Neutrino study made key priority for US nuclear physics

Nature 526, 7574 (2015). http://www.nature.com/doifinder/10.1038/526485a

Author: Davide Castelvecchi

Wish list also includes new particle collider.

Russian secret service to vet research papers

Nature 526, 7574 (2015). http://www.nature.com/doifinder/10.1038/526486a

Author: Quirin Schiermeier

Moscow biology department among the first to require that all manuscripts comply with law on state secrets.

Hunting the Godzilla El Niño

Nature 526, 7574 (2015). http://www.nature.com/doifinder/10.1038/526490a

Author: Quirin Schiermeier

As a massive El Niño warming builds in the equatorial Pacific Ocean, researchers hope to make the most of their chance to study this havoc-wreaking phenomenon.

Ancient civilization: Cracking the Indus script

Nature 526, 7574 (2015). doi:10.1038/526499a

Author: Andrew Robinson

Andrew Robinson reflects on the most tantalizing of all the undeciphered scripts — that used in the civilization of the Indus valley in the third millennium bc.

Bacteriocin production augments niche competition by enterococci in the mammalian gastrointestinal tract

Nature 526, 7575 (2015). doi:10.1038/nature15524

Authors: Sushma Kommineni, Daniel J. Bretl, Vy Lam, Rajrupa Chakraborty, Michael Hayward, Pippa Simpson, Yumei Cao, Pavlos Bousounis, Christopher J. Kristich & Nita H. Salzman

Enterococcus faecalis is both a common commensal of the human gastrointestinal tract and a leading cause of hospital-acquired infections. Systemic infections with multidrug-resistant enterococci occur subsequent to gastrointestinal colonization. Preventing colonization by multidrug-resistant E. faecalis could therefore be a valuable approach towards limiting infection. However, little is known about the mechanisms E. faecalis uses to colonize and compete for stable gastrointestinal niches. Pheromone-responsive conjugative plasmids encoding bacteriocins are common among enterococcal strains and could modulate niche competition among enterococci or between enterococci and the intestinal microbiota. We developed a model of colonization of the mouse gut with E. faecalis, without disrupting the microbiota, to evaluate the role of the conjugative plasmid pPD1 expressing bacteriocin 21 (ref. 4) in enterococcal colonization. Here we show that E. faecalis harbouring pPD1 replaces indigenous enterococci and outcompetes E. faecalis lacking pPD1. Furthermore, in the intestine, pPD1 is transferred to other E. faecalis strains by conjugation, enhancing their survival. Colonization with an E. faecalis strain carrying a conjugation-defective pPD1 mutant subsequently resulted in clearance of vancomycin-resistant enterococci, without plasmid transfer. Therefore, bacteriocin expression by commensal bacteria can influence niche competition in the gastrointestinal tract, and bacteriocins, delivered by commensals that occupy a precise intestinal bacterial niche, may be an effective therapeutic approach to specifically eliminate intestinal colonization by multidrug-resistant bacteria, without profound disruption of the indigenous microbiota.

Preprints called on to support controversial talks

Nature 526, 7574 (2015). doi:10.1038/526479f

Author: Rachel Becker

Scientists on social media grapple with the idea of posting preprints of provocative research presented at meetings.

Palaeoanthropology: Homo sapiens in China 80,000 years ago

Nature 526, 7575 (2015). doi:10.1038/nature15640

Authors: Robin Dennell

A discovery in southern China of human teeth dated to more than 80,000 years old indicates that Homo sapiens was present in the region considerably earlier than had previously been suspected. See Letter p.696

The earliest unequivocally modern humans in southern China

Nature 526, 7575 (2015). doi:10.1038/nature15696

Authors: Wu Liu, María Martinón-Torres, Yan-jun Cai, Song Xing, Hao-wen Tong, Shu-wen Pei, Mark Jan Sier, Xiao-hong Wu, R. Lawrence Edwards, Hai Cheng, Yi-yuan Li, Xiong-xin Yang, José María Bermúdez de Castro & Xiu-jie Wu

The hominin record from southern Asia for the early Late Pleistocene epoch is scarce. Well-dated and well-preserved fossils older than ∼45,000 years that can be unequivocally attributed to Homo sapiens are lacking. Here we present evidence from the newly excavated Fuyan Cave in Daoxian (southern China). This site has provided 47 human teeth dated to more than 80,000 years old, and with an inferred maximum age of 120,000 years. The morphological and metric assessment of this sample supports its unequivocal assignment to H. sapiens. The Daoxian sample is more derived than any other anatomically modern humans, resembling middle-to-late Late Pleistocene specimens and even contemporary humans. Our study shows that fully modern morphologies were present in southern China 30,000–70,000 years earlier than in the Levant and Europe. Our data fill a chronological and geographical gap that is relevant for understanding when H. sapiens first appeared in southern Asia. The Daoxian teeth also support the hypothesis that during the same period, southern China was inhabited by more derived populations than central and northern China. This evidence is important for the study of dispersal routes of modern humans. Finally, our results are relevant to exploring the reasons for the relatively late entry of H. sapiens into Europe. Some studies have investigated how the competition with H. sapiens may have caused Neanderthals’ extinction (see ref. 8 and references therein). Notably, although fully modern humans were already present in southern China at least as early as ∼80,000 years ago, there is no evidence that they entered Europe before ∼45,000 years ago. This could indicate that H. neanderthalensis was indeed an additional ecological barrier for modern humans, who could only enter Europe when the demise of Neanderthals had already started.

Telomerase activation by genomic rearrangements in high-risk neuroblastoma

Nature 526, 7575 (2015). doi:10.1038/nature14980

Authors: Martin Peifer, Falk Hertwig, Frederik Roels, Daniel Dreidax, Moritz Gartlgruber, Roopika Menon, Andrea Krämer, Justin L. Roncaioli, Frederik Sand, Johannes M. Heuckmann, Fakhera Ikram, Rene Schmidt, Sandra Ackermann, Anne Engesser, Yvonne Kahlert, Wenzel Vogel, Janine Altmüller, Peter Nürnberg, Jean Thierry-Mieg, Danielle Thierry-Mieg, Aruljothi Mariappan, Stefanie Heynck, Erika Mariotti, Kai-Oliver Henrich, Christian Gloeckner, Graziella Bosco, Ivo Leuschner, Michal R. Schweiger, Larissa Savelyeva, Simon C. Watkins, Chunxuan Shao, Emma Bell, Thomas Höfer, Viktor Achter, Ulrich Lang, Jessica Theissen, Ruth Volland, Maral Saadati, Angelika Eggert, Bram de Wilde, Frank Berthold, Zhiyu Peng, Chen Zhao, Leming Shi, Monika Ortmann, Reinhard Büttner, Sven Perner, Barbara Hero, Alexander Schramm, Johannes H. Schulte, Carl Herrmann, Roderick J. O’Sullivan, Frank Westermann, Roman K. Thomas & Matthias Fischer

Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.

Mutations driving CLL and their evolution in progression and relapse

Nature 526, 7574 (2015). doi:10.1038/nature15395

Authors: Dan A. Landau, Eugen Tausch, Amaro N. Taylor-Weiner, Chip Stewart, Johannes G. Reiter, Jasmin Bahlo, Sandra Kluth, Ivana Bozic, Mike Lawrence, Sebastian Böttcher, Scott L. Carter, Kristian Cibulskis, Daniel Mertens, Carrie L. Sougnez, Mara Rosenberg, Julian M. Hess, Jennifer Edelmann, Sabrina Kless, Michael Kneba, Matthias Ritgen, Anna Fink, Kirsten Fischer, Stacey Gabriel, Eric S. Lander, Martin A. Nowak, Hartmut Döhner, Michael Hallek, Donna Neuberg, Gad Getz, Stephan Stilgenbauer & Catherine J. Wu

Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL)

The vulnerability of Indo-Pacific mangrove forests to sea-level rise

Nature 526, 7574 (2015). doi:10.1038/nature15538

Authors: Catherine E. Lovelock, Donald R. Cahoon, Daniel A. Friess, Glenn R. Guntenspergen, Ken W. Krauss, Ruth Reef, Kerrylee Rogers, Megan L. Saunders, Frida Sidik, Andrew Swales, Neil Saintilan, Le Xuan Thuyen & Tran Triet

Sea-level rise can threaten the long-term sustainability of coastal communities and valuable ecosystems such as coral reefs, salt marshes and mangroves. Mangrove forests have the capacity to keep pace with sea-level rise and to avoid inundation through vertical accretion of sediments, which allows them to maintain wetland soil elevations suitable for plant growth. The Indo-Pacific region holds most of the world’s mangrove forests, but sediment delivery in this region is declining, owing to anthropogenic activities such as damming of rivers. This decline is of particular concern because the Indo-Pacific region is expected to have variable, but high, rates of future sea-level rise. Here we analyse recent trends in mangrove surface elevation changes across the Indo-Pacific region using data from a network of surface elevation table instruments. We find that sediment availability can enable mangrove forests to maintain rates of soil-surface elevation gain that match or exceed that of sea-level rise, but for 69 per cent of our study sites the current rate of sea-level rise exceeded the soil surface elevation gain. We also present a model based on our field data, which suggests that mangrove forests at sites with low tidal range and low sediment supply could be submerged as early as 2070.

Biodiversity increases the resistance of ecosystem productivity to climate extremes

Nature 526, 7574 (2015). doi:10.1038/nature15374

Authors: Forest Isbell, Dylan Craven, John Connolly, Michel Loreau, Bernhard Schmid, Carl Beierkuhnlein, T. Martijn Bezemer, Catherine Bonin, Helge Bruelheide, Enrica de Luca, Anne Ebeling, John N. Griffin, Qinfeng Guo, Yann Hautier, Andy Hector, Anke Jentsch, Jürgen Kreyling, Vojtěch Lanta, Pete Manning, Sebastian T. Meyer, Akira S. Mori, Shahid Naeem, Pascal A. Niklaus, H. Wayne Polley, Peter B. Reich, Christiane Roscher, Eric W. Seabloom, Melinda D. Smith, Madhav P. Thakur, David Tilman, Benjamin F. Tracy, Wim H. van der Putten, Jasper van Ruijven, Alexandra Weigelt, Wolfgang W. Weisser, Brian Wilsey & Nico Eisenhauer

It remains unclear whether biodiversity buffers ecosystems against climate extremes, which are becoming increasingly frequent worldwide. Early results suggested that the ecosystem productivity of diverse grassland plant communities was more resistant, changing less during drought, and more resilient, recovering more quickly after drought, than that of depauperate communities. However, subsequent experimental tests produced mixed results. Here we use data from 46 experiments that manipulated grassland plant diversity to test whether biodiversity provides resistance during and resilience after climate events. We show that biodiversity increased ecosystem resistance for a broad range of climate events, including wet or dry, moderate or extreme, and brief or prolonged events. Across all studies and climate events, the productivity of low-diversity communities with one or two species changed by approximately 50% during climate events, whereas that of high-diversity communities with 16–32 species was more resistant, changing by only approximately 25%. By a year after each climate event, ecosystem productivity had often fully recovered, or overshot, normal levels of productivity in both high- and low-diversity communities, leading to no detectable dependence of ecosystem resilience on biodiversity. Our results suggest that biodiversity mainly stabilizes ecosystem productivity, and productivity-dependent ecosystem services, by increasing resistance to climate events. Anthropogenic environmental changes that drive biodiversity loss thus seem likely to decrease ecosystem stability, and restoration of biodiversity to increase it, mainly by changing the resistance of ecosystem productivity to climate events.

RAF inhibitors that evade paradoxical MAPK pathway activation

Nature 526, 7574 (2015). doi:10.1038/nature14982

Authors: Chao Zhang, Wayne Spevak, Ying Zhang, Elizabeth A. Burton, Yan Ma, Gaston Habets, Jiazhong Zhang, Jack Lin, Todd Ewing, Bernice Matusow, Garson Tsang, Adhirai Marimuthu, Hanna Cho, Guoxian Wu, Weiru Wang, Daniel Fong, Hoa Nguyen, Songyuan Shi, Patrick Womack, Marika Nespi, Rafe Shellooe, Heidi Carias, Ben Powell, Emily Light, Laura Sanftner, Jason Walters, James Tsai, Brian L. West, Gary Visor, Hamid Rezaei, Paul S. Lin, Keith Nolop, Prabha N. Ibrahim, Peter Hirth & Gideon Bollag

Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed ‘paradox breakers’) that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.

Crystal structure of the 500-kDa yeast acetyl-CoA carboxylase holoenzyme dimer

Nature 526, 7575 (2015). doi:10.1038/nature15375

Authors: Jia Wei & Liang Tong

Acetyl-CoA carboxylase (ACC) has crucial roles in fatty acid metabolism and is an attractive target for drug discovery against diabetes, cancer and other diseases. Saccharomyces cerevisiae ACC (ScACC) is crucial for the production of very-long-chain fatty acids and the maintenance of the nuclear envelope. ACC contains biotin carboxylase (BC) and carboxyltransferase (CT) activities, and its biotin is linked covalently to the biotin carboxyl carrier protein (BCCP). Most eukaryotic ACCs are 250-kilodalton (kDa), multi-domain enzymes and function as homodimers and higher oligomers. They contain a unique, 80-kDa central region that shares no homology with other proteins. Although the structures of the BC, CT and BCCP domains and other biotin-dependent carboxylase holoenzymes are known, there is currently no structural information on the ACC holoenzyme. Here we report the crystal structure of the full-length, 500-kDa holoenzyme dimer of ScACC. The structure is remarkably different from that of the other biotin-dependent carboxylases. The central region contains five domains and is important for positioning the BC and CT domains for catalysis. The structure unexpectedly reveals a dimer of the BC domain and extensive conformational differences compared to the structure of the BC domain alone, which is a monomer. These structural changes reveal why the BC domain alone is catalytically inactive and define the molecular mechanism for the inhibition of eukaryotic ACC by the natural product soraphen A and by phosphorylation of a Ser residue just before the BC domain core in mammalian ACC. The BC and CT active sites are separated by 80 Å, and the entire BCCP domain must translocate during catalysis.

Observation of non-Hermitian degeneracies in a chaotic exciton-polariton billiard

Nature 526, 7574 (2015). doi:10.1038/nature15522

Authors: T. Gao, E. Estrecho, K. Y. Bliokh, T. C. H. Liew, M. D. Fraser, S. Brodbeck, M. Kamp, C. Schneider, S. Höfling, Y. Yamamoto, F. Nori, Y. S. Kivshar, A. G. Truscott, R. G. Dall & E. A. Ostrovskaya

Exciton-polaritons are hybrid light–matter quasiparticles formed by strongly interacting photons and excitons (electron–hole pairs) in semiconductor microcavities. They have emerged as a robust solid-state platform for next-generation optoelectronic applications as well as for fundamental studies of quantum many-body physics. Importantly, exciton-polaritons are a profoundly open (that is, non-Hermitian) quantum system, which requires constant pumping of energy and continuously decays, releasing coherent radiation. Thus, the exciton-polaritons always exist in a balanced potential landscape of gain and loss. However, the inherent non-Hermitian nature of this potential has so far been largely ignored in exciton-polariton physics. Here we demonstrate that non-Hermiticity dramatically modifies the structure of modes and spectral degeneracies in exciton-polariton systems, and, therefore, will affect their quantum transport, localization and dynamical properties. Using a spatially structured optical pump, we create a chaotic exciton-polariton billiard—a two-dimensional area enclosed by a curved potential barrier. Eigenmodes of this billiard exhibit multiple non-Hermitian spectral degeneracies, known as exceptional points. Such points can cause remarkable wave phenomena, such as unidirectional transport, anomalous lasing/absorption and chiral modes. By varying parameters of the billiard, we observe crossing and anti-crossing of energy levels and reveal the non-trivial topological modal structure exclusive to non-Hermitian systems. We also observe mode switching and a topological Berry phase for a parameter loop encircling the exceptional point. Our findings pave the way to studies of non-Hermitian quantum dynamics of exciton-polaritons, which may uncover novel operating principles for polariton-based devices.

Dynamic m6A mRNA methylation directs translational control of heat shock response

Nature 526, 7574 (2015). doi:10.1038/nature15377

Authors: Jun Zhou, Ji Wan, Xiangwei Gao, Xingqian Zhang, Samie R. Jaffrey & Shu-Bing Qian

The most abundant mRNA post-transcriptional modification is N6-methyladenosine (m6A), which has broad roles in RNA biology. In mammalian cells, the asymmetric distribution of m6A along mRNAs results in relatively less methylation in the 5′ untranslated region (5′UTR) compared to other regions. However, whether and how 5′UTR methylation is regulated is poorly understood. Despite the crucial role of the 5′UTR in translation initiation, very little is known about whether m6A modification influences mRNA translation. Here we show that in response to heat shock stress, certain adenosines within the 5′UTR of newly transcribed mRNAs are preferentially methylated. We find that the dynamic 5′UTR methylation is a result of stress-induced nuclear localization of YTHDF2, a well-characterized m6A ‘reader’. Upon heat shock stress, the nuclear YTHDF2 preserves 5′UTR methylation of stress-induced transcripts by limiting the m6A ‘eraser’ FTO from demethylation. Remarkably, the increased 5′UTR methylation in the form of m6A promotes cap-independent translation initiation, providing a mechanism for selective mRNA translation under heat shock stress. Using Hsp70 mRNA as an example, we demonstrate that a single m6A modification site in the 5′UTR enables translation initiation independent of the 5′ end N7-methylguanosine cap. The elucidation of the dynamic features of 5′UTR methylation and its critical role in cap-independent translation not only expands the breadth of physiological roles of m6A, but also uncovers a previously unappreciated translational control mechanism in heat shock response.

Biological techniques: Kidney tissue grown from induced stem cells

Nature 526, 7574 (2015). doi:10.1038/nature15639

Authors: Jamie A. Davies

Engineered human cells that can give rise to every cell type have been induced to generate structures that resemble an embryonic kidney. This advance charts a course towards growing transplantable kidneys in culture. See Letter p.564

Evolution: An avian explosion

Nature 526, 7574 (2015). doi:10.1038/nature15638

Authors: Gavin H. Thomas

The genome sequences of 198 bird species provide an unprecedented combination of breadth and depth of data, and allow the most robust resolution so far of the early evolutionary relationships of modern birds. See Letter p.569

Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis

Nature 526, 7574 (2015). doi:10.1038/nature15695

Authors: Minoru Takasato, Pei X. Er, Han S. Chiu, Barbara Maier, Gregory J. Baillie, Charles Ferguson, Robert G. Parton, Ernst J. Wolvetang, Matthias S. Roost, Susana M. Chuva de Sousa Lopes & Melissa H. Little

The human kidney contains up to 2 million epithelial nephrons responsible for blood filtration. Regenerating the kidney requires the induction of the more than 20 distinct cell types required for excretion and the regulation of pH, and electrolyte and fluid balance. We have previously described the simultaneous induction of progenitors for both collecting duct and nephrons via the directed differentiation of human pluripotent stem cells. Paradoxically, although both are of intermediate mesoderm in origin, collecting duct and nephrons have distinct temporospatial origins. Here we identify the developmental mechanism regulating the preferential induction of collecting duct versus kidney mesenchyme progenitors. Using this knowledge, we have generated kidney organoids that contain nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells. Within these organoids, individual nephrons segment into distal and proximal tubules, early loops of Henle, and glomeruli containing podocytes elaborating foot processes and undergoing vascularization. When transcription profiles of kidney organoids were compared to human fetal tissues, they showed highest congruence with first trimester human kidney. Furthermore, the proximal tubules endocytose dextran and differentially apoptose in response to cisplatin, a nephrotoxicant. Such kidney organoids represent powerful models of the human organ for future applications, including nephrotoxicity screening, disease modelling and as a source of cells for therapy.

A comprehensive phylogeny of birds (Aves) using targeted next-generation DNA sequencing

Nature 526, 7574 (2015). doi:10.1038/nature15697

Authors: Richard O. Prum, Jacob S. Berv, Alex Dornburg, Daniel J. Field, Jeffrey P. Townsend, Emily Moriarty Lemmon & Alan R. Lemmon

Although reconstruction of the phylogeny of living birds has progressed tremendously in the last decade, the evolutionary history of Neoaves—a clade that encompasses nearly all living bird species—remains the greatest unresolved challenge in dinosaur systematics. Here we investigate avian phylogeny with an unprecedented scale of data: >390,000 bases of genomic sequence data from each of 198 species of living birds, representing all major avian lineages, and two crocodilian outgroups. Sequence data were collected using anchored hybrid enrichment, yielding 259 nuclear loci with an average length of 1,523 bases for a total data set of over 7.8 × 107 bases. Bayesian and maximum likelihood analyses yielded highly supported and nearly identical phylogenetic trees for all major avian lineages. Five major clades form successive sister groups to the rest of Neoaves: (1) a clade including nightjars, other caprimulgiforms, swifts, and hummingbirds; (2) a clade uniting cuckoos, bustards, and turacos with pigeons, mesites, and sandgrouse; (3) cranes and their relatives; (4) a comprehensive waterbird clade, including all diving, wading, and shorebirds; and (5) a comprehensive landbird clade with the enigmatic hoatzin (Opisthocomus hoazin) as the sister group to the rest. Neither of the two main, recently proposed Neoavian clades—Columbea and Passerea—were supported as monophyletic. The results of our divergence time analyses are congruent with the palaeontological record, supporting a major radiation of crown birds in the wake of the Cretaceous–Palaeogene (K–Pg) mass extinction.