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Journal Cover   Nature
  [SJR: 14.747]   [H-I: 768]   [2669 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Print) 0028-0836 - ISSN (Online) 1476-4687
   Published by Nature Publishing Group Homepage  [111 journals]
  • Beyond the genome
    • Pages: 273 - 273
      Abstract: Studies of the epigenomic signatures of many healthy and diseased human tissues could provide crucial information to link genetic variation and disease.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518273a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Nature journals offer double-blind review
    • Pages: 274 - 274
      Abstract: Starting in March, Nature and the monthly Nature research journals will offer an alternative to conventional peer review.
      Authors will be able to request that their names and affiliations are withheld from reviewers of their papers — a form of peer review known as
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518274b
      Issue No: Vol. 518, No. 7539 (2015)
       
  • The idea factory
    • Pages: 274 - 274
      Abstract: Science will benefit most from a combination of youthful innovation and hard-won experience.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518274a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Europe needs fresh focus on big-science projects
    • Authors: Olof Hallonsten
      Pages: 275 - 275
      Abstract: Messy governance and a lack of long-term planning threaten the success of the European Spallation Source, says Olof Hallonsten.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-17
      DOI: 10.1038/518275a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Agricultural economics: Trade disruptions hit the poor
    • Pages: 276 - 277
      Abstract: Countries that cut back on food trade to protect against domestic price fluctuations can disrupt the global food system — a sign of the increasing connectedness of the market.Michael Puma of Columbia University in New York and his team used data on wheat and
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518276d
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Information technology: Long-term data storage in DNA
    • Pages: 276 - 276
      Abstract: A DNA-based system could safely store data for millennia.Today's digital systems can store information for only around 50 years, but encoding it in DNA could greatly extend its lifetime. Robert Grass at the Swiss Federal Institute of Technology in Zurich and his colleagues have
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518276b
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Evolution: Fern hybrid does not mind the gap
    • Pages: 276 - 276
      Abstract: Two ferns that last shared an ancestor more than 60 million years ago have interbred — showing that this can still happen even after a long evolutionary gap.As populations separate and evolve over time, they lose the ability to cross-breed. So Carl Rothfels, now
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518276c
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Palaeontology: Ancient mammals displayed diversity
    • Pages: 276 - 276
      Abstract: Two fossils show that early mammals had a more varied anatomy and behaviour than was thought.A team led by Zhe-Xi Luo at the University of Chicago, Illinois, and Qing-Jin Meng at the Beijing Museum of Natural History analysed a 160-million-year-old fossil from China. The
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518276a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Correction
    • Pages: 277 - 277
      Abstract: The Research Highlight 'Capsules collect carbon dioxide' (Nature518, 140;10.1038/518140a2015) stated that all authors are at Harvard University. In fact, Jennifer Lewis and a co-author are at Harvard; her collaborators are at Lawrence Livermore National Laboratory, California, and at
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518277g
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Particle physics: New particles found at collider
    • Pages: 277 - 277
      Abstract: High-energy collisions between protons have unearthed two new particles.Named Ξ′b− and Ξ*b−, the particles were discovered by the LHCb experiment team at the Large Hadron Collider at CERN, Europe's particle-physics laboratory near Geneva, Switzerland. Like protons, the particles
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518277d
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Oceanography: Arctic ice warms from below
    • Pages: 277 - 277
      Abstract: Shrinking Arctic sea ice could cause more-vigorous mixing of ocean heat in northern waters, eventually leading to further melting.Tom Rippeth of Bangor University, UK, and his colleagues measured water temperatures at different depths and locations across the Arctic Ocean. They found that heat rose
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518277e
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Ecology: Traps target tricky toads
    • Pages: 277 - 277
      Abstract: Habitats that attract invasive species can be turned into 'ecological traps' that wipe out the invaders.In Australia, invasive cane toads (Rhinella marina; pictured) are devastating native wildlife, and they have proved difficult to eradicate. To survive the dry season, the toads
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518277b
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Neuroscience: Breathe in to boost brain-fluid flow
    • Pages: 277 - 277
      Abstract: An inwards breath drives the flow of fluid that bathes the human brain.Cerebrospinal fluid cushions the brain, flushes out waste and in rodents seems to be controlled by pulsating blood flow. To find out how the fluid is regulated in humans, Steffi Dreha-Kulaczewski at
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518277c
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Palaeohydrology: Drying lakes linked to extinctions
    • Pages: 277 - 277
      Abstract: Climate change in Australia may have played a part in the extinction of many large animals some 50,000 years ago.The cause of the mass die-off is debated, with some saying that ecological collapse was sparked by human use of fire 40,000 to 60,000 years
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518277a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Journal publishes 200-word papers
    • Authors: Chris Woolston
      Pages: 277 - 277
      Abstract: Researchers are buzzing about a publication that accepts only 'brief ideas'.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-12
      DOI: 10.1038/518277f
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Seven days: 13–19 February 2015
    • Pages: 278 - 279
      Abstract: The week in science: Europe’s spaceplane soars; transgenic apples given go-ahead for US market; and geoengineering risks are highlighted.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518278a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Saudi Arabia opens top-notch laser lab
    • Authors: Alison Abbott
      Pages: 281 - 282
      Abstract: Facility will study biomedical uses at attosecond resolution.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-17
      DOI: 10.1038/518281a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Cybercrime fighters target human error
    • Authors: Erika Check Hayden
      Pages: 282 - 283
      Abstract: Researchers aim to cut passwords and people out of the data-safety equation.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-17
      DOI: 10.1038/518282a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Young scientists lead the way on fresh ideas
    • Authors: Ewen Callaway
      Pages: 283 - 284
      Abstract: Analysis of millions of papers finds that junior biomedical researchers tend to work on more innovative topics than their senior colleagues do.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518283a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Steppe migration rekindles debate on language origin
    • Authors: Ewen Callaway
      Pages: 284 - 285
      Abstract: Eurasian region gains ground as birthplace of Indo-European tongues.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518284a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Biodefence researchers seek 'Homo chippiens'
    • Authors: Sara Reardon
      Pages: 285 - 286
      Abstract: Projects aim to mimic human body using networks of simulated organs.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-17
      DOI: 10.1038/518285a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Radical energy ideas secure US private funds
    • Authors: Jeff Tollefson
      Pages: 286 - 287
      Abstract: Federal start-up funds inspire investment in ARPA-E technologies.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-17
      DOI: 10.1038/518286a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Sex redefined
    • Authors: Claire Ainsworth
      Pages: 288 - 291
      Abstract: The idea of two sexes is simplistic. Biologists now think there is a wider spectrum than that.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518288a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Museums: The endangered dead
    • Authors: Christopher Kemp
      Pages: 292 - 294
      Abstract: The billions of specimens in natural-history museums are becoming more useful for tracking Earth's shrinking biodiversity. But the collections also face grave threats.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518292a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Corruption: Good governance powers innovation
    • Authors: Alina Mungiu-Pippidi
      Pages: 295 - 297
      Abstract: Corruption is a barrier to innovation, warns Alina Mungiu-Pippidi. Greater scrutiny of public spending is needed if science and technology are to fulfil their potential.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518295a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Neuroscience: Halving it all
    • Authors: Douwe Draaisma
      Pages: 298 - 299
      Abstract: Douwe Draaisma enjoys the autobiography of Michael Gazzaniga, who has studied split brains for half a century.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518298a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Books in brief
    • Authors: Barbara Kiser
      Pages: 299 - 299
      Abstract: Barbara Kiser reviews five of the week's best science picks.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518299a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • History of science: Unshadowed lens on the past
    • Authors: Robert P. Crease
      Pages: 300 - 300
      Abstract: Robert P. Crease examines Steven Weinberg's radical retelling of the story of science.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518300a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Theatre: Atomic tragedian
    • Authors: Philip Ball
      Pages: 301 - 301
      Abstract: Philip Ball sees something of Macbeth in a play about J. Robert Oppenheimer, leader of the Manhattan Project.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518301a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Plant genetics: Czech centre marks Mendel anniversary
    • Authors: Anna Matalová, Eva Matalová
      Pages: 303 - 303
      Abstract: This month marks the 150th anniversary of Gregor Mendel's presentation of his famous study 'Experiments in plant hybrids' at a meeting of the Nature Research Society in Brno, Moravia (in today's Czech Republic). His lecture was published a year later in the society's journal.Often
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518303e
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Illegal trade: Tweak Chinese law to end ivory demand
    • Authors: Zhao-Min Zhou
      Pages: 303 - 303
      Abstract: The proposed revisions to China's wildlife protection law of 1988 should aim to make the private ownership of threatened species illegal. This would help to control the country's flourishing trade in illegal animal products. It is also important to tackle the public's demand for such
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518303c
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Physics theory: 'Simple' or 'elegant' criteria are not valid
    • Authors: Richard Dawid
      Pages: 303 - 303
      Abstract: Counter to the impression given by George Ellis and Joe Silk, I have never used or endorsed the slogans “elegance will suffice” and “post-empirical science” regarding theories in fundamental physics (Nature516, 321–323,10.1038/516321a2014). In fact, both contradict
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518303d
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Drug discovery: Early antibiotic from a cranberry bog
    • Authors: Carol L. Moberg
      Pages: 303 - 303
      Abstract: Losee Ling and colleagues refer to Selman Waksman's “platform of natural product drug discovery” (Nature517, 455–459;10.1038/nature140982015; see also K.LewisNature485, 439–440;10.1038/485439a2012), which alludes to Waksman's 1943 discovery
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518303a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Natural history: Rescue Eastern Europe's collections
    • Authors: Boris Kryštufek, Nataliya Abramson, Dražen Kotrošan
      Pages: 303 - 303
      Abstract: The political collapse of Eastern Europe has ravaged its priceless natural history collections. The European Union could rescue many of these as part of its commitment to preserve cultural heritage.In the small, war-torn nations of the western Balkans, for example, natural history collections receive
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518303b
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Vernon B. Mountcastle (1918–2015)
    • Authors: Kevan Martin
      Pages: 304 - 304
      Abstract: Discoverer of the repeating organization of neurons in the mammalian cortex.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518304a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Neuroscience: The cortical connection
    • Authors: Benjamin Scholl, Nicholas J. Priebe
      Pages: 306 - 307
      Abstract: Neurons in the brain's visual cortex receive inputs from thousands of other neurons. But it now emerges that each is strongly connected to only a few others: those most similar to itself. See Letter p.399
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-04
      DOI: 10.1038/nature14201
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Astrophysics: A lithium-rich stellar explosion
    • Authors: Margarita Hernanz
      Pages: 307 - 308
      Abstract: The contribution of explosions known as novae to the lithium content of the Milky Way is uncertain. Radioactive beryllium, which transforms into lithium, has been detected for the first time in one such explosion. See Letter p.381
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518307a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Evolution: Finches sequenced
    • Authors: Magdalena Skipper
      Pages: 308 - 308
      Abstract: Darwin's finches played a key part in the formulation of his theory of evolution by natural selection. They have since become an iconic model for adaptive radiation — 14 species evolved from a common ancestor to occupy different niches on the Galapagos Islands, with 1
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518308a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • 50 & 100 Years Ago
    • Pages: 309 - 309
      Abstract: 50 Years AgoIn a written answer in the House of Commons on February 3, the Minister of Aviation, Mr. R. Jenkins, stated that a conference, attended by all the Member States of the European Launcher Development Organization, met in Paris during January 19–21, to
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518309a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Biochemistry: Breaking methane
    • Authors: Amy C. Rosenzweig
      Pages: 309 - 310
      Abstract: The most powerful oxidant found in nature is compound Q, an enzymatic intermediate that oxidizes methane. New spectroscopic data have resolved the long-running controversy about Q's chemical structure. See Letter p.431
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-01-21
      DOI: 10.1038/nature14199
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Climate science: The future of coastal ocean upwelling
    • Authors: Emanuele Di Lorenzo
      Pages: 310 - 311
      Abstract: An ensemble of climate models predicts that winds along the world's coasts will intensify because of global warming, inducing more ocean upwelling — a process that will affect the health of coastal marine ecosystems. See Letter p.390
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518310a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Epigenomics: Roadmap for regulation
    • Authors: Casey E. Romanoski, Christopher K. Glass, Hendrik G. Stunnenberg, Laurence Wilson, Genevieve Almouzni
      Pages: 314 - 316
      Abstract: A package of papers investigates the functional regulatory elements in genomes that have been obtained from human tissue samples and cell lines. The implications of the project are presented here from three viewpoints. See Articles p.317, p.331, p.337 & p.344 and Letters p.350, p.355, p.360 & p.365
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518314a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Integrative analysis of 111 reference human epigenomes
    • Authors: Roadmap Epigenomics Consortium, Anshul Kundaje, Wouter Meuleman, Jason Ernst, Misha Bilenky, Angela Yen, Alireza Heravi-Moussavi, Pouya Kheradpour, Zhizhuo Zhang, Jianrong Wang, Michael J. Ziller, Viren Amin, John W. Whitaker, Matthew D. Schultz, Lucas D. Ward, Abhishek Sarkar, Gerald Quon, Richard S. Sandstrom, Matthew L. Eaton, Yi-Chieh Wu, Andreas R. Pfenning, Xinchen Wang, Melina Claussnitzer, Yaping Liu, Cristian Coarfa, R. Alan Harris, Noam Shoresh, Charles B. Epstein, Elizabeta Gjoneska, Danny Leung, Wei Xie, R. David Hawkins, Ryan Lister, Chibo Hong, Philippe Gascard, Andrew J. Mungall, Richard Moore, Eric Chuah, Angela Tam, Theresa K. Canfield, R. Scott Hansen, Rajinder Kaul, Peter J. Sabo, Mukul S. Bansal, Annaick Carles, Jesse R. Dixon, Kai-How Farh, Soheil Feizi, Rosa Karlic, Ah-Ram Kim, Ashwinikumar Kulkarni, Daofeng Li, Rebecca Lowdon, GiNell Elliott, Tim R. Mercer, Shane J. Neph, Vitor Onuchic, Paz Polak, Nisha Rajagopal, Pradipta Ray, Richard C. Sallari, Kyle T. Siebenthall, Nicholas A. Sinnott-Armstrong, Michael Stevens, Robert E. Thurman, Jie Wu, Bo Zhang, Xin Zhou, Arthur E. Beaudet, Laurie A. Boyer, Philip L. De Jager, Peggy J. Farnham, Susan J. Fisher, David Haussler, Steven J. M. Jones, Wei Li, Marco A. Marra, Michael T. McManus, Shamil Sunyaev, James A. Thomson, Thea D. Tlsty, Li-Huei Tsai, Wei Wang, Robert A. Waterland, Michael Q. Zhang, Lisa H. Chadwick, Bradley E. Bernstein, Joseph F. Costello, Joseph R. Ecker, Martin Hirst, Alexander Meissner, Aleksandar Milosavljevic, Bing Ren, John A. Stamatoyannopoulos, Ting Wang, Manolis Kellis
      Pages: 317 - 330
      Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/nature14248
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Chromatin architecture reorganization during stem cell differentiation
    • Authors: Jesse R. Dixon, Inkyung Jung, Siddarth Selvaraj, Yin Shen, Jessica E. Antosiewicz-Bourget, Ah Young Lee, Zhen Ye, Audrey Kim, Nisha Rajagopal, Wei Xie, Yarui Diao, Jing Liang, Huimin Zhao, Victor V. Lobanenkov, Joseph R. Ecker, James A. Thomson, Bing Ren
      Pages: 331 - 336
      Abstract: Higher-order chromatin structure is emerging as an important regulator of gene expression. Although dynamic chromatin structures have been identified in the genome, the full scope of chromatin dynamics during mammalian development and lineage specification remains to be determined. By mapping genome-wide chromatin interactions in human
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/nature14222
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Transcription factor binding dynamics during human ES cell differentiation
    • Authors: Alexander M. Tsankov, Hongcang Gu, Veronika Akopian, Michael J. Ziller, Julie Donaghey, Ido Amit, Andreas Gnirke, Alexander Meissner
      Pages: 344 - 349
      Abstract: Pluripotent stem cells provide a powerful system to dissect the underlying molecular dynamics that regulate cell fate changes during mammalian development. Here we report the integrative analysis of genome-wide binding data for 38 transcription factors with extensive epigenome and transcriptional data across the differentiation of
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/nature14233
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Integrative analysis of haplotype-resolved epigenomes across human tissues
    • Authors: Danny Leung, Inkyung Jung, Nisha Rajagopal, Anthony Schmitt, Siddarth Selvaraj, Ah Young Lee, Chia-An Yen, Shin Lin, Yiing Lin, Yunjiang Qiu, Wei Xie, Feng Yue, Manoj Hariharan, Pradipta Ray, Samantha Kuan, Lee Edsall, Hongbo Yang, Neil C. Chi, Michael Q. Zhang, Joseph R. Ecker, Bing Ren
      Pages: 350 - 354
      Abstract: Allelic differences between the two homologous chromosomes can affect the propensity of inheritance in humans; however, the extent of such differences in the human genome has yet to be fully explored. Here we delineate allelic chromatin modifications and transcriptomes among a broad set of human tissues, enabled by a chromosome-spanning haplotype reconstruction strategy. The resulting large collection of haplotype-resolved epigenomic maps reveals extensive allelic biases in both chromatin state and transcription, which show considerable variation across tissues and between individuals, and allow us to investigate cis-regulatory relationships between genes and their control sequences. Analyses of histone modification maps also uncover intriguing characteristics of cis-regulatory elements and tissue-restricted activities of repetitive elements. The rich data sets described here will enhance our understanding of the mechanisms by which cis-regulatory elements control gene expression programs.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/nature14217
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Cell-of-origin chromatin organization shapes the mutational landscape of
           cancer
    • Authors: Paz Polak, Rosa Karlić, Amnon Koren, Robert Thurman, Richard Sandstrom, Michael S. Lawrence, Alex Reynolds, Eric Rynes, Kristian Vlahoviček, John A. Stamatoyannopoulos, Shamil R. Sunyaev
      Pages: 360 - 364
      Abstract: Cancer is a disease potentiated by mutations in somatic cells. Cancer mutations are not distributed uniformly along the human genome. Instead, different human genomic regions vary by up to fivefold in the local density of cancer somatic mutations, posing a fundamental problem for statistical methods used in cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape. However, both somatic mutagenesis and epigenomic features are highly cell-type-specific. We investigated the distribution of mutations in multiple independent samples of diverse cancer types and compared them to cell-type-specific epigenomic features. Here we show that chromatin accessibility and modification, together with replication timing, explain up to 86% of the variance in mutation rates along cancer genomes. The best predictors of local somatic mutation density are epigenomic features derived from the most likely cell type of origin of the corresponding malignancy. Moreover, we find that cell-of-origin chromatin features are much stronger determinants of cancer mutation profiles than chromatin features of matched cancer cell lines. Furthermore, we show that the cell type of origin of a cancer can be accurately determined based on the distribution of mutations along its genome. Thus, the DNA sequence of a cancer genome encompasses a wealth of information about the identity and epigenomic features of its cell of origin.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/nature14221
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Conserved epigenomic signals in mice and humans reveal immune basis of
           Alzheimer’s disease
    • Authors: Elizabeta Gjoneska, Andreas R. Pfenning, Hansruedi Mathys, Gerald Quon, Anshul Kundaje, Li-Huei Tsai, Manolis Kellis
      Pages: 365 - 369
      Abstract: Alzheimer’s disease (AD) is a severe age-related neurodegenerative disorder characterized by accumulation of amyloid-β plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated downregulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune-cell-specific enhancer signatures as well as immune cell expression quantitative trait loci, while decreasing-level enhancer orthologues show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants, and implicate additional loci that do not reach genome-wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/nature14252
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Evolution of Darwin’s finches and their beaks revealed by genome
           sequencing
    • Authors: Sangeet Lamichhaney, Jonas Berglund, Markus Sällman Almén, Khurram Maqbool, Manfred Grabherr, Alvaro Martinez-Barrio, Marta Promerová, Carl-Johan Rubin, Chao Wang, Neda Zamani, B. Rosemary Grant, Peter R. Grant, Matthew T. Webster, Leif Andersson
      Pages: 371 - 375
      Abstract: Darwin’s finches, inhabiting the Galápagos archipelago and Cocos Island, constitute an iconic model for studies of speciation and adaptive evolution. Here we report the results of whole-genome re-sequencing of 120 individuals representing all of the Darwin’s finch species and two close relatives. Phylogenetic analysis reveals
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-11
      DOI: 10.1038/nature14181
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Architecture of the RNA polymerase II–Mediator core initiation
           complex
    • Authors: C. Plaschka, L. Larivière, L. Wenzeck, M. Seizl, M. Hemann, D. Tegunov, E. V. Petrotchenko, C. H. Borchers, W. Baumeister, F. Herzog, E. Villa, P. Cramer
      Pages: 376 - 380
      Abstract: The conserved co-activator complex Mediator enables regulated transcription initiation by RNA polymerase (Pol) II. Here we reconstitute an active 15-subunit core Mediator (cMed) comprising all essential Mediator subunits from Saccharomyces cerevisiae. The cryo-electron microscopic structure of cMed bound to a core initiation complex was
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-04
      DOI: 10.1038/nature14229
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Explosive lithium production in the classical nova V339 Del (Nova Delphini
           2013)
    • Authors: Akito Tajitsu, Kozo Sadakane, Hiroyuki Naito, Akira Arai, Wako Aoki
      Pages: 381 - 384
      Abstract: The origin of lithium (Li) and its production process have long been uncertain. Li could be produced by Big Bang nucleosynthesis, interactions of energetic cosmic rays with interstellar matter, evolved low-mass stars, novae, and supernova explosions. Chemical evolution models and observed stellar Li abundances suggest that at least half the Li may have been produced in red giants, asymptotic giant branch (AGB) stars, and novae. No direct evidence, however, for the supply of Li from evolved stellar objects to the Galactic medium has hitherto been found. Here we report the detection of highly blue-shifted resonance lines of the singly ionized radioactive isotope of beryllium, 7Be, in the near-ultraviolet spectra of the classical nova V339 Del (Nova Delphini 2013) 38 to 48 days after the explosion. 7Be decays to form 7Li within a short time (half-life of 53.22 days). The 7Be was created during the nova explosion via the alpha-capture reaction 3He(α,γ)7Be (ref. 5). This result supports the theoretical prediction that a significant amount of 7Li is produced in classical nova explosions.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/nature14161
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Direct observation of bond formation in solution with femtosecond X-ray
           scattering
    • Authors: Kyung Hwan Kim, Jong Goo Kim, Shunsuke Nozawa, Tokushi Sato, Key Young Oang, Tae Wu Kim, Hosung Ki, Junbeom Jo, Sungjun Park, Changyong Song, Takahiro Sato, Kanade Ogawa, Tadashi Togashi, Kensuke Tono, Makina Yabashi, Tetsuya Ishikawa, Joonghan Kim, Ryong Ryoo, Jeongho Kim, Hyotcherl Ihee, Shin-ichi Adachi
      Pages: 385 - 389
      Abstract: The making and breaking of atomic bonds are essential processes in chemical reactions. Although the ultrafast dynamics of bond breaking have been studied intensively using time-resolved techniques, it is very difficult to study the structural dynamics of bond making, mainly because of its bimolecular nature. It is especially difficult to initiate and follow diffusion-limited bond formation in solution with ultrahigh time resolution. Here we use femtosecond time-resolved X-ray solution scattering to visualize the formation of a gold trimer complex, [Au(CN)2–]3 in real time without the limitation imposed by slow diffusion. This photoexcited gold trimer, which has weakly bound gold atoms in the ground state, undergoes a sequence of structural changes, and our experiments probe the dynamics of individual reaction steps, including covalent bond formation, the bent-to-linear transition, bond contraction and tetramer formation with a time resolution of ∼500 femtoseconds. We also determined the three-dimensional structures of reaction intermediates with sub-ångström spatial resolution. This work demonstrates that it is possible to track in detail and in real time the structural changes that occur during a chemical reaction in solution using X-ray free-electron lasers and advanced analysis of time-resolved solution scattering data.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/nature14163
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Intensification and spatial homogenization of coastal upwelling under
           climate change
    • Authors: Daiwei Wang, Tarik C. Gouhier, Bruce A. Menge, Auroop R. Ganguly
      Pages: 390 - 394
      Abstract: The timing and strength of wind-driven coastal upwelling along the eastern margins of major ocean basins regulate the productivity of critical fisheries and marine ecosystems by bringing deep and nutrient-rich waters to the sunlit surface, where photosynthesis can occur. How coastal upwelling regimes might change in a warming climate is therefore a question of vital importance. Although enhanced land–ocean differential heating due to greenhouse warming has been proposed to intensify coastal upwelling by strengthening alongshore winds, analyses of observations and previous climate models have provided little consensus on historical and projected trends in coastal upwelling. Here we show that there are strong and consistent changes in the timing, intensity and spatial heterogeneity of coastal upwelling in response to future warming in most Eastern Boundary Upwelling Systems (EBUSs). An ensemble of climate models shows that by the end of the twenty-first century the upwelling season will start earlier, end later and become more intense at high but not low latitudes. This projected increase in upwelling intensity and duration at high latitudes will result in a substantial reduction of the existing latitudinal variation in coastal upwelling. These patterns are consistent across three of the four EBUSs (Canary, Benguela and Humboldt, but not California). The lack of upwelling intensification and greater uncertainty associated with the California EBUS may reflect regional controls associated with the atmospheric response to climate change. Given the strong linkages between upwelling and marine ecosystems, the projected changes in the intensity, timing and spatial structure of coastal upwelling may influence the geographical distribution of marine biodiversity.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/nature14235
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Seismic evidence of effects of water on melt transport in the Lau back-arc
           mantle
    • Authors: S. Shawn Wei, Douglas A. Wiens, Yang Zha, Terry Plank, Spahr C. Webb, Donna K. Blackman, Robert A. Dunn, James A. Conder
      Pages: 395 - 398
      Abstract: Processes of melt generation and transport beneath back-arc spreading centres are controlled by two endmember mechanisms: decompression melting similar to that at mid-ocean ridges and flux melting resembling that beneath arcs. The Lau Basin, with an abundance of spreading ridges at different distances from the subduction zone, provides an opportunity to distinguish the effects of these two different melting processes on magma production and crust formation. Here we present constraints on the three-dimensional distribution of partial melt inferred from seismic velocities obtained from Rayleigh wave tomography using land and ocean-bottom seismographs. Low seismic velocities beneath the Central Lau Spreading Centre and the northern Eastern Lau Spreading Centre extend deeper and westwards into the back-arc, suggesting that these spreading centres are fed by melting along upwelling zones from the west, and helping to explain geochemical differences with the Valu Fa Ridge to the south, which has no distinct deep low-seismic-velocity anomalies. A region of low S-wave velocity, interpreted as resulting from high melt content, is imaged in the mantle wedge beneath the Central Lau Spreading Centre and the northeastern Lau Basin, even where no active spreading centre currently exists. This low-seismic-velocity anomaly becomes weaker with distance southward along the Eastern Lau Spreading Centre and the Valu Fa Ridge, in contrast to the inferred increase in magmatic productivity. We propose that the anomaly variations result from changes in the efficiency of melt extraction, with the decrease in melt to the south correlating with increased fractional melting and higher water content in the magma. Water released from the slab may greatly reduce the melt viscosity or increase grain size, or both, thereby facilitating melt transport.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-02
      DOI: 10.1038/nature14113
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Functional organization of excitatory synaptic strength in primary visual
           cortex
    • Authors: Lee Cossell, Maria Florencia Iacaruso, Dylan R. Muir, Rachael Houlton, Elie N. Sader, Ho Ko, Sonja B. Hofer, Thomas D. Mrsic-Flogel
      Pages: 399 - 403
      Abstract: The strength of synaptic connections fundamentally determines how neurons influence each other’s firing. Excitatory connection amplitudes between pairs of cortical neurons vary over two orders of magnitude, comprising only very few strong connections among many weaker ones. Although this highly skewed distribution of connection strengths is observed in diverse cortical areas, its functional significance remains unknown: it is not clear how connection strength relates to neuronal response properties, nor how strong and weak inputs contribute to information processing in local microcircuits. Here we reveal that the strength of connections between layer 2/3 (L2/3) pyramidal neurons in mouse primary visual cortex (V1) obeys a simple rule—the few strong connections occur between neurons with most correlated responses, while only weak connections link neurons with uncorrelated responses. Moreover, we show that strong and reciprocal connections occur between cells with similar spatial receptive field structure. Although weak connections far outnumber strong connections, each neuron receives the majority of its local excitation from a small number of strong inputs provided by the few neurons with similar responses to visual features. By dominating recurrent excitation, these infrequent yet powerful inputs disproportionately contribute to feature preference and selectivity. Therefore, our results show that the apparently complex organization of excitatory connection strength reflects the similarity of neuronal responses, and suggest that rare, strong connections mediate stimulus-specific response amplification in cortical microcircuits.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-04
      DOI: 10.1038/nature14182
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Structure of the key species in the enzymatic oxidation of methane to
           methanol
    • Authors: Rahul Banerjee, Yegor Proshlyakov, John D. Lipscomb, Denis A. Proshlyakov
      Pages: 431 - 434
      Abstract: Methane monooxygenase (MMO) catalyses the O2-dependent conversion of methane to methanol in methanotrophic bacteria, thereby preventing the atmospheric egress of approximately one billion tons of this potent greenhouse gas annually. The key reaction cycle intermediate of the soluble form of MMO (sMMO) is termed compound Q (Q). Q contains a unique dinuclear FeIV cluster that reacts with methane to break an exceptionally strong 105 kcal mol−1 C-H bond and insert one oxygen atom. No other biological oxidant, except that found in the particulate form of MMO, is capable of such catalysis. The structure of Q remains controversial despite numerous spectroscopic, computational and synthetic model studies. A definitive structural assignment can be made from resonance Raman vibrational spectroscopy but, despite efforts over the past two decades, no vibrational spectrum of Q has yet been obtained. Here we report the core structures of Q and the following product complex, compound T, using time-resolved resonance Raman spectroscopy (TR3). TR3 permits fingerprinting of intermediates by their unique vibrational signatures through extended signal averaging for short-lived species. We report unambiguous evidence that Q possesses a bis-μ-oxo diamond core structure and show that both bridging oxygens originate from O2. This observation strongly supports a homolytic mechanism for O-O bond cleavage. We also show that T retains a single oxygen atom from O2 as a bridging ligand, while the other oxygen atom is incorporated into the product. Capture of the extreme oxidizing potential of Q is of great contemporary interest for bioremediation and the development of synthetic approaches to methane-based alternative fuels and chemical industry feedstocks. Insight into the formation and reactivity of Q from the structure reported here is an important step towards harnessing this potential.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-01-21
      DOI: 10.1038/nature14160
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Workplace safety: Risky encounters
    • Authors: Chris Woolston
      Pages: 445 - 446
      Abstract: Of all of the hazards faced by researchers, the biggest threat may be the human element.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/nj7539-445a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Charitable donations: University gifts grow
    • Pages: 447 - 447
      Abstract: Improving times fill schools coffers.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/nj7539-447d
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Turning point: Stacey Gabriel
    • Authors: Virginia Gewin
      Pages: 447 - 447
      Abstract: Genomicist reaches top rank as middle author.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/nj7539-447a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Compliance: Research regulations
    • Pages: 447 - 447
      Abstract: Study on scientific paperwork might cut red tape.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/nj7539-447b
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Motherhood: Biases in US academia
    • Pages: 447 - 447
      Abstract: US academia shows bias against motherhood.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/nj7539-447c
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Good for something
    • Authors: Deborah Walker
      Pages: 450 - 450
      Abstract: Complete control.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2015-02-18
      DOI: 10.1038/518450a
      Issue No: Vol. 518, No. 7539 (2015)
       
  • Genetic and epigenetic fine mapping of causal autoimmune disease variants
    • Authors: Kyle Kai-How Farh, Alexander Marson, Jiang Zhu, Markus Kleinewietfeld, William J. Housley, Samantha Beik, Noam Shoresh, Holly Whitton, Russell J. H. Ryan, Alexander A. Shishkin, Meital Hatan, Marlene J. Carrasco-Alfonso, Dita Mayer, C. John Luckey, Nikolaos A. Patsopoulos, Philip L. De Jager, Vijay K. Kuchroo, Charles B. Epstein, Mark J. Daly, David A. Hafler, Bradley E. Bernstein
      Pages: 337 - 343
      Abstract: Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis
      Citation: Nature 518, 7539 (2015)
      PubDate: 2014-10-29
      DOI: 10.1038/nature13835
      Issue No: Vol. 518, No. 7539 (2014)
       
  • Dissecting neural differentiation regulatory networks through epigenetic
           footprinting
    • Authors: Michael J. Ziller, Reuven Edri, Yakey Yaffe, Julie Donaghey, Ramona Pop, William Mallard, Robbyn Issner, Casey A. Gifford, Alon Goren, Jeffrey Xing, Hongcang Gu, Davide Cacchiarelli, Alexander M. Tsankov, Charles Epstein, John L. Rinn, Tarjei S. Mikkelsen, Oliver Kohlbacher, Andreas Gnirke, Bradley E. Bernstein, Yechiel Elkabetz, Alexander Meissner
      Pages: 355 - 359
      Abstract: Models derived from human pluripotent stem cells that accurately recapitulate neural development in vitro and allow for the generation of specific neuronal subtypes are of major interest to the stem cell and biomedical community. Notch signalling, particularly through the Notch effector HES5, is a major pathway critical for the onset and maintenance of neural progenitor cells in the embryonic and adult nervous system. Here we report the transcriptional and epigenomic analysis of six consecutive neural progenitor cell stages derived from a HES5::eGFP reporter human embryonic stem cell line. Using this system, we aimed to model cell-fate decisions including specification, expansion and patterning during the ontogeny of cortical neural stem and progenitor cells. In order to dissect regulatory mechanisms that orchestrate the stage-specific differentiation process, we developed a computational framework to infer key regulators of each cell-state transition based on the progressive remodelling of the epigenetic landscape and then validated these through a pooled short hairpin RNA screen. We were also able to refine our previous observations on epigenetic priming at transcription factor binding sites and suggest here that they are mediated by combinations of core and stage-specific factors. Taken together, we demonstrate the utility of our system and outline a general framework, not limited to the context of the neural lineage, to dissect regulatory circuits of differentiation.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2014-12-24
      DOI: 10.1038/nature13990
      Issue No: Vol. 518, No. 7539 (2014)
       
  • Modulation of the proteoglycan receptor PTPσ promotes recovery after
           spinal cord injury
    • Authors: Bradley T. Lang, Jared M. Cregg, Marc A. DePaul, Amanda P. Tran, Kui Xu, Scott M. Dyck, Kathryn M. Madalena, Benjamin P. Brown, Yi-Lan Weng, Shuxin Li, Soheila Karimi-Abdolrezaee, Sarah A. Busch, Yingjie Shen, Jerry Silver
      Pages: 404 - 408
      Abstract: Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting. Protein tyrosine phosphatase σ (PTPσ), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs. Here we find in rats that PTPσ has a critical role in converting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. We generated a membrane-permeable peptide mimetic of the PTPσ wedge domain that binds to PTPσ and relieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Our results add a new layer of understanding to the critical role of PTPσ in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2014-12-03
      DOI: 10.1038/nature13974
      Issue No: Vol. 518, No. 7539 (2014)
       
  • Towards a therapy for Angelman syndrome by targeting a long non-coding RNA
    • Authors: Linyan Meng, Amanda J. Ward, Seung Chun, C. Frank Bennett, Arthur L. Beaudet, Frank Rigo
      Pages: 409 - 412
      Abstract: Angelman syndrome is a single-gene disorder characterized by intellectual disability, developmental delay, behavioural uniqueness, speech impairment, seizures and ataxia. It is caused by maternal deficiency of the imprinted gene UBE3A, encoding an E3 ubiquitin ligase. All patients carry at least one copy of paternal UBE3A, which is intact but silenced by a nuclear-localized long non-coding RNA, UBE3A antisense transcript (UBE3A-ATS). Murine Ube3a-ATS reduction by either transcription termination or topoisomerase I inhibition has been shown to increase paternal Ube3a expression. Despite a clear understanding of the disease-causing event in Angelman syndrome and the potential to harness the intact paternal allele to correct the disease, no gene-specific treatment exists for patients. Here we developed a potential therapeutic intervention for Angelman syndrome by reducing Ube3a-ATS with antisense oligonucleotides (ASOs). ASO treatment achieved specific reduction of Ube3a-ATS and sustained unsilencing of paternal Ube3a in neurons in vitro and in vivo. Partial restoration of UBE3A protein in an Angelman syndrome mouse model ameliorated some cognitive deficits associated with the disease. Although additional studies of phenotypic correction are needed, we have developed a sequence-specific and clinically feasible method to activate expression of the paternal Ube3a allele.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2014-12-01
      DOI: 10.1038/nature13975
      Issue No: Vol. 518, No. 7539 (2014)
       
  • Intracellular α-ketoglutarate maintains the pluripotency of embryonic
           stem cells
    • Authors: Bryce W. Carey, Lydia W. S. Finley, Justin R. Cross, C. David Allis, Craig B. Thompson
      Pages: 413 - 416
      Abstract: The role of cellular metabolism in regulating cell proliferation and differentiation remains poorly understood. For example, most mammalian cells cannot proliferate without exogenous glutamine supplementation even though glutamine is a non-essential amino acid. Here we show that mouse embryonic stem (ES) cells grown under conditions that maintain naive pluripotency are capable of proliferation in the absence of exogenous glutamine. Despite this, ES cells consume high levels of exogenous glutamine when the metabolite is available. In comparison to more differentiated cells, naive ES cells utilize both glucose and glutamine catabolism to maintain a high level of intracellular α-ketoglutarate (αKG). Consequently, naive ES cells exhibit an elevated αKG to succinate ratio that promotes histone/DNA demethylation and maintains pluripotency. Direct manipulation of the intracellular αKG/succinate ratio is sufficient to regulate multiple chromatin modifications, including H3K27me3 and ten-eleven translocation (Tet)-dependent DNA demethylation, which contribute to the regulation of pluripotency-associated gene expression. In vitro, supplementation with cell-permeable αKG directly supports ES-cell self-renewal while cell-permeable succinate promotes differentiation. This work reveals that intracellular αKG/succinate levels can contribute to the maintenance of cellular identity and have a mechanistic role in the transcriptional and epigenetic state of stem cells.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2014-12-10
      DOI: 10.1038/nature13981
      Issue No: Vol. 518, No. 7539 (2014)
       
  • Deubiquitinase DUBA is a post-translational brake on interleukin-17
           production in T cells
    • Authors: Sascha Rutz, Nobuhiko Kayagaki, Qui T. Phung, Celine Eidenschenk, Rajkumar Noubade, Xiaoting Wang, Justin Lesch, Rongze Lu, Kim Newton, Oscar W. Huang, Andrea G. Cochran, Mark Vasser, Benjamin P. Fauber, Jason DeVoss, Joshua Webster, Lauri Diehl, Zora Modrusan, Donald S. Kirkpatrick, Jennie R. Lill, Wenjun Ouyang, Vishva M. Dixit
      Pages: 417 - 421
      Abstract: T-helper type 17 (TH17) cells that produce the cytokines interleukin-17A (IL-17A) and IL-17F are implicated in the pathogenesis of several autoimmune diseases. The differentiation of TH17 cells is regulated by transcription factors such as RORγt, but post-translational mechanisms preventing the rampant production of pro-inflammatory IL-17A have received less attention. Here we show that the deubiquitylating enzyme DUBA is a negative regulator of IL-17A production in T cells. Mice with DUBA-deficient T cells developed exacerbated inflammation in the small intestine after challenge with anti-CD3 antibodies. DUBA interacted with the ubiquitin ligase UBR5, which suppressed DUBA abundance in naive T cells. DUBA accumulated in activated T cells and stabilized UBR5, which then ubiquitylated RORγt in response to TGF-β signalling. Our data identify DUBA as a cell-intrinsic suppressor of IL-17 production.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2014-12-03
      DOI: 10.1038/nature13979
      Issue No: Vol. 518, No. 7539 (2014)
       
  • Dynamics of genomic clones in breast cancer patient xenografts at
           single-cell resolution
    • Authors: Peter Eirew, Adi Steif, Jaswinder Khattra, Gavin Ha, Damian Yap, Hossein Farahani, Karen Gelmon, Stephen Chia, Colin Mar, Adrian Wan, Emma Laks, Justina Biele, Karey Shumansky, Jamie Rosner, Andrew McPherson, Cydney Nielsen, Andrew J. L. Roth, Calvin Lefebvre, Ali Bashashati, Camila de Souza, Celia Siu, Radhouane Aniba, Jazmine Brimhall, Arusha Oloumi, Tomo Osako, Alejandra Bruna, Jose L. Sandoval, Teresa Algara, Wendy Greenwood, Kaston Leung, Hongwei Cheng, Hui Xue, Yuzhuo Wang, Dong Lin, Andrew J. Mungall, Richard Moore, Yongjun Zhao, Julie Lorette, Long Nguyen, David Huntsman, Connie J. Eaves, Carl Hansen, Marco A. Marra, Carlos Caldas, Sohrab P. Shah, Samuel Aparicio
      Pages: 422 - 426
      Abstract: Human cancers, including breast cancers, comprise clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution, underpinning important emergent features such as drug resistance and metastasis. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours. However, the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours have not been systematically examined at single-cell resolution. Here we show, using deep-genome and single-cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (
      Citation: Nature 518, 7539 (2015)
      PubDate: 2014-11-26
      DOI: 10.1038/nature13952
      Issue No: Vol. 518, No. 7539 (2014)
       
  • Catalysts from synthetic genetic polymers
    • Authors: Alexander I. Taylor, Vitor B. Pinheiro, Matthew J. Smola, Alexey S. Morgunov, Sew Peak-Chew, Christopher Cozens, Kevin M. Weeks, Piet Herdewijn, Philipp Holliger
      Pages: 427 - 430
      Abstract: The emergence of catalysis in early genetic polymers such as RNA is considered a key transition in the origin of life, pre-dating the appearance of protein enzymes. DNA also demonstrates the capacity to fold into three-dimensional structures and form catalysts in vitro. However, to what degree these natural biopolymers comprise functionally privileged chemical scaffolds for folding or the evolution of catalysis is not known. The ability of synthetic genetic polymers (XNAs) with alternative backbone chemistries not found in nature to fold into defined structures and bind ligands raises the possibility that these too might be capable of forming catalysts (XNAzymes). Here we report the discovery of such XNAzymes, elaborated in four different chemistries (arabino nucleic acids, ANA; 2′-fluoroarabino nucleic acids, FANA; hexitol nucleic acids, HNA; and cyclohexene nucleic acids, CeNA) directly from random XNA oligomer pools, exhibiting in trans RNA endonuclease and ligase activities. We also describe an XNA–XNA ligase metalloenzyme in the FANA framework, establishing catalysis in an entirely synthetic system and enabling the synthesis of FANA oligomers and an active RNA endonuclease FANAzyme from its constituent parts. These results extend catalysis beyond biopolymers and establish technologies for the discovery of catalysts in a wide range of polymer scaffolds not found in nature. Evolution of catalysis independent of any natural polymer has implications for the definition of chemical boundary conditions for the emergence of life on Earth and elsewhere in the Universe.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2014-12-01
      DOI: 10.1038/nature13982
      Issue No: Vol. 518, No. 7539 (2014)
       
  • Structure of human cytoplasmic dynein-2 primed for its power stroke
    • Authors: Helgo Schmidt, Ruta Zalyte, Linas Urnavicius, Andrew P. Carter
      Pages: 435 - 438
      Abstract: Members of the dynein family, consisting of cytoplasmic and axonemal isoforms, are motors that move towards the minus ends of microtubules. Cytoplasmic dynein-1 (dynein-1) plays roles in mitosis and cellular cargo transport, and is implicated in viral infections and neurodegenerative diseases. Cytoplasmic dynein-2 (dynein-2) performs intraflagellar transport and is associated with human skeletal ciliopathies. Dyneins share a conserved motor domain that couples cycles of ATP hydrolysis with conformational changes to produce movement. Here we present the crystal structure of the human cytoplasmic dynein-2 motor bound to the ATP-hydrolysis transition state analogue ADP.vanadate. The structure reveals a closure of the motor’s ring of six AAA+ domains (ATPases associated with various cellular activites: AAA1–AAA6). This induces a steric clash with the linker, the key element for the generation of movement, driving it into a conformation that is primed to produce force. Ring closure also changes the interface between the stalk and buttress coiled-coil extensions of the motor domain. This drives helix sliding in the stalk which causes the microtubule binding domain at its tip to release from the microtubule. Our structure answers the key questions of how ATP hydrolysis leads to linker remodelling and microtubule affinity regulation.
      Citation: Nature 518, 7539 (2015)
      PubDate: 2014-12-01
      DOI: 10.1038/nature14023
      Issue No: Vol. 518, No. 7539 (2014)
       
 
 
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