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Journal Cover Nature
  [SJR: 21.936]   [H-I: 948]   [4296 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Print) 0028-0836 - ISSN (Online) 1476-4687
   Published by NPG Homepage  [135 journals]
  • Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity
    • Authors: 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
      Pages: 187 - 193
      Abstract: 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
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-12-06
      DOI: 10.1038/nature25143
      Issue No: Vol. 552, No. 7684 (2017)
       
  • Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor
           NPL4
    • Authors: 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
      Pages: 194 - 199
      Abstract: 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
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-12-06
      DOI: 10.1038/nature25016
      Issue No: Vol. 552, No. 7684 (2017)
       
  • Electron cryo-microscopy structure of a human TRPM4 channel
    • Authors: Paige A. Winkler, Yihe Huang, Weinan Sun, Juan Du, Wei Lü
      Pages: 200 - 204
      Abstract: 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
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-12-06
      DOI: 10.1038/nature24674
      Issue No: Vol. 552, No. 7684 (2017)
       
  • Structures of the calcium-activated, non-selective cation channel TRPM4
    • Authors: Jiangtao Guo, Ji She, Weizhong Zeng, Qingfeng Chen, Xiao-chen Bai, Youxing Jiang
      Pages: 205 - 209
      Abstract: 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
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-12-06
      DOI: 10.1038/nature24997
      Issue No: Vol. 552, No. 7684 (2017)
       
  • Magnetically gated accretion in an accreting ‘non-magnetic’
           white dwarf
    • Authors: S. Scaringi, T. J. Maccarone, C. D’Angelo, C. Knigge, P. J. Groot
      Pages: 210 - 213
      Abstract: White dwarfs are often found in binary systems with orbital periods ranging from tens of minutes to hours in which they can accrete gas from their companion stars. In about 15 per cent of these binaries, the magnetic field of the white dwarf is strong enough (at 106 gauss or more) to channel the accreted matter along field lines onto the magnetic poles. The remaining systems are referred to as ‘non-magnetic’, because until now there has been no evidence that they have a magnetic field that is strong enough to affect the accretion dynamics. Here we report an analysis of archival optical observations of the ‘non-magnetic’ accreting white dwarf in the binary system MV Lyrae, whose light curve displays quasi-periodic bursts of about 30 minutes duration roughly every 2 hours. The timescale and amplitude of these bursts indicate the presence of an unstable, magnetically regulated accretion mode, which in turn implies the existence of magnetically gated accretion, 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 identified.
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-12-13
      DOI: 10.1038/nature24653
      Issue No: Vol. 552, No. 7684 (2017)
       
  • An electric-eel-inspired soft power source from stacked hydrogels
    • Authors: Thomas B. H. Schroeder, Anirvan Guha, Aaron Lamoureux, Gloria VanRenterghem, David Sept, Max Shtein, Jerry Yang, Michael Mayer
      Pages: 214 - 218
      Abstract: Progress towards the integration of technology into living organisms requires electrical power sources that are biocompatible, mechanically flexible, and able to harness the chemical energy available inside biological systems. Conventional batteries were not designed with these criteria in mind. The electric organ of the knifefish Electrophorus electricus (commonly known as the electric eel) is, however, an example of an electrical power source that operates within biological constraints while featuring power characteristics that include peak potential differences of 600 volts and currents of 1 ampere. Here we introduce an electric-eel-inspired power concept that uses gradients of ions between miniature polyacrylamide hydrogel compartments bounded by a repeating sequence of cation- and anion-selective hydrogel membranes. The system uses a scalable stacking or folding geometry that generates 110 volts at open circuit or 27 milliwatts per square metre per gel cell upon simultaneous, self-registered mechanical contact activation of thousands of gel compartments in series while circumventing power dissipation before contact. Unlike typical batteries, these systems are soft, flexible, transparent, and potentially biocompatible. These characteristics suggest that artificial electric organs could be used to power next-generation implant materials such as pacemakers, implantable sensors, or prosthetic devices in hybrids of living and non-living systems.
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-12-13
      DOI: 10.1038/nature24670
      Issue No: Vol. 552, No. 7684 (2017)
       
  • Force loading explains spatial sensing of ligands by cells
    • Authors: 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
      Pages: 219 - 224
      Abstract: 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 contexts. 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 nanometres. 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 directly. 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 model, 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.
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-12-06
      DOI: 10.1038/nature24662
      Issue No: Vol. 552, No. 7684 (2017)
       
  • Initiation and long-term instability of the East Antarctic Ice Sheet
    • Authors: 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
      Pages: 225 - 229
      Abstract: Antarctica’s continental-scale ice sheets have evolved over the past 50 million years. However, the dearth of ice-proximal geological records limits our understanding of past East Antarctic Ice Sheet (EAIS) behaviour and thus our ability to evaluate its response to ongoing environmental change. The EAIS is marine-terminating and grounded below sea level within the Aurora subglacial basin, indicating that this catchment, which drains ice to the Sabrina Coast, may be sensitive to climate perturbations. Here we show, using marine geological and geophysical data from the continental shelf seaward of the Aurora subglacial basin, that marine-terminating glaciers existed at the Sabrina Coast by the early to middle Eocene epoch. This finding implies the existence of substantial ice volume in the Aurora subglacial basin before continental-scale ice sheets were established about 34 million years ago. Subsequently, ice advanced across and retreated from the Sabrina Coast continental shelf at least 11 times during the Oligocene and Miocene epochs. Tunnel valleys associated with half of these glaciations indicate that a surface-meltwater-rich sub-polar glacial system existed under climate conditions similar to those anticipated with continued anthropogenic warming. Cooling since the late Miocene resulted in an expanded polar EAIS and a limited glacial response to Pliocene warmth in the Aurora subglacial basin catchment. Geological records from the Sabrina Coast shelf indicate that, in addition to ocean temperature, atmospheric temperature and surface-derived meltwater influenced East Antarctic ice mass balance under warmer-than-present climate conditions. Our results imply a dynamic EAIS response with continued anthropogenic warming and suggest that the EAIS contribution to future global sea-level projections may be under-estimated.
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-12-13
      DOI: 10.1038/nature25026
      Issue No: Vol. 552, No. 7684 (2017)
       
  • Large emissions from floodplain trees close the Amazon methane budget
    • Authors: 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
      Pages: 230 - 234
      Abstract: Wetlands are the largest global source of atmospheric methane (CH4), a potent greenhouse gas. However, methane emission inventories from the Amazon floodplain, the largest natural geographic source of CH4 in the tropics, consistently underestimate the atmospheric burden of CH4 determined via remote sensing and inversion modelling, 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 forests and tropical peat swamp forests, 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.
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-12-04
      DOI: 10.1038/nature24639
      Issue No: Vol. 552, No. 7684 (2017)
       
  • A compositional tipping point governing the mobilization and eruption
           style of rhyolitic magma
    • Authors: D. Di Genova, S. Kolzenburg, S. Wiesmaier, E. Dallanave, D. R. Neuville, K. U. Hess, D. B. Dingwell
      Pages: 235 - 238
      Abstract: The most viscous volcanic melts and the largest explosive eruptions on our planet consist of calcalkaline rhyolites. These eruptions have the potential to influence global climate. The eruptive products are commonly very crystal-poor and highly degassed, yet the magma is mostly stored as crystal mushes containing small amounts of interstitial melt with elevated water content. It is unclear how magma mushes are mobilized to create large batches of eruptible crystal-free magma. Further, rhyolitic eruptions can switch repeatedly between effusive and explosive eruption styles and this transition is difficult to attribute to the rheological effects of water content or crystallinity. Here we measure the viscosity of a series of melts spanning the compositional range of the Yellowstone volcanic system and find that in a narrow compositional zone, melt viscosity increases by up to two orders of magnitude. These viscosity variations are not predicted by current viscosity models 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.
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-12-13
      DOI: 10.1038/nature24488
      Issue No: Vol. 552, No. 7684 (2017)
       
  • Pluripotent state transitions coordinate morphogenesis in mouse and human
           embryos
    • Authors: 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
      Pages: 239 - 243
      Abstract: 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 cavity, a fundamental event for all subsequent development. Concomitantly, epiblast cells transit through distinct pluripotent states, before lineage commitment at gastrulation. These pluripotent states have been characterized at the molecular level, 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.
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-11-29
      DOI: 10.1038/nature24675
      Issue No: Vol. 552, No. 7684 (2017)
       
  • Moving beyond microbiome-wide associations to causal microbe
           identification
    • Authors: Neeraj K. Surana, Dennis L. Kasper
      Pages: 244 - 247
      Abstract: Microbiome-wide association studies have established that numerous diseases are associated with changes in the microbiota. These studies typically generate a long list of commensals implicated as biomarkers of disease, with no clear relevance to disease pathogenesis. If the field is to move beyond correlations and begin to address causation, an effective system is needed for refining this catalogue of differentially abundant microbes and to allow subsequent mechanistic studies. 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.
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-12-06
      DOI: 10.1038/nature25019
      Issue No: Vol. 552, No. 7684 (2017)
       
  • Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy
    • Authors: 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
      Pages: 248 - 252
      Abstract: Diabetic retinopathy is an important cause of blindness in adults, and is characterized by progressive loss of vascular cells and slow dissolution of inter-vascular junctions, which result in vascular leakage and retinal oedema. Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization. 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.
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-12-06
      DOI: 10.1038/nature25013
      Issue No: Vol. 552, No. 7684 (2017)
       
  • Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours
    • Authors: 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
      Pages: 253 - 257
      Abstract: Tissue-resident memory CD8+ T (TRM) cells are found at common sites of pathogen exposure, where they elicit rapid and robust protective immune responses. 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.
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-12-06
      DOI: 10.1038/nature24993
      Issue No: Vol. 552, No. 7684 (2017)
       
  • A non-canonical Notch complex regulates adherens junctions and vascular
           barrier function
    • Authors: William J. Polacheck, Matthew L. Kutys, Jinling Yang, Jeroen Eyckmans, Yinyu Wu, Hema Vasavada, Karen K. Hirschi, Christopher S. Chen
      Pages: 258 - 262
      Abstract: The vascular barrier that separates blood from tissues is actively regulated by the endothelium and is essential for transport, inflammation, and haemostasis. Haemodynamic shear stress plays a critical role in maintaining endothelial barrier function, 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 differentiation, angiogenesis and remodelling. 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.
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-11-13
      DOI: 10.1038/nature24998
      Issue No: Vol. 552, No. 7684 (2017)
       
  • RNA polymerase III limits longevity downstream of TORC1
    • Authors: Danny Filer, Maximillian A. Thompson, Vakil Takhaveev, Adam J. Dobson, Ilektra Kotronaki, James W. M. Green, Matthias Heinemann, Jennifer M. A. Tullet, Nazif Alic
      Pages: 263 - 267
      Abstract: Three distinct RNA polymerases transcribe different classes of genes in the eukaryotic nucleus. RNA polymerase (Pol) III is the essential, evolutionarily conserved enzyme that generates short, non-coding RNAs, including tRNAs and 5S rRNA. The historical focus on transcription of protein-coding genes has left the roles of Pol III in organismal physiology relatively unexplored. Target of rapamycin kinase complex 1 (TORC1) regulates Pol III activity, and is also an important determinant of longevity. 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.
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-11-29
      DOI: 10.1038/nature25007
      Issue No: Vol. 552, No. 7684 (2017)
       
  • piRNA-mediated regulation of transposon alternative splicing in the soma
           and germ line
    • Authors: Felipe Karam Teixeira, Martyna Okuniewska, Colin D. Malone, Rémi-Xavier Coux, Donald C. Rio, Ruth Lehmann
      Pages: 268 - 272
      Abstract: Transposable elements can drive genome evolution, but their enhanced activity is detrimental to the host and therefore must be tightly regulated. The Piwi-interacting small RNA (piRNA) pathway is vital for the regulation of transposable elements, by inducing transcriptional silencing or post-transcriptional decay of mRNAs. Here we show that piRNAs and piRNA biogenesis components regulate precursor mRNA splicing of P-transposable element transcripts in vivo, leading to the production of the non-transposase-encoding mature mRNA isoform in Drosophila germ cells. Unexpectedly, we show that the piRNA pathway components do not act to reduce transcript levels of the P-element transposon during P–M hybrid dysgenesis, a syndrome that affects germline development in Drosophila. 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) and Panoramix (Silencio), as well as Heterochromatin protein 1a (HP1a; encoded by Su(var)205). Furthermore, we show that this machinery, together with the piRNA Flamenco cluster, not only controls the accumulation of Gypsy retrotransposon transcripts but also regulates the splicing of Gypsy mRNAs in cultured ovarian somatic cells, a process required for the production of infectious particles that can lead to heritable transposition events. 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.
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-12-06
      DOI: 10.1038/nature25018
      Issue No: Vol. 552, No. 7684 (2017)
       
  • KAT2A coupled with the α-KGDH complex acts as a histone H3
           succinyltransferase
    • Authors: 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
      Pages: 273 - 277
      Abstract: Histone modifications, such as the frequently occurring lysine succinylation, 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.
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-12-06
      DOI: 10.1038/nature25003
      Issue No: Vol. 552, No. 7684 (2017)
       
  • Corrigendum: The 4D nucleome project
    • Authors: 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
      Pages: 278 - 278
      Abstract: 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
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-11-22
      DOI: 10.1038/nature24667
      Issue No: Vol. 552, No. 7684 (2017)
       
  • Erratum: Early members of ‘living fossil’ lineage imply later origin
           of modern ray-finned fishes
    • Authors: Sam Giles, Guang-Hui Xu, Thomas J. Near, Matt Friedman
      Pages: 278 - 278
      Abstract: 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
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-11-22
      DOI: 10.1038/nature25004
      Issue No: Vol. 552, No. 7684 (2017)
       
  • Erratum: Probabilistic reanalysis of twentieth-century sea-level rise
    • Authors: Carling C. Hay, Eric Morrow, Robert E. Kopp, Jerry X. Mitrovica
      Pages: 278 - 278
      Abstract: 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.
      Citation: Nature 552, 7684 (2017)
      PubDate: 2017-11-08
      DOI: 10.1038/nature24466
      Issue No: Vol. 552, No. 7684 (2017)
       
  • Loss of net neutrality could harm research
    • Pages: 147 - 147
      Abstract: Moves to create a multi-speed Internet could push science into the slow lane.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-07842-0
      Issue No: Vol. 552, No. 7684
       
  • Bureaucratic drag dents Japan’s nuclear science
    • Pages: 147 - 148
      Abstract: Japan needs a better way to assess whether research reactors are safe to re-open.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08464-2
      Issue No: Vol. 552, No. 7684
       
  • How to avoid glib interdisciplinarity
    • Pages: 148 - 148
      Abstract: To make progress on the grand challenges, authors, reviewers and editors must take the time to respect each others’ expertise and blind spots.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08465-1
      Issue No: Vol. 552, No. 7684
       
  • Zimbabwe’s new government must commit to science
    • Authors: Dexter Tagwireyi
      Pages: 149 - 149
      Abstract: As a new president takes office, scientists in the country and beyond should urge the administration to make science a priority, says Dexter Tagwireyi.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08268-4
      Issue No: Vol. 552, No. 7684
       
  • Dodgy citations, fusion milestone and a skeleton called Little Foot
    • Pages: 152 - 153
      Abstract: The week in science: 8–14 December 2017.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08462-4
      Issue No: Vol. 552, No. 7684
       
  • Nine researchers sue University of Rochester over sexual-harassment
           allegations
    • Authors: Alexandra Witze
      Pages: 155 - 156
      Abstract: Lawsuit alleges that the institution mishandled complaints about cognitive scientist Florian Jaeger.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08235-z
      Issue No: Vol. 552, No. 7684
       
  • Tasmanian tiger genome offers clues to its extinction
    • Authors: Ewen Callaway
      Pages: 156 - 157
      Abstract: Geneticists analyse DNA from preserved pup, more than 80 years after the last of its kind died.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08368-1
      Issue No: Vol. 552, No. 7684
       
  • Acupuncture in cancer study reignites debate about controversial technique
    • Authors: Jo Marchant
      Pages: 157 - 158
      Abstract: Large study suggests acupuncture could help women stick with unpleasant cancer treatments.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08309-y
      Issue No: Vol. 552, No. 7684
       
  • US graduate students in uproar over proposed tax hike
    • Authors: Helen Shen
      Pages: 158 - 159
      Abstract: Worries over the cost of an education spill over into protests.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-07879-1
      Issue No: Vol. 552, No. 7684
       
  • Argentinian geoscientist faces criminal charges over glacier survey
    • Authors: Jeff Tollefson , Emiliano Rodríguez Mega
      Pages: 159 - 160
      Abstract: Government researcher Ricardo Villalba stands accused of shaping a study to benefit mining interests.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08236-y
      Issue No: Vol. 552, No. 7684
       
  • The science that’s never been cited
    • Pages: 162 - 164
      Abstract: Nature investigates how many papers really end up without a single citation.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08404-0
      Issue No: Vol. 552, No. 7684
       
  • Deploy vaccines to fight superbugs
    • Authors: Rino Rappuoli , David E. Bloom , Steve Black
      Pages: 165 - 167
      Abstract: Immunizations combined with antibiotics could be our best shot at combating drug-resistant microbes, argue Rino Rappuoli, David E. Bloom and Steve Black.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08323-0
      Issue No: Vol. 552, No. 7684
       
  • Five priorities for weather and climate research
    • Authors: Øystein Hov , Deon Terblanche , Sarah Jones , Paolo M. Ruti , Oksana Tarasova
      Pages: 168 - 170
      Abstract: Adapt to how data are made and used, urge Øystein Hov and colleagues.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08463-3
      Issue No: Vol. 552, No. 7684
       
  • Planetariums and the rise of spectacular science
    • Authors: Marek Kukula
      Pages: 172 - 173
      Abstract: Marek Kukula enjoys a cultural history of the theatres that give us a taste of space.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08441-9
      Issue No: Vol. 552, No. 7684
       
  • A manifesto for slow science, the biology of personal space, and an
           intimate look at the neuroscience of food: Books in brief
    • Authors: Barbara Kiser
      Pages: 173 - 173
      Abstract: Barbara Kiser reviews five of the week’s best science picks.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08444-6
      Issue No: Vol. 552, No. 7684
       
  • Lyme disease laid bare
    • Authors: James G. Logan
      Pages: 174 - 174
      Abstract: James G. Logan hails a study of the controversial tick-borne condition.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08442-8
      Issue No: Vol. 552, No. 7684
       
  • Snow leopard conservation status is spot on
    • Snow leopard conservation status is spot on

      Nature 552, 7684 (2017). doi:10.1038/d41586-017-08378-z

      Author: Tom McCarthy

      Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08378-z
      Issue No: Vol. 552, No. 7684
       

  • Pricing not enough for deep carbon cuts
    • Pricing not enough for deep carbon cuts

      Nature 552, 7684 (2017). doi:10.1038/d41586-017-08578-7

      Authors: Michael Mehling & Endre Tvinnereim

      Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08578-7
      Issue No: Vol. 552, No. 7684
       

  • How to spare half a planet
    • How to spare half a planet

      Nature 552, 7684 (2017). doi:10.1038/d41586-017-08579-6

      Authors: Andrew Balmford & Rhys Green

      Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08579-6
      Issue No: Vol. 552, No. 7684
       

  • Medical legacy of sanctions in Iran
    • Medical legacy of sanctions in Iran

      Nature 552, 7684 (2017). doi:10.1038/d41586-017-08580-z

      Authors: Reza Heidari , Mostafa Akbariqomi & Gholamreza Tavoosidana

      Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08580-z
      Issue No: Vol. 552, No. 7684
       

  • Standardize future device connections for computers
    • Standardize future device connections for computers

      Nature 552, 7684 (2017). doi:10.1038/d41586-017-08582-x

      Author: Ricardo Borges

      Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08582-x
      Issue No: Vol. 552, No. 7684
       

  • Ronald Breslow (1931–2017)
    • Authors: Virginia W. Cornish
      Pages: 176 - 176
      Abstract: Organic chemist who took inspiration from nature.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08461-5
      Issue No: Vol. 552, No. 7684
       
  • Early embryos kept in check
    • Authors: Julien G. Dumortier , Jean-Léon Maître
      Pages: 178 - 179
      Abstract: 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.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-07436-w
      Issue No: Vol. 552, No. 7684
       
  • A dark side to omega-3 fatty acids
    • Authors: Keisuke Yanagida , Timothy Hla
      Pages: 180 - 181
      Abstract: 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.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-07678-8
      Issue No: Vol. 552, No. 7684
       
  • Longer life through an odd Pol enzyme
    • Authors: Bruce A. Edgar , Savraj S. Grewal
      Pages: 182 - 183
      Abstract: 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.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-07435-x
      Issue No: Vol. 552, No. 7684
       
  • Viruses hijack a long non-coding RNA
    • Authors: Nicholas S. Heaton , Bryan R. Cullen
      Pages: 184 - 185
      Abstract: ​​​​​​​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.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-07692-w
      Issue No: Vol. 552, No. 7684
       
  • Fifteen minutes
    • Authors: Alex Shvartsman
      Pages: 284 - 284
      Abstract: Turn on, tune in, log off.
      Citation: Nature 552, 7684 (2017)
      DOI: 10.1038/d41586-017-08466-0
      Issue No: Vol. 552, No. 7684
       
 
 
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