselli, U.; Gasparini, F.; Gasparini, U.; Giubilato, P.; Gozzelino, A.; Kanishchev, K.; Lacaprara, S.; Margoni, M.; Meneguzzo, A. T.; Pazzini, J.; Pozzobon, N.; Ronchese, P.; Simonetto, F.; Torassa, E.; Tosi, M.; Zotto, P.; Zucchetta, A.; Zumerle, G.] Ist Nazl Fis Nucl, Sez Padova, Padua, Italy.
   [Bisello, D.; Branca, A.; Carlin, R.; Dall'Osso, M.; Gasparini, F.; Gasparini, U.; Giubilato, P.; Margoni, M.; Meneguzzo, A. T.; Pazzini, J.; Pozzobon, N.; Ronchese, P.; Simonetto, F.; Tosi, M.; Zotto, P.; Zucchetta, A.; Zumerle, G.] Univ Padua, I-35100 Padua, Italy.
   [Ratti, S. P.] Univ Pavia, Ist Nazl Fis Nucl, Sez Pavia, I-27100 Pavia, Italy.
   [Gabusi, M.; Ratti, S. P.; Re, V.; Riccardi, C.; Salvini, P.; Vitulo, P.] Ist Nazl Fis Nucl, Sez Pavia, I-06100 Perugia, Italy.
   [Gabusi, M.; Riccardi, C.; Vitulo, P.] Univ Pavia, Perugia, Italy.
   Univ Perugia, Ist Nazl Fis Nucl, Sez Perugia, I-06100 Perugia, Italy.
   [Biasini, M.; Bilei, G. M.; Ciangottini, D.; Fano, L.; Lariccia, P.; Mantovani, G.; Menichelli, M.; Saha, A.; Santocchia, A.; Spiezia, A.] Ist Nazl Fis Nucl, Sez Perugia, Perugia, Italy.
   [Biasini, M.; Ciangottini, D.; Fano, L.; Lariccia, P.; Mantovani, G.; Santocchia, A.; Spiezia, A.] Univ Perugia, I-06100 Perugia, Italy.
   Univ Pisa, Scuola Normale Super Pisa, Ist Nazl Fis Nucl, Sez Pisa, Pisa, Italy.
   [Androsov, K.; Azzurri, P.; Bagliesi, G.; Bernardini, J.; Boccali, T.; Broccolo, G.; Castaldi, R.; Ciocci, M. A.; Dell'Orso, R.; Donato, S.; Fiori, F.; Foa, L.; Giassi, A.; Grippo, M. T.; Ligabue, F.; Lomtadze, T.; Martini, L.; Messineo, A.; Moon, C. S.; Palla, F.; Rizzi, A.; Savoy-Navarro, A.; Serban, A. T.; Spagnolo, P.; Squillacioti, P.; Tenchini, R.; Tonelli, G.; Venturi, A.; Verdini, P. G.; Vernieri, C.] Ist Nazl Fis Nucl, Sez Pisa, Pisa, Italy.
   [Martini, L.; Messineo, A.; Rizzi, A.; Tonelli, G.] Univ Pisa, I-56100 Pisa, Italy.
   [Broccolo, G.; Donato, S.; Fiori, F.; Foa, L.; Ligabue, F.; Vernieri, C.] Scuola Normale Super Pisa, Rome, Italy.
   Univ Roma, Ist Nazl Fis Nucl, Sez Roma, Rome, Italy.
   [Barone, L.; Cavallari, F.; D'imperio, G.; Del Re, D.; Diemoz, M.; Jorda, C.; Longo, E.; Margaroli, F.; Meridiani, P. M.; Micheli, F.; Nourbakhsh, S.; Organtini, G.; Paramatti, R.; Rahatlou, S.; Rovelli, C.; Santanastasio, F.; Soffi, L.; Traczyk, P.] Ist Nazl Fis Nucl, Sez Roma, Rome, Italy.
   [Barone, L.; D'imperio, G.; Del Re, D.; Longo, E.; Margaroli, F.; Micheli, F.; Nourbakhsh, S.; Organtini, G.; Rahatlou, S.; Santanastasio, F.; Soffi, L.; Traczyk, P.] Univ Roma Tor Vergata, I-00173 Rome, Italy.
   Univ Turin, Univ Piemonte Orientale Novara, Ist Nazl Fis Nucl, Sez Torino, Turin, Italy.
   [Amapane, N.; Arcidiacono, R.; Argiro, S.; Arneodo, M.; Bellan, R.; Biino, C.; Cartiglia, N.; Casasso, S.; Costa, M.; Degano, A.; Demaria, N.; Finco, L.; Mariotti, C.; Maselli, S.; Migliore, E.; Monaco, V.; Musich, M.; Obertino, M. M.; Pacher, L.; Pastrone, N.; Pelliccioni, M.; Angioni, G. L. Pinna; Potenza, A.; Romero, A.; Ruspa, M.; Sacchi, R.; Solano, A.; Staiano, A.; Tamponi, U.] Ist Nazl Fis Nucl, Sez Torino, Turin, Italy.
   [Amapane, N.; Argiro, S.; Bellan, R.; Casasso, S.; Costa, M.; Degano, A.; Finco, L.; Migliore, E.; Monaco, V.; Pacher, L.; Angioni, G. L. Pinna; Potenza, A.; Romero, A.; Sacchi, R.; Solano, A.] Univ Turin, I-10124 Turin, Italy.
   [Arcidiacono, R.; Arneodo, M.; Obertino, M. M.; Ruspa, M.] Univ Piemonte Orientale, Novara, Italy.
   Univ Trieste, Ist Nazl Fis Nucl, Sez Trieste, Trieste, Italy.
   [Belforte, S.; Candelise, V.; Casarsa, M.; Cossutti, F.; Della Ricca, G.; Gobbo, B.; La Licata, C.; Marone, M.; Schizzi, A.; Umer, T.; Zanetti, A.] Ist Nazl Fis Nucl, Sez Trieste, Trieste, Italy.
   [Candelise, V.; Della Ricca, G.; La Licata, C.; Marone, M.; Schizzi, A.; Umer, T.] Univ Trieste, I-34127 Trieste, Italy.
   [Chang, S.; Kropivnitskaya, A.; Nam, S. K.] Kangwon Natl Univ, Chunchon, South Korea.
   [Kim, D. H.; Kim, G. N.; Kim, M. S.; Kong, D. J.; Lee, S.; Oh, Y. D.; Park, H.; Sakharov, A.; Son, D. C.] Kyungpook Natl Univ, Taegu, South Korea.
   [Kim, T. J.] Chonbuk Natl Univ, Jeonju 561756, South Korea.
   [Kim, J. Y.; Song, S.] Chonnam Natl Univ, Inst Universe & Elementary Particles, Kwangju, South Korea.
   [Choi, S.; Gyun, D.; Hong, B.; Jo, M.; Kim, H.; Kim, Y.; Lee, B.; Lee, K. S.; Park, S. K.; Roh, Y.] Korea Univ, Seoul, South Korea.
   [Yoo, H. D.] Seoul Natl Univ, Seoul, South Korea.
   [Choi, M.; Kim, J. H.; Park, I. C.; Ryu, G.; Ryu, M. S.] Univ Seoul, Seoul, South Korea.
   [Choi, Y.; Choi, Y. K.; Goh, J.; Kim, D.; Kwon, E.; Lee, J.; Yu, I.] Sungkyunkwan Univ, Suwon, South Korea.
   [Juodagalvis, A.] Vilnius State Univ, Vilnius, Lithuania.
   [Komaragiri, J. R.; Ali, M. A. B. Md] Univ Malaya, Natl Ctr Particle Phys, Kuala Lumpur, Malaysia.
   [Linares, E. Casimiro; Castilla-Valdez, H.; De La Cruz-Burelo, E.; Heredia-de la Cruz, I.; Hernandez-Almada, A.; Lopez-Fernandez, R.; Sanchez-Hernandez, A.] IPN, Ctr Invest & Estudios Avanzados, Mexico City 07738, DF, Mexico.
   [Carrillo Moreno, S.; Vazquez Valencia, F.] Univ Iberoamer, Mexico City, DF, Mexico.
   [Pedraza, I.; Salazar Ibarguen, H. A.] Benemerita Univ Autonoma Puebla, Puebla, Mexico.
   [Morelos Pineda, A.] Univ Autonoma San Luis Potosi, San Luis Potosi, Mexico.
   [Krofcheck, D.] Univ Auckland, Auckland 1, New Zealand.
   [Butler, P. H.; Reucroft, S.] Univ Canterbury, Christchurch 1, New Zealand.
   [Ahmad, A.; Ahmad, M.; Hassan, Q.; Hoorani, H. R.; Khan, W. A.; Khurshid, T.; Shoaib, M.] Quaid I Azam Univ, Natl Ctr Phys, Islamabad, Pakistan.
   [Bialkowska, H.; Bluj, M.; Boimska, B.; Frueboes, T.; Gorski, M.; Kazana, M.; Nawrocki, K.; Romanowska-Rybinska, K.; Szleper, M.; Zalewski, P.] Natl Ctr Nucl Res, Otwock, Poland.
   [Brona, G.; Bunkowski, K.; Cwiok, M.; Dominik, W.; Doroba, K.; Kalinowski, A.; Konecki, M.; Krolikowski, J.; Misiura, M.; Olszewski, M.; Wolszczak, W.] Univ Warsaw, Inst Expt Phys, Fac Phys, Warsaw, Poland.
   [Bargassa, P.; Beirao Da Cruz E Silva, C.; Faccioli, P.; Ferreira Parracho, P. G.; Gallinaro, M.; Lloret Iglesias, L.; Nguyen, F.; Rodrigues Antunes, J.; Seixas, J.; Varela, J.; Vischia, P.] Lab Instrumentacao & Fis Expt Particulas, Lisbon, Portugal.
   [Afanasiev, S.; Bunin, P.; Gavrilenko, M.; Golutvin, I.; Gorbunov, I.; Kamenev, A.; Karjavin, V.; Konoplyanikov, V.; Lanev, A.; Malakhov, A.; Matveev, V.; Moisenz, P.; Palichik, V.; Perelygin, V.; Shmatov, S.; Skatchkov, N.; Smirnov, V.; Zarubin, A.] Joint Nucl Res Inst, Dubna, Russia.
   [Golovtsov, V.; Ivanov, Y.; Kim, V.; Levchenko, P.; Murzin, V.; Oreshkin, V.; Smirnov, I.; Sulimov, V.; Uvarov, L.; Vavilov, S.; Vorobyev, A.; Vorobyev, An.] Petersburg Nucl Phys Inst, Gatchina, Russia.
   [Andreev, Yu.; Dermenev, A.; Gninenko, S.; Golubev, N.; Kirsanov, M.; Krasnikov, N.; Pashenkov, A.; Tlisov, D.; Toropin, A.] Russian Acad Sci, Inst Nucl Res, Moscow 117312, Russia.
   [Epshteyn, V.; Gavrilov, V.; Lychkovskaya, N.; Popov, V.; Pozdnyakov, I.; Safronov, G.; Semenov, S.; Spiridonov, A.; Stolin, V.; Vlasov, E.; Zhokin, A.] Inst Theoret & Expt Phys, Moscow 117259, Russia.
   [Andreev, V.; Azarkin, M.; Dremin, I.; Kirakosyan, M.; Leonidov, A.; Mesyats, G.; Rusakov, S. V.; Vinogradov, A.] PN Lebedev Phys Inst, Moscow 117924, Russia.
   [Belyaev, A.; Boos, E.; Dubinin, M.; Dudko, L.; Ershov, A.; Gribushin, A.; Klyukhin, V.; Kodolova, O.; Lokhtin, I.; Obraztsov, S.; Petrushanko, S.; Savrin, V.; Snigirev, A.] Moscow MV Lomonosov State Univ, Skobeltsyn Inst Nucl Phys, Moscow, Russia.
   [Azhgirey, I.; Bayshev, I.; Bitioukov, S.; Kachanov, V.; Kalinin, A.; Konstantinov, D.; Krychkine, V.; Petrov, V.; Ryutin, R.; Sobol, A.; Tourtchanovitch, L.; Troshin, S.; Tyurin, N.; Uzunian, A.; Volkov, A.] State Res Ctr Russian Federat, Inst High Energy Phys, Protvino, Russia.
   [Adzic, P.; Ekmedzic, M.; Milosevic, J.; Rekovic, V.] Univ Belgrade, Fac Phys, Belgrade 11001, Serbia.
   [Adzic, P.; Ekmedzic, M.; Milosevic, J.; Rekovic, V.] Univ Belgrade, Vinca Inst Nucl Sci, Belgrade, Serbia.
   [Alcaraz Maestre, J.; Battilana, C.; Calvo, E.; Cerrada, M.; Llatas, M. Chamizo; Colino, N.; De La Cruz, B.; Delgado Peris, A.; Dominguez Vazquez, D.; Escalante Del Valle, A.; Fernandez Bedoya, C.; Fernandez Ramos, J. P.; Flix, J.; Fouz, M. C.; Garcia-Abia, P.; Gonzalez Lopez, O.; Goy Lopez, S.; Hernandez, J. M.; Josa, M. I.; Navarro De Martino, E.; Perez-Calero Yzquierdo, A.; Puerta Pelayo, J.; Quintario Olmeda, A.; Redondo, I.; Romero, L.; Soares, M. S.] CIEMAT, E-28040 Madrid, Spain.
   [Albajar, C.; de Troconiz, J. F.; Missiroli, M.; Moran, D.] Univ Autonoma Madrid, Madrid, Spain.
   [Brun, H.; Cuevas, J.; Menendez, J. Fernandez; Folgueras, S.; Gonzalez Caballero, I.] Univ Oviedo, Oviedo, Spain.
   [Brochero Cifuentes, J. A.; Cabrillo, I. J.; Calderon, A.; Duarte Campderros, J.; Fernandez, M.; Gomez, G.; Graziano, A.; Lopez Virto, A.; Marco, J.; Marco, R.; Martinez Rivero, C.; Matorras, F.; Munoz Sanchez, F. J.; Piedra Gomez, J.; Rodrigo, T.; Rodriguez-Marrero, A. Y.; Ruiz-Jimeno, A.; Scodellaro, L.; Vila, I.; Vilar Cortabitarte, R.] Univ Cantabria, CSIC, Inst Fis Cantabria IFCA, E-39005 Santander, Spain.
   [Abbaneo, D.; Auffray, E.; Auzinger, G.; Bachtis, M.; Baillon, P.; Ball, A. H.; Barney, D.; Benaglia, A.; Bendavid, J.; Benhabib, L.; Benitez, J. F.; Bernet, C.; Bloch, P.; Bocci, A.; Bonato, A.; Bondu, O.; Botta, C.; Breuker, H.; Camporesi, T.; Cerminara, G.; Colafranceschi, S.; D'Alfonso, M.; d'Enterria, D.; Dabrowski, A.; David, A.; De Guio, F.; De Roeck, A.; De Visscher, S.; Di Marco, E.; Dobson, M.; Dordevic, M.; Dupont-Sagorin, N.; Elliott-Peisert, A.; Franzoni, G.; Funk, W.; Gigi, D.; Gill, K.; Giordano, D.; Girone, M.; Glege, F.; Guida, R.; Gundacker, S.; Guthoff, M.; Hammer, J.; Hansen, M.; Harris, P.; Hegeman, J.; Innocente, V.; Janot, P.; Kousouris, K.; Krajczar, K.; Lecoq, P.; Loureno, C.; Magini, N.; Malgeri, L.; Mannelli, M.; Marrouche, J.; Masetti, L.; Meijers, F.; Mersi, S.; Meschi, E.; Moortgat, F.; Morovic, S.; Mulders, M.; Orsini, L.; Pape, L.; Perez, E.; Perrozzi, L.; Petrilli, A.; Petrucciani, G.; Pfeiffer, A.; Pimiae, M.; Piparo, D.; Plagge, M.; Racz, A.; Rolandi, G.; Rovere, M.; Sakulin, H.; Schaefer, C.; Schwick, C.; Sharma, A.; Siegrist, P.; Silva, P.; Simon, M.; Sphicas, P.; Spiga, D.; Steggemann, J.; Stieger, B.; Stoye, M.; Takahashi, Y.; Treille, D.; Tsirou, A.; Veres, G. I.; Wardle, N.; Woehri, H. K.; Wollny, H.; Zeuner, W. D.] CERN, European Org Nucl Res, CH-1211 Geneva, Switzerland.
   [Bertl, W.; Deiters, K.; Erdmann, W.; Horisberger, R.; Ingram, Q.; Kaestli, H. C.; Kotlinski, D.; Renker, D.; Rohe, T.] Paul Scherrer Inst, Villigen, Switzerland.
   [Bachmair, F.; Baeni, L.; Bianchini, L.; Buchmann, M. A.; Casal, B.; Chanon, N.; Dissertori, G.; Dittmar, M.; Donega, M.; Duenser, M.; Eller, P.; Grab, C.; Hits, D.; Hoss, J.; Lustermann, W.; Mangano, B.; Marini, A. C.; Marionneau, M.; Martinez Ruiz del Arbol, P.; Masciovecchio, M.; Meister, D.; Mohr, N.; Musella, P.; Naegeli, C.; Nessi-Tedaldi, F.; Pandolfi, F.; Pauss, F.; Peruzzi, M.; Quittnat, M.; Rebane, L.; Rossini, M.; Starodumov, A.; Takahashi, M.; Theofilatos, K.; Wallny, R.; Weber, H. A.] ETH, Inst Particle Phys, Zurich, Switzerland.
   [Amsler, C.; Canelli, M. F.; Chiochia, V.; De Cosa, A.; Hinzmann, A.; Hreus, T.; Kilminster, B.; Lange, C.; Millan Mejias, B.; Ngadiuba, J.; Pinna, D.; Robmann, P.; Ronga, F. J.; Taroni, S.; Verzetti, M.; Yang, Y.] Univ Zurich, Zurich, Switzerland.
   [Cardaci, M.; Chen, K. H.; Ferro, C.; Kuo, C. M.; Lin, W.; Lu, Y. J.; Volpe, R.; Yu, S. S.] Natl Cent Univ, Chungli 32054, Taiwan.
   [Chang, P.; Chang, Y. H.; Chang, Y. W.; Chao, Y.; Chen, K. F.; Chen, P. H.; Dietz, C.; Grundler, U.; Hou, W-S.; Kao, K. Y.; Liu, Y. F.; Lu, R-S.; Majumder, D.; Petrakou, E.; Tzeng, Y. M.; Wilken, R.] Natl Taiwan Univ, Taipei 10764, Taiwan.
   [Asavapibhop, B.; Singh, G.; Srimanobhas, N.; Suwonjandee, N.] Chulalongkorn Univ, Fac Sci, Dept Phys, Bangkok, Thailand.
   [Adiguzel, A.; Bakirci, M. N.; Cerci, S.; Dozen, C.; Dumanoglu, I.; Eskut, E.; Girgis, S.; Gokbulut, G.; Gurpinar, E.; Hos, I.; Kangal, E. E.; Topaksu, A. Kayis; Onengut, G.; Ozdemir, K.; Ozturk, S.; Polatoz, A.; Cerci, D. Sunar; Tali, B.; Topakli, H.; Vergili, M.] Cukurova Univ, Adana, Turkey.
   [Akin, I. V.; Bilin, B.; Bilmis, S.; Gamsizkan, H.; Isildak, B.; Karapinar, G.; Ocalan, K.; Sekmen, S.; Surat, U. E.; Yalvac, M.; Zeyrek, M.] Middle E Tech Univ, Dept Phys, TR-06531 Ankara, Turkey.
   [Albayrak, E. A.; Guelmez, E.; Kaya, M.; Kaya, O.; Yetkin, T.] Bogazici Univ, Istanbul, Turkey.
   [Cankocak, K.; Vardarli, F. I.] Istanbul Tech Univ, TR-80626 Istanbul, Turkey.
   [Levchuk, L.; Sorokin, P.] Ctr Nat Sci, Kharkov Inst Phys & Technol, Kharkov, Ukraine.
   [Brooke, J. J.; Clement, E.; Cussans, D.; Flacher, H.; Goldstein, J.; Grimes, M.; Heath, G. P.; Heath, H. F.; Jacob, J.; Kreczko, L.; Lucas, C.; Meng, Z.; Newbold, D. M.; Paramesvaran, S.; Poll, A.; Sakuma, T.; Senkin, S.; Smith, V. J.] Univ Bristol, Bristol, Avon, England.
   [Bell, K. W.; Belyaev, A.; Brew, C.; Brown, R. M.; Cockerill, D. J. A.; Coughlan, J. A.; Harder, K.; Harper, S.; Olaiya, E.; Petyt, D.; Shepherd-Themistocleous, C. H.; Thea, A.; Tomalin, I. R.; Williams, T.; Womersley, W. J.; Worm, S. D.] Rutherford Appleton Lab, Didcot OX11 0QX, Oxon, England.
   [Baber, M.; Bainbridge, R.; Buchmuller, O.; Burton, D.; Colling, D.; Cripps, N.; Dauncey, P.; Davies, G.; Della Negra, M.; Dunne, P.; Ferguson, W.; Fulcher, J.; Futyan, D.; Hall, G.; Iles, G.; Jarvis, M.; Karapostoli, G.; Kenzie, M.; Lane, R.; Lucas, R.; Lyons, L.; Magnan, A-M.; Malik, S.; Mathias, B.; Nash, J.; Nikitenko, A.; Pela, J.; Pesaresi, M.; Petridis, K.; Raymond, D. M.; Rogerson, S.; Rose, A.; Seez, C.; Sharp, P.; Tapper, A.; Vazquez Acosta, M.; Virdee, T.; Zenz, S. C.] Univ London Imperial Coll Sci Technol & Med, London, England.
   [Cole, J. E.; Hobson, P. R.; Khan, A.; Kyberd, P.; Leggat, D.; Leslie, D.; Reid, I. D.; Symonds, P.; Teodorescu, L.; Turner, M.] Brunel Univ, Uxbridge UB8 3PH, Middx, England.
   [Dittmann, J.; Hatakeyama, K.; Kasmi, A.; Liu, H.; Scarborough, T.] Baylor Univ, Waco, TX 76798 USA.
   [Charaf, O.; Cooper, S. I.; Henderson, C.; Rumerio, P.] Univ Alabama, Tuscaloosa, AL USA.
   [Avetisyan, A.; Bose, T.; Fantasia, C.; Lawson, P.; Richardson, C.; Rohlf, J.; St John, J.; Sulak, L.] Boston Univ, Boston, MA 02215 USA.
   [Alimena, J.; Berry, E.; Bhattacharya, S.; Christopher, G.; Cutts, D.; Demiragli, Z.; Dhingra, N.; Ferapontov, A.; Garabedian, A.; Heintz, U.; Kukartsev, G.; Laird, E.; Landsberg, G.; Luk, M.; Narain, M.; Segala, M.; Sinthuprasith, T.; Speer, T.; Swanson, J.] Brown Univ, Providence, RI 02912 USA.
   [Breedon, R.; Breto, G.; Calderon De La Barca Sanchez, M.; Chauhan, S.; Chertok, M.; Conway, J.; Conway, R.; Cox, P. T.; Erbacher, R.; Gardner, M.; Ko, W.; Lander, R.; Mulhearn, M.; Pellett, D.; Pilot, J.; Ricci-Tam, F.; Shalhout, S.; Smith, J.; Squires, M.; Stolp, D.; Tripathi, M.; Wilbur, S.; Yohay, R.] Univ Calif Davis, Davis, CA 95616 USA.
   [Cousins, R.; Everaerts, P.; Farrell, C.; Hauser, J.; Ignatenko, M.; Rakness, G.; Takasugi, E.; Valuev, V.; Weber, M.] Univ Calif Los Angeles, Los Angeles, CA USA.
   [Burt, K.; Clare, R.; Ellison, J.; Gary, J. W.; Hanson, G.; Heilman, J.; Rikova, M. Ivova; Jandir, P.; Kennedy, E.; Lacroix, F.; Long, O. R.; Luthra, A.; Malberti, M.; Olmedo Negrete, M.; Shrinivas, A.; Sumowidagdo, S.; Wimpenny, S.] Univ Calif Riverside, Riverside, CA 92521 USA.
   [Branson, J. G.; Cerati, G. B.; Cittolin, S.; D'Agnolo, R. T.; Holzner, A.; Kelley, R.; Klein, D.; Kovalskyi, D.; Letts, J.; Macneill, I.; Olivito, D.; Padhi, S.; Palmer, C.; Pieri, M.; Sani, M.; Sharma, V.; Simon, S.; Tu, Y.; Vartak, A.; Welke, C.; Wuerthwein, F.; Yagil, A.] Univ Calif San Diego, La Jolla, CA 92093 USA.
   [Barge, D.; Bradmiller-Feld, J.; Campagnari, C.; Danielson, T.; Dishaw, A.; Dutta, V.; Flowers, K.; Sevilla, M. Franco; Geffert, P.; George, C.; Golf, F.; Gouskos, L.; Incandela, J.; Justus, C.; Mccoll, N.; Richman, J.; Stuart, D.; To, W.; West, C.; Yoo, J.] Univ Calif Santa Barbara, Santa Barbara, CA 93106 USA.
   [Apresyan, A.; Bornheim, A.; Bunn, J.; Chen, Y.; Duarte, J.; Mott, A.; Newman, H. B.; Pena, C.; Pierini, M.; Spiropulu, M.; Vlimant, J. R.; Wilkinson, R.; Xie, S.; Zhu, R. Y.] CALTECH, Pasadena, CA 91125 USA.
   [Azzolini, V.; Calamba, A.; Carlson, B.; Ferguson, T.; Iiyama, Y.; Paulini, M.; Russ, J.; Vogel, H.; Vorobiev, I.] Carnegie Mellon Univ, Pittsburgh, PA 15213 USA.
   [Cumalat, J. P.; Ford, W. T.; Gaz, A.; Krohn, M.; Luiggi Lopez, E.; Nauenberg, U.; Smith, J. G.; Stenson, K.; Wagner, S. R.] Univ Colorado, Boulder, CO 80309 USA.
   [Alexander, J.; Chatterjee, A.; Chaves, J.; Chu, J.; Dittmer, S.; Eggert, N.; Mirman, N.; Kaufman, G. Nicolas; Patterson, J. R.; Ryd, A.; Salvati, E.; Skinnari, L.; Sun, W.; Teo, W. D.; Thom, J.; Thompson, J.; Tucker, J.; Weng, Y.; Winstrom, L.; Wittich, P.] Cornell Univ, Ithaca, NY USA.
   [Winn, D.] Fairfield Univ, Fairfield, CT 06430 USA.
   [Abdullin, S.; Albrow, M.; Anderson, J.; Apollinari, G.; Bauerdick, L. A. T.; Beretvas, A.; Berryhill, J.; Bhat, P. C.; Bolla, G.; Burkett, K.; Butler, J. N.; Cheung, H. W. K.; Chlebana, F.; Cihangir, S.; Elvira, V. D.; Fisk, I.; Freeman, J.; Gao, Y.; Gottschalk, E.; Gray, L.; Green, D.; Gruenendahl, S.; Gutsche, O.; Hanlon, J.; Hare, D.; Harris, R. M.; Hirschauer, J.; Hooberman, B.; Jindariani, S.; Johnson, M.; Joshi, U.; Kaadze, K.; Klima, B.; Kreis, B.; Kwan, S.; Linacre, J.; Lincoln, D.; Lipton, R.; Liu, T.; Lykken, J.; Maeshima, K.; Marraffino, J. M.; Outschoorn, V. I. Martinez; Maruyama, S.; Mason, D.; McBride, P.; Merkel, P.; Mishra, K.; Mrenna, S.; Nahn, S.; Newman-Holmes, C.; O'Dell, V.; Prokofyev, O.; Sexton-Kennedy, E.; Sharma, S.; Soha, A.; Spalding, W. J.; Spiegel, L.; Taylor, L.; Tkaczyk, S.; Tran, N. V.; Uplegger, L.; Vaandering, E. W.; Vidal, R.; Whitbeck, A.; Whitmore, J.; Yang, F.] Fermilab Natl Accelerator Lab, Batavia, IL 60510 USA.
   [Acosta, D.; Avery, P.; Bortignon, P.; Bourilkov, D.; Carver, M.; Curry, D.; Das, S.; De Gruttola, M.; Di Giovanni, G. P.; Field, R. D.; Fisher, M.; Furic, I. K.; Hugon, J.; Konigsberg, J.; Korytov, A.; Kypreos, T.; Low, J. F.; Matchev, K.; Mei, H.; Milenovic, P.; Mitselmakher, G.; Muniz, L.; Rinkevicius, A.; Shchutska, L.; Snowball, M.; Sperka, D.; Yelton, J.; Zakaria, M.] Univ Florida, Gainesville, FL USA.
   [Hewamanage, S.; Linn, S.; Markowitz, P.; Martinez, G.; Rodriguez, J. L.] Florida Int Univ, Miami, FL 33199 USA.
   [Adams, T.; Askew, A.; Bochenek, J.; Diamond, B.; Haas, J.; Hagopian, S.; Hagopian, V.; Johnson, K. F.; Prosper, H.; Veeraraghavan, V.; Weinberg, M.] Florida State Univ, Tallahassee, FL 32306 USA.
   [Baarmand, M. M.; Hohlmann, M.; Kalakhety, H.; Yumiceva, F.] Florida Inst Technol, Melbourne, FL 32901 USA.
   [Adams, M. R.; Apanasevich, L.; Berry, D.; Betts, R. R.; Bucinskaite, I.; Cavanaugh, R.; Evdokimov, O.; Gauthier, L.; Gerber, C. E.; Hofman, D. J.; Kurt, P.; Moon, D. H.; O'Brien, C.; Gonzalez, I. D. Sandoval; Silkworth, C.; Turner, P.; Varelas, N.] Univ Illinois, Chicago, IL USA.
   [Bilki, B.; Clarida, W.; Dilsiz, K.; Haytmyradov, M.; Merlo, J-P.; Mermerkaya, H.; Mestvirishvili, A.; Moeller, A.; Nachtman, J.; Ogul, H.; Onel, Y.; Ozok, F.; Penzo, A.; Rahmat, R.; Sen, S.; Tan, P.; Tiras, E.; Wetzel, J.; Yi, K.] Univ Iowa, Iowa City, IA USA.
   [Barnett, B. A.; Blumenfeld, B.; Bolognesi, S.; Fehling, D.; Gritsan, A. V.; Maksimovic, P.; Martin, C.; Swartz, M.] Johns Hopkins Univ, Baltimore, MD USA.
   [Baringer, P.; Bean, A.; Benelli, G.; Bruner, C.; Kenny, R. P., III; Malek, M.; Murray, M.; Noonan, D.; Sanders, S.; Sekaric, J.; Stringer, R.; Wang, Q.; Wood, J. S.] Univ Kansas, Lawrence, KS 66045 USA.
   [Chakaberia, I.; Ivanov, A.; Khalil, S.; Makouski, M.; Maravin, Y.; Saini, L. K.; Skhirtladze, N.; Svintradze, I.] Kansas State Univ, Manhattan, KS 66506 USA.
   [Gronberg, J.; Lange, D.; Rebassoo, F.; Wright, D.] Lawrence Livermore Natl Lab, Livermore, CA USA.
   [Baden, A.; Belloni, A.; Calvert, B.; Eno, S. C.; Gomez, J. A.; Hadley, N. J.; Kellogg, R. G.; Kolberg, T.; Lu, Y.; Mignerey, A. C.; Pedro, K.; Skuja, A.; Tonjes, M. B.; Tonwar, S. C.] Univ Maryland, College Pk, MD 20742 USA.
   [Apyan, A.; Barbieri, R.; Bauer, G.; Busza, W.; Cali, I. A.; Chan, M.; Di Matteo, L.; Gomez Ceballos, G.; Goncharov, M.; Gulhan, D.; Klute, M.; Lai, Y. S.; Lee, Y-J.; Levin, A.; Luckey, P. D.; Ma, T.; Paus, C.; Ralph, D.; Roland, C.; Roland, G.; Stephans, G. S. F.; Sumorok, K.; Velicanu, D.; Veverka, J.; Wyslouch, B.; Yang, M.; Zanetti, M.; Zhukova, V.] MIT, Cambridge, MA 02139 USA.
   [Dahmes, B.; Gude, A.; Kao, S. C.; Klapoetke, K.; Kubota, Y.; Mans, J.; Pastika, N.; Rusack, R.; Singovsky, A.; Tambe, N.; Turkewitz, J.] Univ Minnesota, Minneapolis, MN USA.
   [Acosta, J. G.; Oliveros, S.] Univ Mississippi, Oxford, MS USA.
   [Avdeeva, E.; Bloom, K.; Bose, S.; Claes, D. R.; Dominguez, A.; Suarez, R. Gonzalez; Keller, J.; Knowlton, D.; Kravchenko, I.; Lazo-Flores, J.; Meier, F.; Ratnikov, F.; Snow, G. R.; Zvada, M.] Univ Nebraska, Lincoln, NE USA.
   [Dolen, J.; Godshalk, A.; Iashvili, I.; Kharchilava, A.; Kumar, A.; Rappoccio, S.] SUNY Buffalo, Buffalo, NY 14260 USA.
   [Alverson, G.; Barberis, E.; Baumgartel, D.; Chasco, M.; Massironi, A.; Morse, D. M.; Nash, D.; Orimoto, T.; Trocino, D.; Wang, R-J; Wood, D.; Zhang, J.] Northeastern Univ, Boston, MA 02115 USA.
   [Hahn, K. A.; Kubik, A.; Mucia, N.; Odell, N.; Pollack, B.; Pozdnyakov, A.; Schmitt, M.; Stoynev, S.; Sung, K.; Velasco, M.; Won, S.] Northwestern Univ, Evanston, IL USA.
   [Brinkerhoff, A.; Chan, K. M.; Drozdetskiy, A.; Hildreth, M.; Jessop, C.; Karmgard, D. J.; Kellams, N.; Lannon, K.; Lynch, S.; Marinelli, N.; Musienko, Y.; Pearson, T.; Planer, M.; Ruchti, R.; Smith, G.; Valls, N.; Wayne, M.; Wolf, M.; Woodard, A.] Univ Notre Dame, Notre Dame, IN 46556 USA.
   [Antonelli, L.; Brinson, J.; Bylsma, B.; Durkin, L. S.; Flowers, S.; Hart, A.; Hill, C.; Hughes, R.; Kotov, K.; Ling, T. Y.; Luo, W.; Puigh, D.; Rodenburg, M.; Winer, B. L.; Wolfe, H.; Wulsin, H. W.] Ohio State Univ, Columbus, OH 43210 USA.
   [Driga, O.; Elmer, P.; Hardenbrook, J.; Hebda, P.; Hunt, A.; Koay, S. A.; Lujan, P.; Marlow, D.; Medvedeva, T.; Mooney, M.; Olsen, J.; Piroue, P.; Quan, X.; Saka, H.; Stickland, D.; Tully, C.; Werner, J. S.; Zuranski, A.; Brownson, E.] Princeton Univ, Princeton, NJ 08544 USA.
   [Malik, S.; Mendez, H.; Vargas, J. E. Ramirez] Univ Puerto Rico, Mayaguez, PR USA.
   [Barnes, V. E.; Benedetti, D.; Bortoletto, D.; De Mattia, M.; Gutay, L.; Hu, Z.; Jha, M. K.; Jones, M.; Jung, K.; Kress, M.; Leonardo, N.; Miller, D. H.; Neumeister, N.; Radburn-Smith, B. C.; Shi, X.; Shipsey, I.; Silvers, D.; Svyatkovskiy, A.; Wang, F.; Xie, W.; Xu, L.; Zablocki, J.] Purdue Univ, W Lafayette, IN 47907 USA.
   [Parashar, N.; Stupak, J.] Purdue Univ Calumet, Hammond, LA USA.
   [Adair, A.; Akgun, B.; Ecklund, K. M.; Geurts, F. J. M.; Li, W.; Michlin, B.; Padley, B. P.; Redjimi, R.; Roberts, J.; Zabel, J.] Rice Univ, Houston, TX USA.
   [Betchart, B.; Bodek, A.; Covarelli, R.; De Barbaro, P.; Demina, R.; Eshaq, Y.; Ferbel, T.; Garcia-Bellido, A.; Goldenzweig, P.; Han, J.; Harel, A.; Khukhunaishvili, A.; Korjenevski, S.; Petrillo, G.; Vishnevskiy, D.] Univ Rochester, Rochester, NY 14627 USA.
   [Ciesielski, R.; Demortier, L.; Goulianos, K.; Mesropian, C.] Rockefeller Univ, New York, NY 10021 USA.
   [Arora, S.; Barker, A.; Chou, J. P.; Contreras-Campana, C.; Contreras-Campana, E.; Duggan, D.; Ferencek, D.; Gershtein, Y.; Gray, R.; Halkiadakis, E.; Hidas, D.; Kaplan, S.; Lath, A.; Panwalkar, S.; Park, M.; Patel, R.; Salur, S.; Schnetzer, S.; Somalwar, S.; Stone, R.; Thomas, S.; Thomassen, P.; Walker, M.] Rutgers State Univ, Piscataway, NJ USA.
   [Rose, K.; Spanier, S.; York, A.] Univ Tennessee, Knoxville, TN USA.
   [Bouhali, O.; Hernandez, A. Castaneda; Eusebi, R.; Flanagan, W.; Gilmore, J.; Kamon, T.; Khotilovich, V.; Krutelyov, V.; Montalvo, R.; Osipenkov, I.; Pakhotin, Y.; Perloff, A.; Roe, J.; Rose, A.; Safonov, A.; Suarez, I.; Tatarinov, A.; Ulmer, K. A.] Texas A&M Univ, College Stn, TX USA.
   [Akchurin, N.; Cowden, C.; Damgov, J.; Dragoiu, C.; Dudero, P. R.; Faulkner, J.; Kovitanggoon, K.; Kunori, S.; Lee, S. W.; Libeiro, T.; Volobouev, I.] Texas Tech Univ, Lubbock, TX 79409 USA.
   [Appelt, E.; Delannoy, A. G.; Greene, S.; Gurrola, A.; Johns, W.; Maguire, C.; Mao, Y.; Melo, A.; Sharma, M.; Sheldon, P.; Snook, B.; Tuo, S.; Velkovska, J.] Vanderbilt Univ, Nashville, TN 37235 USA.
   [Arenton, M. W.; Boutle, S.; Cox, B.; Francis, B.; Goodell, J.; Hirosky, R.; Ledovskoy, A.; Li, H.; Lin, C.; Neu, C.; Wood, J.] Univ Virginia, Charlottesville, VA USA.
   [Clarke, C.; Harr, R.; Karchin, P. E.; Don, C. Kottachchi Kankanamge; Lamichhane, P.; Sturdy, J.] Wayne State Univ, Detroit, MI USA.
   [Belknap, D. A.; Carlsmith, D.; Cepeda, M.; Dasu, S.; Dodd, L.; Duric, S.; Friis, E.; Hall-Wilton, R.; Herndon, M.; Herve, A.; Klabbers, P.; Lanaro, A.; Lazaridis, C.; Levine, A.; Loveless, R.; Mohapatra, A.; Ojalvo, I.; Perry, T.; Pierro, G. A.; Polese, G.; Ross, I.; Sarangi, T.; Savin, A.; Smith, W. H.; Taylor, D.; Vuosalo, C.; Woods, N.] Univ Wisconsin, Madison, WI 53706 USA.
   [Fruehwirth, R.; Jeitler, M.; Krammer, M.; Wulz, C-E.] Vienna Univ Technol, A-1040 Vienna, Austria.
   [Rabady, D.; Pernie, L.; Genchev, V.; Boudoul, G.; Contardo, D.; Lingemann, J.; Hartmann, F.; Kornmayer, A.; Mohanty, A. K.; Radogna, R.; Silvestris, L.; Giordano, F.; Gennai, S.; Gerosa, R.; Lucchini, M. T.; Marzocchi, B.; Di Guida, S.; Meola, S.; Paolucci, P.; Ciangottini, D.; Spiezia, A.; Donato, S.; Palla, F.; Micheli, F.; Traczyk, P.; Casasso, S.; Finco, L.; Candelise, V.; Stickland, D.] CERN, European Org Nucl Res, CH-1211 Geneva, Switzerland.
   [Beluffi, C.] Univ Strasbourg, Univ Haute Alsace Mulhouse, Inst Pluridisciplinaire Hubert Curien, CNRS,IN2P3, Strasbourg, France.
   [Giammanco, A.] NICPB, Tallinn, Estonia.
   [Popov, A.; Zhukov, V.; Katkov, I.] Moscow MV Lomonosov State Univ, Skobeltsyn Inst Nucl Phys, Moscow, Russia.
   [Chinellato, J.; Tonelli Manganote, E. J.] Univ Estadual Campinas, Campinas, SP, Brazil.
   [Plestina, R.; Bernet, C.] Ecole Polytech, CNRS, IN2P3, Lab Leprince Ringuet, F-91128 Palaiseau, France.
   [Finger, M., Jr.; Tsamalaidze, Z.] Joint Inst Nucl Res, Dubna, Russia.
   [Assran, Y.] Suez Univ, Suez, Egypt.
   [Ellithi Kamel, A.] Cairo Univ, Cairo, Egypt.
   [Mahmoud, M. A.] Fayoum Univ, Al Fayyum, Egypt.
   [Radi, A.] Ain Shams Univ, Cairo, Egypt.
   [Agram, J-L; Conte, E.; Fontaine, J-C.] Univ Haute Alsace, Mulhouse, France.
   [Hempel, M.; Lohmann, W.; Marfin, I.] Brandenburg Tech Univ Cottbus, Cottbus, Germany.
   [Horvath, D.] Inst Nucl Res ATOMKI, Debrecen, Hungary.
   [Vesztergombi, G.; Veres, G. I.] Eotvos Lorand Univ, Budapest, Hungary.
   [Karancsi, J.] Debrecen Univ Med, H-4012 Debrecen, Hungary.
   [Bhowmik, S.; Maity, M.] Visva Bharati Univ, Santini Ketan, W Bengal, India.
   [Wickramage, N.] Univ Ruhuna, Matara, Sri Lanka.
   [Etesami, S. M.] Isfahan Univ Technol, Esfahan, Iran.
   [Fahim, A.] Univ Tehran, Dept Engn Sci, Tehran, Iran.
   [Safarzadeh, B.] Islamic Azad Univ, Sci & Res Branch, Plasma Phys Res Ctr, Tehran, Iran.
   [Androsov, K.; Ciocci, M. A.; Grippo, M. T.; Squillacioti, P.] Univ Siena, I-53100 Siena, Italy.
   [Moon, C. S.] CNRS, IN2P3, Paris, France.
   [Savoy-Navarro, A.] Purdue Univ, W Lafayette, IN 47907 USA.
   [Heredia-de la Cruz, I.] Univ Michoacana, Morelia, Michoacan, Mexico.
   [Matveev, V.; Musienko, Y.] Russian Acad Sci, Inst Nucl Res, Moscow 117312, Russia.
   [Kim, V.] St Petersburg State Polytech Univ, St Petersburg, Russia.
   [Dubinin, M.] CALTECH, Pasadena, CA 91125 USA.
   [Adzic, P.] Univ Belgrade, Fac Phys, Belgrade 11001, Serbia.
   [Colafranceschi, S.] Univ Rome, Fac Ingn, Rome, Italy.
   [Rolandi, G.] Ist Nazl Fis Nucl, Scuola Normale & Sez, Pisa, Italy.
   [Sphicas, P.] Univ Athens, Athens, Greece.
   [Naegeli, C.] Paul Scherrer Inst, Villigen, Switzerland.
   [Starodumov, A.; Nikitenko, A.] Inst Theoret & Expt Phys, Moscow 117259, Russia.
   [Amsler, C.] Albert Einstein Ctr Fundamental Phys, Bern, Switzerland.
   [Bakirci, M. N.; Ozturk, S.; Topakli, H.] Gaziosmanpasa Univ, Tokat, Turkey.
   [Cerci, S.; Cerci, D. Sunar; Tali, B.] Adiyaman Univ, Adiyaman, Turkey.
   [Onengut, G.] Cag Univ, Mersin, Turkey.
   [Gamsizkan, H.] Anadolu Univ, Eskisehir, Turkey.
   [Isildak, B.] Ozyegin Univ, Istanbul, Turkey.
   [Karapinar, G.] Izmir Inst Technol, Izmir, Turkey.
   [Ocalan, K.] Necmettin Erbakan Univ, Konya, Turkey.
   [Albayrak, E. A.; Ozok, F.] Mimar Sinan Univ, Istanbul, Turkey.
   [Kaya, M.] Marmara Univ, Istanbul, Turkey.
   [Kaya, O.] Kafkas Univ, Kars, Turkey.
   [Yetkin, T.] Yildiz Tech Univ, Istanbul, Turkey.
   [Newbold, D. M.; Lucas, R.] Rutherford Appleton Lab, Didcot OX11 0QX, Oxon, England.
   [Belyaev, A.] Univ Southampton, Sch Phys & Astron, Southampton, Hants, England.
   [Milenovic, P.] Univ Belgrade, Fac Phys, Belgrade 11001, Serbia.
   [Milenovic, P.] Vinca Inst Nucl Sci, Belgrade, Serbia.
   [Bilki, B.] Argonne Natl Lab, Argonne, IL 60439 USA.
   [Mermerkaya, H.] Erzincan Univ, Erzincan, Turkey.
   [Bouhali, O.] Texas A&M Univ, Doha, Qatar.
   [Kamon, T.] Kyungpook Natl Univ, Taegu, South Korea.
   [Bediaga, I.; De Miranda, J. M.; Rodrigues, F. Ferreira; Gomes, A.; Massafferri, A.; Dos Reis, A. C.; Rodrigues, A. B.] CBPF, Rio De Janeiro, Brazil.
   [Amato, S.; Akiba, K. Carvalho; De Paula, L.; Francisco, O.; Gandelman, M.; Hicheur, A.; Lopes, J. H.; Tostes, D. Martins; Nasteva, I.; Goicochea, J. M. Otalora; Polycarpo, E.; Potterat, C.; Rangel, M. S.; Guimaraes, V. Salustino; De Paula, B. Souza; Vieira, D.] Univ Fed Rio de Janeiro, Rio De Janeiro, Brazil.
   [An, L.; Gao, Y.; Jing, F.; Li, Y.; Yang, Z.; Yuan, X.; Zhang, Y.; Zhong, L.] Tsinghua Univ, Ctr High Energy Phys, Beijing 100084, Peoples R China.
   [Beaucourt, L.; Chefdeville, M.; Decamp, D.; Deleage, N.; Ghez, Ph.; Lees, J-P.; Marchand, J. F.; Minard, M-N.; Pietrzyk, B.; Qian, W.; T'Jampens, S.; Tisserand, V.; Tournefier, E.] Univ Savoie, CNRS, IN2P3, LAPP, Annecy Le Vieux, France.
   [Ajaltouni, Z.; Baalouch, M.; Cogneras, E.; Deschamps, O.; El Rifai, I.; Grabalosa Gandara, M.; Henrard, P.; Hoballah, M.; Lefevre, R.; Maratas, J.; Monteil, S.; Niess, V.; Perret, P.] Univ Blaise Pascal, Clermont Univ, CNRS, IN2P3,LPC, Clermont Ferrand, France.
   [Adrover, C.; Akar, S.; Aslanides, E.; Cogan, J.; Kanso, W.; Le Gac, R.; Leroy, O.; Mancinelli, G.; Morda, A.; Perrin-Terrin, M.; Serrano, J.; Tsaregorodtsev, A.] Aix Marseille Univ, CPPM, CNRS, IN2P3, Marseille, France.
   [Amhis, Y.; Barsuk, S.; Borsato, M.; Kochebina, O.; Lefrancois, J.; Machefert, F.; Martin Sanchez, A.; Nicol, M.; Robbe, P.; Schune, M-H.; Teklishyn, M.; Vallier, A.; Viaud, B.; Wormser, G.] Univ Paris Sud, CNRS, IN2P3, LAL, F-91405 Orsay, France.
   [Ben-Haim, E.; Charles, M.; Coquereau, S.; David, P.; Del Buono, L.; Henry, L.; Polci, F.] Univ Paris Diderot, Univ Paris 06, LPNHE, CNRS,IN2P3, Paris, France.
   [Albrecht, J.; Brambach, T.; Cauet, Ch.; Deckenhoff, M.; Eitschberger, U.; Ekelhof, R.; Gavardi, L.; Kruse, F.; Meier, F.; Niet, R.; Parkinson, C. J.; Schlupp, M.; Shires, A.; Spaan, B.; Swientek, S.; Wishahi, J.] Tech Univ Dortmund, Fak Phys, Dortmund, Germany.
   [Gutierrez, O. Aquines; Blouw, J.; Britsch, M.; Fontana, M.; Popov, D.; Schmelling, M.; Volyanskyy, D.; Zavertyaev, M.] Max Planck Inst Kernphys, D-69117 Heidelberg, Germany.
   [Bachmann, S.; Bien, A.; Comerma-Montells, A.; De Cian, M.; Dordei, F.; Esen, S.; Faerber, C.; Gersabeck, E.; Grillo, L.; Han, X.; Hansmann-Menzemer, S.; Jaeger, A.; Kolpin, M.; Kreplin, K.; Krocker, G.; Leverington, B.; Marks, J.; Meissner, M.; Neuner, M.; Nikodem, T.; Seyfert, P.; Stahl, M.; Stahl, S.; Uwer, U.; Vesterinen, M.; Wandernoth, S.; Wiedner, D.; Zhelezov, A.] Heidelberg Univ, Inst Phys, Heidelberg, Germany.
   [McNulty, R.; Wallace, R.; Zhang, W. C.] Univ Coll Dublin, Sch Phys, Dublin 2, Ireland.
   [Palano, A.] Sez INFN Bari, Bari, Italy.
   [Carbone, A.; Falabella, A.; Galli, D.; Marconi, U.; Moggi, N.; Mussini, M.; Perazzini, S.; Vagnoni, V.; Valenti, G.; Zangoli, M.] Sez INFN Bologna, Bologna, Italy.
   [Bonivento, W.; Cadeddu, S.; Cardini, A.; Cogoni, V.; Contu, A.; Lai, A.; Liu, B.; Manca, G.; Oldeman, R.; Saitta, B.; Vacca, C.] Sez INFN Cagliari, Cagliari, Italy.
   [Andreotti, M.; Baldini, W.; Bozzi, C.; Calabrese, R.; Corvo, M.; Fiore, M.; Fiorini, M.; Luppi, E.; Pappalardo, L. L.; Shapoval, I.; Tellarini, G.; Tomassetti, L.; Vecchi, S.] Sez INFN Ferrara, Ferrara, Italy.
   [Anderlini, L.; Bizzeti, A.; Frosini, M.; Graziani, G.; Passaleva, G.; Veltri, M.] Sez INFN Firenze, Florence, Italy.
   [Bencivenni, G.; Campana, P.; De Simone, P.; Lanfranchi, G.; Palutan, M.; Rama, M.; Sarti, A.; Sciascia, B.; Gomez, R. Vazquez] INFN Frascati, Lab Nazl, Frascati, Italy.
   [Cardinale, R.; Fontanelli, F.; Gambetta, S.; Patrignani, C.; Petrolini, A.; Pistone, A.] Sez INFN Genova, Genoa, Italy.
   [Calvi, M.; Cassina, L.; Gotti, C.; Khanji, B.; Kucharczyk, M.; Matteuzzi, C.] Sez INFN Milano Bicocca, Milan, Italy.
   [Fu, J.; Geraci, A.; Neri, N.; Palombo, F.] Sez INFN Milano, Milan, Italy.
   [Amerio, S.; Collazuol, G.; Gallorini, S.; Gianelle, A.; Lucchesi, D.; Lupato, A.; Morandin, M.; Rotondo, M.; Sestini, L.; Simi, G.; Stroili, R.] Sez INFN Padova, Padua, Italy.
   [Bedeschi, F.; Cenci, R.; Leo, S.; Marino, P.; Morello, M. J.; Punzi, G.; Stracka, S.; Walsh, J.] Sez INFN Pisa, Pisa, Italy.
   [Carboni, G.; Furfaro, E.; Santovetti, E.; Satta, A.] Sez INFN Roma Tor Vergata, Rome, Italy.
   [Alves, A. A., Jr.; Auriemma, G.; Bocci, V.; Martellotti, G.; Penso, G.; Pinci, D.; Santacesaria, R.; Satriano, C.; Sciubba, A.] Sez INFN Roma La Sapienza, Rome, Italy.
   [Kucharczyk, M.; Dziurda, A.; Kucewicz, W.; Lesiak, T.; Rachwal, B.; Witek, M.; Chrzaszcz, M.] Polish Acad Sci, Henryk Niewodniczanski Inst Nucl Phys, Krakow, Poland.
   [Firlej, M.; Fiutowski, T.; Idzik, M.; Morawski, P.; Moron, J.; Oblakowska-Mucha, A.; Swientek, K.; Szumlak, T.] AGH Univ Sci & Technol, Fac Phys & Appl Comp Sci, Krakow, Poland.
   [Batozskaya, V.; Klimaszewski, K.; Kurek, K.; Szczekowski, M.; Ukleja, A.; Wislicki, W.] Natl Ctr Nucl Res NCBJ, Warsaw, Poland.
   [Cojocariu, L.; Giubega, L.; Grecu, A.; Maciuc, F.; Orlandea, M.; Popovici, B.; Stoica, S.; Straticiuc, M.] Horia Hulubei Natl Inst Phys & Nucl Engn, Bucharest 077125, Romania.
   [Alkhazov, G.; Bondar, N.; Dzyuba, A.; Maev, O.; Sagidova, N.; Shcheglov, Y.; Vorobyev, A.] PNPI, Gatchina, Russia.
   [Belogurov, S.; Belyaev, I.; Egorychev, V.; Golubkov, D.; Kvaratskheliya, T.; Machikhiliyan, I. V.; Polyakov, I.; Savrina, D.; Semennikov, A.; Zhokhov, A.; Golutvin, A.] ITEP, Moscow, Russia.
   [Savrina, D.; Berezhnoy, A.; Korolev, M.; Leflat, A.] Moscow State Univ, SINP, Inst Nucl Phys, Moscow, Russia.
   [Nikitin, N.; Filippov, S.; Gushchin, E.] Russian Acad Sci, Inst Nucl Res, INR RAN, Moscow 117312, Russia.
   [Kravchuk, L.; Bondar, A.; Eidelman, S.; Krokovny, P.; Kudryavtsev, V.; Shekhtman, L.; Poluektov, A.] Budker Inst Nucl Phys SB RAS, Novosibirsk, Russia.
   [Kravchuk, L.; Bondar, A.; Eidelman, S.; Krokovny, P.; Kudryavtsev, V.; Shekhtman, L.; Poluektov, A.] Novosibirsk State Univ, Novosibirsk 630090, Russia.
   [Vorobyev, V.; Artamonov, A.; Belous, K.; Dzhelyadin, R.; Guz, Yu.; Novoselov, A.; Obraztsov, V.; Popov, A.; Romanovsky, V.; Shapkin, M.; Stenyakin, O.; Yushchenko, O.; Badalov, A.] IHEP, Protvino, Russia.
   [Gomez, M. Calvo; Garrido, L.; Gascon, D.; Diaz, R. Graciani; Grauges, E.; Benito, C. Marin; Olloqui, E. Picatoste; Molina, V. Rives; Ruiz, H.; Vilasis-Cardona, X.] Univ Barcelona, Barcelona, Spain.
   [Adeva, B.; Cartelle, P. Alvarez; Suarez, A. Dosil; Albor, V. Fernandez; Torreira, A. Gallas; Pardinas, J. Garcia; Morata, J. A. Hernando; Casasus, M. Plo; Vidal, A. Romero; Silva, J. J. Saborido; Sedes, B. Sanmartin; Rios, C. Santamarina; Regueiro, P. Vazquez; Sierra, C. Vazquez; Diaz, M. Vieites] Univ Santiago de Compostela, Santiago De Compostela, Spain.
   [Bonivento, W.; Contu, A.; Cardinale, R.; Khanji, B.; Fu, J.; Gallorini, S.; Alves, A. A., Jr.; Oblakowska-Mucha, A.; Bondar, N.; Guz, Yu.; Alessio, F.; Archilli, F.; Barschel, C.; Benson, S.; Buytaert, J.; Perez, D. Campora; Garcia, L. Castillo; Cattaneo, M.; Charpentier, Ph.; Vidal, X. Cid; Clemencic, M.; Closier, J.; Coco, V.; Collins, P.; Corti, G.; Couturier, B.; D'Ambrosio, C.; Dettori, F.; Di Canto, A.; Dijkstra, H.; Durante, P.; Ferro-Luzzi, M.; Forty, R.; Frank, M.; Frei, C.; Gaspar, C.; Gligorov, V. V.; Cardoso, L. A. Granado; Gys, T.; Haen, C.; He, J.; Head, T.; van Herwijnen, E.; Jacobsson, R.; Johnson, D.; Joram, C.; Jost, B.; Karacson, M.; Karbach, T. M.; Lacarrere, D.; Langhans, B.; Lindner, R.; Linn, C.; Lohn, S.; Mapelli, A.; Matev, R.; Mathe, Z.; Neubert, S.; Neufeld, N.; Otto, A.; Panman, J.; Altarelli, M. Pepe; Rauschmayr, N.; Rihl, M.; Roiser, S.; Ruf, T.; Schindler, H.; Schmidt, B.; Schopper, A.; Schwemmer, R.; Sridharan, S.; Stagni, F.; Subbiah, V. K.; Teubert, F.; Thomas, E.; Tonelli, D.; Trisovic, A.; Garcia, M. Ubeda; Wicht, J.; Wyllie, K.; Koppenburg, P.; Santos, D. Martinez; Easo, S.; Papanestis, A.; Golutvin, A.; Wilkinson, G.] CERN, European Org Nucl Res, CH-1211 Geneva, Switzerland.
   [Battista, V.; Bay, A.; Blanc, F.; Dorigo, M.; Dupertuis, F.; Fitzpatrick, C.; Giani, S.; Haefeli, G.; Jaton, P.; Khurewathanakul, C.; Komarov, I.; La Thi, V. N.; Lopez-March, N.; Maerki, R.; Martinelli, M.; Muster, B.; Nakada, T.; Nguyen, A. D.; Nguyen, T. D.; Nguyen-Mau, C.; Prisciandaro, J.; Navarro, A. Puig; Rakotomiaramanana, B.; Rouvinet, J.; Schneider, O.; Soomro, F.; Szczypka, P.; Tobin, M.; Tourneur, S.; Tran, M. T.; Veneziano, G.; Xu, Z.] Ecole Polytech Fed Lausanne, CH-1015 Lausanne, Switzerland.
   [Anderson, J.; Bernet, R.; Bowen, E.; Bursche, A.; Chiapolini, N.; Chrzaszcz, M.; Elsasser, Ch.; Graverini, E.; Lionetto, F.; Lowdon, P.; Mueller, K.; Serra, N.; Steinkamp, O.; Storaci, B.; Straumann, U.; Tresch, M.; Vollhardt, A.] Univ Zurich, Inst Phys, Zurich, Switzerland.
   [Aaij, R.; Ali, S.; Van Beuzekom, M.; David, P. N. Y.; De Bruyn, K.; Farinelli, C.; Heijne, V.; Hulsbergen, W.; Jans, E.; Koppenburg, P.; Kozlinskiy, A.; van Leerdam, J.; Merk, M.; Oggero, S.; Pellegrino, A.; Snoek, H.; van Tilburg, J.; Tsopelas, P.; Tuning, N.; de Vries, J. A.; Ketel, T.; Koopman, R. F.; Lambert, R. W.; Santos, D. Martinez; Raven, G.; Schiller, M.; Syropoulos, V.; Tolk, S.] Nikhef Natl Inst Subat Phys, Amsterdam, Netherlands.
   [Ketel, T.; Koopman, R. F.; Lambert, R. W.; Santos, D. Martinez; Raven, G.; Schiller, M.; Syropoulos, V.; Tolk, S.] Vrije Univ Amsterdam, Amsterdam, Netherlands.
   [Shapoval, I.; Dovbnya, A.; Kandybei, S.] NSC KIPT, Kharkov, Ukraine.
   [Raniuk, I.; Okhrimenko, O.] Natl Acad Sci KINR, Inst Nucl Res, Kiev, Ukraine.
   [Niet, R.; Pugatch, V.; Bifani, S.; Farley, N.; Griffith, P.; Kenyon, I. R.; Lazzeroni, C.; Mazurov, A.; McCarthy, J.; Pescatore, L.; Watson, N. K.; Williams, M. P.] Univ Birmingham, Birmingham, W Midlands, England.
   [Adinolfi, M.; Benton, J.; Brook, N. H.; Cook, A.; Coombes, M.; Dalseno, J.; Hampson, T.; Harnew, S. T.; Naik, P.; Price, E.; Prouve, C.; Rademacker, J. H.; Richards, S.; Saunders, D. M.; Skidmore, N.; Souza, D.; Velthuis, J. J.; Voong, D.] Univ Bristol, HH Wills Phys Lab, Bristol BS8 1TL, Avon, England.
   [Barter, W.; Bettler, M-O.; Cliff, H. V.; Evans, H. -M.; Tico, J. Garra; Gibson, V.; Gregson, S.; Haines, S. C.; Jones, C. R.; Sirendi, M.; Smith, J.; Ward, D. R.; Wotton, S. A.; Wright, S.] Univ Cambridge, Cavendish Lab, Cambridge CB3 0HE, England.
   [Back, J. J.; Blake, T.; Craik, D. C.; Crocombe, A. C.; Dossett, D.; Gershon, T.; Kreps, M.; Langenbruch, C.; Latham, T.; O'Hanlon, D. P.; Pilar, T.; Poluektov, A.; Reid, M. M.; Coutinho, R. Silva; Wallace, C.; Whitehead, M.] Univ Warwick, Dept Phys, Coventry CV4 7AL, W Midlands, England.
   [Easo, S.; Nandakumar, R.; Papanestis, A.; Ricciardi, S.; Wilson, F. F.] STFC Rutherford Appleton Lab, Didcot, Oxon, England.
   [Carson, L.; Clarke, P. E. L.; Cowan, G. A.; Eisenhardt, S.; Ferguson, D.; Lambert, D.; Luo, H.; Morris, A. -B.; Muheim, F.; Needham, M.; Playfer, S.] Univ Edinburgh, Sch Phys & Astron, Edinburgh, Midlothian, Scotland.
   [Alexander, M.; Beddow, J.; Dean, C-T.; Eklund, L.; Hynds, D.; Karodia, S.; Longstaff, I.; Ogilvy, S.; Pappagallo, M.; Sail, P.; Skillicorn, I.; Soler, F. J. P.; Spradlin, P.] Univ Glasgow, Sch Phys & Astron, Glasgow, Lanark, Scotland.
   [Affolder, A.; Bowcock, T. J. V.; Brown, H.; Casse, G.; Donleavy, S.; Dreimanis, K.; Farry, S.; Fay, R.; Hennessy, K.; Hutchcroft, D.; Liles, M.; McSkelly, B.; Patel, G. D.; Price, J. D.; Pritchard, A.; Rinnert, K.; Shears, T.; Smith, N. A.] Univ Liverpool, Oliver Lodge Lab, Liverpool L69 3BX, Merseyside, England.
   [Ciezarek, G.; Cunliffe, S.; Currie, R.; Egede, U.; Fol, P.; Golutvin, A.; Hall, S.; McCann, M.; Owen, P.; Patel, M.; Petridis, K.; Redi, F.; Sepp, I.; Smith, E.; Sutcliffe, W.; Websdale, D.] Univ London Imperial Coll Sci Technol & Med, London, England.
   [Appleby, R. B.; Barlow, R. J.; Bird, T.; Bjomstad, P. M.; Borghi, S.; Brett, D.; Brodzicka, J.; Capriotti, L.; Chen, S.; De Capua, S.; Dujany, G.; Gersabeck, M.; Harrison, J.; Hombach, C.; Klaver, S.; Lafferty, G.; McNab, A.; Parkes, C.; Pearce, A.; Reichert, S.; Rodrigues, E.; Perez, P. Rodriguez; Smith, M.] Univ Manchester, Sch Phys & Astron, Manchester, Lancs, England.
   [Cheung, S-F.; Derkach, D.; Evans, T.; Gauld, R.; Greening, E.; Harnew, N.; Hill, D.; Hunt, P.; Hussain, N.; Jalocha, J.; John, M.; Lupton, O.; Malde, S.; Smith, E.; Stevenson, S.; Thomas, C.; Topp-Joergensen, S.; Torr, N.; Wilkinson, G.] Univ Oxford, Dept Phys, Oxford, England.
   [Counts, I.; Ilten, P.; Williams, M.] MIT, Cambridge, MA 02139 USA.
   [Andreassen, R.; Davis, A.; De Silva, W.; Meadows, B.; Sokoloff, M. D.; Sun, L.; Todd, J.] Univ Cincinnati, Cincinnati, OH USA.
   [Andrews, J. E.; Hamilton, B.; Jawahery, A.; Wimberley, J.] Univ Maryland, College Pk, MD 20742 USA.
   [Artuso, M.; Blusk, S.; Borgia, A.; Britton, T.; Ely, S.; Gandini, P.; Garofoli, J.; Gui, B.; Hadjivasiliou, C.; Jurik, N.; Kelsey, M.; Mountain, R.; Pal, B. K.; Skwarnicki, T.; Stone, S.; Wang, J.; Xing, Z.; Zhang, L.] Syracuse Univ, Syracuse, NY USA.
   [Baesso, C.; Torres, M. Cruz; Goebel, C.; Rodriguez, J. Molina] Pontificia Univ Catolica Rio de Janeiro, Rio De Janeiro, Brazil.
   [Baesso, C.; Torres, M. Cruz; Goebel, C.; Rodriguez, J. Molina] Univ Fed Rio de Janeiro, Rio De Janeiro, Brazil.
   [Xie, Y.] Cent China Normal Univ, Inst Particle Phys, Wuhan, Hubei, Peoples R China.
   [Xie, Y.] Tsinghua Univ, Ctr High Energy Phys, Beijing 100084, Peoples R China.
   [Milanes, D. A.] Univ Nacl Colombia, Dept Fis, Bogota, Colombia.
   [Milanes, D. A.] Univ Paris 06, Univ Paris Diderot, CNRS, LPNHE,IN2P3, Paris, France.
   [Gruenberg, O.; Hess, M.; Voss, C.; Waldi, R.] Univ Rostock, Inst Phys, D-18055 Rostock, Germany.
   [Gruenberg, O.; Hess, M.; Voss, C.; Waldi, R.] Heidelberg Univ, Inst Phys, Heidelberg, Germany.
   [Likhomanenko, T.; Malinin, A.; Shevchenko, V.; Ustyuzhanin, A.] Natl Res Ctr Kurchatov Inst, Moscow, Russia.
   [Likhomanenko, T.; Malinin, A.; Shevchenko, V.; Ustyuzhanin, A.] ITEP, Moscow, Russia.
   [Vidal, F. Martinez; Oyanguren, A.; Valls, P. Ruiz; Mayordomo, C. Sanchez] Univ Valencia, CSIC, Inst Fis Corpuscular IFIC, Valencia, Spain.
   [Vidal, F. Martinez; Oyanguren, A.; Valls, P. Ruiz; Mayordomo, C. Sanchez] Univ Barcelona, Barcelona, Spain.
   [Onderwater, C. J. G.; Wilschut, H. W.] Univ Groningen, Van Swinderen Inst, Groningen, Netherlands.
   [Onderwater, C. J. G.; Wilschut, H. W.] Nikhef Natl Inst Subat Phys, Amsterdam, Netherlands.
   [Pesen, E.] Celal Bayar Univ, Manisa, Turkey.
   [Pesen, E.] CERN, European Org Nucl Res, CH-1211 Geneva, Switzerland.
   [Anderlini, L.; Frosini, M.] Univ Florence, Florence, Italy.
   [Andreotti, M.; Calabrese, R.; Corvo, M.; Fiore, M.; Fiorini, M.; Luppi, E.; Pappalardo, L. L.; Shapoval, I.; Tellarini, G.; Tomassetti, L.] Univ Ferrara, I-44100 Ferrara, Italy.
   [Auriemma, G.; Satriano, C.] Univ Basilicata, I-85100 Potenza, Italy.
   [Bizzeti, A.] Univ Modena & Reggio Emilia, Modena, Italy.
   [Calvi, M.; Cassina, L.; Gotti, C.; Khanji, B.; Kucharczyk, M.] Univ Milano Bicocca, Milan, Italy.
   [Gomez, M. Calvo; Vilasis-Cardona, X.] Univ Ramon Llull, LIFAELS, Barcelona, Spain.
   [Carbone, A.; Galli, D.; Perazzini, S.] Univ Bologna, Bologna, Italy.
   [Carboni, G.; Furfaro, E.; Santovetti, E.] Univ Roma Tor Vergata, Rome, Italy.
   [Cardinale, R.; Fontanelli, F.; Gambetta, S.; Patrignani, C.; Petrolini, A.] Univ Genoa, Genoa, Italy.
   [Cenci, R.; Marino, P.; Morello, M. J.; Stracka, S.] Scuola Normale Super Pisa, Pisa, Italy.
   [Geraci, A.] Politecn Milan, I-20133 Milan, Italy.
   [Gomes, A.] Univ Fed Triangulo Mineiro, Uberaba, MG, Brazil.
   [Kucewicz, W.] AGH Univ Sci & Technol, Fac Comp Sci Elect & Telecommun, Krakow, Poland.
   [Lucchesi, D.] Univ Padua, Padua, Italy.
   [Manca, G.; Oldeman, R.; Saitta, B.] Univ Cagliari, Cagliari, Italy.
   Hanoi Univ Sci, Hanoi, Vietnam.
   [Palano, A.] Univ Bari, Bari, Italy.
   [Palombo, F.] Univ Milan, Milan, Italy.
   [Sarti, A.; Penso, G.; Sciubba, A.] Univ Roma La Sapienza, I-00185 Rome, Italy.
   [Punzi, G.] Univ Pisa, Pisa, Italy.
   [Veltri, M.] Univ Urbino, I-61029 Urbino, Italy.
   [Zavertyaev, M.] Russian Acad Sci LPI RAS, PN Lebedev Phys Inst, Moscow, Russia.
C3 Yerevan Physics Institute; Austrian Academy of Sciences; Institute of High Energy Physics of the Austrian Academy of Sciences; Belarusian State University; National Center of Particles & High Energy Physics - Belarus; University of Antwerp; Vrije Universiteit Brussel; Universite Libre de Bruxelles; Ghent University; Universite Catholique Louvain; University of Mons; Centro Brasileiro de Pesquisas Fisicas; Universidade do Estado do Rio de Janeiro; Universidade Federal do ABC (UFABC); Universidade Estadual Paulista; Bulgarian Academy of Sciences; University of Sofia; Chinese Academy of Sciences; Institute of High Energy Physics, CAS; Peking University; Universidad de los Andes (Colombia); University of Split; University of Split; Rudjer Boskovic Institute; University of Cyprus; Charles University Prague; Egyptian Academy of Scientific Research & Technology (ASRT); Egyptian Knowledge Bank (EKB); Egyptian Network of High Energy Physics (ENHEP); National Institute of Chemical Physics & Biophysics (NICPB); University of Helsinki; Helsinki Institute of Physics; Lappeenranta-Lahti University of Technology LUT; CEA; Universite Paris Saclay; Institut Polytechnique de Paris; Ecole Polytechnique; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Universite de Haute-Alsace (UHA); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Universite Lyon 1; Ivane Javakhishvili Tbilisi State University; RWTH Aachen University; RWTH Aachen University; RWTH Aachen University; Helmholtz Association; Deutsches Elektronen-Synchrotron (DESY); University of Hamburg; Helmholtz Association; Karlsruhe Institute of Technology; National Centre of Scientific Research Demokritos; National & Kapodistrian University of Athens; University of Ioannina; HUN-REN; HUN-REN Wigner Research Centre for Physics; HUN-REN; HUN-REN Institute for Nuclear Research; University of Debrecen; National Institute of Science Education & Research (NISER); Panjab University; University of Delhi; Saha Institute of Nuclear Physics; Bhabha Atomic Research Center (BARC); Tata Institute of Fundamental Research (TIFR); Tata Institute of Fundamental Research (TIFR), Mumbai; Institute for Research in Fundamental Sciences IPM; University College Dublin; Istituto Nazionale di Fisica Nucleare (INFN); Universita degli Studi di Bari Aldo Moro; Politecnico di Bari; Istituto Nazionale di Fisica Nucleare (INFN); Universita degli Studi di Bari Aldo Moro; Politecnico di Bari; Istituto Nazionale di Fisica Nucleare (INFN); University of Bologna; Istituto Nazionale di Fisica Nucleare (INFN); University of Bologna; University of Catania; Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); University of Catania; Istituto Nazionale di Fisica Nucleare (INFN); University of Florence; Istituto Nazionale di Fisica Nucleare (INFN); University of Florence; Istituto Nazionale di Fisica Nucleare (INFN); University of Genoa; Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); University of Genoa; University of Milano-Bicocca; Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); University of Milano-Bicocca; University of Naples Federico II; Istituto Nazionale di Fisica Nucleare (INFN); University of Basilicata; Guglielmo Marconi University; Istituto Nazionale di Fisica Nucleare (INFN); University of Naples Federico II; University of Basilicata; Guglielmo Marconi University; University of Padua; Istituto Nazionale di Fisica Nucleare (INFN); University of Trento; Istituto Nazionale di Fisica Nucleare (INFN); University of Padua; Istituto Nazionale di Fisica Nucleare (INFN); University of Pavia; Istituto Nazionale di Fisica Nucleare (INFN); University of Pavia; Istituto Nazionale di Fisica Nucleare (INFN); University of Perugia; Istituto Nazionale di Fisica Nucleare (INFN); University of Perugia; Scuola Normale Superiore di Pisa; Istituto Nazionale di Fisica Nucleare (INFN); University of Pisa; Istituto Nazionale di Fisica Nucleare (INFN); University of Pisa; Scuola Normale Superiore di Pisa; Istituto Nazionale di Fisica Nucleare (INFN); Sapienza University Rome; Istituto Nazionale di Fisica Nucleare (INFN); University of Rome Tor Vergata; Istituto Nazionale di Fisica Nucleare (INFN); University of Eastern Piedmont Amedeo Avogadro; University of Turin; Istituto Nazionale di Fisica Nucleare (INFN); University of Turin; University of Eastern Piedmont Amedeo Avogadro; University of Trieste; Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); University of Trieste; Kangwon National University; Kyungpook National University (KNU); Jeonbuk National University; Chonnam National University; Korea University; Seoul National University (SNU); University of Seoul; Sungkyunkwan University (SKKU); Vilnius University; Universiti Malaya; Instituto Politecnico Nacional - Mexico; CINVESTAV - Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional; Universidad Iberoamericana Ciudad de Mexico; Benemerita Universidad Autonoma de Puebla; Universidad Autonoma de San Luis Potosi; University of Auckland; University of Canterbury; Quaid I Azam University; National Centre for Physics - Pakistan; National Centre for Nuclear Research; University of Warsaw; Laboratorio de Instrumentacao e Fisica Experimental de Particulas; Joint Institute for Nuclear Research - Russia; National Research Centre - Kurchatov Institute; Petersburg Nuclear Physics Institute; Russian Academy of Sciences; Institute for Nuclear Research of the Russian Academy of Sciences; National Research Centre - Kurchatov Institute; Alikhanov Institute for Theoretical & Experimental Physics; Russian Academy of Sciences; Russian Academy of Science Lebedev Physical Institute; Lomonosov Moscow State University; National Research Centre - Kurchatov Institute; Institute of High Energy Physics - IHEP; University of Belgrade; University of Belgrade; Centro de Investigaciones Energeticas, Medioambientales Tecnologicas; Autonomous University of Madrid; University of Oviedo; Consejo Superior de Investigaciones Cientificas (CSIC); Universidad de Cantabria; CSIC - Instituto de Fisica de Cantabria (IFCA); European Organization for Nuclear Research (CERN); Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Zurich; National Central University; National Taiwan University; Chulalongkorn University; Cukurova University; Middle East Technical University; Bogazici University; Istanbul Technical University; Kharkov Institute of Physics & Technology; University of Bristol; UK Research & Innovation (UKRI); Science & Technology Facilities Council (STFC); STFC Rutherford Appleton Laboratory; Imperial College London; Brunel University; Baylor University; University of Alabama System; University of Alabama Tuscaloosa; Boston University; Brown University; University of California System; University of California Davis; University of California System; University of California Los Angeles; University of California System; University of California Riverside; University of California System; University of California San Diego; University of California System; University of California Santa Barbara; California Institute of Technology; Carnegie Mellon University; University of Colorado System; University of Colorado Boulder; Cornell University; Fairfield University; United States Department of Energy (DOE); University of Chicago; Fermi National Accelerator Laboratory; State University System of Florida; 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Purdue University System; Purdue University; Rice University; University of Rochester; Rockefeller University; Rutgers University System; Rutgers University New Brunswick; University of Tennessee System; University of Tennessee Knoxville; Texas A&M University System; Texas A&M University College Station; Texas Tech University System; Texas Tech University; Vanderbilt University; University of Virginia; Wayne State University; University of Wisconsin System; University of Wisconsin Madison; Technische Universitat Wien; European Organization for Nuclear Research (CERN); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Universite de Haute-Alsace (UHA); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); National Institute of Chemical Physics & Biophysics (NICPB); Lomonosov Moscow State University; Universidade Estadual de Campinas; Institut Polytechnique de Paris; Ecole Polytechnique; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Joint Institute for Nuclear Research - Russia; Egyptian Knowledge Bank (EKB); Suez University; Egyptian Knowledge Bank (EKB); Cairo University; Egyptian Knowledge Bank (EKB); Fayoum University; Egyptian Knowledge Bank (EKB); Ain Shams University; Universites de Strasbourg Etablissements Associes; Universite de Haute-Alsace (UHA); Brandenburg University of Technology Cottbus; HUN-REN; HUN-REN Institute for Nuclear Research; Eotvos Lorand University; University of Debrecen; Visva Bharati University; University Ruhuna; Isfahan University of Technology; University of Tehran; Islamic Azad University; University of Siena; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Purdue University System; Purdue University; Universidad Michoacana de San Nicolas de Hidalgo; Russian Academy of Sciences; Institute for Nuclear Research of the Russian Academy of Sciences; Peter the Great St. Petersburg Polytechnic University; California Institute of Technology; University of Belgrade; Sapienza University Rome; Istituto Nazionale di Fisica Nucleare (INFN); National & Kapodistrian University of Athens; Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute; National Research Centre - Kurchatov Institute; Alikhanov Institute for Theoretical & Experimental Physics; University of Bern; Albert Einstein Center for Fundamental Physics; Tokat Gaziosmanpasa University; Adiyaman University; Cag University - Turkey; Anadolu University; Ozyegin University; Izmir Institute of Technology; Necmettin Erbakan University; Mimar Sinan Guzel Sanatlar University; Marmara University; Kafkas University; Yildiz Technical University; UK Research & Innovation (UKRI); Science & Technology Facilities Council (STFC); STFC Rutherford Appleton Laboratory; University of Southampton; University of Belgrade; University of Belgrade; United States Department of Energy (DOE); Argonne National Laboratory; Erzincan Binali Yildirim University; Qatar Foundation (QF); Texas A&M University Qatar; Kyungpook National University (KNU); Centro Brasileiro de Pesquisas Fisicas; Universidade Federal do Rio de Janeiro; Tsinghua University; Centre National de la Recherche Scientifique (CNRS); Universite Savoie Mont Blanc; CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Universite Clermont Auvergne (UCA); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Aix-Marseille Universite; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Universite Paris Saclay; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Universite Paris Cite; Sorbonne Universite; Dortmund University of Technology; Max Planck Society; Ruprecht Karls University Heidelberg; University College Dublin; Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); Istituto Nazionale di Fisica Nucleare (INFN); Polish Academy of Sciences; Institute of Nuclear Physics - Polish Academy of Sciences; AGH University of Krakow; National Centre for Nuclear Research; Horia Hulubei National Institute of Physics & Nuclear Engineering; National Research Centre - Kurchatov Institute; Petersburg Nuclear Physics Institute; National Research Centre - Kurchatov Institute; Alikhanov Institute for Theoretical & Experimental Physics; Lomonosov Moscow State University; National Research Centre - Kurchatov Institute; Institute of High Energy Physics - IHEP; Russian Academy of Sciences; Institute for Nuclear Research of the Russian Academy of Sciences; Russian Academy of Sciences; Budker Institute of Nuclear Physics; Siberian Branch of the Russian Academy of Sciences; Novosibirsk State University; National Research Centre - Kurchatov Institute; Institute of High Energy Physics - IHEP; University of Barcelona; Universidade de Santiago de Compostela; European Organization for Nuclear Research (CERN); Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; University of Zurich; FOM National Institute for Subatomic Physics; Vrije Universiteit Amsterdam; National Academy of Sciences Ukraine; V. M. Glushkov Institute of Cybernetics, National Academy of Sciences of Ukraine; Institute for Nuclear Research of NASU; University of Birmingham; University of Bristol; University of Cambridge; University of Warwick; UK Research & Innovation (UKRI); Science & Technology Facilities Council (STFC); STFC Rutherford Appleton Laboratory; University of Edinburgh; University of Glasgow; University of Liverpool; Imperial College London; University of Manchester; University of Oxford; Massachusetts Institute of Technology (MIT); University System of Ohio; University of Cincinnati; University System of Maryland; University of Maryland College Park; Syracuse University; Pontificia Universidade Catolica do Rio de Janeiro; Universidade Federal do Rio de Janeiro; Central China Normal University; Tsinghua University; Universidad Nacional de Colombia; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute of Nuclear and Particle Physics (IN2P3); Sorbonne Universite; Universite Paris Cite; University of Rostock; Ruprecht Karls University Heidelberg; National Research Centre - Kurchatov Institute; National Research Centre - Kurchatov Institute; Alikhanov Institute for Theoretical & Experimental Physics; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Fisica Corpuscular (IFIC); University of Valencia; University of Barcelona; University of Groningen; FOM National Institute for Subatomic Physics; Celal Bayar University; European Organization for Nuclear Research (CERN); University of Florence; University of Ferrara; University of Basilicata; Universita di Modena e Reggio Emilia; University of Milano-Bicocca; Universitat Ramon Llull; University of Bologna; University of Rome Tor Vergata; University of Genoa; Scuola Normale Superiore di Pisa; Polytechnic University of Milan; Universidade Federal do Triangulo Mineiro; AGH University of Krakow; University of Padua; University of Cagliari; Vietnam National University Hanoi (VNU Hanoi) System; Universita degli Studi di Bari Aldo Moro; University of Milan; Sapienza University Rome; University of Pisa; University of Urbino; Russian Academy of Sciences; Russian Academy of Science Lebedev Physical Institute
RP Khachatryan, V (corresponding author), Yerevan Phys Inst, Yerevan 375036, Armenia.
FU CAPES (Brazil); CNPq (Brazil); FAPERJ (Brazil); FINEP (Brazil); NSFC (China); CNRS/IN2P3 (France); BMBF (Germany); DFG (Germany); HGF (Germany); SFI (Ireland); INFN (Italy); NASU (Ukraine); STFC (UK); NSF (USA); BMWFW (Austria); FWF (Austria); FNRS (Belgium); FWO (Belgium); FAPESP (Brazil); MES (Bulgaria); CAS (China); MoST (China); COLCIENCIAS (Colombia); MSES (Croatia); CSF (Croatia); RPF (Cyprus); MoER (Estonia); ERC IUT (Estonia); ERDF (Estonia); Academy of Finland (Finland); MEC (Finland); HIP (Finland); CEA (France); GSRT (Greece); OTKA (Hungary); NIH (Hungary); DAE (India); DST (India); IPM (Iran); NRF (Republic of Korea); WCU (Republic of Korea); LAS (Lithuania); MOE (Malaysia); UM (Malaysia); CINVESTAV (Mexico); CONACYT (Mexico); SEP (Mexico); UASLP-FAI (Mexico); MBIE (New Zealand); PAEC (Pakistan); MSHE (Poland); NSC (Poland); FCT (Portugal); JINR (Dubna); MON (Russia); RosAtom (Russia); RAS (Russia); RFBR (Russia); MESTD (Serbia); SEIDI (Spain); CPAN (Spain); MST (Taipei); ThEPCenter (Thailand); IPST (Thailand); STAR (Thailand); NSTDA (Thailand); TUBITAK (Turkey); TAEK (Turkey); SFFR (Ukraine); DOE (USA); MPG (Germany); FOM (The Netherlands); NWO (The Netherlands); MNiSW (Poland); NCN (Poland); MEN/IFA (Romania); MinES (Russia); FANO (Russia); MinECo (Spain); SNSF (Switzerland); SER (Switzerland); Marie-Curie programme; European Research Council; EPLANET (European Union); Leventis Foundation; A. P. Sloan Foundation; Alexander von Humboldt Foundation; Belgian Federal Science Policy Office; Fonds pour la Formation a la Recherche dans l'Industrie et dans l'Agriculture (FRIABelgium); Agentschap voor Innovatie door Wetenschap en Technologie (IWT-Belgium); Ministry of Education, Youth and Sports (MEYS) of the Czech Republic; Council of Science and Industrial Research, India; Foundation for Polish Science; European Union, Regional Development Fund; Compagnia di San Paolo (Torino); Consorzio per la Fisica (Trieste); MIUR (Italy) [20108T4XTM]; Thalis programme; Aristeia programme; EU-ESF; Greek NSRF; National Priorities Research Program by Qatar National Research Fund; EPLANET; Marie Sklodowska-Curie Actions; ERC (European Union); Conseil general de Haute-Savoie; Labex ENIGMASS; OCEVU; Region Auvergne (France); XuntaGal (Spain); GENCAT (Spain); Royal Society (UK); Royal Commission for the Exhibition of 1851 (UK); STFC [ST/L00609X/1, ST/L001195/1, ST/K001639/1, ST/L005603/1, ST/K000705/1, PP/E000355/1, ST/L003538/1, ST/M001407/1, ST/K00140X/1, ST/H00100X/1, ST/M004775/1, ST/I005912/1, ST/J50094X/1, ST/M005356/1, ST/M000729/1, ST/H006737/1, ST/J004332/1, LHCb, ST/H00100X/2, ST/K001604/1, ST/K003844/1, ST/H00081X/2, ST/L003163/1, ST/K003410/1, ST/J004901/1, ST/K00137X/1, ST/K003542/1, ST/L003112/1, LHCb Upgrades, ST/J005665/1, ST/K001302/1, ST/I505580/1] Funding Source: UKRI; Direct For Mathematical & Physical Scien; Division Of Physics [1205805, 1151640, 1506130, 1306951, 1211067] Funding Source: National Science Foundation; Division Of Physics; Direct For Mathematical & Physical Scien [1506168, 1505719, 1306040, 1314131, 1120138] Funding Source: National Science Foundation; Science and Technology Facilities Council [1415632, 1096173, ST/M001474/1, ST/L00609X/1, ST/L003163/1, ST/N000250/1, ST/I505580/1, GRIDPP, 1416165, ST/L003163/1 LHCb Upgrades, ST/K001310/1 ATLAS, LHCb Upgrades, ST/M000729/1, 1511824, 1364044, CMS, ST/K003410/1, ST/L001195/1, ST/J005665/1, ST/H00100X/2, ST/H00081X/2, ST/K001256/1, ST/K001639/1, 1369397, ST/K001310/1 LHCb Upgrades, ST/H006737/1, ST/K001310/1 LHCb, ST/K00137X/1, ST/K003844/1, ST/K001310/1, ST/K003844/1 GRIDPP, ST/K001418/1, ST/J004332/1, 1225304, ST/K001604/1, ST/K003542/1, ST/M004775/1, ST/K001310/1 ATLAS Upgrades, LHCb, ST/L005603/1, ST/J004901/1, ST/K000705/1, ST/M005356/1 GRIDPP, ST/M005356/1, ST/K00140X/1, ST/J50094X/1, ST/M001407/1, ST/I005912/1, ST/L003112/1, ST/H00100X/1, ST/K001302/1, PP/E000355/1, 1564711, ST/L00609X/1 GRIDPP, 1299204, ST/L003538/1, ST/I005912/1 GRIDPP, 1225314] Funding Source: researchfish
NR 64
TC 160
Z9 170
U1 0
U2 18
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 4
PY 2015
VL 522
IS 7554
BP 68
EP +
DI 10.1038/nature14474
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ5QP
UT WOS:000355543400030
DA 2026-03-09
ER

PT J
AU Myers, CE
   Yamada, M
   Ji, HT
   Yoo, J
   Fox, W
   Jara-Almonte, J
   Savcheva, A
   DeLuca, EE
AF Myers, Clayton E.
   Yamada, Masaaki
   Ji, Hantao
   Yoo, Jongsoo
   Fox, William
   Jara-Almonte, Jonathan
   Savcheva, Antonia
   DeLuca, Edward E.
TI A dynamic magnetic tension force as the cause of failed solar eruptions
SO NATURE
LA English
DT Article
ID coronal mass ejections; flux rope; prominence eruptions; torus instability; kink instability; plasma; flares; reconnection; equilibrium; catastrophe
AB Coronal mass ejections are solar eruptions driven by a sudden release of magnetic energy stored in the Sun's corona(1). In many cases, this magnetic energy is stored in long-lived, arched structures called magnetic flux ropes(2-5). When a flux rope destabilizes, it can either erupt and produce a coronal mass ejection or fail and collapse back towards the Sun(6-8). The prevailing belief is that the outcome of a given event is determined by a magnetohydrodynamic force imbalance called the torus instability(9-14). This belief is challenged, however, by observations indicating that torus-unstable flux ropes sometimes fail to erupt(15). This contradiction has not yet been resolved because of a lack of coronal magnetic field measurements and the limitations of idealized numerical modelling. Here we report the results of a laboratory experiment(16) that reveal a previously unknown eruption criterion below which torus-unstable flux ropes fail to erupt. We find that such 'failed torus' events occur when the guide magnetic field (that is, the ambient field that runs toroidally along the flux rope) is strong enough to prevent the flux rope from kinking. Under these conditions, the guide field interacts with electric currents in the flux rope to produce a dynamic toroidal field tension force that halts the eruption. This magnetic tension force is missing from existing eruption models, which is why such models cannot explain or predict failed torus events.
C1 [Myers, Clayton E.; Ji, Hantao; Jara-Almonte, Jonathan] Princeton Univ, Dept Astrophys Sci, Princeton, NJ 08544 USA.
   [Myers, Clayton E.; Yamada, Masaaki; Ji, Hantao; Yoo, Jongsoo; Fox, William; Jara-Almonte, Jonathan] Princeton Plasma Phys Lab, Princeton, NJ 08543 USA.
   [Ji, Hantao] Harbin Inst Technol, Lab Space Environm & Phys Sci, Harbin 150001, Heilongjiang, Peoples R China.
   [Savcheva, Antonia; DeLuca, Edward E.] Harvard Smithsonian Ctr Astrophys, Cambridge, MA 02138 USA.
C3 Princeton University; Princeton University; United States Department of Energy (DOE); Princeton Plasma Physics Laboratory; Harbin Institute of Technology; Smithsonian Institution; Harvard University; Smithsonian Astrophysical Observatory
RP Myers, CE (corresponding author), Princeton Univ, Dept Astrophys Sci, Princeton, NJ 08544 USA.
EM cmyers@pppl.gov
FU Department of Energy (DoE) [DE-AC02-09CH11466]; National Science Foundation/DoE Center for Magnetic Self-Organization (CMSO)
NR 43
TC 94
Z9 100
U1 0
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 DEC 24
PY 2015
VL 528
IS 7583
BP 526
EP +
DI 10.1038/nature16188
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900046
PM 26701052
DA 2026-03-09
ER

PT J
AU Kim, K
   Song, B
   Fernandez-Hurtado, V
   Lee, W
   Jeong, WH
   Cui, LJ
   Thompson, D
   Feist, J
   Reid, MTH
   Garcia-Vidal, FJ
   Cuevas, JC
   Meyhofer, E
   Reddy, P
AF Kim, Kyeongtae
   Song, Bai
   Fernandez-Hurtado, Victor
   Lee, Woochul
   Jeong, Wonho
   Cui, Longji
   Thompson, Dakotah
   Feist, Johannes
   Reid, M. T. Homer
   Garcia-Vidal, Francisco J.
   Cuevas, Juan Carlos
   Meyhofer, Edgar
   Reddy, Pramod
TI Radiative heat transfer in the extreme near field
SO NATURE
LA English
DT Article
ID thermal-radiation
AB Radiative transfer of energy at the nanometre length scale is of great importance to a variety of technologies including heat-assisted magnetic recording(1), near-field thermophotovoltaics(2) and lithography(3). Although experimental advances have enabled elucidation of near-field radiative heat transfer in gaps as small as 20-30 nanometres (refs 4-6), quantitative analysis in the extreme near field (less than 10 nanometres) has been greatly limited by experimental challenges. Moreover, the results of pioneering measurements(7,8) differed from theoretical predictions by orders of magnitude. Here we use custom-fabricated scanning probes with embedded thermocouples(9,10), in conjunction with new microdevices capable of periodic temperature modulation, to measure radiative heat transfer down to gaps as small as two nanometres. For our experiments we deposited suitably chosen metal or dielectric layers on the scanning probes and microdevices, enabling direct study of extreme near-field radiation between silica-silica, silicon nitride-silicon nitride and gold-gold surfaces to reveal marked, gap-size-dependent enhancements of radiative heat transfer. Furthermore, our state-of-the-art calculations of radiative heat transfer, performed within the theoretical framework of fluctuational electrodynamics, are in excellent agreement with our experimental results, providing unambiguous evidence that confirms the validity of this theory(11-13) for modelling radiative heat transfer in gaps as small as a few nanometres. This work lays the foundations required for the rational design of novel technologies that leverage nanoscale radiative heat transfer.
C1 [Kim, Kyeongtae; Song, Bai; Lee, Woochul; Jeong, Wonho; Cui, Longji; Thompson, Dakotah; Meyhofer, Edgar; Reddy, Pramod] Univ Michigan, Dept Mech Engn, Ann Arbor, MI 48109 USA.
   [Fernandez-Hurtado, Victor; Feist, Johannes; Garcia-Vidal, Francisco J.; Cuevas, Juan Carlos] Univ Autonoma Madrid, Dept Fis Teor Mat Condensada, E-28049 Madrid, Spain.
   [Fernandez-Hurtado, Victor; Feist, Johannes; Garcia-Vidal, Francisco J.; Cuevas, Juan Carlos] Univ Autonoma Madrid, Condensed Matter Phys Ctr IFIMAC, E-28049 Madrid, Spain.
   [Reid, M. T. Homer] MIT, Dept Math, Cambridge, MA 02139 USA.
   [Garcia-Vidal, Francisco J.] Donostia Int Phys Ctr, Donostia San Sebastian 20018, Spain.
   [Reddy, Pramod] Univ Michigan, Dept Mat Sci & Engn, Ann Arbor, MI 48109 USA.
C3 University of Michigan System; University of Michigan; Autonomous University of Madrid; Autonomous University of Madrid; Massachusetts Institute of Technology (MIT); University of Michigan System; University of Michigan
RP Cuevas, JC (corresponding author), Univ Autonoma Madrid, Dept Fis Teor Mat Condensada, E-28049 Madrid, Spain.
EM juancarlos.cuevas@uam.es; meyhofer@umich.edu; pramodr@umich.edu
FU US Department of Energy Basic Energy Sciences through a grant from the Scanning Probe Microscopy Division [DE-SC0004871]; Army Research Office [W911NF-12-1-0612]; Office of Naval Research [N00014-13-1-0320]; National Science Foundation [CBET 1235691]; Spanish Ministry of Economy and Competitiveness (MINECO) [FIS2014-53488-P]; Comunidad de Madrid [S2013/MIT-2740]; "la Caixa" Foundation; European Research Council [290981]; European Union [FP7-PEOPLE-2013-CIG-618229]; Spanish MINECO [MAT2011-28581-C02-01, MAT2014-53432-C5-5-R]
NR 32
TC 383
Z9 436
U1 17
U2 339
PU NATURE PUBLISHING 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 17
PY 2015
VL 528
IS 7582
BP 387
EP 391
DI 10.1038/nature16070
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CY8SM
UT WOS:000366678600050
PM 26641312
DA 2026-03-09
ER

PT J
AU Polak, P
   Karlic, R
   Koren, A
   Thurman, R
   Sandstrom, R
   Lawrence, MS
   Reynolds, A
   Rynes, E
   Vlahovicek, K
   Stamatoyannopoulos, JA
   Sunyaev, SR
AF Polak, Paz
   Karlic, Rosa
   Koren, Amnon
   Thurman, Robert
   Sandstrom, Richard
   Lawrence, Michael S.
   Reynolds, Alex
   Rynes, Eric
   Vlahovicek, Kristian
   Stamatoyannopoulos, John A.
   Sunyaev, Shamil R.
TI Cell-of-origin chromatin organization shapes the mutational landscape of cancer
SO NATURE
LA English
DT Article
ID somatic mutations; genome; adenocarcinoma; signatures
AB Cancer is a disease potentiated by mutations in somatic cells. Cancer mutations are not distributed uniformly along the human genome. Instead, different human genomic regions vary by up to fivefold in the local density of cancer somatic mutations', posing a fundamental problem for statistical methods used in cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape(1-5). However, both somatic mutagenesis and epigenomic features are highly cell-type-specific(6-7). We investigated the distribution of mutations in multiple independent samples of diverse cancer types and compared them to cell-type-specific epigenomic features. Here we show that chromatin accessibility and modification, together with replication timing, explain up to 86% of the variance in mutation rates along cancer genomes. The best predictors of local somatic mutation density are epigenomic features derived from the most likely cell type of origin of the corresponding malignancy. Moreover, we find that cell-of-origin chromatin features are much stronger determinants of cancer mutation profiles than chromatin features of matched cancer cell lines. Furthermore, we show that the cell type of origin of a cancer can be accurately determined based on the distribution of mutations along its genome. Thus, the DNA sequence of a cancer genome encompasses a wealth of information about the identity and epigenomic features of its cell of origin.
C1 [Polak, Paz; Sunyaev, Shamil R.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA.
   [Polak, Paz; Sunyaev, Shamil R.] Harvard Univ, Sch Med, Boston, MA 02115 USA.
   [Polak, Paz; Koren, Amnon; Lawrence, Michael S.; Sunyaev, Shamil R.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Karlic, Rosa; Vlahovicek, Kristian] Univ Zagreb, Bioinformat Grp, Dept Mol Biol, Div Biol,Fac Sci, Zagreb 10000, Croatia.
   [Koren, Amnon] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
   [Thurman, Robert; Sandstrom, Richard; Reynolds, Alex; Rynes, Eric; Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.
   [Vlahovicek, Kristian] Univ Oslo, Dept Informat, NO-0316 Oslo, Norway.
   [Stamatoyannopoulos, John A.] Univ Washington, Div Oncol, Dept Med, Seattle, WA 98195 USA.
C3 Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Zagreb; Harvard University; Harvard Medical School; University of Washington; University of Washington Seattle; University of Oslo; University of Washington; University of Washington Seattle
RP Sunyaev, SR (corresponding author), Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA.
EM jstam@u.washington.edu; ssunyaev@rics.bwh.harvard.edu
FU NIH [R01 MH101244, U54 CA143874, U01 ES017156, P01 HL53750, U54 HG007010]; Integra-Life Seventh Framework Program [315997]; EMBO [1431/2006]; National Institute of Mental Health [R01MH101244] Funding Source: NIH RePORTER
NR 28
TC 402
Z9 502
U1 0
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 FEB 19
PY 2015
VL 518
IS 7539
BP 360
EP 364
DI 10.1038/nature14221
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400034
PM 25693567
DA 2026-03-09
ER

PT J
AU VanBuren, R
   Bryant, D
   Edger, PP
   Tang, HB
   Burgess, D
   Challabathula, D
   Spittle, K
   Hall, R
   Gu, J
   Lyons, E
   Freeling, M
   Bartels, D
   Ten Hallers, B
   Hastie, A
   Michael, TP
   Mockler, TC
AF VanBuren, Robert
   Bryant, Doug
   Edger, Patrick P.
   Tang, Haibao
   Burgess, Diane
   Challabathula, Dinakar
   Spittle, Kristi
   Hall, Richard
   Gu, Jenny
   Lyons, Eric
   Freeling, Michael
   Bartels, Dorothea
   Ten Hallers, Boudewijn
   Hastie, Alex
   Michael, Todd P.
   Mockler, Todd C.
TI Single-molecule sequencing of the desiccation-tolerant grass Oropetium thomaeum
SO NATURE
LA English
DT Article
ID structural variation; genome comparisons; tandem repeats; dna; reveals; gene; size; identification; transcriptome; annotation
AB Plant genomes, and eukaryotic genomes in general, are typically repetitive, polyploid and heterozygous, which complicates genome assembly(1). The short read lengths of early Sanger and current next-generation sequencing platforms hinder assembly through complex repeat regions, and many draft and reference genomes are fragmented, lacking skewed GC and repetitive intergenic sequences, which are gaining importance due to projects like the Encyclopedia of DNA Elements (ENCODE)(2). Here we report the whole-genome sequencing and assembly of the desiccation-tolerant grass Oropetium thomaeum. Using only single-molecule real-time sequencing, which generates long (>16 kilobases) reads with random errors, we assembled 99% (244 megabases) of the Oropetium genome into 625 contigs with an N50 length of 2.4 megabases. Oropetium is an example of a 'near-complete' draft genome which includes gapless coverage over gene space as well as intergenic sequences such as centromeres, telomeres, transposable elements and rRNA clusters that are typically unassembled in draft genomes. Oropetium has 28,466 protein-coding genes and 43% repeat sequences, yet with 30% more compact euchromatic regions it is the smallest known grass genome. The Oropetium genome demonstrates the utility of single-molecule real-time sequencing for assembling high-quality plant and other eukaryotic genomes, and serves as a valuable resource for the plant comparative genomics community.
C1 [VanBuren, Robert; Bryant, Doug; Mockler, Todd C.] Donald Danforth Plant Sci Ctr, St Louis, MO 63132 USA.
   [Edger, Patrick P.; Burgess, Diane; Freeling, Michael] Univ Calif Berkeley, Dept Plant & Microbial Biol, Berkeley, CA 94720 USA.
   [Edger, Patrick P.] Michigan State Univ, Dept Hort, E Lansing, MI 48323 USA.
   [Tang, Haibao; Lyons, Eric] Univ Arizona, Sch Plant Sci, IPlant Collaborat, Tucson, AZ 85721 USA.
   [Tang, Haibao] Fujian Agr & Forestry Univ, HIST, Ctr Genom & Biotechnol, Fuzhou 350002, Peoples R China.
   [Challabathula, Dinakar; Bartels, Dorothea] Univ Bonn, IMBIO, D-53115 Bonn, Germany.
   [Spittle, Kristi; Hall, Richard; Gu, Jenny] Pacific Biosci, Menlo Pk, CA 94025 USA.
   [Ten Hallers, Boudewijn; Hastie, Alex] BioNano Genom, San Diego, CA 92121 USA.
   [Michael, Todd P.] Ibis Biosci, Carlsbad, CA 92008 USA.
C3 Donald Danforth Plant Science Center; University of California System; University of California Berkeley; Michigan State University; University of Arizona; Fujian Agriculture & Forestry University; University of Bonn
RP VanBuren, R (corresponding author), Donald Danforth Plant Sci Ctr, St Louis, MO 63132 USA.
EM toddpmichael@gmail.com; tmockler@danforthcenter.org
FU National Science foundation [DBI-1401572, DBI-120793]; USDA NIFA [CO471A-B]; Department of Energy [DE-SC0012639, DE-SC-0008769]; Donald Danforth Plant Science Center; Enterprise Rent-A-Car Institute for Renewable Fuels; U.S. Department of Energy (DOE) [DE-SC0012639] Funding Source: U.S. Department of Energy (DOE); Division Of Integrative Organismal Systems; Direct For Biological Sciences [1401572] Funding Source: National Science Foundation
NR 55
TC 236
Z9 267
U1 1
U2 109
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 508
EP U209
DI 10.1038/nature15714
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500046
PM 26560029
DA 2026-03-09
ER

PT J
AU Neyskens, P
   Van Eck, S
   Jorissen, A
   Goriely, S
   Siess, L
   Plez, B
AF Neyskens, P.
   Van Eck, S.
   Jorissen, A.
   Goriely, S.
   Siess, L.
   Plez, B.
TI The temperature and chronology of heavy-element synthesis in low-mass stars
SO NATURE
LA English
DT Article
ID asymptotic giant branch; agb stars; s-process; chemical-composition; niobium abundances; dredge-up; technetium; nucleosynthesis; evolution; models
AB Roughly half of the heavy elements (atomic mass greater than that of iron) are believed to be synthesized in the late evolutionary stages of stars with masses between 0.8 and 8 solar masses. Deep inside the star, nuclei (mainly iron) capture neutrons and progressively build up (through the slow-neutron-capture process(1,2), or s-process) heavier elements that are subsequently brought to the stellar surface by convection. Two neutron sources, activated at distinct temperatures, have been proposed: C-13 and Ne-22, each releasing one neutron per alpha-particle (He-4) captured(1-4). To explain the measured stellar abundances(1-7), stellar evolution models invoking the C-13 neutron source (which operates at temperatures of about one hundred million kelvin) are favoured. Isotopic ratios in primitive meteorites, however, reflecting nucleosynthesis in the previous generations of stars that contributed material to the Solar System, point to higher temperatures (more than three hundred million kelvin), requiring at least a late activation of Ne-22 (ref. 1). Here we report a determination of the s-process temperature directly in evolved low-mass giant stars, using zirconium and niobium abundances, independently of stellar evolution models. The derived temperature supports C-13 as the s-process neutron source. The radioactive pair Zr-93-Nb-93 used to estimate the s-process temperature also provides, together with the pair Tc-99-Ru-99, chronometric information on the time elapsed since the start of the s-process, which we determine to be one million to three million years.
C1 [Neyskens, P.; Van Eck, S.; Jorissen, A.; Goriely, S.; Siess, L.] Univ Libre Bruxelles, Inst Astron & Astrophys, B-1050 Brussels, Belgium.
   [Plez, B.] Univ Montpellier 2, CNRS, Lab Univ & Particules Montpellier, F-34095 Montpellier, France.
C3 Universite Libre de Bruxelles; Centre National de la Recherche Scientifique (CNRS); Universite de Montpellier
RP Van Eck, S (corresponding author), Univ Libre Bruxelles, Inst Astron & Astrophys, CP 226, B-1050 Brussels, Belgium.
EM svaneck@astro.ulb.ac.be
FU FRIA (FNRS) fellowship; CNRS Programme National de Physique Stellaire; Action de recherche concertee (ARC) from the Direction generale de l'Enseignement non obligatoire et de la Recherche scientifique, Communaute francaise de Belgique; Fund for Scientific Research of Flanders (FWO); Research Council of K.U. Leuven; Fonds National de la Recherche Scientifique (FRS-FNRS), Belgium; Royal Observatory of Belgium; Observatoire de Geneve, Switzerland; Thuringer Landessternwarte Tautenburg, Germany
NR 36
TC 46
Z9 47
U1 0
U2 20
PU NATURE PUBLISHING 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 8
PY 2015
VL 517
IS 7533
BP 174
EP U116
DI 10.1038/nature14050
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600030
PM 25567282
DA 2026-03-09
ER

PT J
AU Freudenthal, BD
   Beard, WA
   Perera, L
   Shock, DD
   Kim, T
   Schlick, T
   Wilson, SH
AF Freudenthal, Bret D.
   Beard, William A.
   Perera, Lalith
   Shock, David D.
   Kim, Taejin
   Schlick, Tamar
   Wilson, Samuel H.
TI Uncovering the polymerase-induced cytotoxicity of an oxidized nucleotide
SO NATURE
LA English
DT Article
ID empirical force-field; base excision-repair; molecular-dynamics; oxidative stress; kinetic-analysis; structural basis; nucleic-acids; dna; beta; target
AB Oxidative stress promotes genomic instability and humandiseases(1). A common oxidized nucleoside is 8-oxo-7,8-dihydro-2'-deoxyguanosine, which is found both in DNA (8-oxo-G) and as a free nucleotide (8-oxo- dGTP)(2,3). Nucleotide pools are especially vulnerable to oxidative damage(4). Therefore cells encodeanenzyme(MutT/MTH1) that removes free oxidized nucleotides. This cleansing function is required for cancer cell survival(5,6) and to modulate Escherichia coli antibiotic sensitivity in a DNA polymerase (pol)-dependent manner(7). How polymerases discriminate between damaged and non-damaged nucleotides is not well understood. This analysis is essential given the role of oxidized nucleotides in mutagenesis, cancer therapeutics, and bacterial antibiotics(8). Even with cellular sanitizing activities, nucleotide pools contain enough 8-oxo-dGTP to promote mutagenesis(9,10). This arises from the dual coding potential where 8-oxo-dGTP(anti) base pairs with cytosine and 8-oxo-dGTP(syn) uses its Hoogsteen edge to base pair with adenine(11). Here we use time-lapse crystallography to follow 8-oxo-dGTP insertion opposite adenine or cytosine with human pol beta, to reveal that insertion is accommodated in either the syn-oranti-conformation, respectively. For 8-oxo-dGTP(anti) insertion, a novel divalent metal relieves repulsive interactions between the adducted guanine base and the triphosphate of the oxidized nucleotide. With either templating base, hydrogen-bonding interactions between the bases are lost as the enzyme reopens after catalysis, leading to a cytotoxic nicked DNA repair intermediate. Combining structural snapshots with kinetic and computational analysis reveals how 8-oxo-dGTP uses charge modulation during insertion that can lead to a blocked DNA repair intermediate.
C1 [Freudenthal, Bret D.; Beard, William A.; Perera, Lalith; Shock, David D.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA.
   [Kim, Taejin; Schlick, Tamar] NYU, Dept Chem, New York, NY 10003 USA.
   [Kim, Taejin; Schlick, Tamar] NYU Shanghai, NYU ECNU Ctr Computat Chem, New York, NY 10003 USA.
   [Kim, Taejin; Schlick, Tamar] NYU, Courant Inst Math Sci, New York, NY 10012 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS); New York University; New York University
RP Wilson, SH (corresponding author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA.
EM wilson5@niehs.nih.gov
FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01-E5050158, Z01-ES050161, ZIC-ES043010]; National Institutes of Health [1U19CA105010]; Philip Morris USA Inc.; Philip Morris International; National Institute of Environmental Health Sciences [ZICES043010, ZIAES050158] Funding Source: NIH RePORTER
NR 48
TC 137
Z9 158
U1 0
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 29
PY 2015
VL 517
IS 7536
BP 635
EP U261
DI 10.1038/nature13886
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA2ZL
UT WOS:000348775000048
PM 25409153
DA 2026-03-09
ER

PT J
AU Ku, C
   Nelson-Sathi, S
   Roettger, M
   Sousa, FL
   Lockhart, PJ
   Bryant, D
   Hazkani-Covo, E
   McInerney, JO
   Landan, G
   Martin, WF
AF Ku, Chuan
   Nelson-Sathi, Shijulal
   Roettger, Mayo
   Sousa, Filipa L.
   Lockhart, Peter J.
   Bryant, David
   Hazkani-Covo, Einat
   McInerney, James O.
   Landan, Giddy
   Martin, William F.
TI Endosymbiotic origin and differential loss of eukaryotic genes
SO NATURE
LA English
DT Article
ID false discovery rate; protein family; mitochondrial genm; sequence-analysis; evolution; model; classification; complexity; phylogeny; database
AB Chloroplasts arose from cyanobacteria, mitochondria arose from proteobacteria. Both organelles have conserved their prokaryotic biochemistry, but their genomes are reduced, and most organelle proteins are encoded in the nucleus. Endosymbiotic theory posits that bacterial genes in eukaryotic genomes entered the eukaryotic lineage via organelle ancestors. It predicts episodic influx of prokaryotic genes into the eukaryotic lineage, with acquisition corresponding to endosymbiotic events. Eukaryotic genome sequences, however, increasingly implicate lateral gene transfer, both from prokaryotes to eukaryotes and among eukaryotes, as a source of gene content variation in eukaryotic genomes, which predicts continuous, lineage-specific acquisition of prokaryotic genes in divergent eukaryotic groups. Here we discriminate between these two alternatives by clustering and phylogenetic analysis of eukaryotic gene families having prokaryotic homologues. Our results indicate (1) that gene transfer from bacteria to eukaryotes is episodic, as revealed by gene distributions, and coincides with major evolutionary transitions at the origin of chloroplasts and mitochondria; (2) that gene inheritance in eukaryotes is vertical, as revealed by extensive topological comparison, sparse gene distributions stemming from differential loss; and (3) that continuous, lineage-specific lateral gene transfer, although it sometimes occurs, does not contribute to long-term gene content evolution in eukaryotic genomes.
C1 [Ku, Chuan; Nelson-Sathi, Shijulal; Roettger, Mayo; Sousa, Filipa L.; Martin, William F.] Univ Dusseldorf, Inst Mol Evolut, D-40225 Dusseldorf, Germany.
   [Lockhart, Peter J.] Massey Univ, Inst Fundamental Sci, Palmerston North 4474, New Zealand.
   [Bryant, David] Univ Otago, Dept Math & Stat, Dunedin 9054, New Zealand.
   [Hazkani-Covo, Einat] Open Univ Israel, Dept Nat & Life Sci, IL-43107 Raanana, Israel.
   [McInerney, James O.] Natl Univ Ireland, Dept Biol, Maynooth, Kildare, Ireland.
   [McInerney, James O.] Univ Manchester, Manchester M13 9PL, Lancs, England.
   [Landan, Giddy] Univ Kiel, Inst Microbiol, Genom Microbiol Grp, D-24118 Kiel, Germany.
   [Martin, William F.] Univ Nova Lisboa, Inst Tecnol Quim & Biol, P-2780157 Oeiras, Portugal.
C3 Heinrich Heine University Dusseldorf; Massey University; University of Otago; Open University Israel; Maynooth University; University of Manchester; University of Kiel; Universidade Nova de Lisboa
RP Martin, WF (corresponding author), Univ Dusseldorf, Inst Mol Evolut, D-40225 Dusseldorf, Germany.
EM bill@hhu.de
FU European Research Council [232975, 666053, 281357]; Templeton Foundation [48177]; Open University of Israel Research Fund; German-Israeli Foundation [I-1321-203.13/2015]; New Zealand BioProtection CoRE; German Academic Exchange Service [57076385]; Alexander von Humboldt Foundation
NR 103
TC 218
Z9 246
U1 0
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 AUG 27
PY 2015
VL 524
IS 7566
BP 427
EP +
DI 10.1038/nature14963
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP7LN
UT WOS:000360069300029
PM 26287458
DA 2026-03-09
ER

PT J
AU Cahová, H
   Winz, ML
   Höfer, K
   Nübel, G
   Jäschke, A
AF Cahova, Hana
   Winz, Marie-Luise
   Hoefer, Katharina
   Nuebel, Gabriele
   Jaeschke, Andres
TI NAD captureSeq indicates NAD as a bacterial cap for a subset of regulatory RNAs
SO NATURE
LA English
DT Article
ID escherichia-coli k-12; integration host factor; gene-expression; messenger-rna; acid resistance; nucleotide-sequence; biofilm formation; terminal alkynes; primer formation; stress-response
AB Adistinctive feature of prokaryotic gene expression is the absence of 5'-capped RNA. In eukaryotes, 5',5'-triphosphate-linked 7-methyl-guanosine protects messenger RNA from degradation and modulates maturation, localization and translation(1). Recently, the cofactor nicotinamide adenine dinucleotide (NAD) was reported as a covalent modification of bacterial RNA(2). Given the central role of NAD in redox biochemistry, posttranslational protein modification and signalling(3,4), its attachment to RNA indicates that there are unknown functions of RNA in these processes and undiscovered pathways in RNA metabolism and regulation. The unknown identity of NAD-modified RNAs has so far precluded functional analyses. Here we identify NAD-linked RNAs from bacteria by chemo-enzymatic capture and next-generation sequencing(NAD captureSeq). A mong those identified, specific regulatory small RNAs (sRNAs) and sRNA-like 5'-terminal fragments of certain mRNAs are particularly abundant. Analogous to a eukaryotic cap, 5'-NAD modification is shown in vitro to stabilize RNA against 5'-processing by the RNA-pyrophosphohydrolase RppH(5) and against endonucleolytic cleavage by ribonuclease (RNase) E-6. The nudix phosphohydrolase NudC(7) decaps NAD-RNA and thereby triggers RNase-E-mediated RNA decay, while being inactive against triphosphate-RNA. In vivo, similar to 13% of the abundant sRNA RNAI is NAD-capped in the presence, and similar to 26% in the absence, of functional NudC. To our knowledge, this is the first description of a cap-like structure and a decapping machinery in bacteria.
C1 [Cahova, Hana; Winz, Marie-Luise; Hoefer, Katharina; Nuebel, Gabriele; Jaeschke, Andres] Heidelberg Univ, IPMB, D-69120 Heidelberg, Germany.
C3 Ruprecht Karls University Heidelberg
RP Jäschke, A (corresponding author), Heidelberg Univ, IPMB, D-69120 Heidelberg, Germany.
EM jaeschke@uni-hd.de
FU Alexander-von-Humboldt Foundation; Hartmut Hoffmann-Berling International Graduate School of Molecular & Cellular Biology; Deutsche Forschungsgemeinschaft [SFB 623]; Federal Ministry of Education and Research (BMBF); Helmholtz Initiative on Synthetic Biology
NR 128
TC 215
Z9 253
U1 2
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 MAR 19
PY 2015
VL 519
IS 7543
BP 374
EP +
DI 10.1038/nature14020
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD6AY
UT WOS:000351171900046
PM 25533955
DA 2026-03-09
ER

PT J
AU Spoor, F
   Gunz, P
   Neubauer, S
   Stelzer, S
   Scott, N
   Kwekason, A
   Dean, MC
AF Spoor, Fred
   Gunz, Philipp
   Neubauer, Simon
   Stelzer, Stefanie
   Scott, Nadia
   Kwekason, Amandus
   Dean, M. Christopher
TI Reconstructed Homo habilis type OH 7 suggests deep-rooted species diversity in early Homo
SO NATURE
LA English
DT Article
ID olduvai-gorge; koobi fora; endocranial volumes; cranial capacity; life-history; fossils; evolution; primate; growth; sample
AB Besides Homo erectus (sensu lato), the eastern African fossil record of early Homo has been interpreted as representing either a single variable species, Homo habilis(1), or two species(2-6). In the latter case, however, there is no consensus over the respective groupings, and which of the two includes OH 7, the 1.8-million-year-old H. habilis holotype(7). This partial skull and hand from Olduvai Gorge remains pivotal to evaluating the early evolution of the Homo lineage, and by priority names one or other of the two taxa. However, the distorted preservation of the diagnostically important OH 7 mandible has hindered attempts to compare this specimen with other fossils(8,9). Here we present a virtual reconstruction of the OH 7 mandible, and compare it to other early Homo fossils. The reconstructed mandible is remarkably primitive, with a long and narrow dental arcade more similar to Australopithecus afarensis than to the derived parabolic arcades of Homo sapiens or H. erectus. We find that this shape variability is not consistent with a single species of early Homo. Importantly, the jaw morphology of OH 7 is incompatible with fossils assigned to Homo rudolfensiss(8) and with the A.L. 666-1 Homo maxilla. The latter is morphologically more derived than OH 7 but 500,000 years older(10), suggesting that the H. habilis lineage originated before 2.3 million years ago, thus marking deep-rooted species diversity in the genus Homo. We also reconstructed the parietal bones of OH 7 and estimated its endocranial volume. At between 729 and 824 ml it is larger than any previously published value, and emphasizes the near-complete overlap in brain size among species of early Homo. Our results clarify the H. habilis hypodigm, but raise questions about its phylogenetic relationships. Differences between species of early Homo appear to be characterized more by gnathic diversity than by differences in brain size, which was highly variable within all taxa.
C1 [Spoor, Fred; Gunz, Philipp; Neubauer, Simon; Stelzer, Stefanie; Scott, Nadia] Max Planck Inst Evolutionary Anthropol, Dept Human Evolut, D-04103 Leipzig, Germany.
   [Spoor, Fred; Dean, M. Christopher] UCL, Dept Cell & Dev Biol, London WC1E 6BT, England.
   [Kwekason, Amandus] Natl Museum Tanzania, Museum & House Culture, Dar Es Salaam, Tanzania.
C3 Max Planck Society; University of London; University College London
RP Spoor, F (corresponding author), Max Planck Inst Evolutionary Anthropol, Dept Human Evolut, D-04103 Leipzig, Germany.
EM f.spoor@ucl.ac.uk; gunz@eva.mpg.de
FU Max Planck Society
NR 50
TC 133
Z9 152
U1 0
U2 193
PU NATURE PUBLISHING 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 5
PY 2015
VL 519
IS 7541
BP 83
EP U157
DI 10.1038/nature14224
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC4EQ
UT WOS:000350304000040
PM 25739632
DA 2026-03-09
ER

PT J
AU Baragaña, B
   Hallyburton, I
   Lee, MCS
   Norcross, NR
   Grimaldi, R
   Otto, TD
   Proto, WR
   Blagborough, AM
   Meister, S
   Wirjanata, G
   Ruecker, A
   Upton, LM
   Abraham, TS
   Almeida, MJ
   Pradhan, A
   Porzelle, A
   Martínez, MS
   Bolscher, JM
   Woodland, A
   Norval, S
   Zuccotto, F
   Thomas, J
   Simeons, F
   Stojanovski, L
   Osuna-Cabello, M
   Brock, PM
   Churcher, TS
   Sala, KA
   Zakutansky, SE
   Jiménez-Díaz, MB
   Sanz, LM
   Riley, J
   Basak, R
   Campbell, M
   Avery, VM
   Sauerwein, RW
   Dechering, KJ
   Noviyanti, R
   Campo, B
   Frearson, JA
   Angulo-Barturen, I
   Ferrer-Bazaga, S
   Gamo, FJ
   Wyatt, PG
   Leroy, D
   Siegl, P
   Delves, MJ
   Kyle, DE
   Wittlin, S
   Marfurt, J
   Price, RN
   Sinden, RE
   Winzeler, EA
   Charman, SA
   Bebrevska, L
   Gray, DW
   Campbell, S
   Fairlamb, AH
   Willis, PA
   Rayner, JC
   Fidock, DA
   Read, KD
   Gilbert, IH
AF Baragana, Beatriz
   Hallyburton, Irene
   Lee, Marcus C. S.
   Norcross, Neil R.
   Grimaldi, Raffaella
   Otto, Thomas D.
   Proto, William R.
   Blagborough, Andrew M.
   Meister, Stephan
   Wirjanata, Grennady
   Ruecker, Andrea
   Upton, Leanna M.
   Abraham, Tara S.
   Almeida, Mariana J.
   Pradhan, Anupam
   Porzelle, Achim
   Santos Martinez, Maria
   Bolscher, Judith M.
   Woodland, Andrew
   Norval, Suzanne
   Zuccotto, Fabio
   Thomas, John
   Simeons, Frederick
   Stojanovski, Laste
   Osuna-Cabello, Maria
   Brock, Paddy M.
   Churcher, Tom S.
   Sala, Katarzyna A.
   Zakutansky, Sara E.
   Belen Jimenez-Diaz, Maria
   Maria Sanz, Laura
   Riley, Jennifer
   Basak, Rajshekhar
   Campbell, Michael
   Avery, Vicky M.
   Sauerwein, Robert W.
   Dechering, Koen J.
   Noviyanti, Rintis
   Campo, Brice
   Frearson, Julie A.
   Angulo-Barturen, Inigo
   Ferrer-Bazaga, Santiago
   Javier Gamo, Francisco
   Wyatt, Paul G.
   Leroy, Didier
   Siegl, Peter
   Delves, Michael J.
   Kyle, Dennis E.
   Wittlin, Sergio
   Marfurt, Jutta
   Price, Ric N.
   Sinden, Robert E.
   Winzeler, Elizabeth A.
   Charman, Susan A.
   Bebrevska, Lidiya
   Gray, David W.
   Campbell, Simon
   Fairlamb, Alan H.
   Willis, Paul A.
   Rayner, Julian C.
   Fidock, David A.
   Read, Kevin D.
   Gilbert, Ian H.
TI A novel multiple-stage antimalarial agent that inhibits protein synthesis
SO NATURE
LA English
DT Article
ID elongation-factor 2; plasmodium-falciparum; transmission; malaria; identification; gametocytes; resistance; selection; target; drugs
AB There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.
C1 [Baragana, Beatriz; Hallyburton, Irene; Norcross, Neil R.; Grimaldi, Raffaella; Porzelle, Achim; Woodland, Andrew; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Riley, Jennifer; Frearson, Julie A.; Wyatt, Paul G.; Gray, David W.; Fairlamb, Alan H.; Read, Kevin D.; Gilbert, Ian H.] Univ Dundee, Coll Life Sci, Div Biol Chem & Drug Discovery, Drug Discovery Unit, Dundee DD1 5EH, Scotland.
   [Lee, Marcus C. S.; Abraham, Tara S.; Almeida, Mariana J.; Basak, Rajshekhar; Fidock, David A.] Columbia Univ Coll Phys & Surg, Dept Microbiol & Immunol, New York, NY 10032 USA.
   [Otto, Thomas D.; Rayner, Julian C.] Wellcome Trust Sanger Inst, Malaria Programme, Cambridge CB10 1SA, England.
   [Blagborough, Andrew M.; Ruecker, Andrea; Upton, Leanna M.; Brock, Paddy M.; Churcher, Tom S.; Sala, Katarzyna A.; Zakutansky, Sara E.; Delves, Michael J.; Sinden, Robert E.] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, London SW7 2AZ, England.
   [Meister, Stephan; Winzeler, Elizabeth A.] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA.
   [Proto, William R.; Wirjanata, Grennady; Marfurt, Jutta; Price, Ric N.] Charles Darwin Univ, Menzies Sch Hlth Res, Global Hlth & Trop Med Div, Darwin, NT 0811, Australia.
   [Pradhan, Anupam; Kyle, Dennis E.] Univ S Florida, Coll Publ Hlth, Dept Global Hlth, Tampa, FL 33612 USA.
   [Santos Martinez, Maria; Belen Jimenez-Diaz, Maria; Maria Sanz, Laura; Angulo-Barturen, Inigo; Ferrer-Bazaga, Santiago; Javier Gamo, Francisco] GlaxoSmithKline, Madrid 28760, Spain.
   [Bolscher, Judith M.; Sauerwein, Robert W.; Dechering, Koen J.] TropIQ Hlth Sci, NL-6525 GA Nijmegen, Netherlands.
   [Campbell, Michael; Charman, Susan A.] Monash Univ, Ctr Drug Candidate Optimisat, Parkville, Vic 3052, Australia.
   [Avery, Vicky M.] Griffith Univ, Eskitis Inst, Nathan, Qld 4111, Australia.
   [Noviyanti, Rintis] Eijkman Inst Mol Biol, Malaria Pathogenesis Lab, Jakarta 10430, Indonesia.
   [Campo, Brice; Leroy, Didier; Siegl, Peter; Bebrevska, Lidiya; Campbell, Simon; Willis, Paul A.] Med Malaria Venture, CH-1215 Geneva 15, Switzerland.
   [Wittlin, Sergio] Swiss Trop & Publ Hlth Inst, CH-4051 Basel, Switzerland.
   [Price, Ric N.] Univ Oxford, Ctr Trop Med & Global Hlth, Nuffield Dept Med, Oxford OX3 7LJ, England.
   [Fidock, David A.] Columbia Univ Coll Phys & Surg, Dept Med, Div Infect Dis, New York, NY 10032 USA.
C3 University of Dundee; Columbia University; Wellcome Trust Sanger Institute; Imperial College London; University of California System; University of California San Diego; Charles Darwin University; Menzies School of Health Research; State University System of Florida; University of South Florida; GlaxoSmithKline; Glaxosmithkline United Kingdom; Monash University; Griffith University; Eijkman Institute; University of Basel; Swiss Tropical & Public Health Institute; Swiss School of Public Health (SSPH+); University of Oxford; Columbia University
RP Gilbert, IH (corresponding author), Univ Dundee, Coll Life Sci, Div Biol Chem & Drug Discovery, Drug Discovery Unit, Dundee DD1 5EH, Scotland.
EM k.read@dundee.ac.uk; i.h.gilbert@dundee.ac.uk
FU Medicines for Malaria Venture; Wellcome Trust [100476, 091625, 098051]; Bill and Melinda Gates Foundation [OPP1043501]; National Institutes of Health [R01 AI103058]; European Union (EVIMalaR); European Regional Development Fund; UK Research Partnership Investment Fund; MRC [MR/K010174/1] Funding Source: UKRI; Bill and Melinda Gates Foundation [OPP1043501] Funding Source: Bill and Melinda Gates Foundation; Medical Research Council [MR/K010174/1, MR/K010174/1B] Funding Source: researchfish
NR 36
TC 358
Z9 397
U1 3
U2 127
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 18
PY 2015
VL 522
IS 7556
BP 315
EP +
DI 10.1038/nature14451
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK7PU
UT WOS:000356425400047
PM 26085270
DA 2026-03-09
ER

PT J
AU Parr, BT
   Economou, C
   Herzon, SB
AF Parr, Brendan T.
   Economou, Christos
   Herzon, Seth B.
TI A concise synthesis of (+)-batzelladine B from simple pyrrole-based starting materials
SO NATURE
LA English
DT Article
ID enantioselective total-synthesis; asymmetric-synthesis; batzelladine alkaloids; absolute-configuration; organic-synthesis; (-)-batzelladine-d; derivatives; strategy; revision; complex
AB Alkaloids, secondary metabolites that contain basic nitrogen atoms, are some of the most well-known biologically active natural products in chemistry and medicine(1). Although efficient laboratory synthesis of alkaloids would enable the study and optimization of their biological properties(2), their preparation is often complicated by the basicity and nucleophilicity of nitrogen, its susceptibility to oxidation, and its ability to alter reaction outcomes in unexpected ways-for example, through stereochemical instability and neighbouring group participation. Efforts to address these issues have led to the invention of a large number of protecting groups that temper the reactivity of nitrogen3; however, the use of protecting groups typically introduces additional steps and obstacles into the synthetic route. Alternatively, the use of aromatic nitrogen heterocycles as synthetic precursors can attenuate the reactivity of nitrogen and streamline synthetic strategies(4). Here we use such an approach to achieve a synthesis of the complex anti-HIV alkaloid (1)-batzelladine B in nine steps (longest linear sequence) from simple pyrrole-based starting materials. The route uses several key transformations that would be challenging or impossible to implement using saturated nitrogen heterocycles and highlights some of the advantages of beginning with aromatic reagents.
C1 [Parr, Brendan T.; Economou, Christos; Herzon, Seth B.] Yale Univ, Dept Chem, New Haven, CT 06520 USA.
C3 Yale University
RP Herzon, SB (corresponding author), Yale Univ, Dept Chem, 225 Prospect St, New Haven, CT 06520 USA.
EM seth.herzon@yale.edu
FU National Institutes of Health (NRSA fellowship) [GM110898-01A1]; National Institutes of Health (Chemistry Biology Interface Training Program) [T32GM067543]; Yale University; National Institute of General Medical Sciences [T32GM067543] Funding Source: NIH RePORTER
NR 30
TC 51
Z9 60
U1 1
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 SEP 24
PY 2015
VL 525
IS 7570
BP 507
EP 510
DI 10.1038/nature14902
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR8KI
UT WOS:000361599900048
PM 26375010
DA 2026-03-09
ER

PT J
AU Calo, E
   Flynn, RA
   Martin, L
   Spitale, RC
   Chang, HY
   Wysocka, J
AF Calo, Eliezer
   Flynn, Ryan A.
   Martin, Lance
   Spitale, Robert C.
   Chang, Howard Y.
   Wysocka, Joanna
TI RNA helicase DDX21 coordinates transcription and ribosomal RNA processing
SO NATURE
LA English
DT Article
ID box c/d snorna; p-tefb; 7sk; polymerase; protein; replication; ii/gu; elongation; nucleotide; depletion
AB DEAD-box RNA helicases are vital for the regulation of variousaspects of the RNA life cycle(1), but the molecular underpinnings of their involvement, particularly in mammalian cells, remain poorly understood. Here we show that the DEAD-box RNA helicase DDX21 can sense the transcriptional status of both RNA polymerase (Pol) I and II to control multiple steps of ribosome biogenesis in human cells. We demonstrate that DDX21 widely associates with Pol I-and Pol II-transcribed genes and with diverse species of RNA, most prominently with non-coding RNAs involved in the formation of ribonucleoprotein complexes, including ribosomal RNA, small nucleolar RNAs (snoRNAs) and 7SK RNA. Although broad, these molecular interactions, both at the chromatin and RNA level, exhibit remarkable specificity for the regulation of ribosomal genes. In the nucleolus, DDX21 occupies the transcribed rDNA locus, directly contacts both rRNA and snoRNAs, and promotes rRNA transcription, processing and modification. In the nucleoplasm, DDX21 binds 7SK RNA and, as a component of the 7SK small nuclear ribonucleoprotein (snRNP) complex, is recruited to the promoters of Pol II-transcribed genes encoding ribosomal proteins and snoRNAs. Promoter-bound DDX21 facilitates the release of the positive transcription elongation factor b (P-TEFb) from the 7SK snRNP in a manner that is dependent on its helicase activity, thereby promoting transcription of its target genes. Our results uncover the multifaceted role of DDX21 in multiple steps of ribosome biogenesis, and provide evidence implicating a mammalian RNA helicase in RNA modification and Pol II elongation control.
C1 [Calo, Eliezer; Wysocka, Joanna] Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 USA.
   [Flynn, Ryan A.; Martin, Lance; Spitale, Robert C.; Chang, Howard Y.] Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Flynn, Ryan A.; Martin, Lance; Spitale, Robert C.; Chang, Howard Y.] Stanford Univ, Sch Med, Program Epithelial Biol, Stanford, CA 94305 USA.
   [Wysocka, Joanna] Stanford Univ, Sch Med, Dept Dev Biol, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; Howard Hughes Medical Institute; Stanford University; Stanford University
RP Wysocka, J (corresponding author), Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 USA.
EM howchang@stanford.edu; wysocka@stanford.edu
FU Stanford Medical Scientist Training Program; AP Giannini Foundation; National Institutes of Health [R01-HG004361, R01-ES023168, P50-HG007735, R01-GM095555]; W. M. Keck Foundation; Helen Hay Whitney Foundation;  [T32CA09302]; National Cancer Institute [T32CA009302] Funding Source: NIH RePORTER
NR 37
TC 262
Z9 312
U1 1
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 12
PY 2015
VL 518
IS 7538
BP 249
EP U269
DI 10.1038/nature13923
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300042
PM 25470060
DA 2026-03-09
ER

PT J
AU Paulsen, CE
   Armache, JP
   Gao, Y
   Cheng, YF
   Julius, D
AF Paulsen, Candice E.
   Armache, Jean-Paul
   Gao, Yuan
   Cheng, Yifan
   Julius, David
TI Structure of the TRPA1 ion channel suggests regulatory mechanisms
SO NATURE
LA English
DT Article
ID receptor potential a1; molecular determinants; electron-microscopy; crystal-structure; activation; protein; cold; pain; identification; visualization
AB The TRPA1 ion channel (also known as the wasabi receptor) is a detector of noxious chemical agents encountered in our environment or produced endogenously during tissue injury or drug metabolism. These include a broad class of electrophiles that activate the channel through covalent protein modification. TRPA1 antagonists hold potential for treating neurogenic inflammatory conditions provoked or exacerbated by irritant exposure. Despite compelling reasons to understand TRPA1 function, structural mechanisms underlying channel regulation remain obscure. Here we use single-particle electron cryomicroscopy to determine the structure of full-length human TRPA1 to similar to 4 angstrom resolution in the presence of pharmacophores, including a potent antagonist. Several unexpected features are revealed, including an extensive coiled-coil assembly domain stabilized by polyphosphate co-factors and a highly integrated nexus that converges on an unpredicted transient receptor potential (TRP)-like allosteric domain. These findings provide new insights into the mechanisms of TRPA1 regulation, and establish a blueprint for structure-based design of analgesic and anti-inflammatory agents.
C1 [Paulsen, Candice E.; Gao, Yuan; Julius, David] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA.
   [Armache, Jean-Paul; Gao, Yuan; Cheng, Yifan] Univ Calif San Francisco, Dept Biochem & Biophys, Keck Adv Microscopy Lab, San Francisco, CA 94158 USA.
C3 University of California System; University of California San Francisco; University of California System; University of California San Francisco
RP Julius, D (corresponding author), Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA.
EM ycheng@ucsf.edu; david.julius@ucsf.edu
FU National Institutes of Health [R01NS055299, R01GM098672]; UCSF Program for Breakthrough Biomedical Research; UCSF CVRI; National Institute of Biomedical Imaging and Bioengineering [T32EB009383] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM008284] Funding Source: NIH RePORTER
NR 72
TC 535
Z9 618
U1 2
U2 225
PU NATURE PUBLISHING 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 23
PY 2015
VL 520
IS 7548
BP 511
EP +
DI 10.1038/nature14367
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500036
PM 25855297
DA 2026-03-09
ER

PT J
AU Walz, C
   Scheit, H
   Pietralla, N
   Aumann, T
   Lefol, R
   Ponomarev, VY
AF Walz, C.
   Scheit, H.
   Pietralla, N.
   Aumann, T.
   Lefol, R.
   Ponomarev, V. Yu.
TI Observation of the competitive double-gamma nuclear decay
SO NATURE
LA English
DT Article
ID 2-photon decay; state
AB The double-gamma (gamma gamma)-decay of a quantum system in an excited state is a fundamental second-order process of quantum electrodynamics. In contrast to the well-known single-gamma (gamma)-decay, the gamma-decay is characterized by the simultaneous emission of two gamma quanta, each with a continuous energy spectrum. In nuclear physics, this exotic decay mode has only been observed for transitions between states with spin-parity quantum numbers J(pi) = 0(+) (refs 1-3). Single-gamma decays the main experimental obstacle to observing the yy-decay are strictly forbidden for these 0(+) -> 0(+) transitions. Here we report the observation of the gamma-decay of an excited nuclear state (J(pi) = 11/2(-)) that is directly competing with an allowed y-decay (to ground state J(pi) = 3/2(+)). The branching ratio of the competitive gamma gamma-decay of the 11/2- isomer of Ba-137 to the ground state relative to its single gamma-decay was determined to be (2.05 +/- 0.37) X 10(-6). From the measured angular correlation and the shape of the energy spectra of the individual gamma-rays, the contributing combinations of multipolarities of the gamma radiation were determined. Transition matrix elements calculated using the quasipartide-phonon model reproduce our measurements well. The gamma gamma-decay rate gives access to so far unexplored important nuclear structure information, such as the generalized (off-diagonal) nuclear electric polarizabilities and magnetic susceptibilities(3).
C1 [Walz, C.; Scheit, H.; Pietralla, N.; Aumann, T.; Lefol, R.; Ponomarev, V. Yu.] Tech Univ Darmstadt, Inst Kernphys, D-64289 Darmstadt, Germany.
   [Lefol, R.] Univ Saskatchewan, Dept Phys, Saskatoon, SK S7N 5E2, Canada.
C3 Technical University of Darmstadt; University of Saskatchewan
RP Scheit, H (corresponding author), Tech Univ Darmstadt, Inst Kernphys, Petersenstr 30, D-64289 Darmstadt, Germany.
EM hscheit@ikp.tu-darmstadt.de
FU State of Hesse under the Helmholtz International Center for FAIR; German Research Council (DFG) [SFB 634]
NR 16
TC 29
Z9 32
U1 1
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 15
PY 2015
VL 526
IS 7573
BP 406
EP 409
DI 10.1038/nature15543
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200046
PM 26469051
DA 2026-03-09
ER

PT J
AU Hao, S
   Tang, B
   Wu, ZY
   Ure, K
   Sun, YL
   Tao, HF
   Gao, Y
   Patel, AJ
   Curry, DJ
   Samaco, RC
   Zoghbi, HY
   Tang, JR
AF Hao, Shuang
   Tang, Bin
   Wu, Zhenyu
   Ure, Kerstin
   Sun, Yaling
   Tao, Huifang
   Gao, Yan
   Patel, Akash J.
   Curry, Daniel J.
   Samaco, Rodney C.
   Zoghbi, Huda Y.
   Tang, Jianrong
TI Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice
SO NATURE
LA English
DT Article
ID long-term potentiation; synaptic plasticity; behavioral deficits; mouse model; neurogenesis; adult; enhancement; ltp; extinction; patient
AB Deep brain stimulation (DBS) has improved the prospects for many individuals with diseases affecting motor control, and recently it has shown promise for improving cognitive function as well. Several studies in individuals with Alzheimer disease and in amnesic rats have demonstrated that DBS targeted to the fimbria-fornix(1-3), the region that appears to regulate hippocampal activity, can mitigate defects in hippocampus-dependent memory(3-5). Despite these promising results, DBS has not been tested for its ability to improve cognition in any childhood intellectual disability disorder. Such disorders are a pressing concern: they affect as much as 3% of the population and involve hundreds of different genes. We proposed that stimulating the neural circuits that underlie learning and memory might provide a more promising route to treating these otherwise intractable disorders than seeking to adjust levels of one molecule at a time. We therefore studied the effects of forniceal DBS in a well-characterized mouse model of Rett syndrome (RTT), which is a leading cause of intellectual disability in females. Caused by mutations that impair the function of MeCP2 (ref. 6), RTT appears by the second year of life in humans, causing profound impairment in cognitive, motor and social skills, along with an array of neurological features(7). RTT mice, which reproduce the broad phenotype of this disorder, also show clear deficits in hippocampus-dependent learning and memory and hippocampal synaptic plasticity(8-11). Here we show that forniceal DBS in RTT mice rescues contextual fear memory as well as spatial learning and memory. In parallel, forniceal DBS restores in vivo hippocampal long-term potentiation and hippocampal neurogenesis. These results indicate that forniceal DBS might mitigate cognitive dysfunction in RTT.
C1 [Hao, Shuang; Tang, Bin; Wu, Zhenyu; Ure, Kerstin; Sun, Yaling; Tao, Huifang; Gao, Yan; Patel, Akash J.; Samaco, Rodney C.; Zoghbi, Huda Y.; Tang, Jianrong] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA.
   [Hao, Shuang; Tang, Bin; Wu, Zhenyu; Zoghbi, Huda Y.; Tang, Jianrong] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA.
   [Sun, Yaling; Tao, Huifang; Gao, Yan; Samaco, Rodney C.; Zoghbi, Huda Y.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.
   [Patel, Akash J.; Curry, Daniel J.] Baylor Coll Med, Dept Neurosurg, Houston, TX 77030 USA.
   [Zoghbi, Huda Y.] Baylor Coll Med, Program Dev Biol, Houston, TX 77030 USA.
   [Zoghbi, Huda Y.] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA.
   [Zoghbi, Huda Y.] Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA.
C3 Baylor College of Medicine; Baylor College Medical Hospital; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Howard Hughes Medical Institute
RP Zoghbi, HY (corresponding author), Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA.
EM hzoghbi@bcm.edu; jtang1@bcm.edu
FU W. M. Keck Foundation; Cockrell Family Foundation; Rett Syndrome Research Trust; Carl. C. Anderson, Sr. and Marie Jo Anderson Charitable Foundation [R01NS057819]; Howard Hughes Medical Institute [DP5OD009134, R25 N070694]; IDDRC at Baylor College of Medicine from Eunice Kennedy Shriver National Institute of Child Health & Human Development [U54HD083092]; National Center for Research Resources [C06RR029965]; National Institute of Neurological Disorders and Stroke [R01NS057819] Funding Source: NIH RePORTER
NR 47
TC 144
Z9 169
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 OCT 15
PY 2015
VL 526
IS 7573
BP 430
EP +
DI 10.1038/nature15694
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200051
PM 26469053
DA 2026-03-09
ER

PT J
AU Liu, YH
   Zhang, XN
   Han, C
   Wan, GH
   Huang, XX
   Ivan, C
   Jiang, DH
   Rodriguez-Aguayo, C
   Lopez-Berestein, G
   Rao, PH
   Maru, DM
   Pahl, A
   He, XM
   Sood, AK
   Ellis, LM
   Anderl, J
   Lu, XB
AF Liu, Yunhua
   Zhang, Xinna
   Han, Cecil
   Wan, Guohui
   Huang, Xingxu
   Ivan, Cristina
   Jiang, Dahai
   Rodriguez-Aguayo, Cristian
   Lopez-Berestein, Gabriel
   Rao, Pulivarthi H.
   Maru, Dipen M.
   Pahl, Andreas
   He, Xiaoming
   Sood, Anil K.
   Ellis, Lee M.
   Anderl, Jan
   Lu, Xiongbin
TI TP53 loss creates therapeutic vulnerability in colorectal cancer
SO NATURE
LA English
DT Article
ID crispr-cas9 system; p53 pathway; human-cells; amanitin; inhibition; phenotype
AB TP53, a well-known tumour suppressor gene that encodes p53, is frequently inactivated by mutation or deletion in most human tumours'''. A tremendous effort has been made to restore p53 activity in cancer therapies'''. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment owing to the complexity of p53 signalling. Here we demonstrate that genomic deletion of TP53 frequently encompasses essential neighbouring genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such a gene that is almost always co-deleted with TP53 in human cancers. It encodes the largest and catalytic subunit of the RNA polymerase II complex, which is specifically inhibited by a-amanitin". Our analysis of The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) databases reveals that POLR2A expression levels are tightly correlated with its gene copy numbers in human colorectal cancer. Suppression of POLR2A with alpha-amanitin or small interfering RNAs selectively inhibits the proliferation, survival and tumorigenic potential of colorectal cancer cells with hemizygous TP53 loss in a p53-independent manner. Previous clinical applications of a-amanitin have been limited owing to its liver toxicity'. However, we found that alpha-amanitin-based antibody-drug conjugates are highly effective therapeutic agents with reduced toxicity". Here we show that low doses of alpha-amanitin-conjugated anti-epithelial cell adhesion molecule (EpCAM) antibody lead to complete tumour regression in mouse models of human colorectal cancer with hemizygous deletion of POLR2A. We anticipate that inhibiting POLR2A will be a new therapeutic approach for human cancers containing such common genomic alterations.
C1 [Liu, Yunhua; Han, Cecil; Wan, Guohui; Sood, Anil K.; Lu, Xiongbin] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA.
   [Zhang, Xinna; Ivan, Cristina; Jiang, Dahai; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Dept Gynaecol Oncol & Reprod Med, Houston, TX 77030 USA.
   [Zhang, Xinna; Ivan, Cristina; Jiang, Dahai; Rodriguez-Aguayo, Cristian; Lopez-Berestein, Gabriel; Sood, Anil K.; Lu, Xiongbin] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNAs, Houston, TX 77030 USA.
   [Huang, Xingxu] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China.
   [Rodriguez-Aguayo, Cristian; Lopez-Berestein, Gabriel] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA.
   [Rao, Pulivarthi H.] Baylor Coll Med, Dept Paediat, Houston, TX 77030 USA.
   [Maru, Dipen M.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA.
   [Pahl, Andreas; Anderl, Jan] Heidelberg Pharma GmbH, D-68526 Ladenburg, Germany.
   [He, Xiaoming] Ohio State Univ, Dept Biomed Engn, Columbus, OH 43210 USA.
   [Ellis, Lee M.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, 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; ShanghaiTech University; University of Texas System; UTMD Anderson Cancer Center; Baylor College of Medicine; University of Texas System; UTMD Anderson Cancer Center; University System of Ohio; Ohio State University; University of Texas System; UTMD Anderson Cancer Center
RP Lu, XB (corresponding author), Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA.
EM xlu2@mdanderson.org
FU National Institutes of Health (NIH), MD Anderson Moon Shots Program [R01 CA136549]; NIH [U54 CA151668]; National Cancer Institute [P30CA016672] Funding Source: NIH RePORTER
NR 28
TC 191
Z9 223
U1 2
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 APR 30
PY 2015
VL 520
IS 7549
BP 697
EP U286
DI 10.1038/nature14418
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700054
PM 25901683
DA 2026-03-09
ER

PT J
AU Maskell, DP
   Renault, L
   Serrao, E
   Lesbats, P
   Matadeen, R
   Hare, S
   Lindemann, D
   Engelman, AN
   Costa, A
   Cherepanov, P
AF Maskell, Daniel P.
   Renault, Ludovic
   Serrao, Erik
   Lesbats, Paul
   Matadeen, Rishi
   Hare, Stephen
   Lindemann, Dirk
   Engelman, Alan N.
   Costa, Alessandro
   Cherepanov, Peter
TI Structural basis for retroviral integration into nucleosomes
SO NATURE
LA English
DT Article
ID crystal-structure; virus integrase; core particle; sequence; sites; suite; determinants; inhibition; reveals; binding
AB Retroviral integration is catalysed by a tetramer of integrase (IN) assembled on viral DNA ends in a stable complex, known as the intasome(1,2). How the intasome interfaces with chromosomal DNA, which exists in the form of nucleosomal arrays, is currently unknown. Here we show that the prototype foamy virus (PFV) intasome is proficient at stable capture of nucleosomes as targets for integration. Single-particle cryo-electron microscopy reveals a multivalent intasome-nucleosome interface involving both gyres of nucleosomal DNA and one H2A-H2B heterodimer. While the histone octamer remains intact, the DNA is lifted from the surface of the H2A-H2B heterodimer to allow integration at strongly preferred superhelix location +/- 3.5 positions. Amino acid substitutions disrupting these contacts impinge on the ability of the intasome to engage nucleosomes in vitro and redistribute viral integration sites on the genomic scale. Our findings elucidate the molecular basis for nucleosome capture by the viral DNA recombination machinery and the underlying nucleosome plasticity that allows integration.
C1 [Maskell, Daniel P.; Lesbats, Paul; Cherepanov, Peter] Francis Crick Inst, Chromatin Struct & Mobile DNA, S Mimms EN6 3LD, Herts, England.
   [Renault, Ludovic; Costa, Alessandro] Francis Crick Inst, Clare Hall Labs, Architecture & Dynam Macromol Machines, S Mimms EN6 3LD, Herts, England.
   [Renault, Ludovic] Natl Inst Biol Stand & Control Microscopy & Imagi, S Mimms EN6 3QG, Herts, England.
   [Serrao, Erik; Engelman, Alan N.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA.
   [Matadeen, Rishi] Gorlaeus Lab, NeCEN, NL-2333 Leiden, Netherlands.
   [Hare, Stephen; Cherepanov, Peter] Univ London Imperial Coll Sci Technol & Med, Div Med, London W2 1PG, England.
   [Lindemann, Dirk] Tech Univ Dresden, Inst Virol, D-01307 Dresden, Germany.
C3 National Institute for Biological Standards & Control; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Imperial College London; Technische Universitat Dresden
RP Costa, A (corresponding author), Francis Crick Inst, Clare Hall Labs, Architecture & Dynam Macromol Machines, Blanche Lane, S Mimms EN6 3LD, Herts, England.
EM alessandro.costa@crick.ac.uk; peter.cherepanov@crick.ac.uk
FU European Union [305137]; US National Institute of General Medical Sciences [GM082251-06]; US National Institutes of Health [AI070042-08]; Netherlands Centre for Electron Nanoscopy (NeCEN); Nederlandse Organisatie voor Wetenschappelijk Onderzoek [175.010.2009.001]; European Union's Regional Development Fund through 'Kansen voor West' [21Z.014]; Cancer Research UK [19342, 15852, 15272] Funding Source: researchfish; The Francis Crick Institute [10061] Funding Source: researchfish; The Francis Crick Institute; Cancer Research UK [10065] Funding Source: researchfish
NR 49
TC 118
Z9 133
U1 0
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 JUL 16
PY 2015
VL 523
IS 7560
BP 366
EP +
DI 10.1038/nature14495
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM8KY
UT WOS:000357950900046
PM 26061770
DA 2026-03-09
ER

PT J
AU Porazinski, S
   Wang, HJ
   Asaoka, Y
   Behrndt, M
   Miyamoto, T
   Morita, H
   Hata, S
   Sasaki, T
   Krens, SFG
   Osada, Y
   Asaka, S
   Momoi, A
   Linton, S
   Miesfeld, JB
   Link, BA
   Senga, T
   Castillo-Morales, A
   Urrutia, AO
   Shimizu, N
   Nagase, H
   Matsuura, S
   Bagby, S
   Kondoh, H
   Nishina, H
   Heisenberg, CP
   Furutani-Seiki, M
AF Porazinski, Sean
   Wang, Huijia
   Asaoka, Yoichi
   Behrndt, Martin
   Miyamoto, Tatsuo
   Morita, Hitoshi
   Hata, Shoji
   Sasaki, Takashi
   Krens, S. F. Gabriel
   Osada, Yumi
   Asaka, Satoshi
   Momoi, Akihiro
   Linton, Sarah
   Miesfeld, Joel B.
   Link, Brian A.
   Senga, Takeshi
   Castillo-Morales, Atahualpa
   Urrutia, Araxi O.
   Shimizu, Nobuyoshi
   Nagase, Hideaki
   Matsuura, Shinya
   Bagby, Stefan
   Kondoh, Hisato
   Nishina, Hiroshi
   Heisenberg, Carl-Philipp
   Furutani-Seiki, Makoto
TI YAP is essential for tissue tension to ensure vertebrate 3D body shape
SO NATURE
LA English
DT Article
ID extracellular-matrix; cell-adhesion; zebrafish; medaka; organization; dynamics; pathway; yap/taz; protein; forces
AB Vertebrates have a unique 3D body shape in which correct tissue and organ shape and alignment are essential for function. For example, vision requires the lens to be centred in the eye cup which must in turn be correctly positioned in the head(1). Tissue morphogenesis depends on force generation, force transmission through the tissue, and response of tissues and extracellular matrix to force(2,3). Although a century ago D'Arcy Thompson postulated that terrestrial animal body shapes are conditioned by gravity(4), there has been no animal model directly demonstrating how the aforementioned mechano-morphogenetic processes are coordinated to generate a body shape that withstands gravity. Here we report a unique medaka fish (Oryzias latipes) mutant, hirame (hir), which is sensitive to deformation by gravity. hir embryos display a markedly flattened body caused by mutation of YAP, a nuclear executor of Hippo signalling that regulates organ size. We show that actomyosin-mediated tissue tension is reduced in hir embryos, leading to tissue flattening and tissue misalignment, both of which contribute to body flattening. By analysing YAP function in 3D spheroids of human cells, we identify the Rho GTPase activating protein ARHGAP18 as an effector of YAP in controlling tissue tension. Together, these findings reveal a previously unrecognised function of YAP in regulating tissue shape and alignment required for proper 3D body shape. Understanding this morphogenetic function of YAP could facilitate the use of embryonic stem cells to generate complex organs requiring correct alignment of multiple tissues.
C1 [Porazinski, Sean; Wang, Huijia; Linton, Sarah; Castillo-Morales, Atahualpa; Urrutia, Araxi O.; Bagby, Stefan; Furutani-Seiki, Makoto] Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England.
   [Asaoka, Yoichi; Hata, Shoji; Asaka, Satoshi; Nishina, Hiroshi] Tokyo Med & Dent Univ, Med Res Inst, Dept Dev & Regenerat Biol, Tokyo 1138510, Japan.
   [Behrndt, Martin; Morita, Hitoshi; Krens, S. F. Gabriel; Heisenberg, Carl-Philipp] IST Austria, A-3400 Klosterneuburg, Austria.
   [Miyamoto, Tatsuo; Matsuura, Shinya] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Genet & Cell Biol, Hiroshima 7348553, Japan.
   [Sasaki, Takashi; Shimizu, Nobuyoshi] Keio Univ, Sch Med, Dept Mol Biol, Tokyo 1608582, Japan.
   [Osada, Yumi; Momoi, Akihiro; Kondoh, Hisato; Furutani-Seiki, Makoto] Japan Sci & Technol Agcy JST, ERATO SORST Kondoh Differentiat Signaling Project, Kyoto 6068305, Japan.
   [Miesfeld, Joel B.; Link, Brian A.] Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA.
   [Senga, Takeshi] Nagoya Univ, Grad Sch Med, Div Canc Biol, Nagoya, Aichi 4668550, Japan.
   [Nagase, Hideaki] Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Kennedy Inst Rheumatol, Oxford OX3 7FY, England.
   [Kondoh, Hisato] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan.
   [Kondoh, Hisato] Kyoto Sangyo Univ, Fac Life Sci, Kyoto 6038555, Japan.
C3 University of Bath; Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU); Institute of Science & Technology - Austria; Hiroshima University; Keio University; Japan Science & Technology Agency (JST); Medical College of Wisconsin; Nagoya University; University of Oxford; Kennedy Institute for Rheumatology; University of Osaka; Kyoto Sangyo University
RP Heisenberg, CP (corresponding author), IST Austria, Campus 1, A-3400 Klosterneuburg, Austria.
EM nishina.dbio@mri.tmd.ac.jp; heisenberg@ist.ac.at; furutaniseiki@gmail.com
FU ERATO/SORST projects of JST, Japan; National Institutes of Health [R01EY014167]; Medical Research Council, UK; Grants-in-Aid for Scientific Research [26701006, 25460358, 24651222, 26114005, 15K15017, 25113521, 26293012, 13J08895] Funding Source: KAKEN; MRC [G117/563] Funding Source: UKRI; National Eye Institute [T32EY014537] Funding Source: NIH RePORTER; Austrian Science Fund (FWF) [I 930] Funding Source: researchfish; Medical Research Council [G117/563] Funding Source: researchfish
NR 38
TC 201
Z9 234
U1 1
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 MAY 14
PY 2015
VL 521
IS 7551
BP 217
EP +
DI 10.1038/nature14215
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH9SY
UT WOS:000354377800058
PM 25778702
DA 2026-03-09
ER

PT J
AU Sudmant, PH
   Rausch, T
   Gardner, EJ
   Handsaker, RE
   Abyzov, A
   Huddleston, J
   Zhang, Y
   Ye, K
   Jun, G
   Fritz, MHY
   Konkel, MK
   Malhotra, A
   Stütz, AM
   Shi, XH
   Casale, FP
   Chen, JM
   Hormozdiari, F
   Dayama, G
   Chen, K
   Malig, M
   Chaisson, MJP
   Walter, K
   Meiers, S
   Kashin, S
   Garrison, E
   Auton, A
   Lam, HYK
   Mu, XJ
   Alkan, C
   Antaki, D
   Bae, T
   Cerveira, E
   Chines, P
   Chong, ZC
   Clarke, L
   Dal, E
   Ding, L
   Emery, S
   Fan, X
   Gujral, M
   Kahveci, F
   Kidd, JM
   Kong, Y
   Lameijer, EW
   McCarthy, S
   Flicek, P
   Gibbs, RA
   Marth, G
   Mason, CE
   Menelaou, A
   Muzny, DM
   Nelson, BJ
   Noor, A
   Parrish, NF
   Pendleton, M
   Quitadamo, A
   Raeder, B
   Schadt, EE
   Romanovitch, M
   Schlattl, A
   Sebra, R
   Shabalin, AA
   Untergasser, A
   Walker, JA
   Wang, M
   Yu, FL
   Zhang, CS
   Zhang, J
   Zheng-Bradley, X
   Zhou, WD
   Zichner, T
   Sebat, J
   Batzer, MA
   McCarroll, SA
   Mills, RE
   Gerstein, MB
   Bashir, A
   Stegle, O
   Devine, SE
   Lee, C
   Eichler, EE
   Korbel, JO
AF Sudmant, Peter H.
   Rausch, Tobias
   Gardner, Eugene J.
   Handsaker, Robert E.
   Abyzov, Alexej
   Huddleston, John
   Zhang, Yan
   Ye, Kai
   Jun, Goo
   Fritz, Markus Hsi-Yang
   Konkel, Miriam K.
   Malhotra, Ankit
   Stuetz, Adrian M.
   Shi, Xinghua
   Casale, Francesco Paolo
   Chen, Jieming
   Hormozdiari, Fereydoun
   Dayama, Gargi
   Chen, Ken
   Malig, Maika
   Chaisson, Mark J. P.
   Walter, Klaudia
   Meiers, Sascha
   Kashin, Seva
   Garrison, Erik
   Auton, Adam
   Lam, Hugo Y. K.
   Mu, Xinmeng Jasmine
   Alkan, Can
   Antaki, Danny
   Bae, Taejeong
   Cerveira, Eliza
   Chines, Peter
   Chong, Zechen
   Clarke, Laura
   Dal, Elif
   Ding, Li
   Emery, Sarah
   Fan, Xian
   Gujral, Madhusudan
   Kahveci, Fatma
   Kidd, Jeffrey M.
   Kong, Yu
   Lameijer, Eric-Wubbo
   McCarthy, Shane
   Flicek, Paul
   Gibbs, Richard A.
   Marth, Gabor
   Mason, Christopher E.
   Menelaou, Androniki
   Muzny, Donna M.
   Nelson, Bradley J.
   Noor, Amina
   Parrish, Nicholas F.
   Pendleton, Matthew
   Quitadamo, Andrew
   Raeder, Benjamin
   Schadt, Eric E.
   Romanovitch, Mallory
   Schlattl, Andreas
   Sebra, Robert
   Shabalin, Andrey A.
   Untergasser, Andreas
   Walker, Jerilyn A.
   Wang, Min
   Yu, Fuli
   Zhang, Chengsheng
   Zhang, Jing
   Zheng-Bradley, Xiangqun
   Zhou, Wanding
   Zichner, Thomas
   Sebat, Jonathan
   Batzer, Mark A.
   McCarroll, Steven A.
   Mills, Ryan E.
   Gerstein, Mark B.
   Bashir, Ali
   Stegle, Oliver
   Devine, Scott E.
   Lee, Charles
   Eichler, Evan E.
   Korbel, Jan O.
TI An integrated map of structural variation in 2,504 human genomes
SO NATURE
LA English
DT Article
ID copy number variation; transcriptome; insights; database; impact; cnvs
AB Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.
C1 [Sudmant, Peter H.; Huddleston, John; Hormozdiari, Fereydoun; Malig, Maika; Chaisson, Mark J. P.; Nelson, Bradley J.; Eichler, Evan E.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.
   [Rausch, Tobias; Fritz, Markus Hsi-Yang; Stuetz, Adrian M.; Meiers, Sascha; Raeder, Benjamin; Schlattl, Andreas; Untergasser, Andreas; Zichner, Thomas; Korbel, Jan O.] European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany.
   [Gardner, Eugene J.; Devine, Scott E.] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA.
   [Handsaker, Robert E.; Kashin, Seva; McCarroll, Steven A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
   [Handsaker, Robert E.; Kashin, Seva; McCarroll, Steven A.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA.
   [Abyzov, Alexej; Bae, Taejeong] Mayo Clin, Ctr Individualized Med, Dept Hlth Sci Res, Rochester, MN 55905 USA.
   [Huddleston, John; Eichler, Evan E.] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA.
   [Zhang, Yan; Chen, Jieming; Mu, Xinmeng Jasmine; Zhang, Jing; Gerstein, Mark B.] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
   [Zhang, Yan; Zhang, Jing; Gerstein, Mark B.] Yale Univ, Sch Med, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA.
   [Ye, Kai; Ding, Li; Genomes Project Consortium] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63108 USA.
   [Ye, Kai; Ding, Li] Washington Univ, Dept Genet, St Louis, MO 63108 USA.
   [Jun, Goo; Kidd, Jeffrey M.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.
   [Jun, Goo; Kidd, Jeffrey M.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.
   [Jun, Goo] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA.
   [Konkel, Miriam K.; Walker, Jerilyn A.; Batzer, Mark A.] Louisiana State Univ, Dept Biol Sci, Baton Rouge, LA 70803 USA.
   [Malhotra, Ankit; Cerveira, Eliza; Romanovitch, Mallory; Zhang, Chengsheng; Lee, Charles] Jackson Lab Genom Med, Farmington, CT 06030 USA.
   [Shi, Xinghua; Quitadamo, Andrew] Univ N Carolina, Dept Bioinformat & Genom, Charlotte, NC 28223 USA.
   [Casale, Francesco Paolo; Clarke, Laura; Flicek, Paul; Zheng-Bradley, Xiangqun; Stegle, Oliver; Korbel, Jan O.] European Mol Biol Lab, EBI, Cambridge CB10 1SD, England.
   [Chen, Jieming] Yale Univ, Integrated Grad Program Phys & Engn Biol, New Haven, CT 06520 USA.
   [Dayama, Gargi; Mills, Ryan E.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA.
   [Chen, Ken; Chong, Zechen; Fan, Xian; Zhou, Wanding] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
   [Walter, Klaudia; McCarthy, Shane] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.
   [Garrison, Erik; Marth, Gabor] Boston Coll, Dept Biol, Chestnut Hill, MA 02467 USA.
   [Auton, Adam; Kong, Yu] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA.
   [Lam, Hugo Y. K.] Bina Technol, Roche Sequencing, Redwood City, CA 94065 USA.
   [Mu, Xinmeng Jasmine] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02142 USA.
   [Alkan, Can; Dal, Elif; Kahveci, Fatma] Bilkent Univ, Dept Comp Engn, TR-06800 Ankara, Turkey.
   [Antaki, Danny; Gujral, Madhusudan; Noor, Amina; Sebat, Jonathan] Univ Calif San Diego, La Jolla, CA 92093 USA.
   [Chines, Peter] NHGRI, NIH, Bethesda, MD 20892 USA.
   [Ding, Li] Washington Univ, Dept Med, St Louis, MO 63108 USA.
   [Ding, Li] Siteman Canc Ctr, St Louis, MO 63110 USA.
   [Emery, Sarah; Kidd, Jeffrey M.; Mills, Ryan E.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.
   [Lameijer, Eric-Wubbo] Leiden Univ, Med Ctr, Mol Epidemiol, NL-2300 RA Leiden, Netherlands.
   [Gibbs, Richard A.; Wang, Min; Yu, Fuli] Baylor Coll Med, Houston, TX 77030 USA.
   [Mason, Christopher E.] Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA.
   [Mason, Christopher E.] Weill Cornell Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USA.
   [Mason, Christopher E.] Weill Cornell Med Coll, Feil Family Brain & Mind Res Inst, New York, NY 10065 USA.
   [Menelaou, Androniki] Univ Oxford, Oxford OX3 9DS, England.
   [Menelaou, Androniki] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Med Genet, NL-3584 CG Utrecht, Netherlands.
   [Muzny, Donna M.; Pendleton, Matthew; Schadt, Eric E.; Sebra, Robert; Bashir, Ali] Icahn Sch Med Mt Sinai, New York Sch Nat Sci, Dept Genet & Genom Sci, New York, NY 10029 USA.
   [Parrish, Nicholas F.] Kyoto Univ, Inst Virus Res, Sakyo Ku, Kyoto 6068507, Japan.
   [Shabalin, Andrey A.] Virginia Commonwealth Univ, Ctr Biomarker Res & Precis Med, Richmond, VA 23298 USA.
   [Untergasser, Andreas] Heidelberg Univ, Zentrum Mol Biol, D-69120 Heidelberg, Germany.
   [Gerstein, Mark B.] Yale Univ, Dept Comp Sci, New Haven, CT 06511 USA.
   [Lee, Charles] Ewha Womans Univ, Dept Grad Studies Life Sci, Seoul 120750, South Korea.
C3 University of Washington; University of Washington Seattle; European Molecular Biology Laboratory (EMBL); University System of Maryland; University of Maryland Baltimore; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Mayo Clinic; Howard Hughes Medical Institute; University of Washington; University of Washington Seattle; Yale University; Yale University; Washington University (WUSTL); Washington University (WUSTL); University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Texas System; University of Texas Health Science Center Houston; University of Texas School Public Health; Louisiana State University System; Louisiana State University; Jackson Laboratory; University of North Carolina; University of North Carolina Charlotte; European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute; Yale University; University of Michigan System; University of Michigan; University of Texas System; UTMD Anderson Cancer Center; Wellcome Trust Sanger Institute; Boston College; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Ihsan Dogramaci Bilkent University; University of California System; University of California San Diego; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI); Washington University (WUSTL); Siteman Cancer Center; University of Michigan System; University of Michigan; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Baylor College of Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; University of Oxford; Utrecht University; Utrecht University Medical Center; Icahn School of Medicine at Mount Sinai; Kyoto University; Virginia Commonwealth University; Ruprecht Karls University Heidelberg; Yale University; Ewha Womans University
RP Eichler, EE (corresponding author), Univ Washington, Dept Genome Sci, 3720 15th Ave NE, Seattle, WA 98195 USA.
EM eee@gs.washington.edu; korbel@embl.de
FU NIH [U41HG007497, RO1GM59290, R01HG002898, R01CA166661, P01HG007497, R01HG007068, RR19895, RR029676-01]; Wellcome Trust [WT085532/Z/08/Z, WT104947/Z/14/Z]; German Research Foundation [KO4037/1-1]; European Molecular Biology Laboratory; National Cancer Institute [P30CA016672] Funding Source: NIH RePORTER; National Human Genome Research Institute [R01HG002385] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM008666] Funding Source: NIH RePORTER
NR 39
TC 1640
Z9 1999
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 1
PY 2015
VL 526
IS 7571
BP 75
EP +
DI 10.1038/nature15394
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS5CY
UT WOS:000362095100037
PM 26432246
DA 2026-03-09
ER

PT J
AU Hoshino, A
   Costa-Silva, B
   Shen, TL
   Rodrigues, G
   Hashimoto, A
   Mark, MT
   Molina, H
   Kohsaka, S
   Di Giannatale, A
   Ceder, S
   Singh, S
   Williams, C
   Soplop, N
   Uryu, K
   Pharmer, L
   King, T
   Bojmar, L
   Davies, AE
   Ararso, Y
   Zhang, T
   Zhang, H
   Hernandez, J
   Weiss, JM
   Dumont-Cole, VD
   Kramer, K
   Wexler, LH
   Narendran, A
   Schwartz, GK
   Healey, JH
   Sandstrom, P
   Labori, KJ
   Kure, EH
   Grandgenett, PM
   Hollingsworth, MA
   de Sousa, M
   Kaur, S
   Jain, M
   Mallya, K
   Batra, SK
   Jarnagin, WR
   Brady, MS
   Fodstad, O
   Muller, V
   Pantel, K
   Minn, AJ
   Bissell, MJ
   Garcia, BA
   Kang, Y
   Rajasekhar, VK
   Ghajar, CM
   Matei, I
   Peinado, H
   Bromberg, J
   Lyden, D
AF Hoshino, Ayuko
   Costa-Silva, Bruno
   Shen, Tang-Long
   Rodrigues, Goncalo
   Hashimoto, Ayako
   Mark, Milica Tesic
   Molina, Henrik
   Kohsaka, Shinji
   Di Giannatale, Angela
   Ceder, Sophia
   Singh, Swarnima
   Williams, Caitlin
   Soplop, Nadine
   Uryu, Kunihiro
   Pharmer, Lindsay
   King, Tari
   Bojmar, Linda
   Davies, Alexander E.
   Ararso, Yonathan
   Zhang, Tuo
   Zhang, Haiying
   Hernandez, Jonathan
   Weiss, Joshua M.
   Dumont-Cole, Vanessa D.
   Kramer, Kimberly
   Wexler, Leonard H.
   Narendran, Aru
   Schwartz, Gary K.
   Healey, John H.
   Sandstrom, Per
   Labori, Knut Jorgen
   Kure, Elin H.
   Grandgenett, Paul M.
   Hollingsworth, Michael A.
   de Sousa, Maria
   Kaur, Sukhwinder
   Jain, Maneesh
   Mallya, Kavita
   Batra, Surinder K.
   Jarnagin, William R.
   Brady, Mary S.
   Fodstad, Oystein
   Muller, Volkmar
   Pantel, Klaus
   Minn, Andy J.
   Bissell, Mina J.
   Garcia, Benjamin A.
   Kang, Yibin
   Rajasekhar, Vinagolu K.
   Ghajar, Cyrus M.
   Matei, Irina
   Peinado, Hector
   Bromberg, Jacqueline
   Lyden, David
TI Tumour exosome integrins determine organotropic metastasis
SO NATURE
LA English
DT Article
ID breast-cancer metastasis; bone metastases; in-vivo; cells; growth; niche; microvesicles; proteomics; proteins; vesicles
AB Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver-and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins alpha(6)beta(4) and alpha(6)beta(1) were associated with lung metastasis, while exosomal integrin alpha(v)beta(5) was linked to liver metastasis. Targeting the integrins alpha(6)beta(4) and alpha(v)beta(5) decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.
C1 [Hoshino, Ayuko; Costa-Silva, Bruno; Shen, Tang-Long; Rodrigues, Goncalo; Hashimoto, Ayako; Di Giannatale, Angela; Singh, Swarnima; Williams, Caitlin; Bojmar, Linda; Ararso, Yonathan; Zhang, Haiying; Hernandez, Jonathan; Weiss, Joshua M.; de Sousa, Maria; Brady, Mary S.; Matei, Irina; Peinado, Hector; Lyden, David] Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA.
   [Hoshino, Ayuko; Costa-Silva, Bruno; Shen, Tang-Long; Rodrigues, Goncalo; Hashimoto, Ayako; Di Giannatale, Angela; Singh, Swarnima; Williams, Caitlin; Bojmar, Linda; Ararso, Yonathan; Zhang, Haiying; Hernandez, Jonathan; Weiss, Joshua M.; de Sousa, Maria; Brady, Mary S.; Matei, Irina; Peinado, Hector; Lyden, David] Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA.
   [Shen, Tang-Long] Natl Taiwan Univ, Dept Plant Pathol & Microbiol, Taipei 10617, Taiwan.
   [Shen, Tang-Long] Natl Taiwan Univ, Ctr Biotechnol, Taipei 10617, Taiwan.
   [Rodrigues, Goncalo; de Sousa, Maria] Univ Porto, Abel Salazar Biomed Sci Inst, Grad Program Areas Basic & Appl Biol, P-4099003 Oporto, Portugal.
   [Hashimoto, Ayako] Univ Tokyo, Dept Obstet & Gynecol, Fac Med, Tokyo 1138655, Japan.
   [Mark, Milica Tesic; Molina, Henrik] Rockefeller Univ, Prote Resource Ctr, New York, NY 10065 USA.
   [Kohsaka, Shinji] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA.
   [Ceder, Sophia] Karolinska Inst, Dept Pathol & Oncol, S-17176 Stockholm, Sweden.
   [Soplop, Nadine; Uryu, Kunihiro] Rockefeller Univ, EMRC, New York, NY 10065 USA.
   [Pharmer, Lindsay; King, Tari] Mem Sloan Kettering Canc Ctr, Dept Surg, Breast Serv, New York, NY 10065 USA.
   [Bojmar, Linda; Sandstrom, Per] Linkoping Univ, Fac Hlth Sci, Dept Surg, Cty Council Ostergotland, S-58185 Linkoping, Sweden.
   [Bojmar, Linda; Sandstrom, Per] Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, S-58185 Linkoping, Sweden.
   [Davies, Alexander E.; Bissell, Mina J.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA.
   [Zhang, Tuo] Weill Cornell Med, Genom Resources Core Facil, New York, NY 10021 USA.
   [Hernandez, Jonathan; Jarnagin, William R.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA.
   [Dumont-Cole, Vanessa D.; Kramer, Kimberly; Wexler, Leonard H.; Lyden, David] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA.
   [Narendran, Aru] Alberta Childrens Prov Gen Hosp, Div Pediat Oncol, Calgary, AB T3B 6A8, Canada.
   [Schwartz, Gary K.] Columbia Univ, Sch Med, Div Hematol Oncol, New York, NY 10032 USA.
   [Healey, John H.] Mem Sloan Kettering Canc Ctr, Dept Surg, Orthopaed Serv, New York, NY 10065 USA.
   [Labori, Knut Jorgen] Oslo Univ Hosp, Dept Hepatopancreatobiliary Surg, N-0424 Oslo, Norway.
   [Kure, Elin H.] Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, N-0424 Oslo, Norway.
   [Grandgenett, Paul M.; Hollingsworth, Michael A.] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA.
   [Kaur, Sukhwinder; Jain, Maneesh; Mallya, Kavita; Batra, Surinder K.] Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA.
   [Brady, Mary S.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gastr & Mixed Tumor Serv, New York, NY 10065 USA.
   [Fodstad, Oystein] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Tumor Biol, N-0424 Oslo, Norway.
   [Fodstad, Oystein] Univ Oslo, Inst Clin Med, Fac Med, N-0318 Oslo, Norway.
   [Muller, Volkmar] Univ Med Ctr, Dept Gynecol, D-20246 Hamburg, Germany.
   [Pantel, Klaus] Univ Med Ctr Hamburg Eppendorf, Dept Tumor Biol, D-20246 Hamburg, Germany.
   [Minn, Andy J.] Univ Penn, Abramson Family Canc Res Inst, Dept Radiat Oncol, Philadelphia, PA 19104 USA.
   [Garcia, Benjamin A.] Univ Penn, Perelman Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA.
   [Kang, Yibin] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA.
   [Kang, Yibin] Rutgers Canc Inst New Jersey, New Brunswick, NJ 08903 USA.
   [Rajasekhar, Vinagolu K.] Mem Sloan Kettering Canc Ctr, Dept Med, Breast Med Serv, New York, NY 10065 USA.
   [Ghajar, Cyrus M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA.
   [Peinado, Hector] Spanish Natl Canc Res Ctr CNIO, Dept Mol Oncol, Microenvironm & Metastasis Lab, Madrid 28029, Spain.
   [Bromberg, Jacqueline] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA.
   [Bromberg, Jacqueline] Weill Cornell Med, Dept Med, New York, NY 10021 USA.
C3 Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; National Taiwan University; National Taiwan University; Universidade do Porto; University of Tokyo; Rockefeller University; Memorial Sloan Kettering Cancer Center; Karolinska Institutet; Rockefeller University; Memorial Sloan Kettering Cancer Center; City Council Ostergotland; Linkoping University; Linkoping University; University of California System; University of California Berkeley; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; Cornell University; Weill Cornell Medicine; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Alberta Childrens Hospital; University of Calgary; University Calgary Hospital; Columbia University; Memorial Sloan Kettering Cancer Center; University of Oslo; University of Oslo; University of Nebraska System; University of Nebraska Medical Center; University of Nebraska System; University of Nebraska Medical Center; Memorial Sloan Kettering Cancer Center; University of Oslo; University of Oslo; University of Hamburg; University Medical Center Hamburg-Eppendorf; University of Hamburg; University Medical Center Hamburg-Eppendorf; University of Pennsylvania; University of Pennsylvania; Princeton University; Rutgers University System; Rutgers University New Brunswick; Rutgers University Biomedical & Health Sciences; Rutgers Cancer Institute of New Jersey; Memorial Sloan Kettering Cancer Center; Fred Hutchinson Cancer Center; Centro Nacional de Investigaciones Oncologicas (CNIO); Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine
RP Peinado, H (corresponding author), Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA.
EM hpeinado@cnio.es; bromberj@mskcc.org; dcl2001@med.cornell.edu
FU MSK Cancer Center Support Grant/Core Grant [P30 CA008748]; National Cancer Institute [U01-CA169538]; National Institutes of Health [R01-CA169416]; United States Department of Defense [W81XWH-13-10249, W81XWH-13-1-0425]; Melanoma Research Alliance; Sohn Conference Foundation; Children's Cancer and Blood Foundation; Manning Foundation; Hartwell Foundation; Fundacao para a Ciencia e a Tecnologia; Nancy C. and Daniel P. Paduano Foundation; Feldstein Foundation; Starr Cancer Consortium; Mary Kay Foundation; Pediatric Oncology Experimental Therapeutic Investigator Consortium (POETIC); James Paduano Foundation; Beth Tortolani Foundation; Malcolm Hewitt Weiner Foundation; Theodore A. Rapp Foundation; American Hellenic Educational Progressive Association 5th District Cancer Research Foundation; Charles and Marjorie Holloway Foundation; Sussman Family Fund; Lerner Foundation; Breast Cancer Alliance; Manhasset Women's Coalition Against Breast Cancer; Ministry of Science and Technology Taiwan [101-2918-I-002-016]; JSPS Postdoctoral Fellowships; Susan G. Komen Postdoctoral Fellowship; National Cancer Institute [P30CA008748] Funding Source: NIH RePORTER
NR 50
TC 4104
Z9 4655
U1 41
U2 1653
PU NATURE PUBLISHING 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 19
PY 2015
VL 527
IS 7578
BP 329
EP +
DI 10.1038/nature15756
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9ZN
UT WOS:000365356800046
PM 26524530
DA 2026-03-09
ER

PT J
AU Wall, DH
   Nielsen, UN
   Six, J
AF Wall, Diana H.
   Nielsen, Uffe N.
   Six, Johan
TI Soil biodiversity and human health
SO NATURE
LA English
DT Article
ID particulate matter; ecosystem services; species-diversity; asian dust; food-web; community; assemblages; management; dispersal; infection
AB Soil biodiversity is increasingly recognized as providing benefits to human health because it can suppress disease-causing soil organisms and provide clean air, water and food. Poor land-management practices and environmental change are, however, affecting belowground communities globally, and the resulting declines in soil biodiversity reduce and impair these benefits. Importantly, current research indicates that soil biodiversity can be maintained and partially restored if managed sustainably. Promoting the ecological complexity and robustness of soil biodiversity through improved management practices represents an underutilized resource with the ability to improve human health.
C1 [Wall, Diana H.] Colorado State Univ, Sch Global Environm Sustainabil, Ft Collins, CO 80523 USA.
   [Wall, Diana H.] Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA.
   [Nielsen, Uffe N.] Univ Western Sydney, Hawkesbury Inst Environm, Penrith, NSW 2751, Australia.
   [Six, Johan] ETH, Swiss Fed Inst Technol, Dept Environm Syst Sci, CH-8092 Zurich, Switzerland.
C3 Colorado State University System; Colorado State University Fort Collins; Colorado State University System; Colorado State University Fort Collins; Western Sydney University; Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Wall, DH (corresponding author), Colorado State Univ, Sch Global Environm Sustainabil, Ft Collins, CO 80523 USA.
EM diana.wall@colostate.edu
FU Directorate For Geosciences; Office of Polar Programs (OPP) [1115245] Funding Source: National Science Foundation
NR 89
TC 573
Z9 694
U1 29
U2 1204
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 3
PY 2015
VL 528
IS 7580
BP 69
EP 76
DI 10.1038/nature15744
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000050
PM 26595276
DA 2026-03-09
ER

PT J
AU Klotz, L
   Norman, S
   Vieira, JM
   Masters, M
   Rohling, M
   Dubé, KN
   Bollini, S
   Matsuzaki, F
   Carr, CA
   Riley, PR
AF Klotz, Linda
   Norman, Sophie
   Vieira, Joaquim Miguel
   Masters, Megan
   Rohling, Mala
   Dube, Karina N.
   Bollini, Sveva
   Matsuzaki, Fumio
   Carr, Carolyn A.
   Riley, Paul R.
TI Cardiac lymphatics are heterogeneous in origin and respond to injury
SO NATURE
LA English
DT Article
ID vascular endothelial-cells; vessel development; transgenic mice; prox1; vegf; lymphangiogenesis; progenitors; expression; lineage; heart
AB The lymphatic vasculature is a blind-ended network crucial for tissue-fluid homeostasis, immune surveillance and lipid absorption from the gut. Recent evidence has proposed an entirely venous-derived mammalian lymphatic system. By contrast, here we show that cardiac lymphatic vessels in mice have a heterogeneous cellular origin, whereby formation of at least part of the cardiac lymphatic network is independent of sprouting from veins. Multiple Cre-lox-based lineage tracing revealed a potential contribution from the putative haemogenic endothelium during development, and discrete lymphatic endothelial progenitor populations were confirmed by conditional knockout of Prox1 in Tie2(+) and Vav1(+) compartments. In the adult heart, myocardial infarction promoted a significant lymphangiogenic response, which was augmented by treatment with VEGF-C, resulting in improved cardiac function. These data prompt the re-evaluation of a century-long debate on the origin of lymphatic vessels and suggest that lymphangiogenesis may represent a therapeutic target to promote cardiac repair following injury.
C1 [Klotz, Linda; Dube, Karina N.] UCL, Inst Child Hlth, Mol Med Unit, London WC1N 1EH, England.
   [Norman, Sophie; Vieira, Joaquim Miguel; Masters, Megan; Rohling, Mala; Carr, Carolyn A.; Riley, Paul R.] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3PT, England.
   [Bollini, Sveva] Univ Genoa, Regenerat Med Lab, I-16132 Genoa, Italy.
   [Bollini, Sveva] IRCCS AOU San Martino IST, I-16132 Genoa, Italy.
   [Matsuzaki, Fumio] RIKEN Ctr Dev Biol, Lab Cell Asymmetry, Chuou Ku, Kobe, Hyogo 6500047, Japan.
C3 University of London; University College London; University of Oxford; University of Genoa; University of Genoa; IRCCS AOU San Martino IST; RIKEN
RP Riley, PR (corresponding author), Univ Oxford, Dept Physiol Anat & Genet, S Parks Rd, Oxford OX1 3PT, England.
EM paul.riley@dpag.ox.ac.uk
FU Wellcome Trust; EU FP7 Marie Curie ITN (CardioNet); British Heart Foundation; Grants-in-Aid for Scientific Research [24113006] Funding Source: KAKEN; British Heart Foundation [RG/13/9/30269, PG/13/34/30216, RG/08/003/25264] Funding Source: researchfish
NR 49
TC 401
Z9 480
U1 2
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 JUN 4
PY 2015
VL 522
IS 7554
BP 62
EP U126
DI 10.1038/nature14483
PG 26
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ5QP
UT WOS:000355543400029
PM 25992544
DA 2026-03-09
ER

PT J
AU Yamashita, F
   Fukuyama, E
   Mizoguchi, K
   Takizawa, S
   Xu, SQ
   Kawakata, H
AF Yamashita, Futoshi
   Fukuyama, Eiichi
   Mizoguchi, Kazuo
   Takizawa, Shigeru
   Xu, Shiqing
   Kawakata, Hironori
TI Scale dependence of rock friction at high work rate
SO NATURE
LA English
DT Article
ID slip rates; carbonate faults; high-velocity; seismic slip; stick-slip; earthquake; strength; nucleation; gabbro; lubrication
AB Determination of the frictional properties of rocks is crucial for an understanding of earthquake mechanics, because most earthquakes are caused by frictional sliding along faults. Prior studies using rotary shear apparatus(1-13) revealed a marked decrease in frictional strength, which can cause a large stress drop and strong shaking, with increasing slip rate and increasing work rate. (The mechanical work rate per unit area equals the product of the shear stress and the slip rate.) However, those important findings were obtained in experiments using rock specimens with dimensions of only several centimetres, which are much smaller than the dimensions of a natural fault (of the order of 1,000 metres). Here we use a large-scale biaxial friction apparatus with metre-sized rock specimens to investigate scale-dependent rock friction. The experiments show that rock friction in metre-sized rock specimens starts to decrease at a work rate that is one order of magnitude smaller than that in centimetre-sized rock specimens. Mechanical, visual and material observations suggest that slip-evolved stress heterogeneity on the fault accounts for the difference. On the basis of these observations, we propose that stress-concentrated areas exist in which frictional slip produces more wear materials (gouge) than in areas outside, resulting in further stress concentrations at these areas. Shear stress on the fault is primarily sustained by stress-concentrated areas that undergo a high work rate, so those areas should weaken rapidly and cause the macroscopic frictional strength to decrease abruptly. To verify this idea, we conducted numerical simulations assuming that local friction follows the frictional properties observed on centimetre-sized rock specimens. The simulations reproduced the macroscopic frictional properties observed on the metre-sized rock specimens. Given that localized stress concentrations commonly occur naturally, our results suggest that a natural fault may lose its strength faster than would be expected from the properties estimated from centimetre-sized rock samples.
C1 [Yamashita, Futoshi; Fukuyama, Eiichi; Mizoguchi, Kazuo; Takizawa, Shigeru; Xu, Shiqing; Kawakata, Hironori] Natl Res Inst Earth Sci & Disaster Prevent NIED, Tsukuba, Ibaraki 3050006, Japan.
   [Mizoguchi, Kazuo] Cent Res Inst Elect Power Ind, Abiko, Chiba 2701194, Japan.
   [Kawakata, Hironori] Ritsumeikan Univ, Coll Sci & Engn, Kusatsu 5258577, Japan.
C3 National Research Institute for Earth Science & Disaster Resilience; Central Research Institute of Electric Power Industry - Japan; Ritsumeikan University
RP Yamashita, F (corresponding author), Natl Res Inst Earth Sci & Disaster Prevent NIED, Tsukuba, Ibaraki 3050006, Japan.
EM yamafuto@bosai.go.jp
FU NIED; JSPS KAKENHI [23340131]; Grants-in-Aid for Scientific Research [23340131] Funding Source: KAKEN
NR 30
TC 59
Z9 67
U1 19
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 DEC 10
PY 2015
VL 528
IS 7581
BP 254
EP 257
DI 10.1038/nature16138
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX9VH
UT WOS:000366053300039
PM 26659187
DA 2026-03-09
ER

PT J
AU Nouvellet, P
   Garske, T
   Mills, HL
   Nedjati-Gilani, G
   Hinsley, W
   Blake, IM
   Van Kerkhove, MD
   Cori, A
   Dorigatti, I
   Jombart, T
   Riley, S
   Fraser, C
   Donnelly, CA
   Ferguson, NM
AF Nouvellet, Pierre
   Garske, Tini
   Mills, Harriet L.
   Nedjati-Gilani, Gemma
   Hinsley, Wes
   Blake, Isobel M.
   Van Kerkhove, Maria D.
   Cori, Anne
   Dorigatti, Ilaria
   Jombart, Thibaut
   Riley, Steven
   Fraser, Christophe
   Donnelly, Christl A.
   Ferguson, Neil M.
TI The role of rapid diagnostics in managing Ebola epidemics
SO NATURE
LA English
DT Article
ID virus disease; infection
AB Ebola emerged in West Africa around December 2013 and swept through Guinea, Sierra Leone and Liberia, giving rise to 27,748 confirmed, probable and suspected cases reported by 29 July 2015. Case diagnoses during the epidemic have relied on polymerase chain reaction-based tests. Owing to limited laboratory capacity and local transport infrastructure, the delays from sample collection to test results being available have often been 2 days or more. Point-of-care rapid diagnostic tests offer the potential to substantially reduce these delays. We review Ebola rapid diagnostic tests approved by the World Health Organization and those currently in development. Such rapid diagnostic tests could allow early triaging of patients, thereby reducing the potential for nosocomial transmission. In addition, despite the lower test accuracy, rapid diagnostic test-based diagnosis may be beneficial in some contexts because of the reduced time spent by uninfected individuals in health-care settings where they may be at increased risk of infection; this also frees up hospital beds. We use mathematical modelling to explore the potential benefits of diagnostic testing strategies involving rapid diagnostic tests alone and in combination with polymerase chain reaction testing. Our analysis indicates that the use of rapid diagnostic tests with sensitivity and specificity comparable with those currently under development always enhances control, whether evaluated at a health-care-unit or population level. If such tests had been available throughout the recent epidemic, we estimate, for Sierra Leone, that their use in combination with confirmatory polymerase chain-reaction testing might have reduced the scale of the epidemic by over a third.
C1 [Nouvellet, Pierre; Garske, Tini; Mills, Harriet L.; Nedjati-Gilani, Gemma; Hinsley, Wes; Blake, Isobel M.; Van Kerkhove, Maria D.; Cori, Anne; Dorigatti, Ilaria; Jombart, Thibaut; Riley, Steven; Fraser, Christophe; Donnelly, Christl A.; Ferguson, Neil M.] Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Infect Dis Epidemiol, MRC Ctr Outbreak Anal & Modelling, London W2 1PG, England.
   [Van Kerkhove, Maria D.] Inst Pasteur, Ctr Global Hlth, F-75724 Paris 15, France.
C3 Imperial College London; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris
RP Ferguson, NM (corresponding author), Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Infect Dis Epidemiol, MRC Ctr Outbreak Anal & Modelling, Norfolk Pl, London W2 1PG, England.
EM neil.ferguson@imperial.ac.uk
FU Medical Research Council; Bill and Melinda Gates Foundation; MIDAS network of the National Institute of General Medical Sciences (National Institutes of Health); Health Protection Research Units of the National Institute for Health Research; European Union [278433-PREDEMICS]; Wellcome Trust; MRC [MR/K010174/1] Funding Source: UKRI; Medical Research Council [G0600719B, MR/K010174/1, MR/K010174/1B] Funding Source: researchfish; National Institute for Health Research [NF-SI-0513-10125, NF-SI-0508-10252, HPRU-2012-10080] Funding Source: researchfish
NR 23
TC 95
Z9 112
U1 2
U2 48
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 3
PY 2015
VL 528
IS 7580
BP S109
EP S116
DI 10.1038/nature16041
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000018
PM 26633764
DA 2026-03-09
ER

PT J
AU Peretti, D
   Bastide, A
   Radford, H
   Verity, N
   Molloy, C
   Martin, MG
   Moreno, JA
   Steinert, JR
   Smith, T
   Dinsdale, D
   Willis, AE
   Mallucci, GR
AF Peretti, Diego
   Bastide, Amandine
   Radford, Helois
   Verity, Nicholas
   Molloy, Colin
   Martin, Maria Guerra
   Moreno, Julie A.
   Steinert, Joern R.
   Smith, Tim
   Dinsdale, David
   Willis, Anne E.
   Mallucci, Giovanna R.
TI RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration
SO NATURE
LA English
DT Article
ID binding protein rbm3; alzheimers-disease; hypothermia; hibernation; dysfunction; sections; dynamics; mice; rat; ca1
AB In the healthy adult brain synapses are continuously remodelled through a process of elimination and formation known as structural plasticity(1). Reduction in synapse number is a consistent early feature of neurodegenerative diseases(2,3), suggesting deficient compensatory mechanisms. Although much is known about toxic processes leading to synaptic dysfunction and loss in these disorders(2,3), how synaptic regeneration is affected is unknown. In hibernating mammals, cooling induces loss of synaptic contacts, which are reformed on rewarming, a form of structural plasticity(4,5). We have found that similar changes occur in artificially cooled laboratory rodents. Cooling and hibernation also induce a number of cold-shock proteins in the brain, including the RNA binding protein, RBM3 (ref. 6). The relationship of such proteins to structural plasticity is unknown. Here we show that synapse regeneration is impaired in mouse models of neurodegenerative disease, in association with the failure to induce RBM3. In both prion-infected and 5XFAD (Alzheimer-type) mice(7), the capacity to regenerate synapses after cooling declined in parallel with the loss of induction of RBM3. Enhanced expression of RBM3 in the hippocampus prevented this deficit and restored the capacity for synapse reassembly after cooling. RBM3 overexpression, achieved either by boosting endogenous levels through hypothermia before the loss of the RBM3 response or by lentiviral delivery, resulted in sustained synaptic protection in 5XFAD mice and throughout the course of prion disease, preventing behavioural deficits and neuronal loss and significantly prolonging survival. In contrast, knockdown of RBM3 exacerbated synapse loss in both models and accelerated disease and prevented the neuroprotective effects of cooling. Thus, deficient synapse regeneration, mediated at least in part by failure of the RBM3 stress response, contributes to synapse loss throughout the course of neurodegenerative disease. The data support enhancing cold-shock pathways as potential protective therapies in neurodegenerative disorders.
C1 [Peretti, Diego; Bastide, Amandine; Radford, Helois; Verity, Nicholas; Molloy, Colin; Martin, Maria Guerra; Moreno, Julie A.; Steinert, Joern R.; Smith, Tim; Dinsdale, David; Willis, Anne E.; Mallucci, Giovanna R.] Univ Leicester, Toxicol Unit, MRC, Leicester LE1 9HN, Leics, England.
   [Mallucci, Giovanna R.] Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 0AH, England.
C3 University of Leicester; University of Cambridge
RP Mallucci, GR (corresponding author), Univ Leicester, Toxicol Unit, MRC, Hodgkin Bldg,Lancaster Rd, Leicester LE1 9HN, Leics, England.
EM gm522@cam.ac.uk
FU Medical Research Council, UK; Biotechnology and Biological Sciences Research Council [BB/F02326X/2, BB/I019790/1, BB/F018738/1] Funding Source: researchfish; Medical Research Council [MC_U132681855, MC_U132692719, MC_UP_A600_1023] Funding Source: researchfish; BBSRC [BB/F02326X/2, BB/I019790/1, BB/F018738/1] Funding Source: UKRI; MRC [MC_UP_A600_1023, MC_U132692719, MC_U132681855] Funding Source: UKRI
NR 31
TC 194
Z9 218
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 FEB 12
PY 2015
VL 518
IS 7538
BP 236
EP U215
DI 10.1038/nature14142
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300039
PM 25607368
DA 2026-03-09
ER

PT J
AU Jost, M
   Fernández-Zapata, J
   Polanco, MC
   Ortiz-Guerrero, JM
   Chen, PYT
   Kang, G
   Padmanabhan, S
   Elías-Arnanz, M
   Drennan, CL
AF Jost, Marco
   Fernandez-Zapata, Jesus
   Carmen Polanco, Maria
   Manuel Ortiz-Guerrero, Juan
   Chen, Percival Yang-Ting
   Kang, Gyunghoon
   Padmanabhan, S.
   Elias-Arnanz, Montserrat
   Drennan, Catherine L.
TI Structural basis for gene regulation by a B12-dependent photoreceptor
SO NATURE
LA English
DT Article
ID crystal-structure; dna-binding; light; expression; family; sensor; adenosylcobalamin; photolysis; mechanism; b-12
AB Photoreceptor proteins enable organisms to sense and respond to light. The newly discovered CarH-type photoreceptors use a vitamin B-12 derivative, adenosylcobalamin, as the light-sensing chromophore to mediate light-dependent gene regulation. Here we present crystal structures of Thermus thermophilus CarH in all three relevant states: in the dark, both free and bound to operator DNA, and after light exposure. These structures provide visualizations of how adenosylcobalamin mediates CarH tetramer formation in the dark, how this tetramer binds to the promoter 235 element to repress transcription, and how light exposure leads to a large-scale conformational change that activates transcription. In addition to the remarkable functional repurposing of adenosylcobalamin from an enzyme cofactor to a light sensor, we find that nature also repurposed two independent protein modules in assembling CarH. These results expand the biological role of vitamin B-12 and provide fundamental insight into a new mode of light-dependent gene regulation.
C1 [Jost, Marco; Chen, Percival Yang-Ting; Kang, Gyunghoon; Drennan, Catherine L.] MIT, Dept Chem, Cambridge, MA 02139 USA.
   [Drennan, Catherine L.] MIT, Dept Biol, Cambridge, MA 02139 USA.
   [Drennan, Catherine L.] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA.
   [Fernandez-Zapata, Jesus; Padmanabhan, S.] CSIC, Inst Quim Fis Rocasolano, Madrid 28006, Spain.
   [Carmen Polanco, Maria; Manuel Ortiz-Guerrero, Juan; Elias-Arnanz, Montserrat] Univ Murcia, Fac Biol, Inst Quim Fis Rocasolano,CSIC, Dept Genet & Microbiol,Area Genet,Unidad Asociada, E-30100 Murcia, Spain.
C3 Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Howard Hughes Medical Institute; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Quimica Fisica Blas Cabrera (IQF-CSIC); Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Quimica Fisica Blas Cabrera (IQF-CSIC); University of Murcia
RP Padmanabhan, S (corresponding author), CSIC, Inst Quim Fis Rocasolano, Madrid 28006, Spain.
EM padhu@iqfr.csic.es; melias@um.es; cdrennan@mit.edu
FU National Institutes of Health (NIH) [GM069857]; Ministerio de Economia y Competitividad, Spain [BFU2012-40184-C02-01]; FEDER (Fondo Europeo de Desarrollo Regional) [BFU2012-40184-C02-02]; CSIC-JAE- Predoc (Spain) fellowship; MIT Poitras pre-doctoral fellowship; National Institute of General Medical Sciences (NIGMS) [P41GM103403]; NIH; US Department of Energy Office of Science User Facility [DE-AC02-06CH11357]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]; Department of Energy Office of Biological and Environmental Research; NIGMS [P41GM103393]
NR 64
TC 147
Z9 181
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 OCT 22
PY 2015
VL 526
IS 7574
BP 536
EP U167
DI 10.1038/nature14950
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV1NX
UT WOS:000364026100042
PM 26416754
DA 2026-03-09
ER

PT J
AU Pahlevan, K
   Morbidelli, A
AF Pahlevan, Kaveh
   Morbidelli, Alessandro
TI Collisionless encounters and the origin of the lunar inclination
SO NATURE
LA English
DT Article
ID earth-moon system; fast-spinning earth; giant impact; early evolution; accretion; disk; dynamics; orbit; mars
AB The Moon is generally thought to have formed from the debris ejected by the impact of a planet-sized object with the proto-Earth towards the end of planetary accretion(1,2). Models of the impact process predict that the lunar material was disaggregated into a circumplanetary disk and that lunar accretion subsequently placed the Moon in a near-equatorial orbit(3-6). Forward integration of the lunar orbit from this initial state predicts a modern inclination at least an order of magnitude smaller than the lunar value-a long-standing discrepancy known as the lunar inclination problem(7-9). Here we show that the modern lunar orbit provides a sensitive record of gravitational interactions with Earth-crossing planetesimals that were not yet accreted at the time of the Moon-forming event. The currently observed lunar orbit can naturally be reproduced via interaction with a small quantity of mass (corresponding to 0.0075-0.015 Earth masses eventually accreted to the Earth) carried by a few bodies, consistent with the constraints and models of late accretion(10,11). Although the encounter process has a stochastic element, the observed value of the lunar inclination is among the most likely outcomes for a wide range of parameters. The excitation of the lunar orbit is most readily reproduced via collisionless encounters of planetesimals with the Earth-Moon system with strong dissipation of tidal energy on the early Earth. This mechanism obviates the need for previously proposed (but idealized) excitation mechanisms(12,13), places the Moon-forming event in the context of the formation of Earth, and constrains the pristineness of the dynamical state of the Earth-Moon system.
C1 [Pahlevan, Kaveh; Morbidelli, Alessandro] Univ Cote Azur, Observ Cote Azur, Lab Lagrange, F-06304 Nice 4, France.
C3 Universite Cote d'Azur; Observatoire de la Cote d'Azur
RP Pahlevan, K (corresponding author), Univ Cote Azur, Observ Cote Azur, Lab Lagrange, CNRS Blvd Observ CS 34229, F-06304 Nice 4, France.
EM pahlevan@oca.eu
FU Henri Poincare Fellowship at the Observatoire de la Cote d'Azur (OCA); OCA; City of Nice, France; European Research Council Advanced Grant ACCRETE [290568]; European Research Council (ERC) [290568] Funding Source: European Research Council (ERC)
NR 30
TC 30
Z9 36
U1 0
U2 19
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 492
EP +
DI 10.1038/nature16137
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500042
PM 26607544
DA 2026-03-09
ER

PT J
AU Hige, T
   Aso, Y
   Rubin, GM
   Turner, GC
AF Hige, Toshihide
   Aso, Yoshinori
   Rubin, Gerald M.
   Turner, Glenn C.
TI Plasticity-driven individualization of olfactory coding in mushroom body output neurons
SO NATURE
LA English
DT Article
ID extrinsic neurons; spatial representation; drosophila; body; population; information; behavior; sparse; expression; code
AB Although all sensory circuits ascend to higher brain areas where stimuli are represented in sparse, stimulus-specific activity patterns, relatively little is known about sensory coding on the descending side of neural circuits, as a network converges. In insects, mushroom bodies have been an important model system for studying sparse coding in the olfactory system(1-3), where this format is important for accurate memory formation(4-6). In Drosophila, it has recently been shown that the 2,000 Kenyon cells of the mushroom body converge onto a population of only 34 mushroom body output neurons (MBONs), which fall into 21 anatomically distinct cell types(7,8). Here we provide the first, to our knowledge, comprehensive view of olfactory representations at the fourth layer of the circuit, where we find a clear transition in the principles of sensory coding. We show that MBON tuning curves are highly correlated with one another. This is in sharp contrast to the process of progressive decorrelation of tuning in the earlier layers of the circuit(2,9). Instead, at the population level, odour representations are reformatted so that positive and negative correlations arise between representations of different odours. At the single-cell level, we show that uniquely identifiable MBONs display profoundly different tuning across different animals, but that tuning of the same neuron across the two hemispheres of an individual fly was nearly identical. Thus, individualized coordination of tuning arises at this level of the olfactory circuit. Furthermore, we find that this individualization is an active process that requires a learning-related gene, rutabaga. Ultimately, neural circuits have to flexibly map highly stimulus-specific information in sparse layers onto a limited number of different motor outputs. The reformatting of sensory representations we observe here may mark the beginning of this sensory-motor transition in the olfactory system.
C1 [Hige, Toshihide; Turner, Glenn C.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA.
   [Aso, Yoshinori; Rubin, Gerald M.] Howard Hughes Med Inst, Ashburn, VA 20147 USA.
C3 Cold Spring Harbor Laboratory; Howard Hughes Medical Institute
RP Turner, GC (corresponding author), Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA.
EM turner@cshl.edu
FU NIH [R01 DC010403-01A1]; Postdoctoral Fellowship for Research Abroad from Japan Society for the Promotion of Science; Uehara Memorial Foundation
NR 45
TC 100
Z9 113
U1 0
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 OCT 8
PY 2015
VL 526
IS 7572
BP 258
EP +
DI 10.1038/nature15396
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS9GV
UT WOS:000362399000048
PM 26416731
DA 2026-03-09
ER

PT J
AU Harmand, S
   Lewis, JE
   Feibel, CS
   Lepre, CJ
   Prat, S
   Lenoble, A
   Boës, X
   Quinn, RL
   Brenet, M
   Arroyo, A
   Taylor, N
   Clément, S
   Daver, G
   Brugal, JP
   Leakey, L
   Mortlock, RA
   Wright, JD
   Lokorodi, S
   Kirwa, C
   Kent, DV
   Roche, H
AF Harmand, Sonia
   Lewis, Jason E.
   Feibel, Craig S.
   Lepre, Christopher J.
   Prat, Sandrine
   Lenoble, Arnaud
   Boes, Xavier
   Quinn, Rhonda L.
   Brenet, Michel
   Arroyo, Adrian
   Taylor, Nicholas
   Clement, Sophie
   Daver, Guillaume
   Brugal, Jean-Philip
   Leakey, Louise
   Mortlock, Richard A.
   Wright, James D.
   Lokorodi, Sammy
   Kirwa, Christopher
   Kent, Dennis V.
   Roche, Helene
TI 3.3-million-year-old stone tools from Lomekwi 3, West Turkana, Kenya
SO NATURE
LA English
DT Article
ID raw-material selectivity; omo group; environmental-change; paleosol carbonates; isotopic evidence; human-evolution; hadar formation; bed-i; hominin; gona
AB Human evolutionary scholars have long supposed that the earliest stone tools were made by the genus Homo and that this technological development was directly linked to climate change and the spread of savannah grasslands. New fieldwork in West Turkana, Kenya, has identified evidence of much earlier hominin technological behaviour. We report the discovery of Lomekwi 3, a 3.3-million-year-old archaeological site where in situ stone artefacts occur in spatio-temporal association with Pliocene hominin fossils in a wooded palaeoenvironment. The Lomekwi 3 knappers, with a developing understanding of stone's fracture properties, combined core reduction with battering activities. Given the implications of the Lomekwi 3 assemblage for models aiming to converge environmental change, hominin evolution and technological origins, we propose for it the name 'Lomekwian', which predates the Oldowan by 700,000 years and marks a new beginning to the known archaeological record.
C1 [Harmand, Sonia; Lewis, Jason E.; Leakey, Louise] SUNY Stony Brook, Turkana Basin Inst, Stony Brook, NY 11794 USA.
   [Harmand, Sonia; Arroyo, Adrian; Taylor, Nicholas; Roche, Helene] Univ Paris Ouest Nanterre Def, CNRS, UMR Prehist & Technol 7055, F-92023 Nanterre, France.
   [Harmand, Sonia; Lewis, Jason E.; Feibel, Craig S.; Lepre, Christopher J.; Prat, Sandrine; Lenoble, Arnaud; Boes, Xavier; Quinn, Rhonda L.; Taylor, Nicholas; Clement, Sophie; Brugal, Jean-Philip; Lokorodi, Sammy; Kirwa, Christopher; Roche, Helene] West Turkana Archaeol Project, Nairobi, Kenya.
   [Lewis, Jason E.; Feibel, Craig S.] Rutgers State Univ, Dept Anthropol, New Brunswick, NJ 08901 USA.
   [Lewis, Jason E.; Feibel, Craig S.] Rutgers State Univ, Ctr Human Evolutionary Studies, New Brunswick, NJ 08901 USA.
   [Feibel, Craig S.; Lepre, Christopher J.; Quinn, Rhonda L.; Mortlock, Richard A.; Wright, James D.; Kent, Dennis V.] Rutgers State Univ, Dept Earth & Planetary Sci, Piscataway, NJ 08854 USA.
   [Lepre, Christopher J.; Kent, Dennis V.] Columbia Univ, Lamont Doherty Earth Observ, Palisades, NY 10964 USA.
   [Prat, Sandrine; Boes, Xavier] CNRS, UPR 2147, Dynam Evolut Humaine, F-75014 Paris, France.
   [Lenoble, Arnaud; Brenet, Michel] Univ Bordeaux, CNRS, UMR PACEA 5199, F-33615 Pessac, France.
   [Quinn, Rhonda L.] Seton Hall Univ, Dept Sociol Anthropol & Social Work, S Orange, NJ 07079 USA.
   [Brenet, Michel] Ctr Mixte Rech Archeol, Inrap, F-24620 Campagne, France.
   [Clement, Sophie] Inrap, F-93120 La Courneuve, France.
   [Daver, Guillaume] Univ Poitiers, Inst Paleoprimatol Paleontol Humaine Evolut & Pal, CNRS, UMR 7262, F-86073 Poitiers 9, France.
   [Brugal, Jean-Philip] Aix Marseille Univ, CNRS, MCC, UMR 7269,LAMPEA, F-13094 Aix En Provence 2, France.
   [Kirwa, Christopher] Natl Museums Kenya, Dept Earth Sci, Archaeol Sect, Nairobi, Kenya.
C3 State University of New York (SUNY) System; Stony Brook University; Centre National de la Recherche Scientifique (CNRS); Universite Paris Saclay; Universite Paris Nanterre; Rutgers University System; Rutgers University New Brunswick; Rutgers University System; Rutgers University New Brunswick; Rutgers University System; Rutgers University New Brunswick; Columbia University; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Ecology & Environment (INEE); Universite de Bordeaux; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Ecology & Environment (INEE); Seton Hall University; Universite de Poitiers; Centre National de la Recherche Scientifique (CNRS); Aix-Marseille Universite; Centre National de la Recherche Scientifique (CNRS)
RP Harmand, S (corresponding author), SUNY Stony Brook, Turkana Basin Inst, Stony Brook, NY 11794 USA.
EM sonia.harmand@stonybrook.edu; jason.lewis@stonybrook.edu
FU French Ministry of Foreign Affairs [681/DGM/ATT/RECH, 986/DGM/DPR/PRG]; French National Research Agency [ANR-12-CULT-0006]; Fondation Fyssen; National Geographic Society (Expeditions Council) [EC0569-12]; Rutgers University Research Council; Center for Human Evolutionary Studies; INTM Indigo Group France; Agence Nationale de la Recherche (ANR) [ANR-12-CULT-0006] Funding Source: Agence Nationale de la Recherche (ANR)
NR 64
TC 649
Z9 812
U1 3
U2 230
PU NATURE PUBLISHING 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 21
PY 2015
VL 521
IS 7552
BP 310
EP +
DI 10.1038/nature14464
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CI5RM
UT WOS:000354816500047
PM 25993961
DA 2026-03-09
ER

PT J
AU Kelly, J
   Barends, R
   Fowler, AG
   Megrant, A
   Jeffrey, E
   White, TC
   Sank, D
   Mutus, JY
   Campbell, B
   Chen, Y
   Chen, Z
   Chiaro, B
   Dunsworth, A
   Hoi, IC
   Neill, C
   O'Malley, PJJ
   Quintana, C
   Roushan, P
   Vainsencher, A
   Wenner, J
   Cleland, AN
   Martinis, JM
AF Kelly, J.
   Barends, R.
   Fowler, A. G.
   Megrant, A.
   Jeffrey, E.
   White, T. C.
   Sank, D.
   Mutus, J. Y.
   Campbell, B.
   Chen, Yu
   Chen, Z.
   Chiaro, B.
   Dunsworth, A.
   Hoi, I. -C.
   Neill, C.
   O'Malley, P. J. J.
   Quintana, C.
   Roushan, P.
   Vainsencher, A.
   Wenner, J.
   Cleland, A. N.
   Martinis, John M.
TI State preservation by repetitive error detection in a superconducting quantum circuit
SO NATURE
LA English
DT Article
ID correcting codes; fault-tolerance; realization
AB Quantum computing becomes viable when a quantum state can be protected from environment-induced error. If quantum bits (qubits) are sufficiently reliable, errors are sparse and quantum error correction (QEC)(1-6) is capable of identifying and correcting them. Adding more qubits improves the preservation of states by guaranteeing that increasingly larger clusters of errors will not cause logical failure a key requirement for large-scale systems. Using QEC to extend the qubit lifetime remains one of the outstanding experimental challenges in quantum computing. Here we report the protection of classical states from environmental bit-flip errors and demonstrate the suppression of these errors with increasing system size. We use a linear array of nine qubits, which is a natural step towards the two-dimensional surface code QEC scheme(7), and track errors as they occur by repeatedly performing projective quantum non-demolition parity measurements. Relative to a single physical qubit, we reduce the failure rate in retrieving an input state by a factor of 2.7 when using five of our nine qubits and by a factor of 8.5 when using all nine qubits after eight cycles. Additionally, we tomographically verify preservation of the non-classical Greenberger-Horne-Zeilinger state. The successful suppression of environment-induced errors will motivate further research into the many challenges associated with building a large-scale superconducting quantum computer.
C1 [Kelly, J.; Barends, R.; Fowler, A. G.; Megrant, A.; Jeffrey, E.; White, T. C.; Sank, D.; Mutus, J. Y.; Campbell, B.; Chen, Yu; Chen, Z.; Chiaro, B.; Dunsworth, A.; Hoi, I. -C.; Neill, C.; O'Malley, P. J. J.; Quintana, C.; Roushan, P.; Vainsencher, A.; Wenner, J.; Cleland, A. N.; Martinis, John M.] Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA.
   [Fowler, A. G.] Univ Melbourne, Sch Phys, Ctr Quantum Computat & Commun Technol, Melbourne, Vic 3010, Australia.
   [Megrant, A.] Univ Calif Santa Barbara, Dept Mat, Santa Barbara, CA 93106 USA.
C3 University of California System; University of California Santa Barbara; University of Melbourne; University of California System; University of California Santa Barbara
RP Kelly, J (corresponding author), Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA.
EM julian@physics.ucsb.edu; martinis@physics.ucsb.edu
FU Office of the Director of National Intelligence (ODNI), Intelligence Advanced Research Projects Activity (IARPA) through Army Research Office [W911NF-09-1-0375, W911NF-10-1-0334]; US NSF
NR 27
TC 727
Z9 886
U1 7
U2 189
PU NATURE PUBLISHING 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 5
PY 2015
VL 519
IS 7541
BP 66
EP 69
DI 10.1038/nature14270
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC4EQ
UT WOS:000350304000036
PM 25739628
DA 2026-03-09
ER

PT J
AU Isbell, F
   Craven, D
   Connolly, J
   Loreau, M
   Schmid, B
   Beierkuhnlein, C
   Bezemer, TM
   Bonin, C
   Bruelheide, H
   de Luca, E
   Ebeling, A
   Griffin, JN
   Guo, QF
   Hautier, Y
   Hector, A
   Jentsch, A
   Kreyling, J
   Lanta, V
   Manning, P
   Meyer, ST
   Mori, AS
   Naeem, S
   Niklaus, PA
   Polley, HW
   Reich, PB
   Roscher, C
   Seabloom, EW
   Smith, MD
   Thakur, MP
   Tilman, D
   Tracy, BF
   van der Putten, WH
   van Ruijven, J
   Weigelt, A
   Weisser, WW
   Wilsey, B
   Eisenhauer, N
AF Isbell, Forest
   Craven, Dylan
   Connolly, John
   Loreau, Michel
   Schmid, Bernhard
   Beierkuhnlein, Carl
   Bezemer, T. Martijn
   Bonin, Catherine
   Bruelheide, Helge
   de Luca, Enrica
   Ebeling, Anne
   Griffin, John N.
   Guo, Qinfeng
   Hautier, Yann
   Hector, Andy
   Jentsch, Anke
   Kreyling, Juergen
   Lanta, Vojtech
   Manning, Pete
   Meyer, Sebastian T.
   Mori, Akira S.
   Naeem, Shahid
   Niklaus, Pascal A.
   Polley, H. Wayne
   Reich, Peter B.
   Roscher, Christiane
   Seabloom, Eric W.
   Smith, Melinda D.
   Thakur, Madhav P.
   Tilman, David
   Tracy, Benjamin F.
   van der Putten, Wim H.
   van Ruijven, Jasper
   Weigelt, Alexandra
   Weisser, Wolfgang W.
   Wilsey, Brian
   Eisenhauer, Nico
TI Biodiversity increases the resistance of ecosystem productivity to climate extremes
SO NATURE
LA English
DT Article
ID grassland productivity; stability; diversity; community; drought; population; variability
AB It remains unclear whether biodiversity buffers ecosystems against climate extremes, which are becoming increasingly frequent worldwide(1). Early results suggested that the ecosystem productivity of diverse grassland plant communities was more resistant, changing less during drought, and more resilient, recovering more quickly after drought, than that of depauperate communities(2). However, subsequent experimental tests produced mixed results(3-13). Here we use data from 46 experiments that manipulated grassland plant diversity to test whether biodiversity provides resistance during and resilience after climate events. We show that biodiversity increased ecosystem resistance for a broad range of climate events, including wet or dry, moderate or extreme, and brief or prolonged events. Across all studies and climate events, the productivity of low-diversity communities with one or two species changed by approximately 50% during climate events, whereas that of high-diversity communities with 16-32 species was more resistant, changing by only approximately 25%. By a year after each climate event, ecosystem productivity had often fully recovered, or overshot, normal levels of productivity in both high-and low-diversity communities, leading to no detectable dependence of ecosystem resilience on biodiversity. Our results suggest that biodiversity mainly stabilizes ecosystem productivity, and productivity-dependent ecosystem services, by increasing resistance to climate events. Anthropogenic environmental changes that drive biodiversity loss thus seem likely to decrease ecosystem stability(14), and restoration of biodiversity to increase it, mainly by changing the resistance of ecosystem productivity to climate events.
C1 [Isbell, Forest; Seabloom, Eric W.; Tilman, David] Univ Minnesota Twin Cities, Dept Ecol Evolut & Behav, St Paul, MN 55108 USA.
   [Craven, Dylan; Bruelheide, Helge; Roscher, Christiane; Thakur, Madhav P.; Weigelt, Alexandra; Eisenhauer, Nico] German Ctr Integrat Biodivers Res iDiv, D-04103 Leipzig, Germany.
   [Craven, Dylan; Thakur, Madhav P.; Weigelt, Alexandra; Eisenhauer, Nico] Univ Leipzig, Inst Biol, D-04103 Leipzig, Germany.
   [Connolly, John] Natl Univ Ireland Univ Coll Dublin, Sch Math & Stat, Ecol & Environm Modelling Grp, Dublin 4, Ireland.
   [Loreau, Michel] CNRS, Expt Ecol Stn, Ctr Biodivers Theory & Modelling, F-09200 Moulis, France.
   [Schmid, Bernhard; de Luca, Enrica; Niklaus, Pascal A.] Univ Zurich, Inst Evolutionary Biol & Environm Studies, CH-8057 Zurich, Switzerland.
   [Beierkuhnlein, Carl] Univ Bayreuth, BayCEER, Dept Biogeog, D-95440 Bayreuth, Germany.
   [Bezemer, T. Martijn; van der Putten, Wim H.] Netherlands Inst Ecol NIOO KNAW, Dept Terr Ecol, NL-6700 AB Wageningen, Netherlands.
   [Bonin, Catherine] Iowa State Univ, Dept Agron, Ames, IA 50011 USA.
   [Bruelheide, Helge] Univ Halle Wittenberg, Inst Biol, D-06108 Halle, Germany.
   [Ebeling, Anne] Univ Jena, Inst Ecol, D-07743 Jena, Germany.
   [Griffin, John N.] Swansea Univ, Dept Biosci, Swansea SA2 8PP, W Glam, Wales.
   [Guo, Qinfeng] USDA FS, Eastern Forest Environm Threat Assessment Ctr, Res Triangle Pk, NC 27709 USA.
   [Hautier, Yann] Univ Utrecht, Dept Biol, Ecol & Biodivers Grp, NL-3584 CH Utrecht, Netherlands.
   [Hector, Andy] Univ Oxford, Dept Plant Sci, Oxford OX1 3RB, England.
   [Jentsch, Anke] Univ Bayreuth, BayCEER, Disturbance Ecol, D-95440 Bayreuth, Germany.
   [Kreyling, Juergen] Ernst Moritz Arndt Univ Greifswald, Inst Bot & Landscape Ecol, D-17487 Greifswald, Germany.
   [Lanta, Vojtech] Univ South Bohemia, Fac Sci, Dept Bot, Ceske Budejovice 37005, Czech Republic.
   [Manning, Pete] Univ Bern, Inst Plant Sci, CH-3013 Bern, Switzerland.
   [Meyer, Sebastian T.; Weisser, Wolfgang W.] Tech Univ Munich, Sch Life Sci Weihenstephan, Dept Ecol & Ecosyst Management, D-85354 Freising Weihenstephan, Germany.
   [Mori, Akira S.] Yokohama Natl Univ, Grad Sch Environm & Informat Sci, Yokohama, Kanagawa 2408501, Japan.
   [Naeem, Shahid] Columbia Univ, Dept Ecol Evolut & Environm Biol, New York, NY 10027 USA.
   [Polley, H. Wayne] USDA ARS, Grassland Soil & Water Res Lab, Temple, TX 76502 USA.
   [Reich, Peter B.] Univ Minnesota Twin Cities, Dept Forest Resources, St Paul, MN 55108 USA.
   [Roscher, Christiane] Univ Western Sydney, Hawkesbury Inst Environm, Penrith, NSW 2753, Australia.
   [Roscher, Christiane] UFZ Helmholtz Ctr Environm Res, Community Ecol, D-06120 Halle, Germany.
   [Smith, Melinda D.] Colorado State Univ, Grad Degree Program, Ft Collins, CO 80523 USA.
   [Smith, Melinda D.] Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA.
   [Tilman, David] Univ Calif Santa Barbara, Bren Sch Environm Sci & Management, Santa Barbara, CA 93106 USA.
   [Tracy, Benjamin F.] Virginia Tech, Crop & Soil Environm Sci, Blacksburg, VA 24061 USA.
   [van der Putten, Wim H.] Univ Wageningen & Res Ctr, Nematol Lab, NL-6700 ES Wageningen, Netherlands.
   [van Ruijven, Jasper] Wageningen Univ, Nat Conservat & Plant Ecol Grp, NL-6700 AA Wageningen, Netherlands.
   [Wilsey, Brian] Iowa State Univ, Dept Ecol Evolut & Organismal Biol, Ames, IA 50011 USA.
C3 University of Minnesota System; University of Minnesota Twin Cities; German Research Foundation (DFG); German Centre for Integrative Biodiversity Research (iDiv); Leipzig University; University College Dublin; Centre National de la Recherche Scientifique (CNRS); University of Zurich; University of Bayreuth; Royal Netherlands Academy of Arts & Sciences; Netherlands Institute of Ecology (NIOO-KNAW); Iowa State University; Martin Luther University Halle Wittenberg; Friedrich Schiller University of Jena; Swansea University; United States Department of Agriculture (USDA); United States Forest Service; Utrecht University; University of Oxford; University of Bayreuth; Universitat Greifswald; University of South Bohemia Ceske Budejovice; University of Bern; Technical University of Munich; Yokohama National University; Columbia University; United States Department of Agriculture (USDA); University of Minnesota System; University of Minnesota Twin Cities; Western Sydney University; Helmholtz Association; Helmholtz Center for Environmental Research (UFZ); Colorado State University System; Colorado State University Fort Collins; Colorado State University System; Colorado State University Fort Collins; University of California System; University of California Santa Barbara; Virginia Polytechnic Institute & State University; Wageningen University & Research; Wageningen University & Research; Iowa State University
RP Isbell, F (corresponding author), Univ Minnesota Twin Cities, Dept Ecol Evolut & Behav, St Paul, MN 55108 USA.
EM isbell@umn.edu
FU sDiv, the Synthesis Centre of the German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig [DFG FZT 118]; TULIP Laboratory of Excellence [ANR-10-LABX-41]; URPP Global Change and Biodiversity of the University of Zurich; Division Of Environmental Biology; Direct For Biological Sciences [1120064, 1242531] Funding Source: National Science Foundation; Division Of Environmental Biology; Direct For Biological Sciences [1234162] Funding Source: National Science Foundation
NR 30
TC 1306
Z9 1538
U1 136
U2 2840
PU NATURE PUBLISHING 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 22
PY 2015
VL 526
IS 7574
BP 574
EP U263
DI 10.1038/nature15374
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV1NX
UT WOS:000364026100050
PM 26466564
DA 2026-03-09
ER

PT J
AU Pruttivarasin, T
   Ramm, M
   Porsev, SG
   Tupitsyn, II
   Safronova, MS
   Hohensee, MA
   Häffner, H
AF Pruttivarasin, T.
   Ramm, M.
   Porsev, S. G.
   Tupitsyn, I. I.
   Safronova, M. S.
   Hohensee, M. A.
   Haeffner, H.
TI Michelson-Morley analogue for electrons using trapped ions to test Lorentz symmetry
SO NATURE
LA English
DT Article
ID inertial mass; invariance; violation; anisotropy; cpt
AB All evidence so far suggests that the absolute spatial orientation of an experiment never affects its outcome. This is reflected in the standard model of particle physics by requiring all particles and fields to be invariant under Lorentz transformations. The best-known tests of this important cornerstone of physics are Michelson-Morley-type experiments verifying the isotropy of the speed of light(1-3). For matter, Hughes-Drever-type experiments(4-11) test whether the kinetic energy of particles is independent of the direction of their velocity, that is, whether their dispersion relations are isotropic. To provide more guidance for physics beyond the standard model, refined experimental verifications of Lorentz symmetry are desirable. Here we search for violation of Lorentz symmetry for electrons by performing an electronic analogue of a Michelson-Morley experiment. We split an electron wave packet bound inside a calcium ion into two parts with different orientations and recombine them after a time evolution of 95 milliseconds. As the Earth rotates, the absolute spatial orientation of the two parts of the wave packet changes, and anisotropies in the electron dispersion will modify the phase of the interference signal. To remove noise, we prepare a pair of calcium ions in a superposition of two decoherence-free states, thereby rejecting magnetic field fluctuations common to both ions(12). After a 23-hour measurement, we find a limit of h x 11 millihertz (h is Planck's constant) on the energy variations, verifying the isotropy of the electron's dispersion relation at the level of one part in 10(18), a 100-fold improvement on previous work(9). Alternatively, we can interpret our result as testing the rotational invariance of the Coulomb potential. Assuming that Lorentz symmetry holds for electrons and that the photon dispersion relation governs the Coulomb force, we obtain a fivefold-improved limit on anisotropies in the speed of light(2,3). Our result probes Lorentz symmetry violation at levels comparable to the ratio between the electroweak and Planck energy scales(13). Our experiment demonstrates the potential of quantum information techniques in the search for physics beyond the standard model.
C1 [Pruttivarasin, T.; Ramm, M.; Hohensee, M. A.; Haeffner, H.] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
   [Pruttivarasin, T.] RIKEN, Quantum Metrol Lab, Wako, Saitama 3510198, Japan.
   [Porsev, S. G.; Safronova, M. S.] Univ Delaware, Dept Phys & Astron, Newark, DC 19716 USA.
   [Porsev, S. G.] Petersburg Nucl Phys Inst, Gatchina 188300, Leningrad Distr, Russia.
   [Tupitsyn, I. I.] St Petersburg State Univ, Dept Phys, St Petersburg 198504, Russia.
   [Safronova, M. S.] NIST, Joint Quantum Inst, College Pk, MD 20742 USA.
   [Safronova, M. S.] Univ Maryland, College Pk, MD 20742 USA.
   [Hohensee, M. A.] Lawrence Livermore Natl Lab, Livermore, CA 94550 USA.
C3 University of California System; University of California Berkeley; RIKEN; University of Delaware; National Research Centre - Kurchatov Institute; Petersburg Nuclear Physics Institute; Saint Petersburg State University; National Institute of Standards & Technology (NIST) - USA; University System of Maryland; University of Maryland College Park; United States Department of Energy (DOE); Lawrence Livermore National Laboratory
RP Pruttivarasin, T (corresponding author), Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.
EM thaned.pruttivarasin@riken.jp; hhaeffner@berkeley.edu
FU NSF CAREER programme grant [PHY 0955650]; NSF [PHY 1212442, PHY 1404156]; US Department of Energy, Lawrence Livermore National Laboratory [DE-AC52-07NA27344]; Direct For Mathematical & Physical Scien; Division Of Physics [0955650, 1404156] Funding Source: National Science Foundation; Direct For Mathematical & Physical Scien; Division Of Physics [1212442] Funding Source: National Science Foundation
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   Altschul B, 2010, PHYS REV D, V81, P0, DOI 10.1103/PhysRevD.81.041701
   Bailey QG, 2004, PHYS REV D, V70, P0, DOI 10.1103/PhysRevD.70.076006
   Chou CW, 2010, SCIENCE, V329, P1630, DOI 10.1126/science.1192720
   Chwalla M, 2007, APPL PHYS B-LASERS O, V89, P483, DOI 10.1007/s00340-007-2867-4
   Colladay D, 1998, PHYS REV D, V58, P0, DOI 10.1103/PhysRevD.58.116002
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   Herrmann S, 2009, PHYS REV D, V80, P0, DOI 10.1103/PhysRevD.80.105011
   Hohensee MA, 2013, PHYS REV LETT, V111, P0, DOI 10.1103/PhysRevLett.111.050401
   Horava P, 2009, PHYS REV D, V79, P0, DOI 10.1103/PhysRevD.79.084008
   HUGHES VW, 1960, PHYS REV LETT, V4, P342, DOI 10.1103/PhysRevLett.4.342
   Iskrenova-Tchoukova E, 2008, PHYS REV A, V78, P0, DOI 10.1103/PhysRevA.78.012508
   Jiang DS, 2008, PHYS REV A, V78, P0, DOI 10.1103/PhysRevA.78.022514
   Kostelecky VA, 2011, REV MOD PHYS, V83, P0, DOI 10.1103/RevModPhys.83.11
   Kostelecky VA, 2002, PHYS REV D, V66, P0, DOI 10.1103/PhysRevD.66.056005
   KOSTELECKY VA, 1989, PHYS REV D, V39, P683, DOI 10.1103/PhysRevD.39.683
   Kostelecky VA, 1999, PHYS REV D, V60, P0, DOI 10.1103/PhysRevD.60.116010
   KOSTELECKY VA, 1995, PHYS REV D, V51, P3923, DOI 10.1103/PhysRevD.51.3923
   Kramida A, 2013, NIST ATOMIC SPECTRA DATABASE, V0, P0
   Kreuter A, 2005, PHYS REV A, V71, P0, DOI 10.1103/PhysRevA.71.032504
   Liberati S, 2012, PREPRINT, V0, P0
   Madej AA, 2012, PHYS REV LETT, V109, P0, DOI 10.1103/PhysRevLett.109.203002
   Matveev A, 2013, PHYS REV LETT, V110, P0, DOI 10.1103/PhysRevLett.110.230801
   Michelson AA, 1887, AM J SCI, Vs3-34, P333, DOI 10.2475/AJS.S3-34.203.333
   Müller H, 2005, PHYS REV D, V71, P0, DOI 10.1103/PhysRevD.71.045004
   Müller H, 2003, PHYS REV D, V68, P0, DOI 10.1103/PhysRevD.68.116006
   Nibbelink SG, 2005, PHYS REV LETT, V94, P0, DOI 10.1103/PhysRevLett.94.081601
   Peck SK, 2012, PHYS REV A, V86, P0, DOI 10.1103/PhysRevA.86.012109
   Pospelov M, 2012, PHYS REV D, V85, P0, DOI 10.1103/PhysRevD.85.105001
   Roos CF, 2006, NATURE, V443, P316, DOI 10.1038/nature05101
   Safronova MS, 2008, ADV ATOM MOL OPT PHY, V55, P191, DOI 10.1016/S1049-250X(07)55004-4
   Safronova MS, 2014, PHYS REV LETT, V113, P0, DOI 10.1103/PhysRevLett.113.030801
   Smiciklas M, 2011, PHYS REV LETT, V107, P0, DOI 10.1103/PhysRevLett.107.171604
   Tupitsyn II, 2010, PHYS REV A, V82, P0, DOI 10.1103/PhysRevA.82.042701
   Tupitsyn II, 2005, PHYS REV A, V72, P0, DOI 10.1103/PhysRevA.72.062503
   Wolf P, 2006, PHYS REV LETT, V96, P0, DOI 10.1103/PhysRevLett.96.060801
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NR 41
TC 97
Z9 108
U1 0
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 JAN 29
PY 2015
VL 517
IS 7536
BP 592
EP U357
DI 10.1038/nature14091
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA2ZL
UT WOS:000348775000038
PM 25631446
DA 2026-03-09
ER

PT J
AU Schoch, RR
   Sues, HD
AF Schoch, Rainer R.
   Sues, Hans-Dieter
TI A Middle Triassic stem-turtle and the evolution of the turtle body plan
SO NATURE
LA English
DT Article
ID shell; origin; phylogeny; elements; bone
AB The origin and early evolution of turtles have long been major contentious issues in vertebrate zoology(1-11). This is due to conflicting character evidence from molecules and morphology and a lack of transitional fossils from the critical time interval. The similar to 220-million-year-old stem-turtle Odontochelys from China(12) has a partly formed shell and many turtle-like features in its post-cranial skeleton. Unlike the 214-million-year-old Proganochelys from Germany and Thailand, it retains marginal teeth and lacks a carapace. Odontochelys is separated by a large temporal gap from the similar to 260-million-year-old Eunotosaurus from South Africa, which has been hypothesized as the earliest stem-turtle(4,5). Here we report a new reptile, Pappochelys, that is structurally and chronologically intermediate between Eunotosaurus and Odontochelys and dates from the Middle Triassic period (similar to 240 million years ago). The three taxa share anteroposteriorly broad trunk ribs that are T-shaped in cross-section and bear sculpturing, elongate dorsal vertebrae, and modified limb girdles. Pappochelys closely resembles Odontochelys in various features of the limb girdles. Unlike Odontochelys, it has a cuirass of robust paired gastralia in place of a plastron. Pappochelys provides new evidence that the plastron partly formed through serial fusion of gastralia(3,13). Its skull has small upper and ventrally open lower temporal fenestrae, supporting the hypothesis of diapsid affinities of turtles(2,7-10,14,15).
C1 [Schoch, Rainer R.] Staatliches Museum Nat Kunde Stuttgart, Rosenstein 1, D-70191 Stuttgart, Germany.
   [Sues, Hans-Dieter] Natl Museum Nat Hist, Dept Paleobiol, Washington, DC 20013 USA.
C3 Smithsonian Institution; Smithsonian National Museum of Natural History
RP Schoch, RR (corresponding author), Staatliches Museum Nat Kunde Stuttgart, Rosenstein 1, D-70191 Stuttgart, Germany.
EM rainer.schoch@smns-bw.de; suesh@si.edu
NR 25
TC 131
Z9 151
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 JUL 30
PY 2015
VL 523
IS 7562
BP 584
EP +
DI 10.1038/nature14472
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN7ZL
UT WOS:000358655200043
PM 26106865
DA 2026-03-09
ER

PT J
AU Schur, FKM
   Hagen, WJH
   Rumlová, M
   Ruml, T
   Müller, B
   Kräusslich, HG
   Briggs, JAG
AF Schur, Florian K. M.
   Hagen, Wim J. H.
   Rumlova, Michaela
   Ruml, Tomas
   Mueller, Barbara
   Kraeusslich, Hans-Georg
   Briggs, John A. G.
TI Structure of the immature HIV-1 capsid in intact virus particles at 8.8 Å resolution
SO NATURE
LA English
DT Article
ID major homology region; type-1 gag precursor; n-terminal domain; cryoelectron microscopy; molecular-dynamics; helical structure; in-situ; protein; tomography; visualization
AB Human immunodeficiency virus type 1 (HIV-1) assembly proceeds in two stages. First, the 55 kilodalton viral Gag polyprotein assembles into a hexameric protein lattice at the plasma membrane of the infected cell, inducing budding and release of an immature particle. Second, Gag is cleaved by the viral protease, leading to internal rearrangement of the virus into the mature, infectious form(1). Immature and mature HIV-1 particles are heterogeneous in size and morphology, preventing high-resolution analysis of their protein arrangement in situ by conventional structural biology methods. Here we apply cryo-electron tomography and sub -tomogram averaging methods to resolve the structure of the capsid lattice within intact immature HIV-1 particles at subnanometre resolution, allowing unambiguous positioning of all alpha-helices. The resulting model reveals tertiary and quaternary structural interactions that mediate HIV-1 assembly. Strikingly, these interactions differ from those predicted by the current model based on in vitro-assembled arrays of Gag-derived proteins from Mason-Pfizer monkey virus(2). To validate this difference, we solve the structure of the capsid lattice within intact immature Mason-Pfizer monkey virus particles. Comparison with the immature HIV-1 structure reveals that retroviral capsid proteins, while having conserved tertiary structures, adopt different quaternary arrangements during virus assembly. The approach demonstrated here should be applicable to determine structures of other proteins at subnanometre resolution within heterogeneous environments.
C1 [Schur, Florian K. M.; Hagen, Wim J. H.; Briggs, John A. G.] European Mol Biol Lab, Struct & Computat Biol Unit, D-69117 Heidelberg, Germany.
   [Schur, Florian K. M.; Mueller, Barbara; Kraeusslich, Hans-Georg; Briggs, John A. G.] Univ Klinikum Heidelberg, European Mol Biol Lab, Mol Med Partnership Unit, Heidelberg, Germany.
   [Rumlova, Michaela] Acad Sci Czech Republic, Inst Organ Chem & Biochem, Vvi, CR-16610 Prague, Czech Republic.
   [Rumlova, Michaela] Gilead Res Ctr, Prague 16610, Czech Republic.
   [Rumlova, Michaela] Inst Chem Technol, Dept Biotechnol, CR-16628 Prague, Czech Republic.
   [Ruml, Tomas] Inst Chem Technol, Dept Biochem & Microbiol, CR-16628 Prague, Czech Republic.
   [Mueller, Barbara; Kraeusslich, Hans-Georg] Univ Klinikum Heidelberg, Dept Infect Dis, D-69120 Heidelberg, Germany.
C3 European Molecular Biology Laboratory (EMBL); Ruprecht Karls University Heidelberg; European Molecular Biology Laboratory (EMBL); Czech Academy of Sciences; Institute of Organic Chemistry & Biochemistry of the Czech Academy of Sciences; University of Chemistry & Technology, Prague; University of Chemistry & Technology, Prague; Ruprecht Karls University Heidelberg
RP Briggs, JAG (corresponding author), European Mol Biol Lab, Struct & Computat Biol Unit, Meyerhofstr 1, D-69117 Heidelberg, Germany.
EM john.briggs@embl.de
FU Deutsche Forschungsgemeinschaft [BR 3635/2-1, KR 906/7-1]; Grant Agency of the Czech Republic [14-15326S]; European Molecular Biology Laboratory; Chica und Heinz Schaller Stiftung
NR 46
TC 251
Z9 299
U1 1
U2 173
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 22
PY 2015
VL 517
IS 7535
BP 505
EP 508
DI 10.1038/nature13838
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AZ4MU
UT WOS:000348196500039
PM 25363765
DA 2026-03-09
ER

PT J
AU Chen, LY
   Xu, JQ
   Choi, H
   Pozuelo, M
   Ma, XL
   Bhowmick, S
   Yang, JM
   Mathaudhu, S
   Li, XC
AF Chen, Lian-Yi
   Xu, Jia-Quan
   Choi, Hongseok
   Pozuelo, Marta
   Ma, Xiaolong
   Bhowmick, Sanjit
   Yang, Jenn-Ming
   Mathaudhu, Suveen
   Li, Xiao-Chun
TI Processing and properties of magnesium containing a dense uniform dispersion of nanoparticles
SO NATURE
LA English
DT Article
ID metal-matrix nanocomposites; deformation-behavior; grain-size; strength; mg; alloys; particles; route; steel
AB Magnesium is a light metal, with a density two-thirds that of aluminium, is abundant on Earth and is biocompatible; it thus has the potential to improve energy efficiency and system performance in aerospace, automobile, defence, mobile electronics and biomedical applications(1-5). However, conventional synthesis and processing methods (alloying and thermomechanical processing) have reached certain limits in further improving the properties of magnesium and other metals(6). Ceramic particles have been introduced into metal matrices to improve the strength of the metals(7), but unfortunately, ceramic microparticles severely degrade the plasticity and machinability of metals(7), and nanoparticles, although they have the potential to improve strength while maintaining or even improving the plasticity of metals(8,9), are difficult to disperse uniformly in metal matrices(10-14). Here we show that a dense uniform dispersion of silicon carbide nanoparticles (14 per cent by volume) in magnesium can be achieved through a nanoparticle self-stabilization mechanism in molten metal. An enhancement of strength, stiffness, plasticity and high-temperature stability is simultaneously achieved, delivering a higher specific yield strength and higher specific modulus than almost all structural metals.
C1 [Chen, Lian-Yi; Li, Xiao-Chun] Univ Calif Los Angeles, Dept Mech & Aerosp Engn, Scifacturing Lab, Los Angeles, CA 90095 USA.
   [Chen, Lian-Yi; Xu, Jia-Quan; Pozuelo, Marta; Yang, Jenn-Ming; Li, Xiao-Chun] Univ Calif Los Angeles, Dept Mat Sci & Engn, Los Angeles, CA 90095 USA.
   [Chen, Lian-Yi] Missouri Univ Sci & Technol, Dept Mech & Aerosp Engn, Rolla, MO 65409 USA.
   [Choi, Hongseok] Clemson Univ, Dept Mech Engn, Clemson, SC 29634 USA.
   [Ma, Xiaolong] N Carolina State Univ, Dept Mat Sci & Engn, Raleigh, NC 27695 USA.
   [Bhowmick, Sanjit] Hysitron Inc, Minneapolis, MN 55344 USA.
   [Mathaudhu, Suveen] Univ Calif Riverside, Dept Mech Engn, Riverside, CA 92521 USA.
C3 University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of Missouri System; Missouri University of Science & Technology; Clemson University; North Carolina State University; Hysitron, Inc.; University of California System; University of California Riverside
RP Li, XC (corresponding author), Univ Calif Los Angeles, Dept Mech & Aerosp Engn, Scifacturing Lab, Los Angeles, CA 90095 USA.
EM xcli@seas.ucla.edu
FU National Institute of Standards and Technology (NIST)
NR 45
TC 713
Z9 802
U1 30
U2 884
PU NATURE PUBLISHING 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 24
PY 2015
VL 528
IS 7583
BP 539
EP +
DI 10.1038/nature16445
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CZ3GH
UT WOS:000366991900049
PM 26701055
DA 2026-03-09
ER

PT J
AU Sounier, R
   Mas, C
   Steyaert, J
   Laeremans, T
   Manglik, A
   Huang, WJ
   Kobilka, BK
   Déméné, H
   Granier, S
AF Sounier, Remy
   Mas, Camille
   Steyaert, Jan
   Laeremans, Toon
   Manglik, Aashish
   Huang, Weijiao
   Kobilka, Brian K.
   Demene, Helene
   Granier, Sebastien
TI Propagation of conformational changes during μ-opioid receptor activation
SO NATURE
LA English
DT Article
ID protein-coupled receptor; beta(2)-adrenergic receptor; crystal-structure; nmr-spectroscopy; dynamic process; analgesia; efficacy; rhodopsin; agonist; complex
AB mu-Opioid receptors (mu ORs) are G-protein-coupled receptors that are activated by a structurally diverse spectrum of natural and synthetic agonists including endogenous endorphin peptides, morphine and methadone. The recent structures of the mu OR in inactive(1) and agonist-induced active states (Huang et al., ref. 2) provide snapshots of the receptor at the beginning and end of a signalling event, but little is known about the dynamic sequence of events that span these two states. Here we use solution-state NMR to examine the process of mu OR activation using a purified receptor (mouse sequence) preparation in an amphiphile membrane-like environment. We obtain spectra of the mu OR in the absence of ligand, and in the presence of the high-affinity agonist BU72 alone, or with BU72 and a G protein mimetic nanobody. Our results show that conformational changes in transmembrane segments 5 and 6 (TM5 and TM6), which are required for the full engagement of a G protein, are almost completely dependent on the presence of both the agonist and the G protein mimetic nanobody, revealing a weak allosteric coupling between the agonist-binding pocket and the G-protein-coupling interface (TM5 and TM6), similar to that observed for the beta 2-adrenergic receptor(3). Unexpectedly, in the presence of agonist alone, we find larger spectral changes involving intracellular loop 1 and helix 8 compared to changes in TM5 and TM6. These results suggest that one or both of these domains may play a role in the initial interaction with the G protein, and that TM5 and TM6 are only engaged later in the process of complex formation. The initial interactions between the G protein and intracellular loop 1 and/or helix 8 may be involved in G-protein coupling specificity, as has been suggested for other family A G-protein-coupled receptors.
C1 [Sounier, Remy; Mas, Camille; Granier, Sebastien] Univ Montpellier, Inst Genom Fonct, CNRS, INSERM,U1191,UMR 5203, F-34000 Montpellier, France.
   [Steyaert, Jan; Laeremans, Toon] Vrije Univ Brussel, Struct Biol Brussels, B-1050 Brussels, Belgium.
   [Steyaert, Jan; Laeremans, Toon] VIB, Struct Biol Res Ctr, B-1050 Brussels, Belgium.
   [Manglik, Aashish; Huang, Weijiao; Kobilka, Brian K.] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
   [Demene, Helene] Univ Montpellier, Ctr Biochim Struct, CNRS, INSERM 1054,UMR 5048, F-34090 Montpellier, France.
C3 Universite de Montpellier; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Vrije Universiteit Brussel; Flanders Institute for Biotechnology (VIB); Stanford University; 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)
RP Granier, S (corresponding author), Univ Montpellier, Inst Genom Fonct, CNRS, INSERM,U1191,UMR 5203, F-34000 Montpellier, France.
EM helene@cbs.cnrs.fr; sebastien.granier@igf.cnrs.fr
FU INSERM; CNRS; National Institutes of Health [NIDA-DA036246]
NR 28
TC 212
Z9 242
U1 0
U2 149
PU NATURE PUBLISHING 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 20
PY 2015
VL 524
IS 7565
BP 375
EP +
DI 10.1038/nature14680
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP2NN
UT WOS:000359714000041
PM 26245377
DA 2026-03-09
ER

PT J
AU Johnson, BC
   Minton, DA
   Melosh, HJ
   Zuber, MT
AF Johnson, Brandon C.
   Minton, David A.
   Melosh, H. J.
   Zuber, Maria T.
TI Impact jetting as the origin of chondrules
SO NATURE
LA English
DT Article
ID early solar-system; relative velocity; protoplanetary disk; chondrites; planetesimals; accretion; simulations; constraints; particles; model
AB Chondrules are the millimetre-scale, previously molten, spherules found in most meteorites(1). Before chondrules formed, large differentiating planetesimals had already accreted(2). Volatile-rich olivine reveals that chondrules formed inextremely solid-rich environments, more like impact plumes than the solar nebula(3-5). The unique chondrules in CB chondrites probably formed in a vapour-melt plume produced by a hypervelocity impact(6) with an impact velocity greater than 10 kilometres per second. An acceptable formation model for the overwhelming majority of chondrules, however, has not been established. Here we report that impacts can produce enough chondrules during the first five million years of planetary accretion to explain their observed abundance. Building on a previous study of impact jetting(7), we simulate protoplanetary impacts, finding that material is melted and ejected at high speed when the impact velocity exceeds 2.5 kilometres per second. Using a Monte Carlo accretion code, we estimate the location, timing, sizes, and velocities of chondrule-formingimpacts. Ejecta size estimates(8) indicate that jetted melt will form millimetre-scale droplets. Our radiative transfermodels show that these droplets experience the expected cooling rates of ten to a thousand kelvin per hour(9,10). An impact origin for chondrules implies that meteorites are a byproduct of planet formation rather than leftover building material.
C1 [Johnson, Brandon C.; Zuber, Maria T.] MIT, Dept Earth Atmospher & Planetary Sci, Cambridge, MA 02139 USA.
   [Minton, David A.; Melosh, H. J.] Purdue Univ, Dept Earth Atmospher & Planetary Sci, W Lafayette, IN 47907 USA.
C3 Massachusetts Institute of Technology (MIT); Purdue University System; Purdue University
RP Johnson, BC (corresponding author), MIT, Dept Earth Atmospher & Planetary Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
EM brcjohns@mit.edu
FU NASA [PGG NNX10AU88G]
NR 47
TC 162
Z9 182
U1 2
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 JAN 15
PY 2015
VL 517
IS 7534
BP 339
EP U421
DI 10.1038/nature14105
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300039
PM 25592538
DA 2026-03-09
ER

PT J
AU Park, SY
   Yang, JS
   Schmider, AB
   Soberman, RJ
   Hsu, VW
AF Park, Seung-Yeol
   Yang, Jia-Shu
   Schmider, Angela B.
   Soberman, Roy J.
   Hsu, Victor W.
TI Coordinated regulation of bidirectional COPI transport at the Golgi by CDC42
SO NATURE
LA English
DT Article
ID cisternal maturation; membrane curvature; vesicle formation; arfgap1 promotes; apparatus; complex; yeast
AB The Golgi complex has a central role in the intracellular sorting of secretory proteins(1,2). Anterograde transport through the Golgi has been explained by the movement of Golgi cisternae, known as cisternal maturation(3-5). Because this explanation is now appreciated to be incomplete(6), interest has developed in understanding tubules that connect the Golgi cisternae(7-9). Here we show that the coat protein (COPI) complex sorts anterograde cargoes into these tubules in human cells. Moreover, the small GTPase CDC42 regulates bidirectional Golgi transport by targeting the dual functions of COPI in cargo sorting and carrier formation. CDC42 also directly imparts membrane curvature to promote COPI tubule formation. Our findings further reveal that COPI tubular transport complements cisternal maturation in explaining how anterograde Golgi transport is achieved, and that bidirectional COPI transport is modulated by environmental cues through CDC42.
C1 [Park, Seung-Yeol; Yang, Jia-Shu; Hsu, Victor W.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA.
   [Park, Seung-Yeol; Yang, Jia-Shu; Schmider, Angela B.; Soberman, Roy J.; Hsu, Victor W.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.
   [Schmider, Angela B.; Soberman, Roy J.] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA 02129 USA.
   [Schmider, Angela B.; Soberman, Roy J.] Massachusetts Gen Hosp, Dept Med, Charlestown, MA 02129 USA.
   [Soberman, Roy J.] Massachusetts Gen Hosp, Mol Imaging Core, Charlestown, MA 02129 USA.
C3 Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; 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
RP Hsu, VW (corresponding author), Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, 75 Francis St, Boston, MA 02115 USA.
EM vhsu@research.bwh.harvard.edu
FU National Institutes of Health [R01GM058615, R01AI068871, R01AR065538, 1S10RR027931-01, K01DK089145]; National Research Foundation of Korea [2014R1A6A3A03056673]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR065538] Funding Source: NIH RePORTER
NR 24
TC 73
Z9 88
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 MAY 28
PY 2015
VL 521
IS 7553
BP 529
EP U257
DI 10.1038/nature14457
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ2AN
UT WOS:000355286600045
PM 25945738
DA 2026-03-09
ER

PT J
AU You, HZ
   Rideau, E
   Sidera, M
   Fletcher, SP
AF You, Hengzhi
   Rideau, Emeline
   Sidera, Mireia
   Fletcher, Stephen P.
TI Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation
SO NATURE
LA English
DT Article
ID conjugate addition; substitution-reactions; grignard-reagents; acid; identification; resolution; ligands
AB The development of new reactions forming asymmetric carbon-carbon bonds has enabled chemists to synthesize a broad range of important carbon-containing molecules, including pharmaceutical agents, fragrances and polymers(1). Most strategies to obtain enantiomerically enriched molecules rely on either generating new stereogenic centres from prochiral substrates or resolving racemic mixtures of enantiomers. An alternative strategy dynamic kinetic asymmetric transformation involves the transformation of a racemic starting material into a single enantiomer product, with greater than 50 per cent maximum yield(2,3). The use of stabilized nudeophiles (pK(a) < 25, where K-a is the acid dissociation constant) in palladium-catalysed asymmetric allylic alkylation reactions has proved to be extremely versatile in these processes(4,5). Conversely, the use of non-stabilized nudeophiles in such reactions is difficult and remains a key challenge'. Here we report a copper-catalysed dynamic kinetic asymmetric transformation using racemic substrates and alkyl nudeophiles. These nudeophiles have a pK(a) of >= 50, more than 25 orders of magnitude more basic than the nudeophiles that are typically used in such transformations. Organometallic reagents are generated in situ from alkenes by hydrometallation and give highly enantioenriched products under mild reaction conditions. The method is used to synthesize natural products that possess activity against tuberculosis and leprosy, and an inhibitor of para-aminobenzoate biosynthesis. Mechanistic studies indicate that the reaction proceeds through a rapidly isomerizing intermediate. We anticipate that this approach will be a valuable complement to existing asymmetric catalytic methods.
C1 [You, Hengzhi; Rideau, Emeline; Sidera, Mireia; Fletcher, Stephen P.] Univ Oxford, Dept Chem, Chem Res Lab, Oxford OX1 3TA, England.
C3 University of Oxford
RP Fletcher, SP (corresponding author), Univ Oxford, Dept Chem, Chem Res Lab, 12 Mansfield Rd, Oxford OX1 3TA, England.
EM stephen.fletcher@chem.ox.ac.uk
FU EPSRC [EP/H003711/1]; EPSRC [EP/H003711/1] Funding Source: UKRI; Engineering and Physical Sciences Research Council [EP/H003711/1] Funding Source: researchfish
NR 30
TC 106
Z9 111
U1 2
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 JAN 15
PY 2015
VL 517
IS 7534
BP 351
EP 355
DI 10.1038/nature14089
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300042
PM 25592541
DA 2026-03-09
ER

PT J
AU Saunders, A
   Oldenburg, IA
   Berezovskii, VK
   Johnson, CA
   Kingery, ND
   Elliott, HL
   Xie, T
   Gerfen, CR
   Sabatini, BL
AF Saunders, Arpiar
   Oldenburg, Ian A.
   Berezovskii, Vladimir K.
   Johnson, Caroline A.
   Kingery, Nathan D.
   Elliott, Hunter L.
   Xie, Tiao
   Gerfen, Charles R.
   Sabatini, Bernardo L.
TI A direct GABAergic output from the basal ganglia to frontal cortex
SO NATURE
LA English
DT Article
ID green fluorescent protein; globus-pallidus; cholinergic neurons; indirect pathways; cre-recombinase; nucleus basalis; driver lines; schizophrenia; forebrain; rat
AB The basal ganglia are phylogenetically conserved subcortical nuclei necessary for coordinated motor action and reward learning(1). Current models postulate that the basal ganglia modulate cerebral cortex indirectly via an inhibitory output to thalamus, bidirectionally controlled by direct-and indirect-pathway striatal projection neurons (dSPNs and iSPNs, respectively)(2-4). The basal ganglia thalamic output sculpts cortical activity by interacting with signals from sensory and motor systems(5). Here we describe a direct projection from the globus pallidus externus (GP), a central nucleus of the basal ganglia, to frontal regions of the cerebral cortex (FC). Two cell types make up the GP-FC projection, distinguished by their electrophysiological properties, cortical projections and expression of choline acetyltransferase (ChAT), a synthetic enzyme for the neurotransmitter acetylcholine (ACh). Despite these differences, ChAT(+) cells, which have been historically identified as an extension of the nucleus basalis, as well asChAT(-) cells, release the inhibitory neurotransmitter GABA (c-aminobutyric acid) and are inhibited by iSPNs and dSPNs of dorsal striatum. Thus, GP-FC cells comprise a direct GABAergic/cholinergic projection under the control of striatum that activates frontal cortex in vivo. Furthermore, iSPN inhibition of GP-FC cells is sensitive to dopamine 2 receptor signalling, revealing a pathway by which drugs that target dopamine receptors for the treatment of neuropsychiatric disorders can act in the basal ganglia to modulate frontal cortices.
C1 [Saunders, Arpiar; Oldenburg, Ian A.; Berezovskii, Vladimir K.; Johnson, Caroline A.; Sabatini, Bernardo L.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Neurobiol, Boston, MA 02115 USA.
   [Kingery, Nathan D.] Harvard Univ, Sch Med, Dept Neurobiol, Neurobiol Imaging Facil, Boston, MA 02115 USA.
   [Elliott, Hunter L.; Xie, Tiao] Harvard Univ, Sch Med, Image & Data Anal Core, Boston, MA 02115 USA.
   [Gerfen, Charles R.] NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA.
C3 Howard Hughes Medical Institute; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH)
RP Sabatini, BL (corresponding author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Neurobiol, 220 Longwood Ave, Boston, MA 02115 USA.
EM bsabatini@hms.harvard.edu
FU National Institutes of Health [F31 NS074842, F31-MH093026-01A1, P30 EY12196]; NINDS P30 Core Center grant [NS072030]; NIH [R01 NS046579]; National Eye Institute [P30EY002520, P30EY012196] Funding Source: NIH RePORTER; National Institute of Mental Health [ZIAMH002497] Funding Source: NIH RePORTER
NR 44
TC 232
Z9 282
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 MAY 7
PY 2015
VL 521
IS 7550
BP 85
EP U193
DI 10.1038/nature14179
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH4YS
UT WOS:000354040900038
PM 25739505
DA 2026-03-09
ER

PT J
AU Tombesi, F
   Meléndez, M
   Veilleux, S
   Reeves, JN
   González-Alfonso, E
   Reynolds, CS
AF Tombesi, F.
   Melendez, M.
   Veilleux, S.
   Reeves, J. N.
   Gonzalez-Alfonso, E.
   Reynolds, C. S.
TI Wind from the black-hole accretion disk driving a molecular outflow in an active galaxy
SO NATURE
LA English
DT Article
ID quasar feedback; x-ray; local ulirgs; agn; mergers; driven; energy
AB Powerful winds driven by active galactic nuclei are often thought to affect the evolution of both supermassive black holes and their host galaxies, quenching star formation and explaining the close relationship between black holes and galaxies(1,2). Recent observations of large-scale molecular outflows(3-8) in ultraluminous infrared galaxies support this quasar-feedback idea, because they directly trace the gas from which stars form. Theoreticalmodels(9-12) suggest that these outflows originate as energy-conserving flows driven by fast accretion-disk winds. Proposed connections between large-scale molecular outflows and accretion-disk activity in ultraluminous galaxies were incomplete(3-8) because no accretion-disk wind had been detected. Conversely, studies of powerful accretion-disk wind shave until now focused only on X-ray observations of local Seyfert galaxies(13,14) and a few higher-redshift quasars(15-19). Here we report observations of a powerful accretion-disk wind with a mildly relativistic velocity (a quarter that of light) in the X-ray spectrum of IRAS F11119+3257, a nearby (redshift 0.189) optically classified type 1 ultraluminous infrared galaxy hosting a powerful molecular outflow(6). The active galactic nucleus is responsible for about 80 per cent of the emission, with a quasar-like luminosity(6) of 1.5 x 10(46) ergs per second. The energetics of these two types of wide-angle outflows is consistent with the energy-conserving mechanism(9-12) that is the basis of the quasar feedback(1) in active galactic nuclei that lack powerful radio jets (such jets are an alternative way to drive molecular outflows).
C1 [Tombesi, F.] NASA, Goddard Space Flight Ctr, Xray Astrophys Lab, Greenbelt, MD 20771 USA.
   [Tombesi, F.; Melendez, M.; Veilleux, S.; Reynolds, C. S.] Univ Maryland, Dept Astron, College Pk, MD 20742 USA.
   [Tombesi, F.; Melendez, M.; Veilleux, S.; Reynolds, C. S.] Univ Maryland, CRESST, College Pk, MD 20742 USA.
   [Veilleux, S.; Reynolds, C. S.] Univ Maryland, Joint Space Sci Inst, College Pk, MD 20742 USA.
   [Reeves, J. N.] Keele Univ, Sch Phys & Geog Sci, Astrophys Grp, Keele ST5 5BG, Staffs, England.
   [Reeves, J. N.] Univ Maryland Baltimore Cty, Ctr Space Sci & Technol, Baltimore, MD 21250 USA.
   [Gonzalez-Alfonso, E.] Univ Alcala, Dept Fis & Matemat, E-28871 Madrid, Spain.
C3 National Aeronautics & Space Administration (NASA); NASA Goddard Space Flight Center; University System of Maryland; University of Maryland College Park; University System of Maryland; University of Maryland College Park; University System of Maryland; University of Maryland College Park; Keele University; University System of Maryland; University of Maryland Baltimore County; Universidad de Alcala
RP Tombesi, F (corresponding author), NASA, Goddard Space Flight Ctr, Xray Astrophys Lab, Greenbelt, MD 20771 USA.
EM ftombesi@astro.umd.edu
FU NASA [NNX12AH40G, NHSC/JPL RSA 1427277, 1454738, NNX14AF86G]; STFC; Spanish Ministerio de Economia y Competitividad [AYA2010-21697-C05-0, FIS2012-39162-C06-01]; US National Science Foundation [AST1333514];  [NSF-AST1009583]; NASA [19722, NNX12AH40G, 684363, NNX14AF86G] Funding Source: Federal RePORTER; Division Of Astronomical Sciences; Direct For Mathematical & Physical Scien [1333360, 1333514, 1332858] Funding Source: National Science Foundation
NR 35
TC 326
Z9 348
U1 0
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 MAR 26
PY 2015
VL 519
IS 7544
BP 436
EP +
DI 10.1038/nature14261
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE1WF
UT WOS:000351602800048
PM 25810204
DA 2026-03-09
ER

PT J
AU Pemovska, T
   Johnson, E
   Kontro, M
   Repasky, GA
   Chen, J
   Wells, P
   Cronin, CN
   McTigue, M
   Kallioniemi, O
   Porkka, K
   Murray, BW
   Wennerberg, K
AF Pemovska, Tea
   Johnson, Eric
   Kontro, Mika
   Repasky, Gretchen A.
   Chen, Jeffrey
   Wells, Peter
   Cronin, Ciaran N.
   McTigue, Michele
   Kallioniemi, Olli
   Porkka, Kimmo
   Murray, Brion W.
   Wennerberg, Krister
TI Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation
SO NATURE
LA English
DT Article
ID chronic myeloid-leukemia; patients receiving imatinib; bcr-abl inhibitor; tyrosine kinase; t315i mutant; follow-up; mechanism; cells; resistance; ponatinib
AB The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia(1). Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival(2), but acquired drug resistance remains a challenge(3-5). Point mutations in the ABL1 kinase domain weaken inhibitor binding(6) and represent the most common clinical resistance mechanism. The BCR-ABLI kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib(7,8), which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1 (T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.
C1 [Pemovska, Tea; Repasky, Gretchen A.; Kallioniemi, Olli; Wennerberg, Krister] Univ Helsinki, Inst Mol Med Finland FIMM, FIN-00290 Helsinki, Finland.
   [Johnson, Eric; Chen, Jeffrey; Wells, Peter; Cronin, Ciaran N.; McTigue, Michele; Murray, Brion W.] Pfizer Worldwide Res & Dev, La Jolla Labs, San Diego, CA 92121 USA.
   [Kontro, Mika; Porkka, Kimmo] Univ Helsinki, Hematol Res Unit Helsinki, FIN-00290 Helsinki, Finland.
   [Kontro, Mika; Porkka, Kimmo] Helsinki Univ Hosp, Dept Hematol, Ctr Comprehens Canc, Helsinki 00290, Finland.
C3 University of Helsinki; Pfizer; Pfizer USA; University of Helsinki; University of Helsinki; Helsinki University Central Hospital
RP Wennerberg, K (corresponding author), Univ Helsinki, Inst Mol Med Finland FIMM, FIN-00290 Helsinki, Finland.
EM brion.murray@pfizer.com; krister.wennerberg@fimm.fi
FU Jane and Aatos Erkko Foundation; Academy of Finland; Finnish Cancer Societies; Sigrid Juselius Foundation; Instrumentarium Foundation; FinPharma Doctoral Program-Drug Discovery section
NR 38
TC 191
Z9 213
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 MAR 5
PY 2015
VL 519
IS 7541
BP 102
EP U225
DI 10.1038/nature14119
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC4EQ
UT WOS:000350304000044
PM 25686603
DA 2026-03-09
ER

PT J
AU Fitzgerald, TW
   Gerety, SS
   Jones, WD
   van Kogelenberg, M
   King, DA
   McRae, J
   Morley, KI
   Parthiban, V
   Al-Turki, S
   Ambridge, K
   Barrett, DM
   Bayzetinova, T
   Clayton, S
   Coomber, EL
   Gribble, S
   Jones, P
   Krishnappa, N
   Mason, LE
   Middleton, A
   Miller, R
   Prigmore, E
   Rajan, D
   Sifrim, A
   Tivey, AR
   Ahmed, M
   Akawi, N
   Andrews, R
   Anjum, U
   Archer, H
   Armstrong, R
   Balasubramanian, M
   Banerjee, R
   Baralle, D
   Batstone, P
   Baty, D
   Bennett, C
   Berg, J
   Bernhard, B
   Bevan, AP
   Blair, E
   Blyth, M
   Bohanna, D
   Bourdon, L
   Bourn, D
   Brady, A
   Bragin, E
   Brewer, C
   Brueton, L
   Brunstrom, K
   Bumpstead, SJ
   Bunyan, DJ
   Burn, J
   Burton, J
   Canham, N
   Castle, B
   Chandler, K
   Clasper, S
   Clayton-Smith, J
   Cole, T
   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
   Dean, J
   Deshpande, C
   Devlin, G
   Dixit, A
   Dominiczak, A
   Donnelly, C
   Donnelly, D
   Douglas, A
   Duncan, A
   Eason, J
   Edkins, S
   Ellard, S
   Ellis, P
   Elmslie, F
   Evans, K
   Everest, S
   Fendick, T
   Fisher, R
   Flinter, F
   Foulds, N
   Fryer, A
   Fu, B
   Gardiner, C
   Gaunt, L
   Ghali, N
   Gibbons, R
   Pereira, SLG
   Goodship, J
   Goudie, D
   Gray, E
   Greene, P
   Greenhalgh, L
   Harrison, L
   Hawkins, R
   Hellens, S
   Henderson, A
   Hobson, E
   Holden, S
   Holder, S
   Hollingsworth, G
   Homfray, T
   Humphreys, M
   Hurst, J
   Ingram, S
   Irving, M
   Jarvis, J
   Jenkins, L
   Johnson, D
   Jones, D
   Jones, E
   Josifova, D
   Joss, S
   Kaemba, B
   Kazembe, S
   Kerr, B
   Kini, U
   Kinning, E
   Kirby, G
   Kirk, C
   Kivuva, E
   Kraus, A
   Kumar, D
   Lachlan, K
   Lam, W
   Lampe, A
   Langman, C
   Lees, M
   Lim, D
   Lowther, G
   Lynch, SA
   Magee, A
   Maher, E
   Mansour, S
   Marks, K
   Martin, K
   Maye, U
   McCann, E
   McConnell, V
   McEntagart, M
   McGowan, R
   McKay, K
   McKee, S
   McMullan, DJ
   McNerlan, S
   Mehta, S
   Metcalfe, K
   Miles, E
   Mohammed, S
   Montgomery, T
   Moore, D
   Morgan, S
   Morris, A
   Morton, J
   Mugalaasi, H
   Murday, V
   Nevitt, L
   Newbury-Ecob, R
   Norman, A
   O'Shea, R
   Ogilvie, C
   Park, S
   Parker, MJ
   Patel, C
   Paterson, J
   Payne, S
   Phipps, J
   Pilz, DT
   Porteous, D
   Pratt, N
   Prescott, K
   Price, S
   Pridham, A
   Procter, A
   Purnell, H
   Ragge, N
   Rankin, J
   Raymond, L
   Rice, D
   Robert, L
   Roberts, E
   Roberts, G
   Roberts, J
   Roberts, P
   Ross, A
   Rosser, E
   Saggar, A
   Samant, S
   Sandford, R
   Sarkar, A
   Schweier, S
   Scott, C
   Scott, R
   Selby, A
   Seller, A
   Sequeira, C
   Shannon, N
   Shanrif, S
   Shaw-Smith, C
   Shearing, E
   Shears, D
   Simonic, I
   Simpkin, D
   Singzon, R
   Skitt, Z
   Smith, A
   Smith, B
   Smith, K
   Smithson, S
   Sneddon, L
   Splitt, M
   Squires, M
   Stewart, F
   Stewart, H
   Suri, M
   Sutton, V
   Swaminathan, GJ
   Sweeney, E
   Tatton-Brown, K
   Taylor, C
   Taylor, R
   Tei, M
   Temple, IK
   Thomson, J
   Tolmie, J
   Torokwa, A
   Treacy, B
   Turner, C
   Turnpenny, P
   Tysoe, C
   Vandersteen, A
   Vasudevan, P
   Vogt, J
   Wakeling, E
   Walker, D
   Waters, J
   Weber, A
   Wellesley, D
   Whiteford, M
   Widaa, S
   Wilcox, S
   Williams, D
   Williams, N
   Woods, G
   Wragg, C
   Wright, M
   Yang, F
   Yau, M
   Carter, NP
   Parker, M
   Firth, HV
   FitzPatrick, DR
   Wright, CF
   Barrett, JC
   Hurles, ME
AF Fitzgerald, T. W.
   Gerety, S. S.
   Jones, W. D.
   van Kogelenberg, M.
   King, D. A.
   McRae, J.
   Morley, K. I.
   Parthiban, V.
   Al-Turki, S.
   Ambridge, K.
   Barrett, D. M.
   Bayzetinova, T.
   Clayton, S.
   Coomber, E. L.
   Gribble, S.
   Jones, P.
   Krishnappa, N.
   Mason, L. E.
   Middleton, A.
   Miller, R.
   Prigmore, E.
   Rajan, D.
   Sifrim, A.
   Tivey, A. R.
   Ahmed, M.
   Akawi, N.
   Andrews, R.
   Anjum, U.
   Archer, H.
   Armstrong, R.
   Balasubramanian, M.
   Banerjee, R.
   Baralle, D.
   Batstone, P.
   Baty, D.
   Bennett, C.
   Berg, J.
   Bernhard, B.
   Bevan, A. P.
   Blair, E.
   Blyth, M.
   Bohanna, D.
   Bourdon, L.
   Bourn, D.
   Brady, A.
   Bragin, E.
   Brewer, C.
   Brueton, L.
   Brunstrom, K.
   Bumpstead, S. J.
   Bunyan, D. J.
   Burn, J.
   Burton, J.
   Canham, N.
   Castle, B.
   Chandler, K.
   Clasper, S.
   Clayton-Smith, J.
   Cole, T.
   Collins, A.
   Collinson, M. N.
   Connell, F.
   Cooper, N.
   Cox, H.
   Cresswell, L.
   Cross, G.
   Crow, Y.
   D'Alessandro, M.
   Dabir, T.
   Davidson, R.
   Davies, S.
   Dean, J.
   Deshpande, C.
   Devlin, G.
   Dixit, A.
   Dominiczak, A.
   Donnelly, C.
   Donnelly, D.
   Douglas, A.
   Duncan, A.
   Eason, J.
   Edkins, S.
   Ellard, S.
   Ellis, P.
   Elmslie, F.
   Evans, K.
   Everest, S.
   Fendick, T.
   Fisher, R.
   Flinter, F.
   Foulds, N.
   Fryer, A.
   Fu, B.
   Gardiner, C.
   Gaunt, L.
   Ghali, N.
   Gibbons, R.
   Pereira, S. L. Gomes
   Goodship, J.
   Goudie, D.
   Gray, E.
   Greene, P.
   Greenhalgh, L.
   Harrison, L.
   Hawkins, R.
   Hellens, S.
   Henderson, A.
   Hobson, E.
   Holden, S.
   Holder, S.
   Hollingsworth, G.
   Homfray, T.
   Humphreys, M.
   Hurst, J.
   Ingram, S.
   Irving, M.
   Jarvis, J.
   Jenkins, L.
   Johnson, D.
   Jones, D.
   Jones, E.
   Josifova, D.
   Joss, S.
   Kaemba, B.
   Kazembe, S.
   Kerr, B.
   Kini, U.
   Kinning, E.
   Kirby, G.
   Kirk, C.
   Kivuva, E.
   Kraus, A.
   Kumar, D.
   Lachlan, K.
   Lam, W.
   Lampe, A.
   Langman, C.
   Lees, M.
   Lim, D.
   Lowther, G.
   Lynch, S. A.
   Magee, A.
   Maher, E.
   Mansour, S.
   Marks, K.
   Martin, K.
   Maye, U.
   McCann, E.
   McConnell, V.
   McEntagart, M.
   McGowan, R.
   McKay, K.
   McKee, S.
   McMullan, D. J.
   McNerlan, S.
   Mehta, S.
   Metcalfe, K.
   Miles, E.
   Mohammed, S.
   Montgomery, T.
   Moore, D.
   Morgan, S.
   Morris, A.
   Morton, J.
   Mugalaasi, H.
   Murday, V.
   Nevitt, L.
   Newbury-Ecob, R.
   Norman, A.
   O'Shea, R.
   Ogilvie, C.
   Park, S.
   Parker, M. J.
   Patel, C.
   Paterson, J.
   Payne, S.
   Phipps, J.
   Pilz, D. T.
   Porteous, D.
   Pratt, N.
   Prescott, K.
   Price, S.
   Pridham, A.
   Procter, A.
   Purnell, H.
   Ragge, N.
   Rankin, J.
   Raymond, L.
   Rice, D.
   Robert, L.
   Roberts, E.
   Roberts, G.
   Roberts, J.
   Roberts, P.
   Ross, A.
   Rosser, E.
   Saggar, A.
   Samant, S.
   Sandford, R.
   Sarkar, A.
   Schweier, S.
   Scott, C.
   Scott, R.
   Selby, A.
   Seller, A.
   Sequeira, C.
   Shannon, N.
   Shanrif, S.
   Shaw-Smith, C.
   Shearing, E.
   Shears, D.
   Simonic, I.
   Simpkin, D.
   Singzon, R.
   Skitt, Z.
   Smith, A.
   Smith, B.
   Smith, K.
   Smithson, S.
   Sneddon, L.
   Splitt, M.
   Squires, M.
   Stewart, F.
   Stewart, H.
   Suri, M.
   Sutton, V.
   Swaminathan, G. J.
   Sweeney, E.
   Tatton-Brown, K.
   Taylor, C.
   Taylor, R.
   Tein, M.
   Temple, I. K.
   Thomson, J.
   Tolmie, J.
   Torokwa, A.
   Treacy, B.
   Turner, C.
   Turnpenny, P.
   Tysoe, C.
   Vandersteen, A.
   Vasudevan, P.
   Vogt, J.
   Wakeling, E.
   Walker, D.
   Waters, J.
   Weber, A.
   Wellesley, D.
   Whiteford, M.
   Widaa, S.
   Wilcox, S.
   Williams, D.
   Williams, N.
   Woods, G.
   Wragg, C.
   Wright, M.
   Yang, F.
   Yau, M.
   Carter, N. P.
   Parker, M.
   Firth, H. V.
   FitzPatrick, D. R.
   Wright, C. F.
   Barrett, J. C.
   Hurles, M. E.
TI Large-scale discovery of novel genetic causes of developmental disorders
SO NATURE
LA English
DT Article
ID de-novo mutations; autism spectrum disorders; copy-number variation; intellectual disability; human-disease; framework; children; model
AB Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders(1), up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach(2) to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing(3-11) and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.
C1 [Fitzgerald, T. W.; Gerety, S. S.; Jones, W. D.; van Kogelenberg, M.; King, D. A.; McRae, J.; Morley, K. I.; Parthiban, V.; Al-Turki, S.; Ambridge, K.; Barrett, D. M.; Bayzetinova, T.; Clayton, S.; Coomber, E. L.; Gribble, S.; Jones, P.; Krishnappa, N.; Mason, L. E.; Middleton, A.; Miller, R.; Prigmore, E.; Rajan, D.; Sifrim, A.; Tivey, A. R.; Akawi, N.; Andrews, R.; Banerjee, R.; Bevan, A. P.; Bragin, E.; Bumpstead, S. J.; Burton, J.; Edkins, S.; Ellis, P.; Fu, B.; Pereira, S. L. Gomes; Gray, E.; Jones, D.; Scott, C.; Simpkin, D.; Swaminathan, G. J.; Walker, D.; Widaa, S.; Yang, F.; Carter, N. P.; Firth, H. V.; Wright, C. F.; Barrett, J. C.; Hurles, M. E.] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.
   [Ahmed, M.; Baralle, D.; Bunyan, D. J.; Collins, A.; Collinson, M. N.; Foulds, N.; Harrison, L.; Lachlan, K.; Temple, I. K.; Torokwa, A.; Wellesley, D.] Princess Anne Hosp, Southampton Univ Hosp, Wessex Clin Genet Serv, Southampton SO16 5YA, Hants, England.
   [Ahmed, M.; Baralle, D.; Bunyan, D. J.; Collins, A.; Collinson, M. N.; Foulds, N.; Harrison, L.; Lachlan, K.; Temple, I. K.; Torokwa, A.; Wellesley, D.] Salisbury Dist Hosp, Wessex Reg Genet Lab, Salisbury NHS Fdn Trust, Salisbury SP2 8BJ, Wilts, England.
   [Ahmed, M.; Baralle, D.; Bunyan, D. J.; Collins, A.; Collinson, M. N.; Foulds, N.; Harrison, L.; Lachlan, K.; Temple, I. K.; Torokwa, A.; Wellesley, D.] Univ Southampton, Fac Med, Southampton SO16 6YD, Hants, England.
   [Anjum, U.; Elmslie, F.; Homfray, T.; Mansour, S.; Marks, K.; McEntagart, M.; Saggar, A.; Tatton-Brown, K.; Taylor, R.] Univ London, South West Thames Regonal Genet Ctr, St Georges Healthcare NHS Trust, London SW17 0RE, England.
   [Archer, H.; Davies, S.; Evans, K.; Kumar, D.; McCann, E.; Morgan, S.; Mugalaasi, H.; Pilz, D. T.; Procter, A.] Univ Wales Hosp, Inst Med Genet, Cardiff CF14 4XW, Wales.
   [Archer, H.; Davies, S.; Evans, K.; Kumar, D.; McCann, E.; Morgan, S.; Mugalaasi, H.; Pilz, D. T.; Procter, A.] Glan Clwyd Gen Hosp, Dept Clin Genet, Rhyl LL18 5UJ, Denbighshire, England.
   [Armstrong, R.; Holden, S.; Mehta, S.; Park, S.; Paterson, J.; Raymond, L.; Roberts, J.; Sandford, R.; Simonic, I.; Treacy, B.; Wilcox, S.; Woods, G.; Firth, H. V.] Cambridge Univ Hosp NHS Fdn Trust, East Anglian Med Genet Serv, Cambridge CB2 0QQ, England.
   [Balasubramanian, M.; Ingram, S.; Johnson, D.; Nevitt, L.; Parker, M. J.; Shearing, E.; Smith, K.; Taylor, C.] Sheffield Childrens NHS Trust, Sheffield Reg Genet Serv, Sheffield S10 2TH, S Yorkshire, England.
   [Batstone, P.; D'Alessandro, M.; Dean, J.; McGowan, R.; Ross, A.; Samant, S.] North Scotland Regonal Genet Serv, Dept Med Genet, NHS Grampian, Sch Med, Aberdeen AB25 2ZD, Scotland.
   [Baty, D.; Berg, J.; Goudie, D.; Pratt, N.; Rice, D.; Schweier, S.] Ninewel Is Hosp, East Scotland Reg Genet Serv, Human Genet Unit, Pathol Dept,NHS Tayside, Dundee DD1 9SY, Scotland.
   [Bennett, C.; Blyth, M.; Hobson, E.; Kraus, A.; Prescott, K.; Roberts, P.; Smith, A.; Squires, M.; Thomson, J.] Chapel Allerton Hosp, Yorkshire Regonal Genet Serv, Leeds Teaching Hosp NHS Trust, Dept Clin Genet, Leeds LS7 4SA, W Yorkshire, England.
   [Bernhard, B.; Bourdon, L.; Brady, A.; Canham, N.; Ghali, N.; Holder, S.; Payne, S.; Sequeira, C.; Singzon, R.; Vandersteen, A.; Wakeling, E.] North West London Hosp NHS Trust, North West Thames Reg Genet Ctr, Kennedy Galton Ctr, Harrow HA1 3UJ, Middx, England.
   [Blair, E.; Clasper, S.; Gibbons, R.; Kini, U.; Phipps, J.; Price, S.; Pridham, A.; Purnell, H.; Seller, A.; Shears, D.; Stewart, H.] Oxford Radcliffe Hosp NHS Trust, Oxford Reg Genet Serv, Oxford OX3 7LJ, England.
   [Bohanna, D.; Brueton, L.; Cole, T.; Cooper, N.; Cox, H.; Jarvis, J.; Kirby, G.; Lim, D.; McKay, K.; McMullan, D. J.; Morton, J.; Norman, A.; Patel, C.; Ragge, N.; Shanrif, S.; Tein, M.; Vogt, J.; Williams, D.] Birmingham Womens Hosp, West Midlands Reg Genet Serv, Birmingham Womens NHS Fdn Trust, Birmingham B15 2TG, W Midlands, England.
   [Bourn, D.; Burn, J.; Fisher, R.; Goodship, J.; Hellens, S.; Henderson, A.; Montgomery, T.; Sneddon, L.; Splitt, M.; Wright, M.] Newcastle Upon Tyne Hosp NHS Fdn Trust, Northern Genet Serv, Inst Human Genet, Int Ctr Life, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England.
   [Brewer, C.; Castle, B.; Devlin, G.; Ellard, S.; Everest, S.; Kivuva, E.; Rankin, J.; Shaw-Smith, C.; Turner, C.; Turnpenny, P.; Tysoe, C.] Royal Devon & Exeter Hosp Heavitree, Peninsula Clin Genet Serv, Royal Devon & Exeter NHS Fdn Trust, Dept Clin Genet, Exeter EX1 2ED, Devon, England.
   [Brunstrom, K.; Hollingsworth, G.; Hurst, J.; Jenkins, L.; Lees, M.; Rosser, E.; Scott, R.; Waters, J.] Great Ormond St Hosp Sick Children, North East Thames Regonal Genet Serv, Great Ormond St Hosp Children NHS Fdn Trust, London WC1N 3JH, England.
   [Chandler, K.; Clayton-Smith, J.; Crow, Y.; Donnelly, C.; Gaunt, L.; Jones, E.; Kerr, B.; Metcalfe, K.; Miles, E.; Skitt, Z.] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Ctr Genom Med, St Marys Hosp, Manchester Acad Hlth Sci Ctr, Manchester M13 9WL, Lancs, England.
   [Connell, F.; Deshpande, C.; Fendick, T.; Flinter, F.; Irving, M.; Josifova, D.; Langman, C.; Mohammed, S.; Ogilvie, C.; Robert, L.; Yau, M.] Guys Hosp, South East Thames Reg Genet Ctr, Guys & St Thomas NHS Fdn Trust, London SE1 9RT, England.
   [Cresswell, L.; Kaemba, B.; Kazembe, S.; Vasudevan, P.] Leicester Royal Infirm NHS Trust, Univ Hosp Leicester NHS Trust, Leicestershire Genet Ctr, Leicester LE1 5WW, Leics, England.
   [Cross, G.; Dixit, A.; Eason, J.; Martin, K.; Sarkar, A.; Selby, A.; Shannon, N.; Suri, M.] Nottingham Univ Hosp NHS Trust, Nottingham Reg Genet Serv, Nottingham NG5 1PB, England.
   [Dabir, T.; Donnelly, D.; Humphreys, M.; Joss, S.; Kirk, C.; Magee, A.; McConnell, V.; McKee, S.; McNerlan, S.; Stewart, F.] Belfast City Hosp, Northern Ireland Regonal Genet Ctr, Belfast Hlth & Social Care Trust, Belfast BT9 7AB, Antrim, North Ireland.
   [Davidson, R.; Duncan, A.; Gardiner, C.; Kinning, E.; Lowther, G.; Murday, V.; Tolmie, J.; Whiteford, M.; Williams, N.] Yorkhill Hosp, West Scotland & Reg Genet Cs Serv, NHS Greater Glasgow & Clyde, Inst Med Genet, Glasgow G3 8SJ, Lanark, Scotland.
   [Dominiczak, A.] Univ Glasgow, Coll Med Vet & Life Sci, Glasgow G12 8QQ, Lanark, Scotland.
   [Douglas, A.; Fryer, A.; Greenhalgh, L.; Maye, U.; Roberts, G.; Sutton, V.; Sweeney, E.; Weber, A.] Royal Liverpool Childrens Hosp Alder Hey, Merseyside & Cheshire Genet Serv, Liverpool Womens NHS Fdn Trust, Dept Clin Genet, Liverpool L12 2AP, Merseyside, England.
   [Greene, P.; Lam, W.; Lampe, A.; Maher, E.; Moore, D.; FitzPatrick, D. R.] Univ Edinburgh, Western Gen Hosp, MRC IGMM, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland.
   [Hawkins, R.; Newbury-Ecob, R.; Roberts, E.; Smithson, S.; Wragg, C.] St Michaels Hosp, Bristol Genet Serv Avon Somerset Gloucs & West Wi, Univ Hosp Bristol NHS Fdn Trust, Bristol BS2 8DT, Avon, England.
   [Lynch, S. A.; O'Shea, R.] Our Ladys Childrens Hosp, Natl Ctr Med Genet, Dublin 12, Ireland.
   [Morris, A.] Univ Edinburgh, Sch Mol Genet & Populat Hlth Sci, Sch Med, Edinburgh EH8 9AG, Midlothian, Scotland.
   [Porteous, D.] Univ Edinburgh, Inst Genet & Mol Med, Western Gen Hosp, Edinburgh EH4 2XU, Midlothian, Scotland.
   [Smith, B.] Univ Dundee, Sch Med, Ninewells Hosp & Med Sch, Dundee DD2 4RB, Scotland.
   [Parker, M.] Univ Oxford, Ethox Ctr, Nuffield Dept Populat Hlth, Oxford OX3 7LF, England.
C3 Wellcome Trust Sanger Institute; University of Southampton; Salisbury District Hospital; University of Southampton; University of London; City St Georges, University of London; Cardiff University; University of Cambridge; Sheffield Children's NHS Foundation Trust; University of Aberdeen; University of Leeds; Chapel Allerton Hospital; University of Oxford; Oxford University Hospitals NHS Foundation Trust; Birmingham Women's Hospital; Newcastle Upon Tyne Hospitals NHS Foundation Trust; Newcastle University - UK; University of Exeter; University of London; University College London; Great Ormond Street Hospital for Children NHS Foundation Trust; University of Manchester; Guy's & St Thomas' NHS Foundation Trust; University of Leicester; University Hospitals of Leicester NHS Trust; Nottingham University Hospital NHS Trust; Belfast City Hospital; University of Glasgow; University of Glasgow; Alder Hey Children's NHS Foundation Trust; Alder Hey Children's Hospital; University of Edinburgh; University of Bristol; Our Ladys Children Hospital Crumlin; National Children's Research Centre (NCRC); University of Edinburgh; University of Edinburgh; University of Dundee; University of Oxford
RP Hurles, ME (corresponding author), Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England.
EM meh@sanger.ac.uk
FU Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6]; Scottish Funding Council [HR03006]; Health Innovation Challenge Fund [HICF-1009-003]; Wellcome Trust; Department of Health; Wellcome Trust Sanger Institute [WT098051]; National Institute for Health Research, through the Comprehensive Clinical Research Network; Cambridge South REC [10/H0305/83]; Republic of Ireland REC [GEN/284/12]; MRC [MC_PC_U127561093] Funding Source: UKRI; Cancer Research UK [15934] Funding Source: researchfish; Medical Research Council [MC_PC_U127561093] Funding Source: researchfish; National Institute for Health Research [NF-SI-0510-10282] Funding Source: researchfish
CR Allen AS, 2013, NATURE, V501, P217, DOI 10.1038/nature12439
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NR 27
TC 863
Z9 1011
U1 1
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 MAR 12
PY 2015
VL 519
IS 7542
BP 223
EP +
DI 10.1038/nature14135
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500037
PM 25533962
DA 2026-03-09
ER

PT J
AU Cully, A
   Clune, J
   Tarapore, D
   Mouret, JB
AF Cully, Antoine
   Clune, Jeff
   Tarapore, Danesh
   Mouret, Jean-Baptiste
TI Robots that can adapt like animals
SO NATURE
LA English
DT Article
ID modular robots; rescue robots; locomotion; dogs
AB Robots have transformed many industries, most notably manufacturing(1), and have the power to deliver tremendous benefits to society, such as in search and rescue(2), disaster response(3), health care(4) and transportation(5). They are also invaluable tools for scientific exploration in environments inaccessible to humans, from distant planets(6) to deep oceans(7). A major obstacle to their widespread adoption in more complex environments outside factories is their fragility(6,8). Whereas animals can quickly adapt to injuries, current robots cannot 'think outside the box' to find a compensatory behaviour when they are damaged: they are limited to their pre-specified self-sensing abilities, can diagnose only anticipated failure modes(9), and require a pre-programmed contingency plan for every type of potential damage, an impracticality for complex robots(6,8). A promising approach to reducing robot fragility involves having robots learn appropriate behaviours in response to damage(10,11), but current techniques are slow even with small, constrained search spaces(12). Here we introduce an intelligent trial- and-error algorithm that allows robots to adapt to damage in less than two minutes in large search spaces without requiring self-diagnosis or pre-specified contingency plans. Before the robot is deployed, it uses a novel technique to create a detailed map of the space of high-performing behaviours. This map represents the robot's prior knowledge about what behaviours it can perform and their value. When the robot is damaged, it uses this prior knowledge to guide a trial-and-error learning algorithm that conducts intelligent experiments to rapidly discover a behaviour that compensates for the damage. Experiments reveal successful adaptations for a legged robot injured in five different ways, including damaged, broken, and missing legs, and for a robotic arm with joints broken in 14 different ways. This new algorithm will enable more robust, effective, autonomous robots, and may shed light on the principles that animals use to adapt to injury.
C1 [Cully, Antoine; Tarapore, Danesh; Mouret, Jean-Baptiste] Univ Paris 06, Sorbonne Univ, UMR 7222, ISIR, F-75005 Paris, France.
   [Cully, Antoine; Tarapore, Danesh; Mouret, Jean-Baptiste] CNRS, UMR 7222, ISIR, F-75005 Paris, France.
   [Clune, Jeff] Univ Wyoming, Dept Comp Sci, Laramie, WY 82071 USA.
   [Mouret, Jean-Baptiste] Inria, Team Larsen, F-54600 Villers Les Nancy, France.
   [Mouret, Jean-Baptiste] CNRS, Loria, UMR 7503, F-54500 Vandoeuvre Les Nancy, France.
   [Mouret, Jean-Baptiste] Univ Lorraine, Loria, UMR 7503, F-54500 Vandoeuvre Les Nancy, France.
C3 Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute for Information Sciences & Technologies (INS2I); Centre National de la Recherche Scientifique (CNRS); CNRS - Institute for Information Sciences & Technologies (INS2I); Sorbonne Universite; University of Wyoming; Universite de Lorraine; Inria; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute for Information Sciences & Technologies (INS2I); Universite de Lorraine; Universite de Lorraine; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute for Information Sciences & Technologies (INS2I)
RP Mouret, JB (corresponding author), Univ Paris 06, Sorbonne Univ, UMR 7222, ISIR, F-75005 Paris, France.
EM jean-baptiste.mouret@inria.fr
FU ANR Creadapt project [ANR-12-JS03-0009]; European Research Council (ERC) under European Union [637972]; Direction Generale de l'Armement (DGA) scholarship; Agence Nationale de la Recherche (ANR) [ANR-12-JS03-0009] Funding Source: Agence Nationale de la Recherche (ANR); European Research Council (ERC) [637972] Funding Source: European Research Council (ERC)
NR 35
TC 764
Z9 880
U1 21
U2 664
PU NATURE PUBLISHING 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 28
PY 2015
VL 521
IS 7553
BP 503
EP U476
DI 10.1038/nature14422
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ2AN
UT WOS:000355286600039
PM 26017452
DA 2026-03-09
ER

PT J
AU Frechin, M
   Stoeger, T
   Daetwyler, S
   Gehin, C
   Battich, N
   Damm, EM
   Stergiou, L
   Riezman, H
   Pelkmans, L
AF Frechin, Mathieu
   Stoeger, Thomas
   Daetwyler, Stephan
   Gehin, Charlotte
   Battich, Nico
   Damm, Eva-Maria
   Stergiou, Lilli
   Riezman, Howard
   Pelkmans, Lucas
TI Cell-intrinsic adaptation of lipid composition to local crowding drives social behaviour
SO NATURE
LA English
DT Article
ID plasma-membrane; kinase; raft; transporters; microdomains; adhesion; yeast
AB Cells sense the context in which they grow to adapt their phenotype and allow multicellular patterning by mechanisms of autocrine and paracrine signalling(1,2). However, patterns also form in cell populations exposed to the same signalling molecules and substratum, which often correlate with specific features of the population context of single cells, such as local cell crowding(3). Here we reveal a cell-intrinsic molecular mechanism that allows multicellular patterning without requiring specific communication between cells. It acts by sensing the local crowding of a single cell through its ability to spread and activate focal adhesion kinase (FAK, also known as PTK2), resulting in adaptation of genes controlling membrane homeostasis. In cells experiencing low crowding, FAK suppresses transcription of the ABC transporter A1 (ABCA1) by inhibiting FOXO3 and TAL1. Agent-based computational modelling and experimental confirmation identified membrane-based signalling and feedback control as crucial for the emergence of population patterns of ABCA1 expression, which adapts membrane lipid composition to cell crowding and affects multiple signalling activities, including the suppression of ABCA1 expression itself. The simple design of this cell-intrinsic system and its broad impact on the signalling state of mammalian single cells suggests a fundamental role for a tunable membrane lipid composition in collective cell behaviour.
C1 [Frechin, Mathieu; Stoeger, Thomas; Daetwyler, Stephan; Battich, Nico; Pelkmans, Lucas] Univ Zurich, Inst Mol Life Sci, Fac Sci, CH-8057 Zurich, Switzerland.
   [Stoeger, Thomas; Battich, Nico] ETH, Life Sci Zurich Grad Sch, PhD Program Syst Biol, CH-8057 Zurich, Switzerland.
   [Stoeger, Thomas; Battich, Nico] Univ Zurich, CH-8057 Zurich, Switzerland.
   [Gehin, Charlotte; Riezman, Howard] Univ Geneva, Dept Biochem, CH-1205 Geneva, Switzerland.
   [Damm, Eva-Maria; Stergiou, Lilli] ETH, Inst Mol Syst Biol, CH-8057 Zurich, Switzerland.
C3 University of Zurich; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Zurich; University of Geneva; Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Pelkmans, L (corresponding author), Univ Zurich, Inst Mol Life Sci, Fac Sci, CH-8057 Zurich, Switzerland.
EM lucas.pelkmans@imls.uzh.ch
FU EMBO; Marie Curie fellowship [301650]; Oncosuisse fellowship; Bonizzi Theler fellowship; University of Zurich; SystemsX.ch RTD Project LipidX
NR 38
TC 78
Z9 86
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 JUL 2
PY 2015
VL 523
IS 7558
BP 88
EP +
DI 10.1038/nature14429
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL7RN
UT WOS:000357169500037
PM 26009010
DA 2026-03-09
ER

PT J
AU Ge, JP
   Li, WQ
   Zhao, QC
   Li, NN
   Chen, MF
   Zhi, P
   Li, RC
   Gao, N
   Xiao, BL
   Yang, MJ
AF Ge, Jingpeng
   Li, Wanqiu
   Zhao, Qiancheng
   Li, Ningning
   Chen, Maofei
   Zhi, Peng
   Li, Ruochong
   Gao, Ning
   Xiao, Bailong
   Yang, Maojun
TI Architecture of the mammalian mechanosensitive Piezol channel
SO NATURE
LA English
DT Article
ID activated ion-channel; of-function mutations; gated sodium-channel; crystal-structure; distal arthrogryposis; merkel cells; mechanotransduction; receptors; mechanism; state
AB Piezo proteins are evolutionarily conserved and functionally diverse mechanosensitive cation channels. However, the overall structural architecture and gating mechanisms of Piezo channels have remained unknown. Here we determine the cryo-electron microscopy structure of the full-length (2,547 amino acids) mouse Piezol (Piezol) at a resolution of 4.8 angstrom. Piezol forms a trimeric propeller-like structure (about 900 kilodalton), with the extracellular domains resembling three distal blades and a central cap. The transmembrane region has 14 apparently resolved segments per subunit. These segments form three peripheral wings and a central pore module that encloses a potential ion-conducting pore. The rather flexible extracellular blade domains are connected to the central intracellular domain by three long beam-like structures. This trimeric architecture suggests that Piezol may use its peripheral regions as force sensors to gate the central ion-conducting pore.
C1 [Ge, Jingpeng; Zhao, Qiancheng; Chen, Maofei; Li, Ruochong; Xiao, Bailong; Yang, Maojun] Tsinghua Univ, Sch Life Sci Med, Tsinghua Peking Joint Ctr Life Sci, Beijing 100084, Peoples R China.
   [Ge, Jingpeng; Li, Wanqiu; Li, Ningning; Chen, Maofei; Li, Ruochong; Gao, Ning; Yang, Maojun] Tsinghua Univ, Sch Life Sci, Key Lab Prot Sci, Minist Educ, Beijing 100084, Peoples R China.
   [Zhao, Qiancheng; Zhi, Peng; Xiao, Bailong] Tsinghua Univ, Sch Med, Dept Pharmacol & Pharmaceut Sci, Beijing 100084, Peoples R China.
   [Xiao, Bailong] Tsinghua Univ, IDG McGovern Inst Brain Res, Beijing 100084, Peoples R China.
C3 Tsinghua University; Tsinghua University; Tsinghua University; Tsinghua University
RP Gao, N (corresponding author), Tsinghua Univ, Sch Life Sci, Key Lab Prot Sci, Minist Educ, Beijing 100084, Peoples R China.
EM ninggao@tsinghua.edu.cn; xbailong@biomed.tsinghua.edu.cn; maojunyang@tsinghua.edu.cn
FU Ministry of Science and Technology [2012CB911101, 2011CB910502, 2015CB910102, 2013CB910404]; National Natural Science Foundation of China [21532004, 31570733, 31030020, 31170679, 31422016, 31422027]; Ministry of Education
NR 48
TC 398
Z9 488
U1 6
U2 299
PU NATURE PUBLISHING 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 5
PY 2015
VL 527
IS 7576
BP 64
EP 69
DI 10.1038/nature15247
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV4XV
UT WOS:000364270700043
PM 26390154
DA 2026-03-09
ER

PT J
AU Namburi, P
   Beyeler, A
   Yorozu, S
   Calhoon, GG
   Halbert, SA
   Wichmann, R
   Holden, SS
   Mertens, KL
   Anahtar, M
   Felix-Ortiz, AC
   Wickersham, IR
   Gray, JM
   Tye, KM
AF Namburi, Praneeth
   Beyeler, Anna
   Yorozu, Suzuko
   Calhoon, Gwendolyn G.
   Halbert, Sarah A.
   Wichmann, Romy
   Holden, Stephanie S.
   Mertens, Kim L.
   Anahtar, Melodi
   Felix-Ortiz, Ada C.
   Wickersham, Ian R.
   Gray, Jesse M.
   Tye, Kay M.
TI A circuit mechanism for differentiating positive and negative associations
SO NATURE
LA English
DT Article
ID basolateral amygdala; conditioned fear; reward-seeking; neurons; memory; nucleus; microcircuit; potentiation; expression; plasticity
AB The ability to differentiate stimuli predicting positive or negative outcomes is critical for survival, and perturbations of emotional processing underlie many psychiatric disease states. Synaptic plasticity in the basolateral amygdala complex (BLA) mediates the acquisition of associative memories, both positive(1'2) and negative'. Different populations of BLA neurons may encode fearful or rewarding associations'', but the identifying features of these populations and the synaptic mechanisms of differentiating positive and negative emotional valence have remained unknown. Here we show that BLA neurons projecting to the nucleus accumbens (NAc projectors) or the centromedial amygdala (CeM projectors) undergo opposing synaptic changes following fear or reward conditioning. We find that photostimulation of NAc projectors supports positive reinforcement while photostimulation of CeM projectors mediates negative reinforcement. Photoinhibition of CeM projectors impairs fear conditioning and enhances reward conditioning. We characterize these functionally distinct neuronal populations by comparing their electrophysiological, morphological and genetic features. Overall, we provide a mechanistic explanation for the representation of positive and negative associations within the amygdala.
C1 [Namburi, Praneeth; Beyeler, Anna; Calhoon, Gwendolyn G.; Halbert, Sarah A.; Wichmann, Romy; Holden, Stephanie S.; Mertens, Kim L.; Anahtar, Melodi; Felix-Ortiz, Ada C.; Tye, Kay M.] MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, Cambridge, MA 02139 USA.
   [Namburi, Praneeth; Felix-Ortiz, Ada C.] MIT, Neurosci Grad Program, Cambridge, MA 02139 USA.
   [Yorozu, Suzuko; Gray, Jesse M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
   [Halbert, Sarah A.] Wellesley Coll, Undergrad Program Neurosci, Wellesley, MA 02481 USA.
   [Holden, Stephanie S.; Anahtar, Melodi] MIT, Undergrad Program Neurosci, Cambridge, MA 02139 USA.
   [Mertens, Kim L.] Univ Amsterdam, Masters Program Biomed Sci, NL-1098 XH Amsterdam, Netherlands.
   [Wickersham, Ian R.] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA.
C3 Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Harvard University; Harvard Medical School; Wellesley College; Massachusetts Institute of Technology (MIT); University of Amsterdam; Massachusetts Institute of Technology (MIT)
RP Tye, KM (corresponding author), MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, E25-618, Cambridge, MA 02139 USA.
EM kaytye@mit.edu
FU NIMH [R01-MH102441-01, R01-MH101528-01]; NIDDK [DP2-DK-102256-01]; JPB Foundation (PIIF); JPB Foundation (PNDRF); NARSAD Foundation; Klingenstein Foundation; Whitehall Foundation; Sloan Foundation; Singleton fellowship; Leventhal fellowship; Whitaker fellowship; Swiss National Science Foundation; Simons Center for the Social Brain; Netherlands Organization for Scientific Research (NWO) RUBICON fellowship program; McGovern Institute for Brain Research; Picower Institute for Learning and Memory; MIT Department of Brain and Cognitive Sciences; BRAIN Initiative award from NIMH [U01-MH106018, U01-N5090473]; BRAIN Initiative award from NINDS [U01-MH106018, U01-N5090473]; NSF [IOS-1451202]; BRAIN Initiative award from NEI [U01-MH106018, U01-N5090473]
NR 37
TC 420
Z9 519
U1 2
U2 132
PU NATURE PUBLISHING 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 30
PY 2015
VL 520
IS 7549
BP 675
EP U208
DI 10.1038/nature14366
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700049
PM 25925480
DA 2026-03-09
ER

PT J
AU Flock, T
   Ravarani, CNJ
   Sun, DW
   Venkatakrishnan, AJ
   Kayikci, M
   Tate, CG
   Veprintsev, DB
   Babu, MM
AF Flock, Tilman
   Ravarani, Charles N. J.
   Sun, Dawei
   Venkatakrishnan, A. J.
   Kayikci, Melis
   Tate, Christopher G.
   Veprintsev, Dmitry B.
   Babu, M. Madan
TI Universal allosteric mechanism for Gα activation by GPCRs
SO NATURE
LA English
DT Article
ID multiple sequence alignment; g-protein activation; crystal-structure; structural basis; signal-transduction; binding-site; web server; evolution; ras; helix
AB G protein-coupled receptors (GPCRs) allosterically activate heterotrimeric G proteins and trigger GDP release. Given that there are similar to 800 human GPCRs and 16 different G alpha genes, this raises the question of whether a universal allosteric mechanism governs G alpha activation. Here we show that different GPCRs interact with and activate G alpha proteins through a highly conserved mechanism. Comparison of G alpha with the small G protein Ras reveals how the evolution of short segments that undergo disorder-to-order transitions can decouple regions important for allosteric activation from receptor binding specificity. This might explain how the GPCR-G alpha system diversified rapidly, while conserving the allosteric activation mechanism.
C1 [Flock, Tilman; Ravarani, Charles N. J.; Venkatakrishnan, A. J.; Kayikci, Melis; Tate, Christopher G.; Babu, M. Madan] MRC Lab Mol Biol, Cambridge CB2 0QH, England.
   [Sun, Dawei; Veprintsev, Dmitry B.] Paul Scherrer Inst, Lab Biomol Res, CH-5232 Villigen, Switzerland.
   [Sun, Dawei; Veprintsev, Dmitry B.] Swiss Fed Inst Technol, Dept Biol, CH-8039 Zurich, Switzerland.
C3 MRC Laboratory Molecular Biology; Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute; Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Flock, T (corresponding author), MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England.
EM tflock@mrc-lmb.cam.ac.uk; madanm@mrc-lmb.cam.ac.uk
FU Medical Research Council [MC_U105185859, MC_U105197215]; Swiss National Science Foundation [141898, 133810, 31-135754]; MRC Centenary Award; AFR scholarship from Luxembourg National Research Fund; Boehringer Ingelheim Fond; MRC [MC_U105197215, MC_U105185859] Funding Source: UKRI; Medical Research Council [MC_U105197215, MC_U105185859, 1274107] Funding Source: researchfish
NR 76
TC 294
Z9 335
U1 0
U2 98
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 13
PY 2015
VL 524
IS 7564
BP 173
EP +
DI 10.1038/nature14663
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900022
PM 26147082
DA 2026-03-09
ER

PT J
AU Vietri, M
   Schink, KO
   Campsteijn, C
   Wegner, CS
   Schultz, SW
   Christ, L
   Thoresen, SB
   Brech, A
   Raiborg, C
   Stenmark, H
AF Vietri, Marina
   Schink, Kay O.
   Campsteijn, Coen
   Wegner, Catherine Sem
   Schultz, Sebastian W.
   Christ, Liliane
   Thoresen, Sigrid B.
   Brech, Andreas
   Raiborg, Camilla
   Stenmark, Harald
TI Spastin and ESCRT-III coordinate mitotic spindle disassembly and nuclear envelope sealing
SO NATURE
LA English
DT Article
ID mediated abscission checkpoint; membrane deformation; protein chmp1b; cytokinesis; midbody; complex; filaments; system; cells; motif
AB At the onset of metazoan cell division the nuclear envelope breaks down to enable capture of chromosomes by the microtubule-containing spindle apparatus(1). During anaphase, when chromosomes have separated, the nuclear envelope is reassembled around the forming daughter nuclei(1,2). How the nuclear envelope is sealed, and how this is coordinated with spindle disassembly, is largely unknown. Here we show that endosomal sorting complex required for transport (ESCRT)-III, previously found to promote membrane constriction and sealing during receptor sorting, virus budding, cytokinesis and plasma membrane repair(3-6), is transiently recruited to the reassembling nuclear envelope during late anaphase. ESCRT-III and its regulatory AAA (ATPase associated with diverse cellular activities) ATPase VPS4 are specifically recruited by the ESCRT-III-like protein CHMP7 to sites where the reforming nuclear envelope engulfs spindle microtubules. Subsequent association of another ESCRT-III-like protein, IST1, directly recruits the AAA ATPase spastin to sever microtubules. Disrupting spastin function impairs spindle disassembly and results in extended localization of ESCRT-III at the nuclear envelope. Interference with ESCRT-III functions in anaphase is accompanied by delayed microtubule disassembly, compromised nuclear integrity and the appearance of DNA damage foci in subsequent interphase. We propose that ESCRT-III, VPS4 and spastin cooperate to coordinate nuclear envelope sealing and spindle disassembly at nuclear envelope-microtubule intersection sites during mitotic exit to ensure nuclear integrity and genome safeguarding, with a striking mechanistic parallel to cytokinetic abscission(7).
C1 [Vietri, Marina; Schink, Kay O.; Campsteijn, Coen; Wegner, Catherine Sem; Schultz, Sebastian W.; Christ, Liliane; Thoresen, Sigrid B.; Brech, Andreas; Raiborg, Camilla; Stenmark, Harald] Univ Oslo, Fac Med, Ctr Canc Biomed, N-0379 Oslo, Norway.
   [Vietri, Marina; Schink, Kay O.; Campsteijn, Coen; Wegner, Catherine Sem; Schultz, Sebastian W.; Christ, Liliane; Thoresen, Sigrid B.; Brech, Andreas; Raiborg, Camilla; Stenmark, Harald] Oslo Univ Hosp, Inst Canc Res, Dept Mol Cell Biol, N-0379 Oslo, Norway.
   [Stenmark, Harald] Norwegian Univ Sci & Technol, Fac Med, Ctr Mol Inflammat Res, N-7491 Trondheim, Norway.
C3 University of Oslo; University of Oslo; Norwegian University of Science & Technology (NTNU)
RP Campsteijn, C (corresponding author), Univ Oslo, Fac Med, Ctr Canc Biomed, N-0379 Oslo, Norway.
EM coen.campsteijn@rr-research.no; stenmark@ulrik.uio.no
FU European Research Council; Research Council of Norway through Centres of Excellence [179571]
NR 41
TC 316
Z9 377
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 JUN 11
PY 2015
VL 522
IS 7555
BP 231
EP +
DI 10.1038/nature14408
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700042
PM 26040712
DA 2026-03-09
ER

PT J
AU Amin, SA
   Hmelo, LR
   van Tol, HM
   Durham, BP
   Carlson, LT
   Heal, KR
   Morales, RL
   Berthiaume, CT
   Parker, MS
   Djunaedi, B
   Ingalls, AE
   Parsek, MR
   Moran, MA
   Armbrust, EV
AF Amin, S. A.
   Hmelo, L. R.
   van Tol, H. M.
   Durham, B. P.
   Carlson, L. T.
   Heal, K. R.
   Morales, R. L.
   Berthiaume, C. T.
   Parker, M. S.
   Djunaedi, B.
   Ingalls, A. E.
   Parsek, M. R.
   Moran, M. A.
   Armbrust, E. V.
TI Interaction and signalling between a cosmopolitan phytoplankton and associated bacteria
SO NATURE
LA English
DT Article
ID marine-bacteria; diatoms; growth
AB Interactions between primary producers and bacteria impact the physiology of both partners, alter the chemistry of their environment, and shape ecosystem diversity(1,2). In marine ecosystems, these interactions are difficult to study partly because the major photosynthetic organisms are microscopic, unicellular phytoplankton(3). Coastal phytoplankton communities are dominated by diatoms, which generate approximately 40% of marine primary production and form the base of many marine food webs(4). Diatoms co-occur with specific bacterial taxa(3), but the mechanisms of potential interactions are mostly unknown. Here we tease apart a bacterial consortium associated with a globally distributed diatom and find that a Sulfitobacter species promotes diatom cell division via secretion of the hormone indole-3-acetic acid, synthesized by the bacterium using both diatom-secreted and endogenous tryptophan. Indole-3-acetic acid and tryptophan serve as signalling molecules that are part of a complex exchange of nutrients, including diatom-excreted organosulfur molecules and bacterial-excreted ammonia. The potential prevalence of this mode of signalling in the oceans is corroborated by metabolite and metatranscriptome analyses that show widespread indole-3-acetic acid production by Sulfitobacter-related bacteria, particularly in coastal environments. Our study expands on the emerging recognition that marine microbial communities are part of tightly connected networks by providing evidence that these interactions are mediated through production and exchange of infochemicals.
C1 [Amin, S. A.; van Tol, H. M.; Carlson, L. T.; Heal, K. R.; Morales, R. L.; Berthiaume, C. T.; Parker, M. S.; Djunaedi, B.; Ingalls, A. E.; Armbrust, E. V.] Univ Washington, Sch Oceanog, Seattle, WA 98195 USA.
   [Amin, S. A.] New York Univ Abu Dhabi, Chem Fac, Abu Dhabi, U Arab Emirates.
   [Hmelo, L. R.; Parsek, M. R.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA.
   [Durham, B. P.] Univ Georgia, Dept Microbiol, Athens, GA 30602 USA.
   [Moran, M. A.] Univ Georgia, Dept Marine Sci, Athens, GA 30602 USA.
C3 University of Washington; University of Washington Seattle; New York University; New York University Abu Dhabi; University of Washington; University of Washington Seattle; University System of Georgia; University of Georgia; University System of Georgia; University of Georgia
RP Armbrust, EV (corresponding author), Univ Washington, Sch Oceanog, Seattle, WA 98195 USA.
EM sa132@nyu.edu; armbrust@uw.edu
FU Gordon and Betty Moore Foundation [GBMF3776]; National Science Foundation (NSF) [OCE-1228770, OCE-1205233, OCE-1342694]; NSF/National Institutes of Health Pacific Northwest Consortium; Natural Sciences and Engineering Research Council of Canada; Gordon and Betty Moore Foundation (GBMF) [GBMF3776] Funding Source: Gordon and Betty Moore Foundation (GBMF); Division Of Ocean Sciences; Directorate For Geosciences [1228770, 1342694, 1356010] Funding Source: National Science Foundation
NR 45
TC 859
Z9 996
U1 26
U2 1075
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 4
PY 2015
VL 522
IS 7554
BP 98
EP U253
DI 10.1038/nature14488
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ5QP
UT WOS:000355543400037
PM 26017307
DA 2026-03-09
ER

PT J
AU Mandell, DJ
   Lajoie, MJ
   Mee, MT
   Takeuchi, R
   Kuznetsov, G
   Norville, JE
   Gregg, CJ
   Stoddard, BL
   Church, GM
AF Mandell, Daniel J.
   Lajoie, Marc J.
   Mee, Michael T.
   Takeuchi, Ryo
   Kuznetsov, Gleb
   Norville, Julie E.
   Gregg, Christopher J.
   Stoddard, Barry L.
   Church, George M.
TI Biocontainment of genetically modified organisms by synthetic protein design
SO NATURE
LA English
DT Article
ID escherichia-coli; biological containment; system; recombination; algorithms
AB Genetically modified organisms (GMOs) are increasingly deployed at large scales and in open environments. Genetic biocontainment strategies are needed to prevent unintended proliferation of GMOs in natural ecosystems. Existing biocontainment methods are insufficient because they impose evolutionary pressure on the organism to eject the safeguard by spontaneous mutagenesis or horizontal gene transfer, or because they can be circumvented by environmentally available compounds. Here we computationally redesign essential enzymes in the first organism possessing an altered genetic code (Escherichia coli strain C321.Delta A) to confer metabolic dependence on non-standard amino acids for survival. The resulting GMOs cannot metabolically bypass their biocontainment mechanisms using known environmental compounds, and they exhibit unprecedented resistance to evolutionary escape through mutagenesis and horizontal gene transfer. This work provides a foundation for safer GMOs that are isolated from natural ecosystems by a reliance on synthetic metabolites.
C1 [Mandell, Daniel J.; Lajoie, Marc J.; Mee, Michael T.; Kuznetsov, Gleb; Norville, Julie E.; Gregg, Christopher J.; Church, George M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
   [Lajoie, Marc J.] Harvard Univ, Program Chem Biol, Cambridge, MA 02138 USA.
   [Mee, Michael T.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA.
   [Takeuchi, Ryo; Stoddard, Barry L.] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA.
   [Church, George M.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA.
C3 Harvard University; Harvard Medical School; Harvard University; Boston University; Fred Hutchinson Cancer Center; Harvard University
RP Church, GM (corresponding author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
EM gchurch@genetics.med.harvard.edu
FU US Department of Defense National Defense Science and Engineering Graduate Fellowship; Canadian Institutes of Health Research; Department of Energy [DE-FG02-02ER63445]
NR 47
TC 340
Z9 440
U1 10
U2 355
PU NATURE PUBLISHING 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 5
PY 2015
VL 518
IS 7537
BP 55
EP +
DI 10.1038/nature14121
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7LE
UT WOS:000349098000030
PM 25607366
DA 2026-03-09
ER

PT J
AU Dale, J
   Dey, CJ
   Delhey, K
   Kempenaers, B
   Valcu, M
AF Dale, James
   Dey, Cody J.
   Delhey, Kaspar
   Kempenaers, Bart
   Valcu, Mihai
TI The effects of life history and sexual selection on male and female plumage colouration
SO NATURE
LA English
DT Article
ID sperm competition; social selection; r package; evolution; birds; dichromatism; models; size; regression; information
AB Classical sexual selection theory(1-4) provides a well-supported conceptual framework for understanding the evolution and signalling function of male ornaments. It predicts that males obtain greater fitness benefits than females through multiple mating because sperm are cheaper to produce than eggs. Sexual selection should therefore lead to the evolution of male-biased secondary sexual characters. However, females of many species are also highly ornamented(5-7). The view that this is due to a correlated genetic response to selection on males(1,8) was widely accepted as an explanation for female ornamentation for over 100 years(5) and current theoretical(9,10) and empirical(11-13) evidence suggests that genetic constraints can limit sex-specific trait evolution. Alternatively, female ornamentation can be the outcome of direct selection for signalling needs(7,14). Since few studies have explored interspecific patterns of both male and female elaboration, our understanding of the evolution of animal ornamentation remains incomplete, especially over broad taxonomic scales. Here we use a new method to quantify plumage colour of all similar to 6,000 species of passerine birds to determine the main evolutionary drivers of ornamental colouration in both sexes. We found that conspecific male and female colour elaboration are strongly correlated, suggesting that evolutionary changes in one sex are constrained by changes in the other sex. Both sexes are more ornamented in larger species and in species living in tropical environments. Ornamentation in females (but not males) is increased in cooperative breeders-species in which female-female competition for reproductive opportunities and other resources related to breeding may be high(6). Finally, strong sexual selection on males has antagonistic effects, causing an increase in male colouration but a considerably more pronounced reduction in female ornamentation. Our results indicate that although there may be genetic constraints to sexually independent colour evolution, both female and male ornamentation are strongly and often differentially related to morphological, social and life-history variables.
C1 [Dale, James] Massey Univ, Inst Nat & Math Sci, Auckland 0745, New Zealand.
   [Dey, Cody J.] McMaster Univ, Dept Biol, Hamilton, ON L8S 4K1, Canada.
   [Delhey, Kaspar] Monash Univ, Sch Biol Sci, Clayton, Vic 3800, Australia.
   [Delhey, Kaspar] Max Planck Inst Ornithol, D-78315 Radolfzell am Bodensee, Germany.
   [Kempenaers, Bart; Valcu, Mihai] Max Planck Inst Ornithol, Dept Behav Ecol & Evolutionary Genet, D-82319 Seewiesen, Germany.
C3 Massey University; McMaster University; Monash University; Max Planck Society; Max Planck Society
RP Dale, J (corresponding author), Massey Univ, Inst Nat & Math Sci, Auckland 0745, New Zealand.
EM j.dale@massey.ac.nz
FU Massey University; Australian and Pacific Science Foundation [APSF 10/8]; Natural Sciences and Engineering Research Council of Canada (NSERC) Canadian Graduate Scholarship; Australian Research Council [DE120102323]; Max Planck Society; Australian Research Council [DE120102323] Funding Source: Australian Research Council
NR 85
TC 320
Z9 359
U1 16
U2 456
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 19
PY 2015
VL 527
IS 7578
BP 367
EP +
DI 10.1038/nature15509
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9ZN
UT WOS:000365356800054
PM 26536112
DA 2026-03-09
ER

PT J
AU Ortega, MA
   Hao, Y
   Zhang, Q
   Walker, MC
   van der Donk, WA
   Nair, SK
AF Ortega, Manuel A.
   Hao, Yue
   Zhang, Qi
   Walker, Mark C.
   van der Donk, Wilfred A.
   Nair, Satish K.
TI Structure and mechanism of the tRNA-dependent lantibiotic dehydratase NisB
SO NATURE
LA English
DT Article
ID multiple sequence alignment; precursor lipid ii; in-vitro; biosynthesis; peptide; protein; generation; prenisin
AB Lantibiotics are a class of peptide antibiotics that contain one or more thioether bonds. The lantibiotic nisin is an antimicrobial peptide that is widely used as a food preservative to combat food-borne pathogens(1). Nisin contains dehydroalanine and dehydrobutyrine residues that are formed by the dehydration of Ser/Thr by the lantibiotic dehydratase NisB (ref. 2). Recent biochemical studies revealed that NisB glutamylates Ser/Thr side chains as part of the dehydration process'. However, the molecular mechanism by which NisB uses glutamate to catalyse dehydration remains unresolved. Here we show that this process involves Outamyl-tRNA(Glu) to activate Ser/Thr residues. In addition, the 2.9-angstrom crystal structure of NisB in complex with its substrate peptide NisA reveals the presence of two separate domains that catalyse the Ser/Thr glutamylation and glutamate elimination steps. The co-crystal structure also provides insights into substrate recognition by lantibiotic dehydratases. Our findings demonstrate an unexpected role for aminoacyl-tRNA in the formation of dehydroamino acids in lantibiotics, and serve as a basis for the functional characterization of the many lantibiotic-like dehydratases involved in the biosynthesis of other classes of natural products. [GRAPHICS] .
C1 [Ortega, Manuel A.; Hao, Yue; van der Donk, Wilfred A.; Nair, Satish K.] Univ Illinois, Dept Biochem, Urbana, IL 61801 USA.
   [Zhang, Qi; Walker, Mark C.; van der Donk, Wilfred A.] Univ Illinois, Dept Chem, Urbana, IL 61801 USA.
   [Zhang, Qi; Walker, Mark C.; van der Donk, Wilfred A.] Univ Illinois, Howard Hughes Med Inst, Urbana, IL 61801 USA.
   [Nair, Satish K.] Univ Illinois, Ctr Biophys & Computat Biol, Urbana, IL 61801 USA.
C3 University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; Howard Hughes Medical Institute; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign
RP Nair, SK (corresponding author), Univ Illinois, Dept Biochem, 600 South Mathews Ave, Urbana, IL 61801 USA.
EM vddonk@illinois.edu; s-nair@life.uiuc.edu
FU National Institutes of Health (NIH) [R01 GM 058822, R01 GM079038]; National Institute of General Medical Sciences (NIGMS) NIH Chemistry Biology Interface Training Grant [5T32-GM070421]; Ford Foundation; Lowell P. Hager fellowship from the Department of Biochemistry; NIH [S10 RR027109 A]; National Institute of General Medical Sciences [R01GM079038] Funding Source: NIH RePORTER
NR 49
TC 258
Z9 316
U1 1
U2 173
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JAN 22
PY 2015
VL 517
IS 7535
BP 509
EP +
DI 10.1038/nature13888
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AZ4MU
UT WOS:000348196500040
PM 25363770
DA 2026-03-09
ER

PT J
AU Willis, MJ
   Herried, BG
   Bevis, MG
   Bell, RE
AF Willis, Michael J.
   Herried, Bradley G.
   Bevis, Michael G.
   Bell, Robin E.
TI Recharge of a subglacial lake by surface meltwater in northeast Greenland
SO NATURE
LA English
DT Article
ID ice-sheet; glacier; water; acceleration; system; cap
AB In a warming climate, surface meltwater production on large ice sheets is expected to increase. If this water is delivered to the ice sheet base it may have important consequences for ice dynamics. For example, basal water distributed in a diffuse network can decrease basal friction(1,2) and accelerate ice flow(3-8), whereas channelized basal water can move quickly to the ice margin, where it can alter fjord circulation and submarine melt rates(9,10). Less certain is whether surface meltwater can be trapped and stored in subglacial lakes beneath large ice sheets. Here we show that a subglacial lake in Greenland drained quickly, as seen in the collapse of the ice surface, and then refilled from surface meltwater input. We use digital elevation models from stereo satellite imagery and airborne measurements to resolve elevation changes during the evolution of the surface and basal hydrologic systems at the Flade Isblink ice cap in northeast Greenland. During the autumn of 2011, a collapse basin about 70 metres deep and about 0.4 cubic kilometres in volume formed near the southern summit of the ice cap as a subglacial lake drained into a nearby fjord. Over the next two years, rapid uplift of the floor of the basin (which is approximately 8.4 square kilometres in area) occurred as surface meltwater flowed into crevasses around the basin margin and refilled the subglacial lake. Our observations show that surface meltwater can be trapped and stored at the bed of an ice sheet. Sensible and latent heat released by this trapped meltwater could soften nearby colder basal ice(11) and alter downstream ice dynamics(12,13). Heat transport associated with meltwater trapped in subglacial lakes should be considered when predicting how ice sheet behaviour will change in a warming climate.
C1 [Willis, Michael J.] Cornell Univ, Ithaca, NY 14853 USA.
   [Willis, Michael J.] Univ N Carolina, Dept Geol Sci, Chapel Hill, NC 27599 USA.
   [Herried, Bradley G.] Univ Minnesota, Polar Geospatial Ctr, St Paul, MN 55108 USA.
   [Bevis, Michael G.] Ohio State Univ, Sch Earth Sci, Columbus, OH 43210 USA.
   [Bell, Robin E.] Columbia Univ, Lamont Doherty Earth Observ, Palisades, NY 10964 USA.
C3 Cornell University; University of North Carolina; University of North Carolina Chapel Hill; University of Minnesota System; University of Minnesota Twin Cities; University System of Ohio; Ohio State University; Columbia University
RP Willis, MJ (corresponding author), Cornell Univ, Ithaca, NY 14853 USA.
EM mike.willis@cornell.edu
FU US National Science Foundation [ARC-1111882, ANT-1043681]; Office of Polar Programs (OPP); Directorate For Geosciences [1043681] Funding Source: National Science Foundation
NR 35
TC 76
Z9 85
U1 0
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 FEB 12
PY 2015
VL 518
IS 7538
BP 223
EP U165
DI 10.1038/nature14116
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300036
PM 25607355
DA 2026-03-09
ER

PT J
AU Albertin, CB
   Simakov, O
   Mitros, T
   Wang, ZY
   Pungor, JR
   Edsinger-Gonzales, E
   Brenner, S
   Ragsdale, CW
   Rokhsar, DS
AF Albertin, Caroline B.
   Simakov, Oleg
   Mitros, Therese
   Wang, Z. Yan
   Pungor, Judit R.
   Edsinger-Gonzales, Eric
   Brenner, Sydney
   Ragsdale, Clifton W.
   Rokhsar, Daniel S.
TI The octopus genome and the evolution of cephalopod neural and morphological novelties
SO NATURE
LA English
DT Article
ID binding domain; gene-cluster; generation; alignment; elements; duplication; complexity; database; tophat; origin
AB Coleoid cephalopods (octopus, squid and cuttlefish) are active, resourceful predators with a rich behavioural repertoire(1). They have the largest nervous systems among the invertebrates(2) and present other striking morphological innovations including camera-like eyes, prehensile arms, a highly derived early embryogenesis and a remarkably sophisticated adaptive colouration system(1,3). To investigate the molecular bases of cephalopod brain and body innovations, we sequenced the genome and multiple transcriptomes of the California two-spot octopus, Octopus bimaculoides. We found no evidence for hypothesized whole-genome duplications in the octopus lineage(4-6). The core developmental and neuronal gene repertoire of the octopus is broadly similar to that found across invertebrate bilaterians, except for massive expansions in two gene families previously thought to be uniquely enlarged in vertebrates: the protocadherins, which regulate neuronal development, and the C2H2 superfamily of zinc-finger transcription factors. Extensive messenger RNA editing generates transcript and protein diversity in genes involved in neural excitability, as previously described(7), as well as in genes participating in a broad range of other cellular functions. We identified hundreds of cephalopod-specific genes, many of which showed elevated expression levels in such specialized structures as the skin, the suckers and the nervous system. Finally, we found evidence for large-scale genomic rearrangements that are closely associated with transposable element expansions. Our analysis suggests that substantial expansion of a handful of gene families, along with extensive remodelling of genome linkage and repetitive content, played a critical role in the evolution of cephalopod morphological innovations, including their large and complex nervous systems.
C1 [Albertin, Caroline B.; Ragsdale, Clifton W.] Univ Chicago, Dept Organismal Biol & Anat, Chicago, IL 60637 USA.
   [Simakov, Oleg; Edsinger-Gonzales, Eric; Brenner, Sydney; Rokhsar, Daniel S.] Grad Univ, Okinawa Inst Sci & Technol, Onna, Okinawa 9040495, Japan.
   [Simakov, Oleg] Heidelberg Univ, Ctr Organismal Studies, D-69117 Heidelberg, Germany.
   [Mitros, Therese; Edsinger-Gonzales, Eric; Rokhsar, Daniel S.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
   [Wang, Z. Yan; Pungor, Judit R.; Ragsdale, Clifton W.] Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA.
   [Rokhsar, Daniel S.] US DOE, Joint Genome Inst, Walnut Creek, CA 94598 USA.
C3 University of Chicago; Okinawa Institute of Science & Technology Graduate University; Ruprecht Karls University Heidelberg; University of California System; University of California Berkeley; University of Chicago; United States Department of Energy (DOE); Joint BioEnergy Institute - JBEI; Joint Genome Institute - JGI
RP Ragsdale, CW (corresponding author), Univ Chicago, Dept Organismal Biol & Anat, 1025 E 57Th St, Chicago, IL 60637 USA.
EM cragsdale@uchicago.edu; dsrokhsar@gmail.com
FU Molecular Genetics Unit of the Okinawa Institute of Science and Technology Graduate University; NSF [IOS-1354898, DGE-0903637]; NIH [R03 HD064887, S10RR029668, S10RR027303]; University of Chicago Functional Genomics Facility by NIH [UL1 TR000430]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [T32HD055164] Funding Source: NIH RePORTER; Division Of Integrative Organismal Systems; Direct For Biological Sciences [1354898] Funding Source: National Science Foundation
NR 58
TC 447
Z9 522
U1 14
U2 434
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD AUG 13
PY 2015
VL 524
IS 7564
BP 220
EP +
DI 10.1038/nature14668
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900032
PM 26268193
DA 2026-03-09
ER

PT J
AU Ohyama, T
   Schneider-Mizell, CM
   Fetter, RD
   Aleman, JV
   Franconville, R
   Rivera-Alba, M
   Mensh, BD
   Branson, KM
   Simpson, JH
   Truman, JW
   Cardona, A
   Zlatic, M
AF Ohyama, Tomoko
   Schneider-Mizell, Casey M.
   Fetter, Richard D.
   Aleman, Javier Valdes
   Franconville, Romain
   Rivera-Alba, Marta
   Mensh, Brett D.
   Branson, Kristin M.
   Simpson, Julie H.
   Truman, James W.
   Cardona, Albert
   Zlatic, Marta
TI A multilevel multimodal circuit enhances action selection in Drosophila
SO NATURE
LA English
DT Article
ID multisensory integration; direction-selectivity; nociceptive neurons; wiring specificity; gene-expression; nervous-system; unit responses; nompc; organization; projections
AB Natural events present multiple types of sensory cues each detected by a specialized sensory modality. Combining information from several modalities is essential for the selection of appropriate actions. Key to understanding multimodal computations is determining the structural patterns of multimodal convergence and how these patterns contribute to behaviour. Modalities could converge early, late or at multiple levels in the sensory processing hierarchy. Here we show that combining rnechanosensory and nociceptive cues synergistically enhances the selection of the fastest mode of escape locomotion in Drosophila larvae. In an electron microscopy volume that spans the entire insect nervous system, we reconstructed the multisensory circuit supporting the synergy, spanning multiple levels of the sensory processing hierarchy. The wiring diagram revealed a complex multilevel rnultimorlal convergence architecture. Using behavioural and physiological studies, we identified functionally connected circuit nodes that trigger the fastest locomotor mode, and others that facilitate it, and we provide evidence that multiple levels of multimodal integration contribute to escape mode selection. We propose that the multilevel rnultimoclal convergence architecture may be a general feature of multisensory circuits enabling complex input-output functions and selective tuning to ecologically relevant combinations of cues.
C1 [Ohyama, Tomoko; Schneider-Mizell, Casey M.; Fetter, Richard D.; Aleman, Javier Valdes; Franconville, Romain; Rivera-Alba, Marta; Mensh, Brett D.; Branson, Kristin M.; Simpson, Julie H.; Truman, James W.; Cardona, Albert; Zlatic, Marta] Howard Hughes Med Inst Janelia Res Campus, Ashburn, VA 20147 USA.
RP Cardona, A (corresponding author), Howard Hughes Med Inst Janelia Res Campus, 19700 Helix Dr, Ashburn, VA 20147 USA.
EM cardonaa@hhmi.org; zlaticm@hhmi.org
FU Janelia HHMI; Institute of Neuroinformatics of the University of Zurich; ETH Zurich; SNSF [31003A_132969]; Universitat Zurich Forschungskredit; HHMI Visiting Scientist program at Janelia; Swiss National Science Foundation (SNF) [31003A_132969] Funding Source: Swiss National Science Foundation (SNF)
NR 78
TC 320
Z9 397
U1 5
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 APR 30
PY 2015
VL 520
IS 7549
BP 633
EP U107
DI 10.1038/nature14297
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700041
PM 25896325
DA 2026-03-09
ER

PT J
AU Lewis, SL
   Maslin, MA
AF Lewis, Simon L.
   Maslin, Mark A.
TI Defining the Anthropocene
SO NATURE
LA English
DT Article
ID tropical secondary forests; global carbon-cycle; atmospheric co2; ice-core; human impact; climate; methane; fire; evolution; variability
AB Time is divided by geologists according to marked shifts in Earth's state. Recent global environmental changes suggest that Earth may have entered a new human-dominated geological epoch, the Anthropocene. Here we review the historical genesis of the idea and assess anthropogenic signatures in the geological record against the formal requirements for the recognition of a new epoch. The evidence suggests that of the various proposed dates two do appear to conform to the criteria to mark the beginning of the Anthropocene: 1610 and 1964. The formal establishment of an Anthropocene Epoch would mark a fundamental change in the relationship between humans and the Earth system.
C1 [Lewis, Simon L.; Maslin, Mark A.] UCL, Dept Geog, London WC1E 6BT, England.
   [Lewis, Simon L.] Univ Leeds, Sch Geog, Leeds LS2 9JT, W Yorkshire, England.
C3 University of London; University College London; University of Leeds
RP Lewis, SL (corresponding author), UCL, Dept Geog, Gower St, London WC1E 6BT, England.
EM s.l.lewis@ucl.ac.uk
FU European Research Council (T-FORCES); Philip Leverhulme Prize award; Royal Society Wolfson Research Merit Award
NR 129
TC 2139
Z9 2763
U1 46
U2 1481
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 12
PY 2015
VL 519
IS 7542
BP 171
EP 180
DI 10.1038/nature14258
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500027
PM 25762280
DA 2026-03-09
ER

PT J
AU Kurtova, AV
   Xiao, J
   Mo, QX
   Pazhanisamy, S
   Krasnow, R
   Lerner, SP
   Chen, FJ
   Roh, TT
   Lay, E
   Ho, PL
   Chan, KS
AF Kurtova, Antonina V.
   Xiao, Jing
   Mo, Qianxing
   Pazhanisamy, Senthil
   Krasnow, Ross
   Lerner, Seth P.
   Chen, Fengju
   Roh, Terrence T.
   Lay, Erica
   Ho, Philip Levy
   Chan, Keith Syson
TI Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance
SO NATURE
LA English
DT Article
ID stem-cells; chemotherapy; neoadjuvant; homeostasis; progression; renewal; growth; repair
AB Cytotoxic chemotherapy is effective in debulking tumour masses initially; however, in some patients tumours become progressively unresponsive after multiple treatment cycles. Previous studies have demonstrated that cancer stem cells (CSCs) are selectively enriched after chemotherapy through enhanced survival(1-3). Here we reveal a new mechanism by which bladder CSCs actively contribute to therapeutic resistance via an unexpected proliferative response to repopulate residual tumours between chemotherapy cycles, using human bladder cancer xenografts. Further analyses demonstrate the recruitment of a quiescent label-retaining pool of CSCs into cell division in response to chemotherapy-induced damages, similar to mobilization of normal stem cells during wound repair(4-7). While chemotherapy effectively induces apoptosis, associated prostaglandin E-2 (PGE(2)) release paradoxically promotes neighbouring CSC repopulation. This repopulation can be abrogated by a PGE(2)-neutralizing antibody and celecoxib drug-mediated blockade of PGE(2) signalling. In vivo administration of the cyclooxygenase-2 (COX2) inhibitor celecoxib effectively abolishes a PGE(2)- and COX2-mediated wound response gene signature, and attenuates progressive manifestation of chemoresistance in xenograft tumours, including primary xenografts derived from a patient who was resistant to chemotherapy. Collectively, these findings uncover a new underlying mechanism that models the progressive development of clinical chemoresistance, and implicate an adjunctive therapy to enhance chemotherapeutic response of bladder urothelial carcinomas by abrogating early tumour repopulation.
C1 [Kurtova, Antonina V.; Xiao, Jing; Roh, Terrence T.; Chan, Keith Syson] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.
   [Kurtova, Antonina V.; Chan, Keith Syson] Baylor Coll Med, Program Translat Biol & Mol Med, Houston, TX 77030 USA.
   [Mo, Qianxing; Chen, Fengju; Chan, Keith Syson] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA.
   [Mo, Qianxing; Chen, Fengju; Chan, Keith Syson] Baylor Coll Med, Ctr Cell Gene & Therapy, Houston, TX 77030 USA.
   [Pazhanisamy, Senthil; Krasnow, Ross; Lerner, Seth P.; Lay, Erica; Ho, Philip Levy; Chan, Keith Syson] Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA.
   [Roh, Terrence T.] Baylor Coll Med, Summer Med & Res Training SMART Program, Houston, TX 77030 USA.
C3 Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College Medical Hospital; Baylor College of Medicine; Baylor College of Medicine
RP Chan, KS (corresponding author), Baylor Coll Med, Dept Mol & Cellular Biol, One Baylor Plaza, Houston, TX 77030 USA.
EM kc1@bcm.edu
FU National Cancer Institute [CA129640, CA175397]; V Scholar Award; Dan L Duncan Career Award; Bladder Cancer Partnership; CPRIT pre-doctoral fellowship [RP101499]; AUA Research Scholar Award; CPRIT training grant [RP140102]; National Cancer Institute [P30CA125123, R01CA175397] Funding Source: NIH RePORTER
NR 30
TC 484
Z9 535
U1 2
U2 158
PU NATURE PUBLISHING 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 8
PY 2015
VL 517
IS 7533
BP 209
EP U224
DI 10.1038/nature14034
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY3IM
UT WOS:000347477600038
PM 25470039
DA 2026-03-09
ER

PT J
AU Fillmore, CM
   Xu, CX
   Desai, PT
   Berry, JM
   Rowbotham, SP
   Lin, YJ
   Zhang, HK
   Marquez, VE
   Hammerman, PS
   Wong, KK
   Kim, CF
AF Fillmore, Christine M.
   Xu, Chunxiao
   Desai, Pooja T.
   Berry, Joanne M.
   Rowbotham, Samuel P.
   Lin, Yi-Jang
   Zhang, Haikuo
   Marquez, Victor E.
   Hammerman, Peter S.
   Wong, Kwok-Kin
   Kim, Carla F.
TI EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors
SO NATURE
LA English
DT Article
ID gene-expression; microarray data; cancer; adenocarcinoma; mutations; complexes; polycomb; swi/snf; growth; antagonism
AB Non-small-cell lung cancer is the leading cause of cancer-related death worldwide(1). Chemotherapies such as the topoisomerase II (TopoII) inhibitor etoposide effectively reduce disease in a minority of patients with this cancer(2,3); therefore, alternative drug targets, including epigenetic enzymes, are under consideration for therapeutic intervention(4). A promising potential epigenetic target is the methyltransferase EZH2, which in the context of the polycomb repressive complex 2 (PRC2) is well known to tri-methylate histone H3 at lysine 27 (H3K27me3) and elicit gene silencing(5). Here we demonstrate that EZH2 inhibition has differential effects on the TopoII inhibitor response of non-small-cell lung cancers in vitro and in vivo. EGFR and BRG1 mutations are genetic biomarkers that predict enhanced sensitivity to TopoII inhibitor in response to EZH2 inhibition. BRG1 loss-of-function mutant tumours respond to EZH2 inhibition with increased S phase, anaphase bridging, apoptosis and TopoII inhibitor sensitivity. Conversely, EGFR and BRG1 wild-type tumours upregulate BRG1 in response to EZH2 inhibition and ultimately become more resistant to TopoII inhibitor. EGFR gain-of-function mutant tumours are also sensitive to dual EZH2 inhibition and TopoII inhibitor, because of genetic antagonism between EGFR and BRG1. These findings suggest an opportunity for precision medicine in the genetically complex disease of non-small-cell lung cancer.
C1 [Fillmore, Christine M.; Desai, Pooja T.; Berry, Joanne M.; Rowbotham, Samuel P.; Kim, Carla F.] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA.
   [Fillmore, Christine M.; Rowbotham, Samuel P.; Lin, Yi-Jang; Kim, Carla F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA.
   [Fillmore, Christine M.; Rowbotham, Samuel P.; Kim, Carla F.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA.
   [Xu, Chunxiao; Zhang, Haikuo; Hammerman, Peter S.; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.
   [Xu, Chunxiao; Zhang, Haikuo; Wong, Kwok-Kin] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA.
   [Marquez, Victor E.] NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA.
C3 Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
RP Kim, CF (corresponding author), Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA.
EM carla.kim@childrens.harvard.edu
FU Ladies Auxiliary to the Veterans of Foreign Wars; American Cancer Society [PF-12-151-01-DMC]; Uniting Against Lung Cancer Young Investigator Award; Boston University Undergraduate Research Opportunities Program; American Cancer Society Research Scholar Grant [RSG-08-082-01-MGO]; V Foundation for Cancer Research; Basil O'Conner March of Dimes Starter Award; Harvard Stem Cell Institute; Lung Cancer Research Foundation; National Institutes of Health (NIH) [CA122794, CA140594, CA163896, CA166480, CA154303, CA120964]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; NIH [K08 CA163677];  [RO1 HL090136];  [U01 HL100402 RFA-HL-09-004]; National Cancer Institute [P01CA120964, P01CA154303, R01CA166480] Funding Source: NIH RePORTER
NR 51
TC 220
Z9 268
U1 1
U2 116
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD APR 9
PY 2015
VL 520
IS 7546
BP 239
EP U261
DI 10.1038/nature14122
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CF3NA
UT WOS:000352454600043
PM 25629630
DA 2026-03-09
ER

PT J
AU Hashimshony, T
   Feder, M
   Levin, M
   Hall, BK
   Yanai, I
AF Hashimshony, Tamar
   Feder, Martin
   Levin, Michal
   Hall, Brian K.
   Yanai, Itai
TI Spatiotemporal transcriptomics reveals the evolutionary history of the endoderm germ layer
SO NATURE
LA English
DT Article
ID gene-expression; c-elegans; induction; origin; muscle; gut; differentiation; intestine; lineage; embryos
AB The concept of germ layers has been one of the foremost organizing principles in developmental biology, classification, systematics and evolution for 150 years (refs 1-3). Of the three germ layers, the mesoderm is found in bilaterian animals but is absent in species in the phyla Cnidaria and Ctenophora, which has been taken as evidence that the mesoderm was the final germ layer to evolve(1,4,5). The origin of the ectoderm and endoderm germ layers, however, remains unclear, with models supporting the antecedence of each as well as a simultaneous origin(4,6-9). Here we determine the temporal and spatial components of gene expression spanning embryonic development for all Caenorhabditis elegans genes and use it to determine the evolutionary ages of the germ layers. The gene expression program of the mesoderm is induced after those of the ectoderm and endoderm, thus making it the last germ layer both to evolve and to develop. Strikingly, the C. elegans endoderm and ectoderm expression programs do not co-induce; rather the endoderm activates earlier, and this is also observed in the expression of endoderm orthologues during the embryology of the frog Xenopus tropicalis, the sea anemone Nema-tostella vectensis and the sponge Amphimedon queenslandica. Querying the phylogenetic ages of specifically expressed genes reveals that the endoderm comprises older genes. Taken together, we propose that the endoderm program dates back to the origin of multicellularity, whereas the ectoderm originated as a secondary germ layer freed from ancestral feeding functions.
C1 [Hashimshony, Tamar; Feder, Martin; Levin, Michal; Yanai, Itai] Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel.
   [Hall, Brian K.] Dalhousie Univ, Dept Biol, Halifax, NS B3H 4J1, Canada.
C3 Technion Israel Institute of Technology; Dalhousie University
RP Yanai, I (corresponding author), Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel.
EM yanai@technion.ac.il
FU European Research Council grant (EvoDevoPaths); EMBO Young Investigator Program
NR 47
TC 136
Z9 172
U1 0
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 MAR 12
PY 2015
VL 519
IS 7542
BP 219
EP +
DI 10.1038/nature13996
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500036
PM 25487147
DA 2026-03-09
ER

PT J
AU Slater, HC
   Ross, A
   Ouédraogo, AL
   White, LJ
   Nguon, C
   Walker, PGT
   Ngor, P
   Aguas, R
   Silal, SP
   Dondorp, AM
   La Barre, P
   Burton, R
   Sauerwein, RW
   Drakeley, C
   Smith, TA
   Bousema, T
   Ghani, AC
AF Slater, Hannah C.
   Ross, Amanda
   Ouedraogo, Andre Lin
   White, Lisa J.
   Nguon, Chea
   Walker, Patrick G. T.
   Ngor, Pengby
   Aguas, Ricardo
   Silal, Sheetal P.
   Dondorp, Arjen M.
   La Barre, Paul
   Burton, Robert
   Sauerwein, Robert W.
   Drakeley, Chris
   Smith, Thomas A.
   Bousema, Teun
   Ghani, Azra C.
TI Assessing the impact of next-generation rapid diagnostic tests on Plasmodium falciparum malaria elimination strategies
SO NATURE
LA English
DT Article
ID mediated isothermal amplification; treatment intervention; asymptomatic malaria; infectious reservoir; cost-effectiveness; model; administrations; transmission; performance; microscopy
AB Mass-screen-and-treat and targeted mass-drug-administration strategies are being considered as a means to interrupt transmission of Plasmodium falciparum malaria. However, the effectiveness of such strategies will depend on the extent to which current and future diagnostics are able to detect those individuals who are infectious to mosquitoes. We estimate the relationship between parasite density and onward infectivity using sensitive quantitative parasite diagnostics and mosquito feeding assays from Burkina Faso. We find that a diagnostic with a lower detection limit of 200 parasites per microlitre would detect 55% of the infectious reservoir (the combined infectivity to mosquitoes of the whole population weighted by how often each individual is bitten) whereas a test with a limit of 20 parasites per microlitre would detect 83% and 2 parasites per microlitre would detect 95% of the infectious reservoir. Using mathematical models, we show that increasing the diagnostic sensitivity from 200 parasites per microlitre (equivalent to microscopy or current rapid diagnostic tests) to 2 parasites per microlitre would increase the number of regions where transmission could be interrupted with a mass-screen-and-treat programme from an entomological inoculation rate below 1 to one of up to 4. The higher sensitivity diagnostic could reduce the number of treatment rounds required to interrupt transmission in areas of lower prevalence. We predict that mass-screen-and-treat with a highly sensitive diagnostic is less effective than mass drug administration owing to the prophylactic protection provided to uninfected individuals by the latter approach. In low-transmission settings such as those in Southeast Asia, we find that a diagnostic tool with a sensitivity of 20 parasites per microlitre may be sufficient for targeted mass drug administration because this diagnostic is predicted to identify a similar village population prevalence compared with that currently detected using polymerase chain reaction if treatment levels are high and screening is conducted during the dry season. Along with other factors, such as coverage, choice of drug, timing of the intervention, importation of infections, and seasonality, the sensitivity of the diagnostic can play a part in increasing the chance of interrupting transmission.
C1 [Slater, Hannah C.; Walker, Patrick G. T.; Ghani, Azra C.] Univ London Imperial Coll Sci Technol & Med, Fac Med, MRC Ctr Outbreak Anal & Modelling, Dept Infect Dis Epidemiol, London W2 1PG, England.
   [Ross, Amanda; Smith, Thomas A.] Swiss Trop & Publ Hlth Inst, CH-4002 Basel, Switzerland.
   [Ross, Amanda; Smith, Thomas A.] Univ Basel, CH-4001 Basel, Switzerland.
   [Ouedraogo, Andre Lin] Inst Dis Modelling, Bellevue, WA 98005 USA.
   [Ouedraogo, Andre Lin] Ctr Natl Rech & Format Paludisme, Dept Biomed Sci, Ouagadougou, Burkina Faso.
   [White, Lisa J.; Ngor, Pengby; Aguas, Ricardo; Dondorp, Arjen M.] Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok 10400, Thailand.
   [White, Lisa J.; Dondorp, Arjen M.] Univ Oxford, Nuffield Dept Med, Ctr Trop Med, Oxford OX3 7LJ, England.
   [Nguon, Chea; Ngor, Pengby] Minist Hlth, Natl Malaria Ctr, Phnom Penh 12302, Cambodia.
   [Silal, Sheetal P.] Univ Cape Town, Dept Stat Sci, ZA-7701 Cape Town, South Africa.
   [La Barre, Paul; Burton, Robert] PATH, Seattle, WA 98121 USA.
   [Sauerwein, Robert W.; Bousema, Teun] Radboud Univ Nijmegen, Med Ctr, NL-6525 HP Nijmegen, Netherlands.
   [Drakeley, Chris; Bousema, Teun] Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England.
C3 Imperial College London; Swiss School of Public Health (SSPH+); University of Basel; Swiss Tropical & Public Health Institute; University of Basel; Mahidol Oxford Tropical Medicine Research Unit (MORU); Mahidol University; University of Oxford; University of Cape Town; Radboud University Nijmegen; University of London; London School of Hygiene & Tropical Medicine
RP Slater, HC (corresponding author), Univ London Imperial Coll Sci Technol & Med, Fac Med, MRC Ctr Outbreak Anal & Modelling, Dept Infect Dis Epidemiol, Norfolk Pl, London W2 1PG, England.
EM hannah.slater@imperial.ac.uk
FU Bill and Melinda Gates Foundation [OPP1110500, OPP1032350]; Wellcome-Trust Major Overseas Programme in SE Asia [106698/Z/14/Z]; Gottfried und Julia Bangerter-Rhyner Stiftung; Novartis Foundation for Medical Biological Research [13A13]; Bill & Melinda Gates Foundation (DIAMETER) [OPP1053616]; Netherlands Organization for Higher Education in the Tropics [CF29132006]; Global Good Fund, Bellevue, Washington, USA; Ministry of Health of Burkina Faso; Bill & Melinda Gates Foundation (AFIRM) [OPP1034789]; European Research Council [ERC-2014-StG 639776]; Medicines for Malaria Venture; UK MRC; UK Department for International Development; MRC [MR/L012189/1, MR/K010174/1] Funding Source: UKRI; Bill and Melinda Gates Foundation [OPP1053616, OPP1110500] Funding Source: Bill and Melinda Gates Foundation; Medical Research Council [MR/L012189/1, MR/K010174/1, MR/K010174/1B] Funding Source: researchfish
NR 49
TC 102
Z9 115
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 DEC 3
PY 2015
VL 528
IS 7580
BP S94
EP S101
DI 10.1038/nature16040
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000016
PM 26633771
DA 2026-03-09
ER

PT J
AU Koppes, M
   Hallet, B
   Rignot, E
   Mouginot, J
   Wellner, JS
   Boldt, K
AF Koppes, Michele
   Hallet, Bernard
   Rignot, Eric
   Mouginot, Jeremie
   Wellner, Julia Smith
   Boldt, Katherine
TI Observed latitudinal variations in erosion as a function of glacier dynamics
SO NATURE
LA English
DT Article
ID antarctic peninsula; sediment accumulation; patagonia; evolution; climate; fjords; ice; landscape; variability; glaciation
AB Glacial erosion is fundamental to our understanding of the role of Cenozoic-era climate change in the development of topography worldwide, yet the factors that control the rate of erosion by ice remain poorly understood. In many tectonically active mountain ranges, glaciers have been inferred to be highly erosive, and conditions of glaciation are used to explain both the marked relief typical of alpine settings and the limit on mountain heights above the snowline, that is, the glacial buzzsaw(1). In other high-latitude regions, glacial erosion is presumed to be minimal, where a mantle of cold ice effectively protects landscapes from erosion(2-4). Glacial erosion rates are expected to increase with decreasing latitude, owing to the climatic control on basal temperature and the production of meltwater, which promotes glacial sliding, erosion and sediment transfer. This relationship between climate, glacier dynamics and erosion rate is the focus of recent numerical modelling(5-8), yet it is qualitative and lacks an empirical database. Here we present a comprehensive data set that permits explicit examination of the factors controlling glacier erosion across climatic regimes. We report contemporary ice fluxes, sliding speeds and erosion rates inferred from sediment yields from 15 outlet glaciers spanning 19 degrees of latitude from Patagonia to the Antarctic Peninsula. Although this broad region has a relatively uniform tectonic and geologic history, the thermal regimes of its glaciers range from temperate to polar. We find that basin-averaged erosion rates vary by three orders of magnitude over this latitudinal transect. Our findings imply that climate and the glacier thermal regime control erosion rates more than do extent of ice cover, ice flux or sliding speeds.
C1 [Koppes, Michele] Univ British Columbia, Dept Geog, Vancouver, BC V6T 1Z2, Canada.
   [Hallet, Bernard] Univ Washington, Dept Earth & Space Sci, Seattle, WA 98195 USA.
   [Hallet, Bernard] Univ Washington, Quaternary Res Ctr, Seattle, WA 98195 USA.
   [Rignot, Eric; Mouginot, Jeremie] Univ Calif Irvine, Dept Earth Syst Sci, Irvine, CA 92617 USA.
   [Rignot, Eric] NASA, Jet Prop Lab, Pasadena, CA 91109 USA.
   [Wellner, Julia Smith] Univ Houston, Dept Earth & Atmospher Sci, Houston, TX 77204 USA.
   [Boldt, Katherine] Univ Washington, Sch Oceanog, Seattle, WA 98195 USA.
C3 University of British Columbia; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of California System; University of California Irvine; National Aeronautics & Space Administration (NASA); NASA Jet Propulsion Laboratory (JPL); University of Houston System; University of Houston; University of Washington; University of Washington Seattle
RP Koppes, M (corresponding author), Univ British Columbia, Dept Geog, 1984 West Mall, Vancouver, BC V6T 1Z2, Canada.
EM koppes@geog.ubc.ca
FU US National Science Foundation [OPP 0338371]
NR 52
TC 157
Z9 169
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 OCT 1
PY 2015
VL 526
IS 7571
BP 100
EP +
DI 10.1038/nature15385
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS5CY
UT WOS:000362095100041
PM 26432248
DA 2026-03-09
ER

PT J
AU West, AP
   Khoury-Hanold, W
   Staron, M
   Tal, MC
   Pineda, CM
   Lang, SM
   Bestwick, M
   Duguay, BA
   Raimundo, N
   MacDuff, DA
   Kaech, SM
   Smiley, JR
   Means, RE
   Iwasaki, A
   Shadel, GS
AF West, A. Phillip
   Khoury-Hanold, William
   Staron, Matthew
   Tal, Michal C.
   Pineda, Cristiana M.
   Lang, Sabine M.
   Bestwick, Megan
   Duguay, Brett A.
   Raimundo, Nuno
   MacDuff, Donna A.
   Kaech, Susan M.
   Smiley, James R.
   Means, Robert E.
   Iwasaki, Akiko
   Shadel, Gerald S.
TI Mitochondrial DNA stress primes the antiviral innate immune response
SO NATURE
LA English
DT Article
ID green fluorescent protein; transcription factor; virus; herpes; expression; replication; recognition; infection; autophagy; effector
AB Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nudeoids(1). The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation(2). Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses'. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined(4). Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)-IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity.
C1 [West, A. Phillip; Pineda, Cristiana M.; Lang, Sabine M.; Bestwick, Megan; Raimundo, Nuno; Means, Robert E.; Shadel, Gerald S.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA.
   [Khoury-Hanold, William; Staron, Matthew; Tal, Michal C.; Kaech, Susan M.; Iwasaki, Akiko] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA.
   [Duguay, Brett A.; Smiley, James R.] Univ Alberta, Dept Med Microbiol & Immunol, Li Ka Shing Inst Virol, Edmonton, AB T6G 2S2, Canada.
   [MacDuff, Donna A.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA.
   [Kaech, Susan M.; Iwasaki, Akiko] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
   [Shadel, Gerald S.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA.
C3 Yale University; Yale University; University of Alberta; Washington University (WUSTL); Howard Hughes Medical Institute; Yale University
RP Shadel, GS (corresponding author), Yale Univ, Sch Med, Dept Pathol, 333 Cedar St, New Haven, CT 06520 USA.
EM gerald.shadel@yale.edu
FU United Mitochondrial Disease Foundation; Mitocon; NIH [R01 AG047632, P01 ES011163, R01 A1054359, R01 A1081884, T32 AI055403, F31 AG039163, NRSA F32 DK091042]; Canadian Institutes for Health Research [MOP37995]; Canada Research Chair in Molecular Virology; American Cancer Society [PF-13-035-01-DMC]; Alberta Innovates-Health Solutions; Queen Elizabeth II Graduate Scholarship; National Institute of Allergy and Infectious Diseases [T32AI055403] Funding Source: NIH RePORTER
NR 49
TC 1482
Z9 1670
U1 9
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 APR 23
PY 2015
VL 520
IS 7548
BP 553
EP +
DI 10.1038/nature14156
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500046
PM 25642965
DA 2026-03-09
ER

PT J
AU Burr, DM
   Bridges, NT
   Marshall, JR
   Smith, JK
   White, BR
   Emery, JP
AF Burr, Devon M.
   Bridges, Nathan T.
   Marshall, John R.
   Smith, James K.
   White, Bruce R.
   Emery, Joshua P.
TI Higher-than-predicted saltation threshold wind speeds on Titan
SO NATURE
LA English
DT Article
ID particle-size; mars; earth; forces; venus; sand; simulations; roughness; transport; surfaces
AB Titan, the largest satellite of Saturn, exhibits extensive aeolian, that is, wind-formed, dunes(1,2), features previously identified exclusively on Earth, Mars and Venus. Wind tunnel data collected under ambient and planetary-analogue conditions inform our models of aeolian processes on the terrestrial planets(3,4). However, the accuracy of these widely used formulations in predicting the threshold wind speeds required to move sand by saltation, or by short bounces, has not been tested under conditions relevant for non-terrestrial planets. Here we derive saltation threshold wind speeds under the thick-atmosphere, low-gravity and low-sediment-density conditions on Titan, using a high-pressure wind tunnel(5) refurbished to simulate the appropriate kinematic viscosity for the near-surface atmosphere of Titan. The experimentally derived saltation threshold wind speeds are higher than those predicted by models based on terrestrial-analogue experiments(6,7), indicating the limitations of these models for such extreme conditions. The models can be reconciled with the experimental results by inclusion of the extremely low ratio of particle density to fluid density(8) on Titan. Whereas the density ratio term enables accurate modelling of aeolian entrainment in thick atmospheres, such as those inferred for some extrasolar planets, our results also indicate that for environments with high density ratios, such as in jets on icy satellites or in tenuous atmospheres or exospheres, the correction for low-density-ratio conditions is not required.
C1 [Burr, Devon M.; Emery, Joshua P.] Univ Tennessee, Earth & Planetary Sci Dept, Knoxville, TN 37996 USA.
   [Bridges, Nathan T.] Johns Hopkins Univ, Dept Space, Appl Phys Lab, Laurel, MD 20723 USA.
   [Marshall, John R.] SETI Inst, Mountain View, CA 94043 USA.
   [Smith, James K.] Arizona State Univ, Tempe, AZ 85287 USA.
   [White, Bruce R.] Univ Calif Davis, Dept Mech Engn, Davis, CA 95616 USA.
C3 University of Tennessee System; University of Tennessee Knoxville; Johns Hopkins University; Johns Hopkins University Applied Physics Laboratory; SETI Institute; Arizona State University; Arizona State University-Tempe; University of California System; University of California Davis
RP Burr, DM (corresponding author), Univ Tennessee, Earth & Planetary Sci Dept, 306 EPS Bldg,1412 Circle Dr, Knoxville, TN 37996 USA.
EM dburr1@utk.edu
FU NASA
NR 29
TC 64
Z9 71
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 1
PY 2015
VL 517
IS 7532
BP 60
EP U137
DI 10.1038/nature14088
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AX8SI
UT WOS:000347178400034
PM 25487154
DA 2026-03-09
ER

PT J
AU Floyd, J
   Wu, L
   Burgess, DH
   Izadnegahdar, R
   Mukanga, D
   Ghani, AC
AF Floyd, Jessica
   Wu, Lindsey
   Burgess, Deborah Hay
   Izadnegahdar, Rasa
   Mukanga, David
   Ghani, Azra C.
TI Evaluating the impact of pulse oximetry on childhood pneumonia mortality in resource-poor settings
SO NATURE
LA English
DT Article
ID developing-country; cost-effectiveness; health-workers; children; amoxicillin; prevention; management; district; guidelines; resistance
AB It is estimated that pneumonia is responsible for 15% of childhood deaths worldwide. Recent research has shown that hypoxia and malnutrition are strong predictors of mortality in children hospitalized for pneumonia. It is estimated that 15% of children under 5 who are hospitalized for pneumonia have hypoxaemia and that around 1.5 million children with severe pneumonia require oxygen treatment each year. We developed a deterministic compartmental model that links the care pathway to disease progression to assess the impact of introducing pulse oximetry as a prognostic tool to distinguish severe from non-severe pneumonia in under-5 year olds across 15 countries with the highest burden worldwide. We estimate that, assuming access to supplemental oxygen, pulse oximetry has the potential to avert up to 148,000 deaths if implemented across the 15 countries. By contrast, integrated management of childhood illness alone has a relatively small impact on mortality owing to its low sensitivity. Pulse oximetry can significantly increase the incidence of correctly treated severe cases as well as reduce the incidence of incorrect treatment with antibiotics. We also found that the combination of pulse oximetry with integrated management of childhood illness is highly cost-effective, with median estimates ranging from US$2.97 to $52.92 per disability-adjusted life year averted in the 15 countries analysed. This combination of substantial burden reduction and favourable cost-effectiveness makes pulse oximetry a promising candidate for improving the prognosis for children with pneumonia in resource-poor settings.
C1 [Floyd, Jessica; Wu, Lindsey; Ghani, Azra C.] Univ London Imperial Coll Sci Technol & Med, Fac Med, MRC Ctr Outbreak Anal & Modelling, Dept Infect Dis Epidemiol, London W2 1PG, England.
   [Wu, Lindsey] Univ London London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Immunol & Infect, London WC1E 7HT, England.
   [Burgess, Deborah Hay; Izadnegahdar, Rasa; Mukanga, David] Bill & Melinda Gates Fdn, Seattle, WA 98109 USA.
C3 Imperial College London; University of London; London School of Hygiene & Tropical Medicine; Bill & Melinda Gates Foundation
RP Floyd, J (corresponding author), Univ London Imperial Coll Sci Technol & Med, Fac Med, MRC Ctr Outbreak Anal & Modelling, Dept Infect Dis Epidemiol, Norfolk Pl, London W2 1PG, England.
EM jrf1g15@soton.ac.uk; a.ghani@imperial.ac.uk
FU Bill & Melinda Gates Foundation Diagnostics Modelling Consortium; UK Medical Research Council (MRC); Bill & Melinda Gates Foundation; UK MRC; UK Department for International Development; MRC [MR/K010174/1] Funding Source: UKRI; Medical Research Council [MR/K010174/1, MR/K010174/1B] Funding Source: researchfish
NR 35
TC 78
Z9 84
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 DEC 3
PY 2015
VL 528
IS 7580
BP S53
EP S59
DI 10.1038/nature16043
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000011
PM 26633766
DA 2026-03-09
ER

PT J
AU Naik, S
   Bouladoux, N
   Linehan, JL
   Han, SJ
   Harrison, OJ
   Wilhelm, C
   Conlan, S
   Himmelfarb, S
   Byrd, AL
   Deming, C
   Quinones, M
   Brenchley, JM
   Kong, HH
   Tussiwand, R
   Murphy, KM
   Merad, M
   Segre, JA
   Belkaid, Y
AF Naik, Shruti
   Bouladoux, Nicolas
   Linehan, Jonathan L.
   Han, Seong-Ji
   Harrison, Oliver J.
   Wilhelm, Christoph
   Conlan, Sean
   Himmelfarb, Sarah
   Byrd, Allyson L.
   Deming, Clayton
   Quinones, Mariam
   Brenchley, Jason M.
   Kong, Heidi H.
   Tussiwand, Roxanne
   Murphy, Kenneth M.
   Merad, Miriam
   Segre, Julia A.
   Belkaid, Yasmine
TI Commensal-dendritic-cell interaction specifies a unique protective skin immune signature
SO NATURE
LA English
DT Article
ID t-cells; microbiota; resident; subsets; macrophages; expression; diversity; infection; children; antigens
AB The skin represents the primary interface between the host and the environment. This organ is also home to trillions of microorganisms that play an important role in tissue homeostasis and local immunity(1-4). Skin microbial communities are highly diverse and can be remodelled over time or in response to environmental challenges(5-7). How, in the context of this complexity, individual commensal microorganisms may differentially modulate skin immunity and the consequences of these responses for tissue physiology remains unclear. Here we show that defined commensals dominantly affect skin immunity and identify the cellular mediators involved in this specification. In particular, colonization with Staphylococcus epidermidis induces IL-17A(+) CD8(+) T cells that home to the epidermis, enhance innate barrier immunity and limit pathogen invasion. Commensal-specific T-cell responses result from the coordinated action of skin-resident dendritic cell subsets and are not associated with inflammation, revealing that tissue-resident cells are poised to sense and respond to alterations in microbial communities. This interaction may represent an evolutionary means by which the skin immune system uses fluctuating commensal signals to calibrate barrier immunity and provide heterologous protection against invasive pathogens. These findings reveal that the skin immune landscape is a highly dynamic environment that can be rapidly and specifically remodelled by encounters with defined commensals, findings that have profound implications for our understanding of tissue-specific immunity and pathologies.
C1 [Naik, Shruti; Bouladoux, Nicolas; Linehan, Jonathan L.; Han, Seong-Ji; Harrison, Oliver J.; Wilhelm, Christoph; Himmelfarb, Sarah; Byrd, Allyson L.; Brenchley, Jason M.; Belkaid, Yasmine] NIAID, Immun Barrier Sites Initiat, NIH, Bethesda, MD 20892 USA.
   [Naik, Shruti; Bouladoux, Nicolas; Linehan, Jonathan L.; Han, Seong-Ji; Harrison, Oliver J.; Wilhelm, Christoph; Himmelfarb, Sarah; Byrd, Allyson L.; Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA.
   [Conlan, Sean; Byrd, Allyson L.; Deming, Clayton; Segre, Julia A.] NHGRI, Translat & Funct Genom Branch, Bethesda, MD 20892 USA.
   [Quinones, Mariam] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA.
   [Brenchley, Jason M.] NIAID, Immunopathogenesis Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA.
   [Kong, Heidi H.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA.
   [Tussiwand, Roxanne; Murphy, Kenneth M.] Washington Univ, Sch Med, Dept Pathol & Immunol, Howard Hughes Med Inst, St Louis, MO 63110 USA.
   [Merad, Miriam] Icahn Sch Med Mt Sinai, Dept Oncol Sci, Tisch Canc Inst, New York, NY 10029 USA.
   [Merad, Miriam] Icahn Sch Med Mt Sinai, Inst Immunol, New York, NY 10029 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 Human Genome Research Institute (NHGRI); 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 Cancer Institute (NCI); Washington University (WUSTL); Howard Hughes Medical Institute; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai
RP Belkaid, Y (corresponding author), NIAID, Immun Barrier Sites Initiat, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
EM ybelkaid@niaid.nih.gov
FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID); Human Frontier Science Program; National Cancer Institute [R01CA154947, ZIABC010938] Funding Source: NIH RePORTER; National Human Genome Research Institute [ZIAHG000180] Funding Source: NIH RePORTER; National Institute of Allergy and Infectious Diseases [ZIAAI001115, ZIAAI001029] Funding Source: NIH RePORTER
NR 38
TC 659
Z9 771
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 APR 2
PY 2015
VL 520
IS 7545
BP 104
EP U244
DI 10.1038/nature14052
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE7NE
UT WOS:000352027700046
PM 25539086
DA 2026-03-09
ER

PT J
AU Liebi, M
   Georgiadis, M
   Menzel, A
   Schneider, P
   Kohlbrecher, J
   Bunk, O
   Guizar-Sicairos, M
AF Liebi, Marianne
   Georgiadis, Marios
   Menzel, Andreas
   Schneider, Philipp
   Kohlbrecher, Joachim
   Bunk, Oliver
   Guizar-Sicairos, Manuel
TI Nanostructure surveys of macroscopic specimens by small-angle scattering tensor tomography
SO NATURE
LA English
DT Article
ID x-ray-scattering; collagen fiber orientation; computed-tomography; scanning saxs; bone; spectroscopy; microscopy
AB The mechanical properties of many materials are based on the macroscopic arrangement and orientation of their nanostructure. This nanostructure can be ordered over a range of length scales. In biology, the principle of hierarchical ordering is often used to maximize functionality, such as strength and robustness of the material, while minimizing weight and energy cost. Methods for nanoscale imaging provide direct visual access to the ultrastructure (nanoscale structure that is too small to be imaged using light microscopy), but the field of view is limited and does not easily allow a full correlative study of changes in the ultrastructure over a macroscopic sample. Other methods of probing ultrastructure ordering, such as small-angle scattering of X-rays or neutrons, can be applied to macroscopic samples; however, these scattering methods remain constrained to two-dimensional specimens(1-4) or to isotropically oriented ultrastructures(5-7). These constraints limit the use of these methods for studying nanostructures with more complex orientation patterns, which are abundant in nature and materials science. Here, we introduce an imaging method that combines small-angle scattering with tensor tomography to probe nanoscale structures in three-dimensional macroscopic samples in a non-destructive way. We demonstrate the method by measuring the main orientation and the degree of orientation of nanoscale mineralized collagen fibrils in a human trabecula bone sample with a spatial resolution of 25 micrometres. Symmetries within the sample, such as the cylindrical symmetry commonly observed for mineralized collagen fibrils in bone(8-10), allow for tractable sampling requirements and numerical efficiency. Small-angle scattering tensor tomography is applicable to both biological and materials science specimens, and may be useful for understanding and characterizing smart or bio-inspired materials. Moreover, because the method is non-destructive, it is appropriate for in situ measurements and allows, for example, the role of ultrastructure in the mechanical response of a biological tissue or manufactured material to be studied.
C1 [Liebi, Marianne; Menzel, Andreas; Kohlbrecher, Joachim; Bunk, Oliver; Guizar-Sicairos, Manuel] Paul Scherrer Inst, CH-5232 Villigen, Switzerland.
   [Georgiadis, Marios] ETH, Inst Biomech, CH-8093 Zurich, Switzerland.
   [Schneider, Philipp] Univ Southampton, Bioengn Sci Res Grp, Fac Engn & Environm, Southampton SO17 1BJ, Hants, England.
C3 Swiss Federal Institutes of Technology Domain; Paul Scherrer Institute; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Southampton
RP Liebi, M (corresponding author), Paul Scherrer Inst, CH-5232 Villigen, Switzerland.
EM marianne.liebi@psi.ch; manuel.guizar-sicairos@psi.ch
FU ETH Research Grant [ETH-39 11-1]
NR 37
TC 209
Z9 229
U1 1
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 19
PY 2015
VL 527
IS 7578
BP 349
EP +
DI 10.1038/nature16056
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9ZN
UT WOS:000365356800050
PM 26581291
DA 2026-03-09
ER

PT J
AU Schindler, S
   Gaillard, JM
   Grüning, A
   Neuhaus, P
   Traill, LW
   Tuljapurkar, S
   Coulson, T
AF Schindler, Susanne
   Gaillard, Jean-Michel
   Gruening, Andre
   Neuhaus, Peter
   Traill, Lochran W.
   Tuljapurkar, Shripad
   Coulson, Tim
TI Sex-specific demography and generalization of the Trivers-Willard theory
SO NATURE
LA English
DT Article
ID columbian ground-squirrels; maternal condition; life-history; reproductive success; ratio; age; populations; manipulation; investment; allocation
AB The Trivers-Willard theory(1) proposes that the sex ratio of offspring should vary with maternal condition when it has sex-specific influences on offspring fitness. In particular, mothers in good condition in polygynous and dimorphic species are predicted to produce an excess of sons, whereas mothers in poor condition should do the opposite. Despite the elegance of the theory, support for it has been limited(2,3). Here we extend and generalize the Trivers-Willard theory to explain the disparity between predictions and observations of offspring sex ratio. In polygynous species, males typically have higher mortality rates(4), different age-specific reproductive schedules and more risk-prone life history tactics than females; however, these differences are not currently incorporated into the Trivers-Willard theory. Using two-sex models parameterized with data from free-living mammal populations with contrasting levels of sex differences in demography, we demonstrate how sex differences in life history traits over the entire lifespan can lead to a wide range of sex allocation tactics, and show that correlations between maternal condition and offspring sex ratio alone are insufficient to conclude that mothers adaptively adjust offspring sex ratio.
C1 [Schindler, Susanne; Coulson, Tim] Univ Oxford, Dept Zool, Oxford OX1 3PS, England.
   [Gaillard, Jean-Michel] Univ Lyon 1, UMR 5558, Lab Biometrie & Biol Evolut, F-69622 Villeurbanne, France.
   [Gruening, Andre] Univ Surrey, Dept Comp Sci, Guildford GU2 7XH, Surrey, England.
   [Neuhaus, Peter] Univ Calgary, Dept Biol Sci, Calgary, AB T2N 1N4, Canada.
   [Traill, Lochran W.] Univ Witwatersrand, Sch Anim Plant & Environm Sci, ZA-2050 Johannesburg, South Africa.
   [Tuljapurkar, Shripad] Stanford Univ, Dept Biol, Stanford, CA 94305 USA.
C3 University of Oxford; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Ecology & Environment (INEE); VetAgro Sup; Universite Lyon 1; University of Surrey; University of Calgary; University of Witwatersrand; Stanford University
RP Schindler, S (corresponding author), Univ Oxford, Dept Zool, Oxford OX1 3PS, England.
EM Susanne.Schindler@zoo.ox.ac.uk
FU ERC Advanced Grant; Swiss National Science Foundation [SNF 3100AO-109816]; European Commission (Marie Curie Fellowship) [254442]; Carnegie Corporation of New York [B8749.R01]; Natural Environment Research Council [NE/I023783/2, NE/K014218/1] Funding Source: researchfish; NERC [NE/I023783/2, NE/K014218/1] Funding Source: UKRI
NR 36
TC 71
Z9 75
U1 0
U2 91
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 8
PY 2015
VL 526
IS 7572
BP 249
EP +
DI 10.1038/nature14968
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS9GV
UT WOS:000362399000046
PM 26390152
DA 2026-03-09
ER

PT J
AU Graham, NAJ
   Jennings, S
   MacNeil, MA
   Mouillot, D
   Wilson, SK
AF Graham, Nicholas A. J.
   Jennings, Simon
   MacNeil, M. Aaron
   Mouillot, David
   Wilson, Shaun K.
TI Predicting climate-driven regime shifts versus rebound potential in coral reefs
SO NATURE
LA English
DT Article
ID marine protected areas; great-barrier-reef; phase-shifts; recovery; resilience; fish; management; diversity; fishery; habitat
AB Climate-induced coral bleaching is among the greatest current threats to coral reefs, causing widespread loss of live coral cover(1). Conditions under which reefs bounce back from bleaching events or shift from coral to algal dominance are unknown, making it difficult to predict and plan for differing reef responses under climate change(2). Herewe document and predict long-term reef responses to a major climate-induced coral bleaching event that caused unprecedented region-wide mortality of Indo-Pacific corals. Following loss of >90% live coral cover, 12 of 21 reefs recovered towards pre-disturbance live coral states, while nine reefs underwent regime shifts to fleshy macroalgae. Functional diversity of associated reef fish communities shifted substantially following bleaching, returning towards pre-disturbance structure on recovering reefs, while becoming progressively altered on regime shifting reefs. We identified threshold values for a range of factors that accurately predicted ecosystem response to the bleaching event. Recovery was favoured when reefs were structurally complex and in deeper water, when density of juvenile corals and herbivorous fishes was relatively high and when nutrient loads were low. Whether reefs were inside no-take marine reserves had no bearing on ecosystem trajectory. Although conditions governing regime shift or recovery dynamics were diverse, pre-disturbance quantification of simple factors such as structural complexity and water depth accurately predicted ecosystem trajectories. These findings foreshadow the likely divergent but predictable outcomes for reef ecosystems in response to climate change, thus guiding improved management and adaptation.
C1 [Graham, Nicholas A. J.; MacNeil, M. Aaron; Mouillot, David] James Cook Univ, Australian Res Council Ctr Excellence Coral Reef, Townsville, Qld 4811, Australia.
   [Jennings, Simon] Ctr Environm Fisheries & Aquaculture Sci, Lowestoft NR33 OHT, Suffolk, England.
   [Jennings, Simon] Univ E Anglia, Sch Environm Sci, Norwich NR4 7TJ, Norfolk, England.
   [MacNeil, M. Aaron] Australian Inst Marine Sci, Townsville, Qld 4810, Australia.
   [Mouillot, David] Univ Montpellier 2, ECOSYM, UMR CNRS UM2 5119, F-34095 Montpellier, France.
   [Wilson, Shaun K.] Dept Pk & Wildlife, Perth, WA 6151, Australia.
   [Wilson, Shaun K.] Univ Western Australia, Oceans Inst, Sch Plant Biol, Crawley, WA 6009, Australia.
C3 James Cook University; Centre for Environment Fisheries & Aquaculture Science; University of East Anglia; Australian Institute of Marine Science; Universite de Montpellier; University of Western Australia
RP Graham, NAJ (corresponding author), James Cook Univ, Australian Res Council Ctr Excellence Coral Reef, Townsville, Qld 4811, Australia.
EM nick.graham@jcu.edu.au
FU Australian Research Council [DP1094932, DE130101705]; Leverhulme Trust [F/00 125/M]; Western Indian Ocean Marine Science Association; Natural Environment Research Council [GR3/1154]; Australian Research Council [DP1094932, DE130101705] Funding Source: Australian Research Council
NR 73
TC 635
Z9 728
U1 18
U2 743
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 5
PY 2015
VL 518
IS 7537
BP 94
EP +
DI 10.1038/nature14140
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7LE
UT WOS:000349098000038
PM 25607371
DA 2026-03-09
ER

PT J
AU Wu, CY
   Horibe, T
   Jacobsen, CB
   Toste, FD
AF Wu, Chung-Yeh
   Horibe, Takahiro
   Jacobsen, Christian Borch
   Toste, F. Dean
TI Stable gold(III) catalysts by oxidative addition of a carbon-carbon bond
SO NATURE
LA English
DT Article
ID reductive elimination; aryl halides; gold; reactivity; complexes; fluorination; activation; chemistry; ligands
AB Low-valent late transition-metal catalysis has become indispensable to chemical synthesis, but homogeneous high-valent transition-metal catalysis is underdeveloped, mainly owing to the reactivityofhigh-valent transition-metal complexes and the challenges associated with synthesizing them. Here we report a carbon-carbon bond cleavage at ambient conditions by a Au(I) complex that generates a stable Au(III) cationic complex. In contrast to the well-established soft and carbophilic Au(I) catalyst, this Au(III) complex exhibits hard, oxophilic Lewis acidity. For example, we observed catalytic activation of alpha,beta-unsaturated aldehydes towards selective conjugate additions as well as activation of an unsaturated aldehyde-allene for a [212] cycloaddition reaction. The origin of the regioselectivity and catalytic activity was elucidated by X-ray crystallographic analysis of an isolated Au(III)-activated cinnamaldehyde intermediate. The concepts revealed suggest a strategy for accessing high-valent transition-metal catalysis from readily available precursors.
C1 [Wu, Chung-Yeh; Horibe, Takahiro; Jacobsen, Christian Borch; Toste, F. Dean] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
C3 University of California System; University of California Berkeley
RP Toste, FD (corresponding author), Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
EM fdtoste@berkeley.edu
FU NIHGMS [R01 GM073932]; Taiwan National Science Council; Uehara Memorial Foundation; Lundbeck Foundation; NIH Shared Instrumentation Grant [S10-RR027172]
NR 44
TC 247
Z9 283
U1 1
U2 269
PU NATURE PUBLISHING 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 22
PY 2015
VL 517
IS 7535
BP 449
EP 454
DI 10.1038/nature14104
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AZ4MU
UT WOS:000348196500027
PM 25612049
DA 2026-03-09
ER

PT J
AU Fazal, FM
   Meng, CA
   Murakami, K
   Kornberg, RD
   Block, SM
AF Fazal, Furqan M.
   Meng, Cong A.
   Murakami, Kenji
   Kornberg, Roger D.
   Block, Steven M.
TI Real-time observation of the initiation of RNA polymerase II transcription
SO NATURE
LA English
DT Article
ID preinitiation complex; dna-repair; promoter dna; tfiih; elongation; mechanism; kinase; pc4; atp; backtracking
AB Biochemical and structural studies have shown that the initiation of RNA polymerase II transcription proceeds in the following stages: assembly of the polymerase with general transcription factors and promoter DNA in a 'closed' preinitiation complex (PIC)(1,2); unwinding of about 15 base pairs of the promoter DNA to form an 'open' complex(3,4); scanning downstream to a transcription start site; synthesis of a short transcript, thought to be about 10 nucleotides long; and promoter escape. Here we have assembled a 32-protein, 1.5-megadalton PIC5 derived from Saccharomyces cerevisiae, and observe subsequent initiation processes in real time with optical tweezers(6). Contrary to expectation, scanning driven by the transcription factor IIH7-12 involved the rapid opening of an extended transcription bubble, averaging 85 base pairs, accompanied by the synthesis of a transcript up to the entire length of the extended bubble, followed by promoter escape. PICs that failed to achieve promoter escape nevertheless formed open complexes and extended bubbles, which collapsed back to closed or open complexes, resulting in repeated futile scanning.
C1 [Fazal, Furqan M.; Block, Steven M.] Stanford Univ, Dept Appl Phys, Stanford, CA 94305 USA.
   [Meng, Cong A.] Stanford Univ, Dept Chem, Stanford, CA 94305 USA.
   [Murakami, Kenji; Kornberg, Roger D.] Stanford Univ, Dept Biol Struct, Stanford, CA 94305 USA.
   [Block, Steven M.] Stanford Univ, Dept Biol, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; Stanford University; Stanford University
RP Block, SM (corresponding author), Stanford Univ, Dept Appl Phys, Stanford, CA 94305 USA.
EM kornberg@stanford.edu; sblock@stanford.edu
FU NIH [GM36659, AI21144, GM57035]; NSF
NR 38
TC 79
Z9 109
U1 1
U2 83
PU NATURE PUBLISHING 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 10
PY 2015
VL 525
IS 7568
BP 274
EP +
DI 10.1038/nature14882
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400044
PM 26331540
DA 2026-03-09
ER

PT J
AU Liu, MJ
   Ishida, Y
   Ebina, Y
   Sasaki, T
   Hikima, T
   Takata, M
   Aida, T
AF Liu, Mingjie
   Ishida, Yasuhiro
   Ebina, Yasuo
   Sasaki, Takayoshi
   Hikima, Takaaki
   Takata, Masaki
   Aida, Takuzo
TI An anisotropic hydrogel with electrostatic repulsion between cofacially aligned nanosheets
SO NATURE
LA English
DT Article
ID long-range; clay; diffusion; alignment
AB Machine technology frequently puts magnetic or electrostatic repulsive forces to practical use, as in maglev trains, vehicle suspensions or non-contact bearings(1,2). In contrast, materials design overwhelmingly focuses on attractive interactions, such as in the many advanced polymer-based composites, where inorganic fillers interact with a polymer matrix to improve mechanical properties. However, articular cartilage strikingly illustrates how electrostatic repulsion can be harnessed to achieve unparalleled functional efficiency: it permits virtually friction-less mechanical motion within joints, even under high compression(3,4). Here we describe a composite hydrogel with anisotropic mechanical properties dominated by electrostatic repulsion between negatively charged unilamellar titanate nanosheets(5) embedded within it. Crucial to the behaviour of this hydrogel is the serendipitous discovery of cofacial nanosheet alignment in aqueous colloidal dispersions subjected to a strong magnetic field, which maximizes electrostatic repulsion(6) and thereby induces a quasi-crystalline structural ordering(7,8) over macroscopic length scales and with uniformly large face-to-face nanosheet separation. We fix this transiently induced structural order by transforming the dispersion into a hydrogel(9,10) using light-triggered in situ vinyl polymerization(11). The resultant hydrogel, containing charged inorganic structures that align cofacially in a magnetic flux(12-19), deforms easily under shear forces applied parallel to the embedded nanosheets yet resists compressive forces applied orthogonally. We anticipate that the concept of embedding anisotropic repulsive electrostatics within a composite material, inspired by articular cartilage, will open up new possibilities for developing soft materials with unusual functions.
C1 [Liu, Mingjie; Ishida, Yasuhiro; Aida, Takuzo] RIKEN Ctr Emergent Matter Sci, Wako, Saitama 3510198, Japan.
   [Ebina, Yasuo; Sasaki, Takayoshi] Int Ctr Mat Nanoarchitecton, Natl Inst Mat Sci, Tsukuba, Ibaraki 3050044, Japan.
   [Hikima, Takaaki; Takata, Masaki] RIKEN SPring 8 Ctr, Sayo, Hyogo 6795198, Japan.
   [Aida, Takuzo] Univ Tokyo, Dept Chem & Biotechnol, Sch Engn, Bunkyo Ku, Tokyo 1138656, Japan.
C3 RIKEN; National Institute for Materials Science; RIKEN; University of Tokyo
RP Ishida, Y (corresponding author), RIKEN Ctr Emergent Matter Sci, 2-1 Hirosawa, Wako, Saitama 3510198, Japan.
EM y-ishida@riken.jp; aida@macro.t.u-tokyo.ac.jp
FU [25000005]; Grants-in-Aid for Scientific Research [25000005] Funding Source: KAKEN
NR 30
TC 468
Z9 515
U1 38
U2 1771
PU NATURE PUBLISHING 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 1
PY 2015
VL 517
IS 7532
BP 68
EP 72
DI 10.1038/nature14060
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AX8SI
UT WOS:000347178400036
PM 25557713
DA 2026-03-09
ER

PT J
AU Rajasethupathy, P
   Sankaran, S
   Marshel, JH
   Kim, CK
   Ferenczi, E
   Lee, SY
   Berndt, A
   Ramakrishnan, C
   Jaffe, A
   Lo, M
   Liston, C
   Deisseroth, K
AF Rajasethupathy, Priyamvada
   Sankaran, Sethuraman
   Marshel, James H.
   Kim, Christina K.
   Ferenczi, Emily
   Lee, Soo Yeun
   Berndt, Andre
   Ramakrishnan, Charu
   Jaffe, Anna
   Lo, Maisie
   Liston, Conor
   Deisseroth, Karl
TI Projections from neocortex mediate top-down control of memory retrieval
SO NATURE
LA English
DT Article
ID cellular-resolution; associative memory; remote memory; motor cortex; fear memory; in-vivo; networks; neurons; stimulation; hippocampus
AB Top-down prefrontal cortex inputs to the hippocampus have been hypothesized to be important in memory consolidation, retrieval, and the pathophysiology of major psychiatric diseases; however, no such direct projections have been identified and functionally described. Here we report the discovery of a monosynaptic prefrontal cortex (predominantly anterior cingulate) to hippocampus (CA3 to CA1 region) projection in mice, and find that optogenetic manipulation of this projection (here termed AC-CA) is capable of eliciting contextual memory retrieval. To explore the network mechanisms of this process, we developed and applied tools to observe cellular-resolution neural activity in the hippocampus while stimulating AC-CA projections during memory retrieval in mice behaving in virtual-reality environments. Using this approach, we found that learning drives the emergence of a sparse class of neurons in CA2/CA3 that are highly correlated with the local network and that lead synchronous population activity events; these neurons are then preferentially recruited by the AC-CA projection during memory retrieval. These findings reveal a sparsely implemented memory retrieval mechanism in the hippocampus that operates via direct top-down prefrontal input, with implications for the patterning and storage of salient memory representations.
C1 [Rajasethupathy, Priyamvada; Marshel, James H.; Kim, Christina K.; Ferenczi, Emily; Lee, Soo Yeun; Berndt, Andre; Ramakrishnan, Charu; Jaffe, Anna; Lo, Maisie; Liston, Conor; Deisseroth, Karl] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.
   [Rajasethupathy, Priyamvada; Sankaran, Sethuraman; Deisseroth, Karl] Stanford Univ, CNC Program, Stanford, CA 94305 USA.
   [Kim, Christina K.; Ferenczi, Emily; Lee, Soo Yeun; Berndt, Andre] Stanford Univ, Neurosci Program, Stanford, CA 94305 USA.
   [Liston, Conor; Deisseroth, Karl] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA.
   [Deisseroth, Karl] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Howard Hughes Medical Institute
RP Deisseroth, K (corresponding author), Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.
EM deissero@stanford.edu
FU Defense Advanced Research Projects Agency Neuro-FAST program; National Institute of Mental Health, National Science Foundation; National Institute on Drug Abuse, National Science Foundation; Simons Foundation; Tarlton Foundation; Wiegers Family Fund; Nancy and James Grosfeld Foundation; H.L. Snyder Medical Foundation; Samuel and Betsy Reeves Fund; Ellison Life Sciences Research Foundation (LSRF) fellowship; Simons LSRF fellowship; German Academic Exchange Service DAAD; Fidelity Foundation
NR 50
TC 343
Z9 454
U1 1
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 OCT 29
PY 2015
VL 526
IS 7575
BP 653
EP 659
DI 10.1038/nature15389
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CU8ZH
UT WOS:000363832100039
PM 26436451
DA 2026-03-09
ER

PT J
AU Pommier, A
   Leinenweber, K
   Kohlstedt, DL
   Qi, C
   Garnero, EJ
   Mackwell, SJ
   Tyburczy, JA
AF Pommier, Anne
   Leinenweber, Kurt
   Kohlstedt, David L.
   Qi, Chao
   Garnero, Edward J.
   Mackwell, Stephen J.
   Tyburczy, James A.
TI Experimental constraints on the electrical anisotropy of the lithosphere-asthenosphere system
SO NATURE
LA English
DT Article
ID melt segregation; surface-tension; conductivity; olivine; mantle; boundary; driven; stress; flow; peridotite
AB The relative motion of lithospheric plates and underlying mantle produces localized deformation near the lithosphere-asthenosphere boundary(1). The transition from rheologically stronger lithosphere to weaker asthenosphere may result from a small amount of melt or water in the asthenosphere, reducing viscosity(1-3). Either possibility may explain the seismic and electrical anomalies that extend to a depth of about 200 kilometres(4,5). However, the effect of melt on the physical properties of deformed materials at upper-mantle conditions remains poorly constrained(6). Here we present electrical anisotropy measurements at high temperatures and quasi-hydrostatic pressures of about three gigapascals on previously deformed olivine aggregates and sheared partially molten rocks. For all samples, electrical conductivity is highest when parallel to the direction of prior deformation. The conductivity of highly sheared olivine samples is ten times greater in the shear direction than for undeformed samples. At temperatures above 900 degrees Celsius, a deformed solid matrix with nearly isotropic melt distribution has an electrical anisotropy factor less than five. To obtain higher electrical anisotropy (up to a factor of 100), we propose an experimentally based model in which layers of sheared olivine are alternated with layers of sheared olivine plus MORB or of pure melt. Conductivities are up to 100 times greater in the shear direction than when perpendicular to the shear direction and reproduce stress-driven alignment of the melt. Our experimental results and the model reproduce mantle conductivity-depth profiles for melt-bearing geological contexts. The field data are best fitted by an electrically anisotropic asthenosphere overlain by an isotropic, high-conductivity lower most lithosphere. The high conductivity could arise from partial melting associated with localized deformation resulting from differential plate velocities relative to the mantle, with subsequent upward melt percolation from the asthenosphere.
C1 [Pommier, Anne] Univ Calif San Diego, Scripps Inst Oceanog, Inst Geophys & Planetary Phys, La Jolla, CA 92093 USA.
   [Pommier, Anne; Garnero, Edward J.; Tyburczy, James A.] Arizona State Univ, Sch Earth & Space Explorat, Tempe, AZ 85287 USA.
   [Leinenweber, Kurt] Arizona State Univ, Dept Chem & Biochem, Tempe, AZ 85287 USA.
   [Kohlstedt, David L.; Qi, Chao] Univ Minnesota, Dept Earth Sci, Minneapolis, MN 55455 USA.
   [Mackwell, Stephen J.] Univ Space Res Assoc, Lunar & Planetary Inst, Houston, TX 77058 USA.
C3 University of California System; University of California San Diego; Scripps Institution of Oceanography; Arizona State University; Arizona State University-Tempe; Arizona State University; Arizona State University-Tempe; University of Minnesota System; University of Minnesota Twin Cities; Universities Space Research Association (USRA)
RP Pommier, A (corresponding author), Univ Calif San Diego, Scripps Inst Oceanog, Inst Geophys & Planetary Phys, La Jolla, CA 92093 USA.
EM pommier@ucsd.edu
FU NSF through Cooperative Studies of the Earth's Deep Interior (CSEDI) [1461594, 1265395, 1265428]; COMPRES (the Consortium for Materials Properties Research in Earth Sciences) under National Science Foundation (NSF) [EAR 11-57758]; Directorate For Geosciences; Division Of Earth Sciences [1461594] Funding Source: National Science Foundation; Division Of Earth Sciences; Directorate For Geosciences [1265428, 1265395] Funding Source: National Science Foundation
NR 34
TC 57
Z9 67
U1 0
U2 72
PU NATURE PUBLISHING 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 11
PY 2015
VL 522
IS 7555
BP 202
EP +
DI 10.1038/nature14502
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700036
PM 26062512
DA 2026-03-09
ER

PT J
AU Lang, BT
   Cregg, JM
   DePaul, MA
   Tran, AP
   Xu, K
   Dyck, SM
   Madalena, KM
   Brown, BP
   Weng, YL
   Li, SX
   Karimi-Abdolrezaee, S
   Busch, SA
   Shen, YJ
   Silver, J
AF Lang, Bradley T.
   Cregg, Jared M.
   DePaul, Marc A.
   Tran, Amanda P.
   Xu, Kui
   Dyck, Scott M.
   Madalena, Kathryn M.
   Brown, Benjamin P.
   Weng, Yi-Lan
   Li, Shuxin
   Karimi-Abdolrezaee, Soheila
   Busch, Sarah A.
   Shen, Yingjie
   Silver, Jerry
TI Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury
SO NATURE
LA English
DT Article
ID protein-tyrosine-phosphatase; chondroitin sulfate proteoglycan; functional recovery; bladder function; growth cone; regeneration; plasticity; barrier; domain; model
AB Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting(1-5). Protein tyrosine phosphatase sigma (PTP sigma), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs(6-8). Here we find in rats that PTP sigma has a critical role in converting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. We generated a membrane-permeable peptide mimetic of the PTP sigma wedge domain that binds to PTP sigma and relieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Our results add a new layer of understanding to the critical role of PTP sigma in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.
C1 [Lang, Bradley T.; Cregg, Jared M.; DePaul, Marc A.; Tran, Amanda P.; Madalena, Kathryn M.; Busch, Sarah A.; Silver, Jerry] Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA.
   [Xu, Kui; Shen, Yingjie] Ohio State Univ, Ctr Brain & Spinal Cord Repair, Dept Neurosci, Wexner Med Ctr, Columbus, OH 43210 USA.
   [Dyck, Scott M.; Karimi-Abdolrezaee, Soheila] Univ Manitoba, Regenerat Med Program, Winnipeg, MB R3E 0J9, Canada.
   [Dyck, Scott M.; Karimi-Abdolrezaee, Soheila] Univ Manitoba, Dept Physiol, Winnipeg, MB R3E 0J9, Canada.
   [Brown, Benjamin P.] Baldwin Wallace Univ, Berea, OH 44017 USA.
   [Weng, Yi-Lan] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA.
   [Li, Shuxin] Temple Univ, Sch Med, Ctr Neural Repair & Rehabil, Shriners Hosp Pediat Res Ctr, Philadelphia, PA 19140 USA.
C3 University System of Ohio; Case Western Reserve University; University System of Ohio; Ohio State University; University of Manitoba; University of Manitoba; University System of Ohio; Baldwin Wallace University; Johns Hopkins University; Shriners Hospitals Children Philadelphia; Pennsylvania Commonwealth System of Higher Education (PCSHE); Temple University
RP Silver, J (corresponding author), Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA.
EM JXS10@case.edu
FU National Institute of Neurological Disorders and Stroke [NS025713]; Case Western Reserve University Council; Unite to Fight Paralysis; Brumagin Memorial Fund; Spinal Cord Injury Sucks; United Paralysis Foundation; Kaneko Family Fund
NR 35
TC 380
Z9 439
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 FEB 19
PY 2015
VL 518
IS 7539
BP 404
EP 408
DI 10.1038/nature13974
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400043
PM 25470046
DA 2026-03-09
ER

PT J
AU Vahedi, G
   Kanno, Y
   Furumoto, Y
   Jiang, K
   Parker, SCJ
   Erdos, MR
   Davis, SR
   Roychoudhuri, R
   Restifo, NP
   Gadina, M
   Tang, ZH
   Ruan, YJ
   Collins, FS
   Sartorelli, V
   O'Shea, JJ
AF Vahedi, Golnaz
   Kanno, Yuka
   Furumoto, Yasuko
   Jiang, Kan
   Parker, Stephen C. J.
   Erdos, Michael R.
   Davis, Sean R.
   Roychoudhuri, Rahul
   Restifo, Nicholas P.
   Gadina, Massimo
   Tang, Zhonghui
   Ruan, Yijun
   Collins, Francis S.
   Sartorelli, Vittorio
   O'Shea, John J.
TI Super-enhancers delineate disease-associated regulatory nodes in T cells
SO NATURE
LA English
DT Article
ID genetic architecture; susceptibility loci; identity genes; risk loci; identification; transcription; metaanalysis; expression; differentiation; domains
AB Enhancers regulate spatiotemporal gene expression and impart cellspecific transcriptional outputs that drive cell identity'. Super-enhancers (SEs), also known as stretch-enhancers, are a subset of enhancers especially important for genes associated with cell identity and genetic risk of disease(2-6). CD4(+) T cells are critical for host defence and autoimmunity. Here we analysed maps of mouse T-cell SEs as a non-biased means of identifying key regulatory nodes involved in cell specification. We found that cytokines and cytokine receptors were the dominant class of genes exhibiting SE architecture in T cells. Nonetheless, the locus encoding Bach2, a key negative regulator of effector differentiation, emerged as the most prominent T-cell SE, revealing a network in which SE-associated genes critical for T-cell biology are repressed by BACH2. Disease-associated single-nucleotide polymorphisms for immune-mediated disorders, including rheumatoid arthritis, were highly enriched for T-cell SEs versus typical enhancers or SEs in other cell lineages'. Intriguingly, treatment of T cells with the Janus kinase (JAK) inhibitor tofacitinib disproportionately altered the expression of rheumatoid arthritis risk genes with SE structures. Together, these results indicate that genes with SE architecture in T cells encompass a variety of cytokines and cytokine receptors but are controlled by a 'guardian' transcription factor, itself endowed with an SE. Thus, enumeration of SEs allows the unbiased determination of key regulatory nodes in T cells, which are preferentially modulated by pharmacological intervention.
C1 [Vahedi, Golnaz; Kanno, Yuka; Jiang, Kan; O'Shea, John J.] NIAMSD, Lymphocyte Cell Biol Sect, NIH, Bethesda, MD 20892 USA.
   [Furumoto, Yasuko; Gadina, Massimo] NIAMS, Translat Immunol Sect, NIH, Bethesda, MD 20892 USA.
   [Parker, Stephen C. J.; Erdos, Michael R.; Collins, Francis S.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA.
   [Davis, Sean R.; Roychoudhuri, Rahul; Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.
   [Tang, Zhonghui; Ruan, Yijun] Univ Connecticut, Jackson Lab Genom Med, Farmington, CT 06030 USA.
   [Tang, Zhonghui; Ruan, Yijun] Univ Connecticut, Dept Genet & Dev Biol, Farmington, CT 06030 USA.
   [Sartorelli, Vittorio] NIAMS, La Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS); National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS); National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Jackson Laboratory; University of Connecticut; University of Connecticut; National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS)
RP Vahedi, G (corresponding author), NIAMSD, Lymphocyte Cell Biol Sect, NIH, Bethesda, MD 20892 USA.
EM vahedig@mail.nih.gov; osheaj@arb.niams.nih.gov
FU Sir Henry Dale Fellowship - Wellcome Trust [105663/Z/14/Z]; Sir Henry Dale Fellowship - Royal Society [105663/Z/14/Z]; Intramural Research Program of NIAMS; NCI [R01 CA186714]; Wellcome Trust [105663/Z/14/Z] Funding Source: Wellcome Trust; National Cancer Institute [ZIABC010763] Funding Source: NIH RePORTER; National Human Genome Research Institute [ZIAHG000024] Funding Source: NIH RePORTER; National Institute of Arthritis and Musculoskeletal and Skin Diseases [ZICAR041169, ZIGAR041168, ZIAAR041126, ZIAAR041106, ZIAAR041159, ZICAR041181] Funding Source: NIH RePORTER
NR 32
TC 317
Z9 366
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 APR 23
PY 2015
VL 520
IS 7548
BP 558
EP +
DI 10.1038/nature14154
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500047
PM 25686607
DA 2026-03-09
ER

PT J
AU Vanderburg, A
   Johnson, JA
   Rappaport, S
   Bieryla, A
   Irwin, J
   Lewis, JA
   Kipping, D
   Brown, WR
   Dufour, P
   Ciardi, DR
   Angus, R
   Schaefer, L
   Latham, DW
   Charbonneau, D
   Beichman, C
   Eastman, J
   McCrady, N
   Wittenmyer, RA
   Wright, JT
AF Vanderburg, Andrew
   Johnson, John Asher
   Rappaport, Saul
   Bieryla, Allyson
   Irwin, Jonathan
   Lewis, John Arban
   Kipping, David
   Brown, Warren R.
   Dufour, Patrick
   Ciardi, David R.
   Angus, Ruth
   Schaefer, Laura
   Latham, David W.
   Charbonneau, David
   Beichman, Charles
   Eastman, Jason
   McCrady, Nate
   Wittenmyer, Robert A.
   Wright, Jason T.
TI A disintegrating minor planet transiting a white dwarf
SO NATURE
LA English
DT Article
ID excess infrared radiation; debris disks; dusty disk; frequency; systems; gd-362; candidate; accretion; asteroids; diffusion
AB Most stars become white dwarfs after they have exhausted their nuclear fuel (the Sun will be one such). Between one-quarter and one-half of white dwarfs have elements heavier than helium in their atmospheres(1,2), even though these elements ought to sink rapidly into the stellar interiors (unless they are occasionally replenished) (3-5). The abundance ratios of heavy elements in the atmospheres of white dwarfs are similar to the ratios in rocky bodies in the Solar System(6,7). This fact, together with the existence of warm, dusty debris disks(8-13) surrounding about four per cent of white dwarfs(14-16), suggests that rocky debris from the planetary systems of white-dwarf progenitors occasionally pollutes the atmospheres of the stars(17). The total accreted mass of this debris is sometimes comparable to the mass of large asteroids in the Solar System(1). However, rocky, disintegrating bodies around a white dwarf have not yet been observed. Here we report observations of a white dwarf-WD 1145+017-being transited by at least one, and probably several, disintegrating planetesimals, with periods ranging from 4.5 hours to 4.9 hours. The strongest transit signals occur every 4.5 hours and exhibit varying depths (blocking up to 40 per cent of the star's brightness) and asymmetric profiles, indicative of a small object with a cometary tail of dusty effluent material. The star has a dusty debris disk, and the star's spectrum shows prominent lines from heavy elements such as magnesium, aluminium, silicon, calcium, iron, and nickel. This system provides further evidence that the pollution of white dwarfs by heavy elements might originate from disrupted rocky bodies such as asteroids and minor planets.
C1 [Vanderburg, Andrew; Johnson, John Asher; Bieryla, Allyson; Irwin, Jonathan; Lewis, John Arban; Kipping, David; Brown, Warren R.; Angus, Ruth; Schaefer, Laura; Latham, David W.; Charbonneau, David; Eastman, Jason] Harvard Smithsonian Ctr Astrophys, Cambridge, MA 02138 USA.
   [Rappaport, Saul] MIT, Dept Phys, Cambridge, MA 02139 USA.
   [Rappaport, Saul] MIT, Kavli Inst Astrophys & Space Res, Cambridge, MA 02139 USA.
   [Kipping, David] Columbia Univ, Dept Astron, New York, NY 10027 USA.
   [Dufour, Patrick] Univ Montreal, Dept Phys, Inst Rech Exoplanetes, Montreal, PQ H3C 3J7, Canada.
   [Ciardi, David R.; Beichman, Charles] CALTECH, NASA, Exoplanet Sci Inst, Pasadena, CA 91125 USA.
   [Angus, Ruth] Univ Oxford, Dept Phys, Oxford OX1 3RH, England.
   [McCrady, Nate] Univ Montana, Dept Phys & Astron, Missoula, MT 59812 USA.
   [Wittenmyer, Robert A.] Univ New S Wales, Sch Phys, Sydney, NSW 2052, Australia.
   [Wittenmyer, Robert A.] Univ New S Wales, Australian Ctr Astrobiol, Sydney, NSW 2052, Australia.
   [Wright, Jason T.] Penn State Univ, Dept Astron & Astrophys, University Pk, PA 16802 USA.
   [Wright, Jason T.] Penn State Univ, Ctr Exoplanets & Habitable Worlds, University Pk, PA 16802 USA.
C3 Smithsonian Astrophysical Observatory; Smithsonian Institution; Harvard University; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Columbia University; Universite de Montreal; National Aeronautics & Space Administration (NASA); California Institute of Technology; University of Oxford; University of Montana System; University of Montana; University of New South Wales Sydney; University of New South Wales Sydney; 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 Vanderburg, A (corresponding author), Harvard Smithsonian Ctr Astrophys, 60 Garden St, Cambridge, MA 02138 USA.
EM avanderburg@cfa.harvard.edu
FU National Science Foundation Graduate Research Fellowship [DGE 1144152]; David and Lucile Packard Foundation; Alfred P. Sloan Foundation; Pennsylvania State University; Eberly College of Science; Pennsylvania Space Grant Consortium; David and Lucile Packard Fellowship for Science and Engineering; National Science Foundation [AST-0807690, AST-1109468, AST-1004488]; John Templeton Foundation; Direct For Mathematical & Physical Scien; Division Of Astronomical Sciences [1516242] Funding Source: National Science Foundation
NR 30
TC 380
Z9 425
U1 0
U2 20
PU NATURE PUBLISHING 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 22
PY 2015
VL 526
IS 7574
BP 546
EP 549
DI 10.1038/nature15527
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV1NX
UT WOS:000364026100044
PM 26490620
DA 2026-03-09
ER

PT J
AU Alford, MH
   Peacock, T
   MacKinnon, JA
   Nash, JD
   Buijsman, MC
   Centuroni, LR
   Chao, SY
   Chang, MH
   Farmer, DM
   Fringer, OB
   Fu, KH
   Gallacher, PC
   Graber, HC
   Helfrich, KR
   Jachec, SM
   Jackson, CR
   Klymak, JM
   Ko, DS
   Jan, S
   Johnston, TMS
   Legg, S
   Lee, IH
   Lien, RC
   Mercier, MJ
   Moum, JN
   Musgrave, R
   Park, JH
   Pickering, AI
   Pinkel, R
   Rainville, L
   Ramp, SR
   Rudnick, DL
   Sarkar, S
   Scotti, A
   Simmons, HL
   St Laurent, LC
   Venayagamoorthy, SK
   Wang, YH
   Wang, J
   Yang, YJ
   Paluszkiewicz, T
   Tang, TY
AF Alford, Matthew H.
   Peacock, Thomas
   MacKinnon, Jennifer A.
   Nash, Jonathan D.
   Buijsman, Maarten C.
   Centuroni, Luca R.
   Chao, Shenn-Yu
   Chang, Ming-Huei
   Farmer, David M.
   Fringer, Oliver B.
   Fu, Ke-Hsien
   Gallacher, Patrick C.
   Graber, Hans C.
   Helfrich, Karl R.
   Jachec, Steven M.
   Jackson, Christopher R.
   Klymak, Jody M.
   Ko, Dong S.
   Jan, Sen
   Johnston, T. M. Shaun
   Legg, Sonya
   Lee, I-Huan
   Lien, Ren-Chieh
   Mercier, Matthieu J.
   Moum, James N.
   Musgrave, Ruth
   Park, Jae-Hun
   Pickering, Andrew I.
   Pinkel, Robert
   Rainville, Luc
   Ramp, Steven R.
   Rudnick, Daniel L.
   Sarkar, Sutanu
   Scotti, Alberto
   Simmons, Harper L.
   St Laurent, Louis C.
   Venayagamoorthy, Subhas K.
   Wang, Yu-Huai
   Wang, Joe
   Yang, Yiing J.
   Paluszkiewicz, Theresa
   Tang, Tswen-Yung (David)
TI The formation and fate of internal waves in the South China Sea
SO NATURE
LA English
DT Article
ID baroclinic tides; solitary waves; lee waves; ocean; propagation; model; circulation; generation; prediction; ridge
AB Internal gravity waves, the subsurface analogue of the familiar surface gravity waves that break on beaches, are ubiquitous in the ocean. Because of their strong vertical and horizontal currents, and the turbulent mixing caused by their breaking, they affect a panoply of ocean processes, such as the supply of nutrients for photosynthesis(1), sediment and pollutant transport(2) and acoustic transmission(3); they also pose hazards for man-made structures in the ocean(4). Generated primarily by the wind and the tides, internal waves can travel thousands of kilometres from their sources before breaking(5), making it challenging to observe them and to include them in numerical climate models, which are sensitive to their effects(6,7). For over a decade, studies(8-11) have targeted the South China Sea, where the oceans' most powerful known internal waves are generated in the Luzon Strait and steepen dramatically as they propagate west. Confusion has persisted regarding their mechanism of generation, variability and energy budget, however, owing to the lack of in situ data from the Luzon Strait, where extreme flow conditions make measurements difficult. Here we use new observations and numerical models to (1) show that the waves begin as sinusoidal disturbances rather than arising from sharp hydraulic phenomena, (2) reveal the existence of >200-metre-high breaking internal waves in the region of generation that give rise to turbulence levels >10,000 times that in the open ocean, (3) determine that the Kuroshio western boundary current noticeably refracts the internal wave field emanating from the Luzon Strait, and (4) demonstrate a factor-of-two agreement between modelled and observed energy fluxes, which allows us to produce an observationally supported energy budget of the region. Together, these findings give a cradle-to-grave picture of internal waves on a basin scale, which will support further improvements of their representation in numerical climate predictions.
C1 [Alford, Matthew H.; MacKinnon, Jennifer A.; Centuroni, Luca R.; Johnston, T. M. Shaun; Musgrave, Ruth; Pinkel, Robert; Rudnick, Daniel L.] Univ Calif San Diego, Scripps Inst Oceanog, La Jolla, CA 92037 USA.
   [Alford, Matthew H.; Lien, Ren-Chieh; Pickering, Andrew I.; Rainville, Luc] Univ Washington, Seattle, WA 98105 USA.
   [Peacock, Thomas; Pickering, Andrew I.] MIT, Cambridge, MA 02139 USA.
   [Nash, Jonathan D.; Moum, James N.] Oregon State Univ, Corvallis, OR 97370 USA.
   [Buijsman, Maarten C.] Univ So Mississippi, Stennis Space Ctr, MS 39529 USA.
   [Chao, Shenn-Yu] Univ Maryland, Cambridge, MD 21613 USA.
   [Chang, Ming-Huei; Jan, Sen; Wang, Joe; Yang, Yiing J.; Tang, Tswen-Yung (David)] Natl Taiwan Univ, Inst Oceanog, Taipei 10617, Taiwan.
   [Farmer, David M.] Univ Rhode Isl, Narragansett, RI 02882 USA.
   [Fringer, Oliver B.] Stanford Univ, Stanford, CA 94305 USA.
   [Fu, Ke-Hsien; Lee, I-Huan; Wang, Yu-Huai] Natl Sun Yat Sen Univ, Kaohsiung 80424, Taiwan.
   [Gallacher, Patrick C.; Ko, Dong S.] NRL, Stennis Space Ctr, MS 39529 USA.
   [Graber, Hans C.] Univ Miami, Miami, FL 33149 USA.
   [Helfrich, Karl R.; St Laurent, Louis C.] Woods Hole Oceanog Inst, Falmouth, MA 02543 USA.
   [Jachec, Steven M.] Florida Inst Technol, Melbourne, FL 32901 USA.
   [Jackson, Christopher R.] Global Ocean Associates, Alexandria, VA 22310 USA.
   [Klymak, Jody M.] Univ Victoria, Victoria, BC V8W 3P6, Canada.
   [Legg, Sonya] Princeton Univ, Princeton, NJ 08542 USA.
   [Mercier, Matthieu J.] Inst Mecan Fluides Toulouse, F-31400 Toulouse, France.
   [Park, Jae-Hun] Korea Inst Ocean Sci & Technol, Ansan 426744, South Korea.
   [Ramp, Steven R.] Soliton Ocean Serv, Carmel, CA 93924 USA.
   [Sarkar, Sutanu] Univ Calif San Diego, La Jolla, CA 92037 USA.
   [Scotti, Alberto] Univ N Carolina, Chapel Hill, NC 27599 USA.
   [Simmons, Harper L.] Univ Alaska Fairbanks, Fairbanks, AK 99775 USA.
   [Venayagamoorthy, Subhas K.] Colorado State Univ, Ft Collins, CO 80523 USA.
   [Paluszkiewicz, Theresa] Off Naval Res, Arlington, VA 22217 USA.
C3 University of California System; University of California San Diego; Scripps Institution of Oceanography; University of Washington; University of Washington Seattle; Massachusetts Institute of Technology (MIT); Oregon State University; University of Southern Mississippi; National Taiwan University; University of Rhode Island; Stanford University; National Sun Yat Sen University; United States Department of Defense; United States Navy; United States Naval Research Laboratory; University of Miami; Woods Hole Oceanographic Institution; Florida Institute of Technology; University of Victoria; Princeton University; Universite de Toulouse; Universite Federale Toulouse Midi-Pyrenees (ComUE); Universite Toulouse III - Paul Sabatier; Institut National Polytechnique de Toulouse; Centre National de la Recherche Scientifique (CNRS); Korea Institute of Ocean Science & Technology (KIOST); University of California System; University of California San Diego; University of North Carolina; University of North Carolina Chapel Hill; University of Alaska System; University of Alaska Fairbanks; Colorado State University System; Colorado State University Fort Collins; United States Department of Defense; United States Navy; Office of Naval Research
RP Alford, MH (corresponding author), Univ Calif San Diego, Scripps Inst Oceanog, La Jolla, CA 92037 USA.
EM malford@ucsd.edu
FU US Office of Naval Research; Taiwan National Science Council
NR 58
TC 568
Z9 653
U1 28
U2 479
PU NATURE PUBLISHING 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 7
PY 2015
VL 521
IS 7550
BP 65
EP U381
DI 10.1038/nature14399
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH4YS
UT WOS:000354040900033
PM 25951285
DA 2026-03-09
ER

PT J
AU Gardner, MR
   Kattenhorn, LM
   Kondur, HR
   von Schaewen, M
   Dorfman, T
   Chiang, JJ
   Haworth, KG
   Decker, JM
   Alpert, MD
   Bailey, CC
   Neale, ES
   Fellinger, CH
   Joshi, VR
   Fuchs, SP
   Martinez-Navio, JM
   Quinlan, BD
   Yao, AY
   Mouquet, H
   Gorman, J
   Zhang, BS
   Poignard, P
   Nussenzweig, MC
   Burton, DR
   Kwong, PD
   Piatak, M
   Lifson, JD
   Gao, GP
   Desrosiers, RC
   Evans, DT
   Hahn, BH
   Ploss, A
   Cannon, PM
   Seaman, MS
   Farzan, M
AF Gardner, Matthew R.
   Kattenhorn, Lisa M.
   Kondur, Hema R.
   von Schaewen, Markus
   Dorfman, Tatyana
   Chiang, Jessica J.
   Haworth, Kevin G.
   Decker, Julie M.
   Alpert, Michael D.
   Bailey, Charles C.
   Neale, Ernest S., Jr.
   Fellinger, Christoph H.
   Joshi, Vinita R.
   Fuchs, Sebastian P.
   Martinez-Navio, Jose M.
   Quinlan, Brian D.
   Yao, Annie Y.
   Mouquet, Hugo
   Gorman, Jason
   Zhang, Baoshan
   Poignard, Pascal
   Nussenzweig, Michel C.
   Burton, Dennis R.
   Kwong, Peter D.
   Piatak, Michael, Jr.
   Lifson, Jeffrey D.
   Gao, Guangping
   Desrosiers, Ronald C.
   Evans, David T.
   Hahn, Beatrice H.
   Ploss, Alexander
   Cannon, Paula M.
   Seaman, Michael S.
   Farzan, Michael
TI AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges
SO NATURE
LA English
DT Article
ID immunodeficiency-virus type-1; fusion inhibitor t-20; tyrosine sulfation; n-terminus; potent neutralization; envelope glycoprotein; binding-site; soluble cd4; hiv-1 gp120; antibody
AB Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. Adeno-associated virus (AAV) vectors can stably express HIV-1 broadly neutralizing antibodies (bNAbs)(1,2). However, even the best bNAbs neutralize 10-50% of HIV-1 isolates inefficiently (80% inhibitory concentration (IC80) > 5 mu g ml(-1)), suggesting that high concentrations of these antibodies would be necessary to achieve general protection(3-6). Here we show that eCD4-Ig, a fusion ofCD4-Ig with a small CCR5-mimetic sulfopeptide, binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean half-maximum inhibitory concentration (IC50), 0.05 mu g ml(-1)). Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any bNAb. For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2 and simian immunodeficiency virus isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46 and 3BNC117. Rhesus macaques inoculated with an AAV vector stably expressed 17-77 mu g ml(-1) of fully functional rhesuseCD4-Ig for more than 40 weeks, and these macaques were protected from several infectious challenges with SHIV-AD8. Rhesus eCD4-Ig was also markedly less immunogenic than rhesus forms of four well-characterized bNAbs. Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine.
C1 [Gardner, Matthew R.; Kondur, Hema R.; Dorfman, Tatyana; Bailey, Charles C.; Fellinger, Christoph H.; Joshi, Vinita R.; Quinlan, Brian D.; Farzan, Michael] Scripps Res Inst, Dept Infect Dis, Jupiter, FL 33458 USA.
   [Kattenhorn, Lisa M.; Chiang, Jessica J.; Alpert, Michael D.; Neale, Ernest S., Jr.; Yao, Annie Y.; Desrosiers, Ronald C.] Harvard Univ, Sch Med, New England Primate Res Ctr, Dept Comparat Pathol, Southborough, MA 01772 USA.
   [von Schaewen, Markus; Ploss, Alexander] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA.
   [Haworth, Kevin G.; Cannon, Paula M.] Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA.
   [Decker, Julie M.; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA.
   [Decker, Julie M.; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA.
   [Alpert, Michael D.] Immunathon Inc, Cambridge, MA 02141 USA.
   [Fuchs, Sebastian P.; Martinez-Navio, Jose M.; Desrosiers, Ronald C.] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA.
   [Mouquet, Hugo; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA.
   [Mouquet, Hugo] Inst Pasteur, Dept Immunol, F-75015 Paris, France.
   [Gorman, Jason; Zhang, Baoshan; Kwong, Peter D.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA.
   [Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA.
   [Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA.
   [Nussenzweig, Michel C.] Howard Hughes Med Inst, New York, NY 10065 USA.
   [Burton, Dennis R.] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA.
   [Piatak, Michael, Jr.; Lifson, Jeffrey D.] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Leidos Biomed Res Inc, Frederick, MD 21702 USA.
   [Gao, Guangping] Univ Massachusetts, Sch Med, Gene Therapy Ctr, Worcester, MA 01655 USA.
   [Evans, David T.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53711 USA.
   [Seaman, Michael S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA.
C3 State University System of Florida; University of Florida; Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology; Harvard University; Princeton University; University of Southern California; University of Pennsylvania; University of Pennsylvania; University of Miami; Rockefeller University; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; National Institutes of Health (NIH) - USA; Scripps Research Institute; International AIDS Vaccine Initiative; Scripps Research Institute; Howard Hughes Medical Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; Massachusetts Institute of Technology (MIT); Ragon Institute; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; University of Massachusetts System; University of Massachusetts Worcester; University of Wisconsin System; University of Wisconsin Madison; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center
RP Farzan, M (corresponding author), Scripps Res Inst, Dept Infect Dis, Jupiter, FL 33458 USA.
EM mfarzan@scripps.edu
FU National Institutes of Health (NIH) [R01 AI091476, R01 AI080324, P01 AI100263, RR000168, RO1 AI058715]; Vaccine Research Center, NIAID, NIH; National Cancer Institute, NIH [HHSN261200800001E]; National Cancer Institute; National Institute on Drug Abuse; National Institute on Aging; National Institute of Nursing Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Minority Health and Health Disparities; National Heart Lung and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases [P30AI045008] Funding Source: NIH RePORTER; National Institute on Drug Abuse; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute; National Institute of Allergy and Infectious Diseases; National Heart Lung and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Minority Health and Health Disparities; National Institute on Aging; National Institute of Dental and Craniofacial Research; National Institute of Nursing Research [P30AI073961] Funding Source: NIH RePORTER
NR 50
TC 250
Z9 306
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 MAR 5
PY 2015
VL 519
IS 7541
BP 87
EP U173
DI 10.1038/nature14264
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC4EQ
UT WOS:000350304000041
PM 25707797
DA 2026-03-09
ER

PT J
AU Schoors, S
   Bruning, U
   Missiaen, R
   Queiroz, KCS
   Borgers, G
   Elia, I
   Zecchin, A
   Cantelmo, AR
   Christen, S
   Goveia, J
   Heggermont, W
   Godde, L
   Vinckier, S
   Van Veldhoven, PP
   Eelen, G
   Schoonjans, L
   Gerhardt, H
   Dewerchin, M
   Baes, M
   De Bock, K
   Ghesquière, B
   Lunt, SY
   Fendt, SM
   Carmeliet, P
AF Schoors, Sandra
   Bruning, Ulrike
   Missiaen, Rindert
   Queiroz, Karla C. S.
   Borgers, Gitte
   Elia, Ilaria
   Zecchin, Annalisa
   Cantelmo, Anna Rita
   Christen, Stefan
   Goveia, Jermaine
   Heggermont, Ward
   Godde, Lucica
   Vinckier, Stefan
   Van Veldhoven, Paul P.
   Eelen, Guy
   Schoonjans, Luc
   Gerhardt, Holger
   Dewerchin, Mieke
   Baes, Myriam
   De Bock, Katrien
   Ghesquiere, Bart
   Lunt, Sophia Y.
   Fendt, Sarah-Maria
   Carmeliet, Peter
TI Fatty acid carbon is essential for dNTP synthesis in endothelial cells
SO NATURE
LA English
DT Article
ID growth-factor; metabolism; oxidation; tumor; angiogenesis; glycolysis; culture; kinase; pools
AB The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CFT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenceil endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis.
C1 [Schoors, Sandra; Bruning, Ulrike; Missiaen, Rindert; Queiroz, Karla C. S.; Borgers, Gitte; Zecchin, Annalisa; Cantelmo, Anna Rita; Goveia, Jermaine; Godde, Lucica; Vinckier, Stefan; Eelen, Guy; Schoonjans, Luc; Dewerchin, Mieke; De Bock, Katrien; Ghesquiere, Bart; Carmeliet, Peter] Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Neurovasc Link, B-3000 Leuven, Belgium.
   [Schoors, Sandra; Bruning, Ulrike; Missiaen, Rindert; Queiroz, Karla C. S.; Borgers, Gitte; Zecchin, Annalisa; Cantelmo, Anna Rita; Goveia, Jermaine; Godde, Lucica; Vinckier, Stefan; Eelen, Guy; Schoonjans, Luc; Dewerchin, Mieke; De Bock, Katrien; Ghesquiere, Bart; Carmeliet, Peter] VIB, Lab Angiogenesis & Neurovasc Link, Vesalius Res Ctr, B-3000 Leuven, Belgium.
   [Elia, Ilaria; Christen, Stefan; Fendt, Sarah-Maria] Katholieke Univ Leuven, Dept Oncol, Lab Cellular Metab & Metab Regulat, B-3000 Leuven, Belgium.
   [Elia, Ilaria; Christen, Stefan; Fendt, Sarah-Maria] VIB, Lab Cellular Metab & Metab Regulat, Vesalius Res Ctr, B-3000 Leuven, Belgium.
   [Heggermont, Ward] Katholieke Univ Leuven, Dept Cardiovasc Res, Ctr Mol & Vasc Biol, B-3000 Leuven, Belgium.
   [Heggermont, Ward] UZ Leuven, Div Clin Cardiol, B-3000 Leuven, Belgium.
   [Van Veldhoven, Paul P.] Katholieke Univ Leuven, Lab Lipid Biochem & Prot Interact, B-3000 Leuven, Belgium.
   [Gerhardt, Holger] Katholieke Univ Leuven, Dept Oncol, Vasc Patterning Lab, B-3000 Leuven, Belgium.
   [Gerhardt, Holger] VIB, Vesalius Res Ctr, Vasc Patterning Lab, B-3000 Leuven, Belgium.
   [Gerhardt, Holger] Max Delbruck Ctr Mol Med, Integrat Vasc Biol Lab, D-13125 Berlin, Germany.
   [Baes, Myriam] Katholieke Univ Leuven, Lab Cell Metab, Dept Pharmaceut & Pharmacol Sci, B-3000 Leuven, Belgium.
   [De Bock, Katrien] Katholieke Univ Leuven, Exercise Physiol Res Grp, Dept Kinesiol, B-3000 Leuven, Belgium.
   [Lunt, Sophia Y.] Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA.
C3 KU Leuven; Flanders Institute for Biotechnology (VIB); KU Leuven; Flanders Institute for Biotechnology (VIB); KU Leuven; KU Leuven; University Hospital Leuven; KU Leuven; KU Leuven; Flanders Institute for Biotechnology (VIB); Helmholtz Association; Max Delbruck Center for Molecular Medicine; KU Leuven; KU Leuven; Michigan State University
RP Carmeliet, P (corresponding author), Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Neurovasc Link, B-3000 Leuven, Belgium.
EM sarah-maria.fendt@vib-kuleuven.be; peter.carmeliet@vib-kuleuven.be
FU Institution of Research/Innovation (IWT); Research Foundation Flanders (FWO); Marie Curie-IEF Fellowship; CAPES (Brazil); KU Leuven; Marie Curie CIG; FWO-Odysseusll; Concern Foundation; Bayer Healthcare Pharmaceuticals; Methusalem funding (Flemish Government); FWO; Foundation Leducq Transatlantic Network (ARTEMIS); Foundation against Cancer; European Research Council (ERC) Advanced Research Grant [EU-ERC269073]; AXA Research grant; Department of Defense CDMRP Visionary Postdoctoral Award [W81XWH-12-1-0466];  [IUAP7/03]
NR 35
TC 531
Z9 593
U1 12
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 APR 9
PY 2015
VL 520
IS 7546
BP 192
EP U113
DI 10.1038/nature14362
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CF3NA
UT WOS:000352454600032
PM 25830893
DA 2026-03-09
ER

PT J
AU Zhou, M
   Wang, W
   Karapetyan, S
   Mwimba, M
   Marquées, J
   Buchler, NE
   Dong, XN
AF Zhou, Mian
   Wang, Wei
   Karapetyan, Sargis
   Mwimba, Musoki
   Marques, Jorge
   Buchler, Nicolas E.
   Dong, Xinnian
TI Redox rhythm reinforces the circadian clock to gate immune response
SO NATURE
LA English
DT Article
ID transcription factor; salicylic-acid; arabidopsis; gene; npr1; protein; glutathione; induction; component; distinct
AB Recent studies have shown that in addition to the transcriptional circadian clock, many organisms, including Arabidopsis, have a circadian redox rhythm driven by the organism's metabolic activities(1-3). It has been hypothesized that the redox rhythm is linked to the circadian clock, but the mechanism and the biological significance of this link have only begun to be investigated(4-7). Here we report that the master immune regulator NPR1 (non-expressor of pathogenesis-related gene 1) of Arabidopsis is a sensor of the plant's redox state and regulates transcription of core circadian clock genes even in the absence of pathogen challenge. Surprisingly, acute perturbation in the redox status triggered by the immune signal salicylic acid does not compromise the circadian clock but rather leads to its reinforcement. Mathematical modelling and subsequent experiments show that NPR1 reinforces the circadian clock without changing the period by regulating both the morning and the evening clock genes. This balanced network architecture helps plants gate their immune responses towards the morning and minimize costs on growth at night. Our study demonstrates how a sensitive redox rhythm interacts with a robust circadian clock to ensure proper responsiveness to environmental stimuli without compromising fitness of the organism.
C1 [Zhou, Mian; Wang, Wei; Mwimba, Musoki; Marques, Jorge; Dong, Xinnian] Duke Univ, Howard Hughes Med Inst, Gordon & Betty Moore Fdn, Durham, NC 27708 USA.
   [Zhou, Mian; Wang, Wei; Mwimba, Musoki; Marques, Jorge; Buchler, Nicolas E.; Dong, Xinnian] Duke Univ, Dept Biol, Durham, NC 27708 USA.
   [Karapetyan, Sargis; Buchler, Nicolas E.] Duke Univ, Dept Phys, Durham, NC 27708 USA.
C3 Duke University; Howard Hughes Medical Institute; Duke University; Duke University
RP Dong, XN (corresponding author), Duke Univ, Howard Hughes Med Inst, Gordon & Betty Moore Fdn, Durham, NC 27708 USA.
EM nb69@duke.edu; xdong@duke.edu
FU National Institutes of Health (NIH) [1R01-GM099839-01, 2R01-GM069594-09]; Howard Hughes Medical Institute; Gordon and Betty Moore Foundation [GBMF3032]; Defense Advanced Research Projects Agency (DARPA) Biochronicity Grant [DARPA-BAA-11-66]; NIH [DP2 OD008654-01]; Burroughs Wellcome Fund CASI Award [BWF 1005769.01]; Division Of Integrative Organismal Systems; Direct For Biological Sciences [0929226] Funding Source: National Science Foundation
NR 43
TC 166
Z9 210
U1 4
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 JUL 23
PY 2015
VL 523
IS 7561
BP 472
EP U221
DI 10.1038/nature14449
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN4DD
UT WOS:000358378900039
PM 26098366
DA 2026-03-09
ER

PT J
AU Yan, Z
   Bai, XC
   Yan, CY
   Wu, JP
   Li, ZQ
   Xie, T
   Peng, W
   Yin, CC
   Li, XM
   Scheres, SHW
   Shi, YG
   Yan, N
AF Yan, Zhen
   Bai, Xiao-chen
   Yan, Chuangye
   Wu, Jianping
   Li, Zhangqiang
   Xie, Tian
   Peng, Wei
   Yin, Chang-cheng
   Li, Xueming
   Scheres, Sjors H. W.
   Shi, Yigong
   Yan, Nieng
TI Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution
SO NATURE
LA English
DT Article
ID calcium-release channel; sarcoplasmic-reticulum; electron cryomicroscopy; transmembrane domains; cryo-em; skeletal; purification; region; reconstitution; identification
AB The ryanodine receptors (RyRs) are high-conductance intracellular Ca2+ channels that play a pivotal role in the excitation-contraction coupling of skeletal and cardiac muscles. RyRs are the largest known ion channels, with a homotetrameric organization and approximately 5,000 residues in each protomer. Here we report the structure of the rabbit RyR1 in complex with its modulator FKBP12 at an overall resolution of 3.8 angstrom, determined by single-particle electron cryomicroscopy. Three previously uncharacterized domains, named central, handle and helical domains, display the armadillo repeat fold. These domains, together with the amino-terminal domain, constitute a network of superhelical scaffold for binding and propagation of conformational changes. The channel domain exhibits the voltage-gated ion channel superfamily fold with distinct features. A negative-charge-enriched hairpin loop connecting S5 and the pore helix is positioned above the entrance to the selectivity-filter vestibule. The four elongated S6 segments form a right-handed helical bundle that closes the pore at the cytoplasmic border of the membrane. Allosteric regulation of the pore by the cytoplasmic domains is mediated through extensive interactions between the central domains and the channel domain. These structural features explain high ion conductance by RyRs and the long-range allosteric regulation of channel activities.
C1 [Yan, Zhen; Li, Zhangqiang; Peng, Wei; Yan, Nieng] Tsinghua Univ, Sch Life Sci, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100084, Peoples R China.
   [Yan, Zhen; Yan, Chuangye; Wu, Jianping; Li, Zhangqiang; Xie, Tian; Peng, Wei; Li, Xueming; Shi, Yigong; Yan, Nieng] Tsinghua Univ, Sch Med, Beijing 100084, Peoples R China.
   [Yan, Zhen; Yan, Chuangye; Wu, Jianping; Xie, Tian; Shi, Yigong] Tsinghua Univ, Sch Life Sci, Ministry Educ Key Lab Prot Sci, Beijing 100084, Peoples R China.
   [Yan, Zhen; Yan, Chuangye; Wu, Jianping; Li, Zhangqiang; Xie, Tian; Peng, Wei; Li, Xueming; Shi, Yigong; Yan, Nieng] Tsinghua Univ, Sch Life Sci, Ctr Struct Biol, Tsinghua Peking Joint Ctr Life Sci, Beijing 100084, Peoples R China.
   [Bai, Xiao-chen; Scheres, Sjors H. W.] MRC Lab Mol Biol, Cambridge CB2 0QH, England.
   [Yin, Chang-cheng] Peking Univ, Dept Biophys, Hlth Sci Ctr, Beijing 100191, Peoples R China.
   [Yin, Chang-cheng] Peking Univ, Ctr Prot Sci, Beijing 100191, Peoples R China.
C3 Tsinghua University; Tsinghua University; Tsinghua University; Tsinghua University; MRC Laboratory Molecular Biology; Peking University; Peking University
RP Yan, N (corresponding author), Tsinghua Univ, Sch Life Sci, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100084, Peoples R China.
EM scheres@mrc-lmb.cam.ac.uk; shi-lab@tsinghua.edu.cn; nyan@tsinghua.edu.cn
FU Ministry of Science and Technology of China [2015CB910101, 2011CB910501, 2014ZX09507003006]; National Natural Science Foundation of China [31321062, 31130002, 31125009]; European Union; UK Medical Research Council [MC_UP_A025_1013]; MRC [MC_UP_A025_1013] Funding Source: UKRI; Medical Research Council [MC_UP_A025_1013] Funding Source: researchfish
NR 67
TC 360
Z9 434
U1 13
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 JAN 1
PY 2015
VL 517
IS 7532
BP 50
EP +
DI 10.1038/nature14063
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AX8SI
UT WOS:000347178400032
PM 25517095
DA 2026-03-09
ER

PT J
AU Nuñez, JK
   Lee, ASY
   Engelman, A
   Doudna, JA
AF Nunez, James K.
   Lee, Amy S. Y.
   Engelman, Alan
   Doudna, Jennifer A.
TI Integrase-mediated spacer acquisition during CRISPR-Cas adaptive immunity
SO NATURE
LA English
DT Article
ID human-immunodeficiency-virus; short palindromic repeats; topoisomerase-i mutants; dna strand transfer; escherichia-coli; acquired-resistance; bacterial immunity; gyrase genes; sequence; system
AB Bacteria and archaea insert spacer sequences acquired from foreign DNAs into CRISPR loci to generate immunological memory. The Escherichia coli Cas1-Cas2 complex mediates spacer acquisition in vivo, but the molecular mechanism of this process is unknown. Here we show that the purified Cas1-Cas2 complex integrates oligonucleotide DNA substrates into acceptor DNA to yield products similar to those generated by retroviral integrases and transposases. Cas1 is the catalytic subunit and Cas2 substantially increases integration activity. Protospacer DNA with free 3'-OH ends and supercoiled target DNA are required, and integration occurs preferentially at the ends of CRISPR repeats and at sequences adjacent to cruciform structures abutting AT-rich regions, similar to the CRISPR leader sequence. Our results demonstrate the Cas1-Cas2 complex to be the minimal machinery that catalyses spacer DNA acquisition and explain the significance of CRISPR repeats in providing sequence and structural specificity for Cas1-Cas2-mediated adaptive immunity.
C1 [Nunez, James K.; Lee, Amy S. Y.; Doudna, Jennifer A.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
   [Lee, Amy S. Y.; Doudna, Jennifer A.] Univ Calif Berkeley, Ctr RNA Syst Biol, Berkeley, CA 94720 USA.
   [Engelman, Alan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA.
   [Engelman, Alan] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.
   [Doudna, Jennifer A.] Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA.
   [Doudna, Jennifer A.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.
   [Doudna, Jennifer A.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA.
C3 University of California System; University of California Berkeley; University of California System; University of California Berkeley; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; 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
RP Doudna, JA (corresponding author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA.
EM doudna@berkeley.edu
FU US National Science Foundation [1244557]; NIH [AI070042]; NIH S10 Instrumentation Grants [S10RR029668, S10RR027303]; US National Science Foundation Graduate Research Fellowship; UC Berkeley Chancellor's Graduate Fellowship; American Cancer Society [PF-14-108-01-RMC]; National Institute of General Medical Sciences [T32GM066698] Funding Source: NIH RePORTER
NR 49
TC 274
Z9 356
U1 2
U2 125
PU NATURE PUBLISHING 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 12
PY 2015
VL 519
IS 7542
BP 193
EP +
DI 10.1038/nature14237
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD0NH
UT WOS:000350770500030
PM 25707795
DA 2026-03-09
ER

PT J
AU Martin, DC
   Matuszewski, M
   Morrissey, P
   Neill, JD
   Moore, A
   Cantalupo, S
   Prochaska, JX
   Chang, D
AF Martin, D. Christopher
   Matuszewski, Mateusz
   Morrissey, Patrick
   Neill, James D.
   Moore, Anna
   Cantalupo, Sebastiano
   Prochaska, J. Xavier
   Chang, Daphne
TI A giant protogalactic disk linked to the cosmic web
SO NATURE
LA English
DT Article
ID medium emission observations; ly-alpha emission; intergalactic medium; host galaxy; quasar activity; gas; redshift; spectroscopy; absorption; radiation
AB The specifics of how galaxies form from, and are fuelled by, gas from the intergalactic medium remain uncertain. Hydrodynamic simulations suggest that 'cold accretion flows'-relatively cool (temperatures of the order of 104 kelvin), unshocked gas streaming along filaments of the cosmic web into dark-matter halos(1-3)-are important. These flows are thought to deposit gas and angular momentum into the circumgalactic medium, creating disk-or ring-like structures that eventually coalesce into galaxies that form at filamentary intersections(4,5). Recently, a large and luminous filament, consistent with such a cold accretion flow, was discovered near the quasi-stellar object QSO UM287 at redshift 2.279 using narrow-band imaging(6). Unfortunately, imaging is not sufficient to constrain the physical characteristics of the filament, to determine its kinematics, to explain how it is linked to nearby sources, or to account for its unusual brightness, more than a factor of ten above what is expected for a filament. Here we report a two-dimensional spectroscopic investigation of the emitting structure. We find that the brightest emission region is an extended rotating hydrogen disk with a velocity profile that is characteristic of gas in a darkmatter halo with a mass of 10(13) solar masses. This giant protogalactic disk appears to be connected to a quiescent filament that may extend beyond the virial radius of the halo. The geometry is strongly suggestive of a cold accretion flow.
C1 [Martin, D. Christopher; Matuszewski, Mateusz; Morrissey, Patrick; Neill, James D.] CALTECH, Cahill Ctr Astrophys, Pasadena, CA 91125 USA.
   [Moore, Anna] CALTECH, Cahill Ctr Astrophys, Caltech Opt Observ, Pasadena, CA 91125 USA.
   [Cantalupo, Sebastiano] ETH, Inst Astron, CH-8093 Zurich, Switzerland.
   [Prochaska, J. Xavier] Univ Calif Santa Cruz, Dept Astron & Astrophys, Santa Cruz, CA 95064 USA.
   [Prochaska, J. Xavier] Univ Calif Santa Cruz, Univ Calif Observ, Lick Observ, Santa Cruz, CA 95064 USA.
C3 California Institute of Technology; California Institute of Technology; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of California System; University of California Santa Cruz; University of California System; University of California Santa Cruz
RP Martin, DC (corresponding author), CALTECH, Cahill Ctr Astrophys, 1216 East Calif Blvd,Mail Code 278-17, Pasadena, CA 91125 USA.
EM cmartin@srl.caltech.edu
FU National Science Foundation; California Institute of Technology
NR 35
TC 73
Z9 83
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 AUG 13
PY 2015
VL 524
IS 7564
BP 192
EP +
DI 10.1038/nature14616
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900025
PM 26245373
DA 2026-03-09
ER

PT J
AU Walter, K
   Min, JL
   Huang, J
   Crooks, L
   Memari, Y
   McCarthy, S
   Perry, JRB
   Xu, C
   Futema, M
   Lawson, D
   Iotchkova, V
   Schiffels, S
   Hendricks, AE
   Danecek, P
   Li, R
   Floyd, J
   Wain, LV
   Barroso, I
   Humphries, SE
   Hurles, ME
   Zeggini, E
   Barrett, JC
   Plagnol, V
   Richards, JB
   Greenwood, CMT
   Timpson, NJ
   Durbin, R
   Soranzo, N
   Bala, S
   Clapham, P
   Coates, G
   Cox, T
   Daly, A
   Danecek, P
   Du, Y
   Durbin, R
   Edkins, S
   Ellis, P
   Flicek, P
   Guo, X
   Guo, X
   Huang, L
   Jackson, DK
   Joyce, C
   Keane, T
   Kolb-Kokocinski, A
   Langford, C
   Li, Y
   Liang, J
   Lin, H
   Liu, R
   Maslen, J
   McCarthy, S
   Muddyman, D
   Quail, MA
   Stalker, J
   Sun, J
   Tian, J
   Wang, G
   Wang, J
   Wang, Y
   Wong, K
   Zhang, P
   Barroso, I
   Birney, E
   Boustred, C
   Chen, L
   Clement, G
   Cocca, M
   Danecek, P
   Smith, GD
   Day, INM
   Day-Williams, A
   Down, T
   Dunham, I
   Durbin, R
   Evans, DM
   Gaunt, TR
   Geihs, M
   Greenwood, CMT
   Hart, D
   Hendricks, AE
   Howie, B
   Huang, J
   Hubbard, T
   Hysi, P
   Iotchkova, V
   Jamshidi, Y
   Karczewski, KJ
   Kemp, JP
   Lachance, G
   Lawson, D
   Lek, M
   Lopes, M
   MacArthur, DG
   Marchini, J
   Mangino, M
   Mathieson, I
   McCarthy, S
   Memari, Y
   Metrustry, S
   Min, JL
   Moayyeri, A
   Muddyman, D
   Northstone, K
   Panoutsopoulou, K
   Paternoster, L
   Perry, JRB
   Quaye, L
   Richards, JB
   Ring, S
   Ritchie, GRS
   Schiffels, S
   Shihab, HA
   Shin, SY
   Small, KS
   Artigas, MS
   Soranzo, N
   Southam, L
   Spector, TD
   St Pourcain, B
   Surdulescu, G
   Tachmazidou, I
   Timpson, NJ
   Tobin, MD
   Valdes, AM
   Visscher, PM
   Wain, LV
   Walter, K
   Ward, K
   Wilson, SG
   Wong, K
   Yang, J
   Zeggini, E
   Zhang, F
   Zheng, HF
   Anney, R
   Ayub, M
   Barrett, JC
   Blackwood, D
   Bolton, PF
   Breen, G
   Collier, DA
   Craddock, N
   Crooks, L
   Curran, S
   Curtis, D
   Durbin, R
   Gallagher, L
   Geschwind, D
   Gurling, H
   Holmans, P
   Lee, I
   Lönnqvist, J
   McCarthy, S
   McGuffin, P
   McIntosh, AM
   McKechanie, AG
   McQuillin, A
   Morris, J
   Muddyman, D
   O'Donovan, MC
   Owen, MJ
   Palotie, A
   Parr, JR
   Paunio, T
   Pietilainen, O
   Rehnström, K
   Sharp, SI
   Skuse, D
   St Clair, D
   Suvisaari, J
   Walters, JTR
   Williams, HJ
   Barroso, I
   Bochukova, E
   Bounds, R
   Dominiczak, A
   Durbin, R
   Farooqi, IS
   Hendricks, AE
   Keogh, J
   Marenne, GL
   McCarthy, S
   Morris, A
   Muddyman, D
   O'Rahilly, S
   Porteous, DJ
   Smith, BH
   Tachmazidou, I
   Wheeler, E
   Zeggini, E
   Al Turki, S
   Anderson, CA
   Antony, D
   Barroso, IS
   Beales, P
   Bentham, J
   Bhattacharya, S
   Calissano, M
   Carss, K
   Chatterjee, K
   Cirak, S
   Cosgrove, C
   Durbin, R
   Fitzpatrick, DR
   Floyd, J
   Foley, AR
   Franklin, CS
   Futema, M
   Grozeva, D
   Humphries, SE
   Hurles, ME
   McCarthy, S
   Mitchison, HM
   Muddyman, D
   Muntoni, F
   O'Rahilly, S
   Onoufriadis, A
   Parker, V
   Payne, F
   Plagnol, V
   Raymond, FL
   Roberts, N
   Savage, DB
   Scambler, P
   Schmidts, M
   Schoenmakers, N
   Semple, RK
   Serra, E
   Spasic-Boskovic, O
   Stevens, E
   van Kogelenberg, M
   Vijayarangakannan, P
   Walter, K
   Williamson, KA
   Wilson, C
   Whyte, T
   Ciampi, A
   Greenwood, CMT
   Hendricks, AE
   Li, R
   Metrustry, S
   Oualkacha, K
   Tachmazidou, I
   Xu, CJ
   Zeggini, E
   Bobrow, M
   Bolton, PF
   Durbin, R
   Fitzpatrick, DR
   Griffin, H
   Hurles, ME
   Kaye, J
   Kennedy, K
   Kent, A
   Muddyman, D
   Muntoni, F
   Raymond, FL
   Semple, RK
   Smee, C
   Spector, TD
   Timpson, NJ
   Charlton, R
   Ekong, R
   Futema, M
   Humphries, SE
   Khawaja, F
   Lopes, LR
   Migone, N
   Payne, SJ
   Plagnol, V
   Pollitt, RC
   Povey, S
   Ridout, CK
   Robinson, RL
   Scott, RH
   Shaw, A
   Syrris, P
   Taylor, R
   Vandersteen, AM
   Barrett, JC
   Barroso, I
   Smith, GD
   Durbin, R
   Farooqi, IS
   Fitzpatrick, DR
   Hurles, ME
   Kaye, J
   Kennedy, K
   Langford, C
   McCarthy, S
   Muddyman, D
   Owen, MJ
   Palotie, A
   Richards, JB
   Soranzo, N
   Spector, TD
   Stalker, J
   Timpson, NJ
   Zeggini, E
   Amuzu, A
   Casas, JP
   Chambers, JC
   Cocca, M
   Dedoussis, G
   Gambaro, G
   Gasparini, P
   Gaunt, TR
   Huang, J
   Iotchkova, V
   Isaacs, A
   Johnson, J
   Kleber, ME
   Kooner, JS
   Langenberg, C
   Luan, J
   Malerba, G
   März, W
   Matchan, A
   Min, JL
   Morris, R
   Nordestgaard, BG
   Benn, M
   Ring, S
   Scott, RA
   Soranzo, N
   Southam, L
   Timpson, NJ
   Toniolo, D
   Traglia, M
   Tybjaerg-Hansen, A
   van Duijn, CM
   van Leeuwen, EM
   Varbo, A
   Whincup, P
   Zaza, G
   Zeggini, E
   Zhang, WH
AF Walter, Klaudia
   Min, Josine L.
   Huang, Jie
   Crooks, Lucy
   Memari, Yasin
   McCarthy, Shane
   Perry, John R. B.
   Xu, ChangJiang
   Futema, Marta
   Lawson, Daniel
   Iotchkova, Valentina
   Schiffels, Stephan
   Hendricks, Audrey E.
   Danecek, Petr
   Li, Rui
   Floyd, James
   Wain, Louise V.
   Barroso, Ines
   Humphries, Steve E.
   Hurles, Matthew E.
   Zeggini, Eleftheria
   Barrett, Jeffrey C.
   Plagnol, Vincent
   Richards, J. Brent
   Greenwood, Celia M. T.
   Timpson, Nicholas J.
   Durbin, Richard
   Soranzo, Nicole
   Bala, Senduran
   Clapham, Peter
   Coates, Guy
   Cox, Tony
   Daly, Allan
   Danecek, Petr
   Du, Yuanping
   Durbin, Richard
   Edkins, Sarah
   Ellis, Peter
   Flicek, Paul
   Guo, Xiaosen
   Guo, Xueqin
   Huang, Liren
   Jackson, David K.
   Joyce, Chris
   Keane, Thomas
   Kolb-Kokocinski, Anja
   Langford, Cordelia
   Li, Yingrui
   Liang, Jieqin
   Lin, Hong
   Liu, Ryan
   Maslen, John
   McCarthy, Shane
   Muddyman, Dawn
   Quail, Michael A.
   Stalker, Jim
   Sun, Jianping
   Tian, Jing
   Wang, Guangbiao
   Wang, Jun
   Wang, Yu
   Wong, Kim
   Zhang, Pingbo
   Barroso, Ines
   Birney, Ewan
   Boustred, Chris
   Chen, Lu
   Clement, Gail
   Cocca, Massimiliano
   Danecek, Petr
   Smith, George Davey
   Day, Ian N. M.
   Day-Williams, Aaron
   Down, Thomas
   Dunham, Ian
   Durbin, Richard
   Evans, David M.
   Gaunt, Tom R.
   Geihs, Matthias
   Greenwood, Celia M. T.
   Hart, Deborah
   Hendricks, Audrey E.
   Howie, Bryan
   Huang, Jie
   Hubbard, Tim
   Hysi, Pirro
   Iotchkova, Valentina
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   Lachance, Genevieve
   Lawson, Daniel
   Lek, Monkol
   Lopes, Margarida
   MacArthur, Daniel G.
   Marchini, Jonathan
   Mangino, Massimo
   Mathieson, Iain
   McCarthy, Shane
   Memari, Yasin
   Metrustry, Sarah
   Min, Josine L.
   Moayyeri, Alireza
   Muddyman, Dawn
   Northstone, Kate
   Panoutsopoulou, Kalliope
   Paternoster, Lavinia
   Perry, John R. B.
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   Richards, J. Brent
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   Ritchie, Graham R. S.
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   Geschwind, Daniel
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   Holmans, Peter
   Lee, Irene
   Lonnqvist, Jouko
   McCarthy, Shane
   McGuffin, Peter
   McIntosh, Andrew M.
   McKechanie, Andrew G.
   McQuillin, Andrew
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   Muddyman, Dawn
   O'Donovan, Michael C.
   Owen, Michael J.
   Palotie, Aarno
   Parr, Jeremy R.
   Paunio, Tiina
   Pietilainen, Olli
   Rehnstrom, Karola
   Sharp, Sally I.
   Skuse, David
   St Clair, David
   Suvisaari, Jaana
   Walters, James T. R.
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   Barroso, Ines
   Bochukova, Elena
   Bounds, Rebecca
   Dominiczak, Anna
   Durbin, Richard
   Farooqi, I. Sadaf
   Hendricks, Audrey E.
   Keogh, Julia
   Marenne, Gae Lle
   McCarthy, Shane
   Morris, Andrew
   Muddyman, Dawn
   O'Rahilly, Stephen
   Porteous, David J.
   Smith, Blair H.
   Tachmazidou, Ioanna
   Wheeler, Eleanor
   Zeggini, Eleftheria
   Al Turki, Saeed
   Anderson, Carl A.
   Antony, Dinu
   Barroso, Ines
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   Bentham, Jamie
   Bhattacharya, Shoumo
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   Chatterjee, Krishna
   Cirak, Sebahattin
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   Durbin, Richard
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   Foley, A. Reghan
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   Hurles, Matthew E.
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   O'Rahilly, Stephen
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   Spasic-Boskovic, Olivera
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   Taylor, Rohan
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   Barroso, Ines
   Smith, George Davey
   Durbin, Richard
   Farooqi, I. Sadaf
   Fitzpatrick, David R.
   Hurles, Matthew E.
   Kaye, Jane
   Kennedy, Karen
   Langford, Cordelia
   McCarthy, Shane
   Muddyman, Dawn
   Owen, Michael J.
   Palotie, Aarno
   Richards, J. Brent
   Soranzo, Nicole
   Spector, Timothy D.
   Stalker, Jim
   Timpson, Nicholas J.
   Zeggini, Eleftheria
   Amuzu, Antoinette
   Casas, Juan Pablo
   Chambers, John C.
   Cocca, Massimiliano
   Dedoussis, George
   Gambaro, Giovanni
   Gasparini, Paolo
   Gaunt, Tom R.
   Huang, Jie
   Iotchkova, Valentina
   Isaacs, Aaron
   Johnson, Jon
   Kleber, Marcus E.
   Kooner, Jaspal S.
   Langenberg, Claudia
   Luan, Jian'an
   Malerba, Giovanni
   Maerz, Winfried
   Matchan, Angela
   Min, Josine L.
   Morris, Richard
   Nordestgaard, Borge G.
   Benn, Marianne
   Ring, Susan
   Scott, Robert A.
   Soranzo, Nicole
   Southam, Lorraine
   Timpson, Nicholas J.
   Toniolo, Daniela
   Traglia, Michela
   Tybjaerg-Hansen, Anne
   van Duijn, Cornelia M.
   van Leeuwen, Elisabeth M.
   Varbo, Anette
   Whincup, Peter
   Zaza, Gianluigi
   Zeggini, Eleftheria
   Zhang, Weihua
TI The UK10K project identifies rare variants in health and disease
SO NATURE
LA English
DT Article
ID genome-wide association; low-frequency; incidental findings; common; heritability; exome; apoc3; risk; loci; snp
AB The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7x) or exomes (high read depth, 80x) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.
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   [Nordestgaard, Borge G.; Benn, Marianne; Tybjaerg-Hansen, Anne; Varbo, Anette] Univ Copenhagen, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark.
   [Toniolo, Daniela; Traglia, Michela] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy.
   [Tybjaerg-Hansen, Anne] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem KB3011, DK-2100 Copenhagen, Denmark.
   [Whincup, Peter] St Georges Univ London, Populat Hlth Res Inst, London SW17 0RE, England.
   [Zaza, Gianluigi] Univ Verona, Dept Med, Renal Unit, I-37126 Verona, Italy.
C3 Wellcome Trust Sanger Institute; University of Cambridge; University of Bristol; Sheffield Children's NHS Foundation Trust; University of London; King's College London; University of Cambridge; McGill University; Jewish General Hospital - Montreal; Lady Davis Institute; McGill University; University of London; University College London; University of Bristol; University of Bristol; European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute; University of Colorado System; University of Colorado Denver; Jewish General Hospital - Montreal; McGill University; McGill University; University of London; Queen Mary University London; University of Leicester; University of Leicester; University of Cambridge; University of Cambridge; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; University of London; University College London; McGill University; Beijing Genomics Institute (BGI); University of Copenhagen; King Abdulaziz University; Macau University of Science & Technology; University of Hong Kong; University of Hong Kong; University of London; University College London; Great Ormond Street Hospital for Children NHS Foundation Trust; IRCCS Burlo Garofolo; University of Trieste; University of Bristol; Biogen; Guy's & St Thomas' NHS Foundation Trust; University of London; King's College London; University of Queensland; City St Georges, University of London; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Oxford; Wellcome Centre for Human Genetics; Illumina; University of Oxford; Guy's & St Thomas' NHS Foundation Trust; Harvard University; Harvard Medical School; University of London; University College London; University of Bristol; University of Bristol; University of Bristol; University of Bristol; University Hospitals of Leicester NHS Trust; University of Leicester; Glenfield Hospital; University of Queensland; University of Western Australia; Sir Charles Gairdner Hospital; University of Western Australia; Trinity College Dublin; Queens University - Canada; Royal Infirmary of Edinburgh; University of Edinburgh; University of London; King's College London; University of London; King's College London; South London & Maudsley NHS Trust; University of London; King's College London; University of London; King's College London; Eli Lilly; Lilly Research Laboratories; Cardiff University; University of Sussex; University of London; University College London; 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 London; University College London; University of London; University College London; Finland National Institute for Health & Welfare; University of Edinburgh; University of Helsinki; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Newcastle University - UK; University of Helsinki; University of Aberdeen; University of London; University College London; University of Glasgow; University of Edinburgh; University of Edinburgh; University of Dundee; King Saud Bin Abdulaziz University for Health Sciences; King Abdulaziz Medical City - Riyadh; University of London; University College London; University of Oxford; Wellcome Centre for Human Genetics; University of London; University College London; University of London; University College London; Great Ormond Street Hospital for Children NHS Foundation Trust; University of Cologne; University of Edinburgh; University of Cambridge; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; Radboud University Nijmegen; University of Quebec; University of Quebec Montreal; University of Oxford; Saint James's University Hospital; University of London; University College London; City St Georges, University of London; University of London; University College London; Universidade de Lisboa; University of Turin; Imperial College London; Sheffield Children's NHS Foundation Trust; Guy's & St Thomas' NHS Foundation Trust; University of London; University College London; Great Ormond Street Hospital for Children NHS Foundation Trust; Guy's & St Thomas' NHS Foundation Trust; University of London; London School of Hygiene & Tropical Medicine; Imperial College London; Harokopio University Athens; Catholic University of the Sacred Heart; IRCCS Policlinico Gemelli; Sidra Medical & Research Center; Erasmus University Rotterdam; Erasmus MC; University of London; University College London; UCL Institute of Education; Imperial College London; University of Verona; Medical University of Graz; SYNLAB Group; Ruprecht Karls University Heidelberg; University of Bristol; University of Copenhagen; Copenhagen University Hospital; University of Copenhagen; Copenhagen University Hospital; University of Copenhagen; Vita-Salute San Raffaele University; IRCCS Ospedale San Raffaele; University of Copenhagen; Copenhagen University Hospital; Rigshospitalet; City St Georges, University of London; University of Verona
RP Soranzo, N (corresponding author), Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1HH, England.
EM rd@sanger.ac.uk; ns6@sanger.ac.uk
FU Wellcome Trust [WT091310]; Biotechnology and Biological Sciences Research Council [BB/M020991/1, BB/K015427/1] Funding Source: researchfish; British Heart Foundation [PG/07/045/22690, RG/10/13/28570, RG/10/17/28553, RG/08/008/25291] Funding Source: researchfish; Chief Scientist Office [CZD/16/6/4, SCD/12] Funding Source: researchfish; Economic and Social Research Council [ES/J023299/1, ES/M001660/1] Funding Source: researchfish; Great Ormond Street Hospital Childrens Charity [V1299] Funding Source: researchfish; Medical Research Council [MC_PC_13048, MC_UU_12015/1, MC_UU_12012/5/B, MC_PC_15018, MR/J012165/1, MR/L010305/1, MC_U106179472, MC_UU_12015/2, G0902313, G0800509, G0500870, MR/K013351/1, MC_PC_13046, G0801843, MC_UU_12012/5, G9817803B, MC_UU_12013/4, MR/K000608/1, MC_UU_12013/3, MC_UU_12013/1] Funding Source: researchfish; National Institute for Health Research [NIHR-RP-R3-12-013, NF-SI-0513-10109, NF-SI-0514-10176, NF-SI-0514-10027, NF-SI-0510-10268, NF-SI-0507-10380, NF-SI-0508-10198] Funding Source: researchfish; BBSRC [BB/K015427/1, BB/M020991/1] Funding Source: UKRI; ESRC [ES/J023299/1, ES/M001660/1] Funding Source: UKRI; MRC [MC_PC_13048, MC_UU_12013/3, MC_UU_12015/2, MC_UU_12013/1, G0902313, MR/K013351/1, MC_UU_12013/4, MC_PC_13046, MR/K000608/1, MR/J012165/1, G0800509, G0500870, MC_U106179472, G0801843, MC_UU_12015/1] Funding Source: UKRI
NR 49
TC 759
Z9 870
U1 0
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 OCT 1
PY 2015
VL 526
IS 7571
BP 82
EP +
DI 10.1038/nature14962
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS5CY
UT WOS:000362095100038
PM 26367797
DA 2026-03-09
ER

PT J
AU Narayanan, D
   Turk, M
   Feldmann, R
   Robitaille, T
   Hopkins, P
   Thompson, R
   Hayward, C
   Ball, D
   Faucher-Giguère, CA
   Keres, D
AF Narayanan, Desika
   Turk, Matthew
   Feldmann, Robert
   Robitaille, Thomas
   Hopkins, Philip
   Thompson, Robert
   Hayward, Christopher
   Ball, David
   Faucher-Giguere, Claude-Andre
   Keres, Dusan
TI The formation of submillimetre-bright galaxies from gas infall over a billion years
SO NATURE
LA English
DT Article
ID initial mass function; star-formation; molecular gas; high-redshift; radiative-transfer; stellar feedback; milky-way; elemental abundances; infrared-emission; number counts
AB Submillimetre-bright galaxies at high redshift are the most luminous, heavily star-forming galaxies in the Universe1 and are characterized by prodigious emission in the far-infrared, with a flux of at least five millijanskys at a wavelength of 850micrometres. Theyreside inhaloes with masses about 10(13) times that of the Sun2, have low gas fractions compared to main-sequence disks at a comparable redshift3, trace complex environments(4,5) and are not easily observable at optical wavelengths(6). Their physical origin remains unclear. Simulations have been able to form galaxies with the requisite luminosities, but have otherwise been unable to simultaneously match the stellar masses, star formation rates, gas fractions and environments(7-10). Here we report a cosmological hydrodynamic galaxy formation simulation that is able to forma submillimetre galaxy that simultaneously satisfies the broad range of observed physical constraints. We find that groups of galaxies residing in massive dark matter haloes have increasing rates of star formation that peak at collective rates of about 500-1,000 solarmasses per year at redshifts of two to three, by which time the interstellar medium is sufficiently enriched with metals that the region may be observed as a submillimetre-selected system. The intense star formation rates are fuelled in part by the infall of a reservoir gas supply enabled by stellar feedback at earlier times, not through major mergers. With a lifetime of nearly a billion years, our simulations show that the submillimetre-bright phase of high-redshift galaxies is prolonged and associated with significant mass buildup in early-Universe proto-clusters, and that many submillimetre- bright galaxies are composed of numerous unresolved components (for which there is some observational evidence(11)).
C1 [Narayanan, Desika] Haverford Coll, Haverford, PA 19041 USA.
   [Turk, Matthew] Univ Illinois, Natl Ctr Supercomp Applicat, Urbana, IL 61820 USA.
   [Feldmann, Robert] Univ Calif Berkeley, Dept Astron, Berkeley, CA 94720 USA.
   [Feldmann, Robert] Univ Calif Berkeley, Theoret Astrophys Ctr, Berkeley, CA 94720 USA.
   [Robitaille, Thomas] Max Planck Inst Astron, D-69117 Heidelberg, Germany.
   [Hopkins, Philip; Hayward, Christopher] CALTECH, TAPIR, Pasadena, CA 91125 USA.
   [Thompson, Robert] Univ Western Cape, ZA-7535 Cape Town, South Africa.
   [Thompson, Robert; Ball, David] Univ Arizona, Steward Observ, Tucson, AZ 85721 USA.
   [Hayward, Christopher] Harvard Smithsonian Ctr Astrophys, Cambridge, MA 02138 USA.
   [Ball, David] Whitman Coll, Walla Walla, WA 99362 USA.
   [Faucher-Giguere, Claude-Andre] Northwestern Univ, CIERA, Evanston, IL 60208 USA.
   [Keres, Dusan] Univ Calif San Diego, CASS, La Jolla, CA 92093 USA.
C3 Haverford College; University of Illinois System; University of Illinois Urbana-Champaign; University of California System; University of California Berkeley; University of California System; University of California Berkeley; Max Planck Society; California Institute of Technology; University of the Western Cape; University of Arizona; Smithsonian Astrophysical Observatory; Smithsonian Institution; Harvard University; Whitman College; Northwestern University; University of California System; University of California San Diego
RP Narayanan, D (corresponding author), Haverford Coll, 370 West Lancaster Ave, Haverford, PA 19041 USA.
EM dnarayan@haverford.edu
FU NSF [AST-1009452, AST-1442650, AST-1412836, AST-1412153]; NASA HST [AR-13906.001]; Cottrell College Science Award; Gordon and Betty Moore Foundation [GBMF4561, 776]; Alfred P. Sloan Foundation; NASA [PF3-140106, NNX15AB22G, HF-51304.01-A]; Gordon and Betty Moore Foundation (GBMF) [GBMF4561] Funding Source: Gordon and Betty Moore Foundation (GBMF); Direct For Computer & Info Scie & Enginr; Office of Advanced Cyberinfrastructure (OAC) [1535651] Funding Source: National Science Foundation; Direct For Mathematical & Physical Scien; Division Of Astronomical Sciences [1445357, 1455342, 1005024, 1411920] Funding Source: National Science Foundation; Division Of Astronomical Sciences; Direct For Mathematical & Physical Scien [1412836, 1412153] Funding Source: National Science Foundation
NR 87
TC 169
Z9 190
U1 0
U2 7
PU NATURE PUBLISHING 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 24
PY 2015
VL 525
IS 7570
BP 496
EP +
DI 10.1038/nature15383
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR8KI
UT WOS:000361599900045
PM 26399829
DA 2026-03-09
ER

PT J
AU Kim, KH
   Kim, JG
   Nozawa, S
   Sato, T
   Oang, KY
   Kim, T
   Ki, H
   Jo, J
   Park, S
   Song, C
   Sato, T
   Ogawa, K
   Togashi, T
   Tono, K
   Yabashi, M
   Ishikawa, T
   Kim, J
   Ryoo, R
   Kim, J
   Ihee, H
   Adachi, S
AF Kim, Kyung Hwan
   Kim, Jong Goo
   Nozawa, Shunsuke
   Sato, Tokushi
   Oang, Key Young
   Kim, Taewu
   Ki, Hosung
   Jo, Junbeom
   Park, Sungjun
   Song, Changyong
   Sato, Takahiro
   Ogawa, Kanade
   Togashi, Tadashi
   Tono, Kensuke
   Yabashi, Makina
   Ishikawa, Tetsuya
   Kim, Joonghan
   Ryoo, Ryong
   Kim, Jeongho
   Ihee, Hyotcherl
   Adachi, Shin-ichi
TI Direct observation of bond formation in solution with femtosecond X-ray scattering
SO NATURE
LA English
DT Article
ID free-electron laser; spin-crossover dynamics; real-time observation; excited-state; 100 ps; oligomers; gold; spectroscopy; au(cn)(2)(-); tracking
AB The making and breaking of atomic bonds are essential processes in chemical reactions. Although the ultrafast dynamics of bond breaking have been studied intensively using time-resolved techniques(1-3),, it is very difficult to study the structural dynamics of bond making, mainly because of its bimolecular nature. It is especially difficult to initiate and follow diffusion-limited bond formation in solution with ultrahigh time resolution. Here we use femtosecond time-resolved X-ray solution scattering to visualize the formation of a gold trimer complex, [Au(CN)(2)(-)](3) in real time without the limitation imposed by slow diffusion. This photoexcited gold trimer, which has weakly bound gold atoms in the ground state(4-6), undergoes a sequence of structural changes, and our experiments probe the dynamics of individual reaction steps, including covalent bond formation, the bent-to-linear transition, bond contraction and tetramer formation with a time resolution of 500 femtoseconds. We also determined the three-dimensional structures of reaction intermediates with sub-angstrom spatial resolution. This work demonstrates that it is possible to track in detail and in real time the structural changes that occur during a chemical reaction in solution using X-ray free-electron lasers' and advanced analysis of time-resolved solution scattering data.
C1 [Kim, Kyung Hwan; Kim, Jong Goo; Oang, Key Young; Kim, Taewu; Ki, Hosung; Jo, Junbeom; Park, Sungjun; Ryoo, Ryong; Ihee, Hyotcherl] Inst for Basic Sci Korea, Ctr Nanomat & Chem React, Taejon 305701, South Korea.
   [Kim, Kyung Hwan; Kim, Jong Goo; Oang, Key Young; Kim, Taewu; Ki, Hosung; Jo, Junbeom; Park, Sungjun; Ryoo, Ryong; Ihee, Hyotcherl] Korea Adv Inst Sci & Technol, Dept Chem, Taejon 305701, South Korea.
   [Nozawa, Shunsuke; Sato, Tokushi; Adachi, Shin-ichi] High Energy Accelerator Res Org, Inst Mat Struct Sci, Tsukuba, Ibaraki 3050801, Japan.
   [Song, Changyong; Sato, Takahiro; Ogawa, Kanade; Yabashi, Makina; Ishikawa, Tetsuya] RIKEN SPring 8 Ctr, Sayo, Hyogo 6795148, Japan.
   [Togashi, Tadashi; Tono, Kensuke] Japan Synchrotron Radiat Res Inst, Sayo, Hyogo 6795198, Japan.
   [Kim, Joonghan] Catholic Univ Korea, Dept Chem, Puchon 420743, South Korea.
   [Kim, Jeongho] Inha Univ, Dept Chem, Inchon 402751, South Korea.
   [Adachi, Shin-ichi] Grad Univ Adv Studies, Dept Mat Struct Sci, Sch High Energy Accelerator Sci, Tsukuba, Ibaraki 3050801, Japan.
C3 Institute for Basic Science - Korea (IBS); Korea Advanced Institute of Science & Technology (KAIST); High Energy Accelerator Research Organization (KEK); RIKEN; Japan Synchrotron Radiation Research Institute; Catholic University of Korea; Inha University; Graduate University for Advanced Studies - Japan
RP Ihee, H (corresponding author), Inst for Basic Sci Korea, Ctr Nanomat & Chem React, Taejon 305701, South Korea.
EM hyotcherl.ihee@kaist.ac.kr; shinichi.adachi@kek.jp
FU X-ray Free Electron Laser Priority Strategic Program of MEXT, Japan; PRESTO/JST; Innovative Areas 'Artificial Photosynthesis (AnApple)' from Japan Society for the Promotion of Science [25107527]; Basic Science Research Program through National Research Foundation of Korea - Ministry of Science, ICT & Future Planning [NRF-2014R1A1A1002511];  [IBS-R004-G2]; Grants-in-Aid for Scientific Research [26102014, 25107527] Funding Source: KAKEN
NR 37
TC 216
Z9 235
U1 1
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 FEB 19
PY 2015
VL 518
IS 7539
BP 385
EP 389
DI 10.1038/nature14163
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400039
PM 25693570
DA 2026-03-09
ER

PT J
AU Crane, E
   Bian, Q
   McCord, RP
   Lajoie, BR
   Wheeler, BS
   Ralston, EJ
   Uzawa, S
   Dekker, J
   Meyer, BJ
AF Crane, Emily
   Bian, Qian
   McCord, Rachel Patton
   Lajoie, Bryan R.
   Wheeler, Bayly S.
   Ralston, Edward J.
   Uzawa, Satoru
   Dekker, Job
   Meyer, Barbara J.
TI Condensin-driven remodelling of X chromosome topology during dosage compensation
SO NATURE
LA English
DT Article
ID c. elegans; gene-expression; caenorhabditis-elegans; chromatin interactions; human-cells; hi-c; organization; genome; complex; architecture
AB The three-dimensional organization of a genome plays a critical role in regulating gene expression, yet little is known about the machinery and mechanisms that determine higher-order chromosome structure(1,2). Here we perform genome-wide chromosome conformation capture analysis, fluorescent in situ hybridization (FISH), and RNA-seq to obtain comprehensive three-dimensional (3D) maps of the Caenorhabditis elegans genome and to dissect X chromosome dosage compensation, which balances gene expression between XX hermaphrodites and XO males. The dosage compensation complex (DCC), a condensin complex, binds to both hermaphrodite X chromosomes via sequence-specific recruitment elements on X (rex sites) to reduce chromosome-wide gene expression by half(3-7). Most DCC condensin subunits also act in other condensin complexes to control the compaction and resolution of all mitotic and meiotic chromosomes(5,6). By comparing chromosome structure in wild-type and DCC-defective embryos, we show that the DCC remodels hermaphrodite X chromosomes into a sex-specific spatial conformation distinct from autosomes. Dosage-compensated X chromosomes consist of self-interacting domains (similar to 1 Mb) resembling mammalian topologically associating domains (TADs)(8,9). TADs on X chromosomes have stronger boundaries andmore regular spacing than on autosomes. Many TAD boundaries on X chromosomes coincide with the highest-affinity rex sites and become diminished or lost in DCC-defective mutants, thereby converting the topology of X to a conformation resembling autosomes. rex sites engage in DCC-dependent long-range interactions, with the most frequent interactions occurring between rex sites at DCC-dependent TAD boundaries. These results imply that the DCC reshapes the topology of X chromosomes by forming new TAD boundaries and reinforcing weak boundaries through interactions between its highest-affinity binding sites. As this model predicts, deletion of an endogenous rex site at a DCC-dependent TAD boundary using CRISPR/Cas9 greatly diminished the boundary. Thus, the DCC imposes a distinct higher-order structure onto X chromosomes while regulating gene expression chromosome-wide.
C1 [Crane, Emily; Bian, Qian; Wheeler, Bayly S.; Ralston, Edward J.; Uzawa, Satoru; Meyer, Barbara J.] Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA.
   [Crane, Emily; Bian, Qian; Wheeler, Bayly S.; Ralston, Edward J.; Uzawa, Satoru; Meyer, Barbara J.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
   [McCord, Rachel Patton; Lajoie, Bryan R.; Dekker, Job] Univ Massachusetts, Sch Med, Program Syst Biol, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA.
C3 Howard Hughes Medical Institute; University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of Massachusetts System; University of Massachusetts Worcester
RP Meyer, BJ (corresponding author), Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA.
EM Job.Dekker@umassmed.edu; bjmeyer@berkeley.edu
FU NIGMS [R01 GM030702]; NHGRI [R01 HG003143]; National Human Genome Research Institute [R01HG003143] Funding Source: NIH RePORTER
NR 38
TC 661
Z9 784
U1 3
U2 110
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 9
PY 2015
VL 523
IS 7559
BP 240
EP U299
DI 10.1038/nature14450
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM4ZO
UT WOS:000357695900041
PM 26030525
DA 2026-03-09
ER

PT J
AU Ulmer, S
   Smorra, C
   Mooser, A
   Franke, K
   Nagahama, H
   Schneider, G
   Higuchi, T
   Van Gorp, S
   Blaum, K
   Matsuda, Y
   Quint, W
   Walz, J
   Yamazaki, Y
AF Ulmer, S.
   Smorra, C.
   Mooser, A.
   Franke, K.
   Nagahama, H.
   Schneider, G.
   Higuchi, T.
   Van Gorp, S.
   Blaum, K.
   Matsuda, Y.
   Quint, W.
   Walz, J.
   Yamazaki, Y.
TI High-precision comparison of the antiproton-to-proton charge-to-mass ratio
SO NATURE
LA English
DT Article
ID spectroscopy; electron; cpt; antihydrogen; helium; tests; ion
AB Invariance under the charge, parity, time-reversal (CPT) transformation(1) is one of the fundamental symmetries of the standard model of particle physics. This CPT invariance implies that the fundamental properties of antiparticles and their matter-conjugates are identical, apart from signs. There is a deep link between CPT invariance and Lorentz symmetry-that is, the laws of nature seem to be invariant under the symmetry transformation of spacetime-although it is model dependent(2). A number of high-precision CPT and Lorentz invariance tests-using a co-magnetometer, a torsion pendulum and a maser, among others-have been performed(3), but only a few direct high-precision CPT tests that compare the fundamental properties of matter and antimatter are available(4-8). Here we report high-precision cyclotron frequency comparisons of a single antiproton and a negatively charged hydrogen ion (H-) carried out in a Penning trap system. From 13,000 frequency measurements we compare the charge-to-mass ratio for the antiproton (q/m)(p)- to that for the proton (q/m)(p) and obtain (q/m)(p)/(q/m)(p) - 1 - 1(69) x 10(-12). The measurements were performed at cyclotron frequencies of 29.6 megahertz, so our result shows that the CPT theorem holds at the atto-electronvolt scale. Our precision of 69 parts per trillion exceeds the energy resolution of previous antiproton-toproton mass comparisons(7,9) as well as the respective figure of merit of the standardmodel extension(10) by a factor of four. In addition, we give a limit on sidereal variations in the measured ratio of <720 parts per trillion. By following the arguments of ref. 11, our result can be interpreted as a stringent test of the weak equivalence principle of general relativity using baryonic antimatter, and it sets a new limit on the gravitational anomaly parameter of vertical bar alpha(g) - 1 vertical bar < 8.7 x 10(-7).
C1 [Ulmer, S.; Smorra, C.; Mooser, A.; Franke, K.; Nagahama, H.; Schneider, G.; Higuchi, T.] RIKEN, Ulmer Initiat Res Unit, Wako, Saitama 3510198, Japan.
   [Smorra, C.] CERN, CH-1211 Geneva, Switzerland.
   [Franke, K.; Blaum, K.] Max Planck Inst Kernphys, D-69117 Heidelberg, Germany.
   [Nagahama, H.; Higuchi, 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.
   [Van Gorp, S.; Yamazaki, Y.] RIKEN, Atom Phys Lab, Wako, Saitama 3510198, Japan.
   [Quint, W.] GSI Helmholtzzentrum Schwerionenforsch, D-64291 Darmstadt, Germany.
   [Walz, J.] Helmholtz Inst Mainz, D-55099 Mainz, Germany.
C3 RIKEN; European Organization for Nuclear Research (CERN); Max Planck Society; University of Tokyo; Johannes Gutenberg University of Mainz; RIKEN; Helmholtz Association; GSI Helmholtz-Center for Heavy Ion Research
RP Ulmer, S (corresponding author), RIKEN, Ulmer Initiat Res Unit, 2-1 Hirosawa, Wako, Saitama 3510198, Japan.
EM stefan.ulmer@cern.ch
FU Antiproton Decelerator group; CERN groups; RIKEN Initiative Research Unit Program; RIKEN; RIKEN FPR; RIKEN JRA Program; MEXT [24000008]; Max-Planck Society; IMPRS-PTFS; EU (ERC) [290870-MEFUCO]; BMBF; Helmholtz-Gemeinschaft; CERN; Grants-in-Aid for Scientific Research [24000008] Funding Source: KAKEN
NR 29
TC 113
Z9 129
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 AUG 13
PY 2015
VL 524
IS 7564
BP 196
EP 199
DI 10.1038/nature14861
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900026
PM 26268189
DA 2026-03-09
ER

PT J
AU Rundlöf, M
   Andersson, GKS
   Bommarco, R
   Fries, I
   Hederström, V
   Herbertsson, L
   Jonsson, O
   Klatt, BK
   Pedersen, TR
   Yourstone, J
   Smith, HG
AF Rundlof, Maj
   Andersson, Georg K. S.
   Bommarco, Riccardo
   Fries, Ingemar
   Hederstrom, Veronica
   Herbertsson, Lina
   Jonsson, Ove
   Klatt, Bjorn K.
   Pedersen, Thorsten R.
   Yourstone, Johanna
   Smith, Henrik G.
TI Seed coating with a neonicotinoid insecticide negatively affects wild bees
SO NATURE
LA English
DT Article
ID bombus-impatiens hymenoptera; combined pesticide; treated canola; colony health; pollinators; exposure; clothianidin; megachilidae; traits; impact
AB Understanding the effects of neonicotinoid insecticides on bees is vital because of reported declines in bee diversity and distribution(1-3) and the crucial role bees have as pollinators in ecosystems and agriculture(4). Neonicotinoids are suspected to pose an unacceptable risk to bees, partly because of their systemic uptake in plants(5), and the European Union has therefore introduced a moratorium on three neonicotinoids as seed coatings in flowering crops that attract bees(6). The moratorium has been criticized for being based on weak evidence(7), particularly because effects have mostly been measured on bees that have been artificially fed neonicotinoids(8-11). Thus, the key question is how neonicotinoids influence bees, and wild bees in particular, in real-world agricultural landscapes(11-13). Here we show that a commonly used insecticide seed coating in a flowering crop can have serious consequences for wild bees. In a study with replicated and matched landscapes, we found that seed coating with Elado, an insecticide containing a combination of the neonicotinoid clothianidin and the non-systemic pyrethroid beta-cyfluthrin, applied to oilseed rape seeds, reduced wild bee density, solitary bee nesting, and bumblebee colony growth and reproduction under field conditions. Hence, such insecticidal use can pose a substantial risk to wild bees in agricultural landscapes, and the contribution of pesticides to the global decline of wild bees(1-3) may have been underestimated. The lack of a significant response in honeybee colonies suggests that reported pesticide effects on honeybees cannot always be extrapolated to wild bees.
C1 [Rundlof, Maj; Andersson, Georg K. S.; Hederstrom, Veronica; Yourstone, Johanna; Smith, Henrik G.] Lund Univ, Dept Biol, S-22362 Lund, Sweden.
   [Andersson, Georg K. S.; Herbertsson, Lina; Klatt, Bjorn K.; Smith, Henrik G.] Lund Univ, Ctr Environm & Climate Res, S-22362 Lund, Sweden.
   [Bommarco, Riccardo; Fries, Ingemar] Swedish Univ Agr Sci, Dept Ecol, S-75007 Uppsala, Sweden.
   [Jonsson, Ove] Swedish Univ Agr Sci, Dept Aquat Sci & Assessment, S-75007 Uppsala, Sweden.
   [Jonsson, Ove] Swedish Univ Agr Sci, Ctr Chem Pesticides, S-75007 Uppsala, Sweden.
   [Pedersen, Thorsten R.] Swedish Board Agr, S-55182 Jonkoping, Sweden.
C3 Lund University; Lund University; Swedish University of Agricultural Sciences; Swedish University of Agricultural Sciences; Swedish University of Agricultural Sciences
RP Rundlöf, M (corresponding author), Lund Univ, Dept Biol, S-22362 Lund, Sweden.
EM maj.rundlof@biol.lu.se
FU Swedish Civil Contingencies Agency; Carl Tryggers Foundation for Scientific Research; Royal Physiographic Society; Swedish Research Council [330-2014-6439]; Formas
NR 56
TC 847
Z9 1005
U1 22
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 MAY 7
PY 2015
VL 521
IS 7550
BP 77
EP U162
DI 10.1038/nature14420
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH4YS
UT WOS:000354040900036
PM 25901681
DA 2026-03-09
ER

PT J
AU Wimmer, RD
   Schmitt, LI
   Davidson, TJ
   Nakajima, M
   Deisseroth, K
   Halassa, MM
AF Wimmer, Ralf D.
   Schmitt, L. Ian
   Davidson, Thomas J.
   Nakajima, Miho
   Deisseroth, Karl
   Halassa, Michael M.
TI Thalamic control of sensory selection in divided attention
SO NATURE
LA English
DT Article
ID lateral geniculate-nucleus; primary auditory-cortex; primary visual-cortex; prefrontal cortex; reticular nucleus; receptive-fields; top-down; task; architecture; information
AB How the brain selects appropriate sensory inputs and suppresses distractors is unknown. Given the well-established role of the prefrontal cortex (PFC) in executive function(1), its interactions with sensory cortical areas during attention have been hypothesized to control sensory selection(2-5). To test this idea and, more generally, dissect the circuits underlying sensory selection, we developed a cross-modal divided-attention task in mice that allowed genetic access to this cognitive process. By optogenetically perturbing PFC function in a temporally precise window, the ability of mice to select appropriately between conflicting visual and auditory stimuli was diminished. Equivalent sensory thalamocortical manipulations showed that behaviour was causally dependent on PFC interactions with the sensory thalamus, not sensory cortex. Consistent with this notion, we found neurons of the visual thalamic reticular nucleus (visTRN) to exhibit PFC-dependent changes in firing rate predictive of the modality selected. visTRN activity was causal to performance as confirmed by bidirectional optogenetic manipulations of this subnetwork. Using a combination of electrophysiology and intracellular chloride photometry, we demonstrated that visTRN dynamically controls visual thalamic gain through feedforward inhibition. Our experiments introduce a new subcortical model of sensory selection, in which the PFC biases thalamic reticular subnetworks to control thalamic sensory gain, selecting appropriate inputs for further processing.
C1 [Wimmer, Ralf D.; Schmitt, L. Ian; Nakajima, Miho; Halassa, Michael M.] NYU, Inst Neurosci, Dept Neurosci & Physiol, Langone Med Ctr, New York, NY 10016 USA.
   [Davidson, Thomas J.; Deisseroth, Karl] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.
   [Deisseroth, Karl] Stanford Univ, Cracking Neural Code Program, Stanford, CA 94305 USA.
   [Deisseroth, Karl] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA.
   [Halassa, Michael M.] NYU, Dept Psychiat, Langone Med Ctr, New York, NY 10016 USA.
   [Halassa, Michael M.] NYU, Ctr Neural Sci, New York, NY 10003 USA.
C3 NYU Langone Medical Center; New York University; Stanford University; Stanford University; Stanford University; NYU Langone Medical Center; New York University; New York University
RP Halassa, MM (corresponding author), NYU, Inst Neurosci, Dept Neurosci & Physiol, Langone Med Ctr, 550 1St Ave, New York, NY 10016 USA.
EM michael.halassa@nyumc.org
FU Swiss National Science Foundation [P2LAP3 151786]; Simons Foundation; Sloan Foundation; Brain and Behavior Research Foundation; US National Institutes of Health [R00 NS078115]; Feldstein Medical Foundation; Klingenstein-Simons Fellowship; Biobehavioral Research Award for Innovative New Scientists (BRAINS) from the National Institute of Mental Health [R01 (R01 MH107680)]; National Institute of Mental Health [R25MH094612] Funding Source: NIH RePORTER; Swiss National Science Foundation (SNF) [P2LAP3_151786] Funding Source: Swiss National Science Foundation (SNF)
NR 28
TC 369
Z9 458
U1 4
U2 140
PU NATURE PUBLISHING 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 29
PY 2015
VL 526
IS 7575
BP 705
EP 709
DI 10.1038/nature15398
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CU8ZH
UT WOS:000363832100049
PM 26503050
DA 2026-03-09
ER

PT J
AU Sather, AC
   Lee, HG
   Colombe, JR
   Zhang, AN
   Buchwald, SL
AF Sather, Aaron C.
   Lee, Hong Geun
   Colombe, James R.
   Zhang, Anni
   Buchwald, Stephen L.
TI Dosage delivery of sensitive reagents enables glove-box-free synthesis
SO NATURE
LA English
DT Article
ID fluorine; chemistry; catalyst; paraffin; pharmaceuticals
AB Contemporary organic chemists employ a broad range of catalytic and stoichiometric methods to construct molecules for applications in the material sciences(1), and as pharmaceuticals(2-5), agro-chemicals, and sensors(6). The utility of a synthetic method may be greatly reduced if it relies on a glove box to enable the use of air- and moisture-sensitive reagents or catalysts. Furthermore, many synthetic chemistry laboratories have numerous containers of partially used reagents that have been spoiled by exposure to the ambient atmosphere. This is exceptionally wasteful from both an environmental and a cost perspective. Here we report an encapsulation method for stabilizing and storing air-and moisture-sensitive compounds. We demonstrate this approach in three contexts, by describing single-use capsules that contain all of the reagents (catalysts, ligands, and bases) necessary for the glove-box-free palladium-catalysed carbon-fluorine(7-9), carbon-nitrogen(10,11,) and carbon-carbon(12) bond-forming reactions. This strategy should reduce the number of error-prone, tedious and time-consuming weighing procedures required for such syntheses and should be applicable to a wide range of reagents, catalysts, and substrate combinations.
C1 [Sather, Aaron C.; Lee, Hong Geun; Colombe, James R.; Zhang, Anni; Buchwald, Stephen L.] MIT, Dept Chem, Cambridge, MA 02139 USA.
C3 Massachusetts Institute of Technology (MIT)
RP Buchwald, SL (corresponding author), MIT, Dept Chem, Cambridge, MA 02139 USA.
EM sbuchwal@mit.edu
FU National Institutes of Health [R01GM46059, 1F32GM108092-01A1]; National Science Foundation [1122374]
NR 30
TC 75
Z9 92
U1 1
U2 116
PU NATURE PUBLISHING 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 13
PY 2015
VL 524
IS 7564
BP 208
EP 211
DI 10.1038/nature14654
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO8AM
UT WOS:000359386900029
PM 26268191
DA 2026-03-09
ER

PT J
AU Fröbisch, NB
   Bickelmann, C
   Olori, JC
   Witzmann, F
AF Froebisch, Nadia B.
   Bickelmann, Constanze
   Olori, Jennifer C.
   Witzmann, Florain
TI Deep-time evolution of regeneration and preaxial polarity in tetrapod limb development
SO NATURE
LA English
DT Article
ID larval ontogeny; origin; temnospondyli; ossification; genes; tail
AB Among extant tetrapods, salamanders are unique in showing a reversed preaxial polarity in patterning of the skeletal elements of the limbs, and in displaying the highest capacity for regeneration, including full limb and tail regeneration. These features are particularly striking as tetrapod limb development has otherwise been shown to be a highly conserved process(1,2). It remains elusive whether the capacity to regenerate limbs in salamanders is mechanistically and evolutionarily linked to the aberrant pattern of limb development; both are features classically regarded as unique to urodeles(3). New molecular data suggest that salamander-specific orphan genes play a central role in limb regeneration and may also be involved in the preaxial patterning during limb development(4,5). Here we show that preaxial polarity in limb development was present in various groups of temnospondyl amphibians of the Carboniferous and Permian periods, including the dissorophoids Apateon and Micromelerpeton, as well as the stereospondylomorph Sclerocephalus. Limb regeneration has also been reported in Micromelerpeton(6), demonstrating that both features were already present together in antecedents of modern salamanders 290 million years ago. Furthermore, data from lepospondyl 'microsaurs' on the amniote stem indicate that these taxa may have shown some capacity for limb regeneration and were capable of tail regeneration(7), including re-patterning of the caudal vertebral column that is otherwise only seen in salamander tail regeneration. The data from fossils suggest that salamander-like regeneration is an ancient feature of tetrapods that was subsequently lost at least once in the lineage leading to amniotes. Salamanders are the only modern tetrapods that retained regenerative capacities as well as preaxial polarity in limb development.
C1 [Froebisch, Nadia B.; Bickelmann, Constanze; Witzmann, Florain] Leibniz Inst Evolut & Biodivers Sci, Museum Nat Kunde, D-10115 Berlin, Germany.
   [Olori, Jennifer C.] SUNY Coll Oswego, Dept Biol Sci, Oswego, NY 13126 USA.
   [Witzmann, Florain] Brown Univ, Dept Ecol & Evolutionary Biol, Providence, RI 02912 USA.
C3 Leibniz Institut fur Evolutions und Biodiversitatsforschung; State University of New York (SUNY) System; State University of New York (SUNY) - Oswego; Brown University
RP Fröbisch, NB (corresponding author), Leibniz Inst Evolut & Biodivers Sci, Museum Nat Kunde, Invalidenstr 43, D-10115 Berlin, Germany.
EM nadia.froebisch@mfn-berlin.de
FU DFG Emmy Noether Grant [FR 2647/5-1]; Jackson School of Geosciences; Banks Fellowship; Society of Vertebrate Paleontology Estes Memorial Grant; Paleontological Society Lane Student Award; Feodor-Lynen Fellowship of the Alexander von Humboldt Foundation
NR 28
TC 59
Z9 63
U1 1
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 NOV 12
PY 2015
VL 527
IS 7577
BP 231
EP 234
DI 10.1038/nature15397
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700044
PM 26503047
DA 2026-03-09
ER

PT J
AU Resing, JA
   Sedwick, PN
   German, CR
   Jenkins, WJ
   Moffett, JW
   Sohst, BM
   Tagliabue, A
AF Resing, Joseph A.
   Sedwick, Peter N.
   German, Christopher R.
   Jenkins, William J.
   Moffett, James W.
   Sohst, Bettina M.
   Tagliabue, Alessandro
TI Basin-scale transport of hydrothermal dissolved metals across the South Pacific Ocean
SO NATURE
LA English
DT Article
ID flow-injection-analysis; iron; sea; atlantic; deep; circulation; manganese; seawater; plumes; al
AB Hydrothermal venting along mid-ocean ridges exerts an important control on the chemical composition of sea water by serving as a major source or sink for a number of trace elements in the ocean(1-3). Of these, iron has received considerable attention because of its role as an essential and often limiting nutrient for primary production in regions of the ocean that are of critical importance for the global carbon cycle(4). It has been thought that most of the dissolved iron discharged by hydrothermal vents is lost from solution close to ridge-axis sources(2,5) and is thus of limited importance for ocean biogeochemistry(6). This long-standing view is challenged by recent studies which suggest that stabilization of hydrothermal dissolved iron may facilitate its longrange oceanic transport(7-10). Such transport has been subsequently inferred from spatially limited oceanographic observations(11-13). Here we report data from the US GEOTRACES Eastern Pacific Zonal Transect (EPZT) that demonstrate lateral transport of hydrothermal dissolved iron, manganese, and aluminium from the southern East Pacific Rise (SEPR) several thousand kilometres westward across the South Pacific Ocean. Dissolved iron exhibits nearly conservative (that is, no loss from solution during transport and mixing) behaviour in this hydrothermal plume, implying a greater longevity in the deep ocean than previously assumed(6,14). Based on our observations, we estimate a global hydrothermal dissolved iron input of three to four gigamoles per year to the ocean interior, which is more than fourfold higher than previous estimates(7,11,14). Complementary simulations with a global-scale ocean biogeochemical model suggest that the observed transport of hydrothermal dissolved iron requires some means of physicochemical stabilization and indicate that hydrothermally derived iron sustains a large fraction of Southern Ocean export production.
C1 [Resing, Joseph A.] Univ Washington, Joint Inst Study Atmosphere & Ocean, Seattle, WA 98115 USA.
   [Resing, Joseph A.] NOAA, PMEL, Seattle, WA 98115 USA.
   [Sedwick, Peter N.; Sohst, Bettina M.] Old Dominion Univ, Dept Ocean Earth & Atmospher Sci, Norfolk, VA 23529 USA.
   [German, Christopher R.; Jenkins, William J.] Woods Hole Oceanog Inst, Woods Hole, MA 02543 USA.
   [Moffett, James W.] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA.
   [Tagliabue, Alessandro] Univ Liverpool, Sch Environm Sci, Dept Earth Ocean & Ecol Sci, Liverpool L69 3GP, Merseyside, England.
C3 University of Washington; University of Washington Seattle; National Oceanic Atmospheric Admin (NOAA) - USA; Old Dominion University; Woods Hole Oceanographic Institution; University of Southern California; University of Liverpool
RP Resing, JA (corresponding author), Univ Washington, Joint Inst Study Atmosphere & Ocean, 7600 Sand Point Way NE, Seattle, WA 98115 USA.
EM resing@uw.edu; a.tagliabue@liverpool.ac.uk
FU US National Science Foundation [OCE-1237011, OCE-1237034, OCE-1232991, OCE-1130870, OCE-1131731, OCE-1260273]; N8 consortium; EPSRC [EP/K000225/1]; Humboldt Research Award; JISAO by the PMEL-Earth Oceans Interactions programme; EPSRC [EP/K000209/1, EP/K000225/1] Funding Source: UKRI; Division Of Ocean Sciences; Directorate For Geosciences [1130870, 1237034, 1131731] Funding Source: National Science Foundation; Division Of Ocean Sciences; Directorate For Geosciences [1237011, 1232991] Funding Source: National Science Foundation; Engineering and Physical Sciences Research Council [EP/K000225/1, EP/K000209/1, 1237034] Funding Source: researchfish
NR 51
TC 438
Z9 505
U1 6
U2 297
PU NATURE PUBLISHING 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 9
PY 2015
VL 523
IS 7559
BP 200
EP U140
DI 10.1038/nature14577
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM4ZO
UT WOS:000357695900032
PM 26156374
DA 2026-03-09
ER

PT J
AU Roffet-Salque, M
   Regert, M
   Evershed, RR
   Outram, AK
   Cramp, LJE
   Decavallas, O
   Dunne, J
   Gerbault, P
   Mileto, S
   Mirabaud, S
   Pääkkönen, M
   Smyth, J
   Soberl, L
   Whelton, HL
   Alday-Ruiz, A
   Asplund, H
   Bartkowiak, M
   Bayer-Niemeier, E
   Belhouchet, L
   Bernardini, F
   Budja, M
   Cooney, G
   Cubas, M
   Danaher, EM
   Diniz, M
   Domboroczki, L
   Fabbri, C
   González-Urquijo, JE
   Guilaine, J
   Hachi, S
   Hartwell, BN
   Hofmann, D
   Hohle, I
   Ibáñez, JJ
   Karul, N
   Kherbouche, F
   Kiely, J
   Kotsakis, K
   Lueth, F
   Mallory, JP
   Manen, C
   Marciniak, A
   Maurice-Chabard, B
   McGonigle, MA
   Mulazzani, S
   Özdogan, M
   Peric, OS
   Peric, SR
   Petrasch, J
   Pétrequin, AM
   Pétrequie, P
   Poensgen, U
   Pollard, CJ
   Poplin, F
   Radi, G
   Stadler, P
   Stäuble, H
   Tasic, N
   Urem-Kotsou, D
   Vukovic, JB
   Walsh, F
   Whittle, A
   Wolfram, S
   Zapata-Peña, L
   Zoughlami, J
AF Roffet-Salque, Melanie
   Regert, Martine
   Evershed, Richard R.
   Outram, Alan K.
   Cramp, Lucy J. E.
   Decavallas, Orestes
   Dunne, Julie
   Gerbault, Pascale
   Mileto, Simona
   Mirabaud, Sigrid
   Paakkonen, Mirva
   Smyth, Jessica
   Soberl, Lucija
   Whelton, Helen L.
   Alday-Ruiz, Alfonso
   Asplund, Henrik
   Bartkowiak, Marta
   Bayer-Niemeier, Eva
   Belhouchet, Lotfi
   Bernardini, Federico
   Budja, Mihael
   Cooney, Gabriel
   Cubas, Miriam
   Danaher, Ed M.
   Diniz, Mariana
   Domboroczki, Laszlo
   Fabbri, Cristina
   Gonzalez-Urquijo, Jesus E.
   Guilaine, Jean
   Hachi, Slimane
   Hartwell, Barrie N.
   Hofmann, Daniela
   Hohle, Isabel
   Ibanez, Juan J.
   Karul, Necmi
   Kherbouche, Farid
   Kiely, Jacinta
   Kotsakis, Kostas
   Lueth, Friedrich
   Mallory, James P.
   Manen, Claire
   Marciniak, Arkadiusz
   Maurice-Chabard, Brigitte
   McGonigle, Martin A.
   Mulazzani, Simone
   Ozdogan, Mehmet
   Peric, Olga S.
   Peric, Slavisa R.
   Petrasch, Joerg
   Petrequin, Anne-Marie
   Petrequie, Pierre
   Poensgen, Ulrike
   Pollard, C. Joshua
   Poplin, Francois
   Radi, Giovanna
   Stadler, Peter
   Staeuble, Harald
   Tasic, Nenad
   Urem-Kotsou, Dushka
   Vukovic, Jasna B.
   Walsh, Fintan
   Whittle, Alasdair
   Wolfram, Sabine
   Zapata-Pena, Lydia
   Zoughlami, Jamel
TI Widespread exploitation of the honeybee by early Neolithic farmers
SO NATURE
LA English
DT Article
ID ionization mass-spectrometry; apis-mellifera; beeswax; residues; vessels
AB The pressures on honeybee (Apis mellifera) populations, resulting from threats by modern pesticides, parasites, predators and diseases, have raised awareness of the economic importance and critical role this insect plays in agricultural societies across the globe. However, the association of humans with A. mellifera predates post-industrial-revolution agriculture, as evidenced by the widespread presence of ancient Egyptian bee iconography dating to the Old Kingdom (approximately 2400 BC)(1). There are also indications of Stone Age people harvesting bee products; for example, honey hunting is interpreted from rock art(2) in a prehistoric Holocene context and a beeswax find in a pre-agriculturalist site(3). However, when and where the regular association of A. mellifera with agriculturalists emerged is unknown(4). One of the major products of A. mellifera is beeswax, which is composed of a complex suite of lipids including n-alkanes, n-alkanoic acids and fatty acyl wax esters. The composition is highly constant as it is determined genetically through the insect's biochemistry. Thus, the chemical 'fingerprint' of beeswax provides a reliable basis for detecting this commodity in organic residues preserved at archaeological sites, which we now use to trace the exploitation by humans of A. mellifera temporally and spatially. Here we present secure identifications of beeswax in lipid residues preserved in pottery vessels of Neolithic Old World farmers. The geographical range of bee product exploitation is traced in Neolithic Europe, the Near East and North Africa, providing the palaeoecological range of honeybees during prehistory. Temporally, we demonstrate that bee products were exploited continuously, and probably extensively in some regions, at least from the seventh millennium cal BC, likely fulfilling a variety of technological and cultural functions. The close association of A. mellifera with Neolithic farming communities dates to the early onset of agriculture and may provide evidence for the beginnings of a domestication process.
C1 [Roffet-Salque, Melanie; Evershed, Richard R.; Cramp, Lucy J. E.; Dunne, Julie; Mileto, Simona; Paakkonen, Mirva; Smyth, Jessica; Soberl, Lucija; Whelton, Helen L.] Univ Bristol, Sch Chem, Organ Geochem Unit, Bristol BS8 1TS, Avon, England.
   [Regert, Martine] Univ Nice Sophia Antipolis, CNRS, UMR 7264, CEPAM Cultures & Environm Prehist Antiqu Moyen Ag, F-06300 Nice, France.
   [Outram, Alan K.] Univ Exeter, Dept Archaeol, Exeter EX4 4QE, Devon, England.
   [Cramp, Lucy J. E.; Smyth, Jessica] Univ Bristol, Dept Archaeol & Anthropol, Bristol BS8 1UU, Avon, England.
   [Decavallas, Orestes] Univ Bordeaux Montaigne, F-33607 Pessac, France.
   [Decavallas, Orestes; Mirabaud, Sigrid] Lab Ctr Rech & Restaurat Musees France C2RMF, UMR 171, F-75001 Paris, France.
   [Gerbault, Pascale] UCL, Res Dept Genet Evolut & Environm, London WC1E 6BT, England.
   [Gerbault, Pascale] UCL, Dept Anthropol, London WC1H 0BW, England.
   [Mileto, Simona] Free Univ Berlin, Inst Prahist Archaol, D-14195 Berlin, Germany.
   [Paakkonen, Mirva; Asplund, Henrik] Univ Turku, Dept Archaeol, Turun 20014, Finland.
   [Soberl, Lucija; Budja, Mihael] Univ Ljubljana, Fac Arts, Dept Archaeol, Ljubljana 1000, Slovenia.
   [Alday-Ruiz, Alfonso; Zapata-Pena, Lydia] Univ Basque Country EHU UPV, Dept Geog Prehist & Archaeol, Vitoria 01006, Spain.
   [Bartkowiak, Marta; Marciniak, Arkadiusz] Adam Mickiewicz Univ, Inst Prehist, PL-61614 Poznan, Poland.
   [Bayer-Niemeier, Eva] Museum Quintana Archaol Kunzing, Partnermuseum Archaol Staatssammlung Munchen, D-94550 Kunzing, Germany.
   [Belhouchet, Lotfi] Musee Archeol Sousse, Sousse 4000, Tunisia.
   [Bernardini, Federico] Museo Stor Fis, Ctr Fermi, I-00184 Rome, Italy.
   [Bernardini, Federico] Ctr Studi & Ric Enrico Fermi, I-00184 Rome, Italy.
   [Bernardini, Federico] Abdus Salam Int Ctr Theoret Phys, Multidisciplinary Lab, I-34151 Trieste, Italy.
   [Cooney, Gabriel] Univ Coll Dublin, UCD Sch Archaeol, Dublin 4, Ireland.
   [Cubas, Miriam; Gonzalez-Urquijo, Jesus E.] Univ Cantabria, Int Inst Prehist Res Cantabria, E-39005 Santander, Spain.
   [Danaher, Ed M.] Natl Univ Ireland Univ Coll Galway, Dept Archaeol, Galway, Ireland.
   [Diniz, Mariana] Univ Lisbon, Fac Letras Lisboa, UNIARQ Dept Hist, P-1600214 Lisbon, Portugal.
   [Domboroczki, Laszlo] Istvan Dobo Castle Museum, H-3300 Eger, Hungary.
   [Fabbri, Cristina; Radi, Giovanna] Univ Pisa, Dipartimento Civilta & Forme Sapere, I-56126 Pisa, Italy.
   [Guilaine, Jean; Manen, Claire] Univ Toulouse Jean Jaures, Maison Rech, CNRS UMR TRACES 5608, F-31058 Toulouse 9, France.
   [Hachi, Slimane; Kherbouche, Farid] CNRPAH, Algiers, Algeria.
   [Hartwell, Barrie N.; Mallory, James P.] Queens Univ Belfast, Sch Geog Archaeol & Palaeoecol, Belfast BT7 1NN, Antrim, North Ireland.
   [Hofmann, Daniela] Univ Hamburg, Archaol Inst, D-20146 Hamburg, Germany.
   [Hohle, Isabel] Artes Grad Sch Humanities Cologne, Graduiertenschule Philosoph Fak, D-50931 Cologne, Germany.
   [Ibanez, Juan J.] IMF CSIC, Barcelona 08001, Spain.
   [Karul, Necmi; Ozdogan, Mehmet] Istanbul Univ, Fac Letters, Dept Prehist, TR-34434 Laleli Istanbul, Turkey.
   [Kiely, Jacinta] Eachtra Archaeol Projects, Clashmore, Waterford, Ireland.
   [Kotsakis, Kostas] Aristotle Univ Thessaloniki, Fac Philosophy, Sch Hist & Archaeol, Thessaloniki 54124, Greece.
   [Lueth, Friedrich] German Archaeol Inst, D-14195 Berlin, Germany.
   [Maurice-Chabard, Brigitte] Musee Rolin, F-71400 Autun, France.
   [McGonigle, Martin A.] John Cronin & Associates, Buncrana, Donegal, Ireland.
   [Mulazzani, Simone] Aix Marseille Univ, CNRS, UMR LAMPEA 7269, Ministere Culture & Commun,LabexMed, F-13234 Marseille, France.
   [Mulazzani, Simone] Univ Roma La Sapienza, Dipartimento Biol Ambientale, I-00185 Rome, Italy.
   [Peric, Olga S.; Peric, Slavisa R.] Inst Archaeol Belgrade, Belgrade 11000, Serbia.
   [Petrasch, Joerg] Univ Tubingen, Inst Ur & Fruhgeschichte & Archaol Mittelalters, Abt Jungere Urgeschichte & Fruhgeschichte Schloss, D-72070 Tubingen, Germany.
   [Petrequin, Anne-Marie; Petrequie, Pierre] CNRS, Maison Sci Homme & Environm CN Ledoux, F-25030 Besancon, France.
   [Petrequin, Anne-Marie; Petrequie, Pierre] Univ Franche Comte, F-25030 Besancon, France.
   [Pollard, C. Joshua] Univ Southampton, Fac Humanities, Dept Archaeol, Southampton SO17 1BF, Hants, England.
   [Poplin, Francois] Museum Natl Hist Nat, F-75005 Paris, France.
   [Stadler, Peter] Univ Vienna, Dept Pre & Protohist, A-1190 Vienna, Austria.
   [Staeuble, Harald] Landesamt Archaeol, D-01109 Dresden, Germany.
   [Tasic, Nenad; Vukovic, Jasna B.] Univ Belgrade, Fac Philosophy, Dept Archaeol, Belgrade 11000, Serbia.
   [Urem-Kotsou, Dushka] Democritus Univ Thrace, Dept Hist & Ethnol, Komotini, Greece.
   [Walsh, Fintan] Irish Archaeol Consultancy, Kilcoole, Wicklow, Ireland.
   [Whittle, Alasdair] Cardiff Univ, Dept Archaeol & Conservat, Cardiff CF10 3EU, S Glam, Wales.
   [Wolfram, Sabine] State Museum Archaeol Chemnitz, D-09111 Chemnitz, Germany.
   [Zoughlami, Jamel] Musee Archeol Carthage, Inst Natl Patrimoine Tunis, Carthage, Tunisia.
C3 University of Bristol; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Ecology & Environment (INEE); Universite Cote d'Azur; University of Exeter; University of Bristol; University of London; University College London; University of London; University College London; Free University of Berlin; University of Turku; University of Ljubljana; University of Basque Country; Adam Mickiewicz University; Abdus Salam International Centre for Theoretical Physics (ICTP); University College Dublin; Universidad de Cantabria; Instituto Internacional de Investigaciones Prehistoricas de Cantabria (IIIPC); Ollscoil na Gaillimhe-University of Galway; Universidade de Lisboa; University of Pisa; Universite de Toulouse; Universite de Toulouse - Jean Jaures; National Centre for Prehistoric, Anthropologic & Historic Research - Algeria; Queens University Belfast; University of Hamburg; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Institucion Mila y Fontanals (IMF); Istanbul University; Aristotle University of Thessaloniki; Centre National de la Recherche Scientifique (CNRS); Aix-Marseille Universite; Sapienza University Rome; Eberhard Karls University of Tubingen; Universite Marie et Louis Pasteur; Centre National de la Recherche Scientifique (CNRS); Universite Marie et Louis Pasteur; University of Southampton; Museum National d'Histoire Naturelle (MNHN); University of Vienna; University of Belgrade; Democritus University of Thrace; Cardiff University; Universite de Tunis; Institut National du Patrimoine
RP Roffet-Salque, M (corresponding author), Univ Bristol, Sch Chem, Organ Geochem Unit, Cantocks Close, Bristol BS8 1TS, Avon, England.
EM melanie.salque@bristol.ac.uk; martine.regert@cepam.cnrs.fr; r.p.evershed@bristol.ac.uk; p.gerbault@ucl.ac.uk
FU UK Natural Environment Research Council [R8/H10/63]; English Heritage; European Research Council; Leverhulme Trust; Ministere de la Culture et de la Communication; Ministere de l'Enseignement Superieur et de la Recherche (ACI Jeunes Chercheurs); Natural Environment Research Council; Region PACA; Royal Society; Wellcome Trust; Natural Environment Research Council [NE/F021054/1, 1257864] Funding Source: researchfish; NERC [NE/F021054/1] Funding Source: UKRI
CR Abou-Shaara HF, 2014, VET MED-CZECH, V59, P1, DOI 10.17221/7240-VETMED
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NR 34
TC 147
Z9 182
U1 7
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 NOV 12
PY 2015
VL 527
IS 7577
BP 226
EP +
DI 10.1038/nature15757
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700043
PM 26560301
DA 2026-03-09
ER

PT J
AU Orelle, C
   Carlson, ED
   Szal, T
   Florin, T
   Jewett, MC
   Mankin, AS
AF Orelle, Cedric
   Carlson, Erik D.
   Szal, Teresa
   Florin, Tanja
   Jewett, Michael C.
   Mankin, Alexander S.
TI Protein synthesis by ribosomes with tethered subunits
SO NATURE
LA English
DT Article
ID peptidyl transferase center; rna; translation; mutations; site; transcription; system
AB The ribosome is a ribonucleoprotein machine responsible for protein synthesis. In all kingdoms of life it is composed of two subunits, each built on its own ribosomal RNA (rRNA) scaffold. The independent but coordinated functions of the subunits, including their ability to associate at initiation, rotate during elongation, and dissociate after protein release, are an established model of protein synthesis. Furthermore, the bipartite nature of the ribosome is presumed to be essential for biogenesis, since dedicated assembly factors keep immature ribosomal subunits apart and prevent them from translation initiation(1). Free exchange of the subunits limits the development of specialized orthogonal genetic systems that could be evolved for novel functions without interfering with native translation. Here we show that ribosomes with tethered and thus inseparable subunits (termed Ribo-T) are capable of successfully carrying out protein synthesis. By engineering a hybrid rRNA composed of both small and large subunit rRNA sequences, we produced a functional ribosome in which the subunits are covalently linked into a single entity by short RNA linkers. Notably, Ribo-T was not only functional in vitro, but was also able to support the growth of Escherichia coli cells even in the absence of wild-type ribosomes. We used Ribo-T to create the first fully orthogonal ribosome-messenger RNA system, and demonstrate its evolvability by selecting otherwise dominantly lethal rRNA mutations in the peptidyl transferase centre that facilitate the translation of a problematic protein sequence. Ribo-T can be used for exploring poorly understood functions of the ribosome, enabling orthogonal genetic systems, and engineering ribosomes with new functions.
C1 [Orelle, Cedric; Szal, Teresa; Florin, Tanja; Mankin, Alexander S.] Univ Illinois, Ctr Pharmaceut Biotechnol MC 870, Chicago, IL 60607 USA.
   [Carlson, Erik D.; Jewett, Michael C.] Northwestern Univ, Dept Chem & Biol Engn, Evanston, IL 60208 USA.
   [Carlson, Erik D.; Jewett, Michael C.] Northwestern Univ, Chem Life Proc Inst, Evanston, IL 60208 USA.
C3 University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital; Northwestern University; Northwestern University
RP Mankin, AS (corresponding author), Univ Illinois, Ctr Pharmaceut Biotechnol MC 870, 900 South Ashland Ave, Chicago, IL 60607 USA.
EM m-jewett@northwestern.edu; shura@uic.edu
FU Defense Advanced Research Projects Agency [N66001-12-C-4211]; National Science Foundation [MCB-0943393, MCB-1244455]; David and Lucille Packard Foundation [2011-37152]; Div Of Molecular and Cellular Bioscience; Direct For Biological Sciences [1244455] Funding Source: National Science Foundation
NR 38
TC 187
Z9 234
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 AUG 6
PY 2015
VL 524
IS 7563
BP 119
EP U289
DI 10.1038/nature14862
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO2QS
UT WOS:000359002300044
PM 26222032
DA 2026-03-09
ER

PT J
AU Golledge, NR
   Kowalewski, DE
   Naish, TR
   Levy, RH
   Fogwill, CJ
   Gasson, EGW
AF Golledge, N. R.
   Kowalewski, D. E.
   Naish, T. R.
   Levy, R. H.
   Fogwill, C. J.
   Gasson, E. G. W.
TI The multi-millennial Antarctic commitment to future sea-level rise
SO NATURE
LA English
DT Article
ID ice-sheet; pine island; retreat; model; glaciers; collapse; surface; stability; discharge; thwaites
AB Atmospheric warming is projected to increase global mean surface temperatures by 0.3 to 4.8 degrees Celsius above pre-industrial values by the end of this century(1). If anthropogenic emissions continue unchecked, the warming increase may reach 8-10 degrees Celsius by 2300 (ref. 2). The contribution that large ice sheets will make to sea-level rise under such warming scenarios is difficult to quantify because the equilibrium-response timescale of ice sheets is longer than those of the atmosphere or ocean. Here we use a coupled ice-sheet/ice-shelf model to show that if atmospheric warming exceeds 1.5 to 2 degrees Celsius above present, collapse of the major Antarctic ice shelves triggers a centennial-to millennial-scale response of the Antarctic ice sheet in which enhanced viscous flow produces a long-term commitment (an unstoppable contribution) to sea-level rise. Our simulations represent the response of the present-day Antarctic ice-sheet system to the oceanic and climatic changes of four representative concentration pathways (RCPs) from the Fifth Assessment Report of the Intergovernmental Panel on Climate Change(3). We find that substantial Antarctic ice loss can be prevented only by limiting greenhouse gas emissions to RCP 2.6 levels. Higher-emissions scenarios lead to ice loss from Antarctic that will raise sea level by 0.6-3 metres by the year 2300. Our results imply that greenhouse gas emissions in the next few decades will strongly influence the long-term contribution of the Antarctic ice sheet to global sea level.
C1 [Golledge, N. R.; Naish, T. R.] Victoria Univ Wellington, Antarctic Res Ctr, Wellington 6140, New Zealand.
   [Golledge, N. R.; Naish, T. R.; Levy, R. H.] GNS Sci, Lower Hutt 5011, New Zealand.
   [Kowalewski, D. E.] Worcester State Univ, Dept Earth Environm & Phys, Worcester, MA 01602 USA.
   [Fogwill, C. J.] Univ New S Wales, Climate Change Res Ctr, Sydney, NSW 2052, Australia.
   [Gasson, E. G. W.] Univ Massachusetts, Climate Syst Res Ctr, Amherst, MA 01003 USA.
C3 Victoria University Wellington; Earth Sciences New Zealand; GNS Science - New Zealand; Massachusetts System of Public Higher Education; Worcester State University; University of New South Wales Sydney; University of Massachusetts System; University of Massachusetts Amherst
RP Golledge, NR (corresponding author), Victoria Univ Wellington, Antarctic Res Ctr, Wellington 6140, New Zealand.
EM nicholas.golledge@vuw.ac.nz
FU Royal Society of New Zealand's Marsden Fund [VUW1203]; Antarctic Research Centre; Victoria University of Wellington; ANDRILL; GNS Science (NZ Ministry of Business Innovation and Employment) [C05X1001]; National Science Foundation [ANT-1043712]; Australian Research Council (ARC); Office of Polar Programs (OPP); Directorate For Geosciences [1245899] Funding Source: National Science Foundation
NR 59
TC 331
Z9 372
U1 5
U2 192
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD OCT 15
PY 2015
VL 526
IS 7573
BP 421
EP +
DI 10.1038/nature15706
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200049
PM 26469052
DA 2026-03-09
ER

PT J
AU Kayagaki, N
   Stowe, IB
   Lee, BL
   O'Rourke, K
   Anderson, K
   Warming, S
   Cuellar, T
   Haley, B
   Roose-Girma, M
   Phung, QT
   Liu, PS
   Lill, JR
   Li, H
   Wu, JS
   Kummerfeld, S
   Zhang, J
   Lee, WP
   Snipas, SJ
   Salvesen, GS
   Morris, LX
   Fitzgerald, L
   Zhang, YF
   Bertram, EM
   Goodnow, CC
   Dixit, VM
AF Kayagaki, Nobuhiko
   Stowe, Irma B.
   Lee, Bettina L.
   O'Rourke, Karen
   Anderson, Keith
   Warming, Soren
   Cuellar, Trinna
   Haley, Benjamin
   Roose-Girma, Merone
   Phung, Qui T.
   Liu, Peter S.
   Lill, Jennie R.
   Li, Hong
   Wu, Jiansheng
   Kummerfeld, Sarah
   Zhang, Juan
   Lee, Wyne P.
   Snipas, Scott J.
   Salvesen, Guy S.
   Morris, Lucy X.
   Fitzgerald, Linda
   Zhang, Yafei
   Bertram, Edward M.
   Goodnow, Christopher C.
   Dixit, Vishva M.
TI Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling
SO NATURE
LA English
DT Article
ID cell-death; activation; interleukin-1-beta; pyroptosis; epithelium; receptors; crystals; protease; release; members
AB Intracellular lipopolysaccharide from Gram-negative bacteria including Escherichia colt Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11, causing pyroptotic cell death, interleukin-1 beta processing, and lethal septic shock. How caspase-11 executes these downstream signalling events is largely unknown. Here we show that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1 beta maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice links Gsdmd to the intracellular lipopolysaccharide response. Macrophages from Gsdmd(-/-) mice generated by gene targeting also exhibit defective pyroptosis and interleukin-1 beta secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. In addition, Gsdmd(-1-) mice are protected from a lethal dose of lipopolysaccharide. Mechanistically, caspase-11 cleaves gasdermin D, and the resulting amino-terminal fragment promotes both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify gasdermin D as a critical target of caspase-11 and a key mediator of the host response against Grain-negative bacteria.
C1 [Kayagaki, Nobuhiko; Stowe, Irma B.; Lee, Bettina L.; O'Rourke, Karen; Dixit, Vishva M.] Genentech Inc, Dept Physiol Chem, San Francisco, CA 94080 USA.
   [Anderson, Keith; Warming, Soren; Cuellar, Trinna; Haley, Benjamin; Roose-Girma, Merone] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA.
   [Phung, Qui T.; Liu, Peter S.; Lill, Jennie R.; Li, Hong; Wu, Jiansheng] Genentech Inc, Dept Prot Chem, San Francisco, CA 94080 USA.
   [Kummerfeld, Sarah] Genentech Inc, Dept Bioinformat, San Francisco, CA 94080 USA.
   [Zhang, Juan; Lee, Wyne P.] Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA.
   [Snipas, Scott J.; Salvesen, Guy S.] Sanford Burnham Prebys Med Discovery Inst, Program Cell Death Signaling Networks, La Jolla, CA 92037 USA.
   [Morris, Lucy X.; Fitzgerald, Linda; Zhang, Yafei; Bertram, Edward M.] Australian Natl Univ, John Curtin Sch Med Res, Australian Phen Facil, Canberra, ACT 2601, Australia.
   [Bertram, Edward M.; Goodnow, Christopher C.] Australian Natl Univ, John Curtin Sch Med Res, Dept Immunol & Infect Dis, Canberra, ACT 2601, Australia.
   [Goodnow, Christopher C.] Garvan Inst Med Res, Sydney, NSW 2010, Australia.
   [Goodnow, Christopher C.] UNSW Australia, St Vincents Clin Sch, Darlinghurst, NSW 2010, Australia.
C3 Roche Holding; Roche Holding USA; Genentech; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Genentech; Roche Holding USA; Sanford Burnham Prebys Medical Discovery Institute; Australian National University; John Curtin School of Medical Research; Australian National University; John Curtin School of Medical Research; Garvan Institute of Medical Research; St Vincent's Clinic; University of New South Wales Sydney
RP Kayagaki, N (corresponding author), Genentech Inc, Dept Physiol Chem, San Francisco, CA 94080 USA.
EM kayagaki@gene.com; dixit@gene.com
NR 41
TC 2977
Z9 3377
U1 24
U2 509
PU NATURE PUBLISHING 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 29
PY 2015
VL 526
IS 7575
BP 666
EP 671
DI 10.1038/nature15541
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CU8ZH
UT WOS:000363832100041
PM 26375259
DA 2026-03-09
ER

PT J
AU Selmecki, AM
   Maruvka, YE
   Richmond, PA
   Guillet, M
   Shoresh, N
   Sorenson, AL
   De, S
   Kishony, R
   Michor, F
   Dowell, R
   Pellman, D
AF Selmecki, Anna M.
   Maruvka, Yosef E.
   Richmond, Phillip A.
   Guillet, Marie
   Shoresh, Noam
   Sorenson, Amber L.
   De, Subhajyoti
   Kishony, Roy
   Michor, Franziska
   Dowell, Robin
   Pellman, David
TI Polyploidy can drive rapid adaptation in yeast
SO NATURE
LA English
DT Article
ID site-directed mutagenesis; clonal interference; saccharomyces-cerevisiae; adaptive evolution; candida-albicans; drug-resistance; read alignment; aneuploidy; mutations; instability
AB Polyploidy is observed across the tree of life, yet its influence on evolution remains incompletely understood(1-4). Polyploidy, usually whole-genome duplication, is proposed to alter the rate of evolutionary adaptation. This could occur through complex effects on the frequency or fitness of beneficial mutations(2,5-7). For example, in diverse cell types and organisms, immediately after a whole-genome duplication, newly formed polyploids missegregate chromosomes and undergo genetic instability(8-13). The instability following wholegenome duplications is thought to provide adaptive mutations in microorganisms(13,14) and can promote tumorigenesis in mammalian cells(11,15). Polyploidy may also affect adaptation independently of beneficial mutations through ploidy-specific changes in cell physiology(16). Here we perform in vitro evolution experiments to test directly whether polyploidy can accelerate evolutionary adaptation. Compared with haploids and diploids, tetraploids undergo significantly faster adaptation. Mathematical modelling suggests that rapid adaptation of tetraploids is driven by higher rates of beneficial mutations with stronger fitness effects, which is supported by whole-genome sequencing and phenotypic analyses of evolved clones. Chromosome aneuploidy, concerted chromosome loss, and point mutations all provide large fitness gains. We identify several mutations whose beneficial effects are manifest specifically in the tetraploid strains. Together, these results provide direct quantitative evidence that in some environments polyploidy can accelerate evolutionary adaptation.
C1 [Selmecki, Anna M.; Guillet, Marie; Pellman, David] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.
   [Selmecki, Anna M.; Guillet, Marie; Pellman, David] Harvard Univ, Dept Cell Biol, Sch Med, Boston, MA 02215 USA.
   [Selmecki, Anna M.; Guillet, Marie; Pellman, David] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
   [Maruvka, Yosef E.; Michor, Franziska] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA.
   [Maruvka, Yosef E.; Michor, Franziska] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA.
   [Richmond, Phillip A.; Sorenson, Amber L.; Dowell, Robin] Univ Colorado, BioFrontiers Inst, Boulder, CO 80303 USA.
   [Richmond, Phillip A.; Sorenson, Amber L.; Dowell, Robin] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA.
   [Shoresh, Noam] Broad Inst, Cambridge, MA 02142 USA.
   [De, Subhajyoti] Univ Colorado Sch Med, Dept Med, Aurora, CO 80045 USA.
   [De, Subhajyoti] Colorado Sch Publ Hlth, Dept Biostat & Informat, Aurora, CO 80045 USA.
   [De, Subhajyoti] Univ Colorado Canc Ctr, Mol Oncol Program, Aurora, CO 80045 USA.
   [Kishony, Roy] Harvard Univ, Dept Syst Biol, Sch Med, Boston, MA 02115 USA.
   [Kishony, Roy] Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel.
   [Pellman, David] Childrens Hosp, Dept Pediat Hematol Oncol, Boston, MA 02115 USA.
C3 Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Boston University; University of Colorado System; University of Colorado Boulder; University of Colorado System; University of Colorado Boulder; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Colorado System; University of Colorado Anschutz Medical Campus; Colorado School of Public Health; University of Colorado System; University of Colorado Anschutz Medical Campus; Harvard University; Harvard Medical School; Technion Israel Institute of Technology; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital
RP Selmecki, AM (corresponding author), Creighton Univ Sch Med, Dept Med Microbiol & Immunol, 2500 Calif Plaza, Omaha, NE 68178 USA.
EM AnnaSelmecki@creighton.edu; david_pellman@dfci.harvard.edu
FU Howard Hughes Medical Institute; National Institutes of Health [R37 GM61345, R01 GM081617]; G. Harold & Leila Y. Mathers Charitable Foundation; Dana-Farber Cancer Institute Physical Sciences-Oncology Center [U54CA143798]; Boettcher Foundation's Webb-Waring Biomedical Research Program; National Science Foundation [NSF 1350915]; American Cancer Society Postdoctoral Fellowship; Div Of Molecular and Cellular Bioscience; Direct For Biological Sciences [1350915] Funding Source: National Science Foundation; National Institute of General Medical Sciences [R37GM061345] Funding Source: NIH RePORTER
NR 68
TC 329
Z9 416
U1 1
U2 151
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 19
PY 2015
VL 519
IS 7543
BP 349
EP +
DI 10.1038/nature14187
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD6AY
UT WOS:000351171900040
PM 25731168
DA 2026-03-09
ER

PT J
AU Howe, JA
   Wang, H
   Fischmann, TO
   Balibar, CJ
   Xiao, L
   Galgoci, AM
   Malinverni, JC
   Mayhood, T
   Villafania, A
   Nahvi, A
   Murgolo, N
   Barbieri, CM
   Mann, PA
   Carr, D
   Xia, E
   Zuck, P
   Riley, D
   Painter, RE
   Walker, SS
   Sherborne, B
   de Jesus, R
   Pan, WD
   Plotkin, MA
   Wu, J
   Rindgen, D
   Cummings, J
   Garlisi, CG
   Zhang, RM
   Sheth, PR
   Gill, CJ
   Tang, HF
   Roemer, T
AF Howe, John A.
   Wang, Hao
   Fischmann, Thierry O.
   Balibar, Carl J.
   Xiao, Li
   Galgoci, Andrew M.
   Malinverni, Juliana C.
   Mayhood, Todd
   Villafania, Artjohn
   Nahvi, Ali
   Murgolo, Nicholas
   Barbieri, Christopher M.
   Mann, Paul A.
   Carr, Donna
   Xia, Ellen
   Zuck, Paul
   Riley, Dan
   Painter, Ronald E.
   Walker, Scott S.
   Sherborne, Brad
   de Jesus, Reynalda
   Pan, Weidong
   Plotkin, Michael A.
   Wu, Jin
   Rindgen, Diane
   Cummings, John
   Garlisi, Charles G.
   Zhang, Rumin
   Sheth, Payal R.
   Gill, Charles J.
   Tang, Haifeng
   Roemer, Terry
TI Selective small-molecule inhibition of an RNA structural element
SO NATURE
LA English
DT Article
ID flavin mononucleotide riboswitch; antibacterial drug targets; riboflavin biosynthesis; streptomyces-davawensis; bacillus-subtilis; escherichia-coli; gene-expression; antibiotic roseoflavin; fmn riboswitch; transcription
AB Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors. Here we report the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide, to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate that non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected.
C1 [Howe, John A.; Wang, Hao; Fischmann, Thierry O.; Balibar, Carl J.; Xiao, Li; Galgoci, Andrew M.; Malinverni, Juliana C.; Mayhood, Todd; Villafania, Artjohn; Murgolo, Nicholas; Barbieri, Christopher M.; Mann, Paul A.; Carr, Donna; Xia, Ellen; Painter, Ronald E.; Walker, Scott S.; Sherborne, Brad; de Jesus, Reynalda; Pan, Weidong; Plotkin, Michael A.; Wu, Jin; Rindgen, Diane; Cummings, John; Garlisi, Charles G.; Zhang, Rumin; Sheth, Payal R.; Gill, Charles J.; Tang, Haifeng; Roemer, Terry] Merck Res Labs, Kenilworth, NJ 07033 USA.
   [Nahvi, Ali] Merck Res Labs, West Point, PA 19486 USA.
   [Zuck, Paul; Riley, Dan] Merck Res Labs, N Wales, PA 19454 USA.
C3 Merck & Company; Merck & Company; Merck & Company
RP Roemer, T (corresponding author), Merck Res Labs, Kenilworth, NJ 07033 USA.
EM terry_roemer@merck.com
NR 41
TC 323
Z9 406
U1 9
U2 213
PU NATURE PUBLISHING 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 29
PY 2015
VL 526
IS 7575
BP 672
EP 677
DI 10.1038/nature15542
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CU8ZH
UT WOS:000363832100042
PM 26416753
DA 2026-03-09
ER

PT J
AU Mertens, J
   Wang, QW
   Kim, Y
   Yu, DX
   Pham, S
   Yang, B
   Zheng, Y
   Diffenderfer, KE
   Zhang, J
   Soltani, S
   Eames, T
   Schafer, ST
   Boyer, L
   Marchetto, MC
   Nurnberger, JI
   Calabrese, JR
   Odegaard, KJ
   McCarthy, MJ
   Zandi, PP
   Alba, M
   Nievergelt, CM
   Mi, SL
   Brennand, KJ
   Kelsoe, JR
   Gage, FH
   Yao, J
AF Mertens, Jerome
   Wang, Qiu-Wen
   Kim, Yongsung
   Yu, Diana X.
   Pham, Son
   Yang, Bo
   Zheng, Yi
   Diffenderfer, Kenneth E.
   Zhang, Jian
   Soltani, Sheila
   Eames, Tameji
   Schafer, Simon T.
   Boyer, Leah
   Marchetto, Maria C.
   Nurnberger, John I.
   Calabrese, Joseph R.
   Odegaard, Ketil J.
   McCarthy, Michael J.
   Zandi, Peter P.
   Alba, Martin
   Nievergelt, Caroline M.
   Mi, Shuangli
   Brennand, Kristen J.
   Kelsoe, John R.
   Gage, Fred H.
   Yao, Jun
TI Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder
SO NATURE
LA English
DT Article
ID protein-kinase-c; pyramidal neurons; receptor; behavior; brain; model
AB Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide(1). Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity(2). Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models', such as reduced glial cell number in the prefrontal cortex of patients(4), upregulated activities of the protein kinase A and C pathways(5-7) and changes in neurotransmission(8-11). However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca2+ imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.
C1 [Mertens, Jerome; Wang, Qiu-Wen; Yang, Bo; Zheng, Yi; Yao, Jun] Tsinghua Univ, Sch Life Sci, McGovern Inst Brain Res, State Key Lab Membrane Biol,Tsinghua Peking Joint, Beijing 100084, Peoples R China.
   [Mertens, Jerome; Kim, Yongsung; Yu, Diana X.; Pham, Son; Soltani, Sheila; Eames, Tameji; Schafer, Simon T.; Boyer, Leah; Marchetto, Maria C.; Gage, Fred H.; Yao, Jun] Salk Inst Biol Studies, Genet Lab, La Jolla, CA 92037 USA.
   [Diffenderfer, Kenneth E.] Salk Inst Biol Studies, Stem Cell Core, La Jolla, CA 92037 USA.
   [Zhang, Jian; Mi, Shuangli] Chinese Acad Sci, Beijing Inst Genom, Key Lab Genom & Precis Med, Beijing 100101, Peoples R China.
   [Nurnberger, John I.] Indiana Univ, Dept Psychiat, Indianapolis, IN 46202 USA.
   [Calabrese, Joseph R.] Case Western Reserve Univ, Dept Psychiat, Cleveland, OH 44106 USA.
   [Odegaard, Ketil J.] Univ Bergen, Dept Psychiat, N-5020 Bergen, Norway.
   [McCarthy, Michael J.; Kelsoe, John R.] VA San Diego Healthcare Syst, Dept Psychiat, La Jolla, CA 92151 USA.
   [McCarthy, Michael J.; Nievergelt, Caroline M.; Kelsoe, John R.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA.
   [Zandi, Peter P.] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD 21218 USA.
   [Alba, Martin] Dalhousie Univ, Dept Psychiat, Halifax, NS B3H 2E2, Canada.
   [Brennand, Kristen J.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA.
   [Yao, Jun] Jiangsu Normal Univ, Jiangsu Collaborat Innovat Ctr Language Abil, Xuzhou 221009, Peoples R China.
C3 Tsinghua University; Salk Institute; Salk Institute; Chinese Academy of Sciences; Beijing Institute of Genomics, CAS; Indiana University System; Indiana University Indianapolis; University System of Ohio; Case Western Reserve University; University of Bergen; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA San Diego Healthcare System; University of California System; University of California San Diego; Johns Hopkins University; Dalhousie University; Icahn School of Medicine at Mount Sinai; Jiangsu Normal University
RP Yao, J (corresponding author), Tsinghua Univ, Sch Life Sci, McGovern Inst Brain Res, State Key Lab Membrane Biol,Tsinghua Peking Joint, Beijing 100084, Peoples R China.
EM jkelsoe@ucsd.edu; gage@salk.edu; jyao@mail.tsinghua.edu.cn
FU National Natural Science Foundation of China [31471020, 31161120358, 31123004]; National Basic Research Program of China [2015CB910603, 2011CB510106]; Key Laboratory of Genomic and Precision Medicine, Chinese Academy of Sciences; Engmann Foundation; JPB Foundation; Helmsley Trust; Mather's Foundation; Glenn Foundation for Aging Research; National Institute of Health [MH106056]; New York Stem Cell Foundation - Robertson Award; National Institute of Mental Health [U01 MH92758]; Department of Veterans Affairs [5I01CX000363]; National Institute of Mental Health [R01MH106056] Funding Source: NIH RePORTER
NR 27
TC 428
Z9 489
U1 7
U2 221
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 5
PY 2015
VL 527
IS 7576
BP 95
EP 99
DI 10.1038/nature15526
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV4XV
UT WOS:000364270700050
PM 26524527
DA 2026-03-09
ER

PT J
AU Öberg, KI
   Guzmán, VV
   Furuya, K
   Qi, CH
   Aikawa, Y
   Andrews, SM
   Loomis, R
   Wilner, DJ
AF Oeberg, Karin I.
   Guzman, Viviana V.
   Furuya, Kenji
   Qi, Chunhua
   Aikawa, Yuri
   Andrews, Sean M.
   Loomis, Ryan
   Wilner, David J.
TI The comet-like composition of a protoplanetary disk as revealed by complex cyanides
SO NATURE
LA English
DT Article
ID t-tauri stars; co snow line; chemical-composition; x-ray; organic-molecules; imaging survey; amino-acids; low-mass; dm-tau; chemistry
AB Observations of comets and asteroids show that the solar nebula that spawned our planetary system was rich in water and organic molecules. Bombardment brought these organics to the young Earth's surface(1). Unlike asteroids, comets preserve a nearly pristine record of the solar nebula composition. The presence of cyanides in comets, including 0.01 per cent of methyl cyanide (CH3CN) with respect to water, is of special interest because of the importance of C-N bonds for abiotic amino acid synthesis(2). Comet-like compositions of simple and complex volatiles are found in protostars, and can readily be explained by a combination of gas-phase chemistry (to form, for example, HCN) and an active ice-phase chemistry on grain surfaces that advances complexity(3). Simple volatiles, including water and HCN, have been detected previously in solar nebula analogues, indicating that they survive disk formation or are re-formed in situ(4-7). It has hitherto been unclear whether the same holds for more complex organic molecules outside the solar nebula, given that recent observations show a marked change in the chemistry at the boundary between nascent envelopes and young disks due to accretion shocks(8). Here we report the detection of the complex cyanides CH3CN and HC3N (and HCN) in the protoplanetary disk around the young star MWC 480. We find that the abundance ratios of these nitrogen-bearing organics in the gas phase are similar to those in comets, which suggests an even higher relative abundance of complex cyanides in the disk ice. This implies that complex organics accompany simpler volatiles in protoplanetary disks, and that the rich organic chemistry of our solar nebula was not unique.
C1 [Oeberg, Karin I.; Guzman, Viviana V.; Qi, Chunhua; Andrews, Sean M.; Loomis, Ryan; Wilner, David J.] Harvard Smithsonian Ctr Astrophys, Cambridge, MA 02138 USA.
   [Furuya, Kenji] Leiden Univ, Leiden Observ, NL-2300 CA Leiden, Netherlands.
   [Aikawa, Yuri] Kobe Univ, Nada Ward, Kobe, Hyogo 6570013, Japan.
C3 Smithsonian Institution; Harvard University; Smithsonian Astrophysical Observatory; Leiden University - Excl LUMC; Leiden University; Kobe University
RP Öberg, KI (corresponding author), Harvard Smithsonian Ctr Astrophys, 60 Garden St, Cambridge, MA 02138 USA.
EM koberg@cfa.harvard.edu
FU Simons Collaboration on the Origins of Life (SCOL); Alfred P. Sloan Foundation; David and Lucile Packard Foundation; NASA Origins of Solar Systems [NNX11AK63]; Grants-in-Aid for Scientific Research [23540266, 23103004, 25108004] Funding Source: KAKEN
NR 57
TC 207
Z9 232
U1 0
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 APR 9
PY 2015
VL 520
IS 7546
BP 198
EP U128
DI 10.1038/nature14276
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CF3NA
UT WOS:000352454600033
PM 25855455
DA 2026-03-09
ER

PT J
AU Kato, HE
   Inoue, K
   Abe-Yoshizumi, R
   Kato, Y
   Ono, H
   Konno, M
   Hososhima, S
   Ishizuka, T
   Hoque, MR
   Kunitomo, H
   Ito, J
   Yoshizawa, S
   Yamashita, K
   Takemoto, M
   Nishizawa, T
   Taniguchi, R
   Kogure, K
   Maturana, AD
   Iino, Y
   Yawo, H
   Ishitani, R
   Kandori, H
   Nureki, O
AF Kato, Hideaki E.
   Inoue, Keiichi
   Abe-Yoshizumi, Rei
   Kato, Yoshitaka
   Ono, Hikaru
   Konno, Masae
   Hososhima, Shoko
   Ishizuka, Toru
   Hoque, Mohammad Razuanul
   Kunitomo, Hirofumi
   Ito, Jumpei
   Yoshizawa, Susumu
   Yamashita, Keitaro
   Takemoto, Mizuki
   Nishizawa, Tomohiro
   Taniguchi, Reiya
   Kogure, Kazuhiro
   Maturana, Andres D.
   Iino, Yuichi
   Yawo, Hiromu
   Ishitani, Ryuichiro
   Kandori, Hideki
   Nureki, Osamu
TI Structural basis for Na+ transport mechanism by a light-driven Na+ pump
SO NATURE
LA English
DT Article
ID chloride pump; proton pump; c-elegans; channelrhodopsin; rhodopsin; bacteriorhodopsin; xanthorhodopsin; halorhodopsin; activation; membrane
AB Krokinobacter eikastus rhodopsin 2 (KR2) is the first light-driven Na+ pump discovered, and is viewed as a potential next-generation optogenetics tool. Since the positively charged Schiff base proton, located within the ion-conducting pathway of all light-driven ion pumps, was thought to prohibit the transport of a non-proton cation, the discovery of KR2 raised the question of how it achieves Na+ transport. Here we present crystal structures of KR2 under neutral and acidic conditions, which represent the resting and M-like intermediate states, respectively. Structural and spectroscopic analyses revealed the gating mechanism, whereby the flipping of Asp116 sequesters the Schiff base proton from the conducting pathway to facilitate Na+ transport. Together with the structure-based engineering of the first light-driven K1 pumps, electrophysiological assays in mammalian neurons and behavioural assays in a nematode, our studies reveal the molecular basis for light-driven non-proton cation pumps and thus provide a framework that may advance the development of next-generation optogenetics.
C1 [Kato, Hideaki E.; Kunitomo, Hirofumi; Takemoto, Mizuki; Nishizawa, Tomohiro; Taniguchi, Reiya; Iino, Yuichi; Ishitani, Ryuichiro; Nureki, Osamu] Univ Tokyo, Grad Sch Sci, Dept Biol Sci, Bunkyo Ku, Tokyo 1130032, Japan.
   [Inoue, Keiichi; Abe-Yoshizumi, Rei; Kato, Yoshitaka; Ono, Hikaru; Konno, Masae; Kandori, Hideki] Nagoya Inst Technol, Dept Frontier Mat, Showa Ku, Nagoya, Aichi 4668555, Japan.
   [Inoue, Keiichi; Kandori, Hideki] Nagoya Inst Technol, OptoBioTechnol Res Ctr, Showa Ku, Nagoya, Aichi 4668555, Japan.
   [Inoue, Keiichi] Japan Sci & Technol Agcy, PRESTO, Kawaguchi, Saitama 3320012, Japan.
   [Hososhima, Shoko; Ishizuka, Toru; Hoque, Mohammad Razuanul; Yawo, Hiromu] Tohoku Univ, Grad Sch Life Sci, Dept Dev Biol & Neurosci, Sendai, Miyagi 9808577, Japan.
   [Hososhima, Shoko; Ishizuka, Toru; Hoque, Mohammad Razuanul; Iino, Yuichi; Yawo, Hiromu] Japan Sci & Technol Agcy, CREST, Kawaguchi, Saitama 3320012, Japan.
   [Ito, Jumpei] Nagoya Univ, Grad Sch Bioagr Sci, Dept Bioengn Sci, Chikusa Ku, Nagoya, Aichi 4648601, Japan.
   [Yoshizawa, Susumu; Kogure, Kazuhiro] Univ Tokyo, Atmosphere & Ocean Res Inst, Kashiwa, Chiba 2778564, Japan.
   [Yamashita, Keitaro] RIKEN SPring 8 Ctr, Mikazuki, Hyogo 6795148, Japan.
C3 University of Tokyo; Nagoya Institute of Technology; Nagoya Institute of Technology; Japan Science & Technology Agency (JST); Tohoku University; Japan Science & Technology Agency (JST); Nagoya University; University of Tokyo; RIKEN
RP Nureki, O (corresponding author), Univ Tokyo, Grad Sch Sci, Dept Biol Sci, Bunkyo Ku, 2-11-16 Yayoi, Tokyo 1130032, Japan.
EM kandori@nitech.ac.jp; nureki@bs.s.u-tokyo.ac.jp
FU Platform for Drug Discovery, Informatics and Structural Life Science, of the Ministry of Education, Culture, Sports, Science and Technology (MEXT); JSPS KAKENHI [11J06643, 24115508, 24655009, 25104009, 24681003, 24227004, 25291011]; FIRST program, PRESTO, CREST, JST; Grants-in-Aid for Scientific Research [25115701, 15J08129, 26620005, 26115706, 15K15025, 25670103, 26291069, 15H02800, 25250001, 22247024, 25104009, 14J40214, 24655009, 25115010, 15H01413, 15J06631, 25620011, 25115707, 26430007, 26708001, 24681003, 11J06643, 24115508, 15H02391] Funding Source: KAKEN
NR 48
TC 190
Z9 219
U1 2
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 MAY 7
PY 2015
VL 521
IS 7550
BP 48
EP U347
DI 10.1038/nature14322
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH4YS
UT WOS:000354040900029
PM 25849775
DA 2026-03-09
ER

PT J
AU McConnell, R
   Zhang, H
   Hu, JZ
   Cuk, S
   Vuletic, V
AF McConnell, Robert
   Zhang, Hao
   Hu, Jiazhong
   Cuk, Senka
   Vuletic, Vladan
TI Entanglement with negative Wigner function of almost 3,000 atoms heralded by one photon
SO NATURE
LA English
DT Article
ID standard quantum limit; schrodinger cat state; spin states; ensembles; communication; information; generation; optics
AB Quantum-mechanically correlated (entangled) states of many particles are of interest in quantum information, quantum computing and quantum metrology. Metrologically useful entangled states of large atomic ensembles have been experimentally realized(1-10), but these states display Gaussian spin distribution functions with a non-negative Wigner quasiprobability distribution function. Non-Gaussian entangled states have been produced in small ensembles of ions(11,12), and very recently in large atomic ensembles(13-15). Here we generate entanglement in a large atomic ensemble via an interaction with a very weak laser pulse; remarkably, the detection of a single photon prepares several thousand atoms in an entangled state. We reconstruct a negative-valued Wigner function-an important hallmark of non-classicality-and verify an entanglement depth (the minimum number of mutually entangled atoms) of 2,9106190 out of 3,100 atoms. Attaining such a negative Wigner function and the mutual entanglement of virtually all atoms is unprecedented for an ensemble containing more than a few particles. Although the achieved purity of the state is slightly below the threshold for entanglement-induced metrological gain, further technical improvement should allow the generation of states that surpass this threshold, and of more complex Schrodinger cat states for quantum metrology and information processing. More generally, our results demonstrate the power of heralded methods for entanglement generation, and illustrate how the information contained in a single photon can drastically alter the quantum state of a large system.
C1 [McConnell, Robert; Zhang, Hao; Hu, Jiazhong; Cuk, Senka; Vuletic, Vladan] MIT, Dept Phys, MIT Harvard Ctr Ultracold Atoms, Cambridge, MA 02139 USA.
   [McConnell, Robert; Zhang, Hao; Hu, Jiazhong; Cuk, Senka; Vuletic, Vladan] MIT, Elect Res Lab, Cambridge, MA 02139 USA.
   [Cuk, Senka] Univ Belgrade, Inst Phys, Belgrade 11080, Serbia.
C3 Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); University of Belgrade
RP Vuletic, V (corresponding author), MIT, Dept Phys, MIT Harvard Ctr Ultracold Atoms, Cambridge, MA 02139 USA.
EM vuletic@mit.edu
FU NSF; DARPA (QUASAR); MURI grant through AFOSR; Ministry of Education, Science and Technological Development of the Republic of Serbia [III45016, OI171038]; Division Of Physics; Direct For Mathematical & Physical Scien [1505862, 1125846, 1205554] Funding Source: National Science Foundation
NR 31
TC 179
Z9 201
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 26
PY 2015
VL 519
IS 7544
BP 439
EP +
DI 10.1038/nature14293
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE1WF
UT WOS:000351602800049
PM 25810205
DA 2026-03-09
ER

PT J
AU Lori, C
   Ozaki, S
   Steiner, S
   Böhm, R
   Abel, S
   Dubey, BN
   Schirmer, T
   Hiller, S
   Jenal, U
AF Lori, C.
   Ozaki, S.
   Steiner, S.
   Boehm, R.
   Abel, S.
   Dubey, B. N.
   Schirmer, T.
   Hiller, S.
   Jenal, U.
TI Cyclic di-GMP acts as a cell cycle oscillator to drive chromosome replication
SO NATURE
LA English
DT Article
ID bacterial-dna replication; caulobacter-crescentus; dependent kinases; diguanylate cyclase; response regulator; polar localization; histidine kinases; protein; phosphorylation; progression
AB Fundamental to all living organisms is the capacity to coordinate cell division and cell differentiation to generate appropriate numbers of specialized cells. Whereas eukaryotes use cyclins and cyclin-dependent kinases to balance division with cell fate decisions(1), equivalent regulatory systems have not been described in bacteria. Moreover, the mechanisms used by bacteria to tune division in line with developmental programs are poorly understood. Here we show that Caulobacter crescentus, a bacterium with an asymmetric division cycle, uses oscillating levels of the second messenger cyclic diguanylate (c-di-GMP) to drive its cell cycle. We demonstrate that c-diGMP directly binds to the essential cell cycle kinase CckA to inhibit kinase activity and stimulate phosphatase activity. An upshift of c-di-GMP during the G1-S transition switches CckA from the kinase to the phosphatase mode, thereby allowing replication initiation and cell cycle progression. Finally, we show that during division, c-di-GMP imposes spatial control on CckA to install the replication asymmetry of future daughter cells. These studies reveal c-di-GMP to be a cyclin-like molecule in bacteria that coordinates chromosome replication with cell morphogenesis in Caulobacter. The observation that c-di-GMP-mediated control is conserved in the plant pathogen Agrobacterium tumefaciens suggests a general mechanism through which this global regulator of bacterial virulence and persistence coordinates behaviour and cell proliferation.
C1 [Lori, C.; Ozaki, S.; Steiner, S.; Abel, S.; Jenal, U.] Univ Basel, Biozentrum, Focal Area Infect Biol, CH-4056 Basel, Switzerland.
   [Boehm, R.; Dubey, B. N.; Schirmer, T.; Hiller, S.] Univ Basel, Biozentrum, Focal Area Struct Biol & Biophys, CH-4056 Basel, Switzerland.
C3 University of Basel; University of Basel
RP Jenal, U (corresponding author), Univ Basel, Biozentrum, Focal Area Infect Biol, CH-4056 Basel, Switzerland.
EM urs.jenal@unibas.ch
FU Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellowships; Swiss National Science Foundation [310030B_147090]; ERC Advanced Research Grant; Swiss National Science Foundation (SNF) [310030B_147090] Funding Source: Swiss National Science Foundation (SNF)
NR 46
TC 146
Z9 184
U1 0
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 JUL 9
PY 2015
VL 523
IS 7559
BP 236
EP U278
DI 10.1038/nature14473
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM4ZO
UT WOS:000357695900040
PM 25945741
DA 2026-03-09
ER

PT J
AU Waclaw, B
   Bozic, I
   Pittman, ME
   Hruban, RH
   Vogelstein, B
   Nowak, MA
AF Waclaw, Bartlomiej
   Bozic, Ivana
   Pittman, Meredith E.
   Hruban, Ralph H.
   Vogelstein, Bert
   Nowak, Martin A.
TI A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity
SO NATURE
LA English
DT Article
ID growth in-vitro; stochastic-models; drug-resistance; acquired-resistance; waiting time; hybrid model; cancer; evolution; dynamics; progression
AB Most cancers in humans are large, measuring centimetres in diameter, and composed of many billions of cells(1). An equivalent mass of normal cells would be highly heterogeneous as a result of the mutations that occur during each cell division. What is remarkable about cancers is that virtually every neoplastic cell within a large tumour often contains the same core set of genetic alterations, with heterogeneity confined to mutations that emerge late during tumour growth(2-5). How such alterations expand within the spatially constrained three-dimensional architecture of a tumour, and come to dominate a large, pre-existing lesion, has been unclear. Here we describe a model for tumour evolution that shows how short-range dispersal and cell turnover can account for rapid cell mixing inside the tumour. We show that even a small selective advantage of a single cell within a large tumour allows the descendants of that cell to replace the precursor mass in a clinically relevant time frame. We also demonstrate that the same mechanisms can be responsible for the rapid onset of resistance to chemotherapy. Our model not only provides insights into spatial and temporal aspects of tumour growth, but also suggests that targeting short-range cellular migratory activity could have marked effects on tumour growth rates.
C1 [Waclaw, Bartlomiej] Univ Edinburgh, Sch Phys & Astron, Edinburgh EH9 3FD, Midlothian, Scotland.
   [Bozic, Ivana; Nowak, Martin A.] Harvard Univ, Program Evolutionary Dynam, Cambridge, MA 02138 USA.
   [Bozic, Ivana; Nowak, Martin A.] Harvard Univ, Dept Math, Cambridge, MA 02138 USA.
   [Pittman, Meredith E.; Hruban, Ralph H.; Vogelstein, Bert] Johns Hopkins Univ, Sch Med, Dept Pathol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21231 USA.
   [Vogelstein, Bert] Ludwig Ctr, Baltimore, MD 21287 USA.
   [Vogelstein, Bert] Howard Hughes Med Inst, Johns Hopkins Kimmel Canc Ctr, Baltimore, MD 21287 USA.
   [Nowak, Martin A.] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA.
C3 University of Edinburgh; Harvard University; Harvard University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins Medicine; Howard Hughes Medical Institute; Harvard University
RP Nowak, MA (corresponding author), Harvard Univ, Program Evolutionary Dynam, 1 Brattle Sq, Cambridge, MA 02138 USA.
EM martin_nowak@harvard.edu
FU John Templeton Foundation; Leverhulme Trust Early-Career Fellowship; Royal Society of Edinburgh Personal Research Fellowship; Foundational Questions in Evolutionary Biology [RFP-12-17]; Virginia and D.K. Ludwig Fund for Cancer Research; Lustgarten Foundation for Pancreatic Cancer Research; Sol Goldman Center for Pancreatic Cancer Research; NIH [CA43460, CA62924]; National Cancer Institute [P30CA006973, P50CA062924] Funding Source: NIH RePORTER
NR 100
TC 364
Z9 423
U1 2
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 SEP 10
PY 2015
VL 525
IS 7568
BP 261
EP +
DI 10.1038/nature14971
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CQ9IM
UT WOS:000360927400041
PM 26308893
DA 2026-03-09
ER

PT J
AU Nomura, N
   Verdon, G
   Kang, HJ
   Shimamura, T
   Nomura, Y
   Sonoda, Y
   Hussien, SA
   Qureshi, AA
   Coincon, M
   Sato, Y
   Abe, H
   Nakada-Nakura, Y
   Hino, T
   Arakawa, T
   Kusano-Arai, O
   Iwanari, H
   Murata, T
   Kobayashi, T
   Hamakubo, T
   Kasahara, M
   Iwata, S
   Drew, D
AF Nomura, Norimichi
   Verdon, Gregory
   Kang, Hae Joo
   Shimamura, Tatsuro
   Nomura, Yayoi
   Sonoda, Yo
   Hussien, Saba Abdul
   Qureshi, Aziz Abdul
   Coincon, Mathieu
   Sato, Yumi
   Abe, Hitomi
   Nakada-Nakura, Yoshiko
   Hino, Tomoya
   Arakawa, Takatoshi
   Kusano-Arai, Osamu
   Iwanari, Hiroko
   Murata, Takeshi
   Kobayashi, Takuya
   Hamakubo, Takao
   Kasahara, Michihiro
   Iwata, So
   Drew, David
TI Structure and mechanism of the mammalian fructose transporter GLUT5
SO NATURE
LA English
DT Article
ID cysteine-scanning mutagenesis; glucose-transporter; functional-characterization; crystal-structure; small-intestine; hexose transporter; sugar-transport; membrane; family; sequence
AB The altered activity of the fructose transporter GLUT5, an isoform of the facilitated-diffusion glucose transporter family, has been linked to disorders such as type 2 diabetes and obesity. GLUT5 is also overexpressed in certain tumour cells, and inhibitors are potential drugs for these conditions. Here we describe the crystal structures of GLUT5 from Rattus norvegicus and Bos taurus in open outward-and open inward-facing conformations, respectively. GLUT5 has a major facilitator superfamily fold like other homologous monosaccharide transporters. On the basis of a comparison of the inward-facing structures of GLUT5 and human GLUT1, a ubiquitous glucose transporter, we show that a single point mutation is enough to switch the substrate-binding preference of GLUT5 from fructose to glucose. A comparison of the substrate-free structures of GLUT5 with occluded substrate-bound structures of Escherichia coli XylE suggests that, in addition to global rocker-switch-like re-orientation of the bundles, local asymmetric rearrangements of carboxy-terminal transmembrane bundle helices TM7 and TM10 underlie a 'gated-pore' transport mechanism in such monosaccharide transporters.
C1 [Nomura, Norimichi; Shimamura, Tatsuro; Nomura, Yayoi; Sato, Yumi; Abe, Hitomi; Nakada-Nakura, Yoshiko; Hino, Tomoya; Arakawa, Takatoshi; Murata, Takeshi; Kobayashi, Takuya; Iwata, So] Kyoto Univ, Grad Sch Med, Dept Cell Biol, Sakyo Ku, Kyoto 6068501, Japan.
   [Nomura, Norimichi; Shimamura, Tatsuro; Nomura, Yayoi; Hino, Tomoya; Arakawa, Takatoshi; Murata, Takeshi; Kobayashi, Takuya; Iwata, So] Japan Sci & Technol Agcy, ERATO, Iwata Human Receptor Crystallog Project, Sakyo Ku, Kyoto 6068501, Japan.
   [Nomura, Norimichi; Shimamura, Tatsuro; Nomura, Yayoi; Nakada-Nakura, Yoshiko; Murata, Takeshi; Kobayashi, Takuya; Iwata, So] Japan Sci & Technol Agcy, Res Accelerat Program, Membrane Prot Crystallog Project, Sakyo Ku, Kyoto 6068501, Japan.
   [Verdon, Gregory; Kang, Hae Joo; Sonoda, Yo; Iwata, So; Drew, David] Univ London Imperial Coll Sci Technol & Med, Div Mol Biosci, London SW7 2AZ, England.
   [Verdon, Gregory; Kang, Hae Joo; Iwata, So] Diamond Light Source, Membrane Prot Lab, Chilton OX11 0DE, Oxon, England.
   [Verdon, Gregory; Kang, Hae Joo; Iwata, So] Rutherford Appleton Lab, Res Complex Harwell, Didcot OX11 0FA, Oxon, England.
   [Hussien, Saba Abdul; Qureshi, Aziz Abdul; Coincon, Mathieu; Drew, David] Stockholm Univ, Dept Biochem & Biophys, Ctr Biomembrane Res, SE-10691 Stockholm, Sweden.
   [Kusano-Arai, Osamu; Hamakubo, Takao] Univ Tokyo, Dept Quantitat Biol & Med, Res Ctr Adv Sci & Technol, Meguro Ku, Tokyo 1538904, Japan.
   [Murata, Takeshi; Iwata, So] RIKEN, Syst & Struct Biol Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan.
   [Kasahara, Michihiro] Teikyo Univ, Sch Med, Biophys Lab, Hachioji, Tokyo 1920395, Japan.
C3 Kyoto University; Japan Science & Technology Agency (JST); Japan Science & Technology Agency (JST); Imperial College London; Diamond Light Source; UK Research & Innovation (UKRI); Science & Technology Facilities Council (STFC); STFC Rutherford Appleton Laboratory; Stockholm University; University of Tokyo; RIKEN; Teikyo University
RP Nomura, N (corresponding author), Kyoto Univ, Grad Sch Med, Dept Cell Biol, Sakyo Ku, Konoe Cho, Kyoto 6068501, Japan.
EM nnomura@mfour.med.kyoto-u.ac.jp; s.iwata@mfour.med.kyoto-u.ac.jp; ddrew@dbb.su.se
FU Knut and Alice Wallenberg Foundation; Royal Society; BBSRC [BB/G02325/1]; ERATO Human Receptor Crystallography Project of the Japan Science and Technology Agency (JST); Research Acceleration Program of the JST; Targeted Proteins Research Program of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; MEXT [22570114]; MEXT; Wellcome Trust at the Diamond Light Source Limited [062164/Z/00/Z]; Centre for Biomembrane Research (CBR) - Swedish Foundation for Strategic Research; Human Frontiers Postdoctoral fellowship; EMBO through Young Investigator Program (YIP); BBSRC [BB/G023425/1] Funding Source: UKRI; Grants-in-Aid for Scientific Research [24108007, 15K06968, 25711004, 26102725, 15H04338] Funding Source: KAKEN; Biotechnology and Biological Sciences Research Council [BB/G023425/1] Funding Source: researchfish
NR 55
TC 194
Z9 223
U1 2
U2 136
PU NATURE PUBLISHING 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 15
PY 2015
VL 526
IS 7573
BP 397
EP +
DI 10.1038/nature14909
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CT3TQ
UT WOS:000362730200044
PM 26416735
DA 2026-03-09
ER

PT J
AU Otchy, TM
   Wolff, SBE
   Rhee, JY
   Pehlevan, C
   Kawai, R
   Kempf, A
   Gobes, SMH
   Ölveczky, BP
AF Otchy, Timothy M.
   Wolff, Steffen B. E.
   Rhee, Juliana Y.
   Pehlevan, Cengiz
   Kawai, Risa
   Kempf, Alexandre
   Gobes, Sharon M. H.
   Oelveczky, Bence P.
TI Acute off-target effects of neural circuit manipulations
SO NATURE
LA English
DT Article
ID homeostatic plasticity; memory consolidation; zebra finches; motor cortex; in-vivo; songbird; networks; nucleus; lesions; model
AB Rapid and reversible manipulations of neural activity in behaving animals are transforming our understanding of brain function. An important assumption underlying much of this work is that evoked behavioural changes reflect the function of the manipulated circuits. We show that this assumption is problematic because it disregards indirect effects on the independent functions of downstream circuits. Transient inactivations of motor cortex in rats and nucleus interface (Nif) in songbirds severely degraded task-specific movement patterns and courtship songs, respectively, which are learned skills that recover spontaneously after permanent lesions of the same areas. We resolve this discrepancy in songbirds, showing that Nif silencing acutely affects the function of HVC, a downstream song control nucleus. Paralleling song recovery, the off-target effects resolved within days of Nif lesions, a recovery consistent with homeostatic regulation of neural activity in HVC. These results have implications for interpreting transient circuit manipulations and for understanding recovery after brain lesions.
C1 [Otchy, Timothy M.; Wolff, Steffen B. E.; Rhee, Juliana Y.; Kawai, Risa; Kempf, Alexandre; Gobes, Sharon M. H.; Oelveczky, Bence P.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA.
   [Otchy, Timothy M.] Harvard Univ, Program Neurosci, Cambridge, MA 02138 USA.
   [Pehlevan, Cengiz] Simons Fdn, Ctr Computat Biol, New York, NY 10010 USA.
   [Oelveczky, Bence P.] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA.
C3 Harvard University; Harvard University; Simons Foundation; Harvard University
RP Ölveczky, BP (corresponding author), Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA.
EM olveczky@fas.harvard.edu
FU McKnight Scholars Award; HSFP fellowship; EMBO fellowship; NRSA fellowship; Rubicon fellowship from the Netherlands Organization for Scientific Research
NR 58
TC 259
Z9 310
U1 0
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 DEC 17
PY 2015
VL 528
IS 7582
BP 358
EP +
DI 10.1038/nature16442
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CY8SM
UT WOS:000366678600044
PM 26649821
DA 2026-03-09
ER

PT J
AU Grallert, A
   Boke, E
   Hagting, A
   Hodgson, B
   Connolly, Y
   Griffiths, JR
   Smith, DL
   Pines, J
   Hagan, IM
AF Grallert, Agnes
   Boke, Elvan
   Hagting, Anja
   Hodgson, Ben
   Connolly, Yvonne
   Griffiths, John R.
   Smith, Duncan L.
   Pines, Jonathon
   Hagan, Iain M.
TI A PP1-PP2A phosphatase relay controls mitotic progression
SO NATURE
LA English
DT Article
ID xenopus egg extracts; cell-division cycle; protein phosphatase; schizosaccharomyces-pombe; m-phase; 2a; phosphorylation; kinase; holoenzyme; gene
AB The widespread reorganization of cellular architecture in mitosis is achieved through extensive protein phosphorylation, driven by the coordinated activation of a mitotic kinase network and repression of counteracting phosphatases. Phosphatase activity must subsequently be restored to promote mitotic exit. Although Cdc14 phosphatase drives this reversal in budding yeast, protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) activities have each been independently linked to mitotic exit control in other eukaryotes(1-6). Here we describe a mitotic phosphatase relay in which PP1 reactivation is required for the reactivation of both PP2A-B55 and PP2A-B56 to coordinate mitotic progression and exit in fission yeast. The staged recruitment of PP1 (the Dis2 isoform) to the regulatory sub-units of the PP2A-B55 and PP2A-B56 (B55 also known as Pab1; B56 also known as Par1) holoenzymes sequentially activates each phosphatase. The pathway is blocked in early mitosis because the Cdk1-cyclin B kinase (Cdk1 also known as Cdc2) inhibits PP1 activity, but declining cyclin B levels later in mitosis permit PP1 to auto-reactivate(1,7-10). PP1 first reactivates PP2A-B55; this enables PP2A-B55 in turn to promote the reactivation of PP2A-B56 by dephosphorylating a PP1-docking site in PP2A-B56, thereby promoting the recruitment of PP1. PP1 recruitment to human, mitotic PP2A-B56 holoenzymes and the sequences of these conserved PP1-docking motifs(11,12) suggest that PP1 regulates PP2A-B55 and PP2A-B56 activities in a variety of signalling contexts throughout eukaryotes.
C1 [Grallert, Agnes; Boke, Elvan; Hodgson, Ben; Hagan, Iain M.] Univ Manchester, CRUK Manchester Inst, Cell Div Grp, Manchester M20 4BX, Lancs, England.
   [Hagting, Anja; Pines, Jonathon] Univ Cambridge, Gurdon Inst, Cambridge CB2 1QN, England.
   [Connolly, Yvonne; Griffiths, John R.; Smith, Duncan L.] Univ Manchester, CRUK Manchester Inst, Manchester M20 4BX, Lancs, England.
C3 University of Manchester; University of Cambridge; University of Manchester
RP Hagan, IM (corresponding author), Univ Manchester, CRUK Manchester Inst, Cell Div Grp, Wilmslow Rd, Manchester M20 4BX, Lancs, England.
EM Iain.Hagan@cruk.manchester.ac.uk
FU Cancer Research UK (CRUK) [C147/A16406, C29/A13678]; Cancer Research UK [13678, 16406] Funding Source: researchfish
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NR 47
TC 154
Z9 183
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 JAN 1
PY 2015
VL 517
IS 7532
BP 94
EP U248
DI 10.1038/nature14019
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AX8SI
UT WOS:000347178400042
PM 25487150
DA 2026-03-09
ER

PT J
AU Huang, WJ
   Manglik, A
   Venkatakrishnan, AJ
   Laeremans, T
   Feinberg, EN
   Sanborn, AL
   Kato, HE
   Livingston, KE
   Thorsen, TS
   Kling, RC
   Granier, S
   Gmeiner, P
   Husbands, SM
   Traynor, JR
   Weis, WI
   Steyaert, J
   Dror, RO
   Kobilka, BK
AF Huang, Weijiao
   Manglik, Aashish
   Venkatakrishnan, A. J.
   Laeremans, Toon
   Feinberg, Evan N.
   Sanborn, Adrian L.
   Kato, Hideaki E.
   Livingston, Kathryn E.
   Thorsen, Thor S.
   Kling, Ralf C.
   Granier, Sebastien
   Gmeiner, Peter
   Husbands, Stephen M.
   Traynor, John R.
   Weis, William I.
   Steyaert, Jan
   Dror, Ron O.
   Kobilka, Brian K.
TI Structural insights into μ-opioid receptor activation
SO NATURE
LA English
DT Article
ID crystallizing membrane-proteins; dynamic process; mice lacking; force-field; complex; binding; charmm; model; validation; rhodopsin
AB Activation of the mu-opioid receptor (mu OR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for mu OR activation, here we report a 2.1 angstrom X-ray crystal structure of the murine mu OR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the mu OR binding pocket are subtle and differ from those observed for agonist-bound structures of the beta(2)-adrenergic receptor (beta(2)AR) and the M2 muscarinic receptor. Comparison with active beta(2)AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the mu OR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled receptors.
C1 [Huang, Weijiao; Manglik, Aashish; Venkatakrishnan, A. J.; Feinberg, Evan N.; Sanborn, Adrian L.; Kato, Hideaki E.; Thorsen, Thor S.; Weis, William I.; Dror, Ron O.; Kobilka, Brian K.] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
   [Venkatakrishnan, A. J.; Feinberg, Evan N.; Sanborn, Adrian L.; Dror, Ron O.] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA.
   [Venkatakrishnan, A. J.; Feinberg, Evan N.; Sanborn, Adrian L.; Dror, Ron O.] Stanford Univ, Inst Computat & Math Engn, Stanford, CA 94305 USA.
   [Laeremans, Toon; Steyaert, Jan] Vrije Univ Brussel, Struct Biol Brussels, B-1050 Brussels, Belgium.
   [Laeremans, Toon; Steyaert, Jan] VIB, Struct Biol Res Ctr, B-1050 Brussels, Belgium.
   [Livingston, Kathryn E.; Traynor, John R.] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA.
   [Kling, Ralf C.; Gmeiner, Peter] Univ Erlangen Nurnberg, Dept Chem & Pharm, D-91052 Erlangen, Germany.
   [Granier, Sebastien] Univ Montpellier, Inst Genom Fonct, CNRS, UMR 5203,INSERM,U1191, F-34000 Montpellier, France.
   [Husbands, Stephen M.] Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England.
   [Weis, William I.] Stanford Univ, Sch Med, Dept Struct Biol, Stanford, CA 94305 USA.
C3 Stanford University; Stanford University; Stanford University; Vrije Universiteit Brussel; Flanders Institute for Biotechnology (VIB); University of Michigan System; University of Michigan; University of Erlangen Nuremberg; 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); University of Bath; Stanford University
RP Manglik, A (corresponding author), Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, 279 CampusDrive, Stanford, CA 94305 USA.
EM amanglik@stanford.edu; kobilka@stanford.edu
FU Stanford Medical Scientist Training Program; American Heart Association; National Institutes of Health [R37DA036246, R01GM083118]; Terman Faculty Fellowship; Eli Lilly and Company through the Lilly Research Program; Mathers Foundation; National Institute of General Medical Sciences [R01GM083118] Funding Source: NIH RePORTER
NR 64
TC 727
Z9 842
U1 3
U2 244
PU NATURE PUBLISHING 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 20
PY 2015
VL 524
IS 7565
BP 315
EP +
DI 10.1038/nature14886
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP2NN
UT WOS:000359714000028
PM 26245379
DA 2026-03-09
ER

PT J
AU Prost, S
   Relouzat, F
   Spentchian, M
   Ouzegdouh, Y
   Saliba, J
   Massonnet, G
   Beressi, JP
   Verhoeyen, E
   Raggueneau, V
   Maneglier, B
   Castaigne, S
   Chomienne, C
   Chrétien, S
   Rousselot, P
   Leboulch, P
AF Prost, Stephane
   Relouzat, Francis
   Spentchian, Marc
   Ouzegdouh, Yasmine
   Saliba, Joseph
   Massonnet, Gerald
   Beressi, Jean-Paul
   Verhoeyen, Els
   Raggueneau, Victoria
   Maneglier, Benjamin
   Castaigne, Sylvie
   Chomienne, Christine
   Chretien, Stany
   Rousselot, Philippe
   Leboulch, Philippe
TI Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists
SO NATURE
LA English
DT Article
ID imatinib; stat5; pathway; cited2; hematopoiesis; hif-1-alpha; inhibition; quiescence; activation; resistance
AB Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology(1). In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. Chronic myeloid leukaemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL(2). During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph+: t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukaemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL have improved patient survival markedly. However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined as the point when BCR-ABL transcripts become undetectable in blood cells(3). Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukaemia stem cells (LSCs)(2-4). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor-gamma (PPAR gamma). We found that activation of PPAR gamma by the glitazones decreases expression of STAT5 and its downstreamtargets HIF2 alpha(5) and CITED2(6), which are key guardians of the quiescence and stemness of CML LSCs. When pioglitazone was given temporarily to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool.
C1 [Prost, Stephane; Relouzat, Francis; Ouzegdouh, Yasmine; Saliba, Joseph; Chretien, Stany; Leboulch, Philippe] Inst Emerging Dis & Innovat Therapies iMETI, CEA, F-92265 Fontenay Aux Roses, France.
   [Spentchian, Marc] Hop Mignot, Dept Biol Med, F-78150 Le Chesnay, France.
   [Massonnet, Gerald; Chomienne, Christine; Rousselot, Philippe] Univ Paris Diderot, Hop St Louis,Inst Univ Hematol, UMR S 940, Unite Biol Cellulaire, F-75010 Paris, France.
   [Beressi, Jean-Paul] Hop Mignot, Serv Endocrinol & Diabetol, F-78150 Le Chesnay, France.
   [Verhoeyen, Els] Univ Lyon 1, CNRS, Int Ctr Infectiol Res,ENS Lyon, CIRI,EVIR Team,Inserm,U1111,UMR5308, F-69007 Lyon, France.
   [Verhoeyen, Els] INSERM, U895, Ctr Med Mol C3M, Equipe 3, F-06204 Nice, France.
   [Raggueneau, Victoria] Ctr Hosp Versailles, Lab Hematol, F-78150 Le Chesnay, France.
   [Maneglier, Benjamin] Ctr Hosp Versailles, Serv Biol Med, Unite Pharmacol, F-78150 Le Chesnay, France.
   [Castaigne, Sylvie; Chomienne, Christine; Rousselot, Philippe] Univ Versailles St Quentin En Yvelines, Serv Hematol & Oncol, Hop Mignot, F-78150 Le Chesnay, France.
   [Chretien, Stany] Inst Emerging Dis & Innovat Therapies iMETI, INSERM, F-92265 Fontenay Aux Roses, France.
   [Leboulch, Philippe] Brigham & Womens Hosp, Genet Div, Boston, MA 02115 USA.
   [Leboulch, Philippe] Harvard Univ, Sch Med, Boston, MA 02115 USA.
   [Leboulch, Philippe] Ramathibodi Hosp, Hematol Div, Bangkok 10400, Thailand.
   [Leboulch, Philippe] Mahidol Univ, Bangkok 10400, Thailand.
C3 Universite Paris Saclay; CEA; Centre Hospitalier de Versailles; Universite Paris Cite; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Saint-Louis - APHP; Centre Hospitalier de Versailles; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Ecole Normale Superieure de Lyon (ENS de LYON); Universite Lyon 1; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Cote d'Azur; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre Hospitalier de Versailles; Universite Paris Saclay; Universite Paris Saclay; Centre Hospitalier de Versailles; Universite Paris Saclay; Centre Hospitalier de Versailles; Universite Paris Saclay; CEA; Institut National de la Sante et de la Recherche Medicale (Inserm); Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Mahidol University; Mahidol University
RP Prost, S (corresponding author), Inst Emerging Dis & Innovat Therapies iMETI, CEA, F-92265 Fontenay Aux Roses, France.
EM stephane.prost@cea.fr; pleboulch@rics.bwh.harvard.edu
FU Association Laurette Fugain, Paris, France; Association pour la Recherche sur le Cancer, Villejuif, France; Chaire industrielle de l'Agence Nationale pour la Recherche (ANR)
NR 36
TC 239
Z9 256
U1 0
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 SEP 17
PY 2015
VL 525
IS 7569
BP 380
EP +
DI 10.1038/nature15248
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CR4JL
UT WOS:000361297900044
PM 26331539
DA 2026-03-09
ER

PT J
AU Hu, QC
AF Hu, Qichao
TI The renaissance of lithium metal: SolidEnergy's role in the future of lithium batteries
SO NATURE
LA English
DT Article
ID electrolytes
C1 SolidEnergy Syst Corp, Waltham, MA 02451 USA.
RP Hu, QC (corresponding author), SolidEnergy Syst Corp, 200 West St, Waltham, MA 02451 USA.
NR 12
TC 8
Z9 9
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 OCT 29
PY 2015
VL 526
IS 7575
BP 
EP 
DI 
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CU8ZH
UT WOS:000363832100030
DA 2026-03-09
ER

PT J
AU Hermann, B
   Kern, M
   La Pietra, L
   Simon, J
   Einsle, O
AF Hermann, Bianca
   Kern, Melanie
   La Pietra, Luigi
   Simon, Joerg
   Einsle, Oliver
TI The octahaem MccA is a haem c-copper sulfite reductase
SO NATURE
LA English
DT Article
ID cytochrome-c; nitrite reductase; hydroxylamine oxidoreductase; wolinella-succinogenes; resolution; bacterium; binding; enzyme; lyase
AB The six-electron reduction of sulfite to sulfide is the pivot point of the biogeochemical cycle of the element sulfur'. The octahaem cytochrome c MccA (also known as SirA) catalyses this reaction for dissimilatory sulfite utilization by various bacteria. It is distinct from known sulfite reductases because it has a substantially higher catalytic activity and a relatively low reactivity towards nitrite. The mechanistic reasons for the increased efficiency of MccA remain to be elucidated. Here we show that anoxically purified MccA exhibited a 2- to 5.5-fold higher specific sulfite reductase activity than the enzyme isolated under oxic conditions2. We determined the threedimensional structure of MccA to 2.2 A resolution by single-wavelength anomalous dispersion. We find a homotrimer with an unprecedented fold and haem arrangement, as well as a haem bound to a CX15CH motif'. The heterobimetallic active-site haem 2 has a Cu(I) ion juxtaposed to a haem cat a Fe-Cu distance of 4.4 A. While the combination of metals is reminiscent of respiratory haem-copper oxidases, the oxidation-labile Cu(I) centre of MccA did not seem to undergo a redox transition during catalysis. Intact MccA tightly bound SO2 at haem 2, a dehydration product of the substrate sulfite that was partially turned over due to photoreduction by X-ray irradiation, yielding the reaction intermediate SO. Our data show the biometal copper in a new context and function and provide a chemical rationale for the comparatively high catalytic activity of MccA.
C1 [Hermann, Bianca; Einsle, Oliver] Univ Freiburg, Inst Biochem, Lehrstuhl Biochem, D-79104 Freiburg, Germany.
   [Kern, Melanie; La Pietra, Luigi; Simon, Joerg] Tech Univ Darmstadt, Dept Biol, Microbial Energy Convers & Biotechnol, D-64287 Darmstadt, Germany.
   [Einsle, Oliver] BIOSS Ctr Biol Signalling Studies, D-79104 Freiburg, Germany.
C3 University of Freiburg; Technical University of Darmstadt
RP Einsle, O (corresponding author), Univ Freiburg, Inst Biochem, Lehrstuhl Biochem, Albertstr 21, D-79104 Freiburg, Germany.
EM simon@bio.tu-darmstadt.de; einsle@biochemie.uni-freiburg.de
FU Deutsche Forschungsgemeinschaft [El 520/5, SI 848/7]; BIOSS Centre for Biological Signaling Studies at Albert-Ludwigs-Universitat Freiburg
NR 37
TC 49
Z9 58
U1 0
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 APR 30
PY 2015
VL 520
IS 7549
BP 706
EP U318
DI 10.1038/nature14109
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700056
PM 25642962
DA 2026-03-09
ER

PT J
AU Zorzatto, C
   Machado, JPB
   Lopes, KVG
   Nascimento, KJT
   Pereira, WA
   Brustolini, OJB
   Reis, PAB
   Calil, IP
   Deguchi, M
   Sachetto-Martins, G
   Gouveia, BC
   Loriato, VAP
   Silva, MAC
   Silva, FF
   Santos, AA
   Chory, J
   Fontes, EPB
AF Zorzatto, Cristiane
   Machado, Joao Paulo B.
   Lopes, Kenia V. G.
   Nascimento, Kelly J. T.
   Pereira, Welison A.
   Brustolini, Otavio J. B.
   Reis, Pedro A. B.
   Calil, Iara P.
   Deguchi, Michihito
   Sachetto-Martins, Gilberto
   Gouveia, Bianca C.
   Loriato, Virgilio A. P.
   Silva, Marcos A. C.
   Silva, Fabyano F.
   Santos, Anesia A.
   Chory, Joanne
   Fontes, Elizabeth P. B.
TI NIK1-mediated translation suppression functions as a plant antiviral immunity mechanism
SO NATURE
LA English
DT Article
ID nuclear shuttle protein; differential expression analysis; putative tumor-suppressor; geminivirus; kinase; arabidopsis; defense; stress; nik; sequences
AB Plants and plant pathogens are subject to continuous co-evolutionary pressure for dominance, and the outcomes of these interactions can substantially impact agriculture and food security'. In virusplant interactions, one of the major mechanisms for plant antiviral immunity relies on RNA silencing, which is often suppressed by co-evolving virus suppressors, thus enhancing viral pathogenicity in susceptible hosts'. In addition, plants use the nucleotide-binding and leucine-rich repeat (NB-LRR) domain-containing resistance proteins, which recognize viral effectors to activate effector-triggered immunity in a defence mechanism similar to that employed in nonviral infections'''. Unlike most eukaryotic organisms, plants are not known to activate mechanisms of host global translation suppression to fight viruses'''. Here we demonstrate in Arabidopsis that the constitutive activation of NIK1, a leucine-rich repeat receptor-like kinase (LRR-RLK) identified as a virulence target of the begomovirus nuclear shuttle protein (NSP)(4-6), leads to global translation suppression and translocation of the downstream component RPL 10 to the nucleus, where it interacts with a newly identified MYB-like protein, Lb-INTERACTING MYB DOMAIN-CONTAINING PROTEIN (LIMYB), to downregulate translational machinery genes fully. LIMYB overexpression represses ribosomal protein genes at the transcriptional level, resulting in protein synthesis inhibition, decreased viral messenger RNA association with polysome fractions and enhanced tolerance to begomovirus. By contrast, the loss of LIMYB function releases the repression of translation-related genes and increases susceptibility to virus infection. Therefore, LIMYB links immune receptor LRR-RLK activation to global translation suppression as an antiviral immunity strategy in plants.
C1 [Zorzatto, Cristiane; Machado, Joao Paulo B.; Lopes, Kenia V. G.; Nascimento, Kelly J. T.; Pereira, Welison A.; Brustolini, Otavio J. B.; Reis, Pedro A. B.; Calil, Iara P.; Deguchi, Michihito; Gouveia, Bianca C.; Loriato, Virgilio A. P.; Fontes, Elizabeth P. B.] Univ Fed Vicosa, Bioagro, Natl Inst Sci & Technol Plant Pest Interact, Dept Bioquim & Biol Mol, BR-36570000 Vicosa, MG, Brazil.
   [Zorzatto, Cristiane; Machado, Joao Paulo B.; Lopes, Kenia V. G.; Nascimento, Kelly J. T.; Pereira, Welison A.; Brustolini, Otavio J. B.; Reis, Pedro A. B.; Calil, Iara P.; Deguchi, Michihito; Sachetto-Martins, Gilberto; Gouveia, Bianca C.; Loriato, Virgilio A. P.; Silva, Marcos A. C.; Santos, Anesia A.; Chory, Joanne; Fontes, Elizabeth P. B.] Univ Fed Vicosa, Bioagro, Natl Inst Sci & Technol Plant Pest Interact, BR-36570000 Vicosa, MG, Brazil.
   [Sachetto-Martins, Gilberto] Univ Fed Rio de Janeiro, Dept Genet, BR-21944970 Rio De Janeiro, Brazil.
   [Silva, Fabyano F.] Univ Fed Vicosa, Dept Zootecnia, BR-36570000 Vicosa, MG, Brazil.
   [Chory, Joanne] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA.
   [Chory, Joanne] Salk Inst Biol Studies, Plant Biol Lab, La Jolla, CA 92037 USA.
C3 Universidade Federal de Vicosa; Universidade Federal de Vicosa; Universidade Federal do Rio de Janeiro; Universidade Federal de Vicosa; Howard Hughes Medical Institute; Salk Institute; Salk Institute
RP Fontes, EPB (corresponding author), Univ Fed Vicosa, Bioagro, Natl Inst Sci & Technol Plant Pest Interact, Dept Bioquim & Biol Mol, BR-36570000 Vicosa, MG, Brazil.
EM bbfontes@ufv.br
FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [573600/2008-2, 470287/2011-0]; FAPEMIG [CBB-APQ-00070-09]; US National Institutes of Health [5R01-GM94428]; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); CNPq; CAPES
NR 33
TC 186
Z9 209
U1 10
U2 169
PU NATURE PUBLISHING 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 30
PY 2015
VL 520
IS 7549
BP 679
EP U227
DI 10.1038/nature14171
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700050
PM 25707794
DA 2026-03-09
ER

PT J
AU Neppl, S
   Ernstorfer, R
   Cavalieri, AL
   Lemell, C
   Wachter, G
   Magerl, E
   Bothschafter, EM
   Jobst, M
   Hofstetter, M
   Kleineberg, U
   Barth, JV
   Menzel, D
   Burgdörfer, J
   Feulner, P
   Krausz, F
   Kienberger, R
AF Neppl, S.
   Ernstorfer, R.
   Cavalieri, A. L.
   Lemell, C.
   Wachter, G.
   Magerl, E.
   Bothschafter, E. M.
   Jobst, M.
   Hofstetter, M.
   Kleineberg, U.
   Barth, J. V.
   Menzel, D.
   Burgdoerfer, J.
   Feulner, P.
   Krausz, F.
   Kienberger, R.
TI Direct observation of electron propagation and dielectric screening on the atomic length scale
SO NATURE
LA English
DT Article
ID metal-surfaces; photoemission; spectroscopy
AB The propagation and transport of electrons in crystals is a fundamental process pertaining to the functioning of most electronic devices. Microscopic theories describe this phenomenon as being based on the motion of Bloch wave packets(1). These wave packets are superpositions of individual Bloch states with the group velocity determined by the dispersion of the electronic band structure near the central wavevector in momentum space1. This concept has been verified experimentally in artificial superlattices by the observation of Bloch oscillations(2)-periodic oscillations of electrons in real and momentum space. Here we present a direct observation of electron wave packet motion in a real-space and real-time experiment, on length and time scales shorter than the Bloch oscillation amplitude and period. We show that attosecond metrology(3) (1 as=10(-18) seconds) now enables quantitative insight into weakly disturbed electron wave packet propagation on the atomic length scale without being hampered by scattering effects, which inevitably occur over macroscopic propagation length scales. Weuse sub-femtosecond(less than 10(-15) seconds) extreme-ultraviolet light pulses(3) to launch photoelectron wave packets inside a tungsten crystal that is covered by magnesium films of varied, well-defined thicknesses of a few angstroms(4). Probing the moment of arrival of the wave packets at the surface with attosecond precision reveals free-electron-like, ballistic propagation behaviour inside the magnesium adlayer-constituting the semi-classical limit of Bloch wave packet motion. Real-time access to electron transport through atomic layers and interfaces promises unprecedented insight into phenomena that may enable the scaling of electronic and photonic circuits to atomic dimensions. In addition, this experiment allows us to determine the penetration depth of electrical fields at optical frequencies at solid interfaces on the atomic scale.
C1 [Neppl, S.; Jobst, M.; Barth, J. V.; Menzel, D.; Feulner, P.; Kienberger, R.] Tech Univ Munich, Dept Phys, D-85747 Garching, Germany.
   [Neppl, S.; Magerl, E.; Jobst, M.; Hofstetter, M.; Kleineberg, U.; Krausz, F.; Kienberger, R.] Max Planck Inst Quantum Opt, D-85748 Garching, Germany.
   [Ernstorfer, R.; Menzel, D.] Max Planck Gesell, Fritz Haber Inst, D-14195 Berlin, Germany.
   [Cavalieri, A. L.] Max Planck Inst Struct & Dynam Matter, D-22761 Hamburg, Germany.
   [Cavalieri, A. L.] Univ Hamburg, Fak Math Informat & Nat Wissensch, D-22761 Hamburg, Germany.
   [Cavalieri, A. L.] Ctr Free Electron Laser Sci CFEL, D-22761 Hamburg, Germany.
   [Lemell, C.; Wachter, G.; Burgdoerfer, J.] Vienna Univ Technol, Inst Theoret Phys, A-1040 Vienna, Austria.
   [Bothschafter, E. M.; Hofstetter, M.; Kleineberg, U.; Krausz, F.] Univ Munich, Fak Phys, D-85748 Garching, Germany.
   [Burgdoerfer, J.] Hungarian Acad Sci ATOMKI, Inst Nucl Res, H-4001 Debrecen, Hungary.
C3 Technical University of Munich; Max Planck Society; Max Planck Society; Fritz Haber Institute of the Max Planck Society; Max Planck Society; University of Hamburg; Technische Universitat Wien; University of Munich; HUN-REN; HUN-REN Institute for Nuclear Research; HUN-REN Centre for Energy Research; Institute for Atomic Energy Research - HAS
RP Neppl, S (corresponding author), Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Chem Sci, Berkeley, CA 94720 USA.
EM sneppl@lbl.gov; reinhard.kienberger@tum.de
FU Munich-Centre for Advanced Photonics; FWF special research programs [SFB-041, SFB-049, P21141-N16]; International Max Planck Research School for Advanced Photon Science (IMPRS-APS); ERC; Helmholtz Zentrum Berlin; Austrian Science Fund (FWF) [P 23359] Funding Source: researchfish; Austrian Science Fund (FWF) [P23359] Funding Source: Austrian Science Fund (FWF)
NR 30
TC 159
Z9 171
U1 2
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 15
PY 2015
VL 517
IS 7534
BP 342
EP 346
DI 10.1038/nature14094
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AY8NK
UT WOS:000347810300040
PM 25592539
DA 2026-03-09
ER

PT J
AU Jeon, NJ
   Noh, JH
   Yang, WS
   Kim, YC
   Ryu, S
   Seo, J
   Seok, SI
AF Jeon, Nam Joong
   Noh, Jun Hong
   Yang, Woon Seok
   Kim, Young Chan
   Ryu, Seungchan
   Seo, Jangwon
   Seok, Sang Il
TI Compositional engineering of perovskite materials for high-performance solar cells
SO NATURE
LA English
DT Article
ID efficient; hysteresis
AB Of the many materials and methodologies aimed at producing low-cost, efficient photovoltaic cells, inorganic-organic lead halide perovskite materials(1-17) appear particularly promising for next-generation solar devices owing to their high power conversion efficiency. The highest efficiencies reported for perovskite solar cells so far have been obtained mainly with methylammonium lead halide materials(1-10). Here we combine the promising-owing to its comparatively narrow bandgap-but relatively unstable formamidinium lead iodide (FAPbI(3)) with methylammonium lead bromide (MAPbBr(3)) as the light-harvesting unit in a bilayer solar-cell architecture(13). We investigated phase stability, morphology of the perovskite layer, hysteresis in current-voltage characteristics, and overall performance as a function of chemical composition. Our results show that incorporation of MAPbBr(3) into FAPbI(3) stabilizes the perovskite phase of FAPbI(3) and improves the power conversion efficiency of the solar cell to more than 18 per cent under a standard illumination of 100 milliwatts per square centimetre. These findings further emphasize the versatility and performance potential of inorganic-organic lead halide perovskite materials for photovoltaic applications.
C1 [Jeon, Nam Joong; Noh, Jun Hong; Yang, Woon Seok; Kim, Young Chan; Ryu, Seungchan; Seo, Jangwon; Seok, Sang Il] Korea Res Inst Chem Technol, Div Adv Mat, Taejon 305600, South Korea.
   [Seok, Sang Il] Sungkyunkwan Univ, Dept Energy Sci, Suwon 440746, South Korea.
C3 Korea Research Institute of Chemical Technology (KRICT); Sungkyunkwan University (SKKU)
RP Seok, SI (corresponding author), Korea Res Inst Chem Technol, Div Adv Mat, 141 Gajeong Ro, Taejon 305600, South Korea.
EM seoksi@krict.re.kr
FU Global Research Laboratory (GRL) Program; Global Frontier R&D Program of the Center for Multiscale Energy System - National Research Foundation in Korea; Korea Research Institute of Chemical Technology (KRICT) Program for Future Technology in South Korea
NR 27
TC 5869
Z9 6334
U1 81
U2 5110
PU NATURE PUBLISHING 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 22
PY 2015
VL 517
IS 7535
BP 476
EP +
DI 10.1038/nature14133
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AZ4MU
UT WOS:000348196500032
PM 25561177
DA 2026-03-09
ER

PT J
AU Zheng, XF
   Carstens, JL
   Kim, J
   Scheible, M
   Kaye, J
   Sugimoto, H
   Wu, CC
   LeBleu, VS
   Kalluri, R
AF Zheng, Xiaofeng
   Carstens, Julienne L.
   Kim, Jiha
   Scheible, Matthew
   Kaye, Judith
   Sugimoto, Hikaru
   Wu, Chia-Chin
   LeBleu, Valerie S.
   Kalluri, Raghu
TI Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer
SO NATURE
LA English
DT Article
ID ductal adenocarcinoma; gene-expression; cells; snail; emt; tumors; beta; proliferation; repression; resistance
AB Diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis despite current best therapies; therefore new treatment strategies are urgently required. Numerous studies have suggested that epithelial-to-mesenchymal transition (EMT) contributes to early-stage dissemination of cancer cells and is pivotal for invasion and metastasis of PDAC(1-4). EMT is associated with phenotypic conversion of epithelial cells into mesenchymal-like cells in cell culture conditions, although such defined mesenchymal conversion (with spindle-shaped morphology) of epithelial cells in vivo is rare, with quasi-mesenchymal phenotypes occasionally observed in the tumour (partial EMT)(5,6). Most studies exploring the functional role of EMT in tumours have depended on cell-culture-induced loss-of-function and gain-of-function experiments involving EMT-inducing transcription factors such as Twist, Snail and Zeb1 (refs 2,3,7-10). Therefore, the functional contribution of EMT to invasion and metastasis remains unclear(4,6), and genetically engineered mouse models to address a causal connection are lacking. Here we functionally probe the role of EMT in PDAC by generating mouse models of PDAC with deletion of Snail or Twist, two key transcription factors responsible for EMT. EMT suppression in the primary tumour does not alter the emergence of invasive PDAC, systemic dissemination or metastasis. Suppression of EMT leads to an increase in cancer cell proliferation with enhanced expression of nucleoside transporters in tumours, contributing to enhanced sensitivity to gemcitabine treatment and increased overall survival of mice. Collectively, our study suggests that Snail- or Twist-induced EMT is not rate-limiting for invasion and metastasis, but highlights the importance of combining EMT inhibition with chemotherapy for the treatment of pancreatic cancer.
C1 [Zheng, Xiaofeng; Carstens, Julienne L.; Kim, Jiha; Scheible, Matthew; Kaye, Judith; Sugimoto, Hikaru; LeBleu, Valerie S.; Kalluri, Raghu] Univ Texas MD Anderson Canc Ctr, Metastasis Res Ctr, Dept Canc Biol, Houston, TX 77054 USA.
   [Wu, Chia-Chin] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77054 USA.
   [Kalluri, Raghu] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.
   [Kalluri, Raghu] Rice Univ, Dept Bioengn, Houston, TX 77030 USA.
C3 University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; Baylor College of Medicine; Rice University
RP Kalluri, R (corresponding author), Univ Texas MD Anderson Canc Ctr, Metastasis Res Ctr, Dept Canc Biol, Houston, TX 77054 USA.
EM rkalluri@mdanderson.org
FU NCI [P30CA16672]; Cancer Prevention and Research Institute of Texas; UT MDACC Khalifa Bin Zayed Al Nahya Foundation; National Cancer Institute [P30CA016672] Funding Source: NIH RePORTER
NR 37
TC 1698
Z9 1931
U1 6
U2 463
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD NOV 26
PY 2015
VL 527
IS 7579
BP 525
EP +
DI 10.1038/nature16064
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CW9XW
UT WOS:000365352500050
PM 26560028
DA 2026-03-09
ER

PT J
AU Nakatsuji, S
   Kiyohara, N
   Higo, T
AF Nakatsuji, Satoru
   Kiyohara, Naoki
   Higo, Tomoya
TI Large anomalous Hall effect in a non-collinear antiferromagnet at room temperature
SO NATURE
LA English
DT Article
ID weak ferromagnetism; magnetic-structure; spin structure; mn3sn; phase; spintronics
AB In ferromagnetic conductors, an electric current may induce a transverse voltage drop in zero applied magnetic field: this anomalous Hall effect(1) is observed to be proportional to magnetization, and thus is not usually seen in antiferromagnets in zero field(2). Recent developments in theory and experiment have provided a framework for understanding the anomalous Hall effect using Berry-phase concepts', and this perspective has led to predictions that, under certain conditions, a large anomalous Hall effect may appear in spin liquids and antiferromagnets without net spin magnetization(4-8). Although such a spontaneous Hall effect has now been observed in a spin liquid state(9), a zero-field anomalous Hall effect has hitherto not been reported for antiferromagnets. Here we report empirical evidence for a large anomalous Hall effect in an antiferromagnet that has vanishingly small magnetization. In particular, we find that Mn3Sn, an antiferromagnet that has a non-collinear 120-degree spin order(10,11), exhibits a large anomalous Hall conductivity of around 20 per ohm per centimetre at room temperature and more than 100 per ohm per centimetre at low temperatures, reaching the same order of magnitude as in ferromagnetic metals(3). Notably, the chiral antiferromagnetic state has a very weak and soft ferromagnetic moment of about 0.002 Bohr magnetons per Mn atom (refs 10, 12), allowing us to switch the sign of the Hall effect with a small magnetic field of around a few hundred oersted. This soft response of the large anomalous Hall effect could be useful for various applications including spintronics for example, to develop a memory device that produces almost no perturbing stray fields.
C1 [Nakatsuji, Satoru; Kiyohara, Naoki; Higo, Tomoya] Univ Tokyo, Inst Solid State Phys, Kashiwa, Chiba 2778581, Japan.
   [Nakatsuji, Satoru] Japan Sci & Technol Agcy JST, PRESTO, Kawaguchi, Saitama 3320012, Japan.
C3 University of Tokyo; Japan Science & Technology Agency (JST)
RP Nakatsuji, S (corresponding author), Univ Tokyo, Inst Solid State Phys, Kashiwa, Chiba 2778581, Japan.
EM satoru@issp.u-tokyo.ac.jp
FU PRESTO; Japan Science and Technology Agency; Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers [R2604]; Japanese Society for the Promotion of Science [15H05882, 15H05883];  [25707030]; Grants-in-Aid for Scientific Research [15H05882, 25707030, 15H05883] Funding Source: KAKEN
NR 36
TC 1415
Z9 1543
U1 40
U2 1021
PU NATURE PUBLISHING 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 12
PY 2015
VL 527
IS 7577
BP 212
EP +
DI 10.1038/nature15723
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CV6RC
UT WOS:000364396700040
PM 26524519
DA 2026-03-09
ER

PT J
AU Ogata, H
   Nishikawa, K
   Lubitz, W
AF Ogata, Hideaki
   Nishikawa, Koji
   Lubitz, Wolfgang
TI Hydrogens detected by subatomic resolution protein crystallography in a [NiFe] hydrogenase
SO NATURE
LA English
DT Article
ID catalytic cycle; active-site; electron-density; activation; ligand; bonds; reactivity; spectroscopy; complexes; pathways
AB The enzyme hydrogenase reversibly converts dihydrogen to protons and electrons at a metal catalyst(1). The location of the abundant hydrogens is of key importance for understanding structure and function of the protein(2-6). However, in protein X-ray crystallography the detection of hydrogen atoms is one of the major problems, since they display only weak contributions to diffraction and the quality of the single crystals is often insufficient to obtain sub-angstrom resolution'. Here we report the crystal structure of a standard [NiFe] hydrogenase (similar to 91.3 ltDa molecular mass) at 0.89 angstrom resolution. The strictly anoxically isolated hydrogenase has been obtained in a specific spectroscopic state, the active reduced Ni-R (subform Ni-R1) state. The high resolution, proper refinement strategy and careful modelling allow the positioning of a large part of the hydrogen atoms in the structure. This has led to the direct detection of the products of the heterolytic splitting of dihydrogen into a hydride (H-) bridging the Ni and Fe and a proton (H+) attached to the sulphur of a cysteine ligand. The Ni-H- and Fe-H- bond lengths are 1.58 angstrom and 1.78 angstrom, respectively. Furthermore, we can assign the Fe-CO and Fe-CN- ligands at the active site, and can obtain the hydrogen-bond networks and the preferred proton transfer pathway in the hydrogenase. Our results demonstrate the precise comprehensive information available from ultra-high-resolution structures of proteins as an alternative to neutron diffraction and other methods such as NMR structural analysis.
C1 [Ogata, Hideaki; Nishikawa, Koji; Lubitz, Wolfgang] Max Planck Inst Chem Energy Convers, D-45470 Mulheim, Germany.
C3 Max Planck Society
RP Ogata, H (corresponding author), Max Planck Inst Chem Energy Convers, Stiftstr 34-36, D-45470 Mulheim, Germany.
EM hideaki.ogata@cec.mpg.de; wolfgang.lubitz@cec.mpg.de
FU Max Planck Society; Bundesministerium far Bildung und Forschung (BMBF) [03SF0355C]; EU/Energy Network project SOLAR-H2 [212508]; Cluster of Excellence RESOLV - Deutsche Forschungsgemeinschaft [EXC1069]
NR 43
TC 265
Z9 299
U1 0
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 23
PY 2015
VL 520
IS 7548
BP 571
EP +
DI 10.1038/nature14110
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CG5LX
UT WOS:000353334500050
PM 25624102
DA 2026-03-09
ER

PT J
AU Schultz, MD
   He, YP
   Whitaker, JW
   Hariharan, M
   Mukamel, EA
   Leung, D
   Rajagopal, N
   Nery, JR
   Urich, MA
   Chen, HM
   Lin, S
   Lin, Y
   Jung, I
   Schmitt, AD
   Selvaraj, S
   Ren, B
   Sejnowski, TJ
   Wang, W
   Ecker, JR
AF Schultz, Matthew D.
   He, Yupeng
   Whitaker, John W.
   Hariharan, Manoj
   Mukamel, Eran A.
   Leung, Danny
   Rajagopal, Nisha
   Nery, Joseph R.
   Urich, Mark A.
   Chen, Huaming
   Lin, Shin
   Lin, Yiing
   Jung, Inkyung
   Schmitt, Anthony D.
   Selvaraj, Siddarth
   Ren, Bing
   Sejnowski, Terrence J.
   Wang, Wei
   Ecker, Joseph R.
TI Human body epigenome maps reveal noncanonical DNA methylation variation
SO NATURE
LA English
DT Article
ID pluripotent stem-cells; cpg island shores; disease; tissue; cancer; landscape; methylome; enhancers; genome
AB Understanding the diversity of human tissues is fundamental to disease and requires linking genetic information, which is identical in most of an individual's cells, with epigenetic mechanisms that could have tissue-specific roles. Surveys of DNA methylation in human tissues have established a complex landscape including both tissue-specific and invariant methylation patterns(1,2). Here we report high coverage methylomes that catalogue cytosine methylation in all contexts for the major human organ systems, integrated with matched transcriptomes and genomic sequence. By combining these diverse data types with each individuals' phased genome(3), we identified widespread tissue-specific differential CG methylation (mCG), partially methylated domains, allele-specific methylation and transcription, and the unexpected presence of non-CG methylation (mCH) in almost all human tissues. mCH correlated with tissue-specific functions, and using this mark, we made novel predictions of genes that escape X-chromosome inactivation in specific tissues. Overall, DNA methylation in several genomic contexts varies substantially among human tissues.
C1 [Schultz, Matthew D.; He, Yupeng; Selvaraj, Siddarth] Univ Calif San Diego, Bioinformat Program, La Jolla, CA 92093 USA.
   [Schultz, Matthew D.; He, Yupeng; Hariharan, Manoj; Nery, Joseph R.; Urich, Mark A.; Chen, Huaming; Ecker, Joseph R.] Salk Inst Biol Studies, Genom Anal Lab, La Jolla, CA 92037 USA.
   [Whitaker, John W.; Wang, Wei] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA.
   [Mukamel, Eran A.; Sejnowski, Terrence J.] Salk Inst Biol Studies, Computat Neurobiol Lab, La Jolla, CA 92037 USA.
   [Mukamel, Eran A.] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92037 USA.
   [Leung, Danny; Rajagopal, Nisha; Jung, Inkyung; Schmitt, Anthony D.; Ren, Bing] Ludwig Inst Canc Res, La Jolla, CA 92093 USA.
   [Lin, Shin] Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
   [Lin, Yiing] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA.
   [Ren, Bing] Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, Inst Genom Med, La Jolla, CA 92093 USA.
   [Sejnowski, Terrence J.] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92037 USA.
   [Sejnowski, Terrence J.; Ecker, Joseph R.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA.
   [Wang, Wei] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA.
C3 University of California System; University of California San Diego; Salk Institute; University of California System; University of California San Diego; Salk Institute; University of California System; University of California San Diego; Ludwig Institute for Cancer Research; Stanford University; Washington University (WUSTL); University of California System; University of California San Diego; University of California System; University of California San Diego; Salk Institute; Howard Hughes Medical Institute; University of California System; University of California San Diego
RP Ecker, JR (corresponding author), Salk Inst Biol Studies, Genom Anal Lab, La Jolla, CA 92037 USA.
EM ecker@salk.edu
FU National Institutes of Health (NIH) Epigenome Roadmap Project [U01 ES017166]; National Institute of Neurological Diseases and Stroke grant [R00NS080911]; Gordon and Betty Moore Foundation [GMBF3034]; Mary K. Chapman Foundation; NIH [F32HL110473, K99HL119617]; Mid-America Transplant Services, St Louis; National Institute of General Medical Sciences [T32GM008666] Funding Source: NIH RePORTER
NR 30
TC 495
Z9 593
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 JUL 9
PY 2015
VL 523
IS 7559
BP 212
EP U189
DI 10.1038/nature14465
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CM4ZO
UT WOS:000357695900035
PM 26030523
DA 2026-03-09
ER

PT J
AU Giles, S
   Friedman, M
   Brazeau, MD
AF Giles, Sam
   Friedman, Matt
   Brazeau, Martin D.
TI Osteichthyan-like cranial conditions in an Early Devonian stem gnathostome
SO NATURE
LA English
DT Article
ID incomplete taxa; missing data; braincase; jaws; characters; radiation; placoderm; origin
AB The phylogeny of Silurian and Devonian (443-358 million years(Myr) ago) fishes remains the foremost problem in the study of the origin of modern gnathostomes (jawed vertebrates). A central question concerns themorphology of the last common ancestor of living jawed vertebrates, with competing hypotheses advancing either a chondrichthyan-(1-3) or osteichthyan-like(4,5) model. Here we present Janu-siscus schultzei gen. et sp. nov., an Early Devonian (approximately 415 Myr ago) gnathostome from Siberia previously interpreted as a ray-finned fish(6), which provides important new information about cranial anatomy near the last common ancestor of chondrichthyans and osteichthyans. The skull roof of Janusiscus resembles that of early osteichthyans, with large plates bearing vermiform ridges and partially enclosed sensory canals. High-resolution computed tomography (CT) reveals a braincase bearing characters typically associated with either chondrichthyans (large hypophyseal opening accommodating the internal carotid arteries) or osteichthyans (facial nerve exiting through jugular canal, endolymphatic ducts exiting posterior to the skull roof) but lacking a ventral cranial fissure, the presence of which is considered a derived feature of crown gnathostomes(7,8). A conjunction of well-developed cranial processes in Janusiscus helps unify the comparative anatomy of early jawed vertebrate neurocrania, clarifying primary homologies in 'placoderms', osteichthyans and chondrichthyans. Phylogenetic analysis further supports the chondrichthyan affinities of 'acanthodians', and places Janusiscus and the enigmatic Ramirosuarezia(9) in a polytomy with crown gnathostomes. The close correspondence between the skull roof of Janusiscus and that of osteichthyans suggests that an extensive dermal skeleton was present in the last common ancestor of jawed vertebrates(4), but ambiguities arise from uncertainties in the anatomy of Ramirosuarezia. The unexpected contrast between endoskeletal structure in Janusiscus and its superficially osteichthyan-like dermal skeleton highlights the potential importance of other incompletely known Siluro-Devonian 'bony fishes' for reconstructing patterns of trait evolution near the origin of modern gnathostomes.
C1 [Giles, Sam; Friedman, Matt] Univ Oxford, Dept Earth Sci, Oxford OX1 3AN, England.
   [Brazeau, Martin D.] Nat Biodivers Ctr, NL-2300 RA Leiden, Netherlands.
   [Brazeau, Martin D.] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, Ascot SL5 7PY, Berks, England.
C3 University of Oxford; Naturalis Biodiversity Center; Imperial College London
RP Brazeau, MD (corresponding author), Nat Biodivers Ctr, POB 9517, NL-2300 RA Leiden, Netherlands.
EM m.brazeau@imperial.ac.uk
FU Natural Environment Research Council Cohort [NE/J500045/1]; Philip Leverhulme Prize; John Fell Fund; European Research Council (ERC) under the European Union's Seventh Framework Programme [311092]; Natural Environment Research Council [1093317] Funding Source: researchfish
NR 35
TC 95
Z9 105
U1 0
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 APR 2
PY 2015
VL 520
IS 7545
BP 82
EP U175
DI 10.1038/nature14065
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CE7NE
UT WOS:000352027700041
PM 25581798
DA 2026-03-09
ER

PT J
AU Farh, KKH
   Marson, A
   Zhu, J
   Kleinewietfeld, M
   Housley, WJ
   Beik, S
   Shoresh, N
   Whitton, H
   Ryan, RJH
   Shishkin, AA
   Hatan, M
   Carrasco-Alfonso, MJ
   Mayer, D
   Luckey, CJ
   Patsopoulos, NA
   De Jager, PL
   Kuchroo, VK
   Epstein, CB
   Daly, MJ
   Hafler, DA
   Bernstein, BE
AF Farh, Kyle Kai-How
   Marson, Alexander
   Zhu, Jiang
   Kleinewietfeld, Markus
   Housley, William J.
   Beik, Samantha
   Shoresh, Noam
   Whitton, Holly
   Ryan, Russell J. H.
   Shishkin, Alexander A.
   Hatan, Meital
   Carrasco-Alfonso, Marlene J.
   Mayer, Dita
   Luckey, C. John
   Patsopoulos, Nikolaos A.
   De Jager, Philip L.
   Kuchroo, Vijay K.
   Epstein, Charles B.
   Daly, Mark J.
   Hafler, David A.
   Bernstein, Bradley E.
TI Genetic and epigenetic fine mapping of causal autoimmune disease variants
SO NATURE
LA English
DT Article
ID genome-wide association; regulatory t-cells; susceptibility loci; transcription factors; enhancer landscape; foxp3 occupancy; read alignment; risk loci; expression; common
AB Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4(+) T-cell subsets, regulatory T cells, CD8(+) T cells, B cells, and monocytes. We find that similar to 90% of causal variants are non-coding, with similar to 60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs. Rather, mostnon-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.
C1 [Farh, Kyle Kai-How; Zhu, Jiang; Kleinewietfeld, Markus; Beik, Samantha; Shoresh, Noam; Whitton, Holly; Ryan, Russell J. H.; Shishkin, Alexander A.; Hatan, Meital; Patsopoulos, Nikolaos A.; De Jager, Philip L.; Epstein, Charles B.; Daly, Mark J.; Hafler, David A.; Bernstein, Bradley E.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Farh, Kyle Kai-How; Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
   [Marson, Alexander] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA.
   [Marson, Alexander] Univ Calif San Francisco, Div Infect Dis, Dept Med, San Francisco, CA 94143 USA.
   [Zhu, Jiang; Bernstein, Bradley E.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
   [Zhu, Jiang; Ryan, Russell J. H.; Bernstein, Bradley E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.
   [Zhu, Jiang; Ryan, Russell J. H.; Bernstein, Bradley E.] Harvard Univ, Sch Med, Boston, MA 02114 USA.
   [Zhu, Jiang; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA.
   [Zhu, Jiang; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA.
   [Kleinewietfeld, Markus; Housley, William J.; Hafler, David A.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06511 USA.
   [Kleinewietfeld, Markus; Housley, William J.; Hafler, David A.] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06511 USA.
   [Shishkin, Alexander A.] CALTECH, Pasadena, CA 91125 USA.
   [Carrasco-Alfonso, Marlene J.; Mayer, Dita; Luckey, C. John] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA.
   [Carrasco-Alfonso, Marlene J.; Mayer, Dita; Luckey, C. John] Harvard Univ, Sch Med, Boston, MA 02115 USA.
   [Patsopoulos, Nikolaos A.; De Jager, Philip L.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Genom, Inst Neurosci, Dept Neurol, Boston, MA 02142 USA.
   [Patsopoulos, Nikolaos A.; De Jager, Philip L.] Harvard Univ, Sch Med, Boston, MA 02142 USA.
   [Patsopoulos, Nikolaos A.; De Jager, Philip L.] Harvard Univ, Div Genet, Dept Med, Brigham & Womens Hosp,Med Sch, Boston, MA 02142 USA.
   [Kuchroo, Vijay K.] Harvard Univ, Ctr Neurol Dis, Brigham & Womens Hosp, Sch Med, Boston, MA 02142 USA.
C3 Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Howard Hughes Medical Institute; 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; Yale University; Yale University; California Institute of Technology; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard Medical School
RP Marson, A (corresponding author), Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA.
EM alexander.marson@ucsf.edu
FU NIH Common Fund [ES017155]; National Human Genome Research Institute [HG004570]; National Institute of Allergy and Infectious Disease [AI045757, AI046130, AI070352, AI039671]; National Institute of Neurological Disorders and Stroke [NS24247, NS067305]; National Institute of General Medical Sciences [GM093080]; National Multiple Sclerosis Society [CA1061-A-18]; UCSF Sandler Fellowship; Penates Foundation; Nancy Taylor Foundation; Howard Hughes Medical Institute; National Institute of Allergy and Infectious Diseases [P01AI039671, T32AI007019] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [T32GM007748] Funding Source: NIH RePORTER
NR 67
TC 1416
Z9 1695
U1 4
U2 180
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 19
PY 2015
VL 518
IS 7539
BP 337
EP 343
DI 10.1038/nature13835
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400030
PM 25363779
DA 2026-03-09
ER

PT J
AU Stampfel, G
   Kazmar, T
   Frank, O
   Wienerroither, S
   Reiter, F
   Stark, A
AF Stampfel, Gerald
   Kazmar, Tomas
   Frank, Olga
   Wienerroither, Sebastian
   Reiter, Franziska
   Stark, Alexander
TI Transcriptional regulators form diverse groups with context-dependent regulatory functions
SO NATURE
LA English
DT Article
ID in-vivo; activation; protein; gene; repression; mediator; complex; dissection; motifs; tools
AB One of the most important questions in biology is how transcription factors (TFs) and cofactors control enhancer function and thus gene expression. Enhancer activation usually requires combinations of several TFs(1), indicating that TFs function synergistically and combinatorially(2,3). However, while TF binding has been extensively studied, little is known about how combinations of TFs and cofactors control enhancer function once they are bound. It is typically unclear which TFs participate in combinatorial enhancer activation, whether different TFs form functionally distinct groups, or if certain TFs might substitute for each other in defined enhancer contexts. Here we assess the potential regulatory contributions of TFs and cofactors to combinatorial enhancer control with enhancer complementation assays. We recruited GAL4-DNA-binding-domain fusions of 812 Drosophila TFs and cofactors to 24 enhancer contexts and measured enhancer activities by 82,752 luciferase assays in S2 cells. Most factors were functional in at least one context, yet their contributions differed between contexts and varied from repression to activation (up to 289-fold) for individual factors. Based on functional similarities across contexts, we define 15 groups of TFs that differ in developmental functions and protein sequence features. Similar TFs can substitute for each other, enabling enhancer re-engineering by exchanging TF motifs, and TF-cofactor pairs cooperate during enhancer control and interact physically. Overall, we show that activators and repressors can have diverse regulatory functions that typically depend on the enhancer context. The systematic functional characterization of TFs and cofactors should further our understanding of combinatorial enhancer control and gene regulation.
C1 [Stampfel, Gerald; Kazmar, Tomas; Frank, Olga; Wienerroither, Sebastian; Reiter, Franziska; Stark, Alexander] Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria.
C3 Vienna Biocenter (VBC); Research Institute of Molecular Pathology (IMP)
RP Stark, A (corresponding author), Vienna Bioctr VBC, Res Inst Mol Pathol IMP, Dr Bohr Gasse 7, A-1030 Vienna, Austria.
EM stark@starklab.org
FU European Research Council (ERC) [242922]; Boehringer Ingelheim GmbH; Austrian Research Promotion Agency (FFG); European Research Council (ERC) [242922] Funding Source: European Research Council (ERC)
NR 54
TC 137
Z9 180
U1 0
U2 48
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 3
PY 2015
VL 528
IS 7580
BP 147
EP +
DI 10.1038/nature15545
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX3NO
UT WOS:000365606000066
PM 26550828
DA 2026-03-09
ER

PT J
AU Vincent, JB
   Bodewits, D
   Besse, S
   Sierks, H
   Barbieri, C
   Lamy, P
   Rodrigo, R
   Koschny, D
   Rickman, H
   Keller, HU
   Agarwal, J
   A'Hearn, MF
   Auger, AT
   Barucci, MA
   Bertaux, JL
   Bertini, I
   Capanna, C
   Cremonese, G
   Da Deppo, V
   Davidsson, B
   Debei, S
   De Cecco, M
   El-Maarry, MR
   Ferri, F
   Fornasier, S
   Fulle, M
   Gaskell, R
   Giacomini, L
   Groussin, O
   Guilbert-Lepoutre, A
   Gutierrez-Marques, P
   Gutiérrez, PJ
   Güttler, C
   Hoekzema, N
   Höfner, S
   Hviid, SF
   Ip, WH
   Jorda, L
   Knollenberg, J
   Kovacs, G
   Kramm, R
   Kührt, E
   Küppers, M
   La Forgia, F
   Lara, LM
   Lazzarin, M
   Lee, V
   Leyrat, C
   Lin, ZY
   Moreno, JJL
   Lowry, S
   Magrin, S
   Maquet, L
   Marchi, S
   Marzari, F
   Massironi, M
   Michalik, H
   Moissl, R
   Mottola, S
   Naletto, G
   Oklay, N
   Pajola, M
   Preusker, F
   Scholten, F
   Thomas, N
   Toth, I
   Tubiana, C
AF Vincent, Jean-Baptiste
   Bodewits, Dennis
   Besse, Sebastien
   Sierks, Holger
   Barbieri, Cesare
   Lamy, Philippe
   Rodrigo, Rafael
   Koschny, Detlef
   Rickman, Hans
   Keller, Horst Uwe
   Agarwal, Jessica
   A'Hearn, Michael F.
   Auger, Anne-Therese
   Barucci, M. Antonella
   Bertaux, Jean-Loup
   Bertini, Ivano
   Capanna, Claire
   Cremonese, Gabriele
   Da Deppo, Vania
   Davidsson, Bjoern
   Debei, Stefano
   De Cecco, Mariolino
   El-Maarry, Mohamed Ramy
   Ferri, Francesca
   Fornasier, Sonia
   Fulle, Marco
   Gaskell, Robert
   Giacomini, Lorenza
   Groussin, Olivier
   Guilbert-Lepoutre, Aurelie
   Gutierrez-Marques, P.
   Gutierrez, Pedro J.
   Guettler, Carsten
   Hoekzema, Nick
   Hoefner, Sebastian
   Hviid, Stubbe F.
   Ip, Wing-Huen
   Jorda, Laurent
   Knollenberg, Joerg
   Kovacs, Gabor
   Kramm, Rainer
   Kuehrt, Ekkehard
   Kueppers, Michael
   La Forgia, Fiorangela
   Lara, Luisa M.
   Lazzarin, Monica
   Lee, Vicky
   Leyrat, Cedric
   Lin, Zhong-Yi
   Lopez Moreno, Jose J.
   Lowry, Stephen
   Magrin, Sara
   Maquet, Lucie
   Marchi, Simone
   Marzari, Francesco
   Massironi, Matteo
   Michalik, Harald
   Moissl, Richard
   Mottola, Stefano
   Naletto, Giampiero
   Oklay, Nilda
   Pajola, Maurizio
   Preusker, Frank
   Scholten, Frank
   Thomas, Nicolas
   Toth, Imre
   Tubiana, Cecilia
TI Large heterogeneities in comet 67P as revealed by active pits from sinkhole collapse
SO NATURE
LA English
DT Article
ID deep impact; 67p/churyumov-gerasimenko activity; 9p/tempel 1; dust coma; surface; nuclei; evolution; morphology; outbursts; camera
AB Pits have been observed on many cometary nuclei mapped by spacecraft(1-4). It has been argued that cometary pits are a signature of endogenic activity, rather than impact craters such as those on planetary and asteroid surfaces. Impact experiments(5,6) andmodels(7,8) cannot reproduce the shapes of most of the observed cometary pits, and the predicted collision rates imply that few of the pits are related to impacts(8,9). Alternative mechanisms like explosive activity(10) have been suggested, but the driving process remains unknown. Here we report that pits on comet 67P/Churyumov-Gerasimenko are active, and probably created by a sinkhole process, possibly accompanied by outbursts. We argue that after formation, pits expand slowly in diameter, owing to sublimation-driven retreat of the walls. Therefore, pits characterize how eroded the surface is: a fresh cometary surface will have a ragged structure with many pits, while an evolved surface will look smoother. The size and spatial distribution of pits imply that large heterogeneities exist in the physical, structural or compositional properties of the first few hundred metres below the current nucleus surface.
C1 [Vincent, Jean-Baptiste; Sierks, Holger; Agarwal, Jessica; A'Hearn, Michael F.; Gutierrez-Marques, P.; Guettler, Carsten; Hoekzema, Nick; Hoefner, Sebastian; Kovacs, Gabor; Kramm, Rainer; Oklay, Nilda; Pajola, Maurizio; Tubiana, Cecilia] Max Planck Inst Sonnensyst Forsch, Justus von Liebig Weg 3, D-37077 Gottingen, Germany.
   [Bodewits, Dennis; A'Hearn, Michael F.; Guilbert-Lepoutre, Aurelie] Univ Maryland, Dept Astron, College Pk, MD 20742 USA.
   [Besse, Sebastien; Koschny, Detlef] European Space Res & Technol Ctr ESA, Sci Support Off, NL-2201 AZ Noordwijk, Netherlands.
   [Barbieri, Cesare; La Forgia, Fiorangela; Lazzarin, Monica] Univ Padua, Dept Phys & Astron, I-35122 Padua, Italy.
   [Lamy, Philippe; Auger, Anne-Therese; Capanna, Claire; Groussin, Olivier; Jorda, Laurent] CNRS, Lab Astrophys Marseille, UMR 7326, F-13388 Marseille 13, France.
   [Lamy, Philippe; Auger, Anne-Therese; Capanna, Claire; Groussin, Olivier; Jorda, Laurent] Aix Marseille Univ, F-13388 Marseille 13, France.
   [Rodrigo, Rafael; Davidsson, Bjoern] CSIC, INTA, Ctr Astrobiol, Madrid 28850, Spain.
   [Rodrigo, Rafael] Int Space Sci Inst, CH-3012 Bern, Switzerland.
   [Rickman, Hans] Uppsala Univ, Dept Phys & Astron, S-75120 Uppsala, Sweden.
   [Rickman, Hans] PAS Space Res Ctr, PL-00716 Warsaw, Poland.
   [Keller, Horst Uwe] Tech Univ Carolo Wilhelmina Braunschweig, IGEP, D-38106 Braunschweig, Germany.
   [A'Hearn, Michael F.] Akad Wissensch Gottingen, D-37077 Gottingen, Germany.
   [Barucci, M. Antonella; Fornasier, Sonia; Leyrat, Cedric] Univ Paris Diderot, Univ Paris 06, LESIA Observ Paris, CNRS, F-92195 Meudon, France.
   [Bertaux, Jean-Loup] UVSQ, CNRS, IPSL, LATMOS, F-78280 Guyancourt, France.
   [Bertini, Ivano; Ferri, Francesca; Giacomini, Lorenza; Naletto, Giampiero; Pajola, Maurizio] Univ Padua, Ctr Ateneo Studi Attivita Spaziali Giuseppe Colom, I-35131 Padua, Italy.
   [Cremonese, Gabriele] Osserv Astron Padova, INAF, I-35122 Padua, Italy.
   [Da Deppo, Vania; Naletto, Giampiero] CNR, IFN UOS Padova LUXOR, I-35131 Padua, Italy.
   [Debei, Stefano] Univ Padua, Dept Ind Engn, I-35131 Padua, Italy.
   [De Cecco, Mariolino] Univ Trento, I-38100 Trento, Italy.
   [El-Maarry, Mohamed Ramy; Thomas, Nicolas] Univ Bern, Phys Inst, CH-3012 Bern, Switzerland.
   [Fulle, Marco] INAF Osservatorio Astron, I-34014 Trieste, Italy.
   [Gaskell, Robert] Planetary Sci Inst, Tucson, AZ 85719 USA.
   [Gutierrez, Pedro J.; Lara, Luisa M.; Lopez Moreno, Jose J.] Inst Astrofis Andalucia CSIC, Granada 18008, Spain.
   [Hviid, Stubbe F.; Knollenberg, Joerg; Kuehrt, Ekkehard; Mottola, Stefano; Preusker, Frank; Scholten, Frank] Deutsch Zentrum Luft & Raumfahrt DLR, Inst Planetenforsch, D-12489 Berlin, Germany.
   [Ip, Wing-Huen; Lee, Vicky; Lin, Zhong-Yi] Natl Cent Univ, Grad Inst Astron, Chungli 32054, Taiwan.
   [Kueppers, Michael; Maquet, Lucie; Moissl, Richard] European Space Astron Ctr ESA, Operat Dept, Madrid 28691, Spain.
   [Lowry, Stephen] Univ Kent, Sch Phys Sci, Canterbury CT2 7NZ, Kent, England.
   [Magrin, Sara; Marzari, Francesco] Univ Padua, Deptartment Phys & Astron, I-35131 Padua, Italy.
   [Marchi, Simone] Southwest Res Inst, Solar Syst Explorat Res Virtual Inst, Boulder, CO 80302 USA.
   [Massironi, Matteo] Univ Padua, Dipartimento Geosci, I-35131 Padua, Italy.
   [Michalik, Harald] Tech Univ Carolo Wilhelmina Braunschweig, Inst Datentech & Kommunikat Netze, D-38106 Braunschweig, Germany.
   [Naletto, Giampiero] Univ Padua, Dept Informat Engn, I-35131 Padua, Italy.
   [Toth, Imre] Hungarian Acad Sci, Konkoly Observ, H-1525 Budapest, Hungary.
C3 Max Planck Society; University System of Maryland; University of Maryland College Park; University of Padua; Centre National de la Recherche Scientifique (CNRS); Aix-Marseille Universite; Aix-Marseille Universite; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Centro de Astrobiologia (INTA); Uppsala University; Polish Academy of Sciences; Space Research Centre of the Polish Academy of Sciences; Braunschweig University of Technology; Sorbonne Universite; Universite Paris Cite; Universite PSL; Observatoire de Paris; Centre National de la Recherche Scientifique (CNRS); Universite Paris Saclay; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); Universite Paris Cite; University of Padua; University of Padua; Istituto Nazionale Astrofisica (INAF); Consiglio Nazionale delle Ricerche (CNR); Istituto di Fotonica e Nanotecnologie (IFN-CNR); University of Padua; University of Trento; University of Bern; Istituto Nazionale Astrofisica (INAF); Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Astrofisica de Andalucia (IAA); Helmholtz Association; German Aerospace Centre (DLR); National Central University; European Space Agency; European Space Astronomy Center; University of Kent; University of Padua; Southwest Research Institute; University of Padua; Braunschweig University of Technology; University of Padua; Hungarian Academy of Sciences; HUN-REN; HUN-REN Research Centre for Astronomy & Earth Sciences; Konkoly Thege Miklos Astronomical Institute
RP Vincent, JB (corresponding author), Max Planck Inst Sonnensyst Forsch, Justus von Liebig Weg 3, D-37077 Gottingen, Germany.
EM vincent@mps.mpg.de
FU Germany (DLR); France (CNES); Italy (ASI); Spain (MEC); Sweden (SNSB); ESA Technical Directorate; NASA JPL contract [1267923]
NR 39
TC 164
Z9 172
U1 0
U2 29
PU NATURE RESEARCH
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUL 2
PY 2015
VL 523
IS 7558
BP 63
EP +
DI 10.1038/nature14564
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL7RN
UT WOS:000357169500031
PM 26135448
DA 2026-03-09
ER

PT J
AU Cheng, CJ
   Bahal, R
   Babar, IA
   Pincus, Z
   Barrera, F
   Liu, C
   Svoronos, A
   Braddock, DT
   Glazer, PM
   Engelman, DM
   Saltzman, WM
   Slack, FJ
AF Cheng, Christopher J.
   Bahal, Raman
   Babar, Imran A.
   Pincus, Zachary
   Barrera, Francisco
   Liu, Connie
   Svoronos, Alexander
   Braddock, Demetrios T.
   Glazer, Peter M.
   Engelman, Donald M.
   Saltzman, W. Mark
   Slack, Frank J.
TI MicroRNA silencing for cancer therapy targeted to the tumour microenvironment
SO NATURE
LA English
DT Article
ID peptide-nucleic-acids; in-vivo; cell proliferation; oncomir addiction; translocation; transcriptome; molecules; barriers; delivery; model
AB MicroRNAs are short non-codingRNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, microRNAs are critical cogs innumerous biological processes(1,2), and dysregulated microRNA expression is correlated with many human diseases. Certain microRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed. Tumours that depend on these microRNAs are said to display oncomiR addiction(3-5). Some of the most effective anticancer therapies target oncogenes such as EGFR and HER2; similarly, inhibition of oncomiRs using antisense oligomers (that is, antimiRs) is an evolving therapeutic strategy(6,7). However, the in vivo efficacy of current antimiR technologies is hindered by physiological and cellular barriers to delivery into targeted cells(8). Here we introduce a novel antimiR delivery platform that targets the acidic tumour microenvironment, evades systemic clearance by the liver, and facilitates cell entry via a non-endocytic pathway. We find that the attachment of peptide nucleic acid antimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP) produces a novel construct that could target the tumour microenvironment, transport antimiRs across plasma membranes under acidic conditions such as those found in solid tumours (pH approximately 6), and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma. This study introduces a new model for using antimiRs as anti-cancer drugs, which can have broad impacts on the field of targeted drug delivery.
C1 [Cheng, Christopher J.; Babar, Imran A.; Pincus, Zachary; Liu, Connie; Slack, Frank J.] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06511 USA.
   [Cheng, Christopher J.; Saltzman, W. Mark] Yale Univ, Dept Biomed Engn, New Haven, CT 06511 USA.
   [Cheng, Christopher J.; Barrera, Francisco; Svoronos, Alexander; Engelman, Donald M.] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06511 USA.
   [Bahal, Raman; Glazer, Peter M.] Yale Univ, Dept Therapeut Radiol, New Haven, CT 06511 USA.
   [Braddock, Demetrios T.] Yale Univ, Dept Pathol, New Haven, CT 06511 USA.
C3 Yale University; Yale University; Yale University; Yale University; Yale University
RP Slack, FJ (corresponding author), Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA.
EM fslack@bidmc.harvard.edu
FU Ruth L. Kirschstein Postdoctoral Fellowship from the National Cancer Institute/National Institutes of Health (NCI/NIH) [F32CA174247]; NCI/NIH [R01CA131301, R01CA148996]; National Heart, Lung, and Blood Institute (NHLBI)/NIH [R01HL085416]; National Institute of General Medical Sciences (NIGMS)/NIH [R01GM073857]; National Institute of Environmental Health Sciences (NIEHS)/NIH [R01ES005775]; National Institute of Biomedical Imaging and Bioengineering (NIBIB)/NIH [R01EB000487]; NHLBI/NIH [2T32HL007974]; Yale Comprehensive Cancer Center; National Cancer Institute [P30CA016359] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [T32HL007974] Funding Source: NIH RePORTER; National Institute of Environmental Health Sciences [R01ES005775] Funding Source: NIH RePORTER; National Institute of General Medical Sciences [R01GM073857] Funding Source: NIH RePORTER
NR 37
TC 638
Z9 752
U1 1
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 FEB 5
PY 2015
VL 518
IS 7537
BP 107
EP +
DI 10.1038/nature13905
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7LE
UT WOS:000349098000041
PM 25409146
DA 2026-03-09
ER

PT J
AU Webb, BA
   Forouhar, F
   Szu, FE
   Seetharaman, J
   Tong, L
   Barber, DL
AF Webb, Bradley A.
   Forouhar, Farhad
   Szu, Fu-En
   Seetharaman, Jayaraman
   Tong, Liang
   Barber, Diane L.
TI Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations
SO NATURE
LA English
DT Article
ID skeletal-muscle 6-phosphofructo-1-kinase; allosteric regulation; crystal-structure; platelet isoform; glycolysis; enzyme; system; sites; cells; atp
AB Phosphofructokinase-1 (PFK1), the 'gatekeeper' of glycolysis, catalyses the committed step of the glycolytic pathway by converting fructose-6-phosphate to fructose-1,6-bisphosphate. Allosteric activation and inhibition of PFK1 by over ten metabolites and in response to hormonal signalling fine-tune glycolytic flux to meet energy requirements(1). Mutations inhibiting PFK1 activity cause glycogen storage disease type VII, also known as Tarui disease(2), and mice deficient in muscle PFK1 have decreased fat stores(3). Additionally, PFK1 is proposed to have important roles in metabolic reprogramming in cancer(4,5). Despite its critical role in glucose flux, the biologically relevant crystal structure of the mammalian PFK1 tetramer has not been determined. Here we report the first structures of the mammalian PFK1 tetramer, for the human platelet isoform (PFKP), in complex with ATP-Mg2+ and ADP at 3.1 and 3.4 angstrom, respectively. The structures reveal substantial conformational changes in the enzyme upon nucleotide hydrolysis as well as a unique tetramer interface. Mutations of residues in this interface can affect tetramer formation, enzyme catalysis and regulation, indicating the functional importance of the tetramer. With altered glycolytic flux being a hallmark of cancers(6), these new structures allow a molecular understanding of the functional consequences of somatic PFK1 mutations identified in human cancers. We characterize three of these mutations and show they have distinct effects on allosteric regulation of PFKP activity and lactate production. The PFKP structural blueprint for somatic mutations as well as the catalytic site can guide therapeutic targeting of PFK1 activity to control dysregulated glycolysis in disease.
C1 [Webb, Bradley A.; Barber, Diane L.] Univ Calif San Francisco, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA.
   [Forouhar, Farhad; Szu, Fu-En; Seetharaman, Jayaraman; Tong, Liang] Columbia Univ, Dept Biol Sci, Northeast Struct Genom Consortium, New York, NY 10027 USA.
C3 University of California System; University of California San Francisco; Columbia University
RP Barber, DL (corresponding author), Univ Calif San Francisco, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA.
EM ltong@columbia.edu; diane.barber@ucsf.edu
FU National Institutes of Health [R01 GM047413]; Canadian Institutes of Health Research; University of California, San Francisco, Liver Center [P30 DK026743]; Protein Structure Initiative of the National Institutes of Health [U54-GM094597]; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK026743] Funding Source: NIH RePORTER
NR 40
TC 120
Z9 143
U1 1
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 JUL 2
PY 2015
VL 523
IS 7558
BP 111
EP +
DI 10.1038/nature14405
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CL7RN
UT WOS:000357169500042
PM 25985179
DA 2026-03-09
ER

PT J
AU Liu, N
   Dai, Q
   Zheng, GQ
   He, C
   Parisien, M
   Pan, T
AF Liu, Nian
   Dai, Qing
   Zheng, Guanqun
   He, Chuan
   Parisien, Marc
   Pan, Tao
TI N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions
SO NATURE
LA English
DT Article
ID messenger-rna; hnrnp c; secondary structure; nuclear-rna; reveals; transcriptome; resolution
AB RNA-binding proteins control many aspects of cellular biology through binding single-stranded RNA binding motifs (RBMs)(1-3). However, RBMs can be buried within their local RNA structures'', thus inhibiting RNA-protein interactions. N-6-methyladenosine (m(6)A), the most abundant and dynamic internal modification in eulcaryotic messenger RNA(8-19), can be selectively recognized by the YTHDF2 protein to affect the stability of cytoplasmic mRNAs(15), but how m(6)A achieves its wide-ranging physiological role needs further exploration. Here we show in human cells that m(6)A controls the RNA-structuredependent accessibility of RBMs to affect RNA-protein interactions for biological regulation; we term this mechanism 'the m6A-switch'. We found that m(6)A alters the local structure in mRNA and long non-coding RNA (IncRNA) to facilitate binding of heterogeneous nuclear ribonudeoprotein C (HNRNPC), an abundant nuclear RNAbinding protein responsible for pre-mRNA processing'. Combining photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) and anti-m(6)A immunoprecipitation (MeRIP) approaches enabled us to identify 39,060 m(6)A-switches among HNRNPC-binding sites; and global m(6)A reduction decreased HNRNPC binding at 2,798 high-confidence m(6)A-switches. We determined that these m(6)A-switch-regulated HNRNPC-binding activities affect the abundance as well as alternative splicing of target mRNAs, demonstrating the regulatory role of m(6)A-switches on gene expression and RNA maturation. Our results illustrate how RNA-binding proteins gain regulated access to their RBMs through m6A-dependent RNA structural remodelling, and provide a new direction for investigating RNA-modification-coded cellular biology.
C1 [Liu, Nian; Dai, Qing; He, Chuan] Univ Chicago, Dept Chem, Chicago, IL 60637 USA.
   [Zheng, Guanqun; He, Chuan; Parisien, Marc; Pan, Tao] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA.
   [He, Chuan; Pan, Tao] Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA.
   [He, Chuan] Univ Chicago, Howard Hughes Med Inst, Chicago, IL 60637 USA.
C3 University of Chicago; University of Chicago; University of Chicago; University of Chicago; Howard Hughes Medical Institute
RP Parisien, M (corresponding author), McGill Univ, Fac Dent, Montreal, PQ H3A 0G1, Canada.
EM marc.parisien@mcgill.ca; taopan@uchicago.edu
FU National Institutes of Health EUREKA [GM088599];  [K01HG006699]
NR 30
TC 1648
Z9 1919
U1 12
U2 509
PU NATURE PUBLISHING 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 26
PY 2015
VL 518
IS 7540
BP 560
EP 564
DI 10.1038/nature14234
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC1JP
UT WOS:000350097300052
PM 25719671
DA 2026-03-09
ER

PT J
AU Ziller, MJ
   Edri, R
   Yaffe, Y
   Donaghey, J
   Pop, R
   Mallard, W
   Issner, R
   Gifford, CA
   Goren, A
   Xing, J
   Gu, HC
   Cacchiarelli, D
   Tsankov, AM
   Epstein, C
   Rinn, JL
   Mikkelsen, TS
   Kohlbacher, O
   Gnirke, A
   Bernstein, BE
   Elkabetz, Y
   Meissner, A
AF Ziller, Michael J.
   Edri, Reuven
   Yaffe, Yakey
   Donaghey, Julie
   Pop, Ramona
   Mallard, William
   Issner, Robbyn
   Gifford, Casey A.
   Goren, Alon
   Xing, Jeffrey
   Gu, Hongcang
   Cacchiarelli, Davide
   Tsankov, Alexander M.
   Epstein, Charles
   Rinn, John L.
   Mikkelsen, Tarjei S.
   Kohlbacher, Oliver
   Gnirke, Andreas
   Bernstein, Bradley E.
   Elkabetz, Yechiel
   Meissner, Alexander
TI Dissecting neural differentiation regulatory networks through epigenetic footprinting
SO NATURE
LA English
DT Article
ID partial least-squares; coup-tfi; human es; dna; expression; binding; cells; gene; regionalization; identification
AB Models derived from human pluripotent stem cells that accurately recapitulate neural development in vitro and allow for the generation of specific neuronal subtypes are of major interest to the stem cell and biomedical community. Notch signalling, particularly through the Notch effector HES5, is a major pathway critical for the onset and maintenance of neural progenitor cells in the embryonic and adult nervous system(1-3). Here we report the transcriptional and epigenomic analysis of six consecutive neural progenitor cell stages derived from a HES5::eGFPreporter human embryonic stem cell line(4). Using this system, we aimed to model cell-fate decisions including specification, expansion and patterning during the ontogeny of cortical neural stem and progenitor cells. In order to dissect regulatory mechanisms that orchestrate the stage-specific differentiation process, we developed a computational framework to infer key regulators of each cell-state transition based on the progressive remodelling of the epigenetic landscape and then validated these through a pooled short hairpin RNA screen. We were also able to refine our previous observations on epigenetic priming at transcription factor binding sites and suggest here that they are mediated by combinations of core and stage-specific factors. Taken together, we demonstrate the utility of our system and outline a general framework, not limited to the context of the neural lineage, to dissect regulatory circuits of differentiation.
C1 [Ziller, Michael J.; Donaghey, Julie; Pop, Ramona; Mallard, William; Issner, Robbyn; Gifford, Casey A.; Goren, Alon; Xing, Jeffrey; Gu, Hongcang; Cacchiarelli, Davide; Tsankov, Alexander M.; Epstein, Charles; Rinn, John L.; Mikkelsen, Tarjei S.; Gnirke, Andreas; Bernstein, Bradley E.; Meissner, Alexander] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
   [Ziller, Michael J.; Donaghey, Julie; Pop, Ramona; Gifford, Casey A.; Tsankov, Alexander M.; Rinn, John L.; Meissner, Alexander] Harvard Stem Cell Inst, Cambridge, MA 02138 USA.
   [Ziller, Michael J.; Donaghey, Julie; Pop, Ramona; Mallard, William; Gifford, Casey A.; Tsankov, Alexander M.; Rinn, John L.; Meissner, Alexander] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.
   [Edri, Reuven; Yaffe, Yakey; Elkabetz, Yechiel] Tel Aviv Univ, Dept Cell & Dev Biol, Sackler Sch Med, IL-6997801 Ramat Aviv, Israel.
   [Goren, Alon; Bernstein, Bradley E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.
   [Goren, Alon; Bernstein, Bradley E.] Harvard Univ, Sch Med, Boston, MA 02114 USA.
   [Goren, Alon; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA.
   [Goren, Alon; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA.
   [Kohlbacher, Oliver] Univ Tubingen, Ctr Bioinformat, D-72076 Tubingen, Germany.
   [Kohlbacher, Oliver] Univ Tubingen, Quantitat Biol Ctr, D-72076 Tubingen, Germany.
C3 Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University; Tel Aviv University; Sackler Faculty of Medicine; 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; Eberhard Karls University of Tubingen; Eberhard Karls University of Tubingen
RP Elkabetz, Y (corresponding author), Tel Aviv Univ, Dept Cell & Dev Biol, Sackler Sch Med, IL-6997801 Ramat Aviv, Israel.
EM elkabetz@tauex.tau.ac.il; alexander_meissner@harvard.edu
FU NIH [U01ES017155]; NHGRI [HG006911]; NIGMS [P01GM099117]; New York Stem Cell Foundation; Israel Science Foundation (ISF) [1126/10, 1710/10]; Marie Curie International Reintegration Grant [IRG277151]; Charles H. Hood Foundation; National Institute of General Medical Sciences [P01GM099117] Funding Source: NIH RePORTER
NR 63
TC 152
Z9 187
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 FEB 19
PY 2015
VL 518
IS 7539
BP 355
EP 359
DI 10.1038/nature13990
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400033
PM 25533951
DA 2026-03-09
ER

PT J
AU Perez, C
   Gerber, S
   Boilevin, J
   Bucher, M
   Darbre, T
   Aebi, M
   Reymond, JL
   Locher, KP
AF Perez, Camilo
   Gerber, Sabina
   Boilevin, Jeremy
   Bucher, Monika
   Darbre, Tamis
   Aebi, Markus
   Reymond, Jean-Louis
   Locher, Kaspar P.
TI Structure and mechanism of an active lipid-linked oligosaccharide flippase
SO NATURE
LA English
DT Article
ID binding cassette transporter; x-ray-structure; atp-binding; campylobacter-jejuni; escherichia-coli; transbilayer translocation; crystal-structure; glycosylation; dolichol; export
AB The flipping of membrane-embedded lipids containing large, polar head groups is slow and energetically unfavourable, and is therefore catalysed by flippases, the mechanisms of which are unknown. A prominent example of a flipping reaction is the translocation of lipid-linked oligosaccharides that serve as donors in N-linked protein glycosylation. In Campylobacter jejuni, this process is catalysed by the ABC transporter PglK. Here we present a mechanism of PglK-catalysed lipid-linked oligosaccharide flipping based on crystal structures in distinct states, a newly devised in vitro flipping assay, and in vivo studies. PglK can adopt inward-and outward-facing conformations in vitro, but only outward-facing states are required for flipping. While the pyrophosphate-oligosaccharide head group of lipid-linked oligosaccharides enters the translocation cavity and interacts with positively charged side chains, the lipidic polyprenyl tail binds and activates the transporter but remains exposed to the lipid bilayer during the reaction. The proposed mechanism is distinct from the classical alternating-access model applied to other transporters.
C1 [Perez, Camilo; Gerber, Sabina; Bucher, Monika; Locher, Kaspar P.] ETH, Inst Mol Biol & Biophys, CH-8093 Zurich, Switzerland.
   [Boilevin, Jeremy; Darbre, Tamis; Reymond, Jean-Louis] Univ Bern, Dept Chem & Biochem, CH-3012 Bern, Switzerland.
   [Aebi, Markus] ETH, Inst Microbiol, CH-8093 Zurich, Switzerland.
C3 Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Bern; Swiss Federal Institutes of Technology Domain; ETH Zurich
RP Locher, KP (corresponding author), ETH, Inst Mol Biol & Biophys, CH-8093 Zurich, Switzerland.
EM locher@mol.biol.ethz.ch
FU Swiss National Science Foundation (SNF) [31003A-146191]; ETH; Swiss National Science Foundation (SNF) [31003A_146191] Funding Source: Swiss National Science Foundation (SNF)
NR 61
TC 169
Z9 201
U1 1
U2 140
PU NATURE PUBLISHING 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 27
PY 2015
VL 524
IS 7566
BP 433
EP +
DI 10.1038/nature14953
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP7LN
UT WOS:000360069300030
PM 26266984
DA 2026-03-09
ER

PT J
AU Benson, E
   Mohammed, A
   Gardell, J
   Masich, S
   Czeizler, E
   Orponen, P
   Högberg, B
AF Benson, Erik
   Mohammed, Abdulmelik
   Gardell, Johan
   Masich, Sergej
   Czeizler, Eugen
   Orponen, Pekka
   Hogberg, Bjorn
TI DNA rendering of polyhedral meshes at the nanoscale
SO NATURE
LA English
DT Article
ID single-stranded-dna; folding dna; origami; shapes; nanostructures; junctions
AB It was suggested(1) more than thirty years ago that Watson-Crick base pairing might be used for the rational design of nanometre-scale structures from nucleic acids. Since then, and especially since the introduction of the origami technique(2), DNA nanotechnology has enabled increasingly more complex structures(3-18). But although general approaches for creating DNA origami polygonal meshes and design software are available(14,16,17,19-21), there are still important constraints arising from DNA geometry and sense/antisense pairing, necessitating some manual adjustment during the design process. Here we present a general method of folding arbitrary polygonal digital meshes in DNA that readily produces structures that would be very difficult to realize using previous approaches. The design process is highly automated, using a routeing algorithm based on graph theory and a relaxation simulation that traces scaffold strands through the target structures. Moreover, unlike conventional origami designs built from close-packed helices, our structures have a more open conformation with one helix per edge and are therefore stable under the ionic conditions usually used in biological assays.
C1 [Benson, Erik; Gardell, Johan; Hogberg, Bjorn] Karolinska Inst, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden.
   [Benson, Erik; Gardell, Johan; Hogberg, Bjorn] Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden.
   [Mohammed, Abdulmelik; Czeizler, Eugen; Orponen, Pekka] Aalto Univ, Dept Comp Sci, FI-00076 Aalto, Finland.
   [Masich, Sergej] Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden.
C3 Karolinska Institutet; Karolinska Institutet; Aalto University; Karolinska Institutet
RP Högberg, B (corresponding author), Karolinska Inst, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden.
EM bjorn.hogberg@ki.se
FU Swedish Research Council [2010-5060, 2013-5883]; Swedish Foundation for Strategic Research [FFL12-0219]; Knut and Alice Wallenberg foundation [KAW2014.0241]; Wallenberg Scholars grant; Helsinki Doctoral Education Network on Information and Communications Technology; Swedish Foundation for Strategic Research (SSF) [FFL12-0219] Funding Source: Swedish Foundation for Strategic Research (SSF)
CR Amir Y, 2014, NAT NANOTECHNOL, V9, P353, DOI 10.1038/NNANO.2014.58
   Andersen ES, 2009, NATURE, V459, P73, DOI 10.1038/nature07971
   Bhatia D, 2009, ANGEW CHEM INT EDIT, V48, P4134, DOI 10.1002/anie.200806000
   CHEN JH, 1991, NATURE, V350, P631, DOI 10.1038/350631a0
   Dietz H, 2009, SCIENCE, V325, P725, DOI 10.1126/science.1174251
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NR 30
TC 559
Z9 686
U1 7
U2 333
PU NATURE PUBLISHING 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 23
PY 2015
VL 523
IS 7561
BP 441
EP U139
DI 10.1038/nature14586
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CN4DD
UT WOS:000358378900032
PM 26201596
DA 2026-03-09
ER

PT J
AU von der Ecken, J
   Müller, M
   Lehman, W
   Manstein, DJ
   Penczek, PA
   Raunser, S
AF von der Ecken, Julian
   Mueller, Mirco
   Lehman, William
   Manstein, Dietmar J.
   Penczek, Pawel A.
   Raunser, Stefan
TI Structure of the F-actin-tropomyosin complex
SO NATURE
LA English
DT Article
ID nemaline myopathy; gene acta1; electron-microscopy; muscle actin; cryo-em; crystal-structure; gestalt-binding; atomic model; mutations; filament
AB Filamentous actin (F-actin) is the major protein of muscle thin filaments, and actin microfilaments are the main component of the eukaryotic cytoskeleton. Mutations in different actin isoforms lead to early-onset autosomal dominant non-syndromic hearing loss(1), familial thoracic aortic aneurysms and dissections(2), and multiple variations of myopathies(3). In striated muscle fibres, the binding of myosin motors to actin filaments is mainly regulated by tropomyosin and troponin(4,5). Tropomyosin also binds to F-actin in smooth muscle and in non-muscle cells and stabilizes and regulates the filaments there in the absence of troponin(6). Although crystal structures for monomeric actin (G-actin) are available(7), a high-resolution structure of F-actin is still missing, hampering our understanding of how disease-causing mutations affect the function of thin muscle filaments and microfilaments. Here we report the three-dimensional structure of F-actin at a resolution of 3.7 angstrom in complex with tropomyo sin at a resolution of 6.5 angstrom, determined by electron cryomicroscopy. The structure reveals that the D-loop is ordered and acts as a central region for hydrophobic and electrostatic interactions that stabilize the F-actin filament. We clearly identify map density corresponding to ADP and Mg2+ and explain the possible effect of prominent disease-causing mutants. A comparison of F-actin with G-actin reveals the conformational changes during filament formation and identifies the D-loop as their key mediator. We also confirm that negatively charged tropomyosin interacts with a positively charged groove on F-actin. Comparison of the position of tropomyosin in F-actin-tropomyosin with its position in our previously determined F-actin-tropomyosin-myosin structure(8) reveals a myosin-induced transition of tropomyosin. Our results allow us to understand the role of individual mutations in the genesis of actin- and tropomyosin-related diseases and will serve as a strong foundation for the targeted development of drugs.
C1 [von der Ecken, Julian; Raunser, Stefan] Max Planck Inst Mol Physiol, Dept Struct Biochem, D-44227 Dortmund, Germany.
   [Mueller, Mirco; Manstein, Dietmar J.] Hannover Med Sch, Inst Biophys Chem, D-30625 Hannover, Germany.
   [Lehman, William] Boston Univ, Sch Med, Dept Physiol & Biophys, Boston, MA 02118 USA.
   [Penczek, Pawel A.] Univ Texas Houston, Houston Med Sch, Dept Biochem & Mol Biol, Houston, TX 77030 USA.
C3 Max Planck Society; Hannover Medical School; Boston University; University of Texas System; University of Texas Health Science Center Houston
RP Raunser, S (corresponding author), Max Planck Inst Mol Physiol, Dept Struct Biochem, D-44227 Dortmund, Germany.
EM stefan.raunser@mpi-dortmund.mpg.de
FU Nederlandse Organisatie voor Wetenschappelijk Onderzoek [175.010.2009.001]; European Union's Regional Development Fund through 'Kansen voor West' [21Z.014]; Behrens-Weise foundation; NIH [U54 094598, R01 60635]; DFG [MA1081/19-1, R37HL036153]
NR 66
TC 310
Z9 361
U1 3
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 5
PY 2015
VL 519
IS 7541
BP 114
EP U272
DI 10.1038/nature14033
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC4EQ
UT WOS:000350304000047
PM 25470062
DA 2026-03-09
ER

PT J
AU Schwarz, LA
   Miyamichi, K
   Gao, XJJ
   Beier, KT
   Weissbourd, B
   DeLoach, KE
   Ren, J
   Ibanes, S
   Malenka, RC
   Kremer, EJ
   Luo, LQ
AF Schwarz, Lindsay A.
   Miyamichi, Kazunari
   Gao, Xiaojing J.
   Beier, Kevin T.
   Weissbourd, Brandon
   DeLoach, Katherine E.
   Ren, Jing
   Ibanes, Sandy
   Malenka, Robert C.
   Kremer, Eric J.
   Luo, Liqun
TI Viral-genetic tracing of the input-output organization of a central noradrenaline circuit
SO NATURE
LA English
DT Article
ID locus-coeruleus neurons; canine adenovirus vectors; double-labeling technique; brain-stem neurons; afferent-projections; retrograde transport; cre-recombinase; basal ganglia; cell-body; system
AB Deciphering how neural circuits are anatomically organized with regard to input and output is instrumental in understanding how the brain processes information. For example, locus coeruleus noradrenaline (also known as norepinephrine) (LC-NE) neurons receive input from and send output to broad regions of the brain and spinal cord, and regulate diverse functions including arousal, attention, mood and sensory gating(1-8). However, it is unclear how LC-NE neurons divide up their brain-wide projection patterns and whether different LC-NE neurons receive differential input. Here we developed a set of viral-genetic tools to quantitatively analyse the input-output relationship of neural circuits, and applied these tools to dissect the LC-NE circuit in mice. Rabies-virus-based input mapping indicated that LC-NE neurons receive convergent synaptic input from many regions previously identified as sending axons to the locus coeruleus, as well as from newly identified presynaptic partners, including cerebellar Purkinje cells. The 'tracing the relationship between input and output' method (or TRIO method) enables trans-synaptic input tracing from specific subsets of neurons based on their projection and cell type. We found that LC-NE neurons projecting to diverse output regions receive mostly similar input. Projection-based viral labelling revealed that LC-NE neurons projecting to one output region also project to all brain regions we examined. Thus, the LC-NE circuit overall integrates information from, and broadcasts to, many brain regions, consistent with its primary role in regulating brain states. At the same time, we uncovered several levels of specificity in certain LC-NE sub-circuits. These tools for mapping output architecture and input-output relationship are applicable to other neuronal circuits and organisms. More broadly, our viral-genetic approaches provide an efficient intersectional means to target neuronal populations based on cell type and projection pattern.
C1 [Schwarz, Lindsay A.; Miyamichi, Kazunari; Gao, Xiaojing J.; Beier, Kevin T.; Weissbourd, Brandon; DeLoach, Katherine E.; Ren, Jing; Luo, Liqun] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.
   [Schwarz, Lindsay A.; Miyamichi, Kazunari; Gao, Xiaojing J.; Beier, Kevin T.; Weissbourd, Brandon; DeLoach, Katherine E.; Ren, Jing; Luo, Liqun] Stanford Univ, Dept Biol, Stanford, CA 94305 USA.
   [Miyamichi, Kazunari] Univ Tokyo, Dept Appl Biol Chem, Grad Sch Agr & Life Sci, Tokyo 1138657, Japan.
   [Beier, Kevin T.; Malenka, Robert C.] Stanford Univ, Sch Med, Nancy Pritzker Lab, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA.
   [Ibanes, Sandy; Kremer, Eric J.] Inst Genet Mol Montpellier, CNRS 5535, F-34293 Montpellier, France.
   [Kremer, Eric J.] Univ Montpellier, F-34000 Montpellier, France.
C3 Howard Hughes Medical Institute; Stanford University; Stanford University; University of Tokyo; Stanford University; Universite de Montpellier; Centre National de la Recherche Scientifique (CNRS); Universite de Montpellier
RP Luo, LQ (corresponding author), Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.
EM lluo@stanford.edu
FU Ruth L. Kirschstein National Service Research Award from NIMH; Stanford Bio-X Enlight Foundation Interdisciplinary Fellowship; Stanford Graduate Fellowship; NSF Graduate Research Fellowship; EU FP7 BrainVector [286071]; HHMI Collaborative Innovation Award
NR 39
TC 544
Z9 643
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 AUG 6
PY 2015
VL 524
IS 7563
BP 88
EP U180
DI 10.1038/nature14600
PG 18
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CO2QS
UT WOS:000359002300037
PM 26131933
DA 2026-03-09
ER

PT J
AU Corde, S
   Adli, E
   Allen, JM
   An, W
   Clarke, CI
   Clayton, CE
   Delahaye, JP
   Frederico, J
   Gessner, S
   Green, SZ
   Hogan, MJ
   Joshi, C
   Lipkowitz, N
   Litos, M
   Lu, W
   Marsh, KA
   Mori, WB
   Schmeltz, M
   Vafaei-Najafabadi, N
   Walz, D
   Yakimenko, V
   Yocky, G
AF Corde, S.
   Adli, E.
   Allen, J. M.
   An, W.
   Clarke, C. I.
   Clayton, C. E.
   Delahaye, J. P.
   Frederico, J.
   Gessner, S.
   Green, S. Z.
   Hogan, M. J.
   Joshi, C.
   Lipkowitz, N.
   Litos, M.
   Lu, W.
   Marsh, K. A.
   Mori, W. B.
   Schmeltz, M.
   Vafaei-Najafabadi, N.
   Walz, D.
   Yakimenko, V.
   Yocky, G.
TI Multi-gigaelectronvolt acceleration of positrons in a self-loaded plasma wakefield
SO NATURE
LA English
DT Article
ID code; electrons; osiris
AB Electrical breakdown sets a limit on the kinetic energy that particles in a conventional radio-frequency accelerator can reach. New accelerator concepts must be developed to achieve higher energies and to make future particle colliders more compact and affordable. The plasma wakefield accelerator (PWFA) embodies one such concept, in which the electric field of a plasma wake excited by a bunch of charged particles (such as electrons) is used to accelerate a trailing bunch of particles. To apply plasma acceleration to electron-positron colliders, it is imperative that both the electrons and their antimatter counterpart, the positrons, are efficiently accelerated at high fields using plasmas(1). Although substantial progress has recently been reported on high-field, high-efficiency acceleration of electrons in a PWFA powered by an electron bunch(2), such an electron-driven wake is unsuitable for the acceleration and focusing of a positron bunch. Here we demonstrate a new regime of PWFAs where particles in the front of a single positron bunch transfer their energy to a substantial number of those in the rear of the same bunch by exciting a wakefield in the plasma. In the process, the accelerating field is altered-'self-loaded'-so that about a billion positrons gain five gigaelectronvolts of energy with a narrow energy spread over a distance of just 1.3 metres. They extract about 30 per cent of the wake's energy and form a spectrally distinct bunch with a root-mean-square energy spread as low as 1.8 per cent. This ability to transfer energy efficiently from the front to the rear within a single positron bunch makes the PWFA scheme very attractive as an energy booster to an electron-positron collider.
C1 [Corde, S.; Adli, E.; Allen, J. M.; Clarke, C. I.; Delahaye, J. P.; Frederico, J.; Gessner, S.; Green, S. Z.; Hogan, M. J.; Lipkowitz, N.; Litos, M.; Schmeltz, M.; Walz, D.; Yakimenko, V.; Yocky, G.] SLAC Natl Accelerator Lab, Menlo Pk, CA 94025 USA.
   [Corde, S.] Univ Paris Saclay, Ecole Polytech, CNRS, LOA,ENSTA ParisTech, F-91762 Palaiseau, France.
   [Adli, E.] Univ Oslo, Dept Phys, N-0316 Oslo, Norway.
   [An, W.; Clayton, C. E.; Joshi, C.; Marsh, K. A.; Mori, W. B.; Vafaei-Najafabadi, N.] Univ Calif Los Angeles, Dept Elect Engn, Los Angeles, CA 90095 USA.
   [An, W.; Mori, W. B.] Univ Calif Los Angeles, Dept Phys & Astron, Los Angeles, CA 90095 USA.
   [Lu, W.] Tsinghua Univ, Dept Engn Phys, Beijing 100084, Peoples R China.
C3 Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; Institut Polytechnique de Paris; ENSTA Paris; Centre National de la Recherche Scientifique (CNRS); Ecole Polytechnique; Universite Paris Saclay; University of Oslo; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; Tsinghua University
RP Corde, S (corresponding author), SLAC Natl Accelerator Lab, Menlo Pk, CA 94025 USA.
EM corde@slac.stanford.edu
FU United States Department of Energy (US DOE); DOE [DE-AC02-76SF00515, DE-SC0010064, DE-SC0008491, DE-SC0008316]; Research Council of Norway; NSF [ACI-1339893, PHY-0960344]; NSFC [11425521, 11175102]; National Basic Research Program of China [2013CBA01501]; Direct For Computer & Info Scie & Enginr [1440071] Funding Source: National Science Foundation; Office of Advanced Cyberinfrastructure (OAC) [1440071] Funding Source: National Science Foundation
NR 30
TC 138
Z9 166
U1 3
U2 84
PU NATURE PUBLISHING 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 27
PY 2015
VL 524
IS 7566
BP 442
EP +
DI 10.1038/nature14890
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CP7LN
UT WOS:000360069300032
PM 26310764
DA 2026-03-09
ER

PT J
AU Zhang, CZ
   Spektor, A
   Cornils, H
   Francis, JM
   Jackson, EK
   Liu, SW
   Meyerson, M
   Pellman, D
AF Zhang, Cheng-Zhong
   Spektor, Alexander
   Cornils, Hauke
   Francis, Joshua M.
   Jackson, Emily K.
   Liu, Shiwei
   Meyerson, Matthew
   Pellman, David
TI Chromothripsis from DNA damage in micronuclei
SO NATURE
LA English
DT Article
ID genomic rearrangements; cancer genm; double minutes; mechanisms; evolution; repair; breaks; amplification; architecture; chromosm
AB Genome sequencing has uncovered a new mutational phenomenon in cancer and congenital disorders called chromothripsis. Chromothripsis is characterized by extensive genomic rearrangements and an oscillating pattern of DNA copy number levels, all curiously restricted to one or a few chromosomes. The mechanism for chromothripsis is unknown, but we previously proposed that it could occur through the physical isolation of chromosomes in aberrant nuclear structures called micronuclei. Here, using a combination of live cell imaging and single-cell genome sequencing, we demonstrate that micronucleus formation can indeed generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. These events are restricted to the mis-segregated chromosome and occur within one cell division. We demonstrate that the mechanism for chromothripsis can involve the fragmentation and subsequent reassembly of a single chromatid from a micronucleus. Collectively, these experiments establish a new mutational process of which chromothripsis is one extreme outcome.
C1 [Zhang, Cheng-Zhong; Francis, Joshua M.; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.
   [Zhang, Cheng-Zhong; Spektor, Alexander; Cornils, Hauke; Jackson, Emily K.; Liu, Shiwei; Pellman, David] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.
   [Zhang, Cheng-Zhong; Francis, Joshua M.; Meyerson, Matthew; Pellman, David] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.
   [Zhang, Cheng-Zhong; Spektor, Alexander; Cornils, Hauke; Jackson, Emily K.; Liu, Shiwei; Pellman, David] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA.
   [Spektor, Alexander] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA.
   [Jackson, Emily K.; Pellman, David] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
   [Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA.
   [Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA.
C3 Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Howard Hughes Medical Institute; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute
RP Pellman, D (corresponding author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.
EM david_pellman@dfci.harvard.edu
FU Bridge Project of the Dana-Farber Cancer Institute; Koch Institute of MIT; Claudia Adams Barr Program in Innovative Cancer Research; NIH [GM083299-18]; National Institute of General Medical Sciences [R37GM061345] Funding Source: NIH RePORTER
NR 34
TC 872
Z9 1039
U1 4
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 JUN 11
PY 2015
VL 522
IS 7555
BP 179
EP +
DI 10.1038/nature14493
PG 27
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CK2CI
UT WOS:000356016700031
PM 26017310
DA 2026-03-09
ER

PT J
AU Kimsey, IJ
   Petzold, K
   Sathyamoorthy, B
   Stein, ZW
   Al-Hashimi, HM
AF Kimsey, Isaac J.
   Petzold, Katja
   Sathyamoorthy, Bharathwaj
   Stein, Zachary W.
   Al-Hashimi, Hashim M.
TI Visualizing transient Watson-Crick-like mispairs in DNA and RNA duplexes
SO NATURE
LA English
DT Article
ID rare tautomer hypothesis; structural basis; rotating-frame; nucleic-acids; base-pair; n-15 nmr; relaxation dispersion; chemical-exchange; polymerase-i; replication
AB Rare tautomeric and anionic nucleobases are believed to have fundamental biological roles, but their prevalence and functional importance has remained elusive because they exist transiently, in low abundance, and involve subtle movements of protons that are difficult to visualize. Using NMR relaxation dispersion, we show here that wobble dG.dT and rG.rU mispairs in DNA and RNA duplexes exist in dynamic equilibrium with short-lived, low-populated Watson-Crick-like mispairs that are stabilized by rare enolic or anionic bases. These mispairs can evade Watson-Crick fidelity checkpoints and form with probabilities (10(-3) to 10(-5)) that strongly imply a universal role in replication and translation errors. Our results indicate that rare tautomeric and anionic bases are widespread in nucleic acids, expanding their structural and functional complexity beyond that attainable with canonical bases.
C1 [Kimsey, Isaac J.; Sathyamoorthy, Bharathwaj; Al-Hashimi, Hashim M.] Duke Univ Med Ctr, Dept Biochem & Chem, Durham, NC 27710 USA.
   [Petzold, Katja] Karolinska Inst, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden.
   [Stein, Zachary W.] Univ Michigan, Ann Arbor, MI 48109 USA.
C3 Duke University; Karolinska Institutet; University of Michigan System; University of Michigan
RP Al-Hashimi, HM (corresponding author), Duke Univ Med Ctr, Dept Biochem & Chem, Durham, NC 27710 USA.
EM hashim.al.hashimi@duke.edu
FU NIH [R01GM089846]; Agilent Thought Leader Award; National Institute of General Medical Sciences [R01GM089846] Funding Source: NIH RePORTER
NR 77
TC 208
Z9 240
U1 1
U2 101
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD MAR 19
PY 2015
VL 519
IS 7543
BP 315
EP +
DI 10.1038/nature14227
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CD6AY
UT WOS:000351171900033
PM 25762137
DA 2026-03-09
ER

PT J
AU Taniguchi, K
   Wu, LW
   Grivennikov, SI
   de Jong, PR
   Lian, I
   Yu, FX
   Wang, KP
   Ho, SB
   Boland, BS
   Chang, JT
   Sandborn, WJ
   Hardiman, G
   Raz, E
   Maehara, Y
   Yoshimura, A
   Zucman-Rossi, J
   Guan, KL
   Karin, M
AF Taniguchi, Koji
   Wu, Li-Wha
   Grivennikov, Sergei I.
   de Jong, Petrus R.
   Lian, Ian
   Yu, Fa-Xing
   Wang, Kepeng
   Ho, Samuel B.
   Boland, Brigid S.
   Chang, John T.
   Sandborn, William J.
   Hardiman, Gary
   Raz, Eyal
   Maehara, Yoshihiko
   Yoshimura, Akihiko
   Zucman-Rossi, Jessica
   Guan, Kun-Liang
   Karin, Michael
TI A gp130-Src-YAP module links inflammation to epithelial regeneration
SO NATURE
LA English
DT Article
ID in-vitro; intestinal regeneration; stem-cells; pathway; yap; stat3; il-6; src; tumorigenesis; activation
AB Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that 0130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.
C1 [Taniguchi, Koji; Wu, Li-Wha; Grivennikov, Sergei I.; Wang, Kepeng; Karin, Michael] Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA.
   [Taniguchi, Koji; Lian, Ian; Yu, Fa-Xing; Guan, Kun-Liang; Karin, Michael] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA.
   [Taniguchi, Koji; Lian, Ian; Yu, Fa-Xing; Guan, Kun-Liang; Karin, Michael] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA.
   [Taniguchi, Koji; Maehara, Yoshihiko] Kyushu Univ, Grad Sch Med Sci, Dept Surg & Sci, Fukuoka 8128582, Japan.
   [Taniguchi, Koji; Yoshimura, Akihiko] Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo 1608582, Japan.
   [Wu, Li-Wha] Natl Cheng Kung Univ, Coll Med, Inst Mol Med, Tainan 70101, Taiwan.
   [Grivennikov, Sergei I.] Fox Chase Canc Ctr, Canc Prevent & Control Program, Philadelphia, PA 19111 USA.
   [de Jong, Petrus R.; Raz, Eyal] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA.
   [Lian, Ian; Yu, Fa-Xing; Guan, Kun-Liang; Karin, Michael] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA.
   [Lian, Ian] Lamar Univ, Dept Biol, Beaumont, TX 77710 USA.
   [Yu, Fa-Xing] Fudan Univ, Childrens Hosp, Shanghai 200032, Peoples R China.
   [Yu, Fa-Xing] Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China.
   [Ho, Samuel B.] VA San Diego Healthcare Syst, Dept Med, San Diego, CA 92161 USA.
   [Boland, Brigid S.; Chang, John T.; Sandborn, William J.] Univ Calif San Diego, Sch Med, Dept Med, Inflammatory Bowel Dis Ctr,Div Gastroenterol, La Jolla, CA 92093 USA.
   [Hardiman, Gary] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA.
   [Hardiman, Gary] San Diego State Univ, CSRC, San Diego, CA 92182 USA.
   [Hardiman, Gary] San Diego State Univ, BIMRC, San Diego, CA 92182 USA.
   [Yoshimura, Akihiko] Japan Sci & Technol Agcy, CREST, Tokyo 1020076, Japan.
   [Zucman-Rossi, Jessica] IUH, INSERM, UMR 1162, F-75010 Paris, France.
   [Zucman-Rossi, Jessica] Univ Paris 05, Sorbonne Paris Cite, Fac Med, Labex Immunooncol, F-75006 Paris, France.
C3 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; Kyushu University; Keio University; National Cheng Kung University; Fox Chase Cancer Center; University of California System; University of California San Diego; University of California System; University of California San Diego; Texas State University System; Lamar University; Fudan University; Fudan University; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA San Diego Healthcare System; University of California System; University of California San Diego; Medical University of South Carolina; California State University System; San Diego State University; California State University System; San Diego State University; Japan Science & Technology Agency (JST); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Universite Paris Cite
RP Karin, M (corresponding author), Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA.
EM karinoffice@ucsd.edu
FU Japan Society for the Promotion of Science; Uehara Memorial Foundation Fellowship; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Kanae Foundation for the Promotion of Medical Science; National Science Council of Taiwan [NSC-101-2918-I-006-005, NSC-103-2320-B-006-032]; NIH [R00DK088589, EY022611, CA132809, CA118165-09]; FCCC-Temple University Nodal grant; AACR-Landon Innovator Award in Tumor Microenvironment; Pew Scholar in Biomedical Sciences Program; CCFA [RFA2927]; Croucher Foundation; China Postdoctoral Science Foundation; Research Service of the Department of Veterans Affairs; UCSD Digestive Disease Research Center; National Institute of Diabetes and Digestive and Kidney Diseases [T32DK007202] Funding Source: NIH RePORTER; Grants-in-Aid for Scientific Research [24390321, 25670234] Funding Source: KAKEN
NR 60
TC 548
Z9 608
U1 5
U2 196
PU NATURE PUBLISHING 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 5
PY 2015
VL 519
IS 7541
BP 57
EP U107
DI 10.1038/nature14228
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC4EQ
UT WOS:000350304000034
PM 25731159
DA 2026-03-09
ER

PT J
AU Liang, LM
   Willis-Owen, SAG
   Laprise, C
   Wong, KCC
   Davies, GA
   Hudson, TJ
   Binia, A
   Hopkin, JM
   Yang, IV
   Grundberg, E
   Busche, S
   Hudson, M
   Rönnblom, L
   Pastinen, TM
   Schwartz, DA
   Lathrop, GM
   Moffatt, MF
   Cookson, WOCM
AF Liang, Liming
   Willis-Owen, Saffron A. G.
   Laprise, Catherine
   Wong, Kenny C. C.
   Davies, Gwyneth A.
   Hudson, Thomas J.
   Binia, Aristea
   Hopkin, Julian M.
   Yang, Ivana V.
   Grundberg, Elin
   Busche, Stephan
   Hudson, Marie
   Ronnblom, Lars
   Pastinen, Tomi M.
   Schwartz, David A.
   Lathrop, G. Mark
   Moffatt, Miriam F.
   Cookson, William O. C. M.
TI An epigenome-wide association study of total serum immunoglobulin E concentration
SO NATURE
LA English
DT Article
ID differential dna methylation; t-helper lymphocytes; mendelian randomization; genomewide association; total ige; asthma; eosinophils; expression; metaanalysis; omalizumab
AB Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever' and allergic asthma'''. Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation'. We therefore surveyed epigenetic associations between serum IgE concentrations and methylation at loci concentrated in CpG islands genome wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes. We validated positive results in additional families and in subjects from the general population. Here we show replicated associations with a meta-analysis false discovery rate less than 10-4 between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without asthma and high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining the tenfold higher variance found compared with that derived from large single-nucleotide polymorphism genome-wide association studies'''. This study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases.
C1 [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.
   [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.
   [Willis-Owen, Saffron A. G.; Wong, Kenny C. C.; Binia, Aristea; Moffatt, Miriam F.; Cookson, William O. C. M.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England.
   [Laprise, Catherine] Univ Quebec Chicoutimi, Saguenay, PQ G7H 2B1, Canada.
   [Davies, Gwyneth A.; Hopkin, Julian M.] Swansea Univ, Coll Med, Inst Life Sci, Swansea SA2 8PP, W Glam, Wales.
   [Hudson, Thomas J.] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada.
   [Hudson, Thomas J.] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1A1, Canada.
   [Hudson, Thomas J.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada.
   [Yang, Ivana V.; Schwartz, David A.] Univ Colorado, Sch Med, Denver, CO 80206 USA.
   [Yang, Ivana V.; Schwartz, David A.] Natl Jewish Hlth, Denver, CO 80206 USA.
   [Grundberg, Elin; Busche, Stephan; Pastinen, Tomi M.; Lathrop, G. Mark] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada.
   [Grundberg, Elin; Busche, Stephan; Pastinen, Tomi M.; Lathrop, G. Mark] Genome Quebec Innovat Ctr, Montreal, PQ H3A 1B1, Canada.
   [Hudson, Marie] McGill Univ, Jewish Gen Hosp, Montreal, PQ H3T 1E2, Canada.
   [Hudson, Marie] Lady Davis Res Inst, Montreal, PQ H3T 1E2, Canada.
   [Ronnblom, Lars] Uppsala Univ, SciLifeLab, Dept Med Sci, SE-75144 Uppsala, Sweden.
   [Pastinen, Tomi M.] McGill Univ, Ctr Hlth, Dept Med Genet, Montreal, PQ H3H 1P3, Canada.
C3 Harvard University; Harvard T.H. Chan School of Public Health; Harvard University; Harvard T.H. Chan School of Public Health; Imperial College London; University of Quebec; University of Quebec Chicoutimi; Swansea University; University of Toronto; Ontario Institute for Cancer Research; University of Toronto; University of Toronto; University of Colorado System; University of Colorado Anschutz Medical Campus; University of Colorado Denver; National Jewish Health; McGill University; Jewish General Hospital - Montreal; McGill University; Uppsala University; SciLifeLab; McGill University
RP Cookson, WOCM (corresponding author), Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England.
EM w.cookson@imperial.ac.uk
FU Freemasons' Grand Charity; Wellcome Trust [WT 077959, WT096964]; UK Medical Research Council; Genome Quebec; le Ministere de l'Enseignement superieur; de la Recherche, de la Science et de la Technologie (MESRST), Quebec; McGill University; National Institutes of Health [R01s HL101251-01, P01-E518181]; Medical Research Council [MR/K006525/1, G1000758] Funding Source: researchfish; National Institute for Health Research [NF-SI-0512-10126] Funding Source: researchfish; Wellcome Trust [096964/Z/11/Z] Funding Source: researchfish; MRC [MR/K006525/1] Funding Source: UKRI
NR 36
TC 167
Z9 186
U1 0
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 30
PY 2015
VL 520
IS 7549
BP 670
EP U188
DI 10.1038/nature14125
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CH0DQ
UT WOS:000353689700048
PM 25707804
DA 2026-03-09
ER

PT J
AU Welker, F
   Collins, MJ
   Thomas, JA
   Wadsley, M
   Brace, S
   Cappellini, E
   Turvey, ST
   Reguero, M
   Gelfo, JN
   Kramarz, A
   Burger, J
   Thomas-Oates, J
   Ashford, DA
   Ashton, PD
   Rowsell, K
   Porter, DM
   Kessler, B
   Fischer, R
   Baessmann, C
   Kaspar, S
   Olsen, JV
   Kiley, P
   Elliott, JA
   Kelstrup, CD
   Mullin, V
   Hofreiter, M
   Willerslev, E
   Hublin, JJ
   Orlando, L
   Barnes, I
   MacPhee, RDE
AF Welker, Frido
   Collins, Matthew J.
   Thomas, Jessica A.
   Wadsley, Marc
   Brace, Selina
   Cappellini, Enrico
   Turvey, Samuel T.
   Reguero, Marcelo
   Gelfo, Javier N.
   Kramarz, Alejandro
   Burger, Joachim
   Thomas-Oates, Jane
   Ashford, David A.
   Ashton, Peter D.
   Rowsell, Keri
   Porter, Duncan M.
   Kessler, Benedikt
   Fischer, Roman
   Baessmann, Carsten
   Kaspar, Stephanie
   Olsen, Jesper V.
   Kiley, Patrick
   Elliott, James A.
   Kelstrup, Christian D.
   Mullin, Victoria
   Hofreiter, Michael
   Willerslev, Eske
   Hublin, Jean-Jacques
   Orlando, Ludovic
   Barnes, Ian
   MacPhee, Ross D. E.
TI Ancient proteins resolve the evolutionary history of Darwin's South American ungulates
SO NATURE
LA English
DT Article
ID dental eruption; dna; software; sequence
AB No large group of recently extinct placental mammals remains as evolutionarily cryptic as the approximately 280 genera grouped as 'South American native ungulates'. To Charles Darwin(1,)2, who first collected their remains, they included perhaps the 'strangest animal[s] ever discovered'. Today, much like 180 years ago, it is no clearer whether they had one origin or several, arose before or after the Cretaceous/Palaeogene transition 66.2 million years ago(3), or are more likely to belong with the elephants and sirenians of superorder Afrotheria than with the euungulates (cattle, horses, and allies) of superorder Laurasiatheria(4-6). Morphology-based analyses have proved unconvincing because convergences are pervasive among unrelated ungulate-like placentals. Approaches using ancient DNA have also been unsuccessful, probably because of rapid DNA degradation in semitropical and temperate deposits. Here we apply proteomic analysis to screen bone samples of the Late Quaternary South American native ungulate taxa Toxodon (Notoungulata) and Macrauchenia (Litopterna) for phylogenetically informative protein sequences. For each ungulate, we obtain approximately 90% direct sequence coverage of type I collagen alpha 1-and alpha 2-chains, representing approximately 900 of 1,140 amino-acid residues for each subunit. A phylogeny is estimated from an alignment of these fossil sequences with collagen (I) gene transcripts from available mammalian genomes or mass spectrometrically derived sequence data obtained for this study. The resulting consensus tree agrees well with recent higher-level mammalian phylogenies(7-9). Toxodon and Macrauchenia form a monophyletic group whose sister taxon is not Afrotheria or any of its constituent clades as recently claimed(5,6), but instead crown Perissodactyla (horses, tapirs, and rhinoceroses). These results are consistent with the origin of at least some South American native ungulates(4,6) from 'condylarths', a paraphyletic assembly of archaic placentals. With ongoing improvements in instrumentation and analytical procedures, proteomics may produce a revolution in systematics such as that achieved by genomics, but with the possibility of reaching much further back in time.
C1 [Welker, Frido; Collins, Matthew J.; Thomas, Jessica A.; Wadsley, Marc; Rowsell, Keri; Hofreiter, Michael] Univ York, BioArCh, York YO10 5DD, N Yorkshire, England.
   [Welker, Frido; Hublin, Jean-Jacques] Max Planck Inst Evolutionary Anthropol, Dept Human Evolut, D-04103 Leipzig, Germany.
   [Brace, Selina; Barnes, Ian] Nat Hist Museum, Dept Earth Sci, London SW7 5BD, England.
   [Cappellini, Enrico; Willerslev, Eske; Orlando, Ludovic] Univ Copenhagen, Nat Hist Museum Denmark, Ctr GeoGenet, DK-1350 Copenhagen K, Denmark.
   [Turvey, Samuel T.] Zool Soc London, Inst Zool, London NW1 4RY, England.
   [Reguero, Marcelo; Gelfo, Javier N.] Univ Nacl La Plata, Fac Ciencias Nat & Museo La Plata, CONICET, Div Paleontol Vertebrados,Museo La Plata, RA-1900 La Plata, Buenos Aires, Argentina.
   [Kramarz, Alejandro] Museo Argentino Ciencias Nat Bernardino Rivadavia, Secc Paleontol Vertebrados, Buenos Aires, DF, Argentina.
   [Burger, Joachim] Johannes Gutenberg Univ Mainz, Inst Anthropol, D-55128 Mainz, Germany.
   [Thomas-Oates, Jane] Univ York, Dept Chem, York YO10 5DD, N Yorkshire, England.
   [Ashford, David A.; Ashton, Peter D.] Univ York, Dept Biol, Biosci Technol Facil, York YO10 5DD, N Yorkshire, England.
   [Porter, Duncan M.] Virginia Polytech Inst & State Univ, Dept Biol Sci, Blacksburg, VA 24061 USA.
   [Kessler, Benedikt; Fischer, Roman] Univ Oxford, Target Discovery Inst, Nuffield Dept Med, Oxford OX3 7FZ, England.
   [Baessmann, Carsten; Kaspar, Stephanie] Bruker Daltonik GmbH, Applicat Dev, D-28359 Bremen, Germany.
   [Olsen, Jesper V.; Kelstrup, Christian D.] Univ Copenhagen, Fac Hlth Sci, Novo Nordisk Fdn Ctr Prot Res, DK-2200 Copenhagen, Denmark.
   [Kiley, Patrick; Elliott, James A.] Univ Cambridge, Dept Mat Sci & Met, Cambridge CB3 0FS, England.
   [Mullin, Victoria] Trinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.
   [Hofreiter, Michael] Inst Biochem & Biol, D-14476 Potsdam Ot Golm, Germany.
   [MacPhee, Ross D. E.] Amer Museum Nat Hist, Dept Mammal, New York, NY 10024 USA.
C3 University of York - UK; Max Planck Society; Natural History Museum London; University of Copenhagen; Zoological Society of London; National University of La Plata; Museo La Plata; Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); Museo Argentino de Ciencias Naturales Bernardino Rivadavia (MACN); Johannes Gutenberg University of Mainz; University of York - UK; University of York - UK; Virginia Polytechnic Institute & State University; University of Oxford; Bruker Corporation; Bruker Daltonik GmbH; University of Copenhagen; University of Cambridge; Trinity College Dublin; American Museum of Natural History (AMNH)
RP Barnes, I (corresponding author), Nat Hist Museum, Dept Earth Sci, Cromwell Rd, London SW7 5BD, England.
EM frido.welker@palaeo.eu; matthew.collins@york.ac.uk; i.barnes@nhm.ac.uk; macphee@amnh.org
FU SYNTAX award "Barcode of Death"; European Research Council (ERC); ERC; Engineering and Physical Sciences Research Council [NE/G012237/1]; National Science Foundation [OPP 1142052]; Northern Way Initiative; SYNTHESYS FP7 grant [226506]; Lundbeck Foundation [R70-2010-6286, R109-2012-9995, R38-2008-3048, R155-2013-16338, R24-2008-2527] Funding Source: researchfish; Natural Environment Research Council [NE/J009342/1] Funding Source: researchfish; Novo Nordisk Foundation Center for Protein Research [PI Jesper Velgaard Olsen] Funding Source: researchfish; NERC [NE/J009342/1] Funding Source: UKRI; Directorate For Geosciences; Office of Polar Programs (OPP) [1142104, 1142129, 1142052] Funding Source: National Science Foundation
NR 58
TC 279
Z9 327
U1 4
U2 143
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD JUN 4
PY 2015
VL 522
IS 7554
BP 81
EP U192
DI 10.1038/nature14249
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CJ5QP
UT WOS:000355543400033
PM 25799987
DA 2026-03-09
ER

PT J
AU Carey, BW
   Finley, LWS
   Cross, JR
   Allis, CD
   Thompson, CB
AF Carey, Bryce W.
   Finley, Lydia W. S.
   Cross, Justin R.
   Allis, C. David
   Thompson, Craig B.
TI Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells
SO NATURE
LA English
DT Article
ID ground-state pluripotency; self-renewal; dna demethylation; mouse; differentiation; methylation; expression; phase; escs
AB The role of cellular metabolism in regulating cell proliferation and differentiation remains poorly understood(1). For example, most mammalian cells cannot proliferate without exogenous glutamine supplementation even though glutamine is a non-essential amino acid(1,2). Here we show that mouse embryonic stem (ES) cells grown under conditions that maintain naive pluripotency(3) are capable of proliferation in the absence of exogenous glutamine. Despite this, ES cells consume high levels of exogenous glutamine when the metabolite is available. In comparison to more differentiated cells, naive ES cells utilize both glucose and glutamine catabolism to maintain a high level of intracellular alpha-ketoglutarate (alpha KG). Consequently, naive ES cells exhibit an elevated alpha KG to succinate ratio that promotes histone/DNA demethylation and maintains pluripotency. Direct manipulation of the intracellular alpha KG/succinate ratio is sufficient to regulate multiple chromatin modifications, including H3K27me3 and ten-eleven translocation (Tet)-dependent DNA demethylation, which contribute to the regulation of pluripotency-associated gene expression. In vitro, supplementation with cell-permeable alpha KG directly supports ES-cell self-renewal while cell-permeable succinate promotes differentiation. This work reveals that intracellular alpha KG/succinate levels can contribute to the maintenance of cellular identity and have a mechanistic role in the transcriptional and epigenetic state of stem cells.
C1 [Carey, Bryce W.; Allis, C. David] Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA.
   [Finley, Lydia W. S.; Thompson, Craig B.] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA.
   [Cross, Justin R.] Mem Sloan Kettering Canc Ctr, Donald B & Catherine C Marron Canc Metab Ctr, New York, NY 10065 USA.
C3 Rockefeller University; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center
RP Thompson, CB (corresponding author), Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA.
EM alliscd@mail.rockefeller.edu; thompsonc@mskcc.org
FU National Institutes of Health/National Institute of General Medical Sciences; National Cancer Institute; National Cancer Institute [P30CA008748] Funding Source: NIH RePORTER
NR 30
TC 799
Z9 920
U1 5
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 FEB 19
PY 2015
VL 518
IS 7539
BP 413
EP 416
DI 10.1038/nature13981
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400045
PM 25487152
DA 2026-03-09
ER

PT J
AU Boccaletti, A
   Thalmann, C
   Lagrange, AM
   Janson, M
   Augereau, JC
   Schneider, G
   Milli, J
   Grady, C
   Debes, J
   Langlois, M
   Mouillet, D
   Henning, T
   Dominik, C
   Maire, AL
   Beuzit, JL
   Carson, J
   Dohlen, K
   Engler, N
   Feldt, M
   Fusco, T
   Ginski, C
   Girard, JH
   Hines, D
   Kasper, M
   Mawet, D
   Ménard, F
   Meyer, MR
   Moutou, C
   Olofsson, J
   Rodigas, T
   Sauvage, JF
   Schlieder, J
   Schmid, HM
   Turatto, M
   Udry, S
   Vakili, F
   Vigan, A
   Wahhaj, Z
   Wisniewski, J
AF Boccaletti, Anthony
   Thalmann, Christian
   Lagrange, Anne-Marie
   Janson, Markus
   Augereau, Jean-Charles
   Schneider, Glenn
   Milli, Julien
   Grady, Carol
   Debes, John
   Langlois, Maud
   Mouillet, David
   Henning, Thomas
   Dominik, Carsten
   Maire, Anne-Lise
   Beuzit, Jean-Luc
   Carson, Joseph
   Dohlen, Kjetil
   Engler, Natalia
   Feldt, Markus
   Fusco, Thierry
   Ginski, Christian
   Girard, Julien H.
   Hines, Dean
   Kasper, Markus
   Mawet, Dimitri
   Menard, Franois
   Meyer, Michael R.
   Moutou, Claire
   Olofsson, Johan
   Rodigas, Timothy
   Sauvage, Jean-Francois
   Schlieder, Joshua
   Schmid, Hans Martin
   Turatto, Massimo
   Udry, Stephane
   Vakili, Farrokh
   Vigan, Arthur
   Wahhaj, Zahed
   Wisniewski, John
TI Fast-moving features in the debris disk around AU Microscopii
SO NATURE
LA English
DT Article
ID beta-pictoris; circumstellar disk; evolutionary models; brown dwarfs; dust disk; exoplanets; planet
AB In the 1980s, excess infrared emission was discovered around main-sequence stars; subsequent direct-imaging observations revealed orbiting disks of cold dust to be the source(1). These 'debris disks' were thought to be by-products of planet formation because they often exhibited morphological and brightness asymmetries that may result from gravitational perturbation by planets. This was proved to be true for the beta Pictoris system, in which the known planet generates an observable warp in the disk(2-5). The nearby, young, unusually active late-type star AU Microscopii hosts a well-studied edge-on debris disk; earlier observations in the visible and near-infrared found asymmetric localized structures in the form of intensity variations along the midplane of the disk beyond a distance of 20 astronomical units(6-9). Here we report high-contrast imaging that reveals a series of five large-scale features in the southeast side of the disk, at projected separations of 10-60 astronomical units, persisting over intervals of 1-4 years. All these features appear to move away from the star at projected speeds of 4-10 kilometres per second, suggesting highly eccentric or unbound trajectories if they are associated with physical entities. The origin, localization, morphology and rapid evolution of these features are difficult to reconcile with current theories.
C1 [Boccaletti, Anthony] Univ Paris 06, Univ Paris Diderot, CNRS, Observ Paris,LESIA, F-92190 Meudon, France.
   [Thalmann, Christian; Engler, Natalia; Meyer, Michael R.; Schmid, Hans Martin] ETH, Inst Astron, CH-8093 Zurich, Switzerland.
   [Lagrange, Anne-Marie; Augereau, Jean-Charles; Mouillet, David; Beuzit, Jean-Luc] Univ Grenoble Alpes, IPAG, F-38000 Grenoble, France.
   [Lagrange, Anne-Marie; Augereau, Jean-Charles; Milli, Julien; Beuzit, Jean-Luc; Girard, Julien H.; Kasper, Markus] IPAG, CNRS, F-38000 Grenoble, France.
   [Janson, Markus] Stockholm Univ, Dept Astron, SE-10691 Stockholm, Sweden.
   [Janson, Markus; Henning, Thomas; Carson, Joseph; Olofsson, Johan] Max Planck Inst Astron, D-69117 Heidelberg, Germany.
   [Schneider, Glenn] Univ Arizona, Steward Observ, Tucson, AZ 85721 USA.
   [Milli, Julien; Girard, Julien H.; Vigan, Arthur; Wahhaj, Zahed] ESO, Santiago 19001, Chile.
   [Grady, Carol] Eureka Sci, Oakland, CA 96002 USA.
   [Debes, John; Hines, Dean] Space Telescope Sci Inst, Baltimore, MD 21218 USA.
   [Langlois, Maud] Univ Lyon 1, CNRS, Ctr Rech Astrophys Lyon, ENS L, F-69561 St Genis Laval, France.
   [Langlois, Maud; Dohlen, Kjetil; Fusco, Thierry; Moutou, Claire; Sauvage, Jean-Francois; Vigan, Arthur; Wahhaj, Zahed] Aix Marseille Univ, CNRS, LAM, UMR 7326, F-13388 Marseille, France.
   [Dominik, Carsten] Univ Amsterdam, Astron Inst Anton Pannekoek, NL-1098 XH Amsterdam, Netherlands.
   [Maire, Anne-Lise; Turatto, Massimo] INAF Osservatorio Astron Padova, I-35122 Padua, Italy.
   [Carson, Joseph] Coll Charleston, Dept Phys & Astron, Charleston, SC 29424 USA.
   [Fusco, Thierry; Sauvage, Jean-Francois] Off Natl Etud & Rech Aerosp, F-92322 Chatillon, France.
   [Ginski, Christian] Sterrewacht Leiden, NL-2300 RA Leiden, Netherlands.
   [Kasper, Markus] ESO, D-85748 Garching, Germany.
   [Mawet, Dimitri] CALTECH, Dept Astron, Pasadena, CA 91125 USA.
   [Menard, Franois] INSU France, CNRS, UMI, FCA,UMI 3386, Montpellier, France.
   [Menard, Franois] Univ Chile, Dept Astron, Santiago, Chile.
   [Rodigas, Timothy] Carnegie Inst Sci, Dept Terr Magnetism, Washington, DC 20015 USA.
   [Schlieder, Joshua] NASA, Ames Res Ctr, Space Sci & Astrobiol Div, Moffett Field, CA 94035 USA.
   [Udry, Stephane] Univ Geneva, Observ Geneve, CH-1290 Versoix, Switzerland.
   [Vakili, Farrokh] Univ Nice Sophia Antipolis UNS, CNRS, Lab JL Lagrange, OCA, F-06108 Nice 2, France.
   [Wisniewski, John] Univ Oklahoma, Dept Phys & Astron, Norman, OK 73019 USA.
C3 Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); Universite Paris Cite; Universite PSL; Observatoire de Paris; Swiss Federal Institutes of Technology Domain; ETH Zurich; Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Institut de Planetologie et d'Astrophysique de Grenoble (IPAG); Centre National de la Recherche Scientifique (CNRS); Institut de Planetologie et d'Astrophysique de Grenoble (IPAG); Stockholm University; Max Planck Society; University of Arizona; European Southern Observatory; Eureka Scientific; Space Telescope Science Institute; Ecole Normale Superieure de Lyon (ENS de LYON); Universite Lyon 1; Centre National de la Recherche Scientifique (CNRS); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Aix-Marseille Universite; University of Amsterdam; Istituto Nazionale Astrofisica (INAF); College of Charleston; National Office for Aerospace Studies & Research (ONERA); Universite Paris Saclay; Leiden University; Leiden University - Excl LUMC; California Institute of Technology; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Earth Sciences & Astronomy (INSU); Universite de Montpellier; Universidad de Chile; Carnegie Institution for Science; National Aeronautics & Space Administration (NASA); NASA Ames Research Center; University of Geneva; Centre National de la Recherche Scientifique (CNRS); Universite Cote d'Azur; University of Oklahoma System; University of Oklahoma - Norman
RP Boccaletti, A (corresponding author), Univ Paris 06, Univ Paris Diderot, CNRS, Observ Paris,LESIA, 5 Pl Jules Janssen, F-92190 Meudon, France.
EM anthony.boccaletti@obspm.fr
FU ESO; CNRS; MPIA; INAF; FINES; NOVA; European Commission FP6 programme as part of OPTICON [RII3-Ct-2004-001566]; European Commission FP7 programme as part of OPTICON [226604, 312430]; Swiss National Science Foundation; SNSF; ESO Very Large Telescope [60.A-9249]; NASA/ESA Hubble Space Telescope [12228]; NASA [NAS 5-26555];  [ANR-14-CE33-0018]; Direct For Mathematical & Physical Scien; Division Of Astronomical Sciences [1009203] Funding Source: National Science Foundation
NR 29
TC 101
Z9 110
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 OCT 8
PY 2015
VL 526
IS 7572
BP 230
EP +
DI 10.1038/nature15705
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS9GV
UT WOS:000362399000041
PM 26450055
DA 2026-03-09
ER

PT J
AU Tedstone, AJ
   Nienow, PW
   Gourmelen, N
   Dehecq, A
   Goldberg, D
   Hanna, E
AF Tedstone, Andrew J.
   Nienow, Peter W.
   Gourmelen, Noel
   Dehecq, Amaury
   Goldberg, Daniel
   Hanna, Edward
TI Decadal slowdown of a land-terminating sector of the Greenland Ice Sheet despite warming
SO NATURE
LA English
DT Article
ID surface melt; mass-balance; acceleration; drainage; glacier; system; flow; variability; evolution; elevation
AB Ice flow along land-terminating margins of the Greenland Ice Sheet (GIS) varies considerably in response to fluctuating inputs of surface meltwater to the bed of the ice sheet. Such inputs lubricate the ice-bed interface, transiently speeding up the flow of ice(1,2). Greater melting results in faster ice motion during summer, but slower motion over the subsequent winter, owing to the evolution of an efficient drainage system that enables water to drain from regions of the ice-sheet bed that have a high basal water pressure(2,3). However, the impact of hydrodynamic coupling on ice motion over decadal timescales remains poorly constrained. Here we show that annual ice motion across an 8,000-km(2) land-terminating region of the west GIS margin, extending to 1,100 m above sea level, was 12% slower in 2007-14 compared with 198594, despite a 50% increase in surface meltwater production. Our findings suggest that, over these three decades, hydrodynamic coupling in this section of the ablation zone resulted in a net slow-down of ice motion (not a speed-up, as previously postulated(1)). Increases in meltwater production from projected climate warming may therefore further reduce the motion of land-terminating margins of the GIS. Our findings suggest that these sectors of the ice sheet are more resilient to the dynamic impacts of enhanced meltwater production than previously thought.
C1 [Tedstone, Andrew J.; Nienow, Peter W.; Gourmelen, Noel; Dehecq, Amaury; Goldberg, Daniel] Univ Edinburgh, Sch Geosci, Edinburgh EH8 9XP, Midlothian, Scotland.
   [Dehecq, Amaury] Univ Savoie Mt Blanc, Polytech Annecy Chambery, LISTIC, F-74944 Annecy Le Vieux, France.
   [Hanna, Edward] Univ Sheffield, Dept Geog, Sheffield S10 2TN, S Yorkshire, England.
C3 University of Edinburgh; Universite Savoie Mont Blanc; University of Sheffield
RP Tedstone, AJ (corresponding author), Univ Edinburgh, Sch Geosci, Edinburgh EH8 9XP, Midlothian, Scotland.
EM a.j.tedstone@ed.ac.uk
FU UK Natural Environment Research Council (NERC) [NE/152830X/1, NE/J500021/1]; Scottish Alliance for Geoscience, Environment and Society (SAGES) Postdoctoral/Early Career Researcher Exchange (PECRE) award; University of Edinburgh GeoSciences Moss scholarship; European Space Agency Dragon 3 [10302]; Centre National d'Etudes Spatiales; Natural Environment Research Council [1089772] Funding Source: researchfish; NERC [NE/J500021/1] Funding Source: UKRI
NR 30
TC 130
Z9 142
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 OCT 29
PY 2015
VL 526
IS 7575
BP 692
EP 695
DI 10.1038/nature15722
PG 4
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CU8ZH
UT WOS:000363832100046
PM 26511580
DA 2026-03-09
ER

PT J
AU Fu, YSH
   Zhao, HF
   Piao, SL
   Peaucelle, M
   Peng, SS
   Zhou, GY
   Ciais, P
   Huang, MT
   Menzel, A
   Uelas, JP
   Song, Y
   Vitasse, Y
   Zeng, ZZ
   Janssens, IA
AF Fu, Yongshuo H.
   Zhao, Hongfang
   Piao, Shilong
   Peaucelle, Marc
   Peng, Shushi
   Zhou, Guiyun
   Ciais, Philippe
   Huang, Mengtian
   Menzel, Annette
   Uelas, Josep Pen
   Song, Yang
   Vitasse, Yann
   Zeng, Zhenzhong
   Janssens, Ivan A.
TI Declining global warming effects on the phenology of spring leaf unfolding
SO NATURE
LA English
DT Article
ID climate-change; sensitivity; photoperiod; responses; feedbacks; growth; winter
AB Earlier spring leaf unfolding is a frequently observed response of plants to climate warming(1-4). Many deciduous tree species require chilling for dormancy release, and warming-related reductions in chillingmay counteract the advance of leaf unfolding in response to warming(5,6). Empirical evidence for this, however, is limited to saplings or twigs in climate-controlled chambers(7,8). Using long-termin situ observations of leaf unfolding for seven dominant European tree species at 1,245 sites, here we show that the apparent response of leaf unfolding to climate warming (S-T, expressed in days advance of leaf unfolding per degrees C warming) has significantly decreased from 1980 to 2013 in all monitored tree species. Averaged across all species and sites, S-T decreased by 40% from 4.0 +/- 1.8 days degrees C-1 during 1980-1994 to 2.3 +/- 1.6 days degrees C-1 during 1999-2013. The declining S-T was also simulated by chilling-based phenology models, albeit with a weaker decline (24-30%) than observedin situ. The reduction in S-T is likely to be partly attributable to reduced chilling. Nonetheless, other mechanisms may also have a role, such as 'photo-period limitation' mechanisms that may become ultimately limiting when leaf unfolding dates occur too early in the season. Our results provide empirical evidence for a declining S-T, but also suggest that the predicted strong winter warming in the future may further reduce S-T and therefore result in a slow down in the advance of tree spring phenology.
C1 [Fu, Yongshuo H.; Zhao, Hongfang; Piao, Shilong; Peng, Shushi; Ciais, Philippe; Huang, Mengtian; Zeng, Zhenzhong] Peking Univ, Coll Urban & Environm Sci, Sino French Inst Earth Syst Sci, Beijing 100871, Peoples R China.
   [Fu, Yongshuo H.; Piao, Shilong; Janssens, Ivan A.] Univ Antwerp, Dept Biol, Ctr Excellence PLECO Plant & Vegetat Ecol, B-2610 Antwerp, Belgium.
   [Piao, Shilong] Chinese Acad Sci, Inst Tibetan Plateau Res, Key Lab Alpine Ecol & Biodivers, Beijing 100085, Peoples R China.
   [Piao, Shilong] Chinese Acad Sci, Ctr Excellence Tibetan Earth Sci, Beijing 100085, Peoples R China.
   [Peaucelle, Marc; Peng, Shushi; Ciais, Philippe] UVSQ, CEA CNRS, Lab Sci Climat & Environm, F-91190 Gif Sur Yvette, France.
   [Zhou, Guiyun] Univ Elect Sci & Technol China, Sch Resources & Environm, Chengdu 611731, Peoples R China.
   [Menzel, Annette] Tech Univ Munich, Ecoclimatol, D-85354 Freising Weihenstephan, Germany.
   [Menzel, Annette] Tech Univ Munich, Inst Adv Study, D-85748 Garching, Germany.
   [Uelas, Josep Pen] CREAF, Cerdanyola Valles, Barcelona 08193, Catalonia, Spain.
   [Uelas, Josep Pen] CSIC, Global Ecol Unit CREAF CSIC UAB, Barcelona 08193, Catalonia, Spain.
   [Song, Yang] Univ Illinois, Dept Atmospher Sci, Urbana, IL 61801 USA.
   [Vitasse, Yann] Univ Neuchatel, Inst Geog, CH-2000 Neuchatel, Switzerland.
   [Vitasse, Yann] WSL Swiss Fed Inst Forest Snow & Landscape Res, CH-2000 Neuchatel, Switzerland.
   [Vitasse, Yann] WSL Inst Snow & Avalanche Res SLF, Grp Mt Ecosyst, CH-7260 Davos, Switzerland.
C3 Peking University; University of Antwerp; Chinese Academy of Sciences; Institute of Tibetan Plateau Research, CAS; Chinese Academy of Sciences; CEA; Universite Paris Saclay; University of Electronic Science & Technology of China; Technical University of Munich; Technical University of Munich; University of Barcelona; Centro de Investigacion Ecologica y Aplicaciones Forestales (CREAF-CERCA); Centro de Investigacion Ecologica y Aplicaciones Forestales (CREAF-CERCA); Consejo Superior de Investigaciones Cientificas (CSIC); University of Illinois System; University of Illinois Urbana-Champaign; University of Neuchatel; Swiss Federal Institutes of Technology Domain; Swiss Federal Institute for Forest, Snow & Landscape Research; Swiss Federal Institutes of Technology Domain; Swiss Federal Institute for Forest, Snow & Landscape Research
RP Piao, SL (corresponding author), Peking Univ, Coll Urban & Environm Sci, Sino French Inst Earth Syst Sci, Beijing 100871, Peoples R China.
EM slpiao@pku.edu
FU National Natural Science Foundation of China [41125004, 31321061]; 111 Project [B14001]; National Youth Top-notch Talent Support Program in China; FWO Pegasus Marie Curie Fellowship; European Research Council through Synergy grant [ERC-2013-SyG-610028]; ERC [282250]; University of Antwerp Centre of Excellence "GCE"; European Research Council (ERC) [282250] Funding Source: European Research Council (ERC)
NR 31
TC 794
Z9 905
U1 43
U2 1128
PU NATURE PUBLISHING 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 1
PY 2015
VL 526
IS 7571
BP 104
EP +
DI 10.1038/nature15402
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CS5CY
UT WOS:000362095100042
PM 26416746
DA 2026-03-09
ER

PT J
AU Kjeldsen, KK
   Korsgaard, NJ
   Bjork, AA
   Khan, SA
   Box, JE
   Funder, S
   Larsen, NK
   Bamber, JL
   Colgan, W
   van den Broeke, M
   Siggaard-Andersen, ML
   Nuth, C
   Schomacker, A
   Andresen, CS
   Willerslev, E
   Kjær, KH
AF Kjeldsen, Kristian K.
   Korsgaard, Niels J.
   Bjork, Anders A.
   Khan, Shfaqat A.
   Box, Jason E.
   Funder, Svend
   Larsen, Nicolaj K.
   Bamber, Jonathan L.
   Colgan, William
   van den Broeke, Michiel
   Siggaard-Andersen, Marie-Louise
   Nuth, Christopher
   Schomacker, Anders
   Andresen, Camilla S.
   Willerslev, Eske
   Kjaer, Kurt H.
TI Spatial and temporal distribution of mass loss from the Greenland Ice Sheet since AD 1900
SO NATURE
LA English
DT Article
ID glacier; discharge; margins; origin
AB The response of the Greenland Ice Sheet (GIS) to changes in temperature during the twentieth century remains contentious(1), largely owing to difficulties in estimating the spatial and temporal distribution of ice mass changes before 1992, when Greenland-wide observations first became available(2). The only previous estimates of change during the twentieth century are based on empirical modelling(3-5) and energy balance modelling(6,7). Consequently, no observation-based estimates of the contribution from the GIS to the global-mean sea level budget before 1990 are included in the Fifth Assessment Report of the Intergovernmental Panel on Climate Change(8). Here we calculate spatial ice mass loss around the entire GIS from 1900 to the present using aerial imagery from the 1980s. This allows accurate high-resolution mapping of geomorphic features related to the maximum extent of the GIS during the Little Ice Age(9) at the end of the nineteenth century. We estimate the total ice mass loss and its spatial distribution for three periods: 1900-1983 (75.1 +/- 29.4 gigatonnes per year), 1983-2003 (73.8 +/- 40.5 gigatonnes per year), and 2003-2010 (186.4 +/- 18.9 gigatonnes per year). Furthermore, using two surface mass balance models(10,11) we partition the mass balance into a term for surface mass balance (that is, total precipitation minus total sublimation minus runoff) and a dynamic term. We find that many areas currently undergoing change are identical to those that experienced considerable thinning throughout the twentieth century. We also reveal that the surface mass balance term shows a considerable decrease since 2003, whereas the dynamic term is constant over the past 110 years. Overall, our observation-based findings show that during the twentieth century the GIS contributed at least 25.0 +/- 9.4 millimetres of global-mean sea level rise. Our result will help to close the twentieth-century sea level budget, which remains crucial for evaluating the reliability of models used to predict global sea level rise(1,8).
C1 [Kjeldsen, Kristian K.; Korsgaard, Niels J.; Bjork, Anders A.; Funder, Svend; Larsen, Nicolaj K.; Siggaard-Andersen, Marie-Louise; Schomacker, Anders; Willerslev, Eske; Kjaer, Kurt H.] Univ Copenhagen, Ctr GeoGenet, Nat Hist Museum, DK-1350 Copenhagen, Denmark.
   [Kjeldsen, Kristian K.] Univ Ottawa, Dept Earth Sci, Ottawa, ON K1N 6N5, Canada.
   [Khan, Shfaqat A.] Tech Univ Denmark, Dept Geodesy, DTU Space Natl Space Inst, DK-2800 Lyngby, Denmark.
   [Box, Jason E.; Colgan, William; Andresen, Camilla S.] Geol Survey Denmark & Greenland, Dept Marine Geol & Glaciol, DK-1350 Copenhagen, Denmark.
   [Larsen, Nicolaj K.] Aarhus Univ, Dept Geosci, DK-8000 Aarhus, Denmark.
   [Bamber, Jonathan L.] Univ Bristol, Bristol Glaciol Ctr, Bristol BS8 1SS, Avon, England.
   [Colgan, William] York Univ, Dept Earth & Space Sci & Engn, Toronto, ON M3J 1P3, Canada.
   [van den Broeke, Michiel] Univ Utrecht, Inst Marine & Atmospher Res, NL-80005 Utrecht, Netherlands.
   [Andresen, Camilla S.] Univ Oslo, Dept Geosci, N-0316 Oslo, Norway.
C3 University of Copenhagen; University of Ottawa; Technical University of Denmark; Geological Survey Of Denmark & Greenland; Aarhus University; University of Bristol; York University - Canada; Utrecht University; University of Oslo
RP Kjær, KH (corresponding author), Univ Copenhagen, Ctr GeoGenet, Nat Hist Museum, DK-1350 Copenhagen, Denmark.
EM kurtk@snm.ku.dk
FU Danish Council for Independent Research (FNU) [DFF-0602-02526B, DFF-4181-00126]; Centre for GeoGenetics - Danish National Research Foundation [DNRF94]; Sapere Aude: DFF-Research Talent programme [DFF-4090-00151]; GeoCenter Denmark ("Multi-millennial ice volume changes of the Greenland ice sheet"); Carlsberg Foundation [CF14-0145]; Netherlands Polar Program of the Netherlands Organization of Scientific Research (NWO); European Research Council (EUFP7/ERC) [320816]; NERC [NE/M000869/1] Funding Source: UKRI; Lundbeck Foundation [R70-2010-6286, R24-2008-2527, R109-2012-9995, R38-2008-3048, R155-2013-16338] Funding Source: researchfish; Natural Environment Research Council [NE/M000869/1] Funding Source: researchfish; Villum Fonden [00010100, 00007364] Funding Source: researchfish
NR 57
TC 201
Z9 231
U1 0
U2 154
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD DEC 17
PY 2015
VL 528
IS 7582
BP 396
EP +
DI 10.1038/nature16183
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CY8SM
UT WOS:000366678600052
PM 26672555
DA 2026-03-09
ER

