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  • Baby penguins benefit from fishing bans
    Nature (IF 40.137) Pub Date : 

    Baby penguins benefit from fishing bans Baby penguins benefit from fishing bans, Published online: 17 January 2018; doi:10.1038/d41586-018-00836-6 South African survey provides rare evidence on fishery impacts.

    更新日期:2018-01-17
  • Train robots to self-certify their safe operation
    Nature (IF 40.137) Pub Date : 
    Valentin Robu, David Flynn, David Lane

    Train robots to self-certify their safe operation Train robots to self-certify their safe operation, Published online: 16 January 2018; doi:10.1038/d41586-018-00646-w Train robots to self-certify their safe operation

    更新日期:2018-01-17
  • Support for US postdocs is growing slowly
    Nature (IF 40.137) Pub Date : 

    Support for US postdocs is growing slowly Support for US postdocs is growing slowly, Published online: 16 January 2018; doi:10.1038/d41586-018-00559-8 Report from National Postdoctoral Association highlights progress and pain points.

    更新日期:2018-01-17
  • The dark side of light: how artificial lighting is harming the natural world
    Nature (IF 40.137) Pub Date : 
    Aisling Irwin

    The dark side of light: how artificial lighting is harming the natural world The dark side of light: how artificial lighting is harming the natural world , Published online: 16 January 2018; doi:10.1038/d41586-018-00665-7 The world is lit at night like never before, and ecologists are assessing the damage.

    更新日期:2018-01-17
  • Egyptian tombs depict seldom-seen creatures
    Nature (IF 40.137) Pub Date : 

    Egyptian tombs depict seldom-seen creatures Egyptian tombs depict seldom-seen creatures, Published online: 16 January 2018; doi:10.1038/d41586-018-00790-3 Imaging technique reveals painted details lost to time.

    更新日期:2018-01-17
  • Research kudos does not need a price tag
    Nature (IF 40.137) Pub Date : 
    Tim Caro, Sasha R. X. Dall

    Research kudos does not need a price tag Research kudos does not need a price tag, Published online: 16 January 2018; doi:10.1038/d41586-018-00644-y Research kudos does not need a price tag

    更新日期:2018-01-17
  • Fixing statistics is more than a technical issue
    Nature (IF 40.137) Pub Date : 
    Andrea Saltelli, Philip Stark

    Fixing statistics is more than a technical issue Fixing statistics is more than a technical issue, Published online: 16 January 2018; doi:10.1038/d41586-018-00647-9 Fixing statistics is more than a technical issue

    更新日期:2018-01-17
  • The evolution of attraction, rare brains and how to hack time: Books in brief
    Nature (IF 40.137) Pub Date : 
    Barbara Kiser

    The evolution of attraction, rare brains and how to hack time: Books in brief The evolution of attraction, rare brains and how to hack time: Books in brief, Published online: 16 January 2018; doi:10.1038/d41586-018-00581-w Barbara Kiser reviews five of the week’s best science picks.

    更新日期:2018-01-17
  • Structures of the calcium-activated, non-selective cation channel TRPM4
    Nature (IF 40.137) Pub Date : 2017-12-06
    Jiangtao Guo, Ji She, Weizhong Zeng, Qingfeng Chen, Xiao-chen Bai, Youxing Jiang

    TRPM4 is a calcium-activated, phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) -modulated, non-selective cation channel that belongs to the family of melastatin-related transient receptor potential (TRPM) channels. Here we present the electron cryo-microscopy structures of the mouse TRPM4 channel with and without ATP. TRPM4 consists of multiple transmembrane and cytosolic domains, which assemble into a three-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the channel; ATP binds at the nucleotide-binding domain and inhibits channel activity. TRPM4 has an exceptionally wide filter but is only permeable to monovalent cations; filter residue Gln973 is essential in defining monovalent selectivity. The S1–S4 domain and the post-S6 TRP domain form the central gating apparatus that probably houses the Ca2+- and PtdIns(4,5)P2-binding sites. These structures provide an essential starting point for elucidating the complex gating mechanisms of TRPM4 and reveal the molecular architecture of the TRPM family.

    更新日期:2018-01-08
  • Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4
    Nature (IF 40.137) Pub Date : 2017-12-06
    Zdenek Skrott, Martin Mistrik, Klaus Kaae Andersen, Søren Friis, Dusana Majera, Jan Gursky, Tomas Ozdian, Jirina Bartkova, Zsofia Turi, Pavel Moudry, Marianne Kraus, Martina Michalova, Jana Vaclavkova, Petr Dzubak, Ivo Vrobel, Pavla Pouckova, Jindrich Sedlacek, Andrea Miklovicova, Anne Kutt, Jing Li, Jana Mattova, Christoph Driessen, Q. Ping Dou, Jørgen Olsen, Marian Hajduch, Boris Cvek, Raymond J. Deshaies, Jiri Bartek

    Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb–copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram’s tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.

    更新日期:2018-01-08
  • Electron cryo-microscopy structure of a human TRPM4 channel
    Nature (IF 40.137) Pub Date : 2017-12-06
    Paige A. Winkler, Yihe Huang, Weinan Sun, Juan Du, Wei Lü

    Ca2+-activated, non-selective (CAN) ion channels sense increases of the intracellular Ca2+ concentration, producing a flux of Na+ and/or K+ ions that depolarizes the cell, thus modulating cellular Ca2+ entry. CAN channels are involved in cellular responses such as neuronal bursting activity and cardiac rhythm. Here we report the electron cryo-microscopy structure of the most widespread CAN channel, human TRPM4, bound to the agonist Ca2+ and the modulator decavanadate. Four cytosolic C-terminal domains form an umbrella-like structure with a coiled-coil domain for the ‘pole’ and four helical ‘ribs’ spanning the N-terminal TRPM homology regions (MHRs), thus holding four subunits in a crown-like architecture. We observed two decavanadate-binding sites, one in the C-terminal domain and another in the intersubunit MHR interface. A glutamine in the selectivity filter may be an important determinant of monovalent selectivity. Our structure provides new insights into the function and pharmacology of both the CAN and the TRPM families.

    更新日期:2018-01-08
  • Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity
    Nature (IF 40.137) Pub Date : 2017-12-06
    Vincenzo Sorrentino, Mario Romani, Laurent Mouchiroud, John S. Beck, Hongbo Zhang, Davide D’Amico, Norman Moullan, Francesca Potenza, Adrien W. Schmid, Solène Rietsch, Scott E. Counts, Johan Auwerx

    Alzheimer’s disease is a common and devastating disease characterized by aggregation of the amyloid-β peptide. However, we know relatively little about the underlying molecular mechanisms or how to treat patients with Alzheimer’s disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-β proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-β proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer’s disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-β proteotoxic diseases, such as Alzheimer’s disease.

    更新日期:2018-01-05
  • Magnetically gated accretion in an accreting ‘non-magnetic’ white dwarf
    Nature (IF 40.137) Pub Date : 2017-12-13
    S. Scaringi, T. J. Maccarone, C. D’Angelo, C. Knigge, P. J. Groot

    White dwarfs are often found in binary systems with orbital periods ranging from tens of minutes to hours in which they can accrete gas from their companion stars. In about 15 per cent of these binaries, the magnetic field of the white dwarf is strong enough (at 106 gauss or more) to channel the accreted matter along field lines onto the magnetic poles1,2. The remaining systems are referred to as ‘non-magnetic’, because until now there has been no evidence that they have a magnetic field that is strong enough to affect the accretion dynamics. Here we report an analysis of archival optical observations of the ‘non-magnetic’ accreting white dwarf in the binary system MV Lyrae, whose light curve displays quasi-periodic bursts of about 30 minutes duration roughly every 2 hours. The timescale and amplitude of these bursts indicate the presence of an unstable, magnetically regulated accretion mode, which in turn implies the existence of magnetically gated accretion3,4,5, in which disk material builds up around the magnetospheric boundary (at the co-rotation radius) and then accretes onto the white dwarf, producing bursts powered by the release of gravitational potential energy. We infer a surface magnetic field strength for the white dwarf in MV Lyrae of between 2 × 104 gauss and 1 × 105 gauss, too low to be detectable by other current methods. Our discovery provides a new way of studying the strength and evolution of magnetic fields in accreting white dwarfs and extends the connections between accretion onto white dwarfs, young stellar objects and neutron stars, for which similar magnetically gated accretion cycles have been identified6,7,8,9.

    更新日期:2018-01-05
  • An electric-eel-inspired soft power source from stacked hydrogels
    Nature (IF 40.137) Pub Date : 2017-12-13
    Thomas B. H. Schroeder, Anirvan Guha, Aaron Lamoureux, Gloria VanRenterghem, David Sept, Max Shtein, Jerry Yang, Michael Mayer

    Progress towards the integration of technology into living organisms requires electrical power sources that are biocompatible, mechanically flexible, and able to harness the chemical energy available inside biological systems. Conventional batteries were not designed with these criteria in mind. The electric organ of the knifefish Electrophorus electricus (commonly known as the electric eel) is, however, an example of an electrical power source that operates within biological constraints while featuring power characteristics that include peak potential differences of 600 volts and currents of 1 ampere1,2. Here we introduce an electric-eel-inspired power concept that uses gradients of ions between miniature polyacrylamide hydrogel compartments bounded by a repeating sequence of cation- and anion-selective hydrogel membranes. The system uses a scalable stacking or folding geometry that generates 110 volts at open circuit or 27 milliwatts per square metre per gel cell upon simultaneous, self-registered mechanical contact activation of thousands of gel compartments in series while circumventing power dissipation before contact. Unlike typical batteries, these systems are soft, flexible, transparent, and potentially biocompatible. These characteristics suggest that artificial electric organs could be used to power next-generation implant materials such as pacemakers, implantable sensors, or prosthetic devices in hybrids of living and non-living systems3,4,5,6.

    更新日期:2018-01-05
  • Force loading explains spatial sensing of ligands by cells
    Nature (IF 40.137) Pub Date : 2017-12-06
    Roger Oria, Tina Wiegand, Jorge Escribano, Alberto Elosegui-Artola, Juan Jose Uriarte, Cristian Moreno-Pulido, Ilia Platzman, Pietro Delcanale, Lorenzo Albertazzi, Daniel Navajas, Xavier Trepat, José Manuel García-Aznar, Elisabetta Ada Cavalcanti-Adam, Pere Roca-Cusachs

    Cells can sense the density and distribution of extracellular matrix (ECM) molecules by means of individual integrin proteins and larger, integrin-containing adhesion complexes within the cell membrane. This spatial sensing drives cellular activity in a variety of normal and pathological contexts1,2. Previous studies of cells on rigid glass surfaces have shown that spatial sensing of ECM ligands takes place at the nanometre scale, with integrin clustering and subsequent formation of focal adhesions impaired when single integrin–ligand bonds are separated by more than a few tens of nanometres3,4,5,6. It has thus been suggested that a crosslinking ‘adaptor’ protein of this size might connect integrins to the actin cytoskeleton, acting as a molecular ruler that senses ligand spacing directly3,7,8,9. Here, we develop gels whose rigidity and nanometre-scale distribution of ECM ligands can be controlled and altered. We find that increasing the spacing between ligands promotes the growth of focal adhesions on low-rigidity substrates, but leads to adhesion collapse on more-rigid substrates. Furthermore, disordering the ligand distribution drastically increases adhesion growth, but reduces the rigidity threshold for adhesion collapse. The growth and collapse of focal adhesions are mirrored by, respectively, the nuclear or cytosolic localization of the transcriptional regulator protein YAP. We explain these findings not through direct sensing of ligand spacing, but by using an expanded computational molecular-clutch model10,11, in which individual integrin–ECM bonds—the molecular clutches—respond to force loading by recruiting extra integrins, up to a maximum value. This generates more clutches, redistributing the overall force among them, and reducing the force loading per clutch. At high rigidity and high ligand spacing, maximum recruitment is reached, preventing further force redistribution and leading to adhesion collapse. Measurements of cellular traction forces and actin flow speeds support our model. Our results provide a general framework for how cells sense spatial and physical information at the nanoscale, precisely tuning the range of conditions at which they form adhesions and activate transcriptional regulation.

    更新日期:2018-01-05
  • Initiation and long-term instability of the East Antarctic Ice Sheet
    Nature (IF 40.137) Pub Date : 2017-12-13
    Sean P. S. Gulick, Amelia E. Shevenell, Aleksandr Montelli, Rodrigo Fernandez, Catherine Smith, Sophie Warny, Steven M. Bohaty, Charlotte Sjunneskog, Amy Leventer, Bruce Frederick, Donald D. Blankenship

    Antarctica’s continental-scale ice sheets have evolved over the past 50 million years1,2,3,4. However, the dearth of ice-proximal geological records5,6,7,8 limits our understanding of past East Antarctic Ice Sheet (EAIS) behaviour and thus our ability to evaluate its response to ongoing environmental change. The EAIS is marine-terminating and grounded below sea level within the Aurora subglacial basin, indicating that this catchment, which drains ice to the Sabrina Coast, may be sensitive to climate perturbations9,10,11. Here we show, using marine geological and geophysical data from the continental shelf seaward of the Aurora subglacial basin, that marine-terminating glaciers existed at the Sabrina Coast by the early to middle Eocene epoch. This finding implies the existence of substantial ice volume in the Aurora subglacial basin before continental-scale ice sheets were established about 34 million years ago1,2,3,4. Subsequently, ice advanced across and retreated from the Sabrina Coast continental shelf at least 11 times during the Oligocene and Miocene epochs. Tunnel valleys12 associated with half of these glaciations indicate that a surface-meltwater-rich sub-polar glacial system existed under climate conditions similar to those anticipated with continued anthropogenic warming10,11. Cooling since the late Miocene13 resulted in an expanded polar EAIS and a limited glacial response to Pliocene warmth in the Aurora subglacial basin catchment14,15,16. Geological records from the Sabrina Coast shelf indicate that, in addition to ocean temperature, atmospheric temperature and surface-derived meltwater influenced East Antarctic ice mass balance under warmer-than-present climate conditions. Our results imply a dynamic EAIS response with continued anthropogenic warming and suggest that the EAIS contribution to future global sea-level projections10,11,15,17 may be under-estimated.

    更新日期:2018-01-05
  • Large emissions from floodplain trees close the Amazon methane budget
    Nature (IF 40.137) Pub Date : 2017-12-04
    Sunitha R. Pangala, Alex Enrich-Prast, Luana S. Basso, Roberta Bittencourt Peixoto, David Bastviken, Edward R. C. Hornibrook, Luciana V. Gatti, Humberto Marotta, Luana Silva Braucks Calazans, Cassia Mônica Sakuragui, Wanderley Rodrigues Bastos, Olaf Malm, Emanuel Gloor, John Bharat Miller, Vincent Gauci

    Wetlands are the largest global source of atmospheric methane (CH4)1, a potent greenhouse gas. However, methane emission inventories from the Amazon floodplain2,3, the largest natural geographic source of CH4 in the tropics, consistently underestimate the atmospheric burden of CH4 determined via remote sensing and inversion modelling4,5, pointing to a major gap in our understanding of the contribution of these ecosystems to CH4 emissions. Here we report CH4 fluxes from the stems of 2,357 individual Amazonian floodplain trees from 13 locations across the central Amazon basin. We find that escape of soil gas through wetland trees is the dominant source of regional CH4 emissions. Methane fluxes from Amazon tree stems were up to 200 times larger than emissions reported for temperate wet forests6 and tropical peat swamp forests7, representing the largest non-ebullitive wetland fluxes observed. Emissions from trees had an average stable carbon isotope value (δ13C) of −66.2 ± 6.4 per mil, consistent with a soil biogenic origin. We estimate that floodplain trees emit 15.1 ± 1.8 to 21.2 ± 2.5 teragrams of CH4 a year, in addition to the 20.5 ± 5.3 teragrams a year emitted regionally from other sources. Furthermore, we provide a ‘top-down’ regional estimate of CH4 emissions of 42.7 ± 5.6 teragrams of CH4 a year for the Amazon basin, based on regular vertical lower-troposphere CH4 profiles covering the period 2010–2013. We find close agreement between our ‘top-down’ and combined ‘bottom-up’ estimates, indicating that large CH4 emissions from trees adapted to permanent or seasonal inundation can account for the emission source that is required to close the Amazon CH4 budget. Our findings demonstrate the importance of tree stem surfaces in mediating approximately half of all wetland CH4 emissions in the Amazon floodplain, a region that represents up to one-third of the global wetland CH4 source when trees are combined with other emission sources.

    更新日期:2018-01-05
  • A compositional tipping point governing the mobilization and eruption style of rhyolitic magma
    Nature (IF 40.137) Pub Date : 2017-12-13
    D. Di Genova, S. Kolzenburg, S. Wiesmaier, E. Dallanave, D. R. Neuville, K. U. Hess, D. B. Dingwell

    The most viscous volcanic melts and the largest explosive eruptions1 on our planet consist of calcalkaline rhyolites2,3. These eruptions have the potential to influence global climate4. The eruptive products are commonly very crystal-poor and highly degassed, yet the magma is mostly stored as crystal mushes containing small amounts of interstitial melt with elevated water content5. It is unclear how magma mushes are mobilized to create large batches of eruptible crystal-free magma. Further, rhyolitic eruptions6,7,8 can switch repeatedly between effusive and explosive eruption styles and this transition is difficult to attribute to the rheological effects of water content or crystallinity9,10. Here we measure the viscosity of a series of melts spanning the compositional range of the Yellowstone volcanic system and find that in a narrow compositional zone, melt viscosity increases by up to two orders of magnitude. These viscosity variations are not predicted by current viscosity models11,12 and result from melt structure reorganization, as confirmed by Raman spectroscopy. We identify a critical compositional tipping point, independently documented in the global geochemical record of rhyolites, at which rhyolitic melts fluidize or stiffen and that clearly separates effusive from explosive deposits worldwide. This correlation between melt structure, viscosity and eruptive behaviour holds despite the variable water content and other parameters, such as temperature, that are inherent in natural eruptions. Thermodynamic modelling demonstrates how the observed subtle compositional changes that result in fluidization or stiffening of the melt can be induced by crystal growth from the melt or variation in oxygen fugacity. However, the rheological effects of water and crystal content alone cannot explain the correlation between composition and eruptive style. We conclude that the composition of calcalkaline rhyolites is decisive in determining the mobilization and eruption dynamics of Earth’s largest volcanic systems, resulting in a better understanding of how the melt structure controls volcanic processes.

    更新日期:2018-01-05
  • Pluripotent state transitions coordinate morphogenesis in mouse and human embryos
    Nature (IF 40.137) Pub Date : 2017-11-29
    Marta N. Shahbazi, Antonio Scialdone, Natalia Skorupska, Antonia Weberling, Gaelle Recher, Meng Zhu, Agnieszka Jedrusik, Liani G. Devito, Laila Noli, Iain C. Macaulay, Christa Buecker, Yakoub Khalaf, Dusko Ilic, Thierry Voet, John C. Marioni, Magdalena Zernicka-Goetz

    The foundations of mammalian development lie in a cluster of embryonic epiblast stem cells. In response to extracellular matrix signalling, these cells undergo epithelialization and create an apical surface in contact with a cavity1,2, a fundamental event for all subsequent development. Concomitantly, epiblast cells transit through distinct pluripotent states3,4, before lineage commitment at gastrulation. These pluripotent states have been characterized at the molecular level5, but their biological importance remains unclear. Here we show that exit from an unrestricted naive pluripotent state is required for epiblast epithelialization and generation of the pro-amniotic cavity in mouse embryos. Embryonic stem cells locked in the naive state are able to initiate polarization but fail to undergo lumenogenesis. Mechanistically, exit from naive pluripotency activates an Oct4-governed transcriptional program that results in expression of glycosylated sialomucin proteins and the vesicle tethering and fusion events of lumenogenesis. Similarly, exit of epiblasts from naive pluripotency in cultured human post-implantation embryos triggers amniotic cavity formation and developmental progression. Our results add tissue-level architecture as a new criterion for the characterization of different pluripotent states, and show the relevance of transitions between these states during development of the mammalian embryo.

    更新日期:2018-01-05
  • Moving beyond microbiome-wide associations to causal microbe identification
    Nature (IF 40.137) Pub Date : 2017-12-06
    Neeraj K. Surana, Dennis L. Kasper

    Microbiome-wide association studies have established that numerous diseases are associated with changes in the microbiota1,2. These studies typically generate a long list of commensals implicated as biomarkers of disease, with no clear relevance to disease pathogenesis1,2,3,4,5. If the field is to move beyond correlations and begin to address causation, an effective system is needed for refining this catalogue of differentially abundant microbes and to allow subsequent mechanistic studies1,4. Here we demonstrate that triangulation of microbe–phenotype relationships is an effective method for reducing the noise inherent in microbiota studies and enabling identification of causal microbes. We found that gnotobiotic mice harbouring different microbial communities exhibited differential survival in a colitis model. Co-housing of these mice generated animals that had hybrid microbiotas and displayed intermediate susceptibility to colitis. Mapping of microbe–phenotype relationships in parental mouse strains and in mice with hybrid microbiotas identified the bacterial family Lachnospiraceae as a correlate for protection from disease. Using directed microbial culture techniques, we discovered Clostridium immunis, a previously unknown bacterial species from this family, that—when administered to colitis-prone mice—protected them against colitis-associated death. To demonstrate the generalizability of our approach, we used it to identify several commensal organisms that induce intestinal expression of an antimicrobial peptide. Thus, we have used microbe–phenotype triangulation to move beyond the standard correlative microbiome study and identify causal microbes for two completely distinct phenotypes. Identification of disease-modulating commensals by microbe–phenotype triangulation may be more broadly applicable to human microbiome studies.

    更新日期:2018-01-05
  • Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy
    Nature (IF 40.137) Pub Date : 2017-12-06
    Jiong Hu, Sarah Dziumbla, Jihong Lin, Sofia-Iris Bibli, Sven Zukunft, Julian de Mos, Khader Awwad, Timo Frömel, Andreas Jungmann, Kavi Devraj, Zhixing Cheng, Liya Wang, Sascha Fauser, Charles G. Eberhart, Akrit Sodhi, Bruce D. Hammock, Stefan Liebner, Oliver J. Müller, Clemens Glaubitz, Hans-Peter Hammes, Rüdiger Popp, Ingrid Fleming

    Diabetic retinopathy is an important cause of blindness in adults1,2, and is characterized by progressive loss of vascular cells and slow dissolution of inter-vascular junctions, which result in vascular leakage and retinal oedema3. Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization4,5. Here we identify soluble epoxide hydrolase (sEH) as a key enzyme that initiates pericyte loss and breakdown of endothelial barrier function by generating the diol 19,20-dihydroxydocosapentaenoic acid, derived from docosahexaenoic acid. The expression of sEH and the accumulation of 19,20-dihydroxydocosapentaenoic acid were increased in diabetic mouse retinas and in the retinas and vitreous humour of patients with diabetes. Mechanistically, the diol targeted the cell membrane to alter the localization of cholesterol-binding proteins, and prevented the association of presenilin 1 with N-cadherin and VE-cadherin, thereby compromising pericyte–endothelial cell interactions and inter-endothelial cell junctions. Treating diabetic mice with a specific sEH inhibitor prevented the pericyte loss and vascular permeability that are characteristic of non-proliferative diabetic retinopathy. Conversely, overexpression of sEH in the retinal Müller glial cells of non-diabetic mice resulted in similar vessel abnormalities to those seen in diabetic mice with retinopathy. Thus, increased expression of sEH is a key determinant in the pathogenesis of diabetic retinopathy, and inhibition of sEH can prevent progression of the disease.

    更新日期:2018-01-05
  • Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours
    Nature (IF 40.137) Pub Date : 2017-12-06
    J. Justin Milner, Clara Toma, Bingfei Yu, Kai Zhang, Kyla Omilusik, Anthony T. Phan, Dapeng Wang, Adam J. Getzler, Toan Nguyen, Shane Crotty, Wei Wang, Matthew E. Pipkin, Ananda W. Goldrath

    Tissue-resident memory CD8+ T (TRM) cells are found at common sites of pathogen exposure, where they elicit rapid and robust protective immune responses1,2. However, the molecular signals that control TRM cell differentiation and homeostasis are not fully understood. Here we show that mouse TRM precursor cells represent a unique CD8+ T cell subset that is distinct from the precursors of circulating memory cell populations at the levels of gene expression and chromatin accessibility. Using computational and pooled in vivo RNA interference screens, we identify the transcription factor Runx3 as a key regulator of TRM cell differentiation and homeostasis. Runx3 was required to establish TRM cell populations in diverse tissue environments, and supported the expression of crucial tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Furthermore, we show that human and mouse tumour-infiltrating lymphocytes share a core tissue-residency gene-expression signature with TRM cells that is associated with Runx3 activity. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8+ tumour-infiltrating lymphocytes failed to accumulate in tumours, resulting in greater rates of tumour growth and mortality. Conversely, overexpression of Runx3 enhanced tumour-specific CD8+ T cell abundance, delayed tumour growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of TRM cell differentiation, these results provide insight into the signals that promote T cell residency in non-lymphoid sites, which could be used to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer.

    更新日期:2018-01-05
  • A non-canonical Notch complex regulates adherens junctions and vascular barrier function
    Nature (IF 40.137) Pub Date : 2017-11-13
    William J. Polacheck, Matthew L. Kutys, Jinling Yang, Jeroen Eyckmans, Yinyu Wu, Hema Vasavada, Karen K. Hirschi, Christopher S. Chen

    The vascular barrier that separates blood from tissues is actively regulated by the endothelium and is essential for transport, inflammation, and haemostasis1. Haemodynamic shear stress plays a critical role in maintaining endothelial barrier function2, but how this occurs remains unknown. Here we use an engineered organotypic model of perfused microvessels to show that activation of the transmembrane receptor NOTCH1 directly regulates vascular barrier function through a non-canonical, transcription-independent signalling mechanism that drives assembly of adherens junctions, and confirm these findings in mouse models. Shear stress triggers DLL4-dependent proteolytic activation of NOTCH1 to expose the transmembrane domain of NOTCH1. This domain mediates establishment of the endothelial barrier; expression of the transmembrane domain of NOTCH1 is sufficient to rescue defects in barrier function induced by knockout of NOTCH1. The transmembrane domain restores barrier function by catalysing the formation of a receptor complex in the plasma membrane consisting of vascular endothelial cadherin, the transmembrane protein tyrosine phosphatase LAR, and the RAC1 guanidine-exchange factor TRIO. This complex activates RAC1 to drive assembly of adherens junctions and establish barrier function. Canonical transcriptional signalling via Notch is highly conserved in metazoans and is required for many processes in vascular development, including arterial–venous differentiation3, angiogenesis4 and remodelling5. We establish the existence of a non-canonical cortical NOTCH1 signalling pathway that regulates vascular barrier function, and thus provide a mechanism by which a single receptor might link transcriptional programs with adhesive and cytoskeletal remodelling.

    更新日期:2018-01-05
  • RNA polymerase III limits longevity downstream of TORC1
    Nature (IF 40.137) Pub Date : 2017-11-29
    Danny Filer, Maximillian A. Thompson, Vakil Takhaveev, Adam J. Dobson, Ilektra Kotronaki, James W. M. Green, Matthias Heinemann, Jennifer M. A. Tullet, Nazif Alic

    Three distinct RNA polymerases transcribe different classes of genes in the eukaryotic nucleus1. RNA polymerase (Pol) III is the essential, evolutionarily conserved enzyme that generates short, non-coding RNAs, including tRNAs and 5S rRNA2. The historical focus on transcription of protein-coding genes has left the roles of Pol III in organismal physiology relatively unexplored. Target of rapamycin kinase complex 1 (TORC1) regulates Pol III activity, and is also an important determinant of longevity3. This raises the possibility that Pol III is involved in ageing. Here we show that Pol III limits lifespan downstream of TORC1. We find that a reduction in Pol III extends chronological lifespan in yeast and organismal lifespan in worms and flies. Inhibiting the activity of Pol III in the gut of adult worms or flies is sufficient to extend lifespan; in flies, longevity can be achieved by Pol III inhibition specifically in intestinal stem cells. The longevity phenotype is associated with amelioration of age-related gut pathology and functional decline, dampened protein synthesis and increased tolerance of proteostatic stress. Pol III acts on lifespan downstream of TORC1, and limiting Pol III activity in the adult gut achieves the full longevity benefit of systemic TORC1 inhibition. Hence, Pol III is a pivotal mediator of this key nutrient-signalling network for longevity; the growth-promoting anabolic activity of Pol III mediates the acceleration of ageing by TORC1. The evolutionary conservation of Pol III affirms its potential as a therapeutic target.

    更新日期:2018-01-05
  • piRNA-mediated regulation of transposon alternative splicing in the soma and germ line
    Nature (IF 40.137) Pub Date : 2017-12-06
    Felipe Karam Teixeira, Martyna Okuniewska, Colin D. Malone, Rémi-Xavier Coux, Donald C. Rio, Ruth Lehmann

    Transposable elements can drive genome evolution, but their enhanced activity is detrimental to the host and therefore must be tightly regulated1. The Piwi-interacting small RNA (piRNA) pathway is vital for the regulation of transposable elements, by inducing transcriptional silencing or post-transcriptional decay of mRNAs2. Here we show that piRNAs and piRNA biogenesis components regulate precursor mRNA splicing of P-transposable element transcripts in vivo, leading to the production of the non-transposase-encoding mature mRNA isoform in Drosophila germ cells. Unexpectedly, we show that the piRNA pathway components do not act to reduce transcript levels of the P-element transposon during P–M hybrid dysgenesis, a syndrome that affects germline development in Drosophila3,4. Instead, splicing regulation is mechanistically achieved together with piRNA-mediated changes to repressive chromatin states, and relies on the function of the Piwi–piRNA complex proteins Asterix (also known as Gtsf1)5,6,7 and Panoramix (Silencio)8,9, as well as Heterochromatin protein 1a (HP1a; encoded by Su(var)205). Furthermore, we show that this machinery, together with the piRNA Flamenco cluster10, not only controls the accumulation of Gypsy retrotransposon transcripts11 but also regulates the splicing of Gypsy mRNAs in cultured ovarian somatic cells, a process required for the production of infectious particles that can lead to heritable transposition events12,13. Our findings identify splicing regulation as a new role and essential function for the Piwi pathway in protecting the genome against transposon mobility, and provide a model system for studying the role of chromatin structure in modulating alternative splicing during development.

    更新日期:2018-01-05
  • KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase
    Nature (IF 40.137) Pub Date : 2017-12-06
    Yugang Wang, Yusong R. Guo, Ke Liu, Zheng Yin, Rui Liu, Yan Xia, Lin Tan, Peiying Yang, Jong-Ho Lee, Xin-jian Li, David Hawke, Yanhua Zheng, Xu Qian, Jianxin Lyu, Jie He, Dongming Xing, Yizhi Jane Tao, Zhimin Lu

    Histone modifications, such as the frequently occurring lysine succinylation1,2, are central to the regulation of chromatin-based processes. However, the mechanism and functional consequences of histone succinylation are unknown. Here we show that the α-ketoglutarate dehydrogenase (α-KGDH) complex is localized in the nucleus in human cell lines and binds to lysine acetyltransferase 2A (KAT2A, also known as GCN5) in the promoter regions of genes. We show that succinyl-coenzyme A (succinyl-CoA) binds to KAT2A. The crystal structure of the catalytic domain of KAT2A in complex with succinyl-CoA at 2.3 Å resolution shows that succinyl-CoA binds to a deep cleft of KAT2A with the succinyl moiety pointing towards the end of a flexible loop 3, which adopts different structural conformations in succinyl-CoA-bound and acetyl-CoA-bound forms. Site-directed mutagenesis indicates that tyrosine 645 in this loop has an important role in the selective binding of succinyl-CoA over acetyl-CoA. KAT2A acts as a succinyltransferase and succinylates histone H3 on lysine 79, with a maximum frequency around the transcription start sites of genes. Preventing the α-KGDH complex from entering the nucleus, or expression of KAT2A(Tyr645Ala), reduces gene expression and inhibits tumour cell proliferation and tumour growth. These findings reveal an important mechanism of histone modification and demonstrate that local generation of succinyl-CoA by the nuclear α-KGDH complex coupled with the succinyltransferase activity of KAT2A is instrumental in histone succinylation, tumour cell proliferation, and tumour development.

    更新日期:2018-01-05
  • Loss of net neutrality could harm research
    Nature (IF 40.137) Pub Date : 

    Moves to create a multi-speed Internet could push science into the slow lane.

    更新日期:2017-12-15
  • Bureaucratic drag dents Japan’s nuclear science
    Nature (IF 40.137) Pub Date : 

    Japan needs a better way to assess whether research reactors are safe to re-open.

    更新日期:2017-12-15
  • How to avoid glib interdisciplinarity
    Nature (IF 40.137) Pub Date : 

    To make progress on the grand challenges, authors, reviewers and editors must take the time to respect each others’ expertise and blind spots.

    更新日期:2017-12-15
  • Zimbabwe’s new government must commit to science
    Nature (IF 40.137) Pub Date : 
    Dexter Tagwireyi

    As a new president takes office, scientists in the country and beyond should urge the administration to make science a priority, says Dexter Tagwireyi.

    更新日期:2017-12-15
  • Dodgy citations, fusion milestone and a skeleton called Little Foot
    Nature (IF 40.137) Pub Date : 

    The week in science: 8–14 December 2017.

    更新日期:2017-12-15
  • Nine researchers sue University of Rochester over sexual-harassment allegations
    Nature (IF 40.137) Pub Date : 
    Alexandra Witze

    Lawsuit alleges that the institution mishandled complaints about cognitive scientist Florian Jaeger.

    更新日期:2017-12-15
  • Tasmanian tiger genome offers clues to its extinction
    Nature (IF 40.137) Pub Date : 
    Ewen Callaway

    Geneticists analyse DNA from preserved pup, more than 80 years after the last of its kind died.

    更新日期:2017-12-15
  • Acupuncture in cancer study reignites debate about controversial technique
    Nature (IF 40.137) Pub Date : 
    Jo Marchant

    Large study suggests acupuncture could help women stick with unpleasant cancer treatments.

    更新日期:2017-12-15
  • US graduate students in uproar over proposed tax hike
    Nature (IF 40.137) Pub Date : 
    Helen Shen

    Worries over the cost of an education spill over into protests.

    更新日期:2017-12-15
  • Argentinian geoscientist faces criminal charges over glacier survey
    Nature (IF 40.137) Pub Date : 
    Jeff Tollefson, Emiliano Rodríguez Mega

    Government researcher Ricardo Villalba stands accused of shaping a study to benefit mining interests.

    更新日期:2017-12-15
  • The science that’s never been cited
    Nature (IF 40.137) Pub Date : 

    Nature investigates how many papers really end up without a single citation.

    更新日期:2017-12-15
  • Deploy vaccines to fight superbugs
    Nature (IF 40.137) Pub Date : 
    Rino Rappuoli, David E. Bloom, Steve Black

    Immunizations combined with antibiotics could be our best shot at combating drug-resistant microbes, argue Rino Rappuoli, David E. Bloom and Steve Black.

    更新日期:2017-12-15
  • Five priorities for weather and climate research
    Nature (IF 40.137) Pub Date : 
    Øystein Hov, Deon Terblanche, Sarah Jones, Paolo M. Ruti, Oksana Tarasova

    Adapt to how data are made and used, urge Øystein Hov and colleagues.

    更新日期:2017-12-15
  • Planetariums and the rise of spectacular science
    Nature (IF 40.137) Pub Date : 
    Marek Kukula

    Marek Kukula enjoys a cultural history of the theatres that give us a taste of space.

    更新日期:2017-12-15
  • A manifesto for slow science, the biology of personal space, and an intimate look at the neuroscience of food: Books in brief
    Nature (IF 40.137) Pub Date : 
    Barbara Kiser

    Barbara Kiser reviews five of the week’s best science picks.

    更新日期:2017-12-15
  • Lyme disease laid bare
    Nature (IF 40.137) Pub Date : 
    James G. Logan

    James G. Logan hails a study of the controversial tick-borne condition.

    更新日期:2017-12-15
  • Ronald Breslow (1931–2017)
    Nature (IF 40.137) Pub Date : 
    Virginia W. Cornish

    Organic chemist who took inspiration from nature.

    更新日期:2017-12-15
  • Fifteen minutes
    Nature (IF 40.137) Pub Date : 
    Alex Shvartsman

    Turn on, tune in, log off.

    更新日期:2017-12-15
  • Early embryos kept in check
    Nature (IF 40.137) Pub Date : 
    Julien G. Dumortier, Jean-Léon Maître

    As pluripotent stem cells become primed to give rise to all bodily cell types, they begin to form the amniotic cavity in which the mammalian fetus will grow. A checkpoint that gates this transition has now been identified.

    更新日期:2017-12-15
  • A dark side to omega-3 fatty acids
    Nature (IF 40.137) Pub Date : 
    Keisuke Yanagida, Timothy Hla

    The molecule 19,20-dihydroxydocosapentaenoic acid, formed by the metabolism of a fatty acid involved in normal brain function, promotes the development of a diabetes-associated form of blindness in a mouse model.

    更新日期:2017-12-15
  • Longer life through an odd Pol enzyme
    Nature (IF 40.137) Pub Date : 
    Bruce A. Edgar, Savraj S. Grewal

    The evolutionarily conserved enzyme RNA polymerase III is a driver of protein synthesis and cell growth. It emerges that partial suppression of this essential enzyme extends lifespan in yeast, roundworms and flies.

    更新日期:2017-12-15
  • Viruses hijack a long non-coding RNA
    Nature (IF 40.137) Pub Date : 
    Nicholas S. Heaton, Bryan R. Cullen

    ​​​​​​​Manipulation of host-cell metabolism is an essential aspect of viral replication cycles. Viral co-option of a cellular long non-protein-coding RNA has now been found to be a key step in this process.

    更新日期:2017-12-15
  • Erratum: Probabilistic reanalysis of twentieth-century sea-level rise
    Nature (IF 40.137) Pub Date : 2017-11-08
    Carling C. Hay, Eric Morrow, Robert E. Kopp, Jerry X. Mitrovica

    Nature517, 481–484 (2015); doi:10.1038/nature14093In Fig. 1 of this Letter, which compares our results (black line and shading) to the tide gauge data (red lines), part of the data shown in Fig. 1b (red line) is missing.

    更新日期:2017-12-15
  • Corrigendum: The 4D nucleome project
    Nature (IF 40.137) Pub Date : 2017-11-22
    Job Dekker, Andrew S. Belmont, Mitchell Guttman, Victor O. Leshyk, John T. Lis, Stavros Lomvardas, Leonid A. Mirny, Clodagh C. O’Shea, Peter J. Park, Bing Ren, Joan C. Ritland Politz, Jay Shendure, Sheng Zhong

    Nature549, 219–226 (2017); doi:10.1038/nature23884This Perspective should have contained the following Acknowledgements section: ‘We would like to thank the National Institutes of Health (NIH) Common Fund, the Office of Strategic Coordination and the Office of the NIH

    更新日期:2017-12-15
  • Erratum: Early members of ‘living fossil’ lineage imply later origin of modern ray-finned fishes
    Nature (IF 40.137) Pub Date : 2017-11-22
    Sam Giles, Guang-Hui Xu, Thomas J. Near, Matt Friedman

    Nature549, 265–268 (2017); doi:10.1038/nature23654Owing to an error during the production process, nine Supplementary Data files were inadvertently omitted from the online version of this Letter. The missing files have been added to the Supplementary Information of

    更新日期:2017-12-15
  • Great mentoring is key for the next generation of scientists
    Nature (IF 40.137) Pub Date : 

    The Nature Awards for Mentoring in Science show that it is crucial to support researchers in leading their groups well.

    更新日期:2017-12-06
  • Grows well in sun and warmth — and shade and cold
    Nature (IF 40.137) Pub Date : 

    Trees and shrubs could be less fussy about the climate than scientists thought. That might be good news as the planet warms.

    更新日期:2017-12-06
  • Gene-drive technology needs thorough scrutiny
    Nature (IF 40.137) Pub Date : 

    Scientists must continue to play their part in pointing out the potential environmental dangers.

    更新日期:2017-12-06
  • Wanted: academics wise to the needs of government
    Nature (IF 40.137) Pub Date : 
    Chris Tyler

    Funders should not support policy-relevant work that treats policy impact as an afterthought, advises Chris Tyler.

    更新日期:2017-12-06
  • Arctic fishing, robot explorers and Chinese medicines
    Nature (IF 40.137) Pub Date : 

    The week in science: 1–7 December 2017.

    更新日期:2017-12-06
  • Archaeologists uneasy as Trump shrinks Bears Ears monument lands
    Nature (IF 40.137) Pub Date : 
    Cally Carswell

    Thousands of ancient Native American sites to lose protections.

    更新日期:2017-12-06
  • Huge haul of rare pterosaur eggs excites palaeontologists
    Nature (IF 40.137) Pub Date : 2017-11-30
    John Pickrell

    Embryos found in some fossil eggs suggest that hatchlings struggled to fly.

    更新日期:2017-12-06
  • Bat cave solves mystery of deadly SARS virus — and suggests new outbreak could occur
    Nature (IF 40.137) Pub Date : 
    David Cyranoski

    Chinese scientists find all the genetic building blocks of SARS in a single population of horseshoe bats.

    更新日期:2017-12-06
  • Scientists want in on humanity's next big space station
    Nature (IF 40.137) Pub Date : 
    Elizabeth Gibney

    Space agencies are planning a Deep Space Gateway to orbit the Moon.

    更新日期:2017-12-06
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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