ALBERT

Beschreibung: Gene editing: Running with scissors Nature 535, 7612 (2016). doi:10.1038/535352a Author: John Harris John Harris probes a study on the science and ethics of genome editing.

Beschreibung: The unsung heroes of CRISPR Nature 535, 7612 (2016). http://www.nature.com/doifinder/10.1038/535342a Author: Heidi Ledford The soaring popularity of gene editing has made celebrities of the principal investigators who pioneered the field — but their graduate students and postdocs are often overlooked.

Beschreibung: Scientific literature: Information overload Nature 535, 7612 (2016). doi:10.1038/nj7612-457a Author: Esther Landhuis How to manage the research-paper deluge? Blogs, colleagues and social media can all help.

Beschreibung: Physiology: Pancreatic β-cell heterogeneity revisited Nature 535, 7612 (2016). doi:10.1038/nature18907 Authors: Susan Bonner-Weir & Cristina Aguayo-Mazzucato Two analyses of insulin-producing β-cells reveal differences in what has long been considered a homogeneous population. These differences might reflect changes during maturation or ageing, or distinct cell lineages. See Letter p.430

Beschreibung: Cooperative electrocatalytic alcohol oxidation with electron-proton-transfer mediators Nature 535, 7612 (2016). doi:10.1038/nature18008 Authors: Artavazd Badalyan & Shannon S. Stahl The electrochemical oxidation of alcohols is a major focus of energy and chemical conversion efforts, with potential applications ranging from fuel cells to biomass utilization and fine-chemical synthesis. Small-molecule electrocatalysts for processes of this type are promising targets for further development, as demonstrated by recent advances in nickel catalysts for electrochemical production and oxidation of hydrogen. Complexes with tethered amines that resemble the active site of hydrogenases have been shown both to catalyse hydrogen production (from protons and electrons) with rates far exceeding those of such enzymes and to mediate reversible electrocatalytic hydrogen production and oxidation with enzyme-like performance. Progress in electrocatalytic alcohol oxidation has been more modest. Nickel complexes similar to those used for hydrogen oxidation have been shown to mediate efficient electrochemical oxidation of benzyl alcohol, with a turnover frequency of 2.1 per second. These compounds exhibit poor reactivity with ethanol and methanol, however. Organic nitroxyls, such as TEMPO (2,2,6,6-tetramethyl-1-piperidine N-oxyl), are the most widely studied electrocatalysts for alcohol oxidation. These catalysts exhibit good activity (1–2 turnovers per second) with a wide range of alcohols and have great promise for electro-organic synthesis. Their use in energy-conversion applications, however, is limited by the high electrode potentials required to generate the reactive oxoammonium species. Here we report (2,2′-bipyridine)Cu/nitroxyl co-catalyst systems for electrochemical alcohol oxidation that proceed with much faster rates, while operating at an electrode potential a half-volt lower than that used for the TEMPO-only process. The (2,2′-bipyridine)Cu(II) and TEMPO redox partners exhibit cooperative reactivity and exploit the low-potential, proton-coupled TEMPO/TEMPOH redox process rather than the high-potential TEMPO/TEMPO+ process. The results show how electron-proton-transfer mediators, such as TEMPO, may be used in combination with first-row transition metals, such as copper, to achieve efficient two-electron electrochemical processes, thereby introducing a new concept for the development of non-precious-metal electrocatalysts.

Beschreibung: Bright spots among the world’s coral reefs Nature 535, 7612 (2016). doi:10.1038/nature18607 Authors: Joshua E. Cinner, Cindy Huchery, M. Aaron MacNeil, Nicholas A.J. Graham, Tim R. McClanahan, Joseph Maina, Eva Maire, John N. Kittinger, Christina C. Hicks, Camilo Mora, Edward H. Allison, Stephanie D’Agata, Andrew Hoey, David A. Feary, Larry Crowder, Ivor D. Williams, Michel Kulbicki, Laurent Vigliola, Laurent Wantiez, Graham Edgar, Rick D. Stuart-Smith, Stuart A. Sandin, Alison L. Green, Marah J. Hardt, Maria Beger, Alan Friedlander, Stuart J. Campbell, Katherine E. Holmes, Shaun K. Wilson, Eran Brokovich, Andrew J. Brooks, Juan J. Cruz-Motta, David J. Booth, Pascale Chabanet, Charlie Gough, Mark Tupper, Sebastian C. A. Ferse, U. Rashid Sumaila & David Mouillot Ongoing declines in the structure and function of the world’s coral reefs require novel approaches to sustain these ecosystems and the millions of people who depend on them. A presently unexplored approach that draws on theory and practice in human health and rural development is to systematically identify and learn from the ‘outliers’—places where ecosystems are substantially better (‘bright spots’) or worse (‘dark spots’) than expected, given the environmental conditions and socioeconomic drivers they are exposed to. Here we compile data from more than 2,500 reefs worldwide and develop a Bayesian hierarchical model to generate expectations of how standing stocks of reef fish biomass are related to 18 socioeconomic drivers and environmental conditions. We identify 15 bright spots and 35 dark spots among our global survey of coral reefs, defined as sites that have biomass levels more than two standard deviations from expectations. Importantly, bright spots are not simply comprised of remote areas with low fishing pressure; they include localities where human populations and use of ecosystem resources is high, potentially providing insights into how communities have successfully confronted strong drivers of change. Conversely, dark spots are not necessarily the sites with the lowest absolute biomass and even include some remote, uninhabited locations often considered near pristine. We surveyed local experts about social, institutional, and environmental conditions at these sites to reveal that bright spots are characterized by strong sociocultural institutions such as customary taboos and marine tenure, high levels of local engagement in management, high dependence on marine resources, and beneficial environmental conditions such as deep-water refuges. Alternatively, dark spots are characterized by intensive capture and storage technology and a recent history of environmental shocks. Our results suggest that investments in strengthening fisheries governance, particularly aspects such as participation and property rights, could facilitate innovative conservation actions that help communities defy expectations of global reef degradation.

Beschreibung: Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour Nature 535, 7612 (2016). doi:10.1038/nature18626 Authors: Anthony J. Filiano, Yang Xu, Nicholas J. Tustison, Rachel L. Marsh, Wendy Baker, Igor Smirnov, Christopher C. Overall, Sachin P. Gadani, Stephen D. Turner, Zhiping Weng, Sayeda Najamussahar Peerzade, Hao Chen, Kevin S. Lee, Michael M. Scott, Mark P. Beenhakker, Vladimir Litvak & Jonathan Kipnis Immune dysfunction is commonly associated with several neurological and mental disorders. Although the mechanisms by which peripheral immunity may influence neuronal function are largely unknown, recent findings implicate meningeal immunity influencing behaviour, such as spatial learning and memory. Here we show that meningeal immunity is also critical for social behaviour; mice deficient in adaptive immunity exhibit social deficits and hyper-connectivity of fronto-cortical brain regions. Associations between rodent transcriptomes from brain and cellular transcriptomes in response to T-cell-derived cytokines suggest a strong interaction between social behaviour and interferon-γ (IFN-γ)-driven responses. Concordantly, we demonstrate that inhibitory neurons respond to IFN-γ and increase GABAergic (γ-aminobutyric-acid) currents in projection neurons, suggesting that IFN-γ is a molecular link between meningeal immunity and neural circuits recruited for social behaviour. Meta-analysis of the transcriptomes of a range of organisms reveals that rodents, fish, and flies elevate IFN-γ/JAK-STAT-dependent gene signatures in a social context, suggesting that the IFN-γ signalling pathway could mediate a co-evolutionary link between social/aggregation behaviour and an efficient anti-pathogen response. This study implicates adaptive immune dysfunction, in particular IFN-γ, in disorders characterized by social dysfunction and suggests a co-evolutionary link between social behaviour and an anti-pathogen immune response driven by IFN-γ signalling.

Beschreibung: Biogeochemistry: Nocturnal escape route for marsh gas Nature 535, 7612 (2016). doi:10.1038/535363a Authors: Katey Walter Anthony & Sally MacIntyre A field study of methane emissions from wetlands reveals that more of the gas escapes through diffusive processes than was thought, mostly at night. Because methane is a greenhouse gas, the findings have implications for global warming.

Beschreibung: Scholarly Olympics: How the games have shaped research Nature 536, 7614 (2016). http://www.nature.com/doifinder/10.1038/536018a Authors: Daniel Cressey, Ramin Skibba & Richard Van Noorden A graphical guide to the impact of the Olympics on science.

Beschreibung: China: Change tack to boost basic research Nature 536, 7614 (2016). doi:10.1038/536030a Authors: Raphael K. Didham & Chao-Dong Zhu We agree that China must invest more in basic research, but fear that simply casting more seeds on infertile ground will not yield the anticipated fruit of innovation (W.YangNature534, 467–469; 10.1038/534467a2016). More bottom-up initiatives for

Beschreibung: Endocrine disruptors: Refereed science to guide action on EDCs Nature 536, 7614 (2016). doi:10.1038/536030d Author: Leonardo Trasande In a non-peer-reviewed venue (Nature535, 355; 10.1038/535355c2016), Daniel Dietrich et al. put forward apparently unsubstantiated arguments that in effect dismiss thousands of peer-reviewed academic studies and rigorous evaluations of endocrine-disrupting chemicals (EDCs) by independent scientists and organizations such

Beschreibung: Health research: Mentoring female scientists in Africa Nature 536, 7614 (2016). doi:10.1038/536030c Authors: Rose G. F. Leke & S. Kwedi Nolna As founding members of the Higher Institute for Growth in Health Research (HIGHER) for Women in Cameroon, our mission has been to help young women to enter and sustain careers in biomedical science through a mentoring programme (www.higherwomencam.org).Mentored female researchers spend more

Beschreibung: Floating in my tin can Nature 536, 7614 (2016). doi:10.1038/536120a Author: Gerri Leen Lullaby for life.

Beschreibung: Synthetic biology: Bacteria synchronized for drug delivery Nature 536, 7614 (2016). doi:10.1038/nature18915 Authors: Shibin Zhou A synthetic genetic circuit that mimics the quorum-sensing systems used by bacterial populations to coordinate gene expression enables bacteria to deliver drugs to mouse tumours in repeated and synchronized cycles. See Letter p.81

Beschreibung: Turning point: Kevin Esvelt Nature (2016). doi:10.1038/nj7614-117a Author: Vijee Venkatraman An evolutionary engineer explains precautions for gene drive.

Beschreibung: China: Standardize R&D costing Nature 536, 7614 (2016). doi:10.1038/536030b Authors: Yutao Sun & Cong Cao Figures for China's basic-research spending should not be taken at face value (see W.YangNature534, 467–469; 10.1038/534467a2016). Before comparing gross expenditure on research and development (R&D) with that in developed countries, China's official statistics first need bringing

Beschreibung: Biomedical science: Protection for anaesthetized mice Nature 536, 7614 (2016). doi:10.1038/536036a Authors: Laura Cornelissen & Charles Berde A cognition-enhancing drug called CX546 prevents the neurodegenerative effects of repeated anaesthesia in infant mice by promoting neuronal changes associated with learning and by protecting neurons from death.

Beschreibung: Diabetes: Still a geneticist's nightmare Nature 536, 7614 (2016). doi:10.1038/nature18906 Authors: Stephen S. Rich The largest DNA-sequencing study of type 2 diabetes conducted so far concludes that, contrary to expectation, low-frequency and rare genetic variants do not contribute significantly to disease risk. See Article p.41

Beschreibung: Heart disease: Death-defying plaque cells Nature 536, 7614 (2016). doi:10.1038/nature18916 Authors: Ira Tabas Dead cells are usually removed through their ingestion and destruction by other cells. A study of plaque deposits in arteries shows that dying cells in plaques display a 'don't-eat-me' signal that blocks their removal. See Letter p.86

Beschreibung: Atomic physics: A milestone in quantum computing Nature 536, 7614 (2016). doi:10.1038/536035a Authors: Stephen D. Bartlett Quantum computers require many quantum bits to perform complex calculations, but devices with more than a few bits are difficult to program. A device based on five atomic quantum bits shows a way forward. See Letter p.63

Beschreibung: Quantum physics: Destruction of discrete charge Nature 536, 7614 (2016). doi:10.1038/536038a Authors: Yuli V. Nazarov Electric charge is quantized in units of the electron's charge. An experiment explores the suppression of charge quantization caused by quantum fluctuations and supports a long-standing theory that explains this behaviour. See Letter p.58

Beschreibung: Controlling charge quantization with quantum fluctuations Nature 536, 7614 (2016). doi:10.1038/nature19072 Authors: S. Jezouin, Z. Iftikhar, A. Anthore, F. D. Parmentier, U. Gennser, A. Cavanna, A. Ouerghi, I. P. Levkivskyi, E. Idrisov, E. V. Sukhorukov, L. I. Glazman & F. Pierre In 1909, Millikan showed that the charge of electrically isolated systems is quantized in units of the elementary electron charge e. Today, the persistence of charge quantization in small, weakly connected conductors allows for circuits in which single electrons are manipulated, with applications in, for example, metrology, detectors and thermometry. However, as the connection strength is increased, the discreteness of charge is progressively reduced by quantum fluctuations. Here we report the full quantum control and characterization of charge quantization. By using semiconductor-based tunable elemental conduction channels to connect a micrometre-scale metallic island to a circuit, we explore the complete evolution of charge quantization while scanning the entire range of connection strengths, from a very weak (tunnel) to a perfect (ballistic) contact. We observe, when approaching the ballistic limit, that charge quantization is destroyed by quantum fluctuations, and scales as the square root of the residual probability for an electron to be reflected across the quantum channel; this scaling also applies beyond the different regimes of connection strength currently accessible to theory. At increased temperatures, the thermal fluctuations result in an exponential suppression of charge quantization and in a universal square-root scaling, valid for all connection strengths, in agreement with expectations. Besides being pertinent for the improvement of single-electron circuits and their applications, and for the metal–semiconductor hybrids relevant to topological quantum computing, knowledge of the quantum laws of electricity will be essential for the quantum engineering of future nanoelectronic devices.

Beschreibung: Demonstration of a small programmable quantum computer with atomic qubits Nature 536, 7614 (2016). doi:10.1038/nature18648 Authors: S. Debnath, N. M. Linke, C. Figgatt, K. A. Landsman, K. Wright & C. Monroe Quantum computers can solve certain problems more efficiently than any possible conventional computer. Small quantum algorithms have been demonstrated on multiple quantum computing platforms, many specifically tailored in hardware to implement a particular algorithm or execute a limited number of computational paths. Here we demonstrate a five-qubit trapped-ion quantum computer that can be programmed in software to implement arbitrary quantum algorithms by executing any sequence of universal quantum logic gates. We compile algorithms into a fully connected set of gate operations that are native to the hardware and have a mean fidelity of 98 per cent. Reconfiguring these gate sequences provides the flexibility to implement a variety of algorithms without altering the hardware. As examples, we implement the Deutsch–Jozsa and Bernstein–Vazirani algorithms with average success rates of 95 and 90 per cent, respectively. We also perform a coherent quantum Fourier transform on five trapped-ion qubits for phase estimation and period finding with average fidelities of 62 and 84 per cent, respectively. This small quantum computer can be scaled to larger numbers of qubits within a single register, and can be further expanded by connecting several such modules through ion shuttling or photonic quantum channels.

Beschreibung: eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation Nature 536, 7614 (2016). doi:10.1038/nature18954 Authors: Amy S. Y. Lee, Philip J. Kranzusch, Jennifer A. Doudna & Jamie H. D. Cate Eukaryotic mRNAs contain a 5′ cap structure that is crucial for recruitment of the translation machinery and initiation of protein synthesis. mRNA recognition is thought to require direct interactions between eukaryotic initiation factor 4E (eIF4E) and the mRNA cap. However, translation of numerous capped mRNAs remains robust during cellular stress, early development, and cell cycle progression despite inactivation of eIF4E. Here we describe a cap-dependent pathway of translation initiation in human cells that relies on a previously unknown cap-binding activity of eIF3d, a subunit of the 800-kilodalton eIF3 complex. A 1.4 Å crystal structure of the eIF3d cap-binding domain reveals unexpected homology to endonucleases involved in RNA turnover, and allows modelling of cap recognition by eIF3d. eIF3d makes specific contacts with the cap, as exemplified by cap analogue competition, and these interactions are essential for assembly of translation initiation complexes on eIF3-specialized mRNAs such as the cell proliferation regulator c-Jun (also known as JUN). The c-Jun mRNA further encodes an inhibitory RNA element that blocks eIF4E recruitment, thus enforcing alternative cap recognition by eIF3d. Our results reveal a mechanism of cap-dependent translation that is independent of eIF4E, and illustrate how modular RNA elements work together to direct specialized forms of translation initiation.

Beschreibung: The genetic architecture of type 2 diabetes Nature 536, 7614 (2016). doi:10.1038/nature18642 Authors: Christian Fuchsberger, Jason Flannick, Tanya M. Teslovich, Anubha Mahajan, Vineeta Agarwala, Kyle J. Gaulton, Clement Ma, Pierre Fontanillas, Loukas Moutsianas, Davis J. McCarthy, Manuel A. Rivas, John R. B. Perry, Xueling Sim, Thomas W. Blackwell, Neil R. Robertson, N. William Rayner, Pablo Cingolani, Adam E. Locke, Juan Fernandez Tajes, Heather M. Highland, Josee Dupuis, Peter S. Chines, Cecilia M. Lindgren, Christopher Hartl, Anne U. Jackson, Han Chen, Jeroen R. Huyghe, Martijn van de Bunt, Richard D. Pearson, Ashish Kumar, Martina Müller-Nurasyid, Niels Grarup, Heather M. Stringham, Eric R. Gamazon, Jaehoon Lee, Yuhui Chen, Robert A. Scott, Jennifer E. Below, Peng Chen, Jinyan Huang, Min Jin Go, Michael L. Stitzel, Dorota Pasko, Stephen C. J. Parker, Tibor V. Varga, Todd Green, Nicola L. Beer, Aaron G. Day-Williams, Teresa Ferreira, Tasha Fingerlin, Momoko Horikoshi, Cheng Hu, Iksoo Huh, Mohammad Kamran Ikram, Bong-Jo Kim, Yongkang Kim, Young Jin Kim, Min-Seok Kwon, Juyoung Lee, Selyeong Lee, Keng-Han Lin, Taylor J. Maxwell, Yoshihiko Nagai, Xu Wang, Ryan P. Welch, Joon Yoon, Weihua Zhang, Nir Barzilai, Benjamin F. Voight, Bok-Ghee Han, Christopher P. Jenkinson, Teemu Kuulasmaa, Johanna Kuusisto, Alisa Manning, Maggie C. Y. Ng, Nicholette D. Palmer, Beverley Balkau, Alena Stančáková, Hanna E. Abboud, Heiner Boeing, Vilmantas Giedraitis, Dorairaj Prabhakaran, Omri Gottesman, James Scott, Jason Carey, Phoenix Kwan, George Grant, Joshua D. Smith, Benjamin M. Neale, Shaun Purcell, Adam S. Butterworth, Joanna M. M. Howson, Heung Man Lee, Yingchang Lu, Soo-Heon Kwak, Wei Zhao, John Danesh, Vincent K. L. Lam, Kyong Soo Park, Danish Saleheen, Wing Yee So, Claudia H. T. Tam, Uzma Afzal, David Aguilar, Rector Arya, Tin Aung, Edmund Chan, Carmen Navarro, Ching-Yu Cheng, Domenico Palli, Adolfo Correa, Joanne E. Curran, Denis Rybin, Vidya S. Farook, Sharon P. Fowler, Barry I. Freedman, Michael Griswold, Daniel Esten Hale, Pamela J. Hicks, Chiea-Chuen Khor, Satish Kumar, Benjamin Lehne, Dorothée Thuillier, Wei Yen Lim, Jianjun Liu, Yvonne T. van der Schouw, Marie Loh, Solomon K. Musani, Sobha Puppala, William R. Scott, Loïc Yengo, Sian-Tsung Tan, Herman A. Taylor Jr., Farook Thameem, Gregory Wilson, Tien Yin Wong, Pål Rasmus Njølstad, Jonathan C. Levy, Massimo Mangino, Lori L. Bonnycastle, Thomas Schwarzmayr, João Fadista, Gabriela L. Surdulescu, Christian Herder, Christopher J. Groves, Thomas Wieland, Jette Bork-Jensen, Ivan Brandslund, Cramer Christensen, Heikki A. Koistinen, Alex S. F. Doney, Leena Kinnunen, Tõnu Esko, Andrew J. Farmer, Liisa Hakaste, Dylan Hodgkiss, Jasmina Kravic, Valeriya Lyssenko, Mette Hollensted, Marit E. Jørgensen, Torben Jørgensen, Claes Ladenvall, Johanne Marie Justesen, Annemari Käräjämäki, Jennifer Kriebel, Wolfgang Rathmann, Lars Lannfelt, Torsten Lauritzen, Narisu Narisu, Allan Linneberg, Olle Melander, Lili Milani, Matt Neville, Marju Orho-Melander, Lu Qi, Qibin Qi, Michael Roden, Olov Rolandsson, Amy Swift, Anders H. Rosengren, Kathleen Stirrups, Andrew R. Wood, Evelin Mihailov, Christine Blancher, Mauricio O. Carneiro, Jared Maguire, Ryan Poplin, Khalid Shakir, Timothy Fennell, Mark DePristo, Martin Hrabé de Angelis, Panos Deloukas, Anette P. Gjesing, Goo Jun, Peter Nilsson, Jacquelyn Murphy, Robert Onofrio, Barbara Thorand, Torben Hansen, Christa Meisinger, Frank B. Hu, Bo Isomaa, Fredrik Karpe, Liming Liang, Annette Peters, Cornelia Huth, Stephen P. O’Rahilly, Colin N. A. Palmer, Oluf Pedersen, Rainer Rauramaa, Jaakko Tuomilehto, Veikko Salomaa, Richard M. Watanabe, Ann-Christine Syvänen, Richard N. Bergman, Dwaipayan Bharadwaj, Erwin P. Bottinger, Yoon Shin Cho, Giriraj R. Chandak, Juliana C. N. Chan, Kee Seng Chia, Mark J. Daly, Shah B. Ebrahim, Claudia Langenberg, Paul Elliott, Kathleen A. Jablonski, Donna M. Lehman, Weiping Jia, Ronald C. W. Ma, Toni I. Pollin, Manjinder Sandhu, Nikhil Tandon, Philippe Froguel, Inês Barroso, Yik Ying Teo, Eleftheria Zeggini, Ruth J. F. Loos, Kerrin S. Small, Janina S. Ried, Ralph A. DeFronzo, Harald Grallert, Benjamin Glaser, Andres Metspalu, Nicholas J. Wareham, Mark Walker, Eric Banks, Christian Gieger, Erik Ingelsson, Hae Kyung Im, Thomas Illig, Paul W. Franks, Gemma Buck, Joseph Trakalo, David Buck, Inga Prokopenko, Reedik Mägi, Lars Lind, Yossi Farjoun, Katharine R. Owen, Anna L. Gloyn, Konstantin Strauch, Tiinamaija Tuomi, Jaspal Singh Kooner, Jong-Young Lee, Taesung Park, Peter Donnelly, Andrew D. Morris, Andrew T. Hattersley, Donald W. Bowden, Francis S. Collins, Gil Atzmon, John C. Chambers, Timothy D. Spector, Markku Laakso, Tim M. Strom, Graeme I. Bell, John Blangero, Ravindranath Duggirala, E. Shyong Tai, Gilean McVean, Craig L. Hanis, James G. Wilson, Mark Seielstad, Timothy M. Frayling, James B. Meigs, Nancy J. Cox, Rob Sladek, Eric S. Lander, Stacey Gabriel, Noël P. Burtt, Karen L. Mohlke, Thomas Meitinger, Leif Groop, Goncalo Abecasis, Jose C. Florez, Laura J. Scott, Andrew P. Morris, Hyun Min Kang, Michael Boehnke, David Altshuler & Mark I. McCarthy The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only

Beschreibung: The structural basis of modified nucleosome recognition by 53BP1 Nature 536, 7614 (2016). doi:10.1038/nature18951 Authors: Marcus D. Wilson, Samir Benlekbir, Amélie Fradet-Turcotte, Alana Sherker, Jean-Philippe Julien, Andrea McEwan, Sylvie M. Noordermeer, Frank Sicheri, John L. Rubinstein & Daniel Durocher DNA double-strand breaks (DSBs) elicit a histone modification cascade that controls DNA repair. This pathway involves the sequential ubiquitination of histones H1 and H2A by the E3 ubiquitin ligases RNF8 and RNF168, respectively. RNF168 ubiquitinates H2A on lysine 13 and lysine 15 (refs 7, 8) (yielding H2AK13ub and H2AK15ub, respectively), an event that triggers the recruitment of 53BP1 (also known as TP53BP1) to chromatin flanking DSBs. 53BP1 binds specifically to H2AK15ub-containing nucleosomes through a peptide segment termed the ubiquitination-dependent recruitment motif (UDR), which requires the simultaneous engagement of histone H4 lysine 20 dimethylation (H4K20me2) by its tandem Tudor domain. How 53BP1 interacts with these two histone marks in the nucleosomal context, how it recognizes ubiquitin, and how it discriminates between H2AK13ub and H2AK15ub is unknown. Here we present the electron cryomicroscopy (cryo-EM) structure of a dimerized human 53BP1 fragment bound to a H4K20me2-containing and H2AK15ub-containing nucleosome core particle (NCP-ubme) at 4.5 Å resolution. The structure reveals that H4K20me2 and H2AK15ub recognition involves intimate contacts with multiple nucleosomal elements including the acidic patch. Ubiquitin recognition by 53BP1 is unusual and involves the sandwiching of the UDR segment between ubiquitin and the NCP surface. The selectivity for H2AK15ub is imparted by two arginine fingers in the H2A amino-terminal tail, which straddle the nucleosomal DNA and serve to position ubiquitin over the NCP-bound UDR segment. The structure of the complex between NCP-ubme and 53BP1 reveals the basis of 53BP1 recruitment to DSB sites and illuminates how combinations of histone marks and nucleosomal elements cooperate to produce highly specific chromatin responses, such as those elicited following chromosome breaks.

Beschreibung: Synchronized cycles of bacterial lysis for in vivo delivery Nature 536, 7614 (2016). doi:10.1038/nature18930 Authors: M. Omar Din, Tal Danino, Arthur Prindle, Matt Skalak, Jangir Selimkhanov, Kaitlin Allen, Ellixis Julio, Eta Atolia, Lev S. Tsimring, Sangeeta N. Bhatia & Jeff Hasty The widespread view of bacteria as strictly pathogenic has given way to an appreciation of the prevalence of some beneficial microbes within the human body. It is perhaps inevitable that some bacteria would evolve to preferentially grow in environments that harbour disease and thus provide a natural platform for the development of engineered therapies. Such therapies could benefit from bacteria that are programmed to limit bacterial growth while continually producing and releasing cytotoxic agents in situ. Here we engineer a clinically relevant bacterium to lyse synchronously at a threshold population density and to release genetically encoded cargo. Following quorum lysis, a small number of surviving bacteria reseed the growing population, thus leading to pulsatile delivery cycles. We used microfluidic devices to characterize the engineered lysis strain and we demonstrate its potential as a drug delivery platform via co-culture with human cancer cells in vitro. As a proof of principle, we tracked the bacterial population dynamics in ectopic syngeneic colorectal tumours in mice via a luminescent reporter. The lysis strain exhibits pulsatile population dynamics in vivo, with mean bacterial luminescence that remained two orders of magnitude lower than an unmodified strain. Finally, guided by previous findings that certain bacteria can enhance the efficacy of standard therapies, we orally administered the lysis strain alone or in combination with a clinical chemotherapeutic to a syngeneic mouse transplantation model of hepatic colorectal metastases. We found that the combination of both circuit-engineered bacteria and chemotherapy leads to a notable reduction of tumour activity along with a marked survival benefit over either therapy alone. Our approach establishes a methodology for leveraging the tools of synthetic biology to exploit the natural propensity for certain bacteria to colonize disease sites.

Beschreibung: Neoantigen landscape dynamics during human melanoma–T cell interactions Nature 536, 7614 (2016). doi:10.1038/nature18945 Authors: Els M. E. Verdegaal, Noel F. C. C. de Miranda, Marten Visser, Tom Harryvan, Marit M. van Buuren, Rikke S. Andersen, Sine R. Hadrup, Caroline E. van der Minne, Remko Schotte, Hergen Spits, John B. A. G. Haanen, Ellen H. W. Kapiteijn, Ton N. Schumacher & Sjoerd H. van der Burg Recognition of neoantigens that are formed as a consequence of DNA damage is likely to form a major driving force behind the clinical activity of cancer immunotherapies such as T-cell checkpoint blockade and adoptive T-cell therapy. Therefore, strategies to selectively enhance T-cell reactivity against genetically defined neoantigens are currently under development. In mouse models, T-cell pressure can sculpt the antigenicity of tumours, resulting in the emergence of tumours that lack defined mutant antigens. However, whether the T-cell-recognized neoantigen repertoire in human cancers is constant over time is unclear. Here we analyse the stability of neoantigen-specific T-cell responses and the antigens they recognize in two patients with stage IV melanoma treated by adoptive T-cell transfer. The T-cell-recognized neoantigens can be selectively lost from the tumour cell population, either by overall reduced expression of the genes or loss of the mutant alleles. Notably, loss of expression of T-cell-recognized neoantigens was accompanied by development of neoantigen-specific T-cell reactivity in tumour-infiltrating lymphocytes. These data demonstrate the dynamic interactions between cancer cells and T cells, which suggest that T cells mediate neoantigen immunoediting, and indicate that the therapeutic induction of broad neoantigen-specific T-cell responses should be used to avoid tumour resistance.

Beschreibung: Bright carbonate deposits as evidence of aqueous alteration on (1) Ceres Nature 536, 7614 (2016). doi:10.1038/nature18290 Authors: M. C. De Sanctis, A. Raponi, E. Ammannito, M. Ciarniello, M. J. Toplis, H. Y. McSween, J. C. Castillo-Rogez, B. L. Ehlmann, F. G. Carrozzo, S. Marchi, F. Tosi, F. Zambon, F. Capaccioni, M. T. Capria, S. Fonte, M. Formisano, A. Frigeri, M. Giardino, A. Longobardo, G. Magni, E. Palomba, L. A. McFadden, C. M. Pieters, R. Jaumann, P. Schenk, R. Mugnuolo, C. A. Raymond & C. T. Russell The typically dark surface of the dwarf planet Ceres is punctuated by areas of much higher albedo, most prominently in the Occator crater. These small bright areas have been tentatively interpreted as containing a large amount of hydrated magnesium sulfate, in contrast to the average surface, which is a mixture of low-albedo materials and magnesium phyllosilicates, ammoniated phyllosilicates and carbonates. Here we report high spatial and spectral resolution near-infrared observations of the bright areas in the Occator crater on Ceres. Spectra of these bright areas are consistent with a large amount of sodium carbonate, constituting the most concentrated known extraterrestrial occurrence of carbonate on kilometre-wide scales in the Solar System. The carbonates are mixed with a dark component and small amounts of phyllosilicates, as well as ammonium carbonate or ammonium chloride. Some of these compounds have also been detected in the plume of Saturn’s sixth-largest moon Enceladus. The compounds are endogenous and we propose that they are the solid residue of crystallization of brines and entrained altered solids that reached the surface from below. The heat source may have been transient (triggered by impact heating). Alternatively, internal temperatures may be above the eutectic temperature of subsurface brines, in which case fluids may exist at depth on Ceres today.

Beschreibung: Corrigendum: Structure of promoter-bound TFIID and model of human pre-initiation complex assembly Nature 536, 7614 (2016). doi:10.1038/nature17984 Authors: Robert K. Louder, Yuan He, José Ramón López-Blanco, Jie Fang, Pablo Chacón & Eva Nogales Nature531, 604–609 (2016); doi:10.1038/nature17394In this Article, author Pablo Chacón should have affiliation 4 (Department of Biological Physical Chemistry, Rocasolano Physical Chemistry Institute, CSIC, Serrano 119, Madrid 28006, Spain), not affiliation 3. This error has been corrected

Beschreibung: Corrigendum: Flexible high-temperature dielectric materials from polymer nanocomposites Nature 536, 7614 (2016). doi:10.1038/nature17673 Authors: Qi Li, Lei Chen, Matthew R. Gadinski, Shihai Zhang, Guangzu Zhang, Haoyu U. Li, Elissei Iagodkine, Aman Haque, Long-Qing Chen, Thomas N. Jackson & Qing Wang Nature523, 576–579 (2015); doi:10.1038/nature14647The author Elissei Iagodkine was erroneously omitted from the author list of this Letter. They are associated with the affiliation: Dow Chemical Company, 455 Forest Street, Marlborough, Massachusetts 01752, USA, and the Author

Beschreibung: Architecture of fully occupied GluA2 AMPA receptor–TARP complex elucidated by cryo-EM Nature 536, 7614 (2016). doi:10.1038/nature18961 Authors: Yan Zhao, Shanshuang Chen, Craig Yoshioka, Isabelle Baconguis & Eric Gouaux Fast excitatory neurotransmission in the mammalian central nervous system is largely carried out by AMPA-sensitive ionotropic glutamate receptors. Localized within the postsynaptic density of glutamatergic spines, AMPA receptors are composed of heterotetrameric receptor assemblies associated with auxiliary subunits, the most common of which are transmembrane AMPA receptor regulatory proteins (TARPs). The association of TARPs with AMPA receptors modulates receptor trafficking and the kinetics of receptor gating and pharmacology. Here we report the cryo-electron microscopy (cryo-EM) structure of the homomeric rat GluA2 AMPA receptor saturated with TARP γ2 subunits, which shows how the TARPs are arranged with four-fold symmetry around the ion channel domain and make extensive interactions with the M1, M2 and M4 transmembrane helices. Poised like partially opened ‘hands’ underneath the two-fold symmetric ligand-binding domain (LBD) ‘clamshells’, one pair of TARPs is juxtaposed near the LBD dimer interface, whereas the other pair is near the LBD dimer–dimer interface. The extracellular ‘domains’ of TARP are positioned to not only modulate LBD clamshell closure, but also affect conformational rearrangements of the LBD layer associated with receptor activation and desensitization, while the TARP transmembrane domains buttress the ion channel pore.

Beschreibung: The past, present and future of the PhD thesis Nature 535, 7610 (2016). doi:10.1038/535007a Writing a PhD thesis is a personal and professional milestone for many researchers. But the process needs to change with the times.

Beschreibung: Use Zika to renew focus on birth-defect research Nature 535, 7610 (2016). doi:10.1038/535008a The high-profile of the virus can kick-start work on long-standing problems.

Beschreibung: Astrophysics: No neutrinos from black hole smash Nature 535, 7610 (2016). doi:10.1038/535010c The first hunt for neutrinos coming from the merger of two black holes — which last year produced the first direct detection of gravitational waves — has come up empty.Imre Bartos at Columbia University in New York and his colleagues analysed data from two

Beschreibung: FDA should stand firm on stem-cell treatments Nature 535, 7610 (2016). doi:10.1038/535007b US regulators must regain the upper hand in the approval system.

Beschreibung: Evolution: Lizards tailor tails to local predators Nature 535, 7610 (2016). doi:10.1038/535010d Brightly coloured tails are a common feature of young lizards, and can be tailored to the eyesight of specific local predators.Takeo Kuriyama and his colleagues at Toho University in Funabashi, Japan, collected 15 juvenile Plestiodon latiscutatus lizards from three areas of Japan dominated

Beschreibung: Find the time to discuss new bioweapons Nature 535, 7610 (2016). http://www.nature.com/doifinder/10.1038/535009a Author: Malcolm Dando The Biological Weapons Convention needs to take the assessment of emerging scientific dangers more seriously, argues Malcolm Dando.

Beschreibung: Climate science: Warming shifts plant sex ratio Nature 535, 7610 (2016). doi:10.1038/535011b Climate change seems to be skewing the sex ratios of an alpine herb towards male plants.William Petry at the University of California, Irvine, and his colleagues analysed data on populations of the herb valerian (Valeriana edulis) in the Rocky Mountains of Colorado

Beschreibung: Zoology: Wind powers weeks of non-stop flight Nature 535, 7610 (2016). doi:10.1038/535010a Frigate birds use the power of the wind and rising air to stay airborne for many weeks at a time.Henri Weimerskirch at the CNRS Centre for Biological Studies in Chizé, France, and his colleagues fitted great frigate birds (Fregata minor), with devices

Beschreibung: Neuroimmunology: Reward system boosts immunity Nature 535, 7610 (2016). doi:10.1038/535010b Activating the reward system in the brains of mice directly boosts their immune systems, offering a physiological explanation for the placebo effect.Shai Shen-Orr, Asya Rolls and their colleagues at the Technion–Israel Institute of Technology in Haifa activated neurons in a part of the mouse

Beschreibung: Climate change: Negative carbon emissions needed Nature 535, 7610 (2016). doi:10.1038/535011e Countries' existing promises regarding emissions reductions are unlikely to prevent global warming exceeding 2 °C above pre-industrial temperatures by the end of the century, meaning that large amounts of carbon may need to be removed from the atmosphere.Benjamin Sanderson and his co-workers at the

Beschreibung: Robotics: Soft wheels make robots tough Nature 535, 7610 (2016). doi:10.1038/535011c Wheels built entirely from soft materials can help robots to roll over tricky terrain and resist damage.Aaron Mazzeo and his co-workers at Rutgers University in Piscataway, New Jersey, built a squishy wheel inspired by the inching motions of soft creatures such as earthworms. A

Beschreibung: Science academies blast US government’s planned research-ethics reforms Nature 535, 7610 (2016). http://www.nature.com/doifinder/10.1038/nature.2016.20191 Author: Sara Reardon Panel recommends scrapping proposed changes to 'Common Rule' on human-subjects research.

Beschreibung: Publisher under fire for fake article webpages Nature 535, 7610 (2016). doi:10.1038/535011f Author: Rachel Becker 'Trap’ URLs can help publishers to catch automated downloading, but critics say that the approach is clumsy.

Beschreibung: Dry Amazon could see record fire season Nature 535, 7610 (2016). http://www.nature.com/doifinder/10.1038/nature.2016.20190 Author: Jeff Tollefson Forecasters warn that high ocean temperatures presage intense blazes in rainforest.

Beschreibung: CubeSats set for deep space — if they can hitch a ride Nature 535, 7610 (2016). http://www.nature.com/doifinder/10.1038/535019a Author: Elizabeth Gibney Shoebox-sized craft face a wait to be propelled beyond Earth’s orbit.

Beschreibung: Back to the thesis Nature 535, 7610 (2016). http://www.nature.com/doifinder/10.1038/535022a Authors: Kerri Smith & Noah Baker Late nights, typos, self-doubt and despair. Three leading scientists dust off their theses, and reflect on what the PhD was like for them.

Beschreibung: What’s the point of the PhD thesis? Nature 535, 7610 (2016). http://www.nature.com/doifinder/10.1038/535026a Author: Julie Gould Doctoral courses are slowly being modernized. Now the thesis and viva need to catch up.

Beschreibung: Planetary science: Martian moons formed in situ Nature 535, 7610 (2016). doi:10.1038/535011a The moons of Mars may have formed from a disk of debris kicked up by the impact of a giant meteorite on the planet.Astronomers have struggled to explain the existence of Phobos (pictured) and Deimos, the small, irregularly shaped moons of the

Beschreibung: Cancer biology: Leukaemia cells hide in fat tissue Nature 535, 7610 (2016). doi:10.1038/535011d Cancer-causing stem cells evade chemotherapy by surviving in fat deposits around gonads.Fat tissue supports the growth of normal blood-forming stem cells. Craig Jordan of the University of Colorado Denver and his colleagues found that in a mouse model of one form of leukaemia, gonadal

Beschreibung: Let’s make peer review scientific Nature 535, 7610 (2016). doi:10.1038/535031a Author: Drummond Rennie Thirty years on from the first congress on peer review, Drummond Rennie reflects on the improvements brought about by research into the process — and calls for more.

Beschreibung: Zika raises profile of more common birth-defect virus Nature 535, 7610 (2016). http://www.nature.com/doifinder/10.1038/535017a Author: Declan Butler Cytomegalovirus is a much greater global problem than Zika.

Beschreibung: The week in science: 1–7 July 2016 Nature 535, 7610 (2016). http://www.nature.com/doifinder/10.1038/535012a Chemist killed on Mexican university campus; Juno craft reaches Jupiter orbit; and Nobel laureates defend genetically modified organisms.

Beschreibung: Obama’s top scientist talks shrinking budgets, Donald Trump, and his biggest regret Nature 535, 7610 (2016). http://www.nature.com/doifinder/10.1038/535015a Authors: Sara Reardon & Jeff Tollefson John Holdren tells Nature about the highs and lows of nearly eight years in the White House.

Beschreibung: Conservation: Geniuses of place Nature 535, 7610 (2016). doi:10.1038/535034a Author: Ethan Carr Ethan Carr traces the arc of influence in landscape creation and preservation from 'Capability' Brown to Frederick Law Olmsted and the US National Park Service.

Beschreibung: Validate personal air-pollution sensors Nature 535, 7610 (2016). doi:10.1038/535029a Authors: Alastair Lewis & Peter Edwards Alastair Lewis and Peter Edwards call on researchers to test the accuracy of low-cost monitoring devices before regulators are flooded with questionable air-quality data.

Beschreibung: Expert performance: Don't undervalue the social sciences Nature 535, 7610 (2016). doi:10.1038/535037b Author: Brian Martin Too many physicists, chemists and biologists perceive the social sciences and humanities as less rigorous and less intellectually demanding domains than their own. Research into expert performance calls these attitudes into question.Thousands of hours of deliberate practice are needed to become highly competent in

Beschreibung: North Africa: Stop slaughter of migrating songbirds Nature 535, 7610 (2016). doi:10.1038/535037a Author: Rassim Khelifa A new strategy is needed to stop the illegal trapping and killing of millions of songbirds every year in the Mediterranean region, where gigantic vertical nets intercept major migration flyways (see also Nature529, 452–455;10.1038/529452a2016). In the western

Beschreibung: University jobs: Germany to fund tenure-track posts Nature (2016). doi:10.1038/nj7610-190a Author: Amber Dance Federal government will create 1,000 professorships.

Beschreibung: Intestinal microbiota in health and disease Nature 535, 7610 (2016). doi:10.1038/535047a Authors: Christina Tobin Kåhrström, Nonia Pariente & Ursula Weiss The human gut is home to trillions of microorganisms, which modulate health and disease. This Insight brings together leaders in the field of microbiota–host interactions to provide an overview of basic biological processes and important advances in the development of clinical applications.Jeff Gordon and

Beschreibung: Keep it moving Nature (2016). doi:10.1038/nj7610-189a Author: Søren-Peter Olesen A postdoc job is good for your career, but don't get stuck in an academic cul-de-sac, says Søren-Peter Olesen.

Beschreibung: A microbial perspective of human developmental biology Nature 535, 7610 (2016). doi:10.1038/nature18845 Authors: Mark R. Charbonneau, Laura V. Blanton, Daniel B. DiGiulio, David A. Relman, Carlito B. Lebrilla, David A. Mills & Jeffrey I. Gordon When most people think of human development, they tend to consider only human cells and organs. Yet there is another facet that involves human-associated microbial communities. A microbial perspective of human development provides opportunities to refine our definitions of healthy prenatal and postnatal growth and

Beschreibung: Project management: Food security needs social-science input Nature 535, 7610 (2016). doi:10.1038/535037d Authors: Klaus Nüsslein & Om Parkash Dhankher As members of the Climate- Resilient Open Partnership for Food Security project supported by the World Wide University Network (see go.nature.com/28ygwtc), we contend that basic social-science theory and methods could transform interventions aimed at improving food production.Food security calls for agricultural advances, adaptation

Beschreibung: Fetal tissue: US panel risks infant and researcher lives Nature 535, 7610 (2016). doi:10.1038/535037c Authors: Eugene Gu & Cate Dyer As the chief executives of the biotech companies Ganogen and StemExpress, we are among a broad sweep subpoenaed — along with scientists, graduate students and physicians also engaged in research involving fetal tissue — by the US House Select Investigative Panel on Infant Lives. In

Beschreibung: Microbiome-wide association studies link dynamic microbial consortia to disease Nature 535, 7610 (2016). doi:10.1038/nature18850 Authors: Jack A. Gilbert, Robert A. Quinn, Justine Debelius, Zhenjiang Z. Xu, James Morton, Neha Garg, Janet K. Jansson, Pieter C. Dorrestein & Rob Knight Rapid advances in DNA sequencing, metabolomics, proteomics and computational tools are dramatically increasing access to the microbiome and identification of its links with disease. In particular, time-series studies and multiple molecular perspectives are facilitating microbiome-wide association studies, which are analogous to genome-wide association studies. Early

Beschreibung: The microbiome and innate immunity Nature 535, 7610 (2016). doi:10.1038/nature18847 Authors: Christoph A. Thaiss, Niv Zmora, Maayan Levy & Eran Elinav The intestinal microbiome is a signalling hub that integrates environmental inputs, such as diet, with genetic and immune signals to affect the host's metabolism, immunity and response to infection. The haematopoietic and non-haematopoietic cells of the innate immune system are located strategically at the host–microbiome

Beschreibung: Diet–microbiota interactions as moderators of human metabolism Nature 535, 7610 (2016). doi:10.1038/nature18846 Authors: Justin L. Sonnenburg & Fredrik Bäckhed It is widely accepted that obesity and associated metabolic diseases, including type 2 diabetes, are intimately linked to diet. However, the gut microbiota has also become a focus for research at the intersection of diet and metabolic health. Mechanisms that link the gut microbiota with

Beschreibung: Interactions between the microbiota and pathogenic bacteria in the gut Nature 535, 7610 (2016). doi:10.1038/nature18849 Authors: Andreas J. Bäumler & Vanessa Sperandio The microbiome has an important role in human health. Changes in the microbiota can confer resistance to or promote infection by pathogenic bacteria. Antibiotics have a profound impact on the microbiota that alters the nutritional landscape of the gut and can lead to the expansion

Beschreibung: Astrophysics: Rare data from a lost satellite Nature 535, 7610 (2016). doi:10.1038/535040a Authors: Elizabeth Blanton The Hitomi astronomical satellite observed gas motions in the Perseus galaxy cluster shortly before losing contact with Earth. Its findings are invaluable to studies of cluster physics and cosmology. See Letter p.117

Beschreibung: The microbiota in adaptive immune homeostasis and disease Nature 535, 7610 (2016). doi:10.1038/nature18848 Authors: Kenya Honda & Dan R. Littman In the mucosa, the immune system's T cells and B cells have position-specific phenotypes and functions that are influenced by the microbiota. These cells play pivotal parts in the maintenance of immune homeostasis by suppressing responses to harmless antigens and by enforcing the integrity of

Beschreibung: Chemical physics: Quantum control of light-induced reactions Nature 535, 7610 (2016). doi:10.1038/535042a Authors: David W. Chandler An investigation of how ultracold molecules are broken apart by light reveals surprising, previously unobserved quantum effects. The work opens up avenues of research in quantum optics. See Letter p.122

Beschreibung: Computational neuroscience: Species-specific motion detectors Nature 535, 7610 (2016). doi:10.1038/nature18454 Authors: Thomas Euler & Tom Baden A range of neuronal mechanisms can enable animals to detect the direction of visual motion. Computational models now indicate that a factor as simple as eye size might explain some of this diversity. See Article p.105

Beschreibung: Clarification Nature 535, 7610 (2016). http://www.nature.com/doifinder/10.1038/535020a In the News Feature ‘Mystery in the heavens’ (Nature534, 610–612; 2016), the discussion of the initial radio burst meant to say that over the course of just a few milliseconds, the source’s output matched that of 500 million Suns in the

Beschreibung: Life in the clouds Nature 535, 7610 (2016). doi:10.1038/535192a Author: David B. Litt A long-term problem.

Beschreibung: The quiescent intracluster medium in the core of the Perseus cluster Nature 535, 7610 (2016). doi:10.1038/nature18627 Authors: Clusters of galaxies are the most massive gravitationally bound objects in the Universe and are still forming. They are thus important probes of cosmological parameters and many astrophysical processes. However, knowledge of the dynamics of the pervasive hot gas, the mass of which is much larger than the combined mass of all the stars in the cluster, is lacking. Such knowledge would enable insights into the injection of mechanical energy by the central supermassive black hole and the use of hydrostatic equilibrium for determining cluster masses. X-rays from the core of the Perseus cluster are emitted by the 50-million-kelvin diffuse hot plasma filling its gravitational potential well. The active galactic nucleus of the central galaxy NGC 1275 is pumping jetted energy into the surrounding intracluster medium, creating buoyant bubbles filled with relativistic plasma. These bubbles probably induce motions in the intracluster medium and heat the inner gas, preventing runaway radiative cooling—a process known as active galactic nucleus feedback. Here we report X-ray observations of the core of the Perseus cluster, which reveal a remarkably quiescent atmosphere in which the gas has a line-of-sight velocity dispersion of 164 ± 10 kilometres per second in the region 30–60 kiloparsecs from the central nucleus. A gradient in the line-of-sight velocity of 150 ± 70 kilometres per second is found across the 60-kiloparsec image of the cluster core. Turbulent pressure support in the gas is four per cent of the thermodynamic pressure, with large-scale shear at most doubling this estimate. We infer that a total cluster mass determined from hydrostatic equilibrium in a central region would require little correction for turbulent pressure.

Beschreibung: Photodissociation of ultracold diatomic strontium molecules with quantum state control Nature 535, 7610 (2016). doi:10.1038/nature18314 Authors: M. McDonald, B. H. McGuyer, F. Apfelbeck, C. -H. Lee, I. Majewska, R. Moszynski & T. Zelevinsky Chemical reactions at ultracold temperatures are expected to be dominated by quantum mechanical effects. Although progress towards ultracold chemistry has been made through atomic photoassociation, Feshbach resonances and bimolecular collisions, these approaches have been limited by imperfect quantum state selectivity. In particular, attaining complete control of the ground or excited continuum quantum states has remained a challenge. Here we achieve this control using photodissociation, an approach that encodes a wealth of information in the angular distribution of outgoing fragments. By photodissociating ultracold 88Sr2 molecules with full control of the low-energy continuum, we access the quantum regime of ultracold chemistry, observing resonant and nonresonant barrier tunnelling, matter–wave interference of reaction products and forbidden reaction pathways. Our results illustrate the failure of the traditional quasiclassical model of photodissociation and instead are accurately described by a quantum mechanical model. The experimental ability to produce well-defined quantum continuum states at low energies will enable high-precision studies of long-range molecular potentials for which accurate quantum chemistry models are unavailable, and may serve as a source of entangled states and coherent matter waves for a wide range of experiments in quantum optics.

Beschreibung: Conservation: The rainforest's 'do not disturb' signs Nature 535, 7610 (2016). doi:10.1038/nature18901 Authors: David P. Edwards A study reveals that human-driven disturbances in previously undisturbed Amazon rainforest can cause biodiversity losses as severe as those of deforestation. Urgent policy interventions are needed to preserve forest quality. See Letter p.144

Beschreibung: Neuroscience: In search of the memory molecule Nature 535, 7610 (2016). doi:10.1038/nature18903 Authors: Paul W. Frankland & Sheena A. Josselyn The protein PKM-ζ has been proposed to regulate the maintenance of memory in rodents, but this theory has been questioned. The finding that another isoform of the protein acts as a backup if PKM-ζ is lacking will influence this debate.

Beschreibung: Design of a hyperstable 60-subunit protein icosahedron Nature 535, 7610 (2016). doi:10.1038/nature18010 Authors: Yang Hsia, Jacob B. Bale, Shane Gonen, Dan Shi, William Sheffler, Kimberly K. Fong, Una Nattermann, Chunfu Xu, Po-Ssu Huang, Rashmi Ravichandran, Sue Yi, Trisha N. Davis, Tamir Gonen, Neil P. King & David Baker The icosahedron is the largest of the Platonic solids, and icosahedral protein structures are widely used in biological systems for packaging and transport. There has been considerable interest in repurposing such structures for applications ranging from targeted delivery to multivalent immunogen presentation. The ability to design proteins that self-assemble into precisely specified, highly ordered icosahedral structures would open the door to a new generation of protein containers with properties custom-tailored to specific applications. Here we describe the computational design of a 25-nanometre icosahedral nanocage that self-assembles from trimeric protein building blocks. The designed protein was produced in Escherichia coli, and found by electron microscopy to assemble into a homogenous population of icosahedral particles nearly identical to the design model. The particles are stable in 6.7 molar guanidine hydrochloride at up to 80 degrees Celsius, and undergo extremely abrupt, but reversible, disassembly between 2 molar and 2.25 molar guanidinium thiocyanate. The icosahedron is robust to genetic fusions: one or two copies of green fluorescent protein (GFP) can be fused to each of the 60 subunits to create highly fluorescent ‘standard candles’ for use in light microscopy, and a designed protein pentamer can be placed in the centre of each of the 20 pentameric faces to modulate the size of the entrance/exit channels of the cage. Such robust and customizable nanocages should have considerable utility in targeted drug delivery, vaccine design and synthetic biology.

Beschreibung: Pore-forming activity and structural autoinhibition of the gasdermin family Nature 535, 7610 (2016). doi:10.1038/nature18590 Authors: Jingjin Ding, Kun Wang, Wang Liu, Yang She, Qi Sun, Jianjin Shi, Hanzi Sun, Da-Cheng Wang & Feng Shao Inflammatory caspases cleave the gasdermin D (GSDMD) protein to trigger pyroptosis, a lytic form of cell death that is crucial for immune defences and diseases. GSDMD contains a functionally important gasdermin-N domain that is shared in the gasdermin family. The functional mechanism of action of

Beschreibung: Species-specific wiring for direction selectivity in the mammalian retina Nature 535, 7610 (2016). doi:10.1038/nature18609 Authors: Huayu Ding, Robert G. Smith, Alon Poleg-Polsky, Jeffrey S. Diamond & Kevin L. Briggman Directionally tuned signalling in starburst amacrine cell (SAC) dendrites lies at the heart of the circuit that detects the direction of moving stimuli in the mammalian retina. The relative contributions of intrinsic cellular properties and network connectivity to SAC direction selectivity remain unclear. Here we

Beschreibung: Lanthanum-catalysed synthesis of microporous 3D graphene-like carbons in a zeolite template Nature 535, 7610 (2016). doi:10.1038/nature18284 Authors: Kyoungsoo Kim, Taekyoung Lee, Yonghyun Kwon, Yongbeom Seo, Jongchan Song, Jung Ki Park, Hyunsoo Lee, Jeong Young Park, Hyotcherl Ihee, Sung June Cho & Ryong Ryoo Three-dimensional graphene architectures with periodic nanopores—reminiscent of zeolite frameworks—are of topical interest because of the possibility of combining the characteristics of graphene with a three-dimensional porous structure. Lately, the synthesis of such carbons has been approached by using zeolites as templates and small hydrocarbon molecules that can enter the narrow pore apertures. However, pyrolytic carbonization of the hydrocarbons (a necessary step in generating pure carbon) requires high temperatures and results in non-selective carbon deposition outside the pores. Here, we demonstrate that lanthanum ions embedded in zeolite pores can lower the temperature required for the carbonization of ethylene or acetylene. In this way, a graphene-like carbon structure can be selectively formed inside the zeolite template, without carbon being deposited at the external surfaces. X-ray diffraction data from zeolite single crystals after carbonization indicate that electron densities corresponding to carbon atoms are generated along the walls of the zeolite pores. After the zeolite template is removed, the carbon framework exhibits an electrical conductivity that is two orders of magnitude higher than that of amorphous mesoporous carbon. Lanthanum catalysis allows a carbon framework to form in zeolite pores with diameters of less than 1 nanometre; as such, microporous carbon nanostructures can be reproduced with various topologies corresponding to different zeolite pore sizes and shapes. We demonstrate carbon synthesis for large-pore zeolites (FAU, EMT and beta), a one-dimensional medium-pore zeolite (LTL), and even small-pore zeolites (MFI and LTA). The catalytic effect is a common feature of lanthanum, yttrium and calcium, which are all carbide-forming metal elements. We also show that the synthesis can be readily scaled up, which will be important for practical applications such as the production of lithium-ion batteries and zeolite-like catalyst supports.

Beschreibung: Single-molecule strong coupling at room temperature in plasmonic nanocavities Nature 535, 7610 (2016). doi:10.1038/nature17974 Authors: Rohit Chikkaraddy, Bart de Nijs, Felix Benz, Steven J. Barrow, Oren A. Scherman, Edina Rosta, Angela Demetriadou, Peter Fox, Ortwin Hess & Jeremy J. Baumberg Photon emitters placed in an optical cavity experience an environment that changes how they are coupled to the surrounding light field. In the weak-coupling regime, the extraction of light from the emitter is enhanced. But more profound effects emerge when single-emitter strong coupling occurs: mixed states are produced that are part light, part matter, forming building blocks for quantum information systems and for ultralow-power switches and lasers. Such cavity quantum electrodynamics has until now been the preserve of low temperatures and complicated fabrication methods, compromising its use. Here, by scaling the cavity volume to less than 40 cubic nanometres and using host–guest chemistry to align one to ten protectively isolated methylene-blue molecules, we reach the strong-coupling regime at room temperature and in ambient conditions. Dispersion curves from more than 50 such plasmonic nanocavities display characteristic light–matter mixing, with Rabi frequencies of 300 millielectronvolts for ten methylene-blue molecules, decreasing to 90 millielectronvolts for single molecules—matching quantitative models. Statistical analysis of vibrational spectroscopy time series and dark-field scattering spectra provides evidence of single-molecule strong coupling. This dressing of molecules with light can modify photochemistry, opening up the exploration of complex natural processes such as photosynthesis and the possibility of manipulating chemical bonds.

Beschreibung: Genetic dissection of Flaviviridae host factors through genome-scale CRISPR screens Nature 535, 7610 (2016). doi:10.1038/nature18631 Authors: Caleb D. Marceau, Andreas S. Puschnik, Karim Majzoub, Yaw Shin Ooi, Susan M. Brewer, Gabriele Fuchs, Kavya Swaminathan, Miguel A. Mata, Joshua E. Elias, Peter Sarnow & Jan E. Carette The Flaviviridae are a family of viruses that cause severe human diseases. For example, dengue virus (DENV) is a rapidly emerging pathogen causing an estimated 100 million symptomatic infections annually worldwide. No approved antivirals are available to date and clinical trials with a tetravalent dengue vaccine showed disappointingly low protection rates. Hepatitis C virus (HCV) also remains a major medical problem, with 160 million chronically infected patients worldwide and only expensive treatments available. Despite distinct differences in their pathogenesis and modes of transmission, the two viruses share common replication strategies. A detailed understanding of the host functions that determine viral infection is lacking. Here we use a pooled CRISPR genetic screening strategy to comprehensively dissect host factors required for these two highly important Flaviviridae members. For DENV, we identified endoplasmic-reticulum (ER)-associated multi-protein complexes involved in signal sequence recognition, N-linked glycosylation and ER-associated degradation. DENV replication was nearly completely abrogated in cells deficient in the oligosaccharyltransferase (OST) complex. Mechanistic studies pinpointed viral RNA replication and not entry or translation as the crucial step requiring the OST complex. Moreover, we show that viral non-structural proteins bind to the OST complex. The identified ER-associated protein complexes were also important for infection by other mosquito-borne flaviviruses including Zika virus, an emerging pathogen causing severe birth defects. By contrast, the most significant genes identified in the HCV screen were distinct and included viral receptors, RNA-binding proteins and enzymes involved in metabolism. We found an unexpected link between intracellular flavin adenine dinucleotide (FAD) levels and HCV replication. This study shows notable divergence in host-depenency factors between DENV and HCV, and illuminates new host targets for antiviral therapy.

Beschreibung: Toremifene interacts with and destabilizes the Ebola virus glycoprotein Nature 535, 7610 (2016). doi:10.1038/nature18615 Authors: Yuguang Zhao, Jingshan Ren, Karl Harlos, Daniel M. Jones, Antra Zeltina, Thomas A. Bowden, Sergi Padilla-Parra, Elizabeth E. Fry & David I. Stuart Ebola viruses (EBOVs) are responsible for repeated outbreaks of fatal infections, including the recent deadly epidemic in West Africa. There are currently no approved therapeutic drugs or vaccines for the disease. EBOV has a membrane envelope decorated by trimers of a glycoprotein (GP, cleaved by furin to form GP1 and GP2 subunits), which is solely responsible for host cell attachment, endosomal entry and membrane fusion. GP is thus a primary target for the development of antiviral drugs. Here we report the first, to our knowledge, unliganded structure of EBOV GP, and high-resolution complexes of GP with the anticancer drug toremifene and the painkiller ibuprofen. The high-resolution apo structure gives a more complete and accurate picture of the molecule, and allows conformational changes introduced by antibody and receptor binding to be deciphered. Unexpectedly, both toremifene and ibuprofen bind in a cavity between the attachment (GP1) and fusion (GP2) subunits at the entrance to a large tunnel that links with equivalent tunnels from the other monomers of the trimer at the three-fold axis. Protein–drug interactions with both GP1 and GP2 are predominately hydrophobic. Residues lining the binding site are highly conserved among filoviruses except Marburg virus (MARV), suggesting that MARV may not bind these drugs. Thermal shift assays show up to a 14 °C decrease in the protein melting temperature after toremifene binding, while ibuprofen has only a marginal effect and is a less potent inhibitor. These results suggest that inhibitor binding destabilizes GP and triggers premature release of GP2, thereby preventing fusion between the viral and endosome membranes. Thus, these complex structures reveal the mechanism of inhibition and may guide the development of more powerful anti-EBOV drugs.

Beschreibung: Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases Nature 535, 7610 (2016). doi:10.1038/nature18621 Authors: Ying-Nan P. Chen, Matthew J. LaMarche, Ho Man Chan, Peter Fekkes, Jorge Garcia-Fortanet, Michael G. Acker, Brandon Antonakos, Christine Hiu-Tung Chen, Zhouliang Chen, Vesselina G. Cooke, Jason R. Dobson, Zhan Deng, Feng Fei, Brant Firestone, Michelle Fodor, Cary Fridrich, Hui Gao, Denise Grunenfelder, Huai-Xiang Hao, Jaison Jacob, Samuel Ho, Kathy Hsiao, Zhao B. Kang, Rajesh Karki, Mitsunori Kato, Jay Larrow, Laura R. La Bonte, Francois Lenoir, Gang Liu, Shumei Liu, Dyuti Majumdar, Matthew J. Meyer, Mark Palermo, Lawrence Perez, Minying Pu, Edmund Price, Christopher Quinn, Subarna Shakya, Michael D. Shultz, Joanna Slisz, Kavitha Venkatesan, Ping Wang, Markus Warmuth, Sarah Williams, Guizhi Yang, Jing Yuan, Ji-Hu Zhang, Ping Zhu, Timothy Ramsey, Nicholas J. Keen, William R. Sellers, Travis Stams & Pascal D. Fortin The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.

Beschreibung: Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores Nature 535, 7610 (2016). doi:10.1038/nature18629 Authors: Xing Liu, Zhibin Zhang, Jianbin Ruan, Youdong Pan, Venkat Giri Magupalli, Hao Wu & Judy Lieberman Inflammatory caspases (caspases 1, 4, 5 and 11) are activated in response to microbial infection and danger signals. When activated, they cleave mouse and human gasdermin D (GSDMD) after Asp276 and Asp275, respectively, to generate an N-terminal cleavage product (GSDMD-NT) that triggers inflammatory death (pyroptosis) and release of inflammatory cytokines such as interleukin-1β. Cleavage removes the C-terminal fragment (GSDMD-CT), which is thought to fold back on GSDMD-NT to inhibit its activation. However, how GSDMD-NT causes cell death is unknown. Here we show that GSDMD-NT oligomerizes in membranes to form pores that are visible by electron microscopy. GSDMD-NT binds to phosphatidylinositol phosphates and phosphatidylserine (restricted to the cell membrane inner leaflet) and cardiolipin (present in the inner and outer leaflets of bacterial membranes). Mutation of four evolutionarily conserved basic residues blocks GSDMD-NT oligomerization, membrane binding, pore formation and pyroptosis. Because of its lipid-binding preferences, GSDMD-NT kills from within the cell, but does not harm neighbouring mammalian cells when it is released during pyroptosis. GSDMD-NT also kills cell-free bacteria in vitro and may have a direct bactericidal effect within the cytosol of host cells, but the importance of direct bacterial killing in controlling in vivo infection remains to be determined.

Beschreibung: Subduction controls the distribution and fragmentation of Earth’s tectonic plates Nature 535, 7610 (2016). doi:10.1038/nature17992 Authors: Claire Mallard, Nicolas Coltice, Maria Seton, R. Dietmar Müller & Paul J. Tackley The theory of plate tectonics describes how the surface of Earth is split into an organized jigsaw of seven large plates of similar sizes and a population of smaller plates whose areas follow a fractal distribution. The reconstruction of global tectonics during the past 200 million years suggests that this layout is probably a long-term feature of Earth, but the forces governing it are unknown. Previous studies, primarily based on the statistical properties of plate distributions, were unable to resolve how the size of the plates is determined by the properties of the lithosphere and the underlying mantle convection. Here we demonstrate that the plate layout of Earth is produced by a dynamic feedback between mantle convection and the strength of the lithosphere. Using three-dimensional spherical models of mantle convection that self-consistently produce the plate size–frequency distribution observed for Earth, we show that subduction geometry drives the tectonic fragmentation that generates plates. The spacing between the slabs controls the layout of large plates, and the stresses caused by the bending of trenches break plates into smaller fragments. Our results explain why the fast evolution in small back-arc plates reflects the marked changes in plate motions during times of major reorganizations. Our study opens the way to using convection simulations with plate-like behaviour to unravel how global tectonics and mantle convection are dynamically connected.

Beschreibung: A core viral protein binds host nucleosomes to sequester immune danger signals Nature 535, 7610 (2016). doi:10.1038/nature18317 Authors: Daphne C. Avgousti, Christin Herrmann, Katarzyna Kulej, Neha J. Pancholi, Nikolina Sekulic, Joana Petrescu, Rosalynn C. Molden, Daniel Blumenthal, Andrew J. Paris, Emigdio D. Reyes, Philomena Ostapchuk, Patrick Hearing, Steven H. Seeholzer, G. Scott Worthen, Ben E. Black, Benjamin A. Garcia & Matthew D. Weitzman Viral proteins mimic host protein structure and function to redirect cellular processes and subvert innate defenses. Small basic proteins compact and regulate both viral and cellular DNA genomes. Nucleosomes are the repeating units of cellular chromatin and play an important part in innate immune responses. Viral-encoded core basic proteins compact viral genomes, but their impact on host chromatin structure and function remains unexplored. Adenoviruses encode a highly basic protein called protein VII that resembles cellular histones. Although protein VII binds viral DNA and is incorporated with viral genomes into virus particles, it is unknown whether protein VII affects cellular chromatin. Here we show that protein VII alters cellular chromatin, leading us to hypothesize that this has an impact on antiviral responses during adenovirus infection in human cells. We find that protein VII forms complexes with nucleosomes and limits DNA accessibility. We identified post-translational modifications on protein VII that are responsible for chromatin localization. Furthermore, proteomic analysis demonstrated that protein VII is sufficient to alter the protein composition of host chromatin. We found that protein VII is necessary and sufficient for retention in the chromatin of members of the high-mobility-group protein B family (HMGB1, HMGB2 and HMGB3). HMGB1 is actively released in response to inflammatory stimuli and functions as a danger signal to activate immune responses. We showed that protein VII can directly bind HMGB1 in vitro and further demonstrated that protein VII expression in mouse lungs is sufficient to decrease inflammation-induced HMGB1 content and neutrophil recruitment in the bronchoalveolar lavage fluid. Together, our in vitro and in vivo results show that protein VII sequesters HMGB1 and can prevent its release. This study uncovers a viral strategy in which nucleosome binding is exploited to control extracellular immune signalling.

Beschreibung: Anthropogenic disturbance in tropical forests can double biodiversity loss from deforestation Nature 535, 7610 (2016). doi:10.1038/nature18326 Authors: Jos Barlow, Gareth D. Lennox, Joice Ferreira, Erika Berenguer, Alexander C. Lees, Ralph Mac Nally, James R. Thomson, Silvio Frosini de Barros Ferraz, Julio Louzada, Victor Hugo Fonseca Oliveira, Luke Parry, Ricardo Ribeiro de Castro Solar, Ima C. G. Vieira, Luiz E. O. C. Aragão, Rodrigo Anzolin Begotti, Rodrigo F. Braga, Thiago Moreira Cardoso, Raimundo Cosme de Oliveira Jr, Carlos M. Souza Jr, Nárgila G. Moura, Sâmia Serra Nunes, João Victor Siqueira, Renata Pardini, Juliana M. Silveira, Fernando Z. Vaz-de-Mello, Ruan Carlo Stulpen Veiga, Adriano Venturieri & Toby A. Gardner Concerted political attention has focused on reducing deforestation, and this remains the cornerstone of most biodiversity conservation strategies. However, maintaining forest cover may not reduce anthropogenic forest disturbances, which are rarely considered in conservation programmes. These disturbances occur both within forests, including selective logging and wildfires, and at the landscape level, through edge, area and isolation effects. Until now, the combined effect of anthropogenic disturbance on the conservation value of remnant primary forests has remained unknown, making it impossible to assess the relative importance of forest disturbance and forest loss. Here we address these knowledge gaps using a large data set of plants, birds and dung beetles (1,538, 460 and 156 species, respectively) sampled in 36 catchments in the Brazilian state of Pará. Catchments retaining more than 69–80% forest cover lost more conservation value from disturbance than from forest loss. For example, a 20% loss of primary forest, the maximum level of deforestation allowed on Amazonian properties under Brazil’s Forest Code, resulted in a 39–54% loss of conservation value: 96–171% more than expected without considering disturbance effects. We extrapolated the disturbance-mediated loss of conservation value throughout Pará, which covers 25% of the Brazilian Amazon. Although disturbed forests retained considerable conservation value compared with deforested areas, the toll of disturbance outside Pará’s strictly protected areas is equivalent to the loss of 92,000–139,000 km2 of primary forest. Even this lowest estimate is greater than the area deforested across the entire Brazilian Amazon between 2006 and 2015 (ref. 10). Species distribution models showed that both landscape and within-forest disturbances contributed to biodiversity loss, with the greatest negative effects on species of high conservation and functional value. These results demonstrate an urgent need for policy interventions that go beyond the maintenance of forest cover to safeguard the hyper-diversity of tropical forest ecosystems.

Beschreibung: A CRISPR screen defines a signal peptide processing pathway required by flaviviruses Nature 535, 7610 (2016). doi:10.1038/nature18625 Authors: Rong Zhang, Jonathan J. Miner, Matthew J. Gorman, Keiko Rausch, Holly Ramage, James P. White, Adam Zuiani, Ping Zhang, Estefania Fernandez, Qiang Zhang, Kimberly A. Dowd, Theodore C. Pierson, Sara Cherry & Michael S. Diamond Flaviviruses infect hundreds of millions of people annually, and no antiviral therapy is available. We performed a genome-wide CRISPR/Cas9-based screen to identify host genes that, when edited, resulted in reduced flavivirus infection. Here, we validated nine human genes required for flavivirus infectivity, and these were associated with endoplasmic reticulum functions including translocation, protein degradation, and N-linked glycosylation. In particular, a subset of endoplasmic reticulum-associated signal peptidase complex (SPCS) proteins was necessary for proper cleavage of the flavivirus structural proteins (prM and E) and secretion of viral particles. Loss of SPCS1 expression resulted in markedly reduced yield of all Flaviviridae family members tested (West Nile, Dengue, Zika, yellow fever, Japanese encephalitis, and hepatitis C viruses), but had little impact on alphavirus, bunyavirus, or rhabdovirus infection or the surface expression or secretion of diverse host proteins. We found that SPCS1 dependence could be bypassed by replacing the native prM protein leader sequences with a class I major histocompatibility complex (MHC) antigen leader sequence. Thus, SPCS1, either directly or indirectly via its interactions with unknown host proteins, preferentially promotes the processing of specific protein cargo, and Flaviviridae have a unique dependence on this signal peptide processing pathway. SPCS1 and other signal processing pathway members could represent pharmacological targets for inhibiting infection by the expanding number of flaviviruses of medical concern.

Beschreibung: The nature of mutations induced by replication–transcription collisions Nature 535, 7610 (2016). doi:10.1038/nature18316 Authors: T. Sabari Sankar, Brigitta D. Wastuwidyaningtyas, Yuexin Dong, Sarah A. Lewis & Jue D. Wang The DNA replication and transcription machineries share a common DNA template and thus can collide with each other co-directionally or head-on. Replication–transcription collisions can cause replication fork arrest, premature transcription termination, DNA breaks, and recombination intermediates threatening genome integrity. Collisions may also trigger mutations, which are major contributors to genetic disease and evolution. However, the nature and mechanisms of collision-induced mutagenesis remain poorly understood. Here we reveal the genetic consequences of replication–transcription collisions in actively dividing bacteria to be two classes of mutations: duplications/deletions and base substitutions in promoters. Both signatures are highly deleterious but are distinct from the previously well-characterized base substitutions in the coding sequence. Duplications/deletions are probably caused by replication stalling events that are triggered by collisions; their distribution patterns are consistent with where the fork first encounters a transcription complex upon entering a transcription unit. Promoter substitutions result mostly from head-on collisions and frequently occur at a nucleotide that is conserved in promoters recognized by the major σ factor in bacteria. This substitution is generated via adenine deamination on the template strand in the promoter open complex, as a consequence of head-on replication perturbing transcription initiation. We conclude that replication–transcription collisions induce distinct mutation signatures by antagonizing replication and transcription, not only in coding sequences but also in gene regulatory elements.

Beschreibung: Allosteric coupling from G protein to the agonist-binding pocket in GPCRs Nature 535, 7610 (2016). doi:10.1038/nature18324 Authors: Brian T. DeVree, Jacob P. Mahoney, Gisselle A. Vélez-Ruiz, Soren G. F. Rasmussen, Adam J. Kuszak, Elin Edwald, Juan-Jose Fung, Aashish Manglik, Matthieu Masureel, Yang Du, Rachel A. Matt, Els Pardon, Jan Steyaert, Brian K. Kobilka & Roger K. Sunahara G-protein-coupled receptors (GPCRs) remain the primary conduit by which cells detect environmental stimuli and communicate with each other. Upon activation by extracellular agonists, these seven-transmembrane-domain-containing receptors interact with heterotrimeric G proteins to regulate downstream second messenger and/or protein kinase cascades. Crystallographic evidence from a prototypic GPCR, the β2-adrenergic receptor (β2AR), in complex with its cognate G protein, Gs, has provided a model for how agonist binding promotes conformational changes that propagate through the GPCR and into the nucleotide-binding pocket of the G protein α-subunit to catalyse GDP release, the key step required for GTP binding and activation of G proteins. The structure also offers hints about how G-protein binding may, in turn, allosterically influence ligand binding. Here we provide functional evidence that G-protein coupling to the β2AR stabilizes a ‘closed’ receptor conformation characterized by restricted access to and egress from the hormone-binding site. Surprisingly, the effects of G protein on the hormone-binding site can be observed in the absence of a bound agonist, where G-protein coupling driven by basal receptor activity impedes the association of agonists, partial agonists, antagonists and inverse agonists. The ability of bound ligands to dissociate from the receptor is also hindered, providing a structural explanation for the G-protein-mediated enhancement of agonist affinity, which has been observed for many GPCR–G-protein pairs. Our data also indicate that, in contrast to agonist binding alone, coupling of a G protein in the absence of an agonist stabilizes large structural changes in a GPCR. The effects of nucleotide-free G protein on ligand-binding kinetics are shared by other members of the superfamily of GPCRs, suggesting that a common mechanism may underlie G-protein-mediated enhancement of agonist affinity.

Beschreibung: Election campaigns edge Australia towards climate consensus Nature 534, 7608 (2016). http://www.nature.com/doifinder/10.1038/534443a Author: Nicky Phillips Rival parties avoid carbon controversy of former years.

Beschreibung: Medical devices: Insect-eye camera peers inside gut Nature 534, 7608 (2016). doi:10.1038/534439a Mini cameras at the end of a probe that are designed to 'see' like an insect's compound eye could eventually be used in medical endoscopes.Ömer Cogal and Yusuf Leblebici at the Swiss Federal Institute of Technology in Lausanne built a dome-shaped device measuring 10

Beschreibung: Infections reveal inequality between the sexes Nature 534, 7608 (2016). http://www.nature.com/doifinder/10.1038/534447a Author: Sara Reardon Stark differences between men and women’s immune responses pose medical conundrum.

Beschreibung: Iconic Antarctic geology lab gets the boot Nature 534, 7608 (2016). http://www.nature.com/doifinder/10.1038/nature.2016.20096 Author: Alexandra Witze Florida repository of marine sediments dates back to early days of US polar exploration.

Beschreibung: LIGO detects whispers of another black-hole merger Nature 534, 7608 (2016). http://www.nature.com/doifinder/10.1038/nature.2016.20093 Author: Davide Castelvecchi After historic first discovery last September, twin observatories detected gravitational waves again on Boxing Day.

Beschreibung: Bring climate change back from the future Nature 534, 7608 (2016). http://www.nature.com/doifinder/10.1038/534437a Author: James Watson The ‘shock’ over an Australian extinction shows that we still don’t accept that global warming is a problem for now, says James Watson.